HIV Infection in Adults: Clinical Guidelines

List of Abbreviations

DT** – diphtheria and tetanus toxoid**

ADP – adenosine diphosphate

DTP** – diphtheria, tetanus, and pertussis vaccine**

ALT – alanine aminotransferase

ARVs – antiretroviral drugs (according to ATC classification: Systemic antivirals)

ART – antiretroviral therapy

RIG** – rabies immunoglobulin**

AST – aspartate aminotransferase

ASCT – autologous hematopoietic stem cell transplantation

APS – antiphospholipid syndrome

aPTT – activated partial thromboplastin time

BCG** – tuberculosis vaccine**

VZV – varicella-zoster virus (chickenpox/shingles virus)

IVIG** – intravenous immunoglobulin** (INN according to State Register of Medicines: Normal human immunoglobulin**)

HAV — hepatitis A virus

HBV - hepatitis B virus

HIV – human immunodeficiency virus

VL – viral load – number of HIV RNA copies per 1 ml of biological fluid

WHO – World Health Organization

HPV — human papillomavirus

DIC – disseminated intravascular coagulation

IRIS – immune reconstitution inflammatory syndrome

HBIG – human hepatitis B immunoglobulin

GCS – glucocorticosteroids (according to ATC classification: Systemic corticosteroids)

DLBCL – Diffuse large B-cell lymphoma

DIC – disseminated intravascular coagulation

DM – dispensary monitoring

DNA – deoxyribonucleic acid

GI – gastrointestinal tract

WB – Western blotting

INSTIs – HIV integrase strand transfer inhibitors (according to ATC classification: Integrase inhibitors)

BMI – body mass index

PIs – HIV protease inhibitors (according to ATC classification: Protease inhibitors)

PI/r – ritonavir-boosted HIV protease inhibitors (according to ATC classification: Combinations of antivirals for treatment of HIV infections)

IPV** – inactivated polio vaccine**

IRI – immunoregulatory index

IS – immune status

ITP – idiopathic thrombocytopenic purpura (or primary immune thrombocytopenia)

EIA – enzyme immunoassay

IA — immunochromatographic assay

CLIA – chemiluminescence immunoassay

MMR** – measles, mumps, and rubella vaccine**

CT – computed tomography

BL – Burkitt lymphoma

LDH – lactate dehydrogenase

PLHIV – people living with HIV

LPD – lymphoproliferative disorders

HL – Hodgkin lymphoma

MDS — myelodysplastic syndrome

ICD-10 – International Statistical Classification of Diseases and Related Health Problems 10th Revision

MK – megakaryocytes

HC – healthcare organization

MRI – magnetic resonance imaging

MSM - men who have sex with men

NRTIs – nucleoside/nucleotide reverse transcriptase inhibitors of HIV (according to ATC classification: Nucleoside and nucleotide reverse transcriptase inhibitors)

NNRTIs – non-nucleoside reverse transcriptase inhibitors of HIV (according to ATC classification: Non-nucleoside reverse transcriptase inhibitors)

NHI** – normal human immunoglobulin**

Complete blood count (CBC)

UA – urinalysis

Chest organs – thoracic organs

OPV** – oral polio vaccine**

PBL – plasmablastic lymphoma

PEL – primary effusion lymphoma

PGL – persistent generalized lymphadenopathy

PWID – people who inject drugs

PCV** – pneumococcal conjugate vaccine**

PEP – post-exposure prophylaxis

PCNSL – primary central nervous system lymphoma

PPV** – pneumococcal polysaccharide vaccine**

TIG** – tetanus immunoglobulin**

PCT – programmed chemotherapy

PCR – polymerase chain reaction

PCP – Pneumocystis pneumonia

Rh factor – Rhesus factor

RC – Russian classification of HIV infection

sFMC – soluble fibrin monomer complexes

RNA – ribonucleic acid

TT** – tetanus toxoid**

FFP – fresh frozen plasma

KS – Kaposi sarcoma

SLE – systemic lupus erythematosus

GFR – glomerular filtration rate

AIDS – acquired immunodeficiency syndrome

CVD – cardiovascular disease

CVS – cardiovascular system

TP – thrombocytopenia

TPO – thyroid peroxidase

US – ultrasound examination

UNRR – unique registry record number

Ph-AZT** – Phosphazide**

FDC – fixed-dose combination

CKD – chronic kidney disease

CHBV – chronic viral hepatitis B

CHC – chronic viral hepatitis C

ChP – chemoprophylaxis

CRF – chronic renal failure

CMV – cytomegalovirus infection

CNS – central nervous system

EBV – Epstein-Barr virus

EDTA – Ethylenediaminetetraacetic acid

ECG – electrocardiography

3TC** – Lamivudine**

ABC** – Abacavir**

ABC/3TC** (INN per State Register of Medicines: ABC+3TC**) – Abacavir/Lamivudine** (FDC) (INN per State Register of Medicines: Abacavir+Lamivudine**)

ABC/ZDV/3TC** (INN per State Register of Medicines: ABC+ZDV+3TC**) – Abacavir/Zidovudine/Lamivudine** (FDC) (INN per State Register of Medicines: Abacavir+Zidovudine+Lamivudine**)

ATV** – Atazanavir**

ATV/RTV (INN per State Register of Medicines: ATV+RTV) – Atazanavir/ritonavir (FDC) (INN per State Register of Medicines: Atazanavir+Ritonavir)

AZT/3TC** (INN per State Register of Medicines: AZT+3TC**) – Zidovudine/lamivudine** (FDC) (INN per State Register of Medicines: Zidovudine+Lamivudine**)

BIC/TAF/FTC** (INN per State Register of Medicines: BIC+TAF+FTC**) – Bictegravir/Tenofovir alafenamide/Emtricitabine** (FDC) (INN per State Register of Medicines: Bictegravir+Tenofovir alafenamide+Emtricitabine**)

CAB – Cabotegravir

CD – cluster of differentiation

CD4 – CD4+ lymphocytes (T-lymphocytes with CD4 receptor)

CD8 – CD8+ lymphocytes (T-lymphocytes with CD8 receptor)

CMV – cytomegalovirus

DOR** – Doravirine**

DOR/3TC/TDF** (INN per State Register of Medicines: DOR+3TC+TDF**) – Doravirine/Lamivudine/Tenofovir** (FDC) (INN per State Register of Medicines: Doravirine+Lamivudine+Tenofovir**)

DRV** – Darunavir**

DTG** – Dolutegravir**

DTG/RPV (INN per State Register of Medicines: DTG+RPV) – Dolutegravir/Rilpivirine (FDC) (INN per State Register of Medicines: Dolutegravir+Rilpivirine)

DTG/3TC (INN per State Register of Medicines: DTG+3TC) – Dolutegravir/Lamivudine (FDC) (INN per State Register of Medicines: Dolutegravir+Lamivudine)

EFV** – Efavirenz**

ETR** – Etravirine**

ESV** – Elsulfavirine**

EVG/C/FTC/TAF** (INN per State Register of Medicines: EVG+C+FTC+TAF**) – Cobicistat/Tenofovir alafenamide/Elvitegravir/Emtricitabine** (FDC) (INN per State Register of Medicines: Cobicistat+Tenofovir alafenamide+Elvitegravir+Emtricitabine**)

FPV** – Fosamprenavir**

FTC** – Emtricitabine**

FTR – Fostemsavir

HHV-8 – human herpesvirus type 8

HLA – human leukocyte antigen

HLA-B*5701 – allele 5701 of the B locus of the human major histocompatibility complex

IGRA – interferon-gamma release assay

LPV/RTV** (INN per State Register of Medicines: LPV+RTV**) – Lopinavir/Ritonavir** (FDC) (INN per State Register of Medicines: Lopinavir+Ritonavir**)

MVC** – Maraviroc**

NVP** – Nevirapine**

RAL** – Raltegravir**

RPV – Rilpivirine

RPV/TDF/FTC** (INN per State Register of Medicines: RPV+TDF+FTC**) – Rilpivirine/Tenofovir/Emtricitabine** (FDC) (INN per State Register of Medicines: Rilpivirine+Tenofovir+Emtricitabine**)

RTV**, r** – Ritonavir**

SQV** – Saquinavir**

TAF** – Tenofovir alafenamide**

TDF** – Tenofovir** (active ingredient: Tenofovir disoproxil fumarate)

TDF/3TC/EFV (INN per State Register of Medicines: 3TC+TDF+EFV) – Tenofovir/Lamivudine/Efavirenz (FDC) (INN per State Register of Medicines: Lamivudine+Tenofovir+Efavirenz)

TDF/FTC (INN per State Register of Medicines: TDF+FTC) – Tenofovir/Emtricitabine (INN per State Register of Medicines: Tenofovir+Emtricitabine)

TDF/ESV/FTC** (INN per State Register of Medicines: TDF+ESV+FTC**) – Tenofovir/Elsulfavirine/Emtricitabine** (FDC) (INN per State Register of Medicines: Tenofovir+Elsulfavirine+Emtricitabine**)

TDF/FTC/EFV (INN per State Register of Medicines: TDF+FTC+EFV) – Tenofovir/Emtricitabine/Efavirenz (FDC) (INN per State Register of Medicines: Tenofovir+Emtricitabine+Efavirenz)

ZDV** – Zidovudine**

Terms and Definitions

Antiretroviral therapy (ART) – causal treatment of human immunodeficiency virus infection (HIV infection) that achieves a controlled course of the disease, prescribed for life and based on the simultaneous use of several antiretroviral drugs (according to the ATC classification: Systemic antiviral drugs) acting on different stages of the HIV lifecycle.

Human immunodeficiency virus (HIV) – the causative agent of HIV infection from the retrovirus family, causing the gradual development of immunodeficiency.

Viral load (VL) – the amount of virus in the patient's material (plasma, cerebrospinal fluid, etc.), determined using polymerase chain reaction (PCR) and expressed as the number of copies of HIV ribonucleic acid (RNA) per 1 ml of plasma.

Viral suppression – the goal of ART, which consists of reducing and maintaining the viral load below the level detectable by available tests.

Viral blip (blip) – a single transient increase in viral load to a level of less than 200 copies/mL following an undetectable result.

Genotyping – a method based on the indirect assessment of drug resistance by comparing the consensus HIV RNA sequence with the HIV RNA sequence obtained from the patient.

Immune status (IS) – assessment of the state of the immune system. In HIV infection, the percentage and absolute count of regulatory immune cells (helper T-lymphocytes) and effector cells (cytotoxic T-lymphocytes), which are most important in the pathogenesis of the disease, are examined. It is used to monitor the natural course of HIV infection and assess the effectiveness of ART.

Immunoblotting (IB) – a laboratory immunological method for detecting antibodies in the blood to various HIV proteins. Due to its high specificity, it is used as a confirmatory method after obtaining a positive result at the screening stage.

Immunoregulatory index (IRI) – the ratio of the absolute counts of CD4 and CD8. In healthy individuals, the IRI value is 1 or higher. In HIV infection, inversion of this parameter occurs due to a decrease in the CD4 fraction; progression of immune system damage is accompanied by a decrease in IRI. It is used for prognostic purposes.

Enzyme-linked immunosorbent assay (ELISA) and chemiluminescent immunoassay (CLIA) – laboratory immunological methods for the qualitative determination of total anti-HIV antibodies in the blood. Due to their high sensitivity, they are used as screening methods.

Body mass index (BMI) – a value that allows assessing the degree of correspondence between a person's weight and height and, thus, indirectly estimating whether the weight is underweight, normal, or overweight. It is important when determining adequate doses of pharmacological drugs. Body mass index is calculated by the formula: BMI (kg/m²) = m / h², where m is body mass in kg, h is height in m.

Immunochromatographic assay (ICA) – a laboratory immunological method of analysis based on the principle of thin-layer chromatography, involving a reaction between an antigen and its corresponding antibody in biological materials. It is performed using special test strips, panels, or test cassettes.

People living with HIV (PLHIV) – a collective term defining a person (or persons) belonging to the group of individuals infected with HIV.

Undetectable viral load level – the level of HIV viral load below the detection threshold of the test system (it is recommended to use test systems with a sensitivity threshold of 50 copies/mL).

Low-level viremia – repeated viral load values in the range of 50 – 1000 copies/mL. Low-level viremia is a predictor of the development of HIV drug resistance.

Detectable viral load level – the level of HIV viral load above the detection threshold of the test system (it is recommended to use test systems with a sensitivity threshold of 50 copies/mL).

Polymerase chain reaction (PCR) – a laboratory method for the qualitative and quantitative determination of HIV genetic material, based on the uniqueness of nucleotide sequences of RNA/DNA segments. It has high sensitivity and specificity. Qualitative determination of HIV deoxyribonucleic acid (DNA) in blood lymphocytes is used in adults for the early detection of HIV infection during the established/suspected "serological window" period (in the first weeks after infection, when the amount of specific anti-HIV antibodies produced in the infected person's body is insufficient for detection). Quantitative determination of HIV RNA is used when selecting drugs for ART regimens, to assess ART efficacy, and for prognostic purposes (see "Viral load").

Serodiscordant couples are couples maintaining a long-term sexual relationship in which only one partner has HIV infection.

CD4 – CD4 T-lymphocytes are antigen-recognizing helper T-lymphocytes, an essential component for the induction of a humoral response to T-dependent antigens.

CD8 – CD8⁺ T-lymphocytes are cytotoxic T-lymphocytes (T-killer cells) that lyse target cells bearing foreign antigens or altered autoantigens.

Elite controller is an individual belonging to a small group of HIV-infected patients who manage to suppress viral replication without antiretroviral therapy, such that, despite confirmed serological infection, viral RNA is not detected in blood plasma by PCR. The prevalence of elite controllers capable of long-term suppression of viral replication is less than 1%, while transient control is observed somewhat more frequently.

Active adaptive immunity is immunity that develops following an infectious disease or vaccination, i.e., after contact with an antigen.

Toxoids (according to the ATC classification: Vaccines for bacterial infections) are immunobiological agents (according to the ATC classification: antibacterials for systemic use) for active immunization, representing detoxified bacterial exotoxins that possess immunogenicity and lack toxigenicity.

Antigens are foreign substances that stimulate the immune system to produce antibodies. Antigens can be live (e.g., viruses or bacteria) or inactivated.

Antibodies are proteins produced by the immune system in response to specific antigens that help the body fight infections and neutralize foreign substances.

Vaccine is a suspension of live (usually attenuated) or inactivated microbes (viruses or bacteria) or their fractions, administered to induce active specific immunity and prevent infectious disease and its complications.

Vaccination is the administration of an immunobiological agent (according to the ATC classification: antibacterials for systemic use) (a vaccine, toxoid (according to the ATC classification: Vaccines for bacterial infections), or immunoglobulin) into the human body to induce active specific immunity.

Live attenuated vaccines are immunobiological agents (according to the ATC classification: antibacterials for systemic use) for active immunization containing live microorganisms (bacteria, viruses) with attenuated virulence while preserving immunogenicity (vaccine strains).

Immunization is the artificial creation of specific immunity through the administration of immunobiological agents (according to the ATC classification: antibacterials for systemic use). Immunization can be active and passive. Active immunization is the production of antibodies or the formation of other immune responses through the administration of vaccines or toxoids. Passive immunization is the formation of temporary immunity through the administration of antibodies into the body in the form of immunoglobulins or antitoxic sera (according to the ATC classification: Immune sera).

Immune response is the protective reaction of the immune system to antigens, resulting in the formation of protein molecules—antibodies or immunoglobulins (humoral immunity)—and specific cells (cell-mediated immunity).

Immunoglobulin (Ig) (INN according to the State Register of Medicines: Normal human immunoglobulin**) is a preparation (sterile solution) obtained from donor plasma and containing antibodies. Also referred to as normal immunoglobulin, serum immunoglobulin, or gamma-globulin (IgG). Normal human immunoglobulin** is used for passive immunization of individuals who have been in close contact with patients having certain infectious diseases.

Passive immunity is immunity that arises upon the introduction of antibodies (immunoglobulins) into the body.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

HIV infection is a chronic anthroponotic infectious disease caused by the human immunodeficiency virus, slowly progressive and characterized by damage to the immune system with the development of AIDS. Clinical manifestations of immune system failure include opportunistic infections, malignant neoplasms, dystrophic and autoimmune processes, which, in the absence of specific treatment, lead to the death of the infected person. [1,2,3,4,5]

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The human immunodeficiency virus, first isolated in 1983, belongs to the retrovirus family, a feature of which is the presence of the reverse transcriptase enzyme, which ensures the reverse flow of genetic information: from RNA to DNA. The virus contains two strands of RNA; enzymes required for its replication (reverse transcriptase, integrase, protease); and proteins and glycoproteins (gp41 and gp120) that form the viral envelopes. It is characterized by high variability. Currently, two types of human immunodeficiency virus are known that have certain antigenic differences: HIV-1 and HIV-2, the latter being found mainly in West Africa.

The virus enters cells that have the CD4 receptor on their surface (T-helper cells, monocytes, macrophages, Langerhans cells, follicular dendritic cells, microglia) by binding its glycoproteins to the CD4 molecule and chemokine receptors. Inside the cell, HIV RNA is converted into DNA (reverse transcription), which is integrated into the host cell DNA in the nucleus using the viral enzyme integrase. HIV proteins produced in the cell are acted upon by the protease enzyme, which makes them functionally active. After assembly, virions leave the cell. Thus, the host cell turns into a "factory" for producing new virions (HIV has a very high replicative activity).

Damage to helper T-lymphocytes (CD4) leads to impaired intercellular interactions within the immune system, its functional failure, gradual depletion, and, as a result, progressive immunodeficiency.

A high number of circulating viral particles in the blood ("viral load", VL) determines the probability of a rapid decline in the number of immune cells. There is a clear correlation between the rate of CD4 count decline and the rate of HIV disease progression in the patient.

As a result of impaired helper T-lymphocyte function, spontaneous activation of B-lymphocytes occurs, leading to increased production of nonspecific immunoglobulins and a rise in the concentration of circulating immune complexes.

The result of immune system disorders is a decrease in the body's resistance, leading to a wide range of secondary diseases: secondary (opportunistic) infections, oncological, hematological, autoimmune, and lymphoproliferative disorders.

A characteristic manifestation of HIV infection is chronic inflammation affecting all organs and systems: autoimmune reactions, immune complex diseases, and metabolic disorders lead to vascular endothelial and connective tissue damage with the development of cardiovascular, neurological, endocrine, and musculoskeletal pathology. All of this accounts for the multi-organ involvement and diversity of clinical symptoms.

1.3 Epidemiology of the Disease or Condition

The source of infection is an HIV-infected person at any stage of the disease. The role of an infected person as a source of infection increases during the early and late stages of the disease (the stage of primary manifestations and the stage of secondary diseases with pronounced impairment of immunoreactivity) [1,2,3,4,5,6].

Routes of transmission of the virus: natural (sexual, mother-to-child) and artificial (parenteral - injection, transfusion, transplantation, including when infected material gets onto damaged skin and mucous membranes of the eyes, nose, and oral cavity).

The virus is transmitted through blood, semen, vaginal secretions, and breast milk.

Sexual route has been the dominant mode of HIV transmission in recent years. The probability of infection correlates with the number of sexual partners and increases in the presence of inflammatory and dysplastic diseases of the genital organs and rectum.

Mother-to-child transmission of HIV can occur at any stage of pregnancy, during childbirth, and during breastfeeding. Transmission mostly occurs in the last weeks of pregnancy and during labor. Without prevention, the rate of mother-to-child HIV transmission is about 20%. Breastfeeding nearly doubles the risk of HIV transmission to the child.

Parenteral route is realized when HIV-infected material enters the body's internal environments during medical, paramedical, and ritual procedures. Among parenteral interventions, intravenous blood administration carries the highest risk of infection. There is a high risk of infection associated with: intravenous drug use using non-sterile syringes and needles; transfusion of HIV-infected blood and its components; and the use of medical and non-medical instruments contaminated with biological fluids of an HIV-infected person. In addition, donor organs and tissues used for transplantation can be sources of infection.

1.4 Features of Coding the Disease or Condition

The International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) provides codes for various conditions and medical services related to HIV infection. Coding is intended for statistical accounting and does not imply determination of the severity or prognosis of the disease. In practical use of ICD codes, they may correspond to various categories or stages in clinical classifications of HIV infection [5, 7].

The following are provided below:

Conditions and medical services related to HIV infection, according to ICD-10.

Human immunodeficiency virus [HIV] disease resulting in infectious and parasitic diseases (B20):

B20.0 – HIV disease resulting in mycobacterial infection;

B20.1 – HIV disease resulting in other bacterial infections;

B20.2 – HIV disease resulting in cytomegalovirus disease;

B20.3 – HIV disease resulting in other viral infections;

B20.4 – HIV disease resulting in candidiasis;

B20.5 – HIV disease resulting in other mycoses;

B20.6 – HIV disease resulting in P. jirovecii pneumonia;

B20.7 – HIV disease resulting in multiple infections;

B20.8 – HIV disease resulting in other infectious and parasitic diseases;

B20.9 – HIV disease resulting in unspecified infectious and parasitic diseases.

Human immunodeficiency virus [HIV] disease resulting in malignant neoplasms (B21):

B21.0 – HIV disease resulting in Kaposi sarcoma;

B21.1 – HIV disease resulting in Burkitt lymphoma;

B21.2 – HIV disease resulting in other non-Hodgkin lymphomas;

B21.3 – HIV disease resulting in other malignant neoplasms of lymphoid, haematopoietic and related tissue;

B21.7 – HIV disease resulting in multiple malignant neoplasms;

B21.8 – HIV disease resulting in other malignant neoplasms;

B21.9 – HIV disease resulting in unspecified malignant neoplasm.

Human immunodeficiency virus [HIV] disease resulting in other specified conditions (B22):

B22.0 – HIV disease resulting in encephalopathy;

B22.1 – HIV disease resulting in lymphoid interstitial pneumonitis;

B22.2 – HIV disease resulting in wasting syndrome;

B22.7 – HIV disease resulting in multiple diseases classified elsewhere.

Human immunodeficiency virus [HIV] disease resulting in other conditions (B23):

B23.0 – Acute HIV infection syndrome;

B23.1 – HIV disease resulting in (persistent) generalized lymphadenopathy;

B23.2 – HIV disease resulting in haematological and immunological abnormalities, not elsewhere classified.

B23.8 – HIV disease resulting in other specified conditions.

B24 – Unspecified human immunodeficiency virus [HIV] disease.

F02.4 – Dementia in human immunodeficiency virus [HIV] disease (B22.0);

R75 – Laboratory evidence of human immunodeficiency virus [HIV];

Z11.4 – Special screening examination for human immunodeficiency virus [HIV];

Z20.6 – Contact with and exposure to human immunodeficiency virus [HIV];

Z21 – Asymptomatic human immunodeficiency virus [HIV] infection status;

Z71.7 – Human immunodeficiency virus [HIV] counseling;

Z83.0 – Family history of human immunodeficiency virus [HIV] disease.

The primary ICD-10 statistical surveillance codes used in the Russian Federation for medical reporting on patients with HIV infection (Form No. 61) are codes B20–B24. Since it is now scientifically proven that human immunodeficiency virus carriage does not exist, and the detection of HIV in the human body indicates the presence of a disease with varying rates of progression, the use of code Z21 for patients with a laboratory-confirmed diagnosis is incorrect. Code B23 is recommended instead.

A diagnosis of HIV infection with ICD-10 coding can only be established after a conclusion regarding the disease is made by a physician of the AIDS Prevention and Control Center or another authorized specialized medical organization based on a full diagnostic workup (epidemiological, clinical data, and laboratory tests).

Comments: in practice, many patients with asymptomatic HIV infection have enlarged lymph nodes, and the condition of such patients may correspond to category B23.1. The majority show immunological abnormalities (decreased CD4 count in many patients, and inversion of the CD4/CD8 ratio in almost all) or hematological changes (lymphopenia, anemia, thrombocytopenia). For such patients, it is advisable to use the ICD-10 code B23.2.

1.5 Classification of the disease or condition

According to the HIV infection classification currently in force in Russia (RK, 2006) [4, 5, 7], the stage and phase of the disease are established solely based on clinical manifestations. Viral load and CD4 count are not criteria for determining the clinical stage or phase of the disease.

Russian Clinical Classification of HIV Infection

1. Incubation stage.

2. Stage of primary manifestations.

Course variants:

A. Asymptomatic;

B. Acute HIV infection without secondary diseases;

C. Acute HIV infection with secondary diseases.

3. Subclinical stage.

4. Secondary diseases stage.

4A. Weight loss less than 10%, fungal, viral, and bacterial lesions of the skin and mucous membranes, recurrent pharyngitis, sinusitis, herpes zoster.

Phases: progression in the absence of ART, while on ART;

remission (spontaneous, post-ART, on ART).

4B. Weight loss more than 10%, unexplained diarrhea or fever for more than 1 month, recurrent persistent viral, bacterial, fungal, and protozoal lesions of internal organs, localized Kaposi sarcoma, recurrent or disseminated herpes zoster.

Phases: progression in the absence of ART, while on ART;

remission (spontaneous, post-ART, on ART).

4C. Cachexia. Generalized viral, bacterial, mycobacterial, fungal, protozoal, and parasitic diseases, including: esophageal, bronchial, tracheal, and pulmonary candidiasis; Pneumocystis pneumonia; malignant tumors; central nervous system disorders.

Phases: progression in the absence of ART, while on ART;

remission (spontaneous, post-ART, on ART).

5. Terminal stage.

Characteristics of HIV infection stages

Stage 1 – incubation stage – the period from infection to the body's reaction in the form of clinical manifestations of "acute infection" and/or antibody production. Its duration is usually from 4 weeks to 3 months, but in isolated cases may increase to 1 year. During this period, active HIV replication occurs in the absence of clinical manifestations of the disease, and HIV antibodies may not be detected. The diagnosis of HIV infection at this stage is made based on epidemiological data; it can be laboratory-confirmed by the detection of HIV, its antigens, or nucleic acids in the patient's blood.

Stage 2 – primary manifestations stage. During this period, active HIV replication continues and the body's primary response to pathogen invasion appears in the form of clinical symptoms and/or antibody production. It is believed that a patient may remain in the primary manifestations stage for up to 12 months after seroconversion (appearance of HIV antibodies).

The primary manifestations stage may present in several forms.

Stage 2A – asymptomatic, when any clinical manifestations of HIV infection or opportunistic diseases developing against the background of immunodeficiency are absent. The body's response to HIV invasion manifests solely through antibody production.

Stage 2B – acute HIV infection without secondary diseases may present with diverse clinical symptoms. Most often, these are lymphadenopathy, fever, pharyngitis, rashes (urticarial, papular, petechial) on the skin and mucous membranes. Enlargement of the liver and spleen, and diarrhea may be observed.

Aseptic meningitis sometimes develops, characterized by meningeal syndrome with elevated cerebrospinal fluid pressure in the absence of visual and cytological changes in the fluid. Serous meningitis may occasionally develop.

Because the clinical picture of acute HIV infection often resembles measles, rubella, or infectious mononucleosis, it has been termed "mononucleosis-like syndrome" or "rubella-like syndrome." The similarity to infectious mononucleosis is enhanced by the appearance of broad-plasma lymphocytes (mononuclears) in the blood of patients with acute HIV infection. A mononucleosis-like or rubella-like picture is observed in 15–30% of patients with acute HIV infection; the majority develop 1–2 of the aforementioned symptoms in any combination. Individual patients with HIV infection may experience autoimmune disorders.

The acute stage of HIV infection is recorded in 50–90% of infected individuals in the first 3 months after infection. The onset of the acute infection period generally precedes seroconversion, so when the first clinical symptoms appear, HIV antibodies may not be detected in the patient's blood serum.

In the acute stage of HIV infection, a transient decrease in CD4 levels is frequently observed.

Stage 2B – acute HIV infection with secondary diseases. In 10–15% of cases, patients with acute HIV infection present with a marked decrease in CD4 levels and resultant immunodeficiency-induced secondary diseases of various etiologies (tonsillitis, bacterial pneumonia, candidiasis, herpes virus infection, etc.). These manifestations are typically mild, short-lived, and respond well to therapy, but they can be severe (candidal esophagitis, Pneumocystis pneumonia) and, in rare cases, fatal.

The duration of clinical manifestations of acute HIV infection varies from several days to several months, but is usually 2–3 weeks. An exception is lymph node enlargement, which may persist throughout the entire disease course. Clinical manifestations of acute HIV infection may relapse.

In the vast majority of patients, the primary manifestation stage of HIV infection progresses to the subclinical stage, though in some cases it may progress to the stage of secondary diseases.

Stage 3 – subclinical stage – is characterized by the slow progression of immunodeficiency, compensated by modifications in the immune response and excess CD4 production. HIV antibodies are detected in the blood; the rate of viral replication slows compared to the stage of primary manifestations. The only clinical manifestation of the disease is lymph node enlargement, which is usually generalized (persistent generalized lymphadenopathy, PGL), though it may be absent. Laboratory changes such as anemia and thrombocytopenia may be observed (more commonly in children), sometimes leading to clinical manifestations of hemostatic disorders. The duration of the subclinical stage can range from 2–3 to 20 or more years, averaging 6–7 years. During this period, there is a gradual decrease in CD4 count at an average rate of 50–70 cells/µl per year.

Stage 4 – stage of secondary diseases. HIV replication continues, accompanied by CD4 depletion and the exhaustion of their population. This leads to the development of secondary (opportunistic) infectious and/or oncological diseases against the background of immunodeficiency. Clinical manifestations of opportunistic diseases, alongside PGL—which persists in the majority of patients with HIV infection—determine the clinical picture of the secondary disease stage.

Depending on the severity of secondary diseases, the following are distinguished:

Stage 4A (usually develops 6–7 years after infection). It is characterized by bacterial, fungal, and viral lesions of the mucous membranes and skin, as well as inflammatory diseases of the upper respiratory tract. Stage 4A typically develops in patients with a CD4 count of around 350 cells/µl.

Stage 4B (usually 7–10 years after infection) — skin lesions are deeper and tend to have a protracted course. Lesions of internal organs develop. In addition, localized Kaposi's sarcoma, moderately pronounced constitutional symptoms (weight loss, fever), and peripheral nervous system lesions may be observed. A sign of the transition of HIV infection to stage 4B may be tuberculosis limited to a single anatomical region. For instance, this can be pulmonary tuberculosis, including involvement of bronchial lymph nodes, or extrapulmonary tuberculosis affecting a single organ. Stage 4B typically develops in patients with a CD4 count of 200–350 cells/µl.

Stage 4C (usually 10–12 years after infection) is characterized by the development of severe, life-threatening secondary (opportunistic) diseases, their generalized nature, and central nervous system involvement. Stage 4C typically develops in patients with a CD4 count <200 cells/µl.

Secondary diseases characteristic of stage 4 may not manifest, at least for some time. Therefore, the stage of secondary diseases is divided into a progression phase (in the absence of ART or during ART with insufficient efficacy) and a remission phase (spontaneous, following prior ART, or during effective ART).

Stage 5 – terminal stage – was introduced into the clinical classification of HIV infection in 1989, when highly active ART did not yet exist and, despite adequate (for the time) therapy, the patient's secondary diseases became irreversible, leading to death within a few months of their onset.

Currently, even in patients with CD4 counts close to zero and severe secondary diseases, HIV treatment is not hopeless; therefore, assigning the diagnosis of "HIV infection, terminal stage" is not recommended.

Justification and Formulation of the Diagnosis of HIV Infection

When diagnosing HIV infection, the diagnosis and its justification must be recorded in the medical documentation.

The justification of the diagnosis must indicate the epidemiological, clinical, and laboratory data upon which the diagnosis of HIV infection is established (Articles 589 and 611 of Sanitary Rules and Regulations SanPiN 3.3686-21) [12].

When formulating the diagnosis, the presence of HIV infection is stated, and the stage and phase of the disease are indicated. The stage of the disease is determined by the most severe HIV-related condition the patient has ever experienced.

It is also necessary to indicate the secondary disease that determined the stage of the disease and, if HIV infection is in the progression phase, to specify the disease responsible for this progression phase.

In addition to secondary diseases—i.e., conditions developing as a result of HIV-associated immunodeficiency—other concomitant diseases in HIV-infected patients should be noted and reflected in the diagnosis under the concomitant diagnosis section.

List of Conditions Indicating the Development of Acquired Immunodeficiency Syndrome in a Patient

A diagnosis of AIDS is established if an HIV-infected person presents with at least one of the following conditions (in the absence of other causes for their development):

- Esophageal candidiasis;

- Candidiasis of the trachea, bronchi, or lungs;

- Invasive cervical cancer;

- Coccidioidomycosis (disseminated or extrapulmonary);

- Extrapulmonary cryptococcosis;

- Intestinal cryptosporidiosis with diarrhea > 1 month;

- Cytomegalovirus infection (affecting organs other than the liver, spleen, or lymph nodes) in a patient older than one month;

- Cytomegalovirus retinitis with loss of vision;

- HIV-induced encephalopathy (HIV encephalopathy);

- Herpes simplex virus infection: chronic ulcers lasting more than 1 month, or bronchitis, pneumonia, esophagitis in a patient older than one month;

- Disseminated or extrapulmonary histoplasmosis;

- Intestinal isosporiasis (with diarrhea lasting more than 1 month);

- Kaposi's sarcoma;

- Interstitial lymphocytic pneumonia in a child under 13 years of age;

- Burkitt's lymphoma (or other B-cell non-Hodgkin lymphoma);

- Immunoblastic lymphoma;

- Primary brain lymphoma;

- Mycobacteriosis caused by M. kansasii, M. avium-intracellulare, disseminated or extrapulmonary;

- Pulmonary tuberculosis in an adult or adolescent older than 13 years, in the presence of severe immunodeficiency: CD4 <200 cells/µl or <15% in accordance with the WHO classification of immune dysfunction [3,4,5,7];

- Other undifferentiated disseminated or extrapulmonary mycobacterioses;

- Pneumocystis pneumonia;

- Recurrent pneumonias (two or more episodes within 12 months);

- Progressive multifocal leukoencephalopathy;

- Recurrent salmonella (non-typhoidal) septicemia;

- Cerebral toxoplasmosis in a patient older than one month;

- HIV wasting syndrome.

If an HIV-infected patient has none of the above conditions, the diagnosis of "AIDS" is unjustified.

1.6 Clinical presentation of the disease or condition

The clinical picture of HIV infection is reflected in the classification. See 1.5

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of HIV infection is established by an infectious disease specialist at an AIDS Center or another authorized specialized medical organization through a comprehensive evaluation of epidemiological and clinical data and laboratory tests [3,4,5,8-12].

Diagnosis of HIV infection includes three consecutive stages:

1. Establishing the fact of HIV infection (laboratory conclusion on the presence of serological and/or genetic markers of HIV infection);

2. Establishing a preliminary diagnosis and drawing up a dispensary follow-up plan during the initial examination after registration for dispensary care;

3. Establishing a detailed clinical diagnosis – determining the stage and markers of HIV infection progression (quantitative determination of Human immunodeficiency virus HIV-1 RNA in blood plasma by PCR and blood CD4+ lymphocyte testing) – within 10 days of presentation.

The presence of HIV infection in an individual is established based on epidemiological, clinical, and laboratory data.

A critical part of the diagnosis is the reliable identification of the patient's identity by the physician, typically based on the information specified in cl. 2.1, art. 43 of Federal Law No. 323-FZ of November 21, 2011.

Epidemiological criteria for the diagnosis of HIV infection [11-13]:

1. Factors indicating a very high risk of HIV acquisition:

- Blood transfusion or administration of blood products, organ and tissue transplantation from an HIV-infected individual;

- Birth of an HIV-infected child to the examined woman.

2. Factors indicating a high risk of HIV acquisition:

- Birth of the examined individual to an HIV-infected mother who did not receive prophylaxis for vertical HIV transmission;

- Regular unprotected (without a condom) sexual contact with an HIV-infected patient or sharing parenteral substance use with them.

3. Factors indicating the possibility of HIV acquisition:

- Damage to the skin or mucous membranes with an instrument contaminated with HIV, contact of HIV-infected blood with the mucous membranes or damaged skin of the examined person;

- Sexual contact with an HIV-infected partner: single unprotected contact or regular contact using a condom (potential cases of incorrect use);

- Damage to the skin and mucous membranes by medical instruments contaminated with biological material;

- Blood transfusion, organ and tissue transplantation, parenteral interventions in areas with a high (> 1% of the total population) HIV prevalence; unprotected sexual contact with a partner whose HIV status is unknown (last tested more than 3 months prior to sexual contact), lack of consistent condom use during every sexual contact, substance use, non-medical parenteral interventions.

2.1 Complaints and Anamnesis

To assess the risk of HIV acquisition and select diagnostic tactics during the anamnesis collection, it is recommended to obtain information on [14-22] (2A):

- Behavioral patterns associated with the risk of HIV acquisition;

- Time and route of HIV acquisition (probable or known);

- HIV testing (date of the first positive HIV test, reason for testing, last negative HIV test);

- Presence of diseases sharing the same transmission mechanism as HIV infection (viral hepatitis B and C, sexually transmitted infections) or facilitating HIV acquisition;

- Sexual and reproductive health (current contraception methods, pregnancy history);

- Smoking, alcohol consumption, and other psychoactive substance use.

When collecting the history of present illness, it is recommended to pay attention to a history of conditions that may be consequences of HIV infection (viral, fungal, bacterial lesions of the skin and mucous membranes, recurrent pneumonia, tuberculosis, lymphadenopathy, "mononucleosis-like syndrome", changes in body weight, body habitus) [16,17,23,24] (2A).

When taking the medical history of a patient with suspected HIV, special attention should be paid to potential manifestations of tuberculosis (fever, cough, weight loss, night sweats) [3,5,25] (1A).

2.2 Physical Examination

As part of the physical examination, it is necessary to pay attention to clinical manifestations characteristic of HIV infection and signs indicating past or existing secondary diseases.

During the physical examination of all patients for the purpose of diagnosing HIV infection, determining its stage, the presence of secondary diseases, opportunistic infections, and identifying complications [3,5,25]:

- Assess the general condition, paying attention to changes in body weight, body habitus (presence of lipodystrophy signs);

- Perform a complete examination of the skin and mucous membranes of the entire body, including the perianal and inguinal regions, paying attention to scleral icterus or jaundice of the skin and mucous membranes, herpes zoster rash elements (fresh or scars from previous episodes), seborrheic dermatitis, fungal lesions, Kaposi sarcoma lesions, chancriform lesions, papules, condylomas, and injection marks in people who inject drugs;

- Assess neurological and mental status, paying attention to: symptoms of neuropathy, visual impairment, clarity of consciousness, adequacy of responses to questions, presence of delusions, rate of mental processes (psychomotor retardation or agitation), presence of mood disorders (complaints of depression, apathy, indifference, fatigue, irritability), presence of suicidal ideation, memory and attention disorders, motor clumsiness.

2.3 Laboratory Diagnostics

HIV testing must be voluntary and based on the following principles:

1. Informed consent of the patient;

2. Confidentiality;

3. HIV counselling, including pre- and post-test counselling;

4. Ensuring the reliability of test results and timely reporting to the clinician;

5. Cooperation with medical, social, and psychological support services;

6. Anonymity at the patient's request.

In order to establish a diagnosis of HIV infection, it is necessary to perform a medical examination for HIV in full compliance with the algorithm set forth in Sanitary Rules SP 3.3686-21, approved by the Resolution of the Chief State Sanitary Doctor of the Russian Federation No. 4 of January 28, 2021, and Order of the Russian Ministry of Health No. 1051n of November 12, 2021.

To diagnose HIV infection, combination test assays with simultaneous detection of HIV-1,2 antibodies and HIV-1 p24 antigen must be used. To minimize false-positive and false-negative test results, it is necessary to use test systems with the best characteristics of analytical and diagnostic sensitivity and specificity for the detection of HIV-1,2 antibodies and HIV-1 p24 antigen [368-371].

Upon seeking medical care at a medical organization providing inpatient care, the patient signs general informed consent for medical interventions performed at the medical facility included in the List of Certain Types of Medical Interventions (defined by Order of the Ministry of Health and Social Development of Russia No. 390n of April 23, 2012). Clause 9 of the said Order approves laboratory diagnostic methods, including clinical, biochemical, bacteriological, virological, and immunological methods. In turn, according to Order of the Ministry of Health of the Russian Federation No. 64 of February 21, 2000, "On Approval of the Nomenclature of Clinical Laboratory Tests", the nomenclature of clinical laboratory tests defines immunoserology (cl. 9.2.3) and microbiological methods of virus identification (cl. 9.2.4), which permits ELISA and PCR diagnostics of HIV infection upon signing informed consent for medical intervention.

The objectives of laboratory testing upon registration for clinical follow-up (dispensary observation) for HIV infection include:

- Confirmation of the diagnosis of HIV infection;

- Determination of the degree of immunosuppression (by absolute and percentage counts of CD4 and CD8);

- Identification of indications for chemoprophylaxis of secondary diseases (by absolute and percentage counts of CD4);

- Identification of vital indications for the urgent initiation of ART;

- Detection of secondary diseases, determination of their severity and the need for treatment;

- Detection of comorbid conditions, determination of their severity and the need for treatment.

Nonspecific laboratory signs of HIV infection include:

- Decrease in lymphocyte count, especially CD4;

- Increase in CD8 count;

- Inversion of the CD4/CD8 ratio (decrease to less than 1);

- Increase in immunoglobulin levels, predominantly due to IgG; manifestations of cytopenic syndrome (anemia, leukopenia, thrombocytopenia).

- CD4+ lymphocyte count [32-37] (2B);

- CD8+ lymphocyte count [32-37] (2B);

- Quantitative determination of HIV-1 RNA in blood plasma by PCR [32-40] (2B);

- Complete blood count (CBC), differential [41] (4C);

- Urinalysis [42] (4C);

- General clinical blood biochemistry panel [42] (4C);

- Lipid profile biochemistry blood test [42] (4C).

- Determination of the clinical stage of the disease according to the Russian classification, 2006 [37,161] (5C);

- CD4+ lymphocyte count [37,161] (5C);

- Serum human chorionic gonadotropin (hCG) level testing (to rule out pregnancy) [37,107] (5C);

- Quantitative determination of HIV-1 RNA in blood plasma by PCR [32-40] (2B).

- Syphilis (see relevant clinical guidelines) [249] (3B);

- Viral hepatitis C (see relevant clinical guidelines) [250, 252] (2B);

- Determination of hepatitis C virus (HCV) antibodies (IgM, IgG) in the blood [250, 252] (2B);

- Viral hepatitis B (see relevant clinical guidelines) [250, 252] (2B);

- Determination of hepatitis B virus surface antigen (HBsAg) in the blood [250, 252] (2B);

- Determination of hepatitis B virus core antibodies (anti-HBc IgM, IgG) (if not previously tested) in the blood [250, 252] (2B);

- Toxoplasmosis (see relevant clinical guidelines) [16] (2B);

- Determination of CMV serological markers – detection of IgG and IgM antibodies in blood serum, quantitative PCR determination of cytomegalovirus (Cytomegalovirus) DNA in peripheral blood, quantitative PCR determination of cytomegalovirus (Cytomegalovirus) DNA in cerebrospinal fluid (CMV screening in accordance with the clinical guidelines for CMV) [37] (5C).

- Tuberculosis (see relevant clinical guidelines) [17] (2B).

- Assessment of nephron function via creatinine clearance (Rehberg's test) (see relevant clinical guidelines) [31,37,49, 373] (2B).

- Cytological examination of cervical smear [43,44,45,46,47] (2B).

- Serum total calcium level testing (see relevant clinical guidelines).

- Detection of Cryptococcus neoformans antigen in the blood – diagnosis of cryptococcosis [37,51] (2B);

- Detection of acid-fast bacilli in feces, urine, and sputum – diagnosis of tuberculosis and mycobacteriosis: microscopic examination (bacterioscopy) of sputum for mycobacteria (Mycobacterium spp.), microbiological (culture) examination of sputum for Mycobacterium tuberculosis complex (Mycobacterium tuberculosis complex), PCR detection of Mycobacterium tuberculosis complex DNA in sputum, bronchoalveolar lavage fluid, or bronchial washings, microbiological (culture) examination of urine for mycobacteria (Mycobacterium spp.), microbiological (culture) examination of feces for mycobacteria (Mycobacterium spp.) [37,52,53,54] (2A).

Comments: culture and molecular genetic diagnostics of mycobacterioses are performed in specialized anti-tuberculosis healthcare facilities.

Following the receipt of laboratory and instrumental examination results and specialist consultations, a repeat appointment with an infectious disease specialist is conducted.

The purpose of the follow-up visit is to finalize the disease stage and phase, and to determine the plan for ongoing patient monitoring and treatment.

The patient is counseled on the importance of early initiation of ART and regular adherence to scheduled examinations as part of clinical follow-up.

- Blood creatinine level testing (estimation of glomerular filtration rate) – when selecting TDF** [37,48,49,50,117] (2B);

- Detection of the human leukocyte antigen major histocompatibility complex class I B locus 5701 allele (HLA-B*5701) – when selecting ABC** [37,118,119] (2B);

- Blood total hemoglobin and neutrophil count testing – when selecting ZDV**, AZT** [37,120,121] (2A);

- CD4+ lymphocyte testing – when selecting NVP**, RPV [37,122,123] (3C);

- Blood aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity testing – when selecting ABC**, NVP**, EFV** [37,124] (5C);

- Blood total bilirubin, unconjugated and conjugated bilirubin level testing – when selecting ATV** [37,125] (4C);

- Biochemical blood lipid profile test – when selecting PIs and EFV** [37,126] (4C);

- Screening for osteopenia or high risk thereof (DXA scan (dual-energy X-ray absorptiometry of the lumbar spine, dual-energy X-ray absorptiometry of the proximal femur), blood 25-OH vitamin D level testing, blood total calcium level testing, blood creatinine level testing, blood inorganic phosphorus level testing) – when selecting TDF** [37,49,50,388] (4C).

Monitoring of HIV disease progression and/and or ART efficacy:

1. Until an undetectable viral load is achieved, test every 3 months: CD4+ lymphocyte count, CD4/CD8 ratio (immunoregulatory index, IRI), quantitative determination of human immunodeficiency virus (HIV-1) RNA in blood plasma by PCR [3,4,11,37,57] (5C).

   Comments: if CD4 ≥ 350 cells/mcL and viral load is below the limit of quantification (<50 copies/mL) for the last 18 months of treatment or longer, the above tests may be performed every 6 months.

2. Molecular genetic testing of blood plasma for drug resistance mutations in human immunodeficiency virus (HIV-1) RNA – in the presence of signs of ART failure (see section 3.1.6.) [3,4,11,37,57] (5C).

Monitoring of treatment adverse effects and complications:

1. Complete blood count (CBC) with differential – every 4 months [3,4,11,37,57] (5C);

2. Urinalysis – every 12 months (or every 6 months if clinically indicated) [3,4,11,37,57] (5C);

Comment: the frequency of the above tests may be reduced to once every 6 months if CD4 ≥ 350 cells/mcL and viral load is below the limit of quantification (<50 copies/mL) for the last 18 months of treatment or longer, provided that adverse effects of the administered drugs have been ruled out.

Monitoring of drug hepatotoxicity and/or hepatitis activity:

1. Blood AST activity testing every 4 months [3,4,11,37,57] (5C);

2. Blood ALT activity testing every 4 months [3,4,11,37,57] (5C);

3. Blood total bilirubin level testing every 4 months [3,4,11,37,57] (5C);

4. Blood alkaline phosphatase (ALP) activity testing – as clinically indicated [3,4,11,37,57] (5C);

5. Blood gamma-glutamyl transferase (GGT) activity testing as clinically indicated [3,4,11,37,57] (5C);

Comment: the frequency of the above tests may be reduced to once every 6 months.

If elevated values of one or more biochemical markers are detected, the frequency of testing may be increased (according to the clinical situation).

Monitoring of drug nephrotoxicity and/or existing renal pathology activity:

Blood creatinine level testing with estimation of glomerular filtration rate (recommended using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula) – every 4 months [3,4,11,37,57, 373] (5C);

Comment: The frequency of the above tests may be reduced to once every 6 months if CD4 ≥ 500 cells/mcL and viral load is below the limit of quantification (less than 50 copies/mL) for the last 18 months of treatment or longer, provided that adverse effects of the administered medications have been ruled out based on the previous evaluation and there is no renal pathology.

Monitoring of bone tissue status and treatment adverse effects:

Blood total calcium level testing – every 12 months (see relevant clinical guidelines); [3,4,11,37,57] (5C)

Monitoring of metabolic complications in patients receiving ARVDs:

1. Blood aspartate aminotransferase activity testing [3,4,11,37,57] (5C)

2. Blood alanine aminotransferase activity testing [3,4,11,37,57] (5C)

3. Blood glucose testing [3,4,11,37,57] (5C)

4. Blood creatinine testing [3,4,11,37,57] (5C)

5. Blood triglyceride testing [3,4,11,37,57] (5C)

6. Biochemical blood test for lipid metabolism disorders [3,4,11,37,57] (5C)

7. Blood cholesterol testing at least once every 6 months or according to clinical indications [3,4,11,37,57] (5C).

Monitoring manifestations of various secondary and comorbid conditions:

1. Diagnosis of tuberculosis (see relevant clinical guidelines) – every 6 months in the absence of active tuberculosis; [3,4,11,37,57] (5C)

2. Hepatitis B screening every 12 months (if viral hepatitis B diagnosis is absent):

   - blood test for hepatitis B surface antigen (HBsAg) [3,4,11,37,57] (5C)

   - blood test for hepatitis B core antibody class G (anti-HBc IgG) (see relevant clinical guidelines) [3,4,11,37,57] (5C);

3. Hepatitis C screening every 12 months (if viral hepatitis C diagnosis is absent): determination of total class M and G antibodies (anti-HCV IgG and anti-HCV IgM) to hepatitis C virus in blood (see relevant clinical guidelines) [3,4,11,37,57] (5C).

   Comment: if chronic viral hepatitis B or C has been detected in a patient and treatment has not been administered, it is impractical to repeat the antibody test for chronic viral hepatitis annually.

4. Serum alpha-fetoprotein testing in patients with liver cirrhosis – every 6 months (see relevant clinical guidelines) [3,4,11,37,57] (5C);

5. Determination of antibodies to T. pallidum in blood – every 12 months (in the absence of additional indications) [3,4,11,37,57] (5C);

6. Blood glucose testing – every 12 months (in the absence of additional indications) [3,4,11,37,57] (5C);

7. Biochemical blood test for lipid metabolism disorders – every 12 months (in the absence of additional indications) [3,4,11,37,57] (5C);

8. Calculation of cardiovascular risk using the Framingham Risk Score in individuals over 40 years of age – every 24 months (in the absence of additional indications) [3,4,11,37,57] (5C);

9. Cytological examination of a cervical smear – at least once a year [3,4,11,37,57] (2B);

The schedule and scope of tests during follow-up and ART are presented in Table 3 and Table 4 [4,57-62].

Comment: if elevated values of one or more parameters are detected, the frequency of their monitoring may be increased (depending on the clinical situation).

2.4 Instrumental Diagnostics

The diagnosis of HIV infection does not imply specialized instrumental imaging, but it is used to diagnose opportunistic conditions, the detection of which may affect the disease outcome and patient management tactics, as well as to identify risk factors and comorbidities that influence the timing and selection of the ART regimen.

- chest fluorography [63] (3B) or chest X-ray (targeted chest radiography) (1B) for the diagnosis of tuberculosis [25,37];

- electrocardiogram recording for the diagnosis of cardiovascular diseases [64,65] (4C);

- peripheral blood pressure measurement for the diagnosis of cardiovascular diseases [64,66] (2B);

- abdominal ultrasound (comprehensive) for the diagnosis of gastrointestinal diseases [67] (1A);

- renal and adrenal ultrasound for the diagnosis of kidney and adrenal diseases [68,69,70] (4C);

- calculation of cardiovascular risk using the Framingham Risk Score and assessment of drug-drug interactions when co-administering ART and concurrent cardiological therapy [65,71,72] (4C).

- chest fluorography (3B) or chest X-ray (targeted chest radiography) (1B) – diagnosis of tuberculosis (every 6 months in the absence of active tuberculosis) [25,63];

- electrocardiogram recording – diagnosis of cardiovascular diseases (every 12 months in patients aged over 40 years and/or in the presence of other risk factors) [65,71,72] (4C);

- peripheral blood pressure measurement – diagnosis of cardiovascular diseases (at each visit) [64,66] (2B);

- abdominal ultrasound (comprehensive) – diagnosis of digestive system diseases (every 12 months, in patients with liver cirrhosis – every 6 months) [67] (1A);

- renal and adrenal ultrasound – diagnosis of kidney and adrenal diseases (every 12 months) (4C) [68,69,70];

Comments: other instrumental examinations, including MRI and CT, may also be performed if additional assessment of the patient's condition is required, etc.

2.5 Other Procedures

- identification of neurocognitive disorders and signs of depression using appropriate methods – for the diagnosis of CNS involvement, clarification of the diagnosis, and selection of the ART regimen [73,74,75] (3B);

- mental status assessment [75] (5C);

- for women, determination of reproductive status (assessment of contraception methods used; pregnancy planning; assisted reproductive technologies) – for the selection of the optimal ART regimen [77,78,79,80,81,82,83] (3A);

- for women, speculum examination of the vagina and cervix to detect cervical pathology (see relevant clinical guidelines "Cervical Cancer")

- for women with abnormal cytology results, presence of high-oncogenic-risk HPV, and abnormal colposcopic findings, perform additional diagnostic tests to confirm/exclude the diagnosis (see relevant clinical guidelines "Cervical Cancer") [379] (5C);

- visits (examinations, consultations) with medical specialists depending on the clinical manifestations of secondary conditions (dermatovenerologist, general practitioner/internist, neurologist, otorhinolaryngologist, ophthalmologist, obstetrician-gynecologist, oncologist, and others) [84,85,86,87] (2A).

Comments: based on the results of other diagnostics and specialist consultations at the AIDS Center providing dispensary observation and treatment of the patient, in accordance with current legislation.

- infectious disease specialist visit (examination, consultation) – at 1–2 months from the start of ART; then every 3 months until viral load drops below the limit of detection and CD4 ≥500 cells/µL; thereafter every 6 months (if CD4 ≥500 cells/µL and viral load below the limit of detection) [3,5,8,9,10,108] (5C);

- ophthalmologist visit (examination, consultation) – every 6 months if CD4 <100 cells/µL; every 12 months if CD4 >100 cells/µL [210] (4C);

- obstetrician-gynecologist visit – at clinical stage 3 and CD4 ≥200 cells/µL – every 12 months; in all other cases – every 6 months [3,5,8,9,10,108] (5C);

- neurologist visit (examination, consultation) – every 6 months if CD4 <200 cells/µL; every 12 months if CD4 >200 cells/µL [212] (4C);

- phthisiatrician visit (examination, consultation) – if CD4 <350 cells/µL for re-administration of tuberculosis chemoprophylaxis according to an individualized regimen in areas with high tuberculosis prevalence (see Guidelines for Tuberculosis Chemoprophylaxis in Adult HIV-Infected Patients, 2016) [213] (4C);

- psychiatrist-narcologist (psychiatrist) or medical psychologist visit (examination, consultation) – if indicated [214] (4C);

- dermatovenerologist visit (examination, consultation) – every 12 months, regardless of CD4 count [3,5,8,9,10,108] (5C);

- general practitioner/internist visit (examination, consultation) – every 6 months, regardless of CD4 count [3,5,8,9,10,108] (5C);

- dentist visit (examination, consultation) – every 12 months, regardless of CD4 count [3,5,8,9,10,108] (5C).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Conservative treatment

Currently, the main component of treatment for patients with HIV infection is ART, which helps achieve a controlled course of the disease. Early initiation of ART improves the clinical prognosis of the disease and reduces the prevalence of HIV infection in the population [37,54,57,88].

The goals of ART are:

- increasing life expectancy and preserving (improving) patients' quality of life;

- reducing patient contagiosity, which leads to a significant decrease in the risk of horizontal and vertical HIV transmission;

- financial cost reduction associated with the treatment of secondary diseases and patient disability.

The main objective of ART is to maximally suppress HIV replication, which is accompanied by a decrease in blood HIV RNA levels (viral load) to an undetectable level (by PCR).

The principles of ART are:

- voluntariness – conscious decision-making on the initiation and conduct of treatment, documented by "informed consent";

- timeliness – initiating ART as early as possible;

- continuity – long-term (lifelong) adherence to the ARV intake regimen.

The decision to initiate ART is made by:

- the medical commission for ART prescription of the regional AIDS center, taking into account the results of clinical, laboratory, and instrumental examinations and counseling;

- with the patient's written consent to treatment with specific drugs.

Comment: in case of transferring the authority for patient treatment to another medical organization, the AIDS Center performs a supervisory function.

Comments: Counseling must be conducted from the start of ART and continued during the treatment process to maintain therapy adherence. After counseling, an informed consent for ART or a refusal of ART is signed (see Appendix G).

- the importance of strict adherence to the ART regimen (timing, food, water, meal schedule, etc.);

- potential side effects of ARVs, in the event of which a doctor must be consulted;

- prevention of secondary infections, including Pneumocystis pneumonia, toxoplasmosis, mycobacteriosis, tuberculosis;

- the possibility of developing immune reconstitution inflammatory syndrome, accompanied by a temporary worsening of the clinical condition, with an explanation that this is an indicator of therapy efficacy and is not a reason to cancel or interrupt it.

Comments: ART initiation should be recommended regardless of the CD4 count and viral load level, since ART reduces systemic inflammation and lowers the risk of opportunistic diseases.

Comments: according to the HIV infection classification currently in force in Russia, the stage and phase of the disease are established solely based on clinical manifestations (presence of secondary diseases). Viral load or CD4 count is not a criterion for determining the clinical stage or phase of the disease. In confirmed HIV infection, these parameters do not affect the necessity of chemoprophylaxis for vertical HIV transmission. Delaying ART initiation in this situation leads to an increased risk of perinatal transmission of the human immunodeficiency virus.

- at a CD4 count <200/µl [3,4,5,37,91,92] (2B);

- when HIV infection is detected in a pregnant woman at a gestational age of 13 weeks or more [96] (2B);

- when HIV infection is detected in a pregnant woman with a CD4 count <350/µl and/or viral load >100,000 copies/ml at a gestational age of less than 13 weeks [94,95,96] (3B).

Comments: upon admission under observation of an HIV-infected pregnant woman at a gestational age of 28 weeks or more, ART should be initiated no later than 3 days regardless of indications and viral load (see Clinical Guidelines “HIV Infection in Pregnant Women”, 2021).

- clinical stages 2, 4, and 5 according to the Russian classification [97] (2B);

- at a CD4 count <350/µl [97] (2B);

- viral load >100,000 copies/ml [97] (2B);

- chronic hepatitis B requiring treatment [3,4,37,98] (2A);

- diseases requiring long-term use of immunosuppressive therapy, neurological disorders [3,4,37,99] (5C);

- the need to use assisted reproductive technologies [100] (5C) for an HIV-uninfected partner in stable serodiscordant couples [101].

Comments: in patients older than 50 years, early ART initiation may be considered a priority due to the risk of more rapid disease progression.

Potential benefits of initiating therapy at any stage of acute infection include:

- reducing the severity of acute-stage clinical manifestations;

- lowering HIV viral load and reducing the size of the HIV reservoir;

- decreasing the rate of viral genetic evolution;

- reducing levels of immune activation and systemic inflammation;

- preserving immune function and lymphoid tissue integrity;

- protecting the nervous system;

- preventing damage to the intestinal lymphoid apparatus.

Comments: A viral load exceeding 100,000 copies/ml is considered prognostically unfavorable, yet the disease can progress even at low viral load levels. ART initiation reduces systemic inflammation and decreases immune activation, minimizing the risk of disease onset.

The period between HIV diagnosis and ART initiation should be minimized as much as possible [88,96].

When the patient is ready to start ART and provides consent, treatment can be initiated immediately upon diagnosis, provided there are no clinical contraindications to antiretroviral drugs (according to the ATC classification: systemically acting antivirals) [88,96].

- in severe patient condition requiring stabilization of vital functions and emergency etiotropic treatment of secondary or comorbid conditions (tuberculosis, CNS lesions, etc.) [380] (3B);

- in the presence of a high risk of fatal ART complications due to the development of life-threatening immune reconstitution inflammatory syndrome [102,103] (2B).

Comments: when active tuberculosis is detected, its treatment should be initiated (see Clinical Guidelines for Tuberculosis in Adults) [177].

• In HIV-infected patients with tuberculous meningitis, ART is recommended to be delayed for at least 4 weeks (but initiated within eight weeks) after starting tuberculous meningitis treatment [177] (5C).

Comments: when cryptococcal meningitis is diagnosed, its treatment is initiated, and ART is added after clinical improvement, typically 2–10 weeks after starting antifungal drugs (according to the ATC classification: systemically acting antifungals). Recommendations to delay treatment in such cases aim to reduce the risk of life-threatening immune reconstitution inflammatory syndrome and are based on the lack of data showing reduced mortality in these patient groups with earlier ART initiation.

- when an HIV-infected woman is in the 1st trimester of pregnancy (see Clinical Guidelines “HIV Infection in Pregnant Women”) [104] (2B);

Comments: Considering the low rate of mother-to-child HIV transmission at a gestational age of up to 13 weeks, as well as to avoid potential adverse effects of ARVs on the fetus, ART may be delayed until the end of the 1st trimester of pregnancy—provided there are no indications for rapid ART initiation.

- in "elite controllers" [37,105,106,107] (5C).

Comments: patients with persistently undetectable viral load (VL) and high CD4 counts (> 500 cells/µL) in the absence of ART have a low risk of HIV disease progression. To avoid adverse drug reactions from ARV and in the absence of any indications for starting ART other than the presence of HIV infection, treatment may be deferred until indications arise. A prerequisite for this decision is regular clinical follow-up of the patient with the capability to test CD4+ lymphocytes and VL. At the same time, patients should be informed that the absence of therapy entails an increased level of systemic inflammation and a rise in the risk of comorbidities, even with "elite control".

Comments: This evaluation is performed to obtain baseline data that will allow assessment of the safety and efficacy of the ongoing therapy. Based on the clinical, laboratory, and instrumental studies, the condition of major organs and body systems (CNS, hematopoiesis, kidneys, liver, lungs, cardiovascular system), the presence of co-infections and secondary infections (chronic hepatitis B and C, tuberculosis, toxoplasmosis) and conditions (pregnancy), as well as the activity of viral replication (VL) and the severity of immunosuppression (CD4 count) are assessed. The scope of required investigations is presented in section 2.3.

Comments: Treatment is voluntary and involves active participation by the patient; therefore, a critical component of successful ART is the patient's psychological preparation. An essential part of this is counseling regarding adherence to treatment, its expected efficacy, contraindications, and potential complications of the planned therapy. Women of childbearing potential should be informed about the potential impact of the treatment on the course of pregnancy and fetal development.

Comments: Signing the "Informed Consent for ART" is the logical culmination of the patient's preparation (including psychological) for ART and includes a mandatory discussion with the patient of all provisions contained in the informed consent form.

3.1 Characteristics of ARV drugs and ART regimens are presented in Appendix G1.

Comments: to identify potential contraindications to prescribing a specific ARV drug, the enclosed prescribing information should be carefully studied prior to administration. Attention should be paid to the patient's medical history and life history, and a thorough physical examination along with necessary laboratory and instrumental tests should be performed.

- serum creatinine testing (calculation of glomerular filtration rate) – when selecting TDF** [37,48,49,50,117] (2B);

- screening for the human leukocyte antigen B*5701 allele (HLA-B*5701) – when selecting ABC** [37,118,119] (2B);

- complete blood count for total hemoglobin and neutrophils – when selecting ZDV** [37,120,121] (2A);

- CD4+ lymphocyte testing – when selecting NVP**, RPV [37,122,123] (5C);

- blood aspartate aminotransferase (AST) activity and blood alanine aminotransferase (ALT) activity testing – when selecting ABC**, NVP**, EFV** [37,124] (5C);

- total bilirubin, unconjugated bilirubin, and conjugated bilirubin testing in the blood – when selecting ATV**, ATV/r [37,125] (4C);

- biochemical blood analysis to assess lipid metabolism disorders – when selecting PIs and EFV** [37,126] (4C);

- screening for osteopenia or its high risk – when selecting TDF** [37,48,49,50] (5C).

Comments: adverse outcomes include low ART efficacy, emergence of drug-resistant HIV strains, general toxicity, teratogenicity, hepatotoxicity, decreased ARV concentrations, and others (Table 1).

Table 1 Antiretroviral drugs (according to the ATC classification: systemically acting antivirals) and their combinations not recommended for ART [37].

Table 2. First-line ART regimens for adults by ARV preference

- tenofovir** in combination with lamivudine** plus efavirenz**, including as an FDC (TDF/3TC/EFV) [37,109,110,111,112] (5C), tenofovir** in combination with emtricitabine**, including as an FDC (TDF/FTC), plus efavirenz** [37,109,110,111,112,131,132] (2A);

- tenofovir** in combination with lamivudine** plus dolutegravir** [37,133,134,135] (5C) or tenofovir** in combination with lamivudine/dolutegravir (INN per State Register of Medicines: dolutegravir + lamivudine) as an FDC;

- tenofovir** in combination with emtricitabine**, including as an FDC (TDF/FTC), plus dolutegravir** [37,133,134,135] (2A);

- tenofovir** in combination with lamivudine** plus raltegravir** [3,4,5,37,146] (5C);

- tenofovir** in combination with emtricitabine**, including as an FDC (TDF/FTC), plus raltegravir** [3,4,5,37,146] (5C);

- tenofovir** in combination with lamivudine** plus elsulfavirine** [136,137,138], or tenofovir** in combination with emtricitabine**, including as an FDC (TDF/FTC), plus elsulfavirine** [136, 137, 138] (2B);

- tenofovir/elsulfavirine/emtricitabine** (INN per State Register of Medicines: tenofovir + elsulfavirine + emtricitabine**) as an FDC [138] (5C);

- dolutegravir** plus lamivudine** [138] (5C) or dolutegravir/lamivudine (INN per State Register of Medicines: dolutegravir + lamivudine) as an FDC (5C).

Comments: The preferred regimen of dolutegravir** plus lamivudine** or dolutegravir/lamivudine (INN per State Register of Medicines: dolutegravir + lamivudine) as an FDC may be prescribed to patients who have:

- HBsAg negative;

- blood HIV RNA less than 500,000 copies/mL;

- no resistance to lamivudine** and dolutegravir**.

Preferred regimens may also be prescribed to patients with active tuberculosis (when prescribing dolutegravir** in patients with tuberculosis whose treatment regimen includes rifampicin**, an increased dose of dolutegravir** at 50 mg twice daily is required when coadministered with rifampicin**) and chronic hepatitis B (CHB);

If the ART regimen does not include a booster (ritonavir** or cobicistat** [as part of cobicistat/tenofovir alafenamide/elvitegravir/emtricitabine**]), TAF** and TDF** have a similar short-term risk of a negative impact on renal function and bone mineral density.

- NRTIs: tenofovir**, or abacavir**, or zidovudine**, or phosphazid**, or tenofovir alafenamide** (as an FDC);

- ritonavir**-boosted PIs (atazanavir**, darunavir**, lopinavir**) — used as the third drug in the ART regimen as an alternative to efavirenz**, unboosted atazanavir**, or dolutegravir**;

- NNRTIs rilpivirine, doravirine**, or etravirine** — used as the third drug in the ART regimen as an alternative to efavirenz**, elsulfavirine**, or dolutegravir**;

- fixed-dose combination drugs:

cobicistat/tenofovir alafenamide/elvitegravir/emtricitabine**;

doravirine/lamivudine/tenofovir**,

bictegravir/tenofovir alafenamide/emtricitabine**;

rilpivirine/tenofovir/emtricitabine**;

Comments: the use of drugs specified in special cases is justified under the following circumstances (characteristics of the special case):

- pregnancy or potential pregnancy (exceptions exist);

- neurocognitive disorders;

- elevated aminotransferase levels (ALT and/or AST greater than 2.5 times the upper limit of normal);

- anemia, neutropenia when TDF** cannot be prescribed;

- CD4 <50 cells/µL;

- increased risk of osteopenia;

- renal impairment with creatinine clearance below 30 mL/min (if TDF** is an alternative);

- continuation of previously initiated ART;

- HIV-2;

- inadequate ART adherence;

- presence of hepatitis B;

- elderly age;

- patients with cardiovascular diseases and a high risk of developing them;

- swallowing disorders (use of ETR**).

- when initiating ART, TAF** (as part of an FDC) should be considered as a first-line drug compared to TDF** if there is:

high risk of chronic kidney disease (hypertension, diabetes mellitus, cardiovascular diseases, HIV/HCV coinfection, low CD4 cell counts, age over 65 years, smoking, use of nephrotoxic drugs);

concomitant administration of nephrotoxic drugs [372] (5C).

Table 3. Additional tests prior to prescribing ARVDs of preferred regimens to assess their safety

Comments: DTG** has demonstrated high efficacy and safety during pregnancy; however, women should be informed about a potential increase in the risk of neural tube defects (when dolutegravir** is used from conception to 8-9 weeks of pregnancy).

Comments: Creatinine clearance can be calculated using formulas.

CKD-EPI: GFR = 141 × min (SCr)^α × max (SCr)^-1.209 × 0.993^age

SCr – serum creatinine in mg/dL;

α: -0.329 (F) and -0.411 (M);

women must multiply the final result by 1.018 at the end.

MDRD: GFR = 170 × (SCr)^-0.999 × age^-0.176 × 0.762 (for females only) × blood urea nitrogen (mmol/L) ^-0.17 × serum albumin level (g/L)^0.318.

Cockcroft-Gault: GFR = ((140 — age) × body weight in kg) : SCr (µmol/L).

The final result is multiplied by 1.23 for men and 1.05 for women.

Important to know! To convert blood creatinine concentration from mmol/L to mg/dL, multiply the value by 0.0113.

If protein is detected in the urine and/or the glomerular filtration rate is <60 mL/min, the tests should be repeated in 1 month. If abnormalities persist, patient management should be carried out in cooperation with a general practitioner or nephrologist.

Detailed information on the use of ARVs in patients with renal failure is presented in Appendix G5.

Table 4. Additional tests prior to prescribing alternative and special-case ARV regimens to assess their safety [3,4,5,37] (5C)

Comments: in such cases, consider selecting drugs primarily from alternative regimens, or, if not possible, ARVs prescribed for special cases (Table 5).

Table 5. Selection of ARVs in patients who cannot be prescribed preferred regimens [3,4,5,37,146] (5C)

Comments: Virological efficacy — maximum suppression of viral replication is the main goal of ART; therefore, reducing plasma HIV RNA to undetectable levels is its most important task and an indicator of virological efficacy. ART is considered effective if at 1 month viral load decreases by 10-fold or more, at 3 months of therapy — below 400 copies/mL, and at 6 months — less than 50 copies/mL.

Comments: A short-term increase in viral load up to 10 copies/mL during acute infectious diseases, intoxications, etc., is not considered an objective sign of virological failure and requires a follow-up test no earlier than 1 month after resolution of the condition.

Table 6. Treatment failure criteria and management tactics

- In treatment-naive patients, a decrease in viral load of less than 1 lg (10-fold) at 1 month after starting therapy, and failure to achieve virological suppression of less than 200 copies/mL at 6 months;

- In patients receiving ART who had an undetectable viral load, the appearance of a viral load above 200 copies/mL in 2 repeat tests performed at an interval of 3 weeks or more.

Comments: Viral blips should be distinguished from low-level viremia by re-determining the viral load in 3-4 weeks.

Comments: immunological efficacy — immune system reconstitution — is also an important goal of ART. This process is slow and largely depends on the degree of immunodeficiency at the time ART is initiated. In patients starting treatment against the background of severe immunodeficiency (CD4<200 cells/µL), immune status recovery may take weeks, months, or sometimes years.

Comments: in this situation, the causes of leukopenia/lymphopenia should be analyzed and corrected:

- if the impact of drugs used to treat comorbid diseases and conditions is identified, replace or discontinue them;

- if adverse reactions of ARVs are identified, replace them;

- conduct a thorough examination to identify secondary and comorbid conditions and prescribe treatment, avoiding drugs that cause leukopenia/lymphopenia;

- pay attention to the correction of risk factors (bad habits, hypertension, dyslipidemia, etc.).

In addition, it should be borne in mind that the exacerbation of existing secondary diseases or the appearance of new ones during the initial period of ART may be a manifestation of immune reconstitution inflammatory syndrome (IRIS). In patients with severe immunodeficiency, signs of clinical progression of HIV infection during the first 3–6 months of ART are usually not considered a sign of treatment failure.

Comments: clinical criteria for treatment efficacy — assessment of HIV infection progression and the course of secondary diseases — are the most accessible for the practicing physician and objective in the long term.

Comments: The main cause of virological failure is the emergence of ARV-resistant HIV strains. Continuing ART in this situation generally has low clinical efficacy, does not prevent disease progression, and leads to the development of multiple resistance with a significant limitation of future therapeutic options (Table 8, Appendix B. Patient Management Algorithms)

Comments: The resistance test is performed against the background of ART or within 2-4 weeks after discontinuation of all regimen drugs (the long half-life of NNRTIs should be taken into account). At a viral load of 500 to 1000 copies/mL of plasma, mutations may remain undetected by standard (non-highly sensitive) methods.

Comments: The presence of resistance mutations is determined using molecular diagnostic methods (sequencing). The presence of HIV mutations does not always imply the development of resistance — secondary mutations do not affect the level of drug resistance. For most ARVs, the accumulation of several primary HIV mutations is required for treatment resistance to develop. The resistance test allows not only identifying mutations that have formed in HIV but also determining cross-resistance to other ARVs and identifying active drugs (Table 8, Appendix B. Patient Management Algorithms). Testing for HIV resistance to ARVs should be performed while on ART or within 2-4 weeks after discontinuation. At a viral load <1000 copies/mL, test results may be questionable.

Comments: A characteristic feature of HIV is cross-resistance, i.e., unresponsiveness to drugs the virus has never encountered; it is limited to the same class of drugs. This occurs because primary mutations are identical for different drugs from the same group (class). In the absence of molecular resistance test results, both NRTIs should be replaced and a third drug from a different class should be prescribed.

(Table 7, Appendix B. Patient Management Algorithms)

Table 7. Selection of drugs in second-line ART regimens [37,146]

Comments: in the event of adverse events (any deviations from the norm in the patient's condition, including laboratory parameters), unscheduled examinations should be performed to clarify their relationship with the course of HIV infection and ongoing therapy.

If intolerance to any ARV develops, corrective measures must be taken, and in the absence of an effect, it should be substituted according to the adverse event profile.

In case of mild to moderate adverse events, ART should be continued under observation, and symptomatic treatment prescribed. With prolonged persistence of moderate or development of severe adverse events, ART should be discontinued, the adverse event treated, and the replacement of the drug causing the adverse effect considered. Continuing ART in the presence of severe adverse events may threaten the patient's life.

Comments: After stopping an NNRTI, its molecules are eliminated from the body for a long time (up to 4 weeks), creating concentrations in the zone of low selective pressure, which favors the development of HIV resistance to the entire NNRTI class (cross-resistance). Given this characteristic of NNRTI drugs, if it is necessary to interrupt their intake (e.g., due to side effects, inability to form a sufficient level of adherence to this regimen), the NNRTI should be discontinued while continuing NRTIs (other drugs in the regimen) to avoid the development of NNRTI resistance.

If clinical, immunological, and virological efficacy of treatment is achieved during initial (first-line) therapy, partial or complete modification of the treatment regimen is carried out within the first-line ART.

Comment: changing an effective (undetectable VL against the background of high CD4 counts and absence of clinical manifestation) and well-tolerated ART, the regimen of which is composed of an acceptable combination of drugs and does not contradict clinical guidelines, is carried out as part of ART optimization, the indications for which are:

- high pill burden (to reduce the number of tablets and dosing frequency);

- intake of drugs with high long-term toxicity;

- changes (including probable ones) in the patient's condition requiring therapy adjustment (pregnancy, old age, etc.);

- the onset of diseases whose course or treatment may be adversely affected by ongoing ART;

- the possibility of prescribing a more cost-effective ART regimen.

Currently, 2 approaches are used to optimize ART:

- substitution of individual drugs in the regimen (within the same class or with a class switch);

- transition to a reduced regimen.

In case of substituting individual drugs in the regimen, previous virological history (virological failure, past resistance) should be taken into account and, if necessary, an HIV drug resistance test should be performed.

A possible option for ART optimization is its simplification by reducing the number of active drugs in the treatment regimen (reduced ART regimens). ART can be administered as biotherapy – PI/r** + 3TC** [381] (5C), INSTI+3TC** or FTC** [381] (5C), DTG/RPV [381,382] (5C).

Comments: reduced regimens are primarily indicated for patients with NRTI intolerance.

The condition for prescribing reduced regimens is the presence of a combination of factors in the patient:

- Undetectable VL level for at least 6 months;

- Absence of clinical manifestations of secondary diseases over the past 6 months;

- Absence of resistance to PIs, INSTIs, NNRTIs, or multi-drug resistance;

- Immunity to HBV or concomitant HBV vaccination in the absence of immunity;

- Absence of pregnancy.

3.2 Treatment of secondary and comorbid conditions in HIV infection.

Therapy and treatment regimens for secondary diseases most commonly registered in HIV-infected patients

The severity of a patient's condition may initially be determined by the presence of secondary and comorbid conditions, the treatment of which in most cases takes priority over the initiation of ART and plays an important role in the management of patients with HIV infection.

Comments: Primary prophylaxis of tuberculosis is carried out in accordance with current regulatory documents (Clinical guidelines “Tuberculosis in adults”, 2022 and “Instructions for the chemoprophylaxis of tuberculosis in adult patients with HIV infection”, approved on March 14, 2016).

- Ganciclovir**, 5 mg/kg every 12 hours IV slowly over an hour, for at least 21 days [3,4,5,37,108,222, 223] (2A);

- Valganciclovir**, 900 mg twice daily orally, for at least 21 days [3,4,5,37,108, 223] (2A);

- Valganciclovir**, 900 mg once daily orally for 1 month [3,4,5,37,108, 223] (5C);

- Ganciclovir**, 5 mg/kg once daily IV slowly over an hour for 1 month [3,4,5,37,108,222] (4C).

- #Valacyclovir 1000 mg 3 times daily orally for at least 10 days (Applicable for ICD-10 codes: B20-24, which are included in Government Decree 1180-r). [3,4,5,37,108,224-226] (5C);

- Famciclovir 500 mg 3 times daily orally for at least 10 days. [3,4,5,37,108,224-226] (5C);

- #Acyclovir** 800 mg 5 times daily orally (applicable for ICD-10 codes: B20-24, which are included in Government Decree 1180-r) or #acyclovir** 750 — 1000 mg 3 times daily IV infusion for at least 10 days (applicable for ICD-10 codes: B20-24, which are included in Government Decree 1180-r). [3,4,5,37,108,224-226] (5C).

Table 8 Prophylaxis regimens for toxoplasmosis at CD4 <200 cells/µL

Comments: Prophylaxis is carried out until CD4>200 cells/µL and an undetectable HIV viral load are achieved for more than 3 months. If PaO²<70 mm Hg or the alveolar-arterial oxygen gradient is >35 mm Hg, prednisolone** 1 mg/kg is prescribed with subsequent dose reduction [5], along with oxygen therapy.

- Prophylaxis (at CD4 <200 cells/µL) - #co-trimoxazole [Sulfamethoxazole+Trimethoprim]** 80/400 mg once daily [37] (2B) or 160/800 mg once daily 3 times a week (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108, 234, 235, 254] (2B).

- In case of intolerance to co-trimoxazole [Sulfamethoxazole+Trimethoprim]** - #dapsone** 100 mg (2 tabl.) once daily orally (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [37, 108, 234, 235, 254] (2B).

Comments: Prophylaxis is carried out until CD4> 200 cells/µL and an undetectable HIV viral load are achieved for 3 months.

• Treatment of toxoplasmosis (cerebral form is diagnosed most frequently) is recommended at the slightest suspicion of the disease, without waiting for the results of the examination [108, 232, 233] (2A).

Preferred regimen: Co-trimoxazole [Sulfamethoxazole+Trimethoprim]**, 25/5 mg/kg orally. Or Co-trimoxazole [Sulfamethoxazole+Trimethoprim]** IV infusion. The initial dose was 50/10 mg/kg/day or 75/15 mg/kg/day in two divided doses until clinical improvement (usually 3–5 days), then 37.5/7.5 mg/kg/day for at least 6 weeks (until elimination of at least 75% of brain MRI lesions). After completion of the treatment course, secondary prophylaxis of toxoplasmosis is carried out using trimethoprim 160/800 mg twice daily until CD4 >200 cells/µL and an undetectable HIV viral load are achieved for 6 months.

Chemoprophylaxis of cerebral toxoplasmosis is prescribed according to immunological indications when the CD4 count is <100 cells/µL and in the presence of anti-Toxoplasma IgG antibodies.

Priority regimens: Co-trimoxazole [Sulfamethoxazole+Trimethoprim]** at a trimethoprim dose of 160/800 mg once daily 3 times a week or 80/400 mg once daily.

Alternative regimen: #Dapsone** 100 mg (2 tabl.) once daily orally (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [383] (2B). Preventive therapy for cerebral toxoplasmosis is discontinued when the CD4 count increases to >200 cells/µL against the background of ART for 3 months.

• All HIV-infected patients with confirmed Kaposi's sarcoma are recommended to receive ART, which is the main method for preventing disease progression and achieving clinical improvement [3,37,108]. In severe forms of Kaposi's sarcoma involving internal organs and/or disseminated skin lesions, it is recommended to add anti-tumor chemotherapy drugs (according to the ATC classification: Antineoplastic agents) to standard ART in agreement with an oncologist-chemotherapist [3,4,5,108,167, 236] (2A).

Preferred regimen: Fluconazole** 200 mg orally on the first day, then 100 mg orally once daily until clinical effect is achieved (7–14 days) [3,4,5,108, 238,239] (5C).

Alternative regimens:

- #Itraconazole 100 mg twice daily (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [3,4,5,108,238,239] (5C);

- #Posaconazole** 400 mg twice daily for the first 1–3 days of treatment, then 400 mg daily (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [3,4,5,108,239, 240,242] (2B);

- #Voriconazole** 200 mg orally twice daily or IV loading dose 6 mg/kg twice daily, maintenance dose 3–4 mg/kg twice daily (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108] (5C);

- Caspofungin** 50 mg daily intravenously [108] (5C);

- #Micafungin** 150 mg daily intravenously (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108] (5C);

- #Amphotericin B** 0.3 mg/kg daily as an intravenous infusion (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [3,4,5,108] (5C).

Relapse prevention:

Fluconazole** 100–200 mg orally daily [3,5,108] (5C) or 200 mg 3 times a week until CD4 count increases to >200 cells/µL [243] (2B).

Treatment. Preferred regimen: Fluconazole** 400 mg on the first day, then 200 mg daily orally for 2–3 weeks [3,4,5,108] (5C).

Alternative regimens:

- #Itraconazole 100–200 mg twice daily from 3 weeks to 7 months (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108] (5C);

- #Posaconazole** 400 mg twice daily for the first 3 days of treatment, then 400 mg daily (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108, 240] (5C);

- #Voriconazole** 200 mg orally twice daily or IV loading dose 6 mg/kg twice daily, maintenance dose 3–4 mg/kg twice daily (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108] (5C);

- Caspofungin** 50 mg IV once daily [108] (5C);

- Micafungin** 150 mg IV once daily [108, 241] (2B);

- #Amphotericin B** 0.3–0.7 mg/kg daily as an IV infusion, then the dose is selected individually depending on the severity of the condition (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108] (5C);

- #Amphotericin B [liposomal] 4 mg/kg daily as an IV infusion (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108] (5C).

Induction therapy (at least 8 weeks):

- Clarithromycin** 500 mg twice daily + ethambutol** 15–20 mg/kg once daily + #rifabutin** 5 mg/kg once daily (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108] (5C).

- By decision of the medical commission, in case of intolerance to clarithromycin**, #azithromycin** 500 mg once daily may be included in the combination (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108] (5C).

- In generalized mycobacteriosis, a fourth drug may be used in the regimen: #amikacin** 15 mg/kg/day (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r), or levofloxacin** 500–1000 mg once daily, or #moxifloxacin** 400 mg daily (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108] (5C).

Maintenance therapy:

- Clarithromycin** 500 mg twice daily, ethambutol** 15–20 mg/kg once daily [108] (5C).

Prophylaxis (for all patients with CD4 <50 cells/µL) [108] (5C):

- #Azithromycin** 1250 mg once a week, or clarithromycin** 500 mg twice daily (Applicable for ICD-10 codes B20–B24 included in Government Decree No. 1180-r) [108] (5C).

Comments: Prophylaxis is carried out until CD4 >100 cells/µL and an undetectable HIV viral load are achieved for more than 3 months.

Table 9 Treatment regimen for cryptococcal infection with CNS involvement

- Immunodeficiency (for replacement purposes);

- Idiopathic thrombocytopenia with an autoimmune pathogenesis;

- Severe bacterial and viral secondary and concurrent diseases;

- Autoimmune peripheral neuropathies.

Comments: drug doses and the course of treatment depend on the degree of immunodeficiency, the severity of the patient's condition, and the specific immunoglobulin preparation. Normal human immunoglobulin** is administered intravenously as an infusion. Repeated administration is carried out no earlier than 24 hours later.

Note 1 # - off-label drugs (the use of medicinal products for indications not mentioned in the instructions for use, prescribed in exceptional cases after approval by a medical commission)

Note 2 ** - drugs included in the VGNL list

3.3. Surgical treatment

Not indicated for the treatment of HIV infection. The management of surgical conditions is regulated by the relevant clinical guidelines.

3.4. Other Treatment

Currently, there are no alternative ARV-based methods for treating HIV infection. HIV infection does not require a special diet. Pain management is regulated by the relevant clinical guidelines and when indicated.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Rehabilitation of patients is carried out according to the standards of treatment and rehabilitation for those secondary diseases detected in the patient, depending on the affected organs/body systems.

5. Prevention and Dispensary Observation

5.1 Prevention

Prevention of HIV infection is carried out by state authorities, local self-government bodies, employers, medical organizations, and public associations through the development and implementation of a system of legal, economic, and social measures aimed at preventing the occurrence, spread, and early detection of HIV infection.

Prevention of HIV infection is ensured through [175-180]:

- Development and implementation of HIV prevention programs;

- Implementation of measures for the prevention and early detection of HIV infection, and follow-up care (dispensary observation) for individuals with HIV infection.

- Informing the public about HIV infection and associated diseases;

- Identifying signs of risky behavior in patients and informing such patients about the means and methods of modifying the level of risk and the need for regular medical screening for HIV infection, as well as motivational counseling of such individuals to foster adherence to a healthy lifestyle and avoidance of risky behavior;

- Motivating the target population to undergo HIV testing, including informing citizens about the possibility of medical screening for HIV infection with the provision of contact information for medical organizations where voluntary, including anonymous, screening for HIV infection can be performed;

- Screening for HIV infection based on clinical indications;

- Conducting follow-up care (dispensary observation) for patients with HIV infection;

- Organization and implementation of population screening for HIV infection,

including screening programs.

Contact persons for HIV infection are considered to be medical workers in the event of a risk of HIV infection while providing care to individuals with HIV/AIDS, who had the opportunity to become infected based on the known mechanisms, routes, and factors of transmission of the infectious agent.

As part of the medical care provided by an infectious disease specialist to individuals in contact with HIV, a comprehensive assessment of the type and nature of the contact, the laboratory test results of the source and the contact person, a clinical examination, and counseling of the affected person are carried out. If necessary, a clinical/medical psychologist, narcological psychiatrist, psychotherapist, obstetrician-gynecologist, dermatovenerologist, epidemiologist, or specialists in other fields may be involved in working with the affected persons.

The comprehensive assessment includes:

- Assessment of the type of contact;

- Assessment of the need to prescribe HIV PEP;

- HIV testing of the contact person and the source of infection

(if possible);

- If the source is infected with HIV, determining whether they were receiving ART.

- If the victim is a woman, a pregnancy test must be performed and it must be ascertained whether she is breastfeeding.

Comments: The efficacy of PEP is not 100%. Cases of HIV infection development have been recorded without any convincing explanation for PEP failure. No randomized trials have been conducted regarding PEP. There are case-control study data, observational data, and monkey model data.

- Medical workers and other persons injured while providing care to patients;

- For the following types of contact for which HIV PEP is justified – contact with blood, blood-stained saliva, breast milk, genital secretions, cerebrospinal, amniotic, peritoneal, synovial, pleural, and pericardial fluids;

- For the following types of contact requiring HIV PEP: via mucous membranes (splashing into the eyes, nose, or oral cavity), parenteral.

Comments: HIV PEP is not required in the following cases:

- In case of a proven positive HIV status of the contact person;

- In case of a proven HIV-negative status of the source;

- In case of contact with biological fluids that do not pose a significant risk: tear fluid, saliva without blood admixture, urine, sweat [190, 191, 192] (5C).

Comments: Physicians of the medical organization where the emergency occurred shall provide first aid in the form of self-help by the victim, involvement of junior/mid-level medical personnel in providing first aid, as well as other persons present at the scene of the accident (in accordance with the Decree of the Chief State Sanitary Doctor of the Russian Federation dated January 28, 2021, No. 4 "On Approval of Sanitary Rules and Norms SanPiN 3.3686-21 'Sanitary and epidemiological requirements for the prevention of infectious diseases'"), Order of the Ministry of Health of the Russian Federation of January 9, 2018, No. 1n "On approval of the requirements for the kit of medicines and medical devices for the emergency prophylaxis kit for parenteral infections for the provision of primary health care, emergency medical care, specialized medical care, and palliative medical care"):

- In case of cuts and punctures, immediately remove gloves, wash hands with soap under running water, treat hands with a 70% ethanol solution**, and smear the wound with a 5% alcohol iodine solution** (INN according to State Register of Medicines: Iodine+ [Potassium iodide+Ethanol] **);

- If blood or other biological fluids get on the skin, treat the area with a 70% ethanol solution**, wash with soap and water, and treat again with a 70% ethanol solution**;

- If blood and other biological fluids get onto the mucous membranes of the eyes, nasal cavity, and mouth: rinse the oral cavity with plenty of water and gargle with a 70% ethanol solution**, and rinse the nasal mucosa and eyes abundantly with water (do not rub);

- If blood and other biological fluids get on a lab coat or clothing: remove work clothing and submerge it in a disinfectant solution.

- Discussion of the risk of HIV infection;

- Discussion of the risks and benefits of HIV PEP;

- Discussion of adverse events and side effects of HIV PEP.

Comment: ARV intake should be initiated within the first two hours, but no later than 72 hours. When prescribing HIV PEP, the patient is informed about the prescribed drugs, and comorbid pathology and potential drug-drug interactions are assessed. When additional information becomes available, the regimen is adjusted. Efforts are made to improve adherence when prescribing HIV PEP.

- As the preferred backbone for HIV PEP, #TDF**+3TC** (Applicable to ICD-10 codes B20–24, which are included in Government Decree 1180-r) or #TDF**+FTC** (Applicable to ICD-10 codes B20–24, which are included in Government Decree 1180-r) or #TDF/FTC (Applicable to ICD-10 codes B20–24, which are included in Government Decree 1180-r) is recommended [191] (2B);

- As the preferred third drug for HIV PEP, #RAL** (Applicable to ICD-10 codes B20–24, which are included in Government Decree 1180-r) or #DRV**+r** 800/100 mg (Applicable to ICD-10 codes B20–24, which are included in Government Decree 1180-r) is recommended [37,191] (2B);

- #DTG** may be considered as an alternative third-drug option for HIV PEP (Applicable to ICD-10 codes B20–24, which are included in Government Decree 1180-r) [37,191] (2B);

- #BIC/FTC/TAF** as a FDC may be considered as an alternative regimen option for HIV PEP (Applicable to ICD-10 codes B20–24, which are included in Government Decree 1180-r) [384] (4C).

In the event that an exposure incident is related to the provision of medical care to HIV-infected individuals, the administration of the MO is obliged to immediately take action to register the exposure incident and carry out a set of measures to provide first aid to the victim, as well as organize the provision of a consultation with an infectious disease specialist (or in their absence, as well as on weekends and holidays, the on-duty physician) to the exposed person:

- MO staff must immediately report any exposure incident to the head of the department, their deputy, or a superior supervisor;

- In accordance with established requirements, the authorized person of the MO shall document the exposure incident associated with the risk of HIV transmission during the provision of medical care;

- Injuries sustained by medical workers must be recorded in every MO and documented as an industrial accident with the drawing up of an Industrial Accident Report;

- The authorized person of the MO shall fill out the Industrial Accident Register;

- The authorized person of the MO shall organize an epidemiological investigation to clarify the cause of the injury and establish the link between the cause of the injury and the performance of official duties by the medical worker;

- To ensure timely assistance to exposed persons who suffered injuries while providing medical care, the regional authorities shall maintain a non-reducible stock of rapid tests for the diagnosis of HIV infection (to minimize false-positive and false-negative testing results, test systems with the best characteristics of analytical and diagnostic sensitivity and specificity must be used) [368-371], and ARV drugs used for HIV PEP in authorized MOs, taking into account the organization of round-the-clock access to ART within 2 hours after the injury. The drugs must be located in a place accessible to the institution's staff, including in the evening and at night, on weekends and holidays. The function of prescribing medications in such cases is assigned to the on-duty physician.

5.2 Dispensary monitoring

Dispensary follow-up is a mandatory condition for ART. All patients with diagnosed HIV infection who apply to specialized healthcare institutions (authorized medical organization), after counseling and a clinical examination with the establishment of a clinical diagnosis, are subject to dispensary registration and a comprehensive examination, as well as preparation for ART.

Dispensary follow-up of patients with HIV infection is carried out by a specially trained infectious disease physician from the AIDS and Infectious Diseases Prevention and Control Center or infectious disease physicians from other medical institutions authorized by the executive authority in the field of healthcare (federal, regional, and municipal subordination) who have completed training to work with HIV-infected patients, in cooperation with AIDS center specialists.

The objectives of examination upon dispensary registration for HIV infection include:

- Confirmation of the HIV infection diagnosis;

- Determination of the clinical stage and phase of HIV infection;

- Identification of indications for ART;

- Identification of indications for chemoprophylaxis of secondary diseases;

- Diagnosis, treatment, and prevention of secondary diseases;

- Identification of comorbidities (including those associated with HIV infection), determination of their severity and the need for additional examination and treatment;

- Counseling, establishment of rapport, and psycho-social adaptation of the patient.

The objectives of clinical and laboratory examination performed during ART are:

- Evaluation of the course of HIV infection;

- Evaluation of the efficacy of the therapy administered;

- Evaluation of the safety of the therapy administered;

- Assessment of therapy completeness;

- Identification of secondary and comorbid diseases, indications for their prevention and treatment, and assessment of their clinical course;

- Assessment of patient adherence to therapy and identification of factors disrupting it.

Scheduled diagnostic measures during dispensary observation of HIV-infected patients before and during ART — see section "Disease Diagnosis", subsections 3-5.

Table 10. Schedule of routine examinations in patients receiving ART [150,161,203-209].

Comment: if 1.5 years after initiating ART, the patient has had no clinical manifestations of secondary diseases for 6 months or more, and the two most recent tests performed at an interval of at least 3 months show a CD4 count of ≥ 500 cells/µL and an HIV viral load below the limit of detection, scheduled visits may be conducted at 6-month intervals.

Dispenser observation (clinical follow-up) aims to exercise citizens' rights to improve their quality of life and life expectancy, maintain the work capacity of HIV-infected individuals, preserve health, and prevent delayed diagnosis in persons at risk of HIV infection. The main objective of clinical follow-up is dynamic laboratory and clinical monitoring of health status for disease prevention, timely detection of the infectious process, implementation of treatment, prevention and/or timely detection of complications, opportunistic infections, and secondary diseases, and the provision of psychosocial support to HIV-infected patients [21,31].

Place of observation: The AIDS Center and at the office of the infectious disease specialist working with HIV patients in a medical organization at the patient's place of residence / registration in an authorized medical organization, under the supervision of the medical commission of the AIDS Center [22].

Clinical follow-up by an infectious disease specialist at the place of residence / registration may be carried out after confirmation of the diagnosis and selection of the treatment regimen by specialists of the AIDS Center, under the supervision of an infectious disease specialist from the AIDS Center. In case of virological, immunological, or clinical treatment failure, all decisions regarding changing the treatment regimen and further follow-up tactics are made jointly with the infectious disease specialist of the AIDS Center.

Specialist performing follow-up: Clinical follow-up of patients with HIV infection is carried out by a specially trained infectious disease specialist from the center for the prevention and control of AIDS and infectious diseases and/or infectious disease specialists from other authorized medical organizations (federal, regional, and municipal subordination) who have completed training to work with HIV-infected patients and are responsible in their medical organization.

Duration of clinical follow-up: lifelong.

Scope of clinical follow-up - see section 2 "Disease Diagnosis" and subsection 2 "Clinical Follow-up" of section 5.

As part of clinical follow-up, treatment of HIV infection, prevention and treatment of secondary diseases in HIV infection are carried out in accordance with the section "3. Treatment".

Data entered into the outpatient medical record must be identical to the data entered into the Federal Register of HIV-Infected Individuals (FRHIV) with the completion of the relevant fields: SNILS, unique registry record number (URRN) from the Federal Register of Individuals Infected with the Human Immunodeficiency Virus (FRHIV), place of detection, and must also indicate the population category (Russian citizen resident of the given region, resident of another region, foreign citizen, stateless person; person of no fixed abode, stateless (citizenship unknown); stayed in a penal enforcement system facility, including a pre-trial detention center, colony; date of release).

In addition, it is advisable to indicate the social status of the HIV-infected individual: worker; employee, including an officer of the Ministry of Internal Affairs, Ministry of Defense; retiree; disabled person; preschooler, including attending a preschool educational institution; schoolchild; student, including secondary vocational, higher education; unemployed; does not work and does not study aged: men – 16-59 years, women – 16-54 years; regulated contingent.

The outpatient record also reflects: diagnoses and conditions, concomitant pathology, treatment regimens and reasons for their modification, obstetric history (childbirth, children).

Diagnostic measures upon registration for clinical follow-up - see section 2 "Disease Diagnosis".

6. Organization of Medical Care

Medical care for patients with HIV infection is provided based on standards of medical care and taking into account clinical guidelines (treatment protocols) (see Order of the Russian Ministry of Health No. 438n dated June 23, 2022 "On approval of the standard of primary health care for adults with HIV infection (diagnosis, treatment, and clinical follow-up)" regarding the provision of medical care.

Indications for patient hospitalization: hospitalization of patients with HIV infection is carried out taking into account the severity of the condition and clinical data, depending on the presence of secondary or concomitant diseases.

Discharge from the hospital is carried out after additional examination, selection of adequate therapy, and improvement of the patients' condition.

7. Additional Information

7.1. Fostering patient adherence to clinical follow-up and treatment for HIV infection [216, 217]

Treatment of HIV infection is lifelong and requires patients to strictly follow medical recommendations and the treatment regimen.

Currently, ART is the main component of treatment for patients with HIV infection, through which a controlled course of the disease can be achieved. Early initiation of ART allows achieving not only an improvement in the clinical prognosis of the disease, but also a reduction in the prevalence of HIV infection in the population. Irregular intake of ART can lead to the development of HIV resistance to ARV drugs, ineffectiveness of ongoing treatment, and the need to adjust the ART regimen.

Thus, high treatment adherence, as part of complying with the ART regimen and clinical follow-up, plays a key role in the effectiveness of ongoing therapy, and fulfilling the task of engaging and retaining patients within the existing care system is of paramount importance for public health.

Treatment adherence is defined as:

taking medications in strict accordance with the doctor's prescription, when the patient:

takes the medication on time;

takes it in the dose prescribed by the doctor;

follows dietary recommendations.

WHO recommends a 95% adherence threshold as it provides the best virological response to ongoing therapy. At the same time, it is proposed to establish the following adherence assessment levels:

high – the patient takes ≥ 95% of the prescribed doses of ARV drugs;

moderate – 85–94%;

low – ≤ 85%

Fostering patient adherence to clinical follow-up and treatment of HIV infection is carried out within a multiprofessional patient-centered approach, including the use of digital platforms for patients with the ability to remotely monitor health status (hereinafter referred to as DP). Digital platforms must be integrated with the federal register of HIV-infected individuals, provide tools for monitoring medication intake, receiving consultations, education, and interaction with medical institutions in real time, as well as for analyzing remote monitoring data and patient feedback.

The use of DPs can help ensure compliance with treatment regimens and regular medical monitoring for HIV patients. In addition, the DP can host information on the importance of lifelong treatment for HIV infection and the need to strictly follow medical recommendations.

An additional feature of the DP is the provision of telemedicine consultations, medication reminders, and tracking treatment effectiveness.

Within the framework of the DP, it is possible to use mobile applications and/or web services that allow patients to monitor medication intake in real time, receive reminders about medication intake and doctor appointments, keep a food log and adherence to recommended diets, and provide the ability to book doctor appointments online, receive referrals, test results, and consultations in real time.

Through the DP, it is possible to hold webinars, master classes, and trainings, focusing on the importance of adhering to the treatment regimen.

Based on data collected using the DP, it is possible to determine the patient's level of treatment adherence, providing automated recommendations to the attending physician to improve therapy effectiveness.

In order to implement a multiprofessional approach in healthcare institutions and ensure access of PLWH to non-medical services, care, and support, it is advisable to maintain and expand psycho-social counseling, including within the framework of the School for Patients Infected with the Human Immunodeficiency Virus.

To increase the accessibility of this medical service, organizing the Patient School is also possible through the use of DPs.

In accordance with the standard of primary health care for adults with disease caused by the human immunodeficiency virus (HIV), approved by the order of the Russian Ministry of Health dated June 23, 2022, No. 438n, the School for Patients Infected with the Human Immunodeficiency Virus must be organized with a specified frequency of provision and multiplicity of application.

When organizing the School for Patients Infected with the Human Immunodeficiency Virus

, it is recommended to cover the following topics:

- General information about HIV/AIDS;

- How to maintain your health with HIV infection;

- Availability of treatment for HIV infection;

- Birth of a healthy child;

- Interaction with other people.

When evaluating the effectiveness of digital health applications, it is advisable to pay attention to the following criteria:

- increased patient adherence to treatment (decrease in the number of missed ART doses in patients receiving ART, target level — taking more than 95% of prescribed doses);

- increased adherence to dispensary observation (timely and complete fulfillment of medical recommendations by patients and receipt of necessary medical services);

- decrease in the number of patients with detectable viral load;

- decrease in the number of in-person patient visits for consultations on current issues related to the underlying disease, changes in well-being, and other issues (issuing prescriptions for ART or other medications, obtaining referrals, etc.);

As additional criteria, it is also possible to evaluate:

- reduction in the number of patient hospitalizations under the "HIV infection" profile;

- reduction in mortality from HIV infection;

- increased patient satisfaction with the availability and quality of medical care provided.

- reduction in the physician's rapid response time (shortening the period from the moment of detecting changes in the patient's health status or deviations from the prescribed examination and treatment plan to the consultative interaction with the patient).

7.2. Measures aimed at optimizing ART adherence

Program-level measures [127,217,218,219]:

- Availability of all types of medical care, social support, psychological accompaniment;

- Development, production, registration, and strengthening of the drug supply management system;

- Use of fixed-dose combination drugs; optimization of the medical and social rehabilitation system for psychoactive substance users.

Individual-level measures:

- Patient education and counseling;

- Mutual support;

- Treatment of depression and substance use disorders; reminder and interaction tools;

- Viral load monitoring;

- Pill counting;

- Self-reporting.

7.3. Features of the course of COVID-19 in patients with HIV infection

Given the lifelong nature of HIV infection, the possibility of contracting COVID-19 against the background of immunodeficiency implies more severe manifestations of the disease in comorbid pathology [256,261,262]. The risk of a severe course of COVID-19 / HIV coinfection increases depending on age, sex, and concomitant diseases: cardiovascular diseases, chronic lung diseases, obesity, oncological diseases, diabetes, chronic liver diseases (hepatitis B and C) and gastrointestinal tract diseases, substance abuse [260,262,263].

One of the pathognomonic signs is also the specific damage to macrophages and lymphocytes by the coronavirus, which manifests as lymphopenia and dysregulation of all components of the immune response. Lymphocyte apoptosis is promoted by impaired expression of pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), etc.). An increase in the level of IL-6 and TNF-α inversely correlates with the count of CD4 and CD8 associated with lymphopenia in COVID-19, contributing to the progression of immunodeficiency and gradual depletion, especially in patients with HIV infection in the stage of secondary diseases and without ART [261,266,268,269].

The asymptomatic course of COVID-19 in the general population is observed in at least 20% of cases, while in HIV-infected patients it is noted in only 2.6% [264,266,269].

The severe course of the disease is associated with respiratory failure during the development of acute respiratory distress syndrome (ARDS), sepsis, septic (infectious-toxic) shock, disseminated intravascular coagulation (DIC) syndrome, thrombosis, and thromboembolism [264,265,268,269].

Currently, there is insufficient data on the clinical features of the course of HIV/SARS-CoV-2 coinfection, and they are contradictory. The analysis of clinical symptoms revealed that in COVID-19 patients with HIV infection, the most frequently recorded symptoms were fatigue, weakness (82.1%), loss of smell and/or taste (66.6%), fever (61.5%), dyspnea, difficulty breathing (53.8%), chest pain (48.7%), headache (46%), myalgia and arthralgia (41.0%) [263,266,269]. In some patients, in addition to the respiratory syndrome, signs of gastrointestinal tract damage are observed: nausea, repeated vomiting, diarrhea, which is noted, according to various studies, in up to 30% of cases [264,268].

7.3.1 Diagnosis of concurrent COVID-19 in patients with HIV infection

Multicenter studies of COVID-19 patients with HIV infection have shown that a low CD4 count or the absence of ART are associated with an increased risk of SARS-CoV-2 infection, and patients older than 60 years with a CD4 count <200 cells/µl and chronic comorbid pathology are potentially at a higher risk of a severe course and unfavorable disease prognosis [262,263,265,268].

Patients with HIV/SARS-CoV-2 coinfection more frequently have comorbid conditions (tuberculosis, candidiasis, viral hepatitis, liver, kidney, lung, and gastrointestinal diseases), which complicate the course of COVID-19 and cause significant difficulties in diagnosing the disease [258,259,260,261,265,267].

According to studies, the incidence of COVID-19 in patients with HIV infection was statistically no higher than in people without HIV; therefore, these data suggest that SARS-CoV-2 does not act as an opportunistic pathogen in HIV patients [262,263,268]. The relationship between pronounced immunosuppression in HIV infection and the severity of COVID-19 requires further study.

The diagnosis is established based on a combination of clinical symptoms, laboratory test results (SARS-CoV-2 RNA PCR, presence of elevated IgM class antibody titers to SARS-CoV-2), and characteristic pathological changes on chest CT (spiral computed tomography of the lungs).

Comments: CT has a high sensitivity for detecting lung changes. Bilateral ground-glass interstitial changes of varying extent (CT1–CT4) are characteristic of both COVID-19 and opportunistic diseases in HIV infection with lung involvement: Pneumocystis, candidal, CMV pneumonia, pulmonary tuberculosis; therefore, it is impossible to establish an etiological diagnosis based on CT data alone [263,264,266,269].

Physicians responsible for monitoring HIV-infected individuals with characteristic changes on chest CT (spiral computed tomography of the lungs) should refer them for fibrobronchoscopy (FBS) with bronchoalveolar lavage analysis in the absence of contraindications for differential diagnosis. If FBS cannot be performed, analyze sputum:

- By PCR method to specify the genome of opportunistic pathogens (Pneumocystis, CMV, Candida, mycobacteria);

- By bacteriological method to isolate the pathogen and determine susceptibility to antimicrobial drugs (according to the ATC classification: antibacterials for systemic use) in order to exclude bacterial lower respiratory tract infections;

- To exclude bacterial septic pneumonia in HIV-positive patients, an electrocardiogram and echocardiography are performed.

Comments: regardless of the result of the SARS-CoV-2 PCR swab, isolation of the pathogen by PCR or bacteriological examination of lavage fluid or sputum will allow for the adjustment of etiological therapy.

7.3.2. Differential diagnosis of concurrent COVID-19 in patients with HIV infection

Symptoms of COVID-19, pneumonia of another etiology (Pneumocystis, candidal, CMV), and tuberculosis can be similar (intoxication symptoms, cough, weakness). The only distinguishing feature is that in COVID-19, all symptoms develop rapidly and, without complications, either regress by the 7th day of the disease or further progress.

Pulmonary involvement in HIV infection is characterized by the gradual development of respiratory failure (more than 14–20 days).

In most cases, HIV/SARS-CoV-2 comorbid pathology occurs in patients at a younger age — 35–47 years (71.8%) — than in HIV-negative patients with COVID-19 [260,261,262,268].

7.3.3. Treatment features in patients with concurrent HIV/COVID-19 pathology

Treatment of COVID-19 is carried out in accordance with current protocols of temporary guidelines "Prevention, diagnosis, and treatment of a novel coronavirus infection (COVID-19)".

- Administer glucocorticoid therapy to patients with severe COVID-19 on a personalized basis; [387].

Comments:

- Depending on indications, doses can be increased. The maximum dose of GCS is used for 3–4 days, with mandatory dynamic monitoring of blood glucose and blood pressure, and then reduced as the condition stabilizes;

- The use of steroid hormones (according to the ATC classification: systemic corticosteroids) is not recommended in mild and moderate courses of COVID-19 without oxygen therapy, as it may increase the virus-shedding period.

- For patients with severe COVID-19 and a disease duration of no more than 7 days, to block the "cytokine storm", targeted (biological) therapy combined with GCS should be administered with caution on a personalized basis, taking into account the CD4 count and presence of comorbidities;

Comments: Hormone therapy and immunotherapy for COVID-19 increase the risk of developing/activating bacterial, fungal, and other opportunistic flora; therefore, in HIV-infected patients, these drugs are prescribed with mandatory preliminary determination of IS, and administration is undesirable if the CD4 count is less than 300 cells/µL.

- For patients with CD4 <200 cells/µL, treatment involves the administration of specific agents for the prophylaxis of opportunistic infections (#Co-trimoxazole [Sulfamethoxazole+Trimethoprim]**, fluconazole**) (Applicable to ICD-10 codes B20-24, which are included in Government Decree No. 1180-r) [3,5,37,108,227-231] (2B).

- Patients with HIV infection undergoing diagnosis and treatment of COVID-19 should continue ART at the previous dosage, taking into account drug-drug interactions [387] (4C).

7.4. Vaccination features in HIV-infected patients

Vaccination is a necessary measure for the prevention of infectious complications in HIV-infected adults.

People living with HIV are at an increased risk for a wide range of infections; therefore, vaccination remains an important protection strategy to ensure the health of this vulnerable population [273, 274, 275, 276].

General principles of vaccination in HIV-infected individuals [277, 278]

Inactivated (or killed) vaccines are safe for immunosuppressed individuals and can be administered to HIV-infected patients in the same manner as to HIV-uninfected individuals.

Live vaccines (tuberculosis vaccine**, typhoid vaccine**, poliomyelitis vaccine**, varicella vaccine**, measles, mumps, and rubella vaccine**, and yellow fever vaccine**) may be hazardous to HIV-infected patients. If vaccination against these diseases is necessary, follow the instructions provided with the respective immunobiological product.

Immunoglobulins for post-exposure prophylaxis should be prescribed to HIV-infected individuals under the same indications as for HIV-uninfected individuals.

Comment: Given that vaccination recommendations for HIV-infected adults are often similar to those for HIV-uninfected individuals, there are important differences, as HIV can affect vaccine efficacy and safety, and the use of certain vaccines may be associated with severe side effects.

Recommended doses and timing of vaccine administration may differ depending on HIV status, and a number of vaccines (e.g., live vaccines) are contraindicated in HIV-infected individuals with clinical manifestations of the disease and severe immunosuppression (CD4 <200 cells/µL).

Killed vaccines may be used during pregnancy and breastfeeding if there is a significant risk of infection or other clinical indications. Live vaccines are contraindicated during pregnancy.

Comment: In HIV-infected adults with severe immunodeficiency (CD4 <200 cells/µL or <15%), vaccination should be deferred until the initiation of ART and immune reconstitution, as this will mitigate or eliminate vaccine-associated viremia and potentially improve the immune response to vaccination.

Comment: as HIV infection progresses, the response to both inactivated and live vaccines decreases. Therefore, the use of higher vaccine doses and more frequent revaccination may be considered in HIV-infected patients, although even these measures cannot guarantee sufficient post-vaccination immunity levels.

Comment: following vaccination in HIV-infected individuals, a temporary increase in HIV RNA levels is frequently observed, peaking at 1–3 weeks. This results from cellular immune stimulation and has no clinical or immunological significance.

7.4.1 Recommendations for specific vaccines in the immunization of HIV-infected adults

Live attenuated vaccines

Measles, mumps, and rubella vaccine** (MMR**)

Varicella vaccine**

Comments: Recombinant zoster vaccine (adjuvanted)** should be considered to prevent the development of herpes zoster. The recombinant zoster vaccine (adjuvanted)** is not contraindicated in patients with HIV infection [281, 289 290] (5C).

Inactivated vaccines

• Diphtheria-tetanus toxoid** (adsorbed diphtheria-tetanus toxoid [DT]** for adults, Td**) is recommended for HIV-infected adults, regardless of the severity of immunosuppression, with revaccination every 10 years. Vaccination is performed in the same manner as in HIV-uninfected adults [274,276,280,281,291] (5C).

• Diphtheria, tetanus, and pertussis vaccine** (DTaP**), which is not used in HIV-infected adults, is not recommended for HIV-infected adults [274] (5C).

• Hepatitis A vaccine** is recommended for individuals at increased risk of HAV and its complications, regardless of their HIV status [274] (5C).

• Vaccination against HAV infection (one dose and a booster dose at 6–12 months) is recommended for individuals at increased risk of HAV and its complications, regardless of HIV infection status and immunodeficiency [276,277,286,291,292] (4C).

Comments: Individuals at increased risk of HAV and its complications include:

- Patients with chronic liver diseases;

- MSM;

- PWID;

- Individuals with bleeding disorders;

- Workers in occupations associated with the risk of hepatitis A infection (laboratory personnel);

- Individuals from non-HAV-endemic countries planning travel to regions with intermediate or high prevalence of this infection.

• Hepatitis B vaccine** (HBV vaccine) is recommended for all HIV-infected individuals in the absence of serological markers of HBV. Vaccination against HBV infection is recommended for all HIV-infected individuals in the absence of serological markers of hepatitis B (HBsAg) [276,277,281,293] (5C).

Comments: Vaccination against HBV infection is recommended for adults at increased risk for hepatitis B, regardless of HIV infection status and immunodeficiency [278,283,298] (5C):

- MSM;

- Heterosexuals with multiple sexual partners;

- Patients with sexually transmitted infections;

- Sex workers;

- Sexual partners and family members of HBV carriers;

- PWID;

- Inmates, regardless of gender;

- Patients undergoing hemodialysis;

- Healthcare workers.

• When the CD4 lymphocyte count is 200–500 cells/µL, vaccination is recommended according to the 0-, 1-, 2-, and 12-month schedule, 20 µg [274,277,281,294] (5C).

• In HIV-infected individuals with severe immunosuppression (CD4 <200 cells/µL or <15%) and detectable HIV viral load, vaccination against HBV infection is recommended after initiating ART and restoring immune status [278,283,294,295] (5C).

For HIV-infected individuals vaccinated against HBV with an inadequate immune response (anti-HBs <10 IU/L), revaccination should be considered. A double dose of hepatitis B vaccine** at 3–4 time points (months 0, 1, 6, and 12) may help improve response rates to the HBV vaccine [274,277,278,281,296] (5C).

• If vaccination fails and serum HBsAg is absent, it is recommended to provide counseling on HBV prevention and administer human hepatitis B immunoglobulin post-exposure prophylaxis after any likely contact with HBsAg-infected blood [278,281,283,297] (4C).

Influenza vaccine [inactivated]**

• Influenza vaccination is recommended annually for all HIV-infected individuals regardless of CD4 count [274,277,278,281] (5C).

• Influenza vaccination is recommended to be administered using inactivated vaccines in HIV-infected individuals, including pregnant women [277,299,300,301] (1A).

Comments: The administration of additional doses of influenza vaccine [inactivated]** to HIV-infected individuals to enhance the immune response has been considered, but no recommendations are provided [274,277]

COVID-19 vaccine**

Comments: The use of the COVID-19 vaccine** in HIV-infected patients initiating ART is recommended 4 weeks after starting antiretroviral drugs (according to the ATC classification: systemically acting antiviral drugs) [302]

For HIV-infected patients with a CD4 count below 350 cells/µL and the likelihood of a suboptimal immune response to vaccination, booster vaccination 3 months after primary vaccination may be recommended [314]

Human papillomavirus vaccine (Quadrivalent human papillomavirus recombinant vaccine (types 6, 11, 16, 18)**, Recombinant adsorbed human papillomavirus vaccine containing AS04 adjuvant**)

Meningococcal infection vaccine**

• Meningococcal vaccination is recommended for previously unvaccinated HIV-infected adults using a meningococcal polysaccharide conjugate vaccine against serogroups A, C, W, Y** (2 doses administered 1–2 months apart, with revaccination every 5 years if the risk persists). Meningococcal polysaccharide vaccine against serogroups A and C** is not recommended [274,276,277,281 (5C)];

• Vaccination using meningococcal vaccine** is recommended for HIV-infected adults at increased risk for meningococcal disease, individuals planning travel to meningococcal-endemic countries, and patients with complement component deficiencies and asplenia. [277,278,283] (5C);

Pneumococcal infection vaccine**

• Vaccination using pneumococcal vaccine** is recommended for HIV-infected adults due to the increased risk of pneumococcal infection and its complications [274,278,281,310] (2A).

• Repeated immunization is not recommended [274,277] (5C).

Poliomyelitis vaccine**

• In unvaccinated HIV-infected adults at high risk for poliomyelitis (travel to polio-endemic countries), IPV is recommended. Due to the risk of vaccine-associated paralytic poliomyelitis, OPV** is not recommended for HIV-infected individuals [275,278,283] (5C).

Rabies vaccine**

• Rabies vaccine** (cell-culture) is recommended for HIV-infected individuals for post-exposure prophylaxis and pre-exposure prophylaxis against rabies [275,278,281,283] (5C);

• For rabies post-exposure prophylaxis, it is recommended to combine rabies vaccine** and rabies immunoglobulin** with subsequent antibody titer determination. An additional dose of rabies vaccine** is recommended 4 weeks post-vaccination if neutralizing antibody titers are below 0.5 IU/mL (protective antibody titer > 0.5 IU/mL) [277,278,283] (5C);

• In HIV-infected individuals with severe immunosuppression (CD4 <200 cells/µL or <15%) and detectable HIV RNA viral load, it is recommended to consider pre-exposure vaccination using three doses (days 0, 7, and 28) with antibody titer monitoring after 14 days [277] (5C).

Typhoid vaccine**

• In HIV-infected adults planning travel to typhoid-endemic countries or exposed to a Salmonella typhi carrier, it is recommended to use the parenteral inactivated subunit typhoid vaccine** [276,278,281,283,312] (5C).

• Vaccination (1 dose) is recommended at least 2 weeks prior to anticipated exposure, with revaccination every 3 years. For individuals with a CD4 lymphocyte count <200 cells/µL the interval may be shortened to 2 years [276,277,278,281,283] (5C).

Tick-borne encephalitis vaccine**

• For HIV-infected individuals planning visits to tick-borne encephalitis-endemic regions, vaccination against this infection is recommended. When the CD4 count is > 400 cells/µL, a 3-dose schedule of tick-borne encephalitis vaccine** (months 0, 1, and 9–12) is recommended; when the CD4 count is < 400 cells/µL, a 4-dose schedule of tick-borne encephalitis vaccine** (months 0, 1, 2, and 9–12) should be used. Revaccination intervals do not differ from those recommended for HIV-uninfected individuals [275,277,278,283] (5C).

7.4.2. Recommendations for the use of immunoglobulins for post-exposure prophylaxis in HIV-infected adults

Human hepatitis B immunoglobulin (HBIG)

HBIG for passive immunization is recommended for HIV-infected adults under the same indications as for HIV-uninfected individuals. Prophylactic administration of HBIG is recommended following any potential exposure to blood or other biological fluids from an HBsAg carrier (percutaneous, mucosal, or sexual exposure) [277,281] (5C).

Normal human immunoglobulin** (NHIG**) for hepatitis A prevention

NHIG** for hepatitis A prevention is recommended for HIV-infected adults under the same indications as for HIV-uninfected individuals [277,281,283] (5C):

- Individuals traveling to regions with high prevalence of this infection who have not completed 4 weeks since receiving the first vaccine dose prior to travel;

- Individuals not vaccinated against hepatitis A who are at risk of infection (human normal immunoglobulin** (HNIg**) must be administered no later than 2 weeks after potential exposure);

- Individuals in close contact with a patient with hepatitis A;

- Staff of a childcare facility when a case of hepatitis A is identified therein;

- Individuals in a situation where a common source of infection is possible.

Human normal immunoglobulin** (HNIg**) for measles prophylaxis

• HNIg** is recommended to be prescribed to HIV-infected adults for post-exposure measles prophylaxis regardless of a history of measles vaccination [277,278,313] (5C).

• In HIV-infected individuals who received HNIg** for measles prophylaxis, measles vaccination is recommended to be administered 6 months after its administration [278] (5C).

Rabies immunoglobulin, human** (RIgH**)

• RIgH** for post-exposure rabies prophylaxis is recommended to be prescribed to HIV-infected adults according to the same indications as for HIV-uninfected individuals: single or multiple bites or scratches with skin damage, as well as contact of saliva with mucous membranes [278,283] (5C);

• RIgH** for post-exposure rabies prophylaxis in HIV-infected individuals is recommended to be administered together with the 1st dose of rabies vaccine** followed by determination of the post-vaccination antibody titer [277,278,283] (5C);

• Administration of RIgH** is not required in previously vaccinated individuals whose blood shows neutralizing antibodies at a titer of at least 0.5 IU/mL [278] (5C).

Tetanus immunoglobulin, human** (TIgH**)

TIgH** for tetanus prophylaxis is recommended to be prescribed to HIV-infected adults according to the same indications as for HIV-uninfected individuals [277,278,283] (5C):

- Extensive or contaminated wounds, if the patient has received fewer than 3 doses of tetanus toxoid;

- Lack of information regarding tetanus vaccination. In this case, administration of TIgH** together with adult tetanus-diphtheria toxoid (Td)** is recommended;

- Any wounds, except minor and clean ones, in the presence of contraindications to the administration of tetanus toxoid**;

- Symptoms indicating tetanus.

7.5. HCV/HIV coinfection

HIV-infected patients should receive hepatitis C therapy according to general principles and regimens, just like patients with HCV monoinfection, taking into account economic feasibility.

7.6. Anemia in patients with HIV infection

The development of anemia is the most frequent hematological complication in patients with HIV infection. Up to 95% of patients at various stages of HIV infection have a reduced hemoglobin concentration and red blood cell count [315,316]. In patients receiving combination antiretroviral therapy, the prevalence of anemia is about 46% [315]. According to studies conducted in the USA, anemia develops in 18–32% of patients with HIV infection without acquired immunodeficiency syndrome (AIDS) and 48–85% of patients with AIDS [315,317].

7.6.1 Impact of anemia in HIV patients on prognosis, disease progression, and severity

Despite the widespread use of antiretroviral therapy, the development of anemia in HIV patients remains a serious problem [318]. Regardless of the CD4 count and HIV RNA viral load, anemia is an unfavorable prognostic factor that increases morbidity, mortality, and the severity of HIV infection [315,319]. The use of antiretroviral therapy also contributes to an increase in hemoglobin and red blood cell count [320,321].

The presence and severity of anemia in patients receiving ART were associated with an increased risk of all-cause mortality [322,323,325]. According to international studies, in the presence of anemia with a hemoglobin level of less than 90 g/L, a 28% increase in mortality is shown. At the same time, patients with hemoglobin less than 85 g/L are 3.5 times more likely to die from AIDS compared to patients without anemia [325]. Patients with mild anemia have a 2.2 times higher risk of AIDS-related death compared to patients without anemia.

7.6.2. Features of anemia development in patients with HIV infection

The genesis of anemia development in patients with HIV infection has a complex, multifactorial character. The main cause of decreased hemoglobin concentration and red blood cell count, affecting up to 47% of patients, is anemia of chronic disease with the development of functional iron deficiency [322,327]. The development of iron deficiency anemia with absolute iron deficiency is diagnosed in 20–44% of patients and ranks second as a cause of anemia in patients with HIV infection.

Currently, three main mechanisms for the development of anemia of chronic disease are distinguished by most researchers: alterations in iron metabolism, impaired proliferation and differentiation of erythroid cells, and reduced synthesis and biological activity of erythropoietin (EPO) [322,328,329,330].

7.6.3. Differential diagnosis of anemia of chronic disease and iron deficiency anemia in patients with HIV infection

Anemia is a clinical and hematological syndrome characterized by a decrease in hemoglobin concentration and, in most cases, red blood cells per unit volume of peripheral blood due to impaired red blood cell production or their increased destruction [329]. To verify anemia, it is customary to use the criteria proposed by World Health Organization (WHO) experts (in men, red blood cell count <4 million/µL, hemoglobin <130 g/L, hematocrit <39%; in women, red blood cell count <3.8 million/µL, hemoglobin <120 g/L, hematocrit <36%) [329].

The essence of diagnosing anemia in a patient with HIV infection in almost every case is performing a differential diagnosis between anemia of chronic disease and iron deficiency anemia or a combination with IDA.

The diagnosis of ACD, as well as its differential diagnosis with iron deficiency anemia, is based on the study of iron metabolism parameters, as well as biochemical and clinical signs of inflammation.

Both complete blood count and biochemical parameters can be used for the differential diagnosis of ACD from IDA. When examining the complete blood count, normocytosis and normochromia are characteristic of patients with anemia of inflammation, unlike IDA.

7.6.4. Features of anemia treatment in patients with HIV infection

Currently, three therapeutic strategies are used to correct anemia in various conditions:

1. Blood transfusions;

2. Erythropoiesis-stimulating agents (erythropoietins) (according to the ATC classification: other antianemic preparations);

3. Iron preparations

Erythropoiesis-stimulating agents (according to the ATC classification: other antianemic preparations) are used according to general principles and regimens, just like for the correction of anemia of chronic disease in therapeutic pathology and malignant neoplasms, due to similar mechanisms of anemia development in patients with HIV infection [328].

Table 11 presents iron preparations and their dosages for the correction of anemia in patients with HIV infection.

Table 11 Some intravenous iron preparations and their dosages for the correction of anemia in patients

7.7. Neutropenia in an HIV-infected patient.

In patients with HIV infection, neutropenia is more characteristic of the late stages of the disease. From 5 to 25% of patients with AIDS develop neutropenia [332]. At the same time, there is a direct correlation between the CD4 count and an inverse correlation between the HIV RNA viral load and the neutrophil count [333]. Usually, the neutrophil count drops below the reference limit at a CD4 concentration of 30 cells/µL and below [334].

Table 12 Causes of neutropenia [331]

Table 13 Severity grades of neutropenia according to Toure et al. [335]

Neutropenia is associated with an increased risk of bacterial complications, and the severity and duration of neutropenia are positively associated with the risk of hospitalization in AIDS patients. The risk of bacterial and fungal complications increases significantly at grade 3 neutropenia, evidently being highest in patients with an ANC of less than 500 cells/μL [336].

MECHANISMS OF NEUTROPENIA IN HIV INFECTION

The pathogenesis of neutropenia in HIV infection is multifaceted: direct and indirect myelosuppressive effects of HIV and opportunistic infections such as cytomegalovirus, Mycobacterium avium, Histoplasma, and lymphoproliferative disorders, the incidence of which increases in HIV-positive status; the myelosuppressive effect of medications used in the treatment of HIV infection and conditions comorbid with it, etc. [337].

DIRECT AND INDIRECT MYELOSUPPRESSIVE EFFECTS OF THE VIRUS

The main mechanism of neutropenia in HIV infection is explained by the tropism of this virus for hematopoietic CD34+ cells expressing CD4, CXCR4, and CCR5, which serve as receptors for HIV-1. When these cells interact with the virus, cell differentiation processes are impaired, apoptosis is induced, and the synthesis of compounds such as TNF-alpha, IL-1, and transforming growth factor-beta is stimulated, which exert a suppressive effect on granulopoiesis. The inhibitory effect of antibodies against the viral glycoprotein gp120 on progenitor cells has also been demonstrated. An important role is attributed to HIV infection of bone marrow microenvironment cells, which are critically important for normal hematopoiesis. As the infection progresses, neutrophil dysfunction also increases. A decrease in superoxide anion synthesis, impaired degranulation, and weakened chemotaxis and phagocytosis—necessary for adequate antibacterial activity of neutrophils—have been noted [338].

NEUTROPENIA DUE TO OPPORTUNISTIC INFECTIONS

CMV, like HIV, can directly infect hematopoietic progenitor cells, reducing their sensitivity to growth factors. Additionally, CMV-infected monocytes synthesize the aforementioned interleukin-1, which has a myelosuppressive effect. A similar effect is also characteristic of M. avium and Mycobacterium intracellulare [339].

DRUG-INDUCED NEUTROPENIA

Ganciclovir** and cidofovir are well known for their myelosuppressive potential.

Co-trimoxazole [Sulfamethoxazole + Trimethoprim]**, frequently used for antibacterial prophylaxis and therapy of existing bacterial infection, causes myelosuppression in approximately half of the patients receiving it [341].

Table 14 Types of therapy in HIV infection associated with the risk of neutropenia

7.7.1. NEUTROPENIA AND HIV-ASSOCIATED CONDITIONS

Diffuse large B-cell lymphoma, Burkitt lymphoma, primary CNS lymphoma, Kaposi sarcoma, and cervical cancer are the most characteristic malignancies associated with HIV infection. These nosologies and their treatment are associated with the risk of neutropenia.

NEUTROPENIA DUE TO AUTOIMMUNIZATION IN HIV INFECTION

The development of neutropenia in HIV-positive patients may be promoted by autoimmunization against neutrophils due to B-lymphocyte activation and the production of antineutrophil antibodies (anti-MAC-1) directed against the neutrophil membrane, as well as antibodies to myeloperoxidase and elastase. These antibodies are detected in about half (45%) of HIV-infected individuals, suggesting the importance of this mechanism in the development of neutropenia [342].

Comments: patients with a high risk of neutropenia can be identified based on the presence of the following criteria:

- Zidovudine**-containing ART;

- Presence of an active opportunistic infection;

- Inclusion of ganciclovir** and/or co-trimoxazole [Sulfamethoxazole + Trimethoprim]** in the treatment regimen;

- Excessive alcohol consumption;

- Presence of an HIV-associated malignancy;

- Presence of a concomitant autoimmune disease.

Antiretroviral therapy

Although HIV treatment is a risk factor for neutropenia, the primary therapeutic recommendation regarding neutropenia in HIV-positive patients is ART.

In cases of baseline leukopenia prior to treatment initiation, it is preferable to select a treatment regimen that does not contain zidovudine**. The resulting effect of antiviral treatment is usually accompanied by a reduction in the severity of neutropenia or its complete resolution [343] (4C).

SPECIFIC THERAPY WITH GROWTH STIMULANTS (according to the ATC classification: colony-stimulating factors)

Recombinant human granulocyte colony-stimulating factor [rhG-CSF] (INN according to State Register of Medicines: filgrastim**)

Normally, this factor plays a major role in maintaining granulocyte homeostasis and is one of the main drugs in the treatment of agranulocytosis associated with infectious and inflammatory processes. In addition to its proliferation-stimulating effect, rhG-CSF (INN according to State Register of Medicines: filgrastim**) exerts an activating effect on chemotaxis, adhesion, oxygen metabolism, phagocytosis, etc. These effects are particularly noteworthy, as the loss of functional properties by neutrophils during HIV infection plays an important role in increasing the risk of bacteremia. Given the positive impact on both qualitative and quantitative aspects of neutropenia, the use of rhG-CSF (INN according to State Register of Medicines: filgrastim**) appears evident [344].

7.8 HIV-ASSOCIATED THROMBOCYTOPENIA

Thrombocytopenia can accompany a wide range of clinical conditions, which is generally explained by the high lability of homeostasis leading to quantitative and qualitative platelet alterations. A special group of triggers for decreased blood platelets consists of viral infections, particularly HIV infection. According to various researchers, thrombocytopenia is observed in 10–50% of HIV-infected patients both upon infection and during the course of disease progression [345]. In patients not receiving ART, the frequency of thrombocytopenia is approximately 10 times higher (64.6% vs. 6.9%) than in those receiving antiretroviral treatment [346]. Furthermore, this peripheral blood cell abnormality is more frequently detected in patients with more advanced disease stages. More severe thrombocytopenia is identified in patients with a CD4 count of less than 200 cells/μL, in patients over 45 years of age, and in patients with hematological and oncological diseases [347, 348].

Various mechanisms (immune and non-immune) play a role in the pathogenesis of thrombocytopenia in HIV infection. The first group includes: direct cytotoxic effects of HIV on megakaryocytes and other bone marrow cells; platelet lysis due to immune complexes; and the presence of antiplatelet antibodies. Non-immune mechanisms include the frequent presence of opportunistic infections with antiplatelet potential, as well as adverse effects on thrombopoiesis caused by medications used in HIV treatment. Thrombocytopenia may act as a secondary syndrome related to HIV-associated opportunistic infections, hypersplenism, lymphoma, and the myelosuppressive effect of medications used to treat these lymphomas [349].

7.8.1. Effects of HIV on hematopoiesis.

Nevertheless, a priority role in HIV-associated thrombocytopenia is attributed to platelet destruction by immune complexes, cross-reactivity, and the direct presence of antiplatelet antibodies [350].

It was found that bone marrow progenitor cells express CD4 as well as co-receptors such as CXCR4 and CCR5, which play a key role in host cell and HIV fusion. One of the consequences of megakaryocyte infection is a decrease in cell expression of c-MPL, the thrombopoietin receptor. Primary impairment of hematopoiesis as a cause of thrombocytopenia is more characteristic of late-stage HIV infection and is considered a non-priority mechanism in the development of cytopenia.

7.8.2. Antibody cross-reactivity.

The substrate for HIV antibody cross-reactivity is the structural similarity between viral and platelet antigens. Among the established surface antigens on platelets and HIV, cross-reactivity is demonstrated by the following, respectively: GPIb/IX and gp160, GPIIb/IIIa and gp120, GPIIIa and gp41, GPIIIa a49-66 and nef, etc. [351].

7.8.3. Effect of immune complexes

Blood thrombopoietin concentration in patients with HIV-associated thrombocytopenia can serve as a marker of the mechanism underlying thrombocytopenia development. A high TPO level implies pre-existing maximal bone marrow stimulation, which indicates expected greater efficacy of IVIG** therapy and a TPO receptor agonist (ATC classification: other systemic hemostatics). Conversely, a low blood TPO concentration with normal megakaryocytes implies increased platelet destruction, thereby suggesting the priority use of Fc receptor blockers [352].

7.8.4. Diagnosis of thrombocytopenia

The diagnosis of TP is established when the platelet count in a complete blood count drops below 100 thousand/μL in two blood tests.

Table 15 Diagnostic criteria for thrombocytopenia

+ present, - absent, +/- frequently, -/+ rarely

Diagnostic criteria for immune thrombocytopenia:

Diagnostic criteria for immune thrombocytopenia:

- Isolated thrombocytopenia < 100.0*10⁹/L in two blood tests;

- Visual assessment of platelet count and morphology;

- Determination of increased or normal MKC count in the myelogram;

- Normal spleen dimensions on ultrasound;

- Absence of high HIV RNA viral load;

- Absence of HIV antibodies;

- Determination of antiplatelet antibody levels in high titers.

Diagnosing ITP requires a comprehensive, complete workup.

Diagnostic methods are divided into two groups: essential and potentially informative (Table 16).

Table 16. Evaluation plan for patients with suspected immune thrombocytopenia (ITP)

7.8.5. Classification of thrombocytopenia

Table 17. Classification of thrombocytopenia by duration

Table 18. Classification of thrombocytopenia by nature and severity of hemorrhagic syndrome

7.8.6. Clinical presentation:

- Spontaneous or post-traumatic cutaneous hemorrhagic syndrome (single or generalized petechial rash and ecchymoses;

- Petechiae and ecchymoses on the mucosa;

- Epistaxis and gingival bleeding;

- Menorrhagia and metrorrhagia, less commonly gastrointestinal bleeding;

- Hematuria;

- Severe hemorrhagic syndrome developing at a platelet count of more than 30.0×10⁹/L requires looking for additional causes of bleeding (coagulopathy, vascular pathology).

7.8.7. Treatment of thrombocytopenia

Thrombocytopenia in the presence of hemorrhagic syndrome requires active therapeutic intervention [353].

Table 19. Correlation between platelet count and clinical manifestations

Factors considered in the decision-making process for ITP treatment [354]:

- Presence of active bleeding;

- Platelet count;

- Patient age;

- Comorbidity;

- Patient lifestyle and associated bleeding risk;

- Presence of additional bleeding risk factors (e.g., uremia, chronic liver disease);

- Predictable adverse effects of the proposed treatment method;

- Patient preferences.

A fundamental difference in the therapeutic approach for HIV-associated thrombocytopenia is the priority of ART.

The effectiveness of this approach is explained by various mechanisms of ARV influence on thrombocytopenia, for example:

- Reduction of viral load and, consequently, a decrease in the negative impact of HIV on hematopoiesis;

- An adequate therapeutic approach regarding the existing opportunistic infection playing a role in the development of thrombocytopenia in this clinical situation, due to the restoration of immune competence;

Comment: Considering the immunosuppressive effect of GCS, their use in HIV-infected patients is recommended at the minimum effective dose.

Comment: The advantage of this approach is the absence of a pronounced immunosuppressive effect, which is extremely important in patients with HIV infection, as well as a rapid therapeutic effect.

Eltrombopag** is an agonist of receptors located not only on megakaryocytes and platelets but also on blood stem cells. It binds to the transmembrane domain of thrombopoietin receptors without competing with endogenous thrombopoietin and exhibits immunomodulatory properties through the activation of T-regulatory cells [356].

#Romiplostim – formerly known as AMG531 – is a synthesized protein, an analogue of thrombopoietin that regulates platelet production. It is an Fc-peptidylated protein (peptide antibody) involved in signal transduction and activation of intracellular transcription via binding to thrombopoietin receptors and inducing increased platelet production [353].

Eltrombopag** is a TPO receptor agonist (ATC classification: Other systemic hemostatics) and, according to current guidelines, a second-line therapy drug for patients with refractory ITP [354].

Splenectomy

Comment: Removal of the spleen implies a significant increase in the risk of post-operative sepsis and infectious complications in general; therefore, the feasibility of this approach must be carefully weighed and performed only for vital indications in the event of life-threatening generalized hemorrhagic syndrome.

Considering the direct cytotoxic effect of HIV on megakaryocytes mediated through CXCR4 on the latter, a therapeutic approach involving pharmacological inhibition of this receptor or reduction of its direct expression on the cell surface appears promising.

Indications for hospitalization:

- Grade III–IV hemorrhagic syndrome;

- Severe thrombocytopenia, at least 20×10⁹/L, in the presence of a pronounced history of hemorrhagic syndrome;

- Presence of concomitant diseases worsening the patient's condition;

- Complications from the ongoing therapy;

- Patient non-compliance with the treatment regimen in an outpatient setting.

7.9. HIV-ASSOCIATED LYMPHOMAS

HIV infection is a factor that increases the incidence of both oncological and oncohematological diseases. The risk of lymphoma in an HIV-infected patient is 30–1,000 times higher compared to the uninfected population. This risk, albeit to a lesser extent, persists even against the background of ART. Discontinuation of therapy, leading to a decrease in CD4 cells and an increase in HIV RNA viral load, also increases the risk of lymphoma. Diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), and primary central nervous system lymphoma (PCNSL) are the most frequent oncohematological nosologies in HIV-infected patients. Hodgkin lymphoma (HL), indolent lymphoma (IL), plasmablastic lymphoma (PBL), and primary effusion lymphoma (PEL) are less common than the aforementioned nosologies. At the same time, PCNSL, PEL, and PBL are associated with a lower CD4 count at the time of diagnosis compared to other HIV-associated lymphomas [357].

Against the background of ART, the incidence of lymphomas, especially PBL, has significantly decreased; however, lymphoproliferative disorders remain one of the leading causes of death in HIV-infected individuals [358]. Advanced age, the development of lymphoma against the background of ART, a low CD4 count at the time of lymphoma diagnosis, a high viral load, and a more aggressive histological picture are factors of increased mortality among HIV-positive patients with lymphoma [359].

Among the pathogenesis factors are:

- Immunosuppression. Leads to a decrease in the immune surveillance activity of detecting and destroying cells with an altered genotype. Studies demonstrate an inverse relationship between the risk of lymphoma and the CD4 count. Discontinuation of ART leads to a 6-fold increase in the risk of carcinogenesis stimulation and a 3.7-fold increase in the risk of lymphoma development against the background of falling CD4 counts;

- Oncogenic effect of HIV [360]. A direct correlation has been established between changes in lymphomagenesis and the level of HIV RNA viral load in patients [361];

- Coinfection with other oncogenic viruses [362]. Coinfection with Epstein-Barr virus plays an important role in pathogenesis. Human herpesvirus type 8 also plays a role and is very frequently associated with primary effusion lymphoma.

- B-lymphocyte deregulation. HIV-associated B-cell dysregulation can precede lymphoma by years.

- Genetic characteristics of the infected patient. Heterozygosity for CCR5-D32, a coreceptor required for HIV-1 entry into the cell, demonstrates a lower risk of lymphoma development, whereas a mutation in stromal cell-derived factor 1 (SDF-1) is, conversely, a risk-enhancing factor for lymphomagenesis [361].

7.9.1. Diagnosis

The diagnosis of a lymphoproliferative disorder in all patients is verified based on morphological and immunohistochemical test results. These tests utilize tissues obtained from: a biopsied lymph node, a removed spleen, extranodal tumor tissue, or a core needle biopsy specimen. Lymph node biopsy in HIV-infected patients is not only of primary diagnostic importance, but also acts as a weighty factor in differential diagnosis, which can fundamentally alter the diagnostic picture of the disease under investigation. Differential diagnosis of lymphadenopathy prior to histological confirmation should be carried out primarily with tuberculosis; lymphadenopathy associated with infections must be differentiated from lymph node involvement in solid tumor metastases. In the case of an intracranial mass lesion, stereotactic tumor biopsy is performed followed by morphological and immunohistochemical studies. Lumbar puncture is performed for cytological and microbiological cerebrospinal fluid analysis after consultation with a neurologist and an ophthalmologist (high intracranial pressure significantly increases the risk of neurological complications associated with this procedure). If Burkitt lymphoma is suspected, FISH analysis for the cMYC gene is performed.

Staging of the lymphoproliferative tumor process is performed based on the staging system adopted for the specific lymphoma variant (Ann Arbor for DLBCL, HL, plasmablastic lymphoma; S.B. Murphy for Burkitt lymphoma, etc.).

When formulating the diagnosis, in addition to the standard detailed lymphoma diagnosis, the HIV infection diagnosis must be formulated, including the stage and phase of HIV infection, secondary and concurrent conditions in accordance with current guidelines for the diagnosis and treatment of HIV infection.

The main variants of lymphoproliferative disorders in HIV-associated patients are listed in Table No. 20.

Table 20. Main variants of lymphomas occurring in HIV-infected patients

• All patients with suspected lymphoma and established HIV status are recommended to undergo CD4+ lymphocyte testing and current HIV RNA viral load assessment prior to the initiation of antitumor therapy [385] (5C).

7.9.2. Clinical presentation

In most cases, HIV-associated lymphomas have an extranodal localization involving the stomach, intestines, liver, oral cavity, bone marrow, heart and pericardium, lungs, skin, testes, breasts, and CNS (this was especially frequently detected before the widespread adoption of ART).

One of the specific features of HIV-associated lymphomas is frequent abscess formation and necrotic changes of the mucous membranes in the area of the tumor focus in the serous cavities and the oral cavity. Gastrointestinal tumor biopsy is generally often insufficiently informative due to massive necrotic ulceration, which makes obtaining tumor material difficult.

In most cases, patients are admitted to the hospital at a late stage of the disease: with fever and weight loss (B-symptoms), massive lesions, and high lactate dehydrogenase activity. Most patients with HIV-associated lymphomas present with a combination of multiple nosologies: tuberculosis, bacterial, viral, and fungal infections.

7.9.4. Treatment

• Concurrent administration of ART and chemotherapy courses is considered safe. Given the wide range of modern ART drugs, it is recommended to avoid using drugs such as zidovudine**, cobicistat + tenofovir alafenamide + elvitegravir + emtricitabine**, and ritonavir** in ART regimens concurrently with polychemotherapy [362, 363].

Comment: in patients with high tumor burden and/or high HIV RNA viral load, polychemotherapy begins with a pre-phase of treatment using cyclophosphamide** and dexamethasone** against the background of adequate supportive care.

Prognostic model for assessing the risk of CNS involvement in patients with DLBCL.

Factors:

- Age >60 years;

- Serum LDH level above reference values;

- Patient ECOG performance status >1;

- Disease stage III and IV;

- Extranodal involvement in >1 site;

- Kidney or adrenal gland involvement.

The presence of each factor is assigned 1 point

Additional indications for CNS prophylaxis regardless of the presented prognostic model:

- Presence of HIV infection;

- Testicular lymphoma;

- High-grade lymphoma with MYC and BCL2 and/or BCL6 gene translocation;

- Primary cutaneous DLBCL, leg type;

- Stage IE primary breast DLBCL.

7.9.5. Impact of ART on the treatment of HIV-associated lymphomas

The introduction of ART has significantly increased the life expectancy of HIV-infected patients, and mortality from concurrent infectious diseases has also decreased; therefore, aggressive lymphomas increasingly become the first manifestation of HIV infection. When selecting ART and polychemotherapy regimens for a specific patient, it is necessary to consider the potential for drug-drug interactions between antiretrovirals and drugs used to treat lymphomas. The choice of specific regimens is recommended to be decided jointly by an oncohematologist and an infectious disease specialist. In this case, as a rule, the ART regimen is "adjusted" to the polychemotherapy regimen. Drug interactions can be checked at www.hiv-druginteraction.org.

7.9.6. SPECIFIC NOSOLOGIES

Diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of lymphoma and is classified among HIV-associated lymphomas. Approximately half (45%) of all lymphomas in PLWH belong to this specific type.

Primary effusion lymphoma

Primary effusion lymphoma (PEL) is a rare type of B-cell lymphoma most commonly seen in immunocompromised patients, such as those with HIV and post-transplant patients on immunosuppressive therapy. The main characteristic of PEL is tumor effusions in body cavities without detectable tumor masses.

Burkitt lymphoma

Burkitt lymphoma is a highly proliferative non-Hodgkin lymphoma originating from germinal center B cells with characteristic oncogenic pathways. Translocation in the MYC gene, as well as genetic events in the phosphatidylinositol 3-kinase and cyclin-dependent kinase pathways, lead to high MYC expression, increased cell proliferation, and growth. BL is distinguished by its rapid proliferation rate, with a Ki67 index of 95% or higher.

Compared to the general population, in which BL accounts for 1-2% of non-Hodgkin lymphomas in adults, BL in HIV-infected patients accounts for 10-35% according to various literature sources.

This lymphoma is associated with a higher CD4 count at the time of diagnosis compared to DLBCL.

Primary CNS lymphoma

Primary CNS lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma typically restricted to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. This type of lymphoma accounts for approximately 15% of non-Hodgkin lymphomas in PLWH. The prognosis in this case is unfavorable, with a median survival of 2-4 months; however, this figure is higher in patients undergoing chemotherapy (18 months).

- For HIV-infected patients with PCNSL not receiving ART, its initiation is recommended prior to starting lymphoma therapy;

- Even with a poor performance status and poorly controlled HIV infection, the option of initiating high-dose methotrexate therapy should be considered**;

- For patients with a poor performance status who are consequently not candidates for chemotherapy initiation, radiation therapy alone is recommended as initial therapy [364] (4C).

Radiation therapy

As radiation therapy for PCNSL, whole-brain irradiation at a dose of ≥30 Gy is recommended [365] (5C).

Hodgkin lymphoma

Although HL is not considered an AIDS-defining malignancy, numerous researchers have demonstrated a 5- to 20-fold higher incidence of HL in HIV-infected individuals compared to the general population. Patients with HIV-associated HL more frequently present with B symptoms and advanced stages, involving the bone marrow and spine, as well as extranodal lesions.

Unlike other HIV-associated lymphomas, HL can occur with a moderately reduced immune status and is typically not associated with severe immunodeficiency. An adapted treatment approach involves standard therapy for patients with HL, regardless of HIV status.

Patients with early favorable disease detection should receive 4 cycles of ABVD (bleomycin**, vinblastine**, dacarbazine**) followed by a discussion of radiation therapy. Meanwhile, patients with an unfavorable prognosis (high comorbidity index, high tumor burden) should receive at least 6 cycles of ABVD followed by autologous HSCT.

Baseline BEACOPP (bleomycin**, etoposide**, cyclophosphamide**, vincristine**, procarbazine**, prednisolone**) or switching therapy from ABVD to BEACOPP after 3-4 cycles is the treatment of choice for patients with advanced disease: presence of extranodal involvement, leukemization, skeletal bone involvement.

Hematopoietic stem cell transplantation in HIV-infected patients with lymphomas

Treatment of relapsed and refractory forms of lymphoma in HIV-infected patients should also be carried out in accordance with guidelines for non-HIV-infected patients. The standard of care for second-line therapy or early disease relapse is cytoreductive chemotherapy followed obligatorily by high-dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-HSCT). Upon diagnosis of relapse or insufficient efficacy of first-line therapy, the hematology center where auto-HSCT is planned should be contacted to jointly schedule second-line therapy in order to avoid delays between second-line chemotherapy and auto-HSCT. Only timely high-dose chemotherapy with auto-HSCT guarantees successful treatment of relapsed and refractory lymphomas in the setting of HIV.

8. Pathological anatomy diagnosis

Features of pathologicanatomical autopsy in patients who died of HIV infection.

Bodies of individuals who died from infectious diseases or suspected infectious diseases are subject to mandatory autopsy in accordance with Federal Law No. 323-FZ and Order of the Russian Ministry of Health No. 354n dated June 6, 2013, "On the Procedure for Conducting Pathological Autopsies." The approach to pathological examination generally corresponds to the standard guidelines for comprehensive morphological examination of those who died from infections.

The most important feature of autopsies in infectious diseases is the implementation of a wide range of laboratory and histological studies [220, 221].

Morphological diagnostics of HIV-induced lesions

During macroscopic examination at autopsy, the diagnostic capabilities for HIV infection itself are extremely limited.

Significantly more information can be obtained through histological examination. All macroscopically altered foci are subject to histological examination.

Features of the course and morphological diagnosis of tuberculosis in HIV infection

Tuberculosis should currently be considered the leading secondary disease in HIV infection (B20.0). Tuberculosis may either precede or newly develop against the background of HIV infection. The structure of tuberculosis is dominated by involvement of various lymph node groups—mediastinal, abdominal, and peripheral lymph nodes. Among other organ involvements, lesions of the kidneys, spleen, liver, adrenal glands, pancreas, thyroid gland, uterus, ovaries, testes, epididymis, prostate gland, etc., are possible.

Following pathomorphological examination, various forms of pulmonary tuberculosis were detected in the majority of deceased HIV patients, disseminated tuberculosis was diagnosed in more than 90% of patients, and isolated pulmonary involvement was observed extremely rarely.

Features of the course and morphological diagnosis of pneumocystosis in HIV infection. B20.6

Clinically significant lesions in humans are caused by the pneumocystosis pathogen P. jirovecii only under conditions of severe immunodeficiency, most commonly in premature newborns, patients with profound immunodeficiencies, and late-stage HIV patients. Clinical diagnosis is based on signs of progressively worsening severe respiratory failure over weeks and months combined with minimal or moderate characteristic radiological findings. Accessible laboratory diagnostic methods are lacking. Cytological studies of bronchoalveolar lavage fluid or sputum are of great importance in clinical diagnosis.

Macroscopically, the lungs in pneumocystosis may have characteristic features. In typical cases, this diagnosis can be established based on unusually large, non-collapsible lungs of "rubbery" consistency, with a smooth, shiny cut surface and the absence of other causes for such changes.

The course of Pneumocystis pneumonia comprises 3 stages. Microscopic examination in the edematous stage reveals very characteristic changes. In the acute phase of the disease, pneumocystis organisms are found on the surface of the mucous membrane of small bronchi, staining well with the PAS reaction and, especially, with Grocott's methenamine silver stain.

The most typical finding is the accumulation of pneumocysts in alveolar ducts and alveolar spaces. With a relatively protracted disease course, thickening of the interalveolar septa and their infiltration by monocytes, lymphocytes, and plasma cells are noted. In some cases, the development of fibro-cystic changes and dyselectasis with alternating atelectatic areas and emphysematously expanded alveoli is observed.

Features of the course and morphological diagnosis of toxoplasmosis in HIV infection. B20.8

In HIV infection, brain involvement is most characteristic of toxoplasmosis. In the acute phase of the process, toxoplasms are detected both within nerve cells and extracellularly. Necrotic changes occur with a weakly expressed exudative, predominantly microglial reaction. Secondary focal aseptic colliquative necrosis is possible as a result of vascular damage. Necrotic foci can be single or multiple. Subsequently, the necrotic tissue is resorbed with the formation of cysts.

In addition to the brain, toxoplasmosis may also involve the lymph nodes, liver, and other organs.

Features of the clinical course and morphological diagnosis of cryptococcosis in HIV infection. B20.5

Macroscopically, cryptococcosis can be suspected only in cases of massive involvement of the pia mater, when it becomes somewhat thickened and acquires a gelatinous appearance. In autopsy practice, histological examination is of primary diagnostic importance, revealing rounded, pale-staining formations close in size to erythrocytes upon hematoxylin-eosin staining. It is highly characteristic of cryptococci to be located within microcysts in the brain parenchyma and other organs with minimal cellular reaction.

Features of the clinical course and morphological diagnosis of cytomegalovirus infection in HIV infection. B20.2

The detection of characteristically transformed cells upon histological examination reliably indicates the replicative form of this infection. An immunohistochemical assay can be used as an additional diagnostic method to detect affected cells prior to the development of cytomegalic transformation. Lymphohistiocytic and eosinophilic infiltration is characteristically observed around cells containing viral inclusions.

Cytomegalic lesions are detected in the adrenal glands, kidneys, lungs, liver, brain, retina, thyroid gland, and other organs, as well as in the mucous membranes of the gastrointestinal tract and the endothelium of various organs.

Features of the clinical course and morphological diagnosis of herpesvirus infection in HIV infection. B20.3

Focal necrotizing encephalitis is encountered in autopsy practice. Histological examination reveals focal necrosis with varying degrees of glial proliferation and vasculitis. The most characteristic feature is the appearance of cells with hyperchromatic nuclei; distinct basophilic intranuclear inclusions are sometimes identified. Aphthous lesions of the mucous membranes are also observed.

Immunohistochemical study of herpes simplex virus-induced lesions demonstrates two principal forms: with viral antigen expression in cells of the reticuloendothelial system without involvement of parenchymal cells, and combined viral involvement of both reticuloendothelial and parenchymal cells. In the latter case, there are distinct morphological signs of herpesvirus tissue damage, most frequently in the form of small necrotic nodules.

Neoplastic processes in HIV infection

Kaposi sarcoma (B21.0), associated with human herpesvirus type 8 in young patients, is a classic HIV/AIDS-associated pathology. Primary localization occurs on the skin and oral mucosa as red-brown vascular papules or nodular masses. Metastasis to the lungs, lymph nodes, and gastrointestinal organs is possible. Cases of KS with primary mucosal involvement have been observed. Patch, plaque, and nodular stages are distinguished.

HIV-infected patients with the development of KS (so-called epidemic type KS) are characterized by young age and the presence of visceral manifestations in addition to skin elements.

Primary CNS lymphoma (B21.2) is an isolated extranodal B-cell tumor.

The development of generalized forms of involvement is characteristic, with involvement of all lymph node groups and various internal organs (spleen, liver, lungs, intestines, etc.). Recently, an increased frequency of many other tumors against the background of HIV infection has been noted, including squamous cell carcinoma of the cervix caused by the human papillomavirus.

Guidelines on the principles of pathomorphological diagnosis of HIV infection, formulation of the autopsy diagnosis, and coding in accordance with ICD-10.

General principles of postmortem diagnosis of HIV infection include:

- Establishing HIV status;

- Diagnosis of immunodeficiency state at autopsy;

- Diagnosis of opportunistic infections and other secondary diseases at autopsy;

- Coordination of the final diagnosis with specialists of the AIDS center;

- Clinical and Mortality Conference (CMC / KILI) in the medical facility in case of diagnostic discrepancy.

In formulating the diagnosis of HIV infection, it is necessary to consider clinical criteria, laboratory test results (ELISA, Western blot, immunogram [absolute and relative CD4 count, viral load]), and characterize the morphological manifestations of HIV infection.

In the absence or impossibility of correct interpretation of ELISA / Western blot data, the detection of HIV RNA or DNA must be taken into account.

- State of lymphoid tissue – hyperplasia or lymphoid depletion of lymph nodes and spleen;

- Presence of HIV encephalitis or HIV encephalopathy;

- Weight loss – degree of wasting;

- Identification of marker infections or tumors with evaluation of their role in the genesis of death.

The absence of signs of immunodeficiency state allows one to speak of HIV infection in the acute or subclinical stage; in these cases, it is most frequently considered a concomitant disease in the presence of other conditions to which the fatal outcome can be attributed (viral hepatitis, lobar pneumonia, influenza, etc.).

When formulating the diagnosis and evaluating cases of HIV infection with AIDS manifestation, it is mandatory to consider the presence of drug addiction, as well as chronic viral hepatitis (as a rule, B+C or C). It is precisely chronic viral hepatitis in its terminal stage with characteristic complications (esophageal and gastric bleeding, gastrointestinal phlegmon with ascites-peritonitis, etc.) that has increasingly become the underlying cause of death in cases where HIV infection is classified under combined, competing, or concomitant diseases.

If a patient had infectious and/or oncological diseases, including tuberculosis (e.g., fibrocavernous, cirrhotic) prior to the diagnosis of HIV infection, in the event of a fatal outcome, the underlying cause of death should generally be considered the infectious or oncological disease, while HIV infection may occupy the position of a comorbid or concomitant disease / condition (depending on the stage of HIV infection).

In the presence of conditions belonging to the AIDS-defining list, it is mandatory to indicate "AIDS" in the diagnosis after the phase of HIV infection. All conditions related to AIDS require clear confirmation using appropriate methods and inclusion in the HIV infection diagnosis.

Without objective confirmation of AIDS-indicator pathology at autopsy (e.g., in the presence of only an attending physician's entry in medical records), AIDS as a cause of death is not included in the diagnosis.

Taking international data into account, all B-cell non-Hodgkin lymphomas should also be classified as AIDS-defining conditions.

To establish the concept of "severe immunodeficiency" and classify manifestations of tuberculosis and other infectious diseases as AIDS, the laboratory criterion should be a CD4 count <200 cells/µL (in accordance with WHO requirements) at the last examination. If the immunogram shows a higher CD4 count, the decision to classify the pathological process as AIDS should be made taking into account the morphological signs of HIV infection and manifestations of immunodeficiency, pooling a medical commission if necessary.

If the diagnosis includes ICD-10 codes B20.7, B21.7, or B22.7, it is required to specify all secondary diseases identified in the patient.

Examples of recommended diagnosis construction (see Appendix A3.8)

Criteria for Evaluating the Quality of Medical Care

Table 21. Criteria for assessing the quality of outpatient medical care

References

Appendix A1. Working Group Composition

Elena G. Belova² – Candidate of Medical Sciences, Infectious Diseases Physician at the HIV Prevention Department, Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department

Timur P. Bessarab² – Candidate of Medical Sciences, Head of the HIV Prevention Department, Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department

Lyudmila A. Volova² – Candidate of Medical Sciences, Chief Freelance Specialist in HIV Infection of the Russian Ministry of Health in the Ural Federal District, Chief Physician of the Yamalo-Nenets District Center for Prevention and Control of AIDS and Infectious Diseases

Madina M. Gadjikulieva² - Doctor of Medical Sciences, Professor at the Department of Infectious Diseases and Epidemiology, A.I. Evdokimov Moscow State University of Medicine and Dentistry, Russian Ministry of Health

Margarita D. Geine² – Clinical Laboratory Diagnostics Physician at the Central HIV Diagnostics Laboratory, Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department

Denis A. Gusev² – Doctor of Medical Sciences, Professor, Chief Freelance Specialist in HIV Infection of the Russian Ministry of Health in the Northwestern Federal District, Chief Physician of the S.P. Botkin Clinical Infectious Diseases Hospital

Elena V. Denisova² - General Practitioner at the Prevention Department, Center for Prevention and Control of AIDS, Moscow Healthcare Department

Galina A. Dudina - Doctor of Medical Sciences, Professor at the Department of Oncology, Hematology and Radiology, Pediatric Faculty, N.I. Pirogov Russian National Research Medical University, Head of the Hematology and Hemoblastosis Chemotherapy Department, Senior Researcher at the Research Department of Oncohematology and Secondary Immunodeficiencies, A.S. Loginov Moscow Clinical Scientific Center, Moscow Healthcare Department

Evgeny V. Ivannikov² – Head of the Outpatient Department, Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department

Oleg A. Kozyrev¹ – Candidate of Medical Sciences, Chief Freelance Specialist in HIV Infection of the Russian Ministry of Health in the Southern Federal District, Chief Physician of the Volgograd Regional Center for Prevention and Control of AIDS and Infectious Diseases

Evgeny V. Kryukov – Doctor of Medical Sciences, Professor, Academician of the Russian Academy of Sciences, Major General of the Medical Service, Head of the S.M. Kirov Military Medical Academy, Russian Ministry of Defense

Anna V. Kuznetsova¹ – Candidate of Medical Sciences, Chief Freelance Specialist in HIV Infection of the Russian Ministry of Health in the Far Eastern Federal District, Chief Physician of the Center for Prevention and Control of AIDS and Infectious Diseases of the Ministry of Health of Khabarovsk Krai

Natalya G. Litvinova² – Infectious Diseases Physician at the Outpatient Department, Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department

Chingiz K. Mabudzade - Junior Researcher at the Research Department of Oncohematology and Secondary Immunodeficiencies, A.S. Loginov Moscow Clinical Scientific Center, Moscow Healthcare Department

Aleksey I. Mazus – Doctor of Medical Sciences, Head of the Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department, and the International Virology Center at the Medical Institute of RUDN University, Chief Freelance Specialist in HIV Infection of the Ministry of Health of the Russian Federation and the Moscow Healthcare Department, Chairman of the Board of the National Virology Association

Dinara R. Nabiullina² – Infectious Diseases Physician at the Outpatient Department, Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department

Margarita V. Nagibina² – Doctor of Medical Sciences, Infectious Diseases Physician at the HIV Prevention Department, Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department, Associate Professor at the Department of Infectious Diseases and Epidemiology, A.I. Evdokimov Moscow State University of Medicine and Dentistry, Russian Ministry of Health

Arman A. Oganisyan - Hematologist at the Hematology and Hemoblastosis Chemotherapy Department, A.S. Loginov Moscow Clinical Scientific Center, Moscow Healthcare Department

Aleksandr Ya. Olshansky² – Candidate of Medical Sciences, Head of the Central HIV Diagnostics Laboratory, Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department

Yuri G. Parkhomenko – Doctor of Medical Sciences, Professor, Head of the Department of Pathology, Infectious Diseases Hospital No. 2, Moscow Healthcare Department, Chief Researcher at the Research Institute of Human Morphology

Larisa L. Pozdnyakova – Chief Freelance Specialist in HIV Infection of the Russian Ministry of Health in the Siberian Federal District, Chief Physician of the City Clinical Infectious Diseases Hospital No. 1, Novosibirsk Region

Oleg A. Rukavitsyn – Doctor of Medical Sciences, Professor, Head of the Hematology Center, Main Military Clinical Hospital named after Academician N.N. Burdenko, Chief Hematologist of the Ministry of Defense of the Russian Federation

Valery T. Sakhin – Candidate of Medical Sciences, Head of the Resuscitation and Intensive Care Unit of the Cardiocenter, A.A. Vishnevsky National Medical Research Center of High Medical Technologies, Russian Ministry of Defense

Egor M. Serebryakov² – Head of the Organizational and Methodological Department for HIV Infection, Moscow Healthcare Department and Moscow City Center for Prevention and Control of AIDS

Nikita A. Smirnov² - Infectious Diseases Physician at the Organizational and Methodological Department for HIV Infection, Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department

Igor E. Khatkov - Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Director of the A.S. Loginov Moscow Clinical Scientific Center, Moscow Healthcare Department, Chief Freelance Oncologist of Moscow.

Vsevolod A. Zinserling – Doctor of Medical Sciences, Professor, Head of the Research Department of Pathomorphology, Center for Preclinical and Translational Research, Professor at the Faculty of Medicine, V.A. Almazov Northwestern Federal Medical Research Center, Ministry of Health of the Russian Federation, Head of the City Center for Infectious Pathology at the S.P. Botkin Clinical Infectious Diseases Hospital, Professor at Saint Petersburg University

Elena V. Tsyganova² – Candidate of Medical Sciences, Chief Freelance Specialist in HIV Infection of the Russian Ministry of Health in the Central Federal District, Deputy Chief Freelance Specialist in Infectious Diseases of the Moscow Healthcare Department, Head of the Research and Clinical Department, Moscow City Center for Prevention and Control of AIDS, Moscow Healthcare Department

Shtanev Denis Vladimirovich¹ – Chief freelance specialist in HIV infection of the Russian Ministry of Health in the North Caucasian Federal District, Chief Physician of the Stavropol Krai Specialized Center for Prevention and Control of AIDS and Infectious Diseases

Yapparov Rafael Galievich – Chief freelance specialist in HIV infection of the Russian Ministry of Health in the Privolzhsky Federal District, Chief Physician of the Republican Center for Prevention and Control of AIDS and Infectious Diseases of the Republic of Bashkortostan.

1 is a member of the National Association of Specialists in the Prevention, Diagnosis and Treatment of HIV Infection.

2 is a member of the National Association of Virology

Conflict of interest. All Working Group members have confirmed the absence of financial support/conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for assessing the quality and strength of evidence:

- Reviews of published meta-analyses;

- Systematic reviews with evidence tables;

- Expert consensus;

- Significance assessment in accordance with the rating scheme

(schemes attached).

The guidelines were discussed and approved by members of the National Association of Specialists in the Prevention, Treatment, and Diagnosis of HIV Infection, and the working group of the Profiling Commission for the Diagnosis and Treatment of HIV Infection of the Russian Ministry of Health.

In these clinical guidelines, all information is ranked by the level of reliability (evidence) based on the quantity and quality of studies on the issue. The evidence base for the recommendations consisted of publications included in the Cochrane Library, EMBASE, PUBMED, and MEDLINE databases. The significance of the recommendations is assessed in accordance with the classification of their reliability and evidence levels (rating scheme).

The method used to formulate the recommendations was expert consensus.

Methods for guideline validation:

- Internal expert review;

- Compliance analysis with regulatory framework;

- External expert review;

- Evidence analysis methodology.

Selection of publications as potential sources of evidence based on the validity level of each study.

The impact of the evidence level assigned to a publication on the strength of the recommendations derived from it.

To minimize potential errors due to the subjective factor, each study was evaluated independently by at least two independent members of the working group. Any differences in evaluations were discussed by the full working group. If consensus could not be reached, independent experts among the most experienced specialists of territorial AIDS prevention and control centers were involved.

The target audience of these clinical guidelines includes specialists with higher medical education in the following specialties:

- Infectious diseases;

- Internal medicine;

- General practice (family medicine);

- Obstetrics and gynecology;

- Epidemiology;

- Clinical laboratory diagnostics.

The clinical guidelines can be used in the development of training and methodological packages for the training and professional development of physicians.

Scales for assessing levels of reliable evidence (LRE) for diagnostic, preventive, therapeutic and rehabilitation methods (interventions) and the scale for assessing levels of recommendation consensus (LRC) for preventive, diagnostic, therapeutic and rehabilitation methods (interventions).

Scale for assessing levels of reliability of evidence (LRE) for diagnostic methods (diagnostic interventions)

Rating scale for levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Grading system for the levels of evidentiary certainty (LEC) of recommendations for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines: once every three years.

Appendix A3. Reference Materials

HIV infection and the legislation of the Russian Federation

Federal Law No. 38-FZ dated March 30, 1995 "On Preventing the Spread in the Russian Federation of the Disease Caused by the Human Immunodeficiency Virus (HIV Infection)"

Federal Law No. 52-FZ dated March 30, 1999 "On the Sanitary and Epidemiological Welfare of the Population"

Federal Law No. 181-FZ dated November 24, 1995 (as amended on July 29, 2018) "On Social Protection of Disabled Persons in the Russian Federation"

Federal Law No. 323-FZ dated November 21, 2011 "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation"

Order of the Ministry of Health of the Russian Federation No. 64 dated February 21, 2000 "On Approval of the Nomenclature of Clinical Laboratory Tests"

Order of the Ministry of Health of the Russian Federation No. 354n dated June 6, 2013, "On the Procedure for Performing Pathological Autopsies"

Order of the Ministry of Health of the Russian Federation No. 438n dated June 23, 2022, "On Approval of the Standard of Primary Health Care for Adults with HIV Infection (Diagnostics, Treatment, and Dispensary Follow-up)"

Order of the Ministry of Health of the Russian Federation No. 1288n dated December 4, 2020, "On Amendments to Order of the Ministry of Health of the Russian Federation No. 198n dated March 19, 2020, 'On the Temporary Procedure for Organizing the Work of Medical Organizations to Implement Measures for the Prevention and Reduction of Risks of the Spread of the Novel Coronavirus Infection COVID-19'"

Order of the Ministry of Health of the Russian Federation No. 689n dated November 8, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population with Human Immunodeficiency Virus (HIV Infection) Disease"

Order of the Ministry of Health of the Russian Federation No. 1051n dated November 12, 2021, "On Approval of the Procedure for Giving Informed Voluntary Consent to Medical Intervention and Refusal of Medical Intervention, the Form of Informed Voluntary Consent to Medical Intervention, and the Form of Refusal of Medical Intervention"

Order of the Ministry of Health of the Russian Federation No. 1129n dated October 20, 2020, "On Approval of the Rules for Conducting Mandatory Medical Examination to Detect Human Immunodeficiency Virus (HIV Infection)"

Order of the Ministry of Health of the Russian Federation No. 911n dated December 24, 2018, "On Approval of Requirements for State Health Information Systems of the Subjects of the Russian Federation, Medical Information Systems of Medical Organizations, and Information Systems of Pharmaceutical Organizations"

Order of the Ministry of Health of the Russian Federation No. 965n dated November 30, 2017, "On Approval of the Procedure for Organizing and Providing Medical Care Using Telemedicine Technologies"

Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care"

Order of the Ministry of Health of the Russian Federation No. 1n dated January 9, 2018, "On Approval of the Requirements for the Equipment of Emergency Prophylaxis Kits for Parenteral Infections with Medicines and Medical Devices for the Provision of Primary Health Care, Emergency Medical Care, Specialized Medical Care, and Palliative Medical Care"

Order of the Ministry of Health and Social Development of Russia No. 69n dated January 31, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients with Infectious Diseases"

Order of the Ministry of Health and Social Development of Russia No. 107 dated February 12, 2007, "On Approval of the Exemplary Procedure for Organizing the Counseling of HIV-Infected Patients under Dispensary Surveillance"

Order of the Ministry of Health and Social Development No. 390n dated April 23, 2012, "On Approval of the List of Certain Types of Medical Interventions for Which Citizens Give Informed Voluntary Consent When Choosing a Physician and Medical Organization to Receive Primary Health Care"

Resolution of the Government of the Russian Federation No. 1512 dated December 28, 2016, "On Approval of the Regulations on Organizing the Supply of Antiviral Medicines for Medical Use to Persons Infected with Human Immunodeficiency Virus, Including Coinfection with Hepatitis B and C Viruses, and the Regulations on Organizing the Supply of Antibacterial and Antituberculosis Medicines for Medical Use to Persons Suffering from Multidrug-Resistant Tuberculosis" (with amendments and additions)

Resolution of the Government of the Russian Federation No. 426 dated April 8, 2017, "On Approval of the Rules for Maintaining the Federal Register of Persons Infected with Human Immunodeficiency Virus and the Federal Register of Persons Suffering from Tuberculosis"

State Strategy for Countering the Spread of HIV Infection in the Russian Federation for the Period up to 2030 (approved by Order of the Government of the Russian Federation No. 3468-r dated December 21, 2020)

Clinical Guidelines "Tuberculosis in Adults", 2022

Guidelines for Chemoprophylaxis of Tuberculosis in Adult HIV-Infected Patients, 2016

Clinical Guidelines "HIV Infection in Pregnant Women", 2021

Appendix A3.1 Characteristics of Antiretroviral Drugs (according to the ATC classification: Systemic Antivirals) and ART Regimens

Antiretroviral drugs (ARVDs) (according to the ATC classification: systemic antivirals) disrupt the stages of the HIV life cycle and thereby prevent its reproduction (replication). The following ATC groups of ARVDs are used in clinical practice:

- Nucleoside reverse transcriptase inhibitors (NRTIs) (according to ATC: Nucleoside and nucleotide reverse transcriptase inhibitors) block the process of reverse transcription (synthesis of proviral DNA on a viral RNA template) by incorporating into the synthesized DNA chain and terminating its further assembly;

- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) (according to the ATC classification: non-nucleoside reverse transcriptase inhibitors) block the viral enzyme reverse transcriptase required for reverse transcription;

- Protease inhibitors (PIs) (according to the ATC classification: HIV protease inhibitors) block the formation of mature HIV proteins and, ultimately, the assembly of new viruses;

- CCR5 chemokine receptor antagonists (according to the ATC classification: Other antivirals) target receptors used by the virus to enter the host cell;

- HIV integrase inhibitors (IIs) (according to the ATC classification: integrase inhibitors) block the integration of proviral DNA into human DNA, which is carried out by the viral enzyme integrase.

ART Regimens:

First-line, second-line, etc., ART regimens and rescue (salvage) regimens are distinguished

First-line regimens are defined as regimens prescribed to patients who have not previously received ART. A first-line ART regimen typically includes 2 NRTIs (nucleoside backbone) and a third drug, which may be an NNRTI, INSTI, or a PI combined with ritonavir** (boosted PI – PI/r). First-line regimens also include those prescribed to a patient when switching from initial regimens to replace the original first-line regimens (preferred, alternative, or special-case regimens), provided the reasons for the regimen change are not related to treatment failure (e.g., due to ARV intolerance, concomitant drug intake, etc.).

Second-line and subsequent regimens refer to ART regimens used in the event of treatment failure of the previous-line regimens.

Salvage regimens are non-standard regimens used when second-line and subsequent regimens fail. They typically include drugs from various classes, selected individually based on the analysis of viral resistance to ARVs and previous therapy.

Preferred, alternative, and special-case ART regimens are distinguished.

Preferred regimens are optimal across a combination of parameters: efficacy, safety (lowest probability of life-threatening side effects), tolerability (incidence of side effects), convenience of administration, cost-effectiveness, including for specific patient groups.

Alternative regimens are prescribed if for any reason a preferred regimen cannot be used. Alternative regimens are inferior to preferred ones in some parameter or are less studied.

If neither preferred nor alternative regimens can be prescribed due to the patient having a condition corresponding to a special case, non-standard treatment regimens are used. In special cases, regimens are used whose efficacy is less studied, or adverse events are more pronounced compared to preferred or alternative regimens, or their cost is significantly higher.

When choosing a treatment regimen for an individual patient from a "public health" perspective, it is recommended to first consider the possibility of prescribing preferred regimens. 

Appendix A3.2 Informed consent for antiretroviral therapy

I, ______________________________________________________________________

(Full name, home address, contact phone number)

________________________________________________________________________

hereby confirm my voluntary consent to my treatment with medicinal products aimed at preventing the progression of HIV infection:

________________________________________________________________________

________________________________________________________________________

________________________________________________________________________

________________________________________________________________________

I confirm that I have been informed about:

that the antiretroviral therapy proposed to me has been prescribed based on clinical and laboratory indications and is aimed at suppressing the replication of the human immunodeficiency virus in my body and slowing down the progression of HIV infection, which will increase the duration and improve the quality of my life.

that to date, there is no cure for HIV infection.

that all antiretroviral drugs (according to the ATC classification: system-acting antiviral drugs) prescribed to me are approved for use in the Russian Federation and are provided free of charge.

that antiretroviral drugs (according to the ATC classification: system-acting antiviral drugs), like other medicinal products, may cause adverse events, information about which has been provided to me by my attending physician.

that the antiretroviral therapy prescribed to me may be discontinued at my own request or by decision of the attending physician due to my non-compliance with the drug intake regimen and/or examination schedule.

I undertake to:

to undergo laboratory examinations and consultations according to the schedule established by the attending physician for the purpose of timely monitoring of the treatment prescribed to me;

to take the prescribed medicinal products in accordance with the dosing regimen and instructions of the attending physician;

to promptly inform the attending physician about all changes in the treatment regimen, as well as changes in my condition, if I believe this is related to the prescribed treatment.

I am informed that in accordance with the requirements of Federal Law of the Russian Federation No. 323-FZ, in case of violation of the schedule of laboratory examinations and/or visits to the attending physician, I will be invited to the medical organization by phone or through a home visit by polyclinic specialists.

Patient _____________________ ___________________ Date __________

(Full name) (Signature)

Physician ____________________

_________________________ Date __________ (Full name) (Signature)

Appendix A3.3 Informed refusal

Refusal of types of medical interventions included in the list of certain types of medical interventions for which citizens give informed voluntary consent when choosing a physician and a medical organization for receiving primary health care and/or antiretroviral therapy

I, _____________________________________________________________________ (Citizen's full name)

born on "_____" _______________ g., registered at: ________________________________________________________________________ (Citizen's residential address) when receiving primary health care at (name of medical organization) 

refuse the following types of medical interventions included in the List of Certain Types of Medical Interventions for Which Citizens Give Informed Voluntary Consent When Choosing a Physician and a Medical Organization for Receiving Primary Health Care, approved by Order of the Ministry of Health and Social Development of the Russian Federation No. 390n dated April 23, 2012 (registered by the Ministry of Justice of the Russian Federation on May 5, 2012, No. 24082) (hereinafter referred to as types of medical interventions):

1. Interviewing, including identification of complaints, taking anamnesis

2. Examination, including palpation, percussion, auscultation, vaginal examination (for women), rectal examination.

3. Anthropometric examinations.

4. Thermometry.

5. Tonometry.

6. Non-invasive examinations of visual organs and visual functions.

7. Non-invasive examinations of auditory organs and auditory functions.

8. Examination of the nervous system functions (sensory and motor spheres).

9. Laboratory diagnostic methods, including clinical, biochemical, bacteriological, virological, immunological.

10. Functional diagnostic methods, including electrocardiography.

11. X-ray examination methods, including chest fluorography (for individuals over 15 years of age) and chest radiography (targeted chest radiography), ultrasound examinations.

12. Administration of medicinal products as prescribed by a physician, including intramuscularly, intravenously, subcutaneously, intradermally.

13. Antiretroviral therapy.

14. Other: ______________________________________________________________________ (name of another type of medical intervention)

Medical worker ______________________________________________________________________

(position, full name of the medical worker)

has explained to me in an accessible form my state of health, diagnosis, objectives, nature, and necessity of diagnostic and therapeutic measures. It has been explained that the antiretroviral therapy proposed to me is aimed at suppressing the replication of the human immunodeficiency virus in my body and slowing down the progression of HIV infection, which will increase the duration and improve the quality of my life. It has been explained that the provision of antiretroviral drugs (according to the ATC classification: system-acting antiviral drugs) is carried out free of charge. The possible consequences of refusing medical intervention / antiretroviral therapy (underline as appropriate) have been explained and are clear to me, including the likelihood of developing complications of the disease (condition), and that refusing antiretroviral therapy may lead to the progression of HIV infection with the development of life-threatening manifestations, such as disseminated tuberculosis, Pneumocystis pneumonia, central nervous system lesions caused by various infections, development of oncological diseases, etc., up to death. It has been explained that if the need arises for a medical intervention for which this refusal is executed, I have the right to execute

informed voluntary consent for such a type of medical intervention. Hereby, I confirm my voluntary refusal of antiretroviral therapy, the consequences of the refusal have been explained to me, and I assume responsibility for my state of health.

Reason for refusal:

___________________________________________________________________________________________________________________________________________________________________________________

(Signature) (Citizen's full name)

_______________________________________

(Signature) (Medical worker's full name)

"____" __________ 20 ____

Appendix A3.4 ARV dosing depending on creatinine clearance

1,2 after hemodialysis; data obtained from patients are limited; pharmacokinetic studies showed no need for dosage adjustment

Appendix A3.5 Switching ARVs upon development of drug intolerance

Appendix A3.6 Antiretroviral drugs (by ATC classification: systemically acting antivirals) in the clinical and pharmacological classification

Appendix A3.7 Post-exposure chemoprophylaxis

Determining the category of HIV infection risk level and prescribing post-exposure chemoprophylaxis for healthcare workers in case of emergency situations involving exposure to blood and other biological fluids containing HIV

³OPIM – semen, vaginal secretions, cerebrospinal, synovial, pleural, peritoneal, pericardial, amniotic fluid, tissues.

Contact with OPIM is assessed on a case-by-case basis; however, such contact typically does not pose a high risk of infection for medical personnel.

⁴Skin integrity is considered compromised if there are abrasions, dermatitis, cracks, or open wounds.

Contact of virus-containing materials with intact skin generally poses no risk of infection; however, if the contact area was large and the contact duration was prolonged, the possibility of infection should be taken into account.

⁵The combination of these factors (e.g., large-bore needles and deep penetration) implies a very high risk of HIV infection, i.e., corresponds to HIV infection risk categories 2 and 3.

Post-exposure chemoprophylaxis of HIV infection in case of an emergency situation involving blood and other biological fluids containing HIV

During pregnancy, post-exposure chemoprophylaxis for HIV infection in healthcare workers is carried out according to an individual regimen.

Appendix A3.8 Examples of recommended pathological anatomy diagnosis construction

1. Primary disease: B20.0. HIV disease, stage 4B, progression phase on ART. AIDS. (positive immunoblot no., date; CD4+ lymphocyte count; CD4/CD8; lymphoid depletion of all groups of lymph nodes).

Secondary disease: Generalized tuberculosis in the progression phase with involvement of the lungs, liver, kidneys, spleen, adrenal glands, pancreas, miliary dissemination, infiltrative-ulcerative intestinal tuberculosis (ileum, cecum, colon throughout), tuberculous meningoencephalitis, total caseous lymphadenitis of all groups of lymph nodes (sputum AFB positive, stool AFB positive, luminescence microscopy no., date; intravital CSF – MTB DNA detected, PCR assay no., date).

Complications: Pulmonary edema. Cerebral edema. Cachexia.

Concomitant diseases: Chronic viral hepatitis C (blood ELISA positive no., date).

2. Primary disease: B20.6. HIV disease, stage 4B, progression phase in the absence of ART. AIDS. (positive immunoblot no., date; CD4 count; CD4/CD8; lymphoid depletion of all groups of lymph nodes).

Secondary disease: Bilateral total Pneumocystis pneumonia (PAS positive exudate reaction, sharply positive immunohistochemical test with Pneumocystis jirovecii antibodies, 8 points on the Allred scale).

Pulmonary complications: Pulmonary edema. Cerebral edema.

3. Underlying disease: B20.8. HIV disease, stage 4B, progressive phase in the absence of ART. AIDS. (immunoblot positive no., date; CD4+ lymphocyte count; CD4/CD8 ratio; lymphoid depletion of all lymph node groups).

Secondary disease: Cerebral toxoplasmosis involving the parietal, frontal, and temporal lobes (Toxoplasma gondii DNA detected intravitally in CSF, PCR assay no., date)

Complications: Cerebral edema. Cachexia.

Concomitant diseases: Chronic viral hepatitis B and C (blood ELISA positive no., date).

4. Underlying disease: B20.5. HIV disease, stage 4B, progressive phase on ART. AIDS. (immunoblot positive no., date; CD4+ lymphocyte count; CD4/CD8 ratio; lymphoid depletion of all lymph node groups).

Secondary disease: Generalized cryptococcosis involving the brain (cryptococcal leptomeningitis (CSF bacteriological study intravitally identified Cr. neoformans, no., date; histobacterioscopy - PAS reaction for mycotic structures positive), lungs, and lymph nodes.

Complications: Cerebral edema and swelling.

5. Underlying disease: B20.7. HIV disease, stage 5, progressive phase in the absence of ART. AIDS. (immunoblot positive no., date; CD4+ lymphocyte count; CD4/CD8 ratio; lymphoid depletion of all lymph node groups).

Secondary diseases: Generalized tuberculosis in the progressive phase involving the lungs, liver, kidneys, spleen, and lymph nodes (miliary dissemination). Polysegmental Pneumocystis pneumonia. Herpetic meningoencephalitis. Generalized cytomegalovirus infection involving the lungs, adrenal glands, and intestines.

Complications: Pulmonary edema. Cerebral edema. Cachexia.

Concomitant diseases: Chronic viral hepatitis C.

6. Underlying disease: B18.2. Chronic viral hepatitis C (blood ELISA positive, no., date) resulting in micronodular liver cirrhosis, liver weight.

Concurrent disease: B20.7. HIV disease, stage 4B, progressive phase in the absence of ART. AIDS (immunoblot positive no., date; CD4+ lymphocyte count; CD4/CD8 ratio; lymphoid depletion of all lymph node groups).

Secondary diseases: Polysegmental microfocal bacterial fibrinous-purulent pneumonia (intravitally in sputum, bacteriological study no., date). Oropharyngeal candidiasis, candidal esophagitis.

Complications: Portal hypertension syndrome - splenomegaly (spleen weight), esophageal varices, ascites. Hemorrhagic syndrome - petechial hemorrhages on the skin of the extremities and trunk, hemorrhages in the intestinal mucosa, subepicardial and subpleural hemorrhages; thrombocytopenia. Liver failure (jaundice of the skin and mucous membranes, acholic feces, determination of blood alanine aminotransferase activity, determination of blood aspartate aminotransferase activity, determination of total blood bilirubin level, determination of free and conjugated blood bilirubin levels). Cerebral edema. Pulmonary edema. Cachexia.

7. Underlying disease: Post-injection phlegmon of the left upper extremity (bacteriological study S. aureus, culture no., date).

Background disease: Drug addiction (according to anamnesis, long-term injecting drug use, post-injection fistulas in the groin areas, traces of multiple injections in the right cubital fossa and forearm).

Concurrent disease: B20.2. HIV disease, stage 4B, progressive phase in the absence of ART. AIDS (immunoblot positive no., date; CD4+ lymphocyte count; CD4/CD8 ratio; lymphoid depletion of all lymph node groups).

Secondary disease: Generalized cytomegalovirus infection involving the lungs, intestines, brain, adrenal gland, and kidneys. B20.2.

Complications: Septicopyemia - purulent metastases and microbial emboli in the brain, kidneys, and lungs (bacteriological study S. aureus, culture no., date), disseminated intravascular coagulation (DIC) syndrome. Diffuse alveolar damage of the lungs, acute phase with hyaline membrane formation.

8. Underlying disease: B20.0. HIV disease, stage 4B, progressive phase, in the absence of ART. AIDS (immunoblot positive no., date; immune status CD4, CD8, CD4/CD8, no., date, lymphoid depletion of all lymph node groups).

Secondary disease: Generalized tuberculosis in the progressive phase involving the lungs (bilateral disseminated microfocal tuberculosis, MBT.

Appendix B. Physician Action Algorithms

Figure 1 Algorithm of actions in case of virological failure after 6 months of starting ART

Figure 2 Algorithm for correcting anemia in HIV-infected patients [357].

Figure 3 Algorithm for the treatment of adult HIV-infected patients with ITP

Appendix C. Patient Information

After establishing the diagnosis of HIV infection, a discussion is held with the patient about the disease, its prognosis, and the proposed treatment regimen. The discussion is conducted in a format accessible to them, involving a psychologist if necessary. Given the lifelong intake of medications and the need to develop maximum adherence to follow-up and treatment, the patient's understanding of the therapy goals and their individual satisfaction with treatment are assessed at each visit. The assessment includes active screening for adverse events of long-term ART and psychological barriers to treatment adherence, inattention to which will lead to missed doses by the patient.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Questionnaire for determining risk factors for non-adherence in patients with HIV infection

Russian title: Questionnaire for determining risk factors for non-adherence in patients with HIV infection

Source: Fedyaeva O.N., Sirota N.A. Risk factors for non-adherence to antiretroviral therapy in HIV-infected patients and methods for their identification. Meditsinskiy Sovet. 2014;(7):77-79.

Type (underline):

• rating scale

• index

• questionnaire

• other (specify)

Purpose: to determine risk factors for cART non-adherence in HIV-infected patients

Content and interpretation:

Appendix G2. Framingham risk score

Russian title: Framingham Cardiovascular Risk Score

Original title: Framingham risk score

Source: Wilson P. W. F. et al. Prediction of coronary health disease using risk factor categories // Circulation. 1998. Vol. 97. No. 18. P. 1837–1847.

Type (underline):

• rating scale

• index

• questionnaire

• other (specify)

Purpose: estimation of 10-year cardiovascular disease risk

Contents:

Interpretation:

Appendix G3. ECOG scale

Russian title: WHO performance status scale (ECOG scale)

Original title: The ECOG Scale of Performance Status

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982;5(6):649–65

Type (underline):

• rating scale

• index

• questionnaire

• other (specify)

Purpose: clinical assessment of the patient's general condition

Content and interpretation:

Appendix G4. Sheehan Anxiety Scale

Russian title: Sheehan Patient-Rated Anxiety Scale

Original title: Sheehan Patient-Rated Anxiety Scale – (SPRAS), (David V. Sheehan, 1983).

Source: Sheehan D.V., Sheehan Kr. // Int. J. Psychiatr. Med. – 1983. – N 12. – P. 243-266.

Type (underline):

• rating scale

• index

• questionnaire

• other (specify):

Purpose: screening and self-assessment of anxiety-related disorders in adults.

Content (template):

Instructions.

Determine how much you have been bothered by the symptoms listed below over the past week. Mark your answer number on the answer sheet.

Key (interpretation):

The total score on the scale is equal to the sum of the scores of all items. Thus, the total score can range from 0 to 140.

0–29 – absence of clinically significant anxiety,

30–79 – clinically significant anxiety,

80 and above – severe anxiety disorder, panic disorder.