HIV Infection in Children: Clinical Guidelines

List of Abbreviations

Ag Antigen

ARV Antiretroviral drugs (ATC: J05A direct-acting antivirals)

ART Antiretroviral therapy

Ab Antibody

ATC Anatomical Therapeutic Chemical Classification System recommended by the World Health Organization

IV Intravenous administration

VH Viral hepatitis

HBV Viral hepatitis B

HCV Viral hepatitis C

HIV Human immunodeficiency virus

VL Viral load

HSV Herpes simplex virus

IRIS Immune reconstitution inflammatory syndrome

WHO World Health Organization

FO Follow-up observation

DNA Deoxyribonucleic acid

FR Follow-up registry

GI Gastrointestinal tract

WB Western blotting

EI Entry inhibitor (ATC: J05AX other antivirals)

ID Immunodeficiency

INSTI HIV integrase strand transfer inhibitors (ATC: J05AJ integrase inhibitors)

IC Immune category

BMI Body mass index

PI HIV protease inhibitors (ATC: J05AE protease inhibitors)

IRI Immunoregulatory index, CD4/CD8 T-lymphocyte ratio

ELISA Enzyme-linked immunosorbent assay

CLIA Chemiluminescence immunoassay

QAQ Quantitative assessment of adherence

CD Cognitive disorders

CT Computed tomography

IU International units

MoH Ministry of Health

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

INR International normalized ratio

MO Medical organization

MRI Magnetic resonance imaging

BW Body weight

NRTI Nucleoside (nucleotide) reverse transcriptase inhibitors of HIV (Nucleosides and nucleotides reverse transcriptase inhibitors of HIV, ATC: J05AF)

NA Nucleic acid

NCD Neurocognitive disorders

NNRTI Non-nucleoside reverse transcriptase inhibitors of HIV (ATC: J05AG)

AR Adverse reaction

AE Adverse event

PEP Post-exposure prophylaxis

MTCT Mother-to-child transmission of HIV

PMTCT Prevention of mother-to-child transmission of HIV

BSA Body surface area

BS Surface area

PCR Polymerase chain reaction

RCC Russian Clinical Classification of HIV Infection, 2006

RNA Ribonucleic Acid

QD Once daily (dosing frequency)

RF Russian Federation

SP Sanitary Rules

AIDS Acquired Immunodeficiency Syndrome

F-AZT Phosphazide** (ATC: J05AF)

FDC Fixed-dose combinations

FE Federal District

CMV Cytomegalovirus infection

CNS Central nervous system

3TC Lamivudine** (ATC: J05AF05)

ABC Abacavir** (ATC: J05AF06)

ATV Atazanavir** (ATC: J05AE08)

BIC+TAF+FTC Bictegravir + tenofovir alafenamide + emtricitabine** (combination drug) (ATC: J05AR20)

CD4 CD4-receptor-bearing T-lymphocytes

CD8 CD8-receptor-bearing T-lymphocytes

DRV Darunavir** (ATC: J05AE10)

DTG Dolutegravir** (ATC: J05AX12)

EFV Efavirenz** (ATC: J05AG03)

EMA European Medicines Agency

ETR Etravirine** (ATC: J05AG04)

FDA US Food and Drug Administration

FPV Fosamprenavir** (ATC: J05AE07)

FTC Emtricitabine** (ATC: J05AF09)

EVG+COBI+TAF+FTC Cobicistat + tenofovir alafenamide + elvitegravir + emtricitabine** (combination drug) (ATC: J05AR09)

HADS Hospital Anxiety and Depression Scale

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

LPV+r Lopinavir+Ritonavir** (combination drug) (ATC: J05AR10)

NVP Nevirapine** (ATC: J05AG01)

PedsQL Pediatric Quality of Life Inventory

PENTA Paediatric European Network for Treatment of AIDS

RAL Raltegravir** (ATC: J05AX08)

RPV Rilpivirine (ATC: J05AG05)

RTV, /r Ritonavir** (ATC: J05AE03)

TAF Tenofovir alafenamide** (ATC: J05AF13)

TDF Tenofovir** (active moiety: tenofovir disoproxil fumarate (J05AF07)

TMP+SMX Co-trimoxazole [Sulfamethoxazole+Trimethoprim] ** (ATC: J01EE01)

XTC Either 3TC (lamivudine**), or FTC (emtricitabine)

ZDV Zidovudine** (ATC: J05AF01)

** Drug included in the National List of Vital and Essential Drugs for medical use

Terms and Definitions

People living with HIV is a collective term defining an individual's or individuals' belonging to the group of HIV-infected persons.

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

Age

Perinatal period ranges from 22 weeks of gestation to the 7th day of life

Neonatal period is the first 28 days of life

Pediatric age ranges from birth to 17 years 11 months 29 days

Infancy is the first year of life

Adolescence ranges from 10 years to 17 years 11 months 29 days (early – 10–13 years, late – 14–17 years).

Virus

Human immunodeficiency virus is the causative agent of HIV infection from the retrovirus group, lentivirus family, causing the gradual development of immunodeficiency.

Viral load is an indicator of viral replicative activity, the number of HIV RNA copies per 1 ml of the patient's biological fluid (blood, cerebrospinal fluid, etc.). At an undetectable viral load level, the number of HIV RNA copies is below the test system's detection threshold, while at a detectable level, it is above the test system's detection threshold. It is used to assess ART efficacy; it is recommended to use test systems with a detection threshold of no higher than 50 copies/ml of plasma.

Virological suppression is the goal of ART, which consists in reducing and maintaining the viral load in the blood below the level detectable by highly sensitive test systems (HIV RNA <50 copies/ml of plasma).

Virological failure is the inability to achieve or maintain a viral load at <200 copies/ml of plasma after 24 weeks of ART.

Virological reversion is a persistent increase in viral load >200 copies/ml of plasma after achieving virological suppression on ART.

Viral blip is an isolated detection of a measurable VL in patients with virological suppression (not exceeding 500 copies/ml), followed by a return to an undetectable VL. It is associated with spontaneous activation of HIV replicative activity.

Low-level virological response is a twice-confirmed VL >200 copies/ml of plasma after 24 weeks of ART in a patient who has not achieved virological suppression.

Low-level viremia is a measurable viral load of <200 copies/ml of plasma persisting during ART.

Vertical transmission

Perinatal HIV exposure is the contact of an infant with an HIV-infected mother throughout gestation, labor, and breastfeeding. Traditionally, the perinatal period lasts from 22 weeks of gestation up to and including the 7th day of the child's life. The term "vertical infection" implies transmission during pregnancy and childbirth. The concept of "perinatal HIV exposure" was introduced due to the lack of a suitable term to combine all children infected by their mothers naturally – during pregnancy, childbirth, and breastfeeding – into a single group.

Prevention of mother-to-child transmission of HIV is a set of measures to prevent fetal and infant HIV infection from the mother during pregnancy, childbirth, and breastfeeding.

Diagnostics

Immunoblotting is a laboratory method for detecting antibodies to various HIV antigens in the blood individually for each antigen. It is used as a confirmatory test following a positive ELISA or ECLIA result.

Enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescence immunoassay (ECLIA) are laboratory methods for the detection of HIV antibodies in the blood.

Polymerase chain reaction is a laboratory method for the qualitative and quantitative determination of HIV genetic material, based on the uniqueness of nucleotide sequences in RNA/DNA regions. It features high sensitivity and specificity. Qualitative determination of HIV DNA in blood lymphocytes is used in adults for the early diagnosis of HIV infection during an established or suspected "serological window" period (in the first weeks after infection, when the amount of specific HIV antibodies produced in the infected person's body is insufficient for detection). Quantitative determination of HIV RNA is used when selecting drugs for antiretroviral therapy (ART) regimens, assessing ART efficacy, and for prognostic purposes (see "Viral load"). Molecular methods are essential for early diagnosis in infants born to HIV-seropositive mothers.

Immunology

Immune status is an assessment of the immune system's state. In HIV infection, the percentage and absolute count of regulatory immune cells (CD4+ T lymphocytes) and effector immune cells (CD8+ T lymphocytes)—which are most important in the pathogenesis of the disease—are investigated. It is used to monitor the natural course of HIV infection and evaluate ART efficacy. The percentage is determined relative to the total leukocyte count. The absolute count is expressed as the number of cells per 1 microliter, i.e., 1 mm³.

Immunoregulatory index is the ratio of the absolute counts of CD4+ and CD8+ T lymphocytes. In individuals with an intact immune system, the IRI value is 1 or higher. In HIV infection, an inversion of this parameter occurs due to a decrease in the proportion of CD4+ T lymphocytes; the progression of immune system damage is accompanied by a decrease in the IRI. It is used for prognostic purposes.

CD4+ T lymphocytes (literally "cluster of differentiation 4") represent a transmembrane glycoprotein, a molecule on the surface of regulatory T lymphocytes (T-helper cells) that acts as a coreceptor participating in the immune functions of these cells and serves as a marker when studying T-lymphocyte subpopulations. CD4 cells function as the "conductors of the immune response".

CD8+ T lymphocytes (literally "cluster of differentiation 8") represent a transmembrane glycoprotein, a molecule on the surface of effector T lymphocytes (cytotoxic lymphocytes) that acts as a coreceptor participating in the immune functions of these cells and serves as a marker when studying T-lymphocyte subpopulations. CD8 cells lyse target cells bearing foreign antigens or altered autoantigens on their surface.

Treatment

Antiretroviral therapy is causal treatment for human immunodeficiency virus infection (HIV infection) that achieves a controlled course of the disease, is prescribed for life, and is based on the simultaneous use of several antiretroviral drugs acting on different stages of the HIV life cycle.

Presumptive HIV therapy in newborns is the administration of a three-drug ART regimen to newborns at high risk of HIV acquisition. Presumptive HIV therapy provides early treatment initiation for infants in whom HIV infection will be confirmed. It also serves as post-exposure prophylaxis, preventing the transmission of the human immunodeficiency virus from mother to child.

Resistance mutations are alterations in the genome of structural and functional (enzymatic) components of HIV that render it less sensitive to antiretroviral drugs.

Resistance is the insensitivity of HIV to one or more antiretroviral drugs.

Cross-resistance is the presence of shared resistance mutations among several drugs of the same class.

Genetic barrier to resistance is the ability of an antiretroviral drug to retain activity against HIV despite the emergence of resistance mutations in its genome.

Adverse reaction is a noxious and unintended response to a medicinal product related to its use, implying at least a possible causal relationship between the medicinal product and the adverse event.

Adverse event is any untoward medical occurrence in a patient administered a medicinal product, regardless of a causal relationship with this treatment. An adverse event can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

HIV infection is a disease caused by the human immunodeficiency virus; it is a chronic anthroponotic infectious disease characterized by specific damage to the immune system, leading to its gradual destruction until the development of acquired immunodeficiency syndrome (AIDS), which is accompanied by opportunistic infections and secondary malignancies [1].

AIDS is a condition developing against the background of HIV infection, characterized by the onset of one or more AIDS-indicator diseases. AIDS is an epidemiological concept used for the epidemiological surveillance of HIV infection [1].

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

The causative agent of HIV infection is the human immunodeficiency virus, which belongs to the lentivirus subfamily of the Retroviridae family. There are two types of the virus: HIV-1 and HIV-2.

HIV infection is caused by an RNA-containing virus belonging to the Retroviridae family, genus Lentivirus. HIV enters the body through infected fluids such as blood, breast milk, semen, and vaginal secretions. The targets for HIV are cells carrying the CD4 receptor, predominantly immunoregulatory T-helper lymphocytes. The subsequent development of the infectious process leads to a gradual decrease in CD4 levels and the IRI. As a result, HIV on the one hand undermines the protective function of the human immune system, and on the other hand creates conditions for the persistence of nonspecific inflammatory activation. In addition, CD4 receptors are present on certain other cells—monocytes, eosinophils, megakaryocytes, Langerhans cells, pulmonary alveolar macrophages, brain dendritic cells, and epithelial cells of the intestine and cervix. All of these, alongside T lymphocytes, are target cells for HIV, and many of them, having a longer lifespan, act as viral reservoirs in the body of an infected person.

The consequence of damage to CD4-bearing cells is a spectrum of disorders of altered homeostasis: ranging from antimicrobial and antitumor defense failure to chronic inflammatory diseases affecting all organs and systems. Conditions not directly linked to HIV infection include autoimmune reactions, immune complex diseases, and metabolic disorders leading to vascular endothelial and connective tissue damage. Thus, disease progression leads to the appearance of HIV-associated secondary infections and tumors, as well as HIV-related and non-HIV-related diseases—cardiovascular, neurological, renal, and osteoarticular pathology.

1.3 Epidemiology of the Disease or Condition

The source of HIV infection is individuals infected with HIV at any stage of the disease, including the incubation period.

Mechanism and routes of transmission

HIV infection can be transmitted through both natural and artificial mechanisms of transmission.

The natural transmission mechanism of HIV includes:

— contact transmission, which occurs predominantly through sexual contact (both homosexual and heterosexual) and via contact of mucous membranes or broken skin with blood;

— vertical transmission (transmission of the virus from an HIV-infected mother to her child during pregnancy, childbirth, and breastfeeding).

The artificial transmission mechanism includes:

— iatrogenic/artificial transmission via non-medical invasive procedures, including intravenous drug use (sharing syringes, needles, and other injection equipment and materials), tattooing, and cosmetic, manicure, and pedicure procedures using non-sterile instruments;

— iatrogenic/artificial transmission via invasive interventions in medical organizations. HIV transmission can occur through transfusions of blood, its components and products, organ and tissue transplantations, the use of donor semen or donor breast milk from an HIV-infected donor, as well as via parenteral medical instruments and medical devices that are contaminated with HIV and have not been processed in accordance with regulatory requirements.

The main transmission factors of the causative agent are human biological fluids (blood, blood components, semen, vaginal secretions, breast milk).

Current features of the epidemic process of HIV infection in Russia

The proportion of injection drug users in the structure of primary HIV-infected patients decreased to 39% in 2018; HIV infection has spread beyond traditional high-risk groups into the general population. Currently, there is a trend toward an increase in the proportion of women among those infected with HIV; in 2018, the proportion of women was 41% [2–4]. The increasing burden of HIV infection among women of fertile age and the rising number of deliveries in HIV-positive women cause an annual increase in the number of children with a diagnosed HIV infection, which persists despite significant successes in PMTCT [2, 5].

According to state statistical reporting forms, by the end of 2020, more than 10,000 HIV-infected children were identified in Russia [2, 5–7]. For children in the first years of life, the main risk factor for infection is being born to an HIV-infected mother. For adolescents, transmission routes are the same as in adults—sexual contact with HIV-infected individuals and intravenous drug use. For children of all age groups, possible routes of infection include blood and blood product transfusion and the use of HIV-contaminated medical instruments.

1.4 Features of Coding the Disease or Condition

The International Statistical Classification of Diseases and Related Health Problems, 10th Revision, provides codes for various conditions and medical services related to HIV infection [8, 9]. Coding is intended for statistical accounting and does not imply determining 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.

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

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 Pneumocystis 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 disease;

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

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, hematopoietic 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;

B22 Human immunodeficiency virus [HIV] disease resulting in other specified diseases:

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;

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

B23.0 Acute HIV infection syndrome;

B23.1 HIV disease resulting in persistent generalized lymphadenopathy;

B23.2 HIV disease resulting in hematological and immunological abnormalities, not elsewhere classified;

B23.8 HIV disease resulting in other specified conditions;

B24 Human immunodeficiency virus [HIV] disease, unspecified.

R75 Laboratory evidence of human immunodeficiency virus [HIV].

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

Z21 Asymptomatic human immunodeficiency virus [HIV] infection status.

When diagnosing HIV infection, it is inappropriate to use code Z21 in children with confirmed HIV infection. The main codes of the statistical observation form No. 61 of ICD-10 used in the Russian Federation when compiling medical reports on patients with HIV infection (2) 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 confirmed diagnosis of HIV infection is incorrect. Instead, the use of codes B23.1 and B23.2 is recommended [10].

For children with perinatal HIV contact, ICD-10 codes R75 and Z20.6 (R75/Z20.6) are used [9].

1.5 Classification of the disease or condition

According to the HIV infection classification currently in effect in Russia, the stage and phase of the disease are established solely on the basis of clinical manifestations—by the presence and significance of secondary diseases. Viral load levels and CD4 counts are not criteria for determining the clinical stage or phase of the disease [10–12].

Russian Clinical Classification (RC) of HIV Infection

1 Incubation stage

2 Primary manifestations stage:

2A. Asymptomatic;

2B Acute HIV infection without secondary diseases;

2C Acute HIV infection with secondary diseases

3 Subclinical stage

4 Secondary diseases stage:

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

— progression phase (in the absence of ART; during ART);

— remission phase (spontaneous; following previously administered ART; during ART)

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

— progression phase (in the absence of ART; during ART);

— remission phase (spontaneous; following previously administered ART; during ART)

4C Cachexia; generalized viral, bacterial, mycobacterial, fungal, protozoal, and parasitic diseases; Pneumocystis pneumonia; candidiasis of the esophagus, bronchi, trachea, or lungs; malignant tumors; central nervous system lesions

— progression phase (in the absence of ART; during ART);

— remission phase (spontaneous; following previously administered ART; during ART)

The classification variant approved by Order No. 166 of the Ministry of Health and Social Development of Russia dated March 17, 2006 [11], also provided for stage 5—"terminal". However, currently, due to the advent of effective ART, assigning this stage is not recommended [10].

In cases where, against the background of HIV infection, at least one of the secondary diseases has a degree of manifestation corresponding to the criteria for acquired immunodeficiency syndrome (28 in total), AIDS is indicated after the disease phase [10, 11].

List of conditions indicating the presence of AIDS in a patient [10–15]:

1. Bacterial infections (multiple or recurrent) in a child under 13 years of age;

2. Esophageal candidiasis;

3. Candidiasis of the trachea, bronchi, or lungs;

4. Cervical cancer (invasive);

5. Coccidioidomycosis (disseminated or extrapulmonary);

6. Extrapulmonary cryptococcosis;

7. Intestinal cryptosporidiosis with diarrhea >1 month;

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

9. Cytomegalovirus retinitis with vision loss;

10. HIV-associated encephalopathy;

11. Herpes simplex virus infection: chronic ulcers lasting >1 month, or bronchitis, pneumonia, or esophagitis in a patient older than one month of age;

12. Histoplasmosis, disseminated or extrapulmonary;

13. Intestinal isosporiasis (with diarrhea lasting >1 month);

14. Kaposi sarcoma;

15. Interstitial lymphoid pneumonia in a child under 13 years of age;

16. Burkitt lymphoma;

17. Immunoblastic lymphoma;

18. Primary cerebral lymphoma;

19. Mycobacterial infections caused by *M. kansasii* or *M. avium-intracellulare*, disseminated or extrapulmonary;

20. Pulmonary tuberculosis in a patient older than 13 years (Russian criteria for cases in which tuberculosis should be considered an AIDS-defining condition in HIV-infected patients: severe immunodeficiency confirmed by laboratory methods or diagnosed based on clinical manifestations of HIV infection; dissemination of the tuberculosis process; significant decrease in reactivity recorded during morphological examination of tissues involved in the tuberculosis process, e.g., a lymph node);

21. Extrapulmonary tuberculosis (Russian criteria for cases in which tuberculosis should be considered an AIDS-defining condition in HIV-infected patients — see item 20);

22. Other unspecified disseminated or extrapulmonary mycobacterioses;

23. Pneumocystis pneumonia;

24. Recurrent pneumonia (two or more episodes within 12 months);

25. Progressive multifocal leukoencephalopathy;

26. Recurrent non-typhoidal salmonella septicemia;

27. Cerebral toxoplasmosis in a patient older than one month of age;

28. HIV wasting syndrome.

Classification of Immune Disorders

In HIV-infected children, 4 degrees of immune system status are distinguished: no immunosuppression, mild immunosuppression, advanced immunosuppression, and severe immunosuppression. Immune status is assessed based on the absolute count and percentage of CD4 lymphocytes according to the child's age (Table 1) [10, 12–17].

Table 1. Classification of immune categories in children by age

1.6 Clinical presentation of the disease or condition

The clinical course of HIV infection without antiretroviral therapy is presented below.

Incubation period. This is the period from the moment of infection to the body's response to virus invasion (appearance of clinical symptoms or antibody production), usually lasting 1–3 months; however, in the presence of immunodeficiency states in patients receiving antitumor drugs L01 (cytostatics) or antiretroviral drugs, it may extend up to 12 months. During this period, HIV antibodies are not detected in the infected individual, which increases the risk of transmission, including during the provision of medical care.

Primary manifestations of HIV infection. In 30–50% of infected individuals, symptoms of acute HIV infection appear, accompanied by various manifestations: fever, lymphadenopathy, nonspecific (maculopapular, urticarial, petechial) rashes on the skin and mucous membranes, myalgia or arthralgia, diarrhea, headache, nausea and vomiting, enlargement of the liver and spleen, and meningeal syndrome. These symptoms occur against the background of high viral load and a decrease in CD4 lymphocyte counts in various combinations, with varying degrees of severity and duration. In rare cases, severe secondary diseases leading to patient death may develop already at this stage in the absence of antiretroviral therapy. During this period, the frequency of medical visits by infected individuals increases; the risk of transmission is high due to the high viral load and large amount of virus in the blood.

According to the Russian Guidelines, Stage 2 may have several clinical variants. Variant 2A (asymptomatic) is characterized by the absence of any clinical manifestations of HIV infection and is manifested solely by antibody production (seroconversion). Variant 2B, acute infection without secondary diseases, presents with diverse clinical symptoms: fever, polymorphic skin and mucous membrane rashes, lymphadenopathy, pharyngitis, hepatosplenomegaly, diarrhea, meningism. Sometimes this clinical variant is called "mononucleosis-like syndrome" because mononuclear cells may be detected in the blood during this period. Prominent symptoms are detected in 15–30% of patients, while the rest exhibit 1–2 of the above symptoms in any combination. A transient decrease in CD4 levels is frequently recorded in this variant. Variant 2C, acute infection with secondary diseases, is characterized by a significant decrease in CD4 levels, resulting in secondary diseases of various etiologies (candidiasis, herpes infection, etc.) due to immunodeficiency. Their manifestations are usually mild and short-lived, but in infants, especially with intrauterine infection, they can be severe (sepsis, Pneumocystis pneumonia) and even fatal.

Prognostically, the asymptomatic course of the primary manifestations stage of HIV infection is more favorable. The earlier in gestational age the infection occurred, the more severe the course of this stage and the higher the likelihood of rapid HIV progression and patient death in the absence of ART.

Subclinical stage. In this stage, the infected individual remains a source of infection for a long time. It is characterized by a slow decline in CD4 counts and a low HIV replication rate. The main clinical manifestation is persistent generalized lymphadenopathy, which is characterized by the enlargement of at least two lymph nodes in at least two non-contiguous groups (excluding inguinal), measuring more than 0.5 cm in diameter in children, persisting for at least 3 months. Upon examination, the lymph nodes are usually elastic, painless, not fused to surrounding tissue, and the overlying skin is unchanged.

The duration of the subclinical stage varies from 2 to 20 or more years, but averages 6–7 years. In children with perinatal infection, this stage may be absent if HIV infection has a steadily progressive course from the primary manifestations stage.

Stage of secondary diseases. Against the background of ongoing HIV replication and increasing immunodeficiency, secondary diseases (infectious, autoimmune, oncological) appear. Infections of viral, bacterial, and fungal origin initially have a fairly benign course and resolve with standard therapies; initially, these are predominantly skin and mucosal lesions. As CD4 lymphocyte counts progressively decline, organ-specific and generalized lesions develop, leading to patient death in the absence of ART.

According to the Russian Guidelines, Stage 4A is characterized by bacterial, fungal, and viral lesions of the mucous membranes and skin, and inflammatory diseases of the upper respiratory tract. In Stage 4B, skin lesions are deeper and prone to a protracted course. Lesions of internal organs and the peripheral nervous system, and localized Kaposi sarcoma begin to develop. Stage 4C is characterized by the development of severe, life-threatening secondary diseases, their generalized nature, and central nervous system involvement. Spontaneously or due to therapy, the clinical manifestations of secondary diseases may disappear. Therefore, this stage distinguishes progression phases (in the absence of antiretroviral therapy or during antiretroviral therapy) and remission phases (spontaneous, following prior antiretroviral therapy, or during ongoing antiretroviral therapy).

In pediatric practice, the rate of infectious disease progression differs from the natural course of HIV infection in adults toward more rapid progression in young children. Additionally, in children, the first sign of HIV progression may be growth and/or psychomotor development delay, preceding the full-blown clinical picture of secondary diseases.

The most typical manifestations of HIV infection in children (according to Russian Guidelines stages, 2006) [13–16, 18, 19]:

In Stage 3:

— persistent generalized lymphadenopathy.

In Stage 4A:

— weight loss of less than 10%;

— prolonged unexplained hepatosplenomegaly;

— fungal nail infection;

— angular cheilitis;

— recurrent oral ulcerations;

— persistent/recurrent unexplained parotitis;

— herpes zoster;

— recurrent or chronic upper respiratory tract infections (otitis media, sinusitis, tonsillitis).

In Stage 4B:

— weight loss of more than 10%;

— persistent unexplained diarrhea (more than 14 days);

— persistent unexplained fever (more than 30 days);

— persistent oral candidiasis at an age older than two months;

— hairy leukoplakia of the tongue;

— ulceronecrotic gingivitis or periodontitis;

— pulmonary tuberculosis;

— severe recurrent bacterial pneumonias;

— lymphoid interstitial pneumonia;

— anemia with a hemoglobin level <80 g/L;

— neutropenia <0.5 × 10⁹/L;

— thrombocytopenia <50 × 10⁹/L.

In stage 4B:

— wasting syndrome;

— Pneumocystis pneumonia;

— severe recurrent bacterial infections excluding pneumonia (meningitis, bone and joint infections, empyema, etc.);

— herpes simplex virus infection – skin and mucous membrane lesions persisting for more than 30 days, ulceronecrotic forms, visceral form;

— HIV encephalopathy;

— candidiasis of the esophagus, trachea, bronchi;

— cytomegalovirus infection starting at an age older than 1 month – retinitis, central nervous system involvement, and involvement of other internal organs;

— cerebral toxoplasmosis at an age older than 1 month;

— extrapulmonary cryptococcosis, including cryptococcal meningitis;

— disseminated deep mycosis (e.g., extrapulmonary histoplasmosis, coccidioidomycosis, penicilliosis);

— chronic cryptosporidiosis (with diarrheal syndrome);

— chronic isosporiasis;

— disseminated infection caused by non-tuberculous mycobacteria;

— progressive multifocal leukoencephalopathy;

— extrapulmonary tuberculosis;

— cryptococcal meningitis;

— HIV-associated myocardial dystrophy;

— HIV-associated nephropathy;

— primary lymphomas.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria

The diagnosis of HIV infection is established in accordance with the clinical guidelines and based on a combination of epidemiological data, clinical examination results, and laboratory tests (including the detection of HIV DNA or RNA), with justification of the diagnosis documented in medical records. The diagnosis of "HIV infection" is established by a physician at the AIDS Prevention and Control Center or by a physician of an authorized specialized medical organization that carries out diagnostic, therapeutic, preventive, and antiepidemic measures for HIV infection [1, 10, 12, 19].

The main areas of diagnostic research in children are:

— diagnosis of HIV infection;

— assessment of clinical and laboratory markers of HIV progression;

— assessment of clinical and laboratory indicators of ART efficacy (see Section 3. Treatment, including drug and non-drug therapies, dietotherapy, pain management, medical indications and contraindications for treatment methods);

— assessment of clinical and laboratory indicators of ART safety (see Section 3. Treatment, including drug and non-drug therapies, dietotherapy, pain management, medical indications and contraindications for treatment methods, and Section 5. Prevention and dispensary monitoring, medical indications and contraindications for prevention methods).

The diagnosis of HIV infection in children aims at early detection of HIV infection, which is necessary to address the main tasks of combating the spread of HIV infection: reducing morbidity and mortality from AIDS [1–4, 20]

Epidemiological criteria for the diagnosis of HIV infection [1, 3, 10, 12, 14, 16]:

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

— blood transfusion or blood products, organ and tissue transplantation from an HIV-infected person;

2. Factors indicating a high risk of HIV transmission:

— birth of a child to an HIV-infected mother who did not receive PMTCT;

— regular unprotected (without condom use) sexual contact with an HIV-infected patient or sharing parenteral psychoactive substance use with them;

3. Factors indicating a definite risk of HIV transmission:

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

— sexual contact with an HIV-infected partner: single unprotected or regular with condom use (cases of improper use are possible);

— sexual contact, parenteral drug use in areas where HIV is prevalent among the risk group to which the patient belongs;

— blood transfusion, organ and tissue transplantation, parenteral interventions in areas with a high (> 1% of the total population) HIV prevalence rate;

4. Factors indicating the possibility of HIV transmission:

— sexual contact, use of psychoactive substances, parenteral interventions in areas with a low HIV prevalence rate.

2.1 Complaints and Anamnesis

• For the purpose of early detection of HIV infection, it is not recommended during a child's examination to rule out the possibility of HIV infection solely based on the absence of complaints in the patient [21] (C4).

Comment: The presence of complaints in an HIV-infected child depends on the timing of infection. With vertical transmission in the early intrauterine period, complaints appear in the first days after birth and reflect intrauterine HIV infection – hypotrophy, lethargy or irritable crying, decreased muscle tone, head retraction, fever, shortness of breath, cough, loose stools, skin rashes, skin pallor, cyanosis, and others. When infected shortly before birth or during delivery, complaints appear 3-4 months after birth. Infection through breastfeeding can occur throughout the lactation period, so the timing of the first complaints and their nature become uncertain. With horizontal HIV infection in adolescents, as in adults, complaints may be absent for a long time.

Comment: Given the spread of HIV infection in the general population of Russia, the feminization of the epidemic process, the increasing proportion of seronegative mothers, the prolonged absence of specific complaints and pathognomonic symptoms, it is advisable to suspect HIV infection in a child with any atypical course of the disease and/or upon identifying an epidemiological history (regardless of the social status of the child's family). Considering the analysis results of late HIV detection in Russian children and aiming for the earliest possible detection of the disease, this recommendation primarily applies to primary care medical organization specialists [3–5, 20, 24, 25].

2.2 Physical Examination

• For the purpose of the earliest possible detection of HIV infection, it is not recommended to rule out the possibility of HIV infection in children solely based on the absence of clinical manifestations of the disease in the patient [30] (C5).

Comment: Physical examination findings depend on the stage of HIV infection in the child and, in the absence of ART, can range from no clinical manifestations to severe manifestations of opportunistic infections. The presence of complaints in an HIV-infected child depends on the timing of infection. With vertical transmission in the early intrauterine period, clinical manifestations can be detected in the first days after birth in the form of intrauterine growth restriction and secondary infections. When infected shortly before birth or during delivery, clinical manifestation occurs in the first months of the child's life in the form of acute retroviral syndrome – non-specific symptoms such as fever, respiratory catarrh, stomatitis, rash, dyspepsia; however, this is not observed in all children. Infection through breastfeeding can occur throughout the lactation period, so the timing of the onset of the first symptoms of HIV infection becomes uncertain. With horizontal HIV infection in adolescents, as in adults, the clinical picture of the acute stage of infection may be absent, and clinical manifestations of the disease may appear only in the stage of secondary diseases [1–5, 20, 24, 25].

o fever lasting more than 1 month;

o enlargement of lymph nodes in two or more groups lasting over 1 month;

o diarrhea lasting more than 1 month;

o unexplained weight loss of 10% or more;

o protracted, recurrent, and relapsing pneumonia, or pneumonia unresponsive to standard therapy;

o protracted and recurrent purulent-bacterial or parasitic diseases, sepsis;

o subacute encephalitis and neurocognitive disorders in previously healthy individuals;

o oral hairy leukoplakia;

o chronic and recurrent bacterial, fungal, and viral diseases of the skin and mucous membranes, including recurrent pyoderma;

o chronic inflammatory diseases of the female reproductive system of unclear etiology;

o anemia and other cytopenias (leukopenia, thrombocytopenia, lymphopenia) of unclear etiology;

in children under 13 years of age:

o prolonged unexplained hepato-(spleno)megaly;

o persistent/recurrent unexplained parotitis;

o psychomotor and physical developmental delay;

o neutropenia <0.5 × 10⁹/L;

o thrombocytopenia <50 × 10⁹/L.

Comment: Interpreting clinical manifestations in the early stages of HIV infection in the absence of marked immune status impairment may be challenging due to the lack of typical manifestations characteristic of advanced stages of the disease, which present as severe opportunistic infections and AIDS-defining conditions.

Interpreting clinical manifestations in children born to HIV-infected mothers presents certain difficulties because such children, even if not infected with HIV, are often born premature, show signs of intrauterine growth restriction, may be infected by maternal herpesviruses (herpes simplex, cytomegalovirus, Epstein-Barr, and others), hepatitis B and C viruses, Toxoplasma, and other pathogens, and also exhibit marked delays in psychomotor and physical development, often caused by psychosocial maladaptation.

• It is strongly recommended to order HIV testing when children present with the following established diagnoses in order to detect HIV infection and initiate treatment, as these conditions are AIDS-defining [14]:

o Kaposi sarcoma [35–38] (B2);

o cerebral lymphoma [39–41] (C4);

o T-cell leukemia [42] (C5);

o pulmonary and extrapulmonary tuberculosis [43–45] (B2);

o cytomegalovirus disease [46] (C4);

o generalized or chronic forms of herpes simplex virus infection [47] (C4);

o recurrent herpes zoster [47] (C4);

o infectious mononucleosis (in individuals over 13 years of age) [47, 48, 49] (B3);

o pneumocystosis (pneumonia) [50, 51] (B2);

o toxoplasmosis involving the central nervous system [50] (C4);

o cryptococcosis (extrapulmonary) [52] (C4);

o cryptosporidiosis [50] (C4);

o isosporiasis [50, 53] (C4);

o histoplasmosis [54] (C4);

o candidiasis of the esophagus, bronchi, trachea, or lungs [50] (C4);

o deep mycosis [50] (C4);

o atypical mycobacteriosis [50] (C4);

o progressive multifocal leukoencephalopathy [39, 50, 55] (C4);

o cervical cancer (invasive) [36, 37, 56] (C4);

o coccidioidomycosis (disseminated or extrapulmonary) [50] (C4);

o lymphoma (including non-Hodgkin, immunoblastic, Burkitt lymphoma, Hodgkin disease, and others) [36, 37, 41] (C4);

o recurrent salmonella (nontyphoidal) septicemia [57] (C4);

o bacterial infections (multiple or recurrent) in a child under 13 years of age [50] [58, 59] (B2);

o lymphoid interstitial pneumonia in a child under 13 years of age [60, 61] (C4);

o oncological disease in children under 13 years of age [41] (C4).

Comment: special attention should be paid to assessing:

— general condition (body temperature, activity, physical development, weight and height gain);

— condition of the skin and mucous membranes (detection of jaundice, manifestations of fungal infections, herpes simplex and zoster, seborrheic and other dermatitis, neoplastic lesions, oral hairy leukoplakia, and other pathological changes);

— status of peripheral lymph nodes (detection of persistent generalized lymphadenopathy);

— status of the parotid gland (detection of persistent parotitis);

— respiratory system (detection of dyspnea, catarrhal changes);

— cardiovascular system (determination of heart percussion borders and auscultatory changes);

— size of the liver and spleen;

— gastrointestinal tract status (detection of diarrheal syndrome);

— endocrine system status (detection of thyroid abnormalities);

— neurological and mental status (detection of depression and neurocognitive disorders: consciousness, mood, sleep, vision, neuropathic manifestations, cognitive processes – memory, attention, academic performance, etc.); in younger children, psychomotor development is assessed.

2.3 Laboratory Diagnostics

The screening of children born to HIV-infected mothers aims to identify the maximum possible number of HIV-infected individuals in the shortest possible time. In the absence of treatment, mortality among HIV-infected infants during the first year of life is extremely high [64]. During this period, early HIV testing, rapid turnaround of results, and immediate initiation of ART are of vital importance.

Laboratory diagnosis of HIV infection involves methods for detecting HIV genetic material (RNA, DNA) — molecular biological blood testing for human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV-1), its antigens — determination of human immunodeficiency virus HIV-1 p24 antigen in the blood, as well as methods for detecting HIV antibodies — determination of class M and G antibodies (IgM, IgG) to human immunodeficiency virus HIV-1 in the blood, and determination of class M and G antibodies (IgM, IgG) to human immunodeficiency virus HIV-2 in the blood. HIV genetic material can be detected as early as the 7th day after infection, the p24 antigen on the 15th day, the first antibodies by the 30th day, and late antibodies in 3–4 months.

A laboratory criterion for confirming HIV infection in children is obtaining two or more positive results for HIV RNA or DNA detection by PCR [65]. If laboratory confirmation of HIV infection is obtained in a child within no more than 2 weeks, it is necessary to conduct an examination by an HIV specialist to establish the clinical stage, immune category, identify secondary diseases, and decide on the initiation of ART.

A laboratory criterion for the absence of HIV infection is obtaining two or more negative results for HIV RNA or DNA detection by PCR, obtained at the age of over 14 days in the absence of breastfeeding from birth (for children of HIV-infected mothers, examinations should be carried out at designated intervals) [65].

Upon obtaining laboratory criteria for the absence of HIV infection using HIV nucleic acid detection methods in a child of a seropositive mother, it is necessary to continue further examination to determine IgM and IgG antibodies to human immunodeficiency virus HIV-1 in the blood and human immunodeficiency virus HIV-1 p24 antigen in the blood once every 3 months (starting from 9–12 months of age) until the cessation of maternal antibodies circulation in the child's blood (if a negative test result is obtained, a repeat examination is carried out after 1 month; upon obtaining laboratory criteria for the absence of HIV infection, deregistering children at risk of HIV infection from dispensary observation is carried out by a decision of the medical commission in the presence of a combination of deregistration criteria (see the section Prevention and dispensary observation, medical indications and contraindications for the use of prevention methods).

Recommended diagnostic methods for HIV infection and examination schedules for various categories of children are presented in Appendix A3. Reference materials and Appendix B. Physician action algorithms.

o if HIV infection is detected in the mother (and/or father);

o if HIV infection is detected in a nursing mother;

o in the absence of perinatal HIV contact, if risk factors for infection or clinical and laboratory signs of HIV infection are identified;

o for children left without parental care.

Comment: Diagnosis of HIV infection in children born to HIV-seropositive mothers is carried out taking into account the circulation of maternal antibodies in the child's blood up to 18 months of age, which makes methods for determining HIV antibodies uninformative.

• In order to detect HIV infection at the earliest possible stages, it is recommended to use HIV RNA or DNA detection — molecular biological blood testing for human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV-1) — in children with perinatal HIV contact under 18 months of age, as well as in individuals in the incubation period [1,16,74–76,81,88,94–96] (A1).

Comment: Diagnosis of HIV infection in children born to HIV-seropositive mothers is carried out taking into account the circulation of maternal antibodies in the child's bloodstream up to 18 months of age, which makes methods for determining HIV antibodies uninformative. In children born to HIV-infected seronegative mothers, antibody production generally occurs 1–4 months from the moment of the last potential exposure episode (delivery and breastfeeding). In children with perinatal HIV contact, the qualitative HIV DNA detection method allows the detection of intracellular DNA in peripheral blood mononuclear cells in 20–55% of children during the first week of life, in > 90% of children at 2–4 weeks of age, and in 100% of children at 3 months and 6 months of age. The quantitative HIV RNA detection method (viral load) allows the detection of extracellular viral RNA in plasma in 25–58% of children during the first week of life, in 89% of children at 1 month of age, and in 90–100% of children from 2 to 3 months of age [16,77–88].

When diagnosing HIV infection in a child aged 14–21 days receiving ART, it is advisable to use HIV DNA detection by PCR. The informative value of HIV RNA detection by PCR may be impaired in children receiving combination perinatal transmission prophylaxis with three ARV drugs due to a potentially low level of viremia in newborns and its suppression during treatment. Therefore, in this category of children, it is more advisable to use molecular methods aimed at the qualitative detection of HIV nucleic acids.

2.3.1. Screening for HIV infection in children of HIV-seropositive mothers under 18 months of age receiving formula feeding from birth

o within the first 48 hours of life (cord blood must not be tested); if a positive result is obtained, repeat testing as soon as possible;

o if a negative result is obtained, repeat testing at the age of 21–28 days; if a positive result is obtained, repeat testing as soon as possible;

Comment: If factors of increased risk of mother-to-child HIV transmission during pregnancy are identified:

— the mother did not receive ART during pregnancy;

— the mother received ART during pregnancy, but viral suppression was not achieved (HIV RNA >50 copies/ml) by 36 weeks of pregnancy and/or within 4 weeks prior to delivery, or HIV testing in the mother was not performed or was incomplete;

— the mother had acute HIV infection during pregnancy;

— a positive rapid test was detected in the mother during labor

testing the child in the first 2 days after birth allows for early detection of HIV infection and early initiation of ART.

Molecular biological blood testing for human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV-1) performed in the first days after birth identifies children infected in utero and does not detect children infected during the week before delivery and during labor. If a child was infected with HIV less than 10 days before the examination, the result of the HIV nucleic acid test may be false-negative; therefore, negative results of tests performed in the first 7–10 days of life are not taken into account subsequently [1,16,77,81,84,307].

The diagnostic sensitivity of molecular biological methods increases significantly by 2 weeks of age, and early detection of infection allows switching from presumptive HIV therapy to therapeutic doses of ART.

• It is strongly recommended that all children born to HIV-infected mothers undergo after completion of the ART course (prophylactic in children with low risk of infection or presumptive therapy in children with high risk of infection) molecular biological blood tests for human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV-1) at designated intervals using methods aimed at detecting HIV DNA or RNA [1,16,74,81,88,94–96,307] (B2):

o 2 weeks after the end of the prophylactic ART course, i.e., at 6 weeks of age in children with a low risk of infection and at 8 weeks of age in children with a high risk of infection; if a positive test result is obtained, perform a second (confirmatory) test as soon as possible;

o if a negative test result is obtained, perform a second (confirmatory) test at 4–6 months of age; if a positive result of this test is obtained, perform a second (confirmatory) test as soon as possible.

2.3.2. Screening for HIV infection in children born to HIV-positive mothers aged 18 months and older who have not been screened using HIV nucleic acid testing and have been formula-fed from birth

2.3.3. Screening for HIV infection in children born to HIV-positive mothers and receiving breastfeeding

o at birth, at 14–21 days, and at 4–6 weeks [84, 90-94, 307, 308, 309] (C4);

o 2 weeks after cessation of the ART course and at the age of 4–6 months [1,16,81,88,94-96,307] (C2);

o then throughout the entire breastfeeding period (every 3 months) and after complete cessation of breastfeeding (at 4–6 weeks, 3 months, 6 months) [1,93,307,308,309] (C3).

Comment: The risk of mother-to-child transmission of HIV via breastfeeding is 16–30% or more in addition to the risk of transmission during pregnancy and childbirth; therefore, HIV-infected women are strongly advised against breastfeeding and feeding with expressed breast milk. Despite this, some mothers make a conscious decision to breastfeed (most often due to religious or family reasons and AIDS denialism). In recent years, there has been an increase in the proportion of women who were seronegative during pregnancy and childbirth, in whom HIV infection is detected during breastfeeding or after its cessation. The possibility of transmission via breastfeeding persists until the very last breastfeeding episode [68].

2.3.4. Scope of examinations upon registering a child with HIV infection for clinical dispensary observation

Objectives of diagnostic evaluation upon enrolling a child for medical follow-up (dispensary registration):

— establishing a clinical diagnosis of HIV infection;

— determining the severity of immune system impairment to predict disease progression and determine management tactics;

— identifying indications for prompt initiation of ART;

— identifying indications for primary prophylaxis of secondary diseases;

— identifying secondary diseases and indications for their treatment;

— identifying comorbid conditions and indications for their treatment.

o CD4+ lymphocyte testing with determination of the percentage and absolute count of CD4 lymphocytes and assessment of the severity of immune system impairment according to immune categories depending on the child's age, to identify indications for prompt initiation of ART (see Table 1) [97–99] (B2).

Comment: In treatment-naive children with HIV infection, immune system depletion occurs as the disease progresses, manifested by a decrease in the percentage and absolute count of CD4 lymphocytes, which leads to the development of secondary diseases, including opportunistic infections. It is currently shown that the absolute CD4 lymphocyte count is a more reliable prognostic factor for HIV disease progression than their percentage, because the development of secondary diseases and opportunistic infections depends on the number of circulating cells, which can be low despite a high percentage in the setting of leukopenia and lymphopenia. At the same time, in children under 5 years of age, determining the percentage of CD4 lymphocytes remains a reliable alternative indicator of immune system status.

CD4 lymphocyte counts are not relevant for initiating ART, as it is indicated for all children regardless of immune status and other clinical and laboratory parameters. However, the decision on prompt initiation of ART, as well as on the initiation and administration of prophylaxis and treatment for secondary infections, is made based on age-specific percentages and absolute counts of CD4 lymphocytes [16,17,77,100,101].

o CD8+ lymphocyte testing with determination of the percentage and absolute count of CD8 lymphocytes and calculation of the immunoregulatory index (IRI), which is the ratio of absolute CD4 to CD8 values, to determine prognosis [102,103] (C4).

Comment: as a result of HIV infection, the absolute CD4 lymphocyte count gradually decreases, leading to an inversion of the CD4/CD8 ratio (normally, the ratio of CD4 to CD8 lymphocytes is greater than 1.0). As a rule, even in patients in the asymptomatic stage of HIV infection, as well as in the absence of an immunodeficient state, this index decreases to less than 1.0. As HIV infection progresses and the CD4 lymphocyte population becomes depleted, the IRI decreases significantly below 1.0. The IRI has important prognostic significance because it is a reliable predictor of HIV disease progression and mortality, regardless of quantitative CD4 and CD8 lymphocyte counts. In addition, a decrease in the IRI during ongoing ART is a predictor of viral load increase and virological failure [104–112].

o quantitative determination of Human immunodeficiency virus HIV-1 RNA in blood plasma by PCR ("viral load") to determine the disease prognosis [113] (B2);

o complete blood count (CBC) with differential to assess the general condition of the patient and select antiretroviral drugs (ARVD) [114,115] (B3);

o biochemical blood test for lipid metabolism disorders to assess the general condition of the patient, evaluate the patient's nutritional status, and select ARVD (C5) [116], and for lipid profile assessment (A3) [116];

o detection of the human leukocyte antigen B major histocompatibility complex locus B allele 5701 (HLA B*5701) to determine susceptibility to abacavir** when prescribing ART [117–121] (A1);

o urinalysis to assess the general condition of the patient [122,123] (A4);

o screening for viral hepatitis C (see relevant clinical guidelines): determination of antibodies to Hepatitis C virus in blood; screening for viral hepatitis B (see relevant clinical guidelines): determination of Hepatitis B virus surface antigen (HBsAg) in blood [124] (C4);

o determination of class G (IgG) and class M (IgM) antibodies to Toxoplasma gondii in blood for early disease detection [125] (C4);

o determination of class M and G antibodies (IgM, IgG) to Cytomegalovirus in blood for early disease detection [126] (C4);

o tuberculosis screening (see relevant clinical guidelines) [127,128] (A2).

o determination of Cryptococcus neoformans antigen in blood to diagnose cryptococcosis and determine indications for starting treatment [129] (C4);

o determination of acid-fast bacilli in stool, urine, and sputum to diagnose mycobacteriosis and determine indications for starting treatment: microscopic examination of sputum for mycobacteria (Mycobacterium spp.), microbiological (culture) examination of sputum for Mycobacterium tuberculosis complex, determination of Mycobacterium tuberculosis complex DNA in sputum, microbiological (culture) examination of stool for mycobacteria (Mycobacterium spp.) [130] (B2); or in bronchial washings by PCR (see relevant clinical guidelines).

Comment: diagnosis of mycobacterioses is performed using the laboratory facilities of the phthisiology service.

Comment: The patient is counseled on the necessity of early initiation of ART and regular scheduled examinations within the framework of clinical dispensary monitoring.

2.3.5 Evaluation of the state dynamics in a child with HIV infection under dispensary observation (during monitoring and ART)

1) HIV disease progression and/or ART efficacy [131-136] (B2):

o CD4+ lymphocyte testing [136] (A2);

o testing of the CD4/CD8 lymphocyte ratio [136] (A2);

o quantitative determination of human immunodeficiency virus type 1 (HIV-1) RNA in blood plasma by PCR [135] (B2);

o molecular genetic testing of blood plasma for drug resistance mutations in human immunodeficiency virus type 1 (HIV-1) RNA — in the presence of signs of ART failure (see section "Treatment, including drug and non-drug therapies, diet therapy, pain management, medical indications and contraindications for the use of treatment methods");

2) HIV progression and detection of treatment side effects: complete blood count (CBC) with differential; comprehensive metabolic panel (biochemical blood test); lipid metabolism panel [136] (A2); urinalysis [137] (C4);

3) manifestations of secondary and comorbid conditions: tuberculosis screening (see relevant clinical guidelines) in the absence of active tuberculosis [38,131,138] (B2); screening for hepatitis B virus in the absence of a hepatitis B diagnosis [131,138] (B2); screening for hepatitis C virus in the absence of a hepatitis C diagnosis [124] (C4); determination of antibodies to Treponema pallidum in the blood — as indicated (see relevant clinical guidelines) [131] (C5).

4) drug hepatotoxicity and/or hepatitis activity [139,140-142] (B3):

o determination of blood aspartate aminotransferase and alanine aminotransferase activities;

o testing of total bilirubin levels in the blood;

o determination of blood alkaline phosphatase activity — if cytolytic syndrome is detected;

o determination of blood gamma-glutamyl transferase activity — if cytolytic syndrome is detected;

5) drug nephrotoxicity and/or activity of existing renal pathology [139,141,142] (B3); blood creatinine level [401,402,403] (B3);

6) bone tissue status and treatment side effects [143] (C4):

o testing of total serum calcium levels;

o testing of inorganic blood phosphorus and urine phosphorus levels;

7) serum alpha-fetoprotein testing every 6 months in children with liver cirrhosis (see relevant clinical guidelines) [144] (C5);

8) cytological examination of the cervical smear — in sexually active young women for the timely diagnosis of precancerous cervical conditions (see relevant clinical guidelines) [145] (C5).

Comment: If markers of chronic viral hepatitis B or C are detected, diagnostic measures aimed at establishing or ruling out the clinical diagnosis are required, in accordance with the clinical guidelines for these diseases.

In the event that chronic viral hepatitis B or C has been diagnosed in a patient and treatment has not been administered, it is impractical to repeat the screening test for chronic viral hepatitis markers annually.

The schedule and scope of tests during monitoring and ART administration are presented in Appendix A3.

When the CD4 lymphocyte count corresponds to the 1st immune category and the viral load is below the limit of quantification (less than 50 copies/mL) for the last 24 months of ART, tests scheduled every 3 months may be performed every 6 months (in the absence of pathology). If elevated values of one or more biochemical markers are detected, the frequency of their monitoring may be increased (according to the clinical situation).

Comment: Currently, it is recommended to initiate ART in all patients after HIV diagnosis regardless of clinical and laboratory parameters. In addition to the proven efficacy of ART in patients with clinical manifestations of HIV infection and impaired immunity, a significant reduction in the risk of disease progression and mortality has been proven in asymptomatic patients initiating ART with high CD4 counts.

Indications for rapid ART initiation include age under 1 year; clinical manifestations of HIV corresponding to stages 2B, 4B, and 4C regardless of age; CD4 lymphocyte count $\le$ 500 cells/mm³ in children aged 1–5 years and $\le$ 200 cells/mm³ in children older than 5 years (see section 3.1, table 2).

2.4 Instrumental Diagnostics

Diagnosis of HIV infection does not imply special instrumental imaging examinations.

Instrumental examinations are used to diagnose secondary diseases, the detection of which can affect the outcome of the disease and patient treatment tactics, as well as risk factors and comorbidities that affect the timing of initiation and selection of the ART regimen.

2.4.1. Instrumental diagnostic procedures during dispensary monitoring of an HIV-infected child

o chest radiography [45,147–149] (B2);

o electrocardiography (according to age specifics) [150] (C4);

o abdominal ultrasound (comprehensive) [151] (C4);

o renal and adrenal ultrasound [152,153] (C4).

o fluorography or chest radiography for children aged 15 years and older: once every 6 months in the absence of active tuberculosis [45,147–149] (B2);

o electrocardiography (according to age specifics) [150] (A3);

o abdominal ultrasound (comprehensive) [151] (C4): once every 12 months, in children with liver cirrhosis — once every 6 months;

o renal and adrenal ultrasound [152,153] (C4);

o other instrumental examinations if indicated.

2.5 Other Procedures

Comment: Resistance testing is performed during ongoing ART, or at the latest within 2^weeks after stopping all drugs in the regimen (the long half-life of NNRTIs should be taken into account). At viral loads from 500 to 1,000 copies/mL of plasma, mutations may remain undetected using standard (non-highly sensitive) methods.

2.5.1. Consultations by medical specialists

During the dispensary monitoring of HIV-infected children before and during ART, the schedule of periodic routine consultations with medical specialists should be followed in accordance with the List of Examinations for Preventive Medical Examinations of Minors [1], and specialist consultations should also be performed when indicated.

Structural and functional disorders of the cardiovascular system are detected in HIV-infected children with a frequency of 62–76%, while often remaining undetected due to a lack of vigilance among physicians monitoring the HIV-infected child [392-394]. Early initiation of ART and its continuous administration contribute to the improvement of the cardiovascular system [392,395,397-400]; however, the frequency of its involvement may increase with late ART initiation, poor adherence to treatment, presence of comorbidities, and as a result of side effects of antiretroviral drugs [394-399]. Research and observational data show that regardless of ART status, HIV-infected children should undergo regular examinations by a pediatric cardiologist [392,394,395,397,399].

2.5.2. Central nervous system involvement caused by human immunodeficiency virus

Comment: The examination is performed by the physician responsible for monitoring the HIV-infected child or by a medical psychologist of the medical organization responsible for monitoring the HIV-infected child. For children under 6 years of age, the Strebeleva method is used; for children aged 6 to 17 years, the Wechsler Intelligence Scale for Children (version not lower than 3.0) is used.

Comment: In children with perinatally acquired HIV receiving ART, the most frequent manifestations of HIV infection currently are neurological and cognitive disorders of multifactorial origin, including the formation of HIV reservoirs in the central nervous system within the first days after infection, irreversible CNS damage prior to ART initiation, ongoing low-level HIV replication in the CNS, and neuroinflammation despite effective ART [316, 317, 318]. The overall detection rate of neurological disorders and neurocognitive disorders in children reaches 90%, with HIV encephalopathy, HIV encephalitis, and motor disorders being the most frequently registered. 50% of patients receiving ART have pronounced cognitive deficits [6].

Comment: Considering the neurotropic nature of the human immunodeficiency virus and the high frequency of CNS involvement and mental sphere disorders in HIV-infected patients (even in the absence of clinical manifestations of brain damage), as well as potential difficulties in the differential diagnosis of these pathological processes, all children should undergo a comprehensive clinical-psychological and neuropsychological examination as a measure aimed at identifying CNS and mental sphere pathology, regardless of clinical manifestations, immune status, and viral load. It has been shown that pathological changes in the cerebral cortex occur before the onset of impairments detected by neuropsychological tests and significantly earlier than clinical symptoms. Brain neuroimaging using MRI is essential for early clinical diagnosis, patient management, and selection of further therapy tactics [66, 156–161, 281, 316, 381, 386, 390].

2.5.3. Clinical, psychological, neuropsychological, and social examination of a child with HIV infection aimed at improving adherence to monitoring and treatment

This type of examination is performed by a medical psychologist of the medical organization responsible for monitoring the HIV-infected child, or in their absence, by the physician responsible for monitoring the HIV-infected child.

Comment: Disclosure of HIV status is particularly important in adolescence, as it helps prevent horizontal and vertical transmission of HIV infection and reliably affects adherence to monitoring and ART, ART efficacy, quality of life, social sphere, and other aspects of life for a child living with HIV.

Comment: It has been reliably established that achieving and long-term maintenance of virological suppression requires an ART adherence level of 95% or higher. The consequences of reduced and, in particular, low adherence to ART include the development of resistance to ARVDs; increased frequency of hospitalizations; decreased treatment efficacy and increased probability of HIV infection progression and death; the need to prescribe second- and subsequent-line ART regimens, the cost of which usually significantly exceeds the cost of first-line therapy; and ongoing transmission of HIV in the population.

o 8-item Morisky Medication Adherence Scale: [168, 169] (B3):

- adapted for adolescents aged 11–17 years;

- adapted for legal representatives of children under 11 years of age. [168, 169] (B3).

o pill count using the formula:

where x is compliance in percentage; a is the number of pills (doses) prescribed to the patient; b is the number of pills (doses) remaining with the patient

o To diagnose the level of medication adherence, apply at least two methods: viral load testing plus a questionnaire or pill count.

Comment: Mental disorders are detected in HIV-infected children significantly more often than in the general population and serve as predictors of HIV infection progression, poor ART adherence, and reduced quality of life. The prevalence of mental disorders in HIV-infected children ranges from 20 to 61%, with 25% of children having more than one mental disorder. High anxiety is registered with a frequency of up to 46%, depression in 20–41%, psychosomatization in 18%, suicidal ideation in 16%, social phobia in 13%, oppositional defiant disorder and attention deficit hyperactivity disorder in 12%, and seizures in 8%. Depression is an important risk factor for reduced ART duration and non-compliance with the treatment regimen. The cumulative probability of long-term continuation of the ART line is significantly higher in patients with less pronounced depressive symptoms: patients adhere to the treatment regimen much better [175–178].

Testing of children under 15 years of age is carried out only in the presence of their legal representatives.

If it is impossible to perform a comprehensive neuropsychological and social examination and support, including issues of treatment adherence, during dispensary monitoring of a child with HIV infection at the place of residence, such a child must be referred to a specialized regional, district, okrug, or federal medical organization that employs pediatric neurologists, child psychiatrists/psychotherapists, and medical psychologists with experience working with HIV-infected children, and has the capability to perform neuroimaging.

Information on ART adherence and methods for its enhancement and maintenance is presented in Section 7. Additional Information; the algorithm for social and psychological support, including the assessment and correction of adherence, neurocognitive disorders, and depression, is presented in Appendix B. Physician Action Algorithms; characteristics of research methods for adherence, quality of life, and anxiety/depression are presented in Appendices G1–G4. Assessment scales, questionnaires, and other patient status assessment tools are provided in the clinical guidelines; the classification of neurocognitive disorders is presented in Section 7. Additional Information.

[1] Order of the Russian Ministry of Health No. 514n dated August 10, 2017, "On the Procedure for Conducting Preventive Medical Examinations of Minors" (as amended by Orders of the Russian Ministry of Health No. 410n dated July 3, 2018, No. 396n dated June 13, 2019, No. 1235n dated November 19, 2020)

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

The main objective of treating HIV infection in children at the present stage is to preserve health for a full and productive life in adulthood. ART is the only specific treatment method for HIV infection capable of saving the life of an HIV-infected child and ensuring its high quality. There are two goals of ART in children: reducing AIDS-related mortality and reducing morbidity [1].

The main mechanism for achieving these goals is the maximum and reliable suppression of HIV replication in the body through the prescription of ART.

General information about ART is presented in Appendix 7. Additional Information.

The principles of ART are:

— voluntariness — conscious decision-making on the initiation and conduct of treatment, documented by "informed consent"; if the legal representative of the child refuses therapy, legal measures must be taken to initiate (resume) therapy for the child;

— timeliness — initiating ART as early as possible;

— continuity — long-term (lifelong) compliance with the ARV intake regimen.

A critical condition for conducting ART in a child is the readiness and ability of the child themselves or their caregivers to follow all medical prescriptions. Preparation for ART consists of assessing the child's condition and counseling the child (according to age) and/or their caregivers. Based on the counseling results, the physician draws conclusions about the social and psychological status of the child or caregivers and their ability to follow the rules for storing and dosing medications and to adhere to the regimen [188–191].

Thus, before starting ART, it is necessary to discuss the following key issues with the patient or their legal representative:

— the importance of strict adherence to the ART regimen (timing, dietary, fluid intake, and other regimen aspects);

— potential adverse reactions of ARVs, in the event of which it is necessary to consult a physician;

— signs of frequent diseases in HIV-infected children requiring urgent diagnosis and treatment;

— prevention of opportunistic infections, including Pneumocystis pneumonia;

— the importance of routine vaccinations;

— feeding and nutrition of an HIV-infected child: optimal diet, recommendations for the use of dietary supplements, and nutritional features in case of loss of appetite or impaired ability to feed. For infants under one year of age, a consultation with the parent/guardian on formula feeding is required;

— the possibility of developing immune reconstitution inflammatory syndrome (IRIS) accompanied by a temporary deterioration of the clinical condition, explaining that this is an indicator of the effectiveness of ongoing therapy and is not a reason for its cancellation or interruption.

Comment: Counseling of children must be carried out from the start of ART and continued throughout treatment, adapting its form and content in accordance with the age characteristics of the child [188–191].

After counseling, the person legally responsible for a child under 15 years of age signs informed consent to ART or refuses it (see Appendix A3. Reference Materials). Upon reaching the age of 15, the adolescent has the right to medical confidentiality and signs informed consent independently. If the parents or other legal representative of a person under the age of 15, or the legal representative of a person recognized as legally incompetent in accordance with the established procedure, refuses medical intervention necessary to save their life, the medical organization has the right to apply to the court to protect the interests of such person [2].

Features of ARV use in children:

— before prescribing abacavir**, testing must be performed to detect the HLA-B*5701 allele of the human major histocompatibility complex locus B (HLA B*5701);

— rilpivirine should not be prescribed at a viral load > 100,000 copies/mL of plasma;

— in children over 12 years of age with a viral load > 100,000 copies/mL of plasma, tenofovir** is preferred over abacavir**;

— zidovudine** should not be prescribed in the presence of anemia, thrombocytopenia, or lymphopenia, and if these abnormalities develop during its use, it should be replaced with abacavir** or — in children over 12 years of age — with tenofovir**;

— efavirenz** should be used in children receiving rifampicin** (rifampicin** is used in children from 3 years of age) or triazole antifungal drugs for the treatment of opportunistic infections;

— nevirapine** is not used in infants under one year of age if it was used in the mother and/or child for the prevention of vertical transmission. Nevirapine** should not be prescribed to post-pubertal girls with CD4 > 250 cells/mm3;

— protease inhibitors (PIs) boosted with ritonavir** are used in children (boosting involves adding a low dose of ritonavir** to improve PI pharmacodynamics);

— the use of combined ARVs reduces the burden of lifelong therapy and improves treatment compliance. The use of fixed-dose combinations is determined by the characteristics of their component single drugs and is possible upon reaching the child's age and body weight specified in the package leaflet of the combination drug (see Appendix A3. Reference Materials, including the correspondence of indications and contraindications, methods of administration, and drug dosages, according to the drug's instructions for use).

When deciding on the choice of ARVs for a child, their advantages and disadvantages should be taken into account and correlated with the course of HIV infection, the presence of opportunistic and comorbid diseases requiring treatment, laboratory parameters, child care specifics, and other factors that, in the opinion of the attending physician, may affect the tolerability, efficacy, and safety of ART (see Table 10. Advantages and Disadvantages of Various ARVs in Section 7. Additional Information). An acceptable starting regimen should be selected for each child from the preferred drug class, or from the alternative class if indicated.

Rules for calculating dosages are presented in Section 7. Additional Information and Appendix A3. Reference Materials (Table 20. Recommended ARV Doses in Children and Specifics of Their Application).

Development of the ARV intake regimen is presented in Section 7. Additional Information.

3.1 Indications for ART Initiation

Comment: Modern diagnostic approaches make it possible to detect HIV infection in children infected during pregnancy and childbirth as early as the first days and weeks of life: in 55–76% at birth and in all children aged 6 weeks to 3 months (74, 311).

Numerous clinical studies and observations have demonstrated that early initiation of ART (in the first days and weeks of life) dramatically affects the course of HIV infection in children: the size of viral reservoirs is significantly reduced (322); virological control is improved (328); the functions of the immune system, primarily CD4 and CD8 lymphocytes, are improved (329, 330); the metabolic profile improves, leading to a lower incidence of cardiovascular disease (321, 322); the risk of death is reduced (333); the risk of neuropsychiatric disorders is significantly reduced (334-336); seroreversion (disappearance of HIV antibodies) occurs in almost half of the children (325, 337, 338); the time to achieve virological suppression is shortened (339); and sustained suppression of viral replication and HIV reservoirs (based on total HIV DNA quantification) persists into adolescence (340).

Table 2. Indications for rapid initiation of ART in children

Comment: when detecting HIV infection (or admitting under observation) in a child with advanced stages of HIV infection and pronounced clinical manifestations against the background of very low CD4 lymphocyte counts, it should be ensured before starting ART that there are no secondary infections requiring urgent etiotropic treatment. If ART is prescribed first, a life-threatening immune reconstitution inflammatory syndrome may develop. In tuberculosis, ART is generally initiated no later than 2 ^weeks after starting anti-tuberculosis treatment; in cryptococcal meningitis, ART is initiated no earlier than 2 weeks after starting antifungal therapy (typically after 5 weeks).

ART may be delayed for a short period required for confirmatory testing and patient preparation for treatment.

3.2 Selection of the Initial ART Regimen

The classification of ARV drugs is presented in Section 7. Additional Information.

The information provided below on the use of ARV drugs in children may differ from the instructions for medical use of medicinal products registered in the Russian Federation. When selecting ART regimens and ARV dosages, recommendations from the World Health Organization, the European Pediatric Treatment of HIV Network (PENTA), the European AIDS Clinical Society (EACS), the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (US Department of Health and Human Services), Russian experts, as well as prescribing information approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), were taken into account [16,81,202,203,281,294]. The justification is the Decree of the Government of the Russian Federation dated May 16, 2022, No. 1180-r (as amended by the Decree of the Government of the Russian Federation dated August 1, 2023, No. 2064-r) on approval of the List of diseases or conditions (groups of diseases or conditions) in which the use of a medicinal product is permitted in accordance with indications (characteristics) of the medicinal product not specified in its instructions for medical use.

The starting treatment regimen (first-line ART) is prescribed to "naive" patients who have not received ARV drugs as treatment, and consists of 2 NRTIs and a third drug: either 1 NNRTI, or 1 PI, or 1 INSTI (Table 3).

Comment: The basis of the starting ART regimen is the simultaneous use of three drugs to suppress various stages of viral replication, i.e., belonging to different classes. As starting therapy, a combination of two nucleoside/nucleotide reverse transcriptase inhibitors and one drug from the protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or HIV integrase inhibitor group is used: 2 NRTIs + 1 PI, or 2 NRTIs + 1 NNRTI, or 2 NRTIs + 1 INSTI.

Comment: The use of suboptimal ART regimens leads to the development of HIV resistance and loss of control over the infection. A special situation is provided for HIV-infected children with suppressed HIV viral load during tuberculosis treatment using rifampicin** (contraindicated under 3 years of age): if it is impossible to use a full ART regimen during this period, the child is switched to a 3-NRTI regimen. Currently, there are no data on the feasibility of simplifying (simplification of) the ART regimen to bi- and monotherapy in children with stable HIV infection and complete viral suppression (such a possibility has been proven in randomized clinical trials in adult patients).

Comment: ARV combinations are divided into preferred, alternative, and those used in special situations. When choosing a starting therapy regimen, the possibility of using preferred drugs/regimens should be considered first.

o Younger than 2 weeks: nevirapine** [210,211]; (B2)

o From 2 weeks to 6 years: lopinavir+ritonavir** [211,212] (A2)

o From 2 to 6 years: raltegravir** [209, 413]; (B2)

o Older than 6 years: dolutegravir** [214] (C4).

o Older than 6 years: Bictegravir+Tenofovir alafenamide+Emtricitabine** [302,303]; (C4).

o Younger than 2 weeks: zidovudine** + #lamivudine** [230,341-346] (C4);

o From 2 weeks to 3 months: #abacavir** + #lamivudine** [230,281,341-353] (B2);

o Older than 3 months: abacavir** + lamivudine** [230,281,341-353] (B2);

o Older than 12 years: tenofovir** + lamivudine** or tenofovir** + emtricitabine or abacavir** + lamivudine** [16,96,169] (C5)

o From 2 weeks to 3 years: nevirapine** [204,216,217] (B2);

o From 2 to 6 years: #etravirine** [301,404] (C4);

o Older than 3 years: efavirenz** [204,217,218] (C4);

o Older than 6 years: lopinavir+ritonavir** [219] (B2) or raltegravir** or efavirenz** [209, 307] (B2) [206] (A2);

o Older than 12 years: efavirenz** [209, 307] (B2).

o From 2 weeks to 3 months: zidovudine** + #lamivudine** [216] (B2)

o Older than 3 months: zidovudine** + lamivudine** [216] (B2)

o Older than 3 years: phosphazid** [412] (C5) + lamivudine** [216]. (B2)

o Over 6 years: Cobicistat + Tenofovir alafenamide + Elvitegravir + Emtricitabine** [221,405] (C4);

o Over 12 years: Rilpivirine + Tenofovir + Emtricitabine** [222] (4C).

Comment: Alternative regimens include drugs with more pronounced side effects or more complex dosing, etc., and may be used when contraindications to preferred drugs/regimens are identified due to various reasons (laboratory abnormalities, potential drug-drug interactions, expected intolerance and toxicity, age-specific features, potential pregnancy, etc.).

Comment: The category of drugs used in special cases includes ARVs that are less studied or have age-specific application features, etc. These drugs are prescribed only if there is no choice from the preferred or alternative group.

Subsequent lines of therapy (second and subsequent, salvage lines) are prescribed in case of virological failure of the previous line of therapy, selected taking into account the results of HIV drug resistance testing and expert opinion.

The prescription of ART and the choice of regimen are decided by a medical commission after reviewing the indications and contraindications for specific ARVs and calculating appropriate therapeutic doses.

The choice of treatment regimen is made taking into account the child's somatic status and potential drug-drug interactions in case of treatment of secondary/co-morbid conditions to avoid significant fluctuations in plasma drug concentrations. Special attention is required for: decreased liver and kidney function, which slows down the clearance of drugs metabolized by them; administration of tuberculosis drugs; hormonal and anticonvulsant drugs. In complex cases, alternative treatment regimens (for both HIV infection and comorbidities) should be selected or a clinical pharmacologist should be involved to recalculate drug doses.

Table 3. Initial ART drugs according to the child's age [96,221–224]

3.3 Modification of the Initial ART Regimen

The main objectives of ART in children are:

— achieving and long-term maintenance of clinical, immunological, and virological efficacy of ART;

— long-term safety of ART (minimization of ARV side effects);

— good tolerability of ARVs;

— building and maintaining high adherence to treatment.

During ART, the question of replacing one or two drugs in the regimen or the entire regimen altogether frequently arises.

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: among the factors underlying the need to change therapy, the main ones in children are:

— low adherence to treatment;

— toxicity and intolerance to therapy;

— availability of new data on the possibility of using more effective drugs or combinations in a child than the current therapy;

— need to use drugs incompatible with the prescribed ARVs;

— ineffectiveness of ongoing therapy and obvious disease progression confirmed by clinical, immunological, and virological parameters (may result from low treatment adherence, intolerance, or development of resistance).

Specific causes of treatment failure in children and management tactics upon the emergence of toxicity/intolerance signs of ARVs are presented in Section 7. Additional Information.

3.3.1 Modification of the ART Regimen in Case of Treatment Failure

The efficacy of ART is assessed throughout the entire period of ART administration. Clinical, immunological, and virological parameters are used to determine ART efficacy. Criteria for evaluating the virological efficacy of treatment are most clearly formulated, to a lesser extent for clinical efficacy, while there is no consensus regarding immunological efficacy.

Second-line ^ART — this is the next regimen prescribed immediately after detecting first-line ART failure—clinical, and/or immunological, and/or virological.

Assessment of virological efficacy of ART

The most common causes of virological failure are described in Section 7. Additional Information (including factors influencing the outcome of the disease or condition).

The algorithm for assessing the virological efficacy of ART in children is outlined in Appendix B. Physician Action Algorithms.

Comment: The following viral load dynamics indicate treatment efficacy: a decline of more than 1 log₁₀ at 4 weeks of treatment; a decline of more than 3 log₁₀ at 12 weeks of treatment; a decline to undetectable levels (<50 copies/mL plasma) at 24 weeks of treatment. It is not recommended to use test systems with a sensitivity threshold of 200 copies/mL and higher to assess virological efficacy, as they may fail to detect incomplete suppression of HIV replication, which contributes to the replenishment of latent HIV reservoirs and the emergence of drug-resistant HIV strains, hinders successful immune system recovery, and may lead to disease progression [227–229].

Comment: Virological ineffectiveness (failure) of ART is understood as incomplete suppression of HIV replication (failure to achieve virological suppression) or viral load rebound after achieving undetectable levels, assessed at least 24 weeks after the start of the current ART regimen.

In children with a high viral load before ART initiation, a viral load > 200 copies may be detected after 24 weeks of ART. When HIV protease inhibitors are used in the initial ART regimen, a viral load reduction of 1.5–2.0 log₁₀ (50–100-fold) compared to the baseline level allows continuing the previously chosen therapeutic regimen and intensifying efforts to improve treatment adherence. In children receiving non-nucleoside reverse transcriptase inhibitors in their initial ART regimen, the lack of virological suppression may be associated with the development of drug resistance, which will require an ART switch.

A short-term increase in viral load (usually up to 1,000 copies/mL) may be associated with vaccination, administration of globulin fractions, intoxication, an unrelated concomitant illness, and is not considered virological failure if the viral load drops to an undetectable level (<50 copies/mL) 1 month after resolution.

Comment: When deciding on switching the initial ART regimen in infants, one should not rush — drug choices in children are limited — but neither should this process be delayed, especially if the child is receiving an NNRTI.

The decision to switch to second-line ART is made by the medical commission taking into account the individual characteristics of the child, after a detailed assessment of viral load dynamics, treatment adherence, clinical and immunological efficacy, and laboratory parameters, and upon obtaining convincing evidence that continuing the first-line ART is inappropriate.

To select active second-line drugs, it is strongly recommended to perform HIV drug susceptibility testing—a molecular genetic study of blood plasma for drug resistance mutations in the RNA of the human immunodeficiency virus type 1 (HIV-1). The new regimen should include at least 2 ARVs with high anti-HIV activity.

Assessment of ART Clinical Efficacy

o progressive deterioration of neurological parameters, including two or more of the following signs: impaired brain growth, cognitive impairment, onset of motor dysfunctions;

o growth failure (despite adequate nutrition and in the absence of other causes);

o disease progression, defined as transition from one clinical stage to another;

o appearance of new or progression of previously identified secondary infections/diseases.

Commentary: Clinical treatment failure is the most unfavorable outcome due to the potential rapid progression of HIV infection.

In children who initiated ART against the background of low immune status parameters, with rapid positive CD4 dynamics and a progressive decrease in viral load, the appearance of new secondary diseases in the first weeks and months of treatment may indicate treatment efficacy and the development of immune reconstitution inflammatory syndrome, in which tuberculosis infection and cryptococcal meningitis can be the most severe. Before starting ART (especially against the background of pronounced and severe immunodeficiency), it is recommended to thoroughly screen the child for tuberculosis and other secondary diseases.

If disease progression is not associated with neurological disorders or growth restriction, immunological and virological parameters should be taken into account when deciding on modifying therapy.

Assessment of ART Immunological Efficacy

Commentary: Clear immunological criteria for ART failure are currently lacking [225]. In the majority of patients receiving ART, an increase in CD4 lymphocyte levels occurs over many years of treatment: with pronounced and severe immunodeficiency at baseline, immune status recovery is very slow, and in some patients increases insignificantly.

There are currently no methods aimed at stimulating the growth of CD4 lymphocyte counts. It is generally accepted that the immunological effect is achieved if the percentage and/or absolute count of CD4 lymphocytes exceeds the age-related thresholds for severe immunodeficiency. Increasing CD4 to a level safe regarding the development of opportunistic infections (i.e., greater than 200 cells/mm³) is considered acceptable, while an increase to more than 350 cells/mm³ is an adequate treatment result.

In the case of lymphopenia, the possible causes should be analyzed and appropriate corrections made: replacing ARVs and concomitant therapy drugs that have a leukopenic effect, screening to identify secondary and comorbid conditions, etc.

Switching ART Due to Virological Failure

The most critical task when prescribing second- and subsequent-line therapy is to achieve complete virological suppression.

Commentary: Resistance testing is performed while on ART, or at most within 2^weeks after discontinuing all drugs in the regimen (the long half-life of NNRTI should be taken into account). At viral loads from 500 to 1,000 copies/mL of plasma, mutations may remain undetected using standard (non-ultrasensitive) methods.

Commentary: HIV protease inhibitors have a high genetic barrier to resistance, and their use rarely leads to the development of HIV drug resistance, making it possible to use another boosted protease inhibitor with better tolerability in case of virological failure. When replacing protease inhibitors with drugs from other classes, it should be taken into account that many of them have a lower barrier to resistance, which requires high adherence to treatment [246–248].

Commentary: The M184V/I mutation increases the antiviral activity of zidovudine** and tenofovir**. Adherence to this recommendation depends on the child's age, dosing frequency, number of drugs and tablets/solutions, and ART adherence.

Table 4. Potential options for ART regimens in case of failure of the previous line of therapy

Commentary: A correlation has been demonstrated between the degree of ARV CNS penetration and HIV RNA levels in the CNS, as well as the frequency and severity of neurological manifestations, including HIV-associated dementia. The following ARVs possess good CNS penetration in children: zidovudine**, nevirapine**, efavirenz**, abacavir**, atazanavir**+ritonavir**, lamivudine**, lopinavir+ritonavir**; lower CNS penetration has been noted for tenofovir**, emtricitabine** [255, 256]. More detailed, updated information is presented in Table 21. Scale for assessing the degree of ARV CNS penetration in Appendix A3. Reference Materials.

3.3.2 Modification of ART regimens in case of adverse reactions and drug interactions

Assessment of the safety of ongoing ART involves the prevention and detection of adverse reactions associated with antiretroviral drugs, as well as management tactics for the child should they occur.

Commentary: The following adverse reactions are distinguished during ART in children:

— mitochondrial dysfunction (lactic acidosis, hepatotoxicity, cardiotoxicity, pancreatitis, peripheral neuropathy);

— metabolic disorders (lipid metabolism disorders - lipodystrophy, hyperlipidemia; hyperglycemia and insulin resistance);

— osteopenia, osteoporosis, and osteonecrosis;

— renal impairment;

— hematological disorders (anemia, neutropenia, and thrombocytopenia);

— allergic reactions (skin rashes and hypersensitivity reactions).

The last 2 groups of AEs are classified as rapid (usually manifesting in the first few weeks of treatment), while the rest are delayed.

Comment: In certain cases (toxic effects, drug interactions, lack of medication, etc.), a treatment regimen involving the temporary discontinuation of all drugs included in the ART combination may be used (in the absence of severe immunosuppression) to avoid the selection of resistant HIV strains. There is reliable data lacking regarding the duration of the interruption (without consequences for the patient), while continuing only one or two drugs may increase the replicative activity of the virus and contribute to the emergence of resistance mutations. Such an interruption is possible in extreme cases only under the monitoring of CD4+ lymphocytes and viral load in patients with moderate immunosuppression. If an NNRTI was part of the ART regimen, after its discontinuation it is recommended to continue 2 NRTIs for 10–14 days to avoid the monotherapy effect and the development of HIV drug resistance to NNRTIs (the elimination half-life of NNRTIs is significantly longer than that of other ARVs, which leads to the maintenance of low NNRTI levels — in the absence of other ARVs — within the zone of high selective pressure and the generation of resistance mutations).

When choosing the strategy of temporary discontinuation of all drugs, it should be taken into account that it is associated with a rapid increase in viral load and the potential rapid progression of HIV infection.

When modifying an ART regimen, it is necessary to review all other medications taken by the patient, taking into account potential drug-drug interactions.

The management strategy for a child presenting with signs of ARV toxicity/intolerance is outlined in Section 7. Additional Information.

[1] Decree of the Government of the Russian Federation No. 2203-r dated October 20, 2016, "On Approval of the State Strategy for Combating the Spread of HIV Infection in the Russian Federation for the Period up to 2020 and Beyond".

[2] Federal Law No. 323-FZ dated November 21, 2011, "On the Fundamentals of Healthcare Protection in the Russian Federation".

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation is a comprehensive set of medical and psychological measures aimed at the complete or partial restoration of impaired and/or compensation for lost functions of a damaged organ or body system, the maintenance of body functions during the resolution of an acute pathological process or an exacerbation of a chronic pathological process in the body, as well as the prevention, early diagnosis, and correction of potential functional disorders of damaged organs or body systems, the prevention and reduction of the degree of potential disability, the improvement of quality of life, the preservation of the patient's working capacity, and their social integration [304].

Medical rehabilitation is carried out in medical organizations and includes the combined use of natural therapeutic factors, pharmacotherapy, non-pharmacological therapy, and other methods [304]

The principle of medical rehabilitation is the comprehensive implementation of a patient-centered, problem-oriented, and multidisciplinary approach [305].

Comment. In HIV-infected children, pathological conditions caused by HIV infection—the neurotropism of the human immunodeficiency virus, the chronic course of the disease, chronic immune system activation, late initiation of antiretroviral therapy, prolonged use of drugs with an unfavorable metabolic profile, as well as concomitant diseases and conditions—are detected with high frequency. All organs and systems are involved in the pathological process in HIV infection, primarily the central nervous, cardiovascular, and respiratory systems. In early childhood, HIV encephalopathy manifests as psychomotor development delay; in adolescents, cognitive disorders (impairments in memory, attention, thinking), behavioral disorders, and mental disorders come to the forefront [306,407]. These pathological conditions lead to impaired formation and maintenance of medication adherence in the child, reduced efficacy of antiretroviral therapy, the development of immune deficiency, and the progression of HIV infection with an unfavorable outcome.

For sanatorium-treatment (spa) care in HIV-infected children, selection should be carried out on a general basis [1]. HIV infection in a child is not a direct indication for sanatorium-treatment care; however, given its multimorbid nature, sanatorium treatment is intended to exert a favorable effect on the course of HIV infection and comorbid diseases/conditions, promote the integration of children into the social environment, and positively influence adherence to monitoring and treatment.

[1] Appendix No. 3 to the Order of the Ministry of Health of the Russian Federation No. 1029n dated September 28, 2020, "On Approval of Lists of Medical Indications and Contraindications for Sanatorium-Treatment Care".

5. Prevention and Dispensary Observation

5.1. Prevention of mother-to-child transmission of HIV infection

Prevention of HIV infection in children implies, first of all, compliance with the PMTCT protocol, as well as the entire set of anti-epidemic measures provided for by sanitary rules and the legislation of the Russian Federation [1,259–261].

Prevention of mother-to-child transmission of HIV is a comprehensive task, the solution of which depends on the successful implementation of the following stages:

— primary prevention of HIV infection in women of reproductive age;

— early detection of HIV infection in women of childbearing age;

— prescribing ART to HIV-infected women planning pregnancy;

— prescribing ART to all HIV-infected pregnant women;

— choosing the mode of delivery depending on the woman's viral load levels prior to delivery;

— prescribing ART during labor;

— prescribing ART to the infant;

— avoiding breastfeeding;

— counseling the mother throughout pregnancy, during labor, and after the birth of the child on issues related to the prevention of mother-to-child transmission of HIV.

o maternal HIV infection [267–271,408] (A1);

o a positive rapid HIV test result in the mother [267–271,408] (A1);

o epidemiological indications [264,265] (C5).

Comment: Chemoprophylaxis of mother-to-child HIV transmission is carried out by prescribing ARVs to the woman during pregnancy and labor, as well as to the newborn. In exceptional cases (if the woman, contrary to recommendations, does not refuse to breastfeed the child), these drugs are prescribed for prophylactic purposes to the mother and/or the child during the breastfeeding period.

Epidemiological indications include:

— maternal parenteral drug use during pregnancy,

— regular unprotected sexual intercourse with an HIV-positive sexual partner who has a detectable or unknown HIV viral load level.

Comment: If more than 72 hours (3 days) have passed since the child's last possible exposure to infection (after birth or after the last breast milk feeding), prescribing chemoprophylaxis is inappropriate due to its ineffectiveness [369], since active viral replication in cells begins 24 hours after HIV enters the body [320].

• The stay in the maternity hospital of a post-partum woman with a positive rapid HIV test result and her newborn child is recommended to be extended until confirmatory HIV test results are obtained in order to determine further management tactics [1, 310,311, 312] (B3).

Recalculation of the ARV dose in a newborn should be performed at least once every 10 days.

The ART regimen for newborns should be determined taking into account maternal and infant factors that affect the risk of perinatal HIV transmission

Table 5. Dosage of #zidovudine** for chemoprophylaxis using a monotherapy regimen (oral or intravenous administration) (230, 307)

Comments. Criteria for low risk of mother-to-child HIV transmission:

— maternal receipt of ART during pregnancy;

— viral suppression in the HIV-infected mother by 36 weeks of pregnancy and/or within 4 weeks prior to delivery of less than 50 copies/mL.

Dosage of zidovudine** is provided based on the results of long-term studies on the pharmacokinetics, efficacy, and safety of zidovudine** in newborns, including premature infants [190,230,281,307,354-358].

Comment. Criteria for high risk of mother-to-child HIV transmission:

— mother did not receive ART during pregnancy;

— mother received ART during pregnancy, but viral suppression (HIV RNA <50 copies/mL) was not achieved by 36 weeks of pregnancy and/or within 4 weeks prior to delivery, or this screening was not performed or was only partially performed in the mother;

— presence of acute HIV infection in the mother during pregnancy or during breastfeeding;

— presence of HIV infection in a breastfeeding mother;

— a positive rapid test result was detected in the mother during labor (drug administration may be discontinued later if the presence of HIV infection is not confirmed by a standard method);

One of the factors ensuring very low rates of mother-to-child transmission (< 1%) is the high frequency of prescribing combination ART to newborns at high risk of HIV infection, including premature infants [273]. Presumptive HIV therapy serves, on the one hand, as the initiation of ART in those infants in whom HIV infection is subsequently confirmed, and on the other hand, it acts as effective post-exposure prophylaxis in infants at high risk of HIV infection, preventing infant HIV acquisition, as it is known that the majority of mother-to-child HIV transmission events occur before and during labor; breastfeeding significantly increases the likelihood of infant infection (by 16–30%).

In HIV-infected infants who initiated ART in the first hours after birth, a reduction in the size of viral reservoirs has been demonstrated, the disease has a more favorable course, the risk of central nervous system and cardiovascular system damage is reduced, and functional cure is achieved [321,322].

Zidovudine**, #lamivudine**, and nevirapine** are the most thoroughly studied and are recommended for use as part of presumptive therapy in newborns, including premature infants, at high risk of HIV infection.

Dosage of antiretroviral drugs is provided based on the results of long-term studies of pharmacokinetics, efficacy, and safety in newborns, including premature infants, for #lamivudine** [190,230,281,307,341-346,357-362]; zidovudine** [190,230,281,307,346,354-362]; nevirapine** [190,230,281,307, 357-365].

If the infant was put to the breast or fed with the milk of an HIV-infected woman, it is recommended to initiate prophylaxis within the first 6 hours after cessation of breastfeeding. At the same time, it is recommended to screen the infant for HIV nucleic acids as soon as possible (quantitative determination of human immunodeficiency virus type 1 (HIV-1) RNA in blood plasma by PCR; Determination of human immunodeficiency virus DNA by PCR, qualitative assay) and to continue prophylaxis only if negative test results are obtained. If two positive results are obtained, address the issue of initiating ART in the infant.

• #Abacavir** is not recommended as part of a routine presumptive HIV therapy regimen, but may be used in special situations [307-309] (C5).

Comment: in situations where zidovudine** is unavailable or the infant has zidovudine**-associated toxicity, abacavir** can be considered as an alternative to zidovudine**. This substitution should be considered when there may be an increased risk of zidovudine toxicity, for example, in young infants with anemia or neutropenia. In Russia, abacavir** is not approved for use in infants under 3 months of age. Sufficient data have been accumulated on the safety of #abacavir** in newborns and infants under 3 months of age [190,230,281,307,347-353]. WHO has approved the use of #abacavir** in term infants under 1 month of age at a dose of 2 mg/kg (single dose) administered twice daily. Prior to the use of #abacavir**, a negative test result for the HLA-B*5701 allele (determination of the HLA-B27 antigen by flow cytometry) must be confirmed (308,309).

Table 6. Dosage of #zidovudine**, #lamivudine**, and #nevirapine** in infants during a course of presumptive therapy (combination ART)¹(230,307)

Notes:

¹ these same antiretroviral drug doses are used when administering ART to infants under 4 weeks of age upon obtaining positive results from HIV nucleic acid testing.

² dosing recommendations were derived using pharmacokinetic modeling.

Table 7. Simplified schedule for #zidovudine** administration twice daily with a fixed single dose¹ (281,307)

Note: ¹ Used when adherence issues arise during a prophylactic course with a presumptive ART regimen.

Comment: It is important to evaluate the newborn at 21-28 days of age in order to decide, before the end of the course, whether to switch to therapeutic ART doses (in case of a positive test result for HIV nucleic acid by qualitative PCR assay for human immunodeficiency virus DNA ), or to complete the course at 6 weeks of age (in case of a negative test result for HIV nucleic acid by qualitative PCR assay for human immunodeficiency virus DNA ).

o continue #zidovudine** at the prescribed dose (see Table 6) until 4 weeks of age, and then switch to the doses presented in Table 8;

o prescribe #lamivudine** at the dose presented in Table 6 until 4 weeks of age, and then switch to the doses presented in Table 8;

o prescribe #nevirapine** at the dose presented in Table 6 until 2 weeks of age, and then switch to the doses presented in Table 8.

o it is possible to replace #nevirapine** with lopinavir/ritonavir** in term newborns from 14 days of life (42 weeks of gestation).

Comment: ARV doses should be modified according to age and gestational age.

o with #zidovudine** and #lamivudine** – up to 4 weeks of age, and then switch to the doses presented in Table 8;

o with #nevirapine** – up to 2 weeks of age, and then switch to the doses presented in Table 8, or to lopinavir/ritonavir**.

Comment: Immediate transition from presumptive therapy in an infant at high risk for HIV infection to HIV treatment upon confirmation of HIV infection plays a critical role, as it ensures sustained HIV suppression, helps reduce viral reservoirs, and prevents the formation of new reservoirs, leading to a favorable course of HIV infection (328). A gap between the prophylactic ART course and the initiation of treatment leads to uncontrolled activation of HIV replicative activity, a rapid increase in viral load, and the development of NNRTI drug resistance.

The dosing of ART is based on the results of long-term pharmacokinetic, efficacy, and safety studies in newborns, including premature infants, of lamivudine** (190,203,230,281,307,341-346,357-362); zidovudine** (190,230,281,307,346,354-362); nevirapine** (190,230,281,307, 357-365), taking into account Decree of the Government of the Russian Federation No. 1180-r dated May 16, 2022 (as amended by Decree of the Government of the Russian Federation No. 2064-r dated August 1, 2023) approving the List of Diseases or Conditions (Groups of Diseases or Conditions) in which the use of a medicinal product is permitted in accordance with the indications (characteristics) of the medicinal product not specified in the instructions for its use.

ARV doses should be modified according to age and gestational age.

Table 8. Dosing of #zidovudine**, #lamivudine**, and #nevirapine**, lopinavir/ritonavir** in children with confirmed HIV infection receiving combination ART (230,307)

Feeding of infants born to HIV-infected mothers

Comment: Putting an infant to the breast or feeding them breast milk from an HIV-infected woman increases the risk of HIV transmission. Additional risk factors during breastfeeding include nipple fissures, maternal breast abscess, and infant stomatitis. To prevent infection in infants born to HIV-infected women, they must be exclusively formula-fed after birth. Lactation suppression measures are carried out in agreement with the mother.

o prolong the prophylactic ARV course to 6 weeks in breastfed infants (LoE 2, GoR B) [268,273,281,366,367];

o prescribe #nevirapine** to a breastfed infant for the entire duration of breastfeeding plus 7 days after its complete cessation, if the mother is not receiving ART [268,273,281,366,367] (B2), see Table 9.

Table 9. Prophylactic dose of #nevirapine** in breastfed infants [281]

5.2. Prevention of Pneumocystis pneumonia and other opportunistic infections

Primary and secondary prophylaxis of secondary infections differ in timing and scope of interventions (see Table 15. Prophylaxis of the First Episode of Opportunistic Infections in HIV-Infected Children, Table 16. Prophylaxis of Recurrent Opportunistic Infections in HIV-Infected Children in Section 7. Additional Information).

o prescribe co-trimoxazole (Sulfamethoxazole+Trimethoprim)** in prophylactic dosages to all children born to HIV-infected mothers, starting from 6 weeks of age and until HIV infection is ruled out, in order to prevent diseases associated with protozoa (Pneumocystis and Toxoplasma) and bacteria (nonspecific respiratory and enteric pathogens);

o in children with confirmed HIV infection, use prophylactic co-trimoxazole (Sulfamethoxazole+Trimethoprim)** administration from 6 weeks to 12 months of age, and subsequently if CD4 counts drop to levels corresponding to severe immunodeficiency (continue until CD4 counts rise to the 2nd or 1st immune category, respectively).

Comment: Timely initiation of ART is a universal method of prevention and prognosis improvement in the treatment of secondary diseases and opportunistic infections. Primary prophylaxis of secondary infections is prescribed to prevent the first episode of infection, whereas secondary prophylaxis is prescribed after the resolution of an acute condition associated with a secondary disease to prevent recurrent episodes. The indication for secondary infection prophylaxis is a decrease in CD4 lymphocytes corresponding to the severe immunodeficiency criteria based on the child's age. It should be noted that in infants under one year of age, the incidence of opportunistic infections (particularly Pneumocystis pneumonia) does not correlate with CD4 counts.

5.3. Post-exposure prophylaxis of HIV infection: selection of ARV drugs in children

Post-exposure prophylaxis (PEP) in children refers to a set of interventions prescribed to prevent HIV transmission—in this context, following exposures not related to mother-to-child transmission [280]. Post-exposure prophylaxis is a reliable method for reducing the risk of infection when high adherence to treatment is maintained.

When providing post-exposure prophylaxis, follow the Sanitary Rules and Norms SanPiN 3.3686-21 "Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases", approved on January 28, 2021 [1].

o administer antiretroviral drugs to the child within the first two hours after exposure and no later than 72 hours [1,281,282,320,372-376] (C5);

o administer a 28-day course of ART using a regimen consisting of three ARVs [1,281,282,372-376] (B2);

o for children aged 12 years and older, prescribe: as the preferred backbone of the regimen – #TDF** + #3TC** or TDF+FTC [281,282,372,373,375,376] (B2); as the preferred third drug – #LPV+#/r** [281,282,372,373,375,376] (B2) or #DTG** [281] (C5); as an alternative third drug – #DRV** + #/r** or #ATV** + #/r** or #RAL** [281,282,372,373,375,376] (B2), provided they are available and there are no age restrictions;

o for children under 12 years of age, prescribe the preferred ART regimen #ZDV** + #3TC** + #LPV+r** [281,372-374,376] (B3) or #ZDV** + #3TC** + #DTG** [281] (C5); as an alternative third drug – #NVP [373,374] (B3) or #ATV** + #/r** [282] (B2) or #DRV** + #/r** [282] (B2) or #RAL** [281,372-376] (C5), depending on the child's age (see Table 3).

Comment: If indicated, PEP should be initiated as early as possible after the exposure has occurred. When prescribing HIV PEP, the patient is informed about the medications, and comorbidities and potential drug-drug interactions are assessed. The regimen is adjusted as additional information becomes available. When prescribing HIV PEP, efforts are made to enhance adherence to treatment and follow-up.

The use of abacavir** is limited by the necessity of screening for the human leukocyte antigen (HLA) class I B locus allele 5701 (HLA-B*5701).

5.4. Clinical follow-up and dispensary observation

Children at risk of HIV infection, as well as those with a confirmed diagnosis of HIV infection, are subject to dispensary follow-up.

The organization of dispensary follow-up is carried out in accordance with the registration group.

Dispensary Registration Group I

Contingents:

Children who are seropositive by EIA or CIA, but have negative or indeterminate immunoblot results, are subject to dispensary follow-up in Group I, excluding children with perinatal exposure born to HIV-seropositive mothers and children whose mothers have been diagnosed with HIV infection.

For detailed information, see SanPiN 3.3686-21 "Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases", Section VI "Prevention of HIV Infection" [1].

Dispensary Registration Group II

Contingents:

Children with HIV exposure involving a risk of HIV transmission are subject to dispensary follow-up in Group II, excluding children with perinatal exposure born to HIV-seropositive mothers and children whose mothers have been diagnosed with HIV infection.

For the selection of ARVs for PEP, see above. For detailed information, see SanPiN 3.3686-21 "Sanitary and Epidemiological Requirements for the Prevention of Infectious Diseases", Section VI "Prevention of HIV Infection" [1].

Dispensary Registration Group III

Contingents:

Children with a confirmed diagnosis of HIV infection are subject to dispensary follow-up in Group III.

The goal of dispensary follow-up for HIV-infected children is to increase their life expectancy and maintain its quality. The main objectives are to foster adherence to dispensary follow-up and antiretroviral therapy, timely identify indications for chemoprophylaxis and treatment of secondary diseases in patients, and ensure the provision of timely medical care, including psychological support and treatment of comorbidities.

Once a child is diagnosed with HIV infection, specialists at territorial AIDS prevention and control centers complete accounting form No. 311/u "Report on the Confirmation of Diagnosis in a Child Born to an HIV-Infected Mother". The heads of territorial AIDS prevention and control centers bear responsibility for the accuracy of completion. Within 10 days, accounting form No. 311/u is sent to the Federal State Institution "Research Clinical Institute of Pediatrics" of the Russian Ministry of Health. Subsequently, the form is submitted every 6 months [6].

Location of follow-up: AIDS Center or its branch.

Specialist performing dispensary follow-up: Pediatrician of the AIDS Center/branch, or in their absence, an infectious disease physician of the AIDS Center/branch.

Duration of dispensary follow-up: Lifelong.

Scope of dispensary follow-up:

Dispensary follow-up of children with HIV infection includes:

— clinical and laboratory examination upon enrollment and at designated intervals to assess the progression of HIV infection;

— prescription and administration of ART;

— assessment of the efficacy and safety of ART;

— detection, treatment, and prevention of secondary and comorbid conditions;

— measures to improve adherence to dispensary follow-up and ART.

Clinical, laboratory, and instrumental examinations are outlined in Section 2. Diagnosis of the Disease or Condition, Medical Indications and Contraindications for Diagnostic Methods, and Appendix B. Physician Action Algorithms.

Assessment of the efficacy and safety of ART is outlined in Section 2. Diagnosis of the Disease or Condition, Medical Indications and Contraindications for Diagnostic Methods, and Section 7. Additional Information.

The administration of ART is outlined in the following sections: 3. Treatment, Including Drug and Non-Drug Therapies, Dietotherapy, Pain Management, Medical Indications and Contraindications for Treatment Methods; 7. Additional Information, Appendix A3. Reference Materials, Including Conformity of Indications and Contraindications, Methods of Administration and Doses of Medicinal Products, Instructions for Medical Use of Medicinal Products; Appendix B. Physician Action Algorithms.

Prevention of Pneumocystis pneumonia is outlined in paragraph 5.2 of this section.

Measures to improve and assess adherence to dispensary follow-up and ART are outlined in Sections: 2. Diagnosis of the Disease or Condition, Medical Indications and Contraindications for Diagnostic Methods; 3. Treatment, Including Drug and Non-Drug Therapies, Dietotherapy, Pain Management, Medical Indications and Contraindications for Treatment Methods, 7. Additional Information; Appendices G1-G4. Rating Scales, Questionnaires, and Other Assessment Tools for Patient Status Provided in Clinical Guidelines.

Routine examinations of a patient by the physician responsible for monitoring an HIV-infected child within the framework of clinical observation of HIV-infected children are carried out:

— in the absence of ART: at least once every 3 months;

— during ART: at 2 and 4–8 weeks after the initiation of ART, then every 3 months;

— during ART in the remission phase upon achieving clinical, virological, and immunological effects for 2 years or more: at least once every 6 months (see Table 23 and Table 24) [1,10,19,101,202,203].

The decision to initiate ART is made:

— by the medical commission for ART prescription of the territorial AIDS center;

— taking into account the age of the child, the results of clinical, laboratory, and instrumental examinations, and counseling of parents/caregivers (see sections: 2. Diagnosis of HIV infection, medical indications and contraindications for the use of diagnostic methods; 3. Treatment, 7. Additional information);

— with the written consent of the child or their parents (see sections: 3. Treatment, including pharmacotherapy and non-pharmacological therapy, diet therapy, pain management, medical indications and contraindications for the use of treatment methods; Appendix A3. Reference materials, including compliance of indications and contraindications, routes of administration, and doses of medicinal products, instructions for medical use of the medicinal product).

IV clinical observation group

Contingents:

Children born to HIV-infected mothers who were seropositive during pregnancy and childbirth are subject to clinical observation in group IV.

Within 10 days after the birth of a child to an HIV-seropositive mother, accounting form No. 309/u "Notice of a newborn born to an HIV-infected mother", filled out by obstetrician-gynecologists in obstetric care facilities, is sent to the territorial AIDS Center. The territorial center for the prevention and control of AIDS sends accounting form No. 309/u to the Federal State Institution "Republican Clinical Hospital for Infectious Diseases" of the Russian Ministry of Health within 3 days [6].

Upon receiving documented confirmation of the absence of HIV infection within 10 days after the removal of the diagnosis, accounting form No. 310/u "Report on the removal from clinical observation of a child born to an HIV-infected mother", filled out by specialists of territorial centers for the prevention and control of AIDS, is sent to the Federal State Institution "Republican Clinical Hospital for Infectious Diseases" of the Russian Ministry of Health. This form is also filled out when the child leaves the region or in the event of their death (item 13 indicates the cause of death of the child).

Responsibility for the accuracy of completion lies with the chief physicians of the territorial centers for the prevention and control of AIDS [6].

Upon receiving documented confirmation of the presence of HIV infection, see Group III of clinical observation. Clinical observation of children with a confirmed diagnosis of HIV infection.

Place of observation: outpatient clinic at the place of residence jointly with the AIDS Center or its branch.

Specialist performing clinical observation: district pediatrician jointly with a pediatrician of the AIDS Center/or branch, or in their absence, an infectious disease physician of the AIDS Center/or branch.

Duration of clinical observation: until the diagnosis of HIV infection is ruled out, but for at least 6 months, or until the diagnosis of HIV infection is confirmed, followed by transfer to clinical observation group III for lifelong monitoring.

Scope of dispensary follow-up:

Clinical observation of children born to HIV-infected mothers who were seropositive during pregnancy and childbirth includes:

— implementation of prevention of perinatal HIV transmission in the child;

— clinical and laboratory examination at scheduled intervals aimed at early detection of HIV infection and early initiation of ART or ruling out HIV infection;

— prevention of Pneumocystis pneumonia in children under 12 months of age;

— removal from clinical observation of children with documented absence of HIV infection or transfer to clinical observation group III upon documented confirmation of HIV infection.

Prevention of perinatal HIV transmission in the child is outlined in clause 5.1. Prevention of mother-to-child transmission of HIV.

Clinical and laboratory examination is outlined in sections: 2. Diagnosis of HIV infection, medical indications and contraindications for the use of diagnostic methods and Appendix B. Physician Action Algorithms.

Prevention of Pneumocystis pneumonia is outlined in paragraph 5.2 of this section.

During the clinical observation of children born to HIV-infected mothers who were seropositive during pregnancy and childbirth, the following is carried out:

— examination and physical assessment: performed within 5 working days after discharge from the obstetric care facility, then every 10 days when recalculating ARV doses, and subsequently at each visit for HIV testing;

— counseling on adherence to clinical observation and ART: performed at each contact with the mother/caregiver;

— feeding counseling: performed in the obstetric care facility, and subsequently (in case of continued breastfeeding) at each contact with the mother, involving medical psychologists and peer counselors if necessary.

The decision on the documented absence of HIV infection is made:

— by the medical commission for removal from clinical observation of the territorial AIDS center;

— taking into account the age of the child, the results of clinical and laboratory testing, and the feeding method.

Removal from clinical observation:

1) Children of HIV-infected seropositive mothers examined by molecular methods at scheduled intervals who received exclusively formula feeding from birth

The removal of a child from clinical observation is carried out by a decision of the medical commission based on a set of data confirming the absence of HIV infection and the absence of the risk of HIV infection [1,10,19,101,202,203]:

— the child is older than 6 months;

— plus at least 2 negative results of testing for HIV nucleic acids using molecular biological blood testing for human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV-1) at scheduled intervals (the first result obtained at the age of not earlier than 6 weeks, the second not earlier than 4 months);

— plus two or more negative results of tests for HIV antibodies/antigens by ELISA/ECLIA (testing for the level of classes M, G (IgM, IgG) antibodies to human immunodeficiency virus HIV-1/2, p24 antigen (Human immunodeficiency virus HIV 1/2 + Agp24) in the blood) with an interval of at least 1 month, performed at the age of older than 6 months (while there is no pronounced hypogammaglobulinemia at the time of blood testing for HIV antibodies);

— plus there are no clinical manifestations that can be regarded as manifestations of HIV infection;

— plus the child was not put to the breast of an HIV-infected woman, and the risk of nosocomial/latrogenic transmission is excluded.

2) Children of HIV-infected seropositive mothers not examined by molecular methods who received exclusively formula feeding from birth

The removal of a child from clinical observation is carried out by a decision of the medical commission based on a set of data confirming the absence of HIV infection and the absence of the risk of HIV infection [1,10,19,101,202,203]:

— the child is older than 18 months;

— plus two or more negative results of tests for HIV antibodies/antigens by ELISA/ECLIA (testing for the level of classes M, G (IgM, IgG) antibodies to human immunodeficiency virus HIV-1/2, p24 antigen (Human immunodeficiency virus HIV 1/2 + Agp24) in the blood) with an interval of at least 1 month, performed at the age of older than 18 months (while there is no pronounced hypogammaglobulinemia at the time of blood testing for HIV antibodies);

— plus there are no clinical manifestations that can be regarded as manifestations of HIV infection;

— plus the child was not put to the breast of an HIV-infected woman, and the risk of nosocomial/latrogenic transmission is excluded.

3) Children of HIV-infected seropositive mothers who received breastfeeding

The removal of a child from clinical observation is carried out by a decision of the medical commission based on a set of data confirming the absence of HIV infection and the absence of the risk of HIV infection [1,10,19,101,202,203]:

— the child was not put to the breast and did not receive breast milk from an HIV-infected woman for the last 9 months;

— plus the child under the age of 18 months had negative results in molecular biological blood testing for human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV-1) at 4–6 weeks, 3 months, 6 months after cessation of breastfeeding and obtained at least 2 negative results of testing for HIV antibodies/antigens (testing for the level of classes M, G (IgM, IgG) antibodies to human immunodeficiency virus HIV-1/2, p24 antigen (Human immunodeficiency virus HIV 1/2 + Agp24) in the blood) (with an interval of at least 1 month and in the absence of pronounced hypogammaglobulinemia), performed at least 6 months after complete cessation of breastfeeding;

or

— the child over the age of 18 months obtained negative results of testing for HIV antibodies/antigens by ELISA/ECLIA (testing for the level of classes M, G (IgM, IgG) antibodies to human immunodeficiency virus HIV-1/2, p24 antigen (Human immunodeficiency virus HIV 1/2 + Agp24) in the blood) at 4–6 weeks, 3 months, 6 months after cessation of breastfeeding (while there is no pronounced hypogammaglobulinemia at the time of blood testing for HIV antibodies);

— plus there are no clinical manifestations that can be regarded as manifestations of HIV infection;

— plus the risk of artificial transmission is excluded.

The protocol of the medical commission meeting on removing a child with perinatal exposure to HIV infection from dispensary follow-up must contain: mother's ID data and child's data (surname, name, patronymic, date of birth, place of residence, epidemiological number); data on the nature of the provided PMPI; description of the type of feeding; data on the absence of clinical manifestations and laboratory abnormalities that can be regarded as manifestations of HIV infection; results of tests for HIV NA (at least two); results of tests for HIV antibodies (least two); results of tests confirming the absence of hypogammaglobulinemia; notes and recommendations; decision.

Group V of DF

Target populations:

Children of any age born to mothers with diagnosed HIV infection are subject to dispensary follow-up in Group V.

As a rule, this situation is possible when a mother contracts HIV infection in the late stages of pregnancy or during breastfeeding, which is associated with a high risk of infection of the fetus or child.

Place of follow-up: outpatient clinic at the place of residence in cooperation with the AIDS Center or its branch.

Specialist performing clinical observation: district pediatrician jointly with a pediatrician of the AIDS Center/or branch, or in their absence, an infectious disease physician of the AIDS Center/or branch.

Duration of DF: until the documented exclusion of HIV infection followed by removal from DF, or documented confirmation of the diagnosis of HIV infection followed by transfer to Group III of DF.

Scope of dispensary follow-up:

Dispensary follow-up of children born to mothers with diagnosed HIV infection includes:

— if the child is being breastfed — immediate cessation of breastfeeding and immediate prescription of a 6-week course of preventive therapy using 3 ARV drugs (the child belongs to the high-risk group for HIV infection); the choice of drugs is made in accordance with the child's age, see cl. 5.3. Post-exposure prophylaxis of HIV infection: choice of ARV drugs in children and Section 3. Treatment, including drug and non-drug therapies, diet therapy, pain management, medical indications and contraindications for the use of treatment methods;

— clinical and laboratory examination aimed at detecting HIV infection and initiating ART, or at excluding HIV infection;

— prevention of Pneumocystis pneumonia in children under 12 months of age;

— removal from DF of children with documented absence of HIV infection or transfer to Group III of DF with documented confirmation of HIV infection.

Clinical and laboratory examination is outlined in sections: 2. Diagnosis of HIV infection, medical indications and contraindications for the use of diagnostic methods and Appendix B. Physician Action Algorithms.

Prevention of Pneumocystis pneumonia is outlined in paragraph 5.2 of this section.

Testing for HIV infection:

— if the child is under 18 months of age, testing for HIV infection is prescribed in the same way as in children of seropositive mothers — using molecular diagnostic methods (molecular biological examination of blood for human immunodeficiency virus HIV-1) and taking into account breastfeeding;

— if the child is older than 18 months and more than 6 months have passed since the last intake of maternal breast milk, testing for HIV antibodies using standard ELISA/ECLIA methods (determination of the level of classes M, G (IgM, IgG) antibodies to human immunodeficiency virus HIV-1/2, p24 antigen in the blood) is performed once (and if the child is under 3 years old, it is recommended to test for HIV antibodies at the age of 3 years).

The decision on the documented absence of HIV infection is made:

— by the medical commission for removal from clinical observation of the territorial AIDS center;

— taking into account the age, clinical and laboratory test results, and the type of feeding of the child.

The procedure for removal from DF — see the corresponding situation in Section Group IV of DF. Dispensary follow-up of children with perinatal exposure born to HIV-infected seropositive mothers.

6. Organization of Medical Care

Primary specialized health care for children is provided by infectious disease specialists and/or pediatricians of the AIDS Center in cooperation with primary care pediatricians.

Specialized medical care for HIV infection in inpatient settings for children with HIV infection and children born to HIV-infected mothers is provided in obstetric-gynecological and pediatric inpatient departments, as well as in the inpatient facility of a medical organization providing specialized medical care for the profile "infectious diseases" in beds allocated for these purposes.

Indications for the provision of specialized medical care for the profile "infectious diseases" (hospitalization of the patient) for HIV infection are:

— the need for diagnosis and treatment of secondary diseases in cases where outpatient treatment is impossible, including those requiring patient isolation (except for tuberculosis, hematological, and oncological diseases) — stages 2B, 4B, 4C (progression phase), 5;

— prescription or adjustment of the ART regimen in severe immunosuppression with a high risk of developing a severe "immune reconstitution inflammatory syndrome");

— the need for examinations that cannot be performed on an outpatient basis, including instrumental (invasive, radiological) examinations when establishing the stage of HIV infection;

— conducting differential diagnosis of secondary and somatic diseases, organization of medical and social expert evaluation;

— conditions requiring medical care due to the development of severe adverse events during ART;

— the need to monitor and improve adherence to follow-up and treatment, with a comprehensive assessment and correction of CNS and psychosocial disorders, including neuroimaging diagnostic studies, clinical-psychological, neuropsychological, and social examinations; development and implementation of comprehensive rehabilitation measures aimed at psychocorrection of cognitive parameters, behavioral disorders, and socialization of children and adolescents;

— the presence of other indications, including social ones (children left without parental care before placement in an infant home, pregnant women to ensure adherence to three-stage prophylaxis, etc.).

For children with HIV infection, specialized medical care associated with the manifestation of HIV infection (in secondary diseases) is provided in inpatient settings by infectious disease specialists in cooperation with pediatricians based on clinical guidelines (treatment protocols), as well as taking into account standards and procedures for medical care.

Indications for patient discharge are the achievement of the objectives set upon hospitalization or a justified decision on the inexpediency of further stay in an inpatient setting:

1. achievement of remission or stabilization of the course of HIV infection;

2. completion of differential diagnosis and determination of treatment tactics, or cure of the secondary/concomitant disease;

3. management of adverse events associated with ART;

4. completion of a course of measures aimed at the psychocorrection of cognitive and behavioral disorders and socialization with the formation of recommendations for the patient's further routing;

5. completion of the planned medical and social expert evaluation;

6. the decision on the inexpediency of further stay in inpatient conditions made by the medical commission.

7. Additional Information

7.1. Characteristics of ART in children

Two goals of ART in children are distinguished: the first is to increase life expectancy and improve its quality by creating conditions for the formation, preservation, and restoration of the immune system and preventing clinical progression of the disease, and the second is to prevent the transmission of HIV infection in the population.

Reduction in AIDS-related mortality. To date, HIV infection remains an incurable disease, and viral eradication cannot be achieved. The only specific method of treating HIV infection today is lifelong ART. Antiretroviral drugs block HIV replication, which manifests as a decrease in the viral load in the blood down to an undetectable level. This leads to the restoration of the CD4 lymphocyte subpopulation and/or the prevention of immunodeficiency development and, consequently, to the prevention of the onset or alleviation of the course of secondary diseases. As a result, the patient's quality of life improves and life expectancy increases. ART is administered for life, without scheduled breaks or drug discontinuation.

Reduction in morbidity. An equally important task of ART is the prevention of the horizontal spread of HIV infection, as well as vertical transmission from mother to child.

ART consists of a combination of antiretroviral drugs that disrupt the viral life cycle. HIV has high replicative activity and variability, i.e., the ability to vary its RNA and thus develop viable mutations in the presence of ARV drugs. An effective way to suppress HIV replication long-term and overcome the development of resistance to ARV drugs is to prescribe combination ART regimens, foster high patient adherence to treatment without missing doses or violating the dosing schedule, and monitor adverse therapy effects that may lead to patient refusal of therapy.

Currently, the following classes of ARV drugs are used to treat HIV infection in children in Russia:

— nucleoside and nucleotide reverse transcriptase inhibitors. They act at an early stage of viral replication and inhibit viral DNA synthesis: abacavir**, zidovudine**, lamivudine**, emtricitabine**, tenofovir disoproxil fumarate**, tenofovir alafenamide (as part of a fixed-dose combination drug), phosphazide**;

— non-nucleoside reverse transcriptase inhibitors: nevirapine**, efavirenz**, etravirine**, rilpivirine (** as part of a fixed-dose combination drug);

— HIV integrase inhibitors. They prevent the integration of HIV DNA into the host cell's genetic material: raltegravir**, dolutegravir**, elvitegravir** (as part of a fixed-dose combination drug), bictegravir** (as part of a fixed-dose combination drug);

— protease inhibitors. They act at a late stage of viral replication and inhibit the maturation of viral mRNA: atazanavir**, darunavir**, lopinavir**, ritonavir**, fosamprenavir**.

Guidelines for dose calculation and determining the ARV administration schedule in children

ARVs are prescribed to children strictly at an age-appropriate therapeutic dose, or the single and daily doses for each drug are calculated based on the child's body weight (mg/kg) or body surface area (mg/m²). It is important to stick to the standard calculation method to facilitate any necessary adjustments.

For children, calculating the drug dose per square meter of body surface area is more accurate and is performed using nomograms to calculate body surface area from weight and height according to the Mosteller formula:

ARV doses should be adjusted (without exceeding acceptable therapeutic limits) when body weight changes by 10% or more; otherwise, drug pharmacokinetics will become insufficiently effective over time, which may lead to the emergence of resistant HIV strains.

It is necessary to clearly establish the times at which medications will be administered (separately for each drug): for once-daily dosing, the drug is given every 24 hours; for twice-daily dosing, every 12 hours.

If there is suspicion of potential non-adherence to the dosing schedule or if poor ART adherence is identified, preference should be given to simple regimens with a small number of medications, a high barrier to resistance, and the lowest possible side effects.

Untimely administration or missing a dose of the medication is unacceptable. Selecting drugs with synchronized administration times helps improve treatment adherence.

When prescribing ARVs to children, it is necessary to consider the specifics of administration in relation to meals (e.g., PIs must be given to the child with food). Some ARVs cannot be given together; others cannot be taken with antacids or antituberculosis drugs. Most ARVs should not be washed down with grapefruit juice. Before prescribing ARVs, the instructions and recommendations for their use must be thoroughly studied.

Readministration of ARVs is permitted in case of vomiting, which is a frequent side effect of most ARVs in children (especially infants and young children) during the first days (sometimes weeks) of treatment. This side effect should not be the reason for immediately discontinuing treatment. As practice shows, children adapt well over time to taking ARVs even with unpleasant tastes. If vomiting occurs less than 30 minutes after taking the drug, a full single dose must be given again.

In the first days of treatment, ARVs should be administered (potentially concurrently) with an interval of approximately 30 minutes; then, as the child gets used to it, the interval between different drugs should be reduced to a few minutes. Do not mix different liquid and powder formulations of ARVs in the same container!

Keeping a diary, especially in the first months of treatment, in which the child, their parents, or caregivers record all administered ARV doses and note all side effects of therapy, significantly helps the attending physician assess the safety and efficacy of therapy and make timely adjustments if necessary.

Pros and cons of ARVs of different classes

Table 10. Advantages and disadvantages of various ARVs

ART Failure in Children

When assessing the causes of ART failure in children, unlike adults, the following factors must be considered: dependence on adults; organoleptic properties of ARVs; unstable pharmacokinetics; and difficulties in achieving high adherence, particularly during adolescence. Identified failure in the setting of insufficient ART adherence is not always accompanied by the development of resistance: achieving high treatment adherence may allow for the preservation of the current ART regimen. Confirmed failure of ongoing therapy is an indication for switching to the next-line ART regimen.

Main Causes of Virological ART Failure

1. ART adherence-related:

— presence of conditions/diseases that impair the ability to adhere to the ART regimen (mental disorders, neurocognitive impairment, gastrointestinal mucosal lesions, swallowing disorders, etc.);

— psychosocial factors;

— unavailability of ARVs (inability to obtain them on time, stockouts, etc.);

— adverse reactions to ARVs;

— adverse events;

— high pill burden or dosing frequency.

2. HIV-related:

— infection with an ARV-resistant HIV strain;

— prior ART failure;

— natural resistance of the HIV strain to ARVs;

— high viral load before ART initiation and inadequately selected ART regimen.

3. ART-related:

— suboptimal pharmacokinetics, frequently observed in younger children;

— insufficient antiretroviral activity of the ART regimen;

— low genetic barrier to ARV resistance;

— step-by-step (add-on) addition of drugs to the ART regimen;

— non-compliance with dietary restrictions;

— non-compliance with time intervals between ARV doses;

— drug-drug interactions;

— incorrectly calculated doses.

Reducing the Risk of Adverse Reactions to ART in Children

Differential diagnosis of complications arising in children during ART is challenging due to the complex nature of their development (in particular, the effects of the human immunodeficiency virus itself, drug toxicity, congenital anomalies and diseases, lack of clear diagnostic criteria, and insufficient data accumulated on the use of latest-generation ARVs in children). Nevertheless, factors contributing to a reduced risk of ART side effects can be identified:

— identification of predispositions/risk factors;

— identification and evaluation of the course of comorbid and secondary HIV-related diseases;

— careful selection of ARVs taking into account the child's age and the parameters indicated above;

— prescription of drugs from the preferred category;

— correct selection of drug dosage and dosing frequency;

— assessment of potential drug-drug interactions;

— clinical and laboratory monitoring of the safety of ART and concomitant therapy;

— clinical, immunological, and virological monitoring of the efficacy of ongoing ART.

Before initiating ART, counseling is conducted with parents/caregivers and the children themselves regarding potential side effects of therapy and the possibility of immune reconstitution inflammatory syndrome (IRIS):

— it is explained that at the beginning of therapy, all ARVs typically cause transient side effects: nausea, vomiting, diarrhea;

— the causes of potential side effects and main management strategies are explained: symptomatic therapy, adjustment of the dosing regimen, psychological support;

— symptoms of potential severe, life-threatening adverse reactions and the action plan in the event of their occurrence in the child are discussed.

Management Tactics for a Child Presenting with Signs of ARV Toxicity/Intolerance

— In the event of life-threatening side effects, all drugs are discontinued immediately (simultaneously). It is strongly recommended to hospitalize the child in an intensive care unit. After the complete resolution of symptoms, ART may be resumed; the drug associated with the reaction must be replaced with one having a different toxicity profile. If a hypersensitivity reaction develops, that drug must never be prescribed again.

— In the event of moderate adverse reactions, therapy may be continued until causal relationships are established, after which the drug that caused the adverse reaction is replaced.

— In the event of mild adverse reactions, symptomatic treatment is prescribed, and ART may be continued.

— Before deciding to change a drug, it is recommended to recalculate the dose prescribed to the child and ensure it lies within the therapeutic range. If it is impossible to determine which specific drug is causing the pronounced side effect, the entire regimen should be changed. When changing therapy, it is recommended to avoid combinations of drugs that cause similar adverse reactions. To prevent ARV side effects or when they appear, the age-appropriate therapeutic dose should not be reduced.

7.2. ART and follow-up adherence and assessment of ART adherence

High ART efficacy is attributed to the potent antiretroviral potential of modern drugs used to treat HIV infection: highly active ART regimens maintain viral loads below the detectable level in 95% of patients for 4 ^years or more [283]. When ART adherence drops below 95%, the rate of emergence of ARV resistance mutations can reach 50% [283]. A complete and sustained ART effect is possible only with a high level of adherence to treatment and follow-up [284–287].

Adherence is "the extent to which a patient's behavior—taking medications, following diets, executing lifestyle changes—corresponds with agreed recommendations from health care providers" [288].

The concept of adherence in HIV infection includes:

— ART adherence — the patient's willingness and ability to initiate and take all medications of the prescribed ART regimen at the scheduled time, with the established frequency, and fulfilling all necessary requirements for ARV administration as prescribed by the attending physician;

— treatment adherence — the degree of the patient's participation in their own treatment process;

— compliance — the degree to which a patient's behavior matches clinical guidelines.

The lowest level of follow-up and ART adherence is observed among adolescents, which requires special approaches and efforts from the staff of medical organizations providing care to HIV-infected children, since the consequences of low adherence are low rates of morbidity decline among adolescents and increased mortality [284–287]. For adolescents, everyday life factors, as well as psychosocial and medical factors, are of significant importance [289].

The consequences of reduced and, in particular, low ART adherence are:

— inadequate ARV levels, in the presence of which the virus multiplies and ARV-resistant viral variants emerge;

— increased hospitalization rates;

— reduced treatment efficacy;

— progression of immunodeficiency, increased likelihood of HIV disease progression and death;

— the need to prescribe second- and subsequent-line ART regimens, the cost of which typically significantly exceeds the cost of the first-line therapy regimen;

— continued spread of HIV in the population.

The most important regimen in a patient's life is first-line ART, which, with careful drug selection and ongoing work with the patient on adherence, can remain successful for many years. When selecting a starting ART regimen in children, preference should be given to once-daily drugs with good palatability, fixed-dose combinations, and child-friendly dosage forms, which helps increase the duration of maintaining this regimen [290].

Factors Affecting Adherence

There is a large number of factors that can affect the level of ART adherence, both impairing it and improving it.

Improving ART adherence and retention in care requires identifying and understanding all potential barriers a patient may face, as well as developing methods and approaches to overcome these barriers. When providing ART to children, adherence should be assessed both from the child's perspective and from that of their caregivers.

A significant (p=0.001) positive effect on ART adherence is exerted by the following factors:

— pronounced effect: self-monitoring of adherence;

— moderate effect: trust in the healthcare provider, understanding by the patient of the necessity and benefits of ART, and social support;

— minor effect: age and male gender.

A significant (p=0.001) negative effect on ART adherence is exerted by the following factors:

— moderate effect: substance use, cautious attitude of the patient towards ART, symptoms of depression, and stigma;

— small effect: presence of protease inhibitors in the ART regimen, frequency of ARV intake, financial constraints of the patient;

— minor effect: pill burden and disease duration.

CD4 count (p=0.64) and ART duration (p=0.92) did not have a statistically significant effect on ART adherence [291].

Thus, predictors of ART adherence are diverse factors spanning three main domains: biomedical, socio-economic, and individual psychological.

Diagnostics and methods for assessing adherence and factors influencing adherence

Methods used in clinical practice to assess treatment adherence have their advantages and disadvantages. The most reliable method is measuring viral load; however, this often detects the consequences of poor adherence, sometimes too late, after resistance to ARVs has already developed. Table 11 presents the characteristics of various methods for assessing ART adherence [286].

Table 11. Characteristics of various methods for assessing treatment adherence

The prevalence of neurocognitive disorders in HIV-infected children is up to 37% in the mild and moderate stages of HIV infection and up to 60% in the advanced clinical/AIDS stage. Psychological assessment is conducted by the attending physician, medical psychologist, or psychotherapist, and includes mandatory diagnosis of anxiety/depression, cognitive disorders, and assessment of the quality of life either of the child themselves or of the child's legal representative (see Table 12). After completing a corrective course—including medical (including psychiatric) care, psychological correction, and social adaptation—re-evaluations are performed (see sections: 2.5. Other diagnostic studies; Appendix B. Physician action algorithms; Appendices G1–G4. Assessment scales, questionnaires, and other patient status assessment tools).

In the absence of anxiety and depression, a comprehensive clinical-psychological and neuropsychological assessment aimed at detecting impairments in cognitive functions such as attention, memory, thinking, and speech should be performed once every 6 months in HIV-infected children aged 11 years and older, or in the legal representatives of children under 11 years of age.

Table 12. Age-related features of psychological test use in children

Classification of HIV-associated neurocognitive disorders (HAND) (Frascati criteria 2007) [292,293]

I. Asymptomatic neurocognitive impairment (ANI)

1. Acquired cognitive impairment of at least 1 SD (standard deviation) below the demographic mean normative value in at least 2 cognitive domains:

— Attention/working memory;

— Verbal/language;

— Abstraction/executive function;

— Complex perceptual-motor skills;

— Memory, including learning and recall;

— Simple motor skills or sensory perceptual abilities;

— Information processing speed.

2. Cognitive impairment does not affect daily activities

3. Cognitive impairment does not meet the criteria for delirium or dementia

4. Other causes have been ruled out

II. Mild neurocognitive disorder (MND)

1. Acquired cognitive impairment of at least 1 SD (standard deviation) below the demographic mean normative value in at least 2 cognitive domains:

— Attention/working memory;

— Verbal/language;

— Abstraction/executive function;

— Complex perceptual-motor skills;

— Memory, including learning and recall;

— Simple motor skills or sensory perceptual abilities

— Information processing speed.

2. Cognitive impairment results in at least mild impairment of daily activities (at least 1 of the following):

— Self-report of decreased mental capacity, impairment in occupational performance, household chores, or socialization

— Reports from others regarding a decrease in the patient's mental capacity leading to impairment in occupational performance, household chores, or socialization.

3. Cognitive impairment does not meet the criteria for delirium or dementia

4. Other causes have been ruled out

III. HIV-associated dementia (HAD)

1. Severe acquired cognitive impairment involving at least 2 domains (usually impairments in multiple domains, especially new learning, slowed information processing, attention/concentration deficits). Cognitive impairment must be assessed using neuropsychological tests and show ≥2 SD (standard deviation) below the normative mean for the corresponding demographic in at least 2 cognitive domains:

— Attention/working memory;

— Verbal/language;

— Abstraction/executive function;

— Complex perceptual-motor skills;

— Memory, including learning and recall;

— Simple motor skills or sensory perceptual abilities

2. Cognitive impairment results in significant impairment of daily activities (work, domestic life, social activity)

3. Cognitive impairment does not meet the criteria for delirium or dementia

4. Other causes have been ruled out

Methods for improving ART adherence and retention in care

HIV infection is a chronic disease requiring lifelong treatment, during which treatment fatigue is almost inevitably encountered. High treatment adherence is not an outcome, but a process that requires ongoing effort from both the patient and healthcare providers, psychological support staff, and other care providers. Table 13 lists the main practical methods for overcoming adherence barriers [294], and Table 14 outlines strategies aimed at establishing, maintaining, and correcting treatment adherence [294].

Table 13. Practical methods for overcoming ART adherence barriers

Methods for improving adherence to pharmacotherapy, medical follow-up, and lifestyle modification depending on the level of assessed adherence can be found in Section XIX. Appendix G2. Assessment scales, questionnaires, and other tools for evaluating the patient's condition provided in the clinical guidelines.

Table 14. Strategies aimed at engagement and retention in care, and improving ART adherence [294]

7.3 Prevention of secondary infections in HIV-infected children

Table 15. Prophylaxis of the first episode of opportunistic infections in HIV-infected children [101]

• All patients with HIV infection are recommended influenza A and B prophylaxis (C5) [101] as follows:

o Initiation and discontinuation of pre-exposure prophylaxis in children with clinical categories 3 and 4 according to epidemiological indications

o Initiation of post-exposure prophylaxis:

· Children with clinical categories 3 and 4

· Children with clinical categories 1 and 2 if vaccination is not feasible

o Drugs

· #Oseltamivir**: > 3 months < 1 yr: 3 mg/kg q.d. (# for children under 1 year of age) [409]; ≥ 1 yr – 12 yrs: ≤ 15 kg – 30 mg q.d., >15–23 kg – 45 mg q.d., >23–40 kg – 60 mg q.d., >40 kg – 75 mg q.d.; > 13 yrs: 75 mg q.d.

· Zanamivir: ≥ 5 yrs – 10 mg (2 inhalations) q.d.

o Start within 48 hours after exposure

o Continue for 7 days after household exposure, 14 days after exposure in a group/community setting

o If a vaccine was administered after exposure, chemoprophylaxis should be continued for 2 weeks post-vaccination.

Table 16. Secondary prophylaxis of opportunistic infections in HIV-infected children [101]

Criteria for Evaluating the Quality of Medical Care

Quality of care criteria for primary health care in children with HIV infection (ICD-10 codes: B20, B21, B22, B23, B24, R75, Z21, Z20.6)

Quality assessment criteria for specialized medical care for children with HIV infection (ICD-10 codes: B20, B21, B22, B23, B24, R75, Z21, Z20.6)

References

Appendix A1. Working Group Composition

*member of the National Association of Specialists in the Prevention, Diagnosis, and Treatment of HIV Infection.

Conflict of Interest. All Working Group members have confirmed no financial support/conflict of interest to disclose.

Appendix A2. Methodology for Developing Clinical Guidelines

The clinical guidelines were developed to establish uniform organizational and methodological approaches to diagnostic algorithms, management, and treatment of children with HIV infection in the Russian Federation.

Objectives of the Guidelines:

• implementation of modern, evidence-based organizational algorithms for the diagnosis of HIV infection for early active detection and the use of antiretroviral drugs to reduce mortality, improve quality of life, and increase life expectancy in children with HIV infection;

• expanding the coverage of dispensary monitoring and ART in HIV-infected children, increasing its efficacy and safety;

• providing data on recommended antiretroviral drugs and pharmacoeconomically sound ART regimens used for the treatment of HIV-infected children in the Russian Federation;

• establishing a unified approach to prescribing preferred first-line ART regimens to ensure maximum therapeutic efficacy, high adherence, and low probability of adverse events and pathogen resistance;

• introducing uniform criteria for assessing the efficacy of ongoing ART;

• reducing patient contagiousness and, consequently, decreasing the risk of infection spread and the activity of the HIV epidemic process in the Russian Federation;

The Guidelines take into account the requirements and provisions stipulated by the Procedure for the Provision of Medical Care for Disease Caused by the Human Immunodeficiency Virus (HIV Infection) and the Standards of Medical Care for Children with Disease Caused by the Human Immunodeficiency Virus (HIV Infection).

Clinical guidelines for the diagnosis, monitoring, and treatment of HIV infection in children are intended for directors and physicians of AIDS centers, infectious disease specialists and pediatricians involved in the care of HIV-infected patients, students, clinical residents, PhD students, and faculty of state higher and secondary professional education institutions.

Target audience for these clinical guidelines: specialists with higher medical education in the following specialties:

1. Infectious Diseases

2. Pediatrics

3. Neonatology

4. General Practice (Family Medicine)

5. Obstetrics and Gynecology

6. Epidemiology.

The clinical guidelines can be used in the development of training and methodological packages for the training and professional development of physicians.

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.

The clinical guidelines were formulated through expert consensus based on clinical experience in pediatric HIV infection. The evidence base for the recommendations includes publications from the Cochrane Library, EMBASE, PUBMED, and MEDLINE databases. All recommendations are ranked according to international criteria for levels of evidence (reliability) and grades of recommendation (convincingness) depending on the quantity and quality of studies on the issue.

Table 17. Scale for grading levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 18. Scale for grading levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 19. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Therapeutic doses of ARVs in children

(ARV doses for ART courses in newborns for PMTCT are discussed in section 5.1. Prevention of Mother-to-Child Transmission of HIV)

ARVs registered in the Russian Federation are listed in accordance with the State Register of Medicines as of October 2020.

ARV dosing data are presented in accordance with current instructions for medicinal products registered in the Russian Federation, as well as taking into account ARV dosing recommendations for children approved by the FDA and recommended by PENTA based on clinical trial results and practical experience.

The package insert included with any ARV should be carefully reviewed before prescribing.

Dose recalculation in children is performed when body weight changes by 10%.

BSA should be calculated using the Mosteller formula:

Table 20. Recommended therapeutic doses of ARVs in children and specific aspects of their use

2. Assessment of ARV CNS penetration score

Table 21. ARV CNS penetration effectiveness score [410,411]¹

Notes: ¹ ARVs specified in these clinical guidelines are presented; ² level 4 corresponds to the highest degree of penetration, level 1 to the lowest; ³ as part of the combined antiviral drug rilpivirine+tenofovir+emtricitabine**; ⁴ as part ofೀರ್ the combined antiviral drug cobicistat+tenofovir alafenamide+elvitegravir+emtricitabine**

3. Diagnosis of HIV infection

Table 22. Recommended diagnostic methods for HIV infection in children of various categories

Notes:

¹ - Determination of antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV 1) in blood; Determination of antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-2 (Human immunodeficiency virus HIV 2) in blood; Testing for antibodies of classes M, G (IgM, IgG) to human immunodeficiency virus HIV-1/2 and antigen p24 (Human immunodeficiency virus HIV ½ + Agp24) in blood; Determination of human immunodeficiency virus HIV-1 antigen p24 (Human immunodeficiency virus HIV-1) in blood

² - Molecular biological blood test for human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV-1); Determination of human immunodeficiency virus DNA by PCR, qualitative assay; Quantitative determination of human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV-1) RNA in blood plasma by PCR

4. Monitoring of a child with HIV infection

Table 23. Schedule and scope of examination of an HIV-infected child during monitoring, initiation, and administration of ART¹

Notes:

¹ Examination of children under 1 year of age is carried out monthly (infants in their 1st month of life every 10 days). Examinations are performed by the district pediatrician and pediatric specialists of the outpatient clinic, as well as within the framework of specialized medical care.

² Results of tests obtained at designated intervals during follow-up prior to treatment initiation may be used

³ Dispensary follow-up of children without immunodeficiency, in remission on ART and with stable suppression of HIV VL for more than 2 years may be carried out once every 6 months

⁴ Physical examination with assessment of physical development (body weight, height, indices)

⁵ X-ray examination is performed in adolescents with HIV infection starting from 15 years of age twice a year

⁶ The study includes: general clinical blood chemistry test, test panels to assess the degree of hepatocellular insufficiency, to assess liver cell damage (degree of cytolysis), and to assess cholestatic syndrome

** The test is performed when clinically indicated

5. Assessment of ART Efficacy and Safety in Children

Table 24. List of minimum requirements for clinical and laboratory assessment of ART efficacy and safety in children

Notes

¹ in children receiving nevirapine**, serum transaminase levels are tested every 2 weeks during the first month of treatment, then once a month for the next 3 months, then every 3 months

² evaluation of lipid metabolism disorders is recommended to be performed every 12 months from the start of ART

³ in the presence of clinical and immunological efficacy of cART (VL <50 copies/ml for at least 96 weeks, CD4 lymphocyte count corresponding to the ^1st immune category), high adherence to treatment and follow-up

SAMPLE

6. Informed Consent for Antiretroviral Therapy in a Child with HIV Infection Under 15 Years of Age

(signed by the legal representative caring for the child)

with medicinal products aimed at preventing the progression of the disease caused by the human immunodeficiency virus.

I confirm that it has been explained to me:

· why this treatment is necessary for my child;

· the action of the medications prescribed to my child;

· how the prescribed medications must be administered to my child;

· potential side effects of the medications prescribed to my child;

· that my child must undergo regular examinations, including blood tests, to monitor the course of HIV infection and the prescribed treatment, and to detect potential drug side effects;

· the schedule according to which I must bring the child for examination;

· that the therapeutic effect can be achieved through strict compliance with all recommendations given to me by my child's attending physician.

I realize that:

· based on my child's health status, they need treatment for HIV infection;

· medications prescribed to my child must suppress viral replication in their body and slow down the progression of HIV infection;

· the better I adhere to the medication regimen for my child, the higher the likelihood of increasing their life expectancy and quality of life;

· even with absolute compliance by me with all rules for administering medications to my child, a cure for HIV infection will not occur;

· the treatment prescribed to my child may be discontinued at any time at my request;

· if a threat to my child's health arises as a result of the treatment, I will be informed thereof to make a decision on the advisability of its continuation;

· if a threat to my child's life arises as a result of the treatment, this treatment may be discontinued by decision of the attending physician. In this case, the reasons for this decision must be explained to me;

· all medicinal products prescribed to my child are approved for use in Russia;

· as with any medicinal product, the drugs prescribed to my child may cause certain adverse reactions, information about which has been provided to me by my attending physician;

I undertake to:

· bring my child for medical examinations according to the established schedule to monitor the effects of the drugs prescribed to them, fill out the questionnaires provided for this purpose, and give consent for blood collection for laboratory tests;

· administer the medicinal products prescribed to my child strictly in accordance with the attending physician's prescription;

· follow the attending physician's recommendations regarding the care and feeding of my child;

· inform the attending physician of any non-adherence to the prescribed medication regimen or discontinuation of treatment for any reason;

· inform the attending physician of any changes in my child's state of health and do so immediately (within 24 hours) if I believe these changes are related to the medications prescribed to my child;

· not administer any medicinal products to my child or give them vaccinations without consulting the attending physician (even if medications and vaccinations are prescribed by another doctor). If the administration of such medications is unavoidable (e.g., in emergency cases), inform the attending physician immediately;

· inform the physician who prescribed medications to my child in an emergency case that the child is receiving drugs for the treatment of HIV infection.

SAMPLE

7. Informed 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

(signed by the legal representative caring for the child)

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 of 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, anamnesis collection.

2. Examination, including palpation, percussion, auscultation, vaginal examination (for women), rectal examination.

3. Anthropometric studies.

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 diagnostic methods, including fluorography (for individuals over 15 years of age) and 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)}

By the medical worker _____________________________________________________________________________

(position, full name of the medical worker)

my child's state of health and diagnosis have been explained to me in an accessible form, and the goals, nature, and necessity of diagnostic and therapeutic measures have been outlined. It has been explained that the antiretroviral therapy proposed for my child is aimed at suppressing the replication of the human immunodeficiency virus in their body and slowing down the progression of HIV infection, which will increase the duration and improve the quality of their life. It has been explained that antiretroviral drugs are provided free of charge. The potential 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 in my child with the development of life-threatening manifestations such as disseminated tuberculosis, Pneumocystis pneumonia, lesions of the central nervous system by various infections, the development of oncological diseases, etc., up to death. It has been explained that if there is a need to perform a medical intervention for which this refusal is issued, I have the right to execute an informed voluntary consent for such a type of medical intervention. Hereby, I confirm my voluntary refusal to administer antiretroviral therapy to my child; the consequences of the refusal have been explained to me, and I assume responsibility for my child's state of health.

Reason for refusal:

SAMPLE

8. Informed consent for antiretroviral therapy in a child with HIV infection aged 15 years and older

I confirm that it has been explained to me:

· 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 prescribed to me are approved for use in the Russian Federation and are provided free of charge.

· that antiretroviral drugs, like other medicinal products, may cause adverse events, information about which has been provided to me by the 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-adherence to the medication regimen and/or examination schedule.

I undertake to:

· to undergo laboratory examinations and consultations according to the schedule established by the attending physician in order to timely monitor the prescribed treatment;

· to take the medicinal products prescribed to me in accordance with the dosing regimen and instructions of the attending physician;

· to inform the attending physician as soon as possible 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 for laboratory examinations and/or visits to the attending physician, I will be invited to the medical organization by phone/through home visits by polyclinic specialists.

Patient _____________________ ____________________ Date _______________

(Full Name) (signature)

Physician ________________________ ___________________ Date ________________ (Full Name) (signature)

SAMPLE

9. Informed 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 for a child with HIV infection aged 15 years and older

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 of 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, anamnesis collection.

2. Examination, including palpation, percussion, auscultation, vaginal examination (for women), rectal examination.

3. Anthropometric studies.

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 diagnostic methods, including fluorography (for individuals over 15 years of age) and radiography, ultrasound examinations.

12. Administration of medicinal products as prescribed by a physician, including intramuscularly, intravenously, subcutaneously, intradermally.

15. Antiretroviral therapy

16. Other: _______________________________________________________________________

^{(name of another type of medical intervention)}

By the medical worker _____________________________________________________________________________

(position, full name of the medical worker)

My state of health and diagnosis have been explained to me in an accessible form, and the goals, nature, and necessity of diagnostic and treatment procedures have been outlined. It has been explained that the antiretroviral therapy proposed to me is aimed at suppressing the reproduction of the human immunodeficiency virus in my body and slowing the progression of HIV infection, which will increase my life expectancy and improve its quality. It has been explained that antiretroviral drugs are provided free of charge. The possible consequences of refusing medical intervention/antiretroviral therapy (underline as appropriate) have been explained to me and are understood, including the probability of developing complications of the disease (condition), and that my refusal of 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 involvement by various infections, the development of oncological diseases, and others, up to and including 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 an informed voluntary consent to 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 full responsibility for my state of health.

Reason for refusal:

10. Body Mass Index in Children

In children aged two years and older:

BMI formula:

BMI calculation: [weight (kg)/height (cm)/height (cm)] × 10,000

The resulting BMI is evaluated in percentiles using growth charts.

Appendix B. Physician Action Algorithms

Algorithm for diagnosing HIV infection in children born to HIV-seropositive mothers in the absence of breastfeeding

See sections: 2. Diagnosis of HIV infection, medical indications and contraindications for the use of diagnostic methods, 5. Prophylaxis and follow-up care, medical indications and contraindications for the use of prophylactic methods.

Algorithm for prescribing ART to HIV-infected children

See sections: 2. Diagnosis of HIV infection, medical indications and contraindications for the use of diagnostic methods, 3. Treatment, including drug and non-drug therapy, dietary therapy, pain management, medical indications and contraindications for the use of treatment methods, 5. Prophylaxis and follow-up care, medical indications and contraindications for the use of prophylactic methods, 7. Additional information.

Algorithm for assessing the virological efficacy of ART in children

Notes to the algorithm:

- In children with viral load >100,000 and especially >500,000 copies/mL before starting ART, a slower decline may occur (primarily in infants in the first year of life and in children with late-diagnosed HIV infection).

See sections: 2. Diagnosis of HIV infection, medical indications and contraindications for the use of diagnostic methods, 3. Treatment, including drug and non-drug therapy, dietary therapy, pain management, medical indications and contraindications for the use of treatment methods, 5. Prophylaxis and follow-up care, medical indications and contraindications for the use of prophylactic methods, 7. Additional information.

Algorithm for assessing and correcting adherence to drug therapy within the framework of medical, social, and psychological support for an HIV-infected child

See sections: 2. Diagnosis of HIV infection, medical indications and contraindications for the use of diagnostic methods, 3. Treatment, including drug and non-drug therapy, dietary therapy, pain management, medical indications and contraindications for the use of treatment methods, 7. Additional information, Appendices G1–G4.

Appendix C. Patient Information

After establishing the diagnosis of HIV infection, a discussion is held with the child's caregiver regarding the disease, its prognosis, and the proposed treatment regimen. As the child grows older and rapport is established, a discussion is held with the patient directly in an accessible form, involving a clinical psychologist if necessary. The scope of information provided must be agreed upon with the guardian in advance to avoid undesirable premature disclosure of the HIV status to the child. Given the lifelong administration of drugs and the need to develop maximum adherence, at each visit the patient's understanding of the purpose of therapy and their individual satisfaction with treatment are assessed. The assessment includes active screening for adverse reactions and events during long-term ART and psychological barriers to treatment adherence, inattention to which will lead to missed doses by the patient, especially in adolescence.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Morisky-Green ART Adherence Scale

Russian name: Morisky Medication Adherence Scale.

Original name: Medication Adherence Scale.

Source: Morisky D.E., Green L.W., Levine D.M. Concurrent and Predictive Validity of a Self-Reported Measure of Medication Adherence. Medical Care, Vol. 24, No. 1 (Jan., 1986), pp. 67-74.

Type: rating scale.

Purpose: A clinical and psychological test method designed for the preliminary assessment of adherence and screening identification of non-adherent patients in routine medical practice. Used for inclusion in standard medical examination programs for individuals with chronic conditions. It can be applied to identify a cohort requiring additional attention due to insufficient treatment adherence. Used in scientific research as a primary tool and as a benchmark for comparison when developing new, more detailed, and specialized scales.

Content: The Morisky-Green scale consists of 8 items concerning the patient's attitude toward taking medications. The scale is designed to be completed by the patient themselves; if necessary, the physician can read the questions aloud and record the responses. In the original scale, each item is scored on a "Yes–No" basis. Each item is scored on a "Yes–No" basis. For questions 1–4 and 6–8, a "No" response is scored as 1 point; for question 5, a "Yes" response is scored as 1 point. Questionnaires for quantitative assessment of treatment adherence can be administered in both automated and manual modes.

Key: Patients scoring 8 out of 8 points are considered highly adherent, those scoring 6–7 points are moderately adherent, and those scoring less than 6 points are poorly adherent.

Explanations: Treatment adherence is the degree to which a patient follows medical recommendations, such as lifestyle modifications or taking medications. Meanwhile, compliance is the result of contact between the physician and the patient, as the physician's role is not limited to unilaterally issuing recommendations, nor the patient's role to unilaterally perceiving them. In a strict sense, compliance refers to the percentage of prescribed medications for long-term (including lifelong) administration taken at the correct time and in the correct dosage. The Morisky-Green scale is built precisely on this understanding of compliance. Numerous studies have confirmed that high adherence according to the Morisky-Green scale significantly correlates with the achievement of long-term treatment goals.

Questions for assessing ART adherence using the Morisky-Green scale

For the child:

For the child's legal representative:

Appendix G2. Hospital Anxiety and Depression Scale (HADS)

Russian name: Hospital Anxiety and Depression Scale (HADS).

Original title: The Hospital Anxiety and Depression Scale.

Sources: Andryushchenko A.V., Drobizhev M.Y., Dobrovolsky A.V. Comparative evaluation of CES-D, BDI, and HADS(D) scales in the diagnosis of depression in general medical practice. S.S. Korsakov Journal of Neurology and Psychiatry, 2003, No. 5, 11–17. Zigmond A.S., Snaith R.P. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 1983; 67:361–70.

Type: rating scale.

Purpose: The Hospital Anxiety and Depression Scale is a rapid screening tool for assessing the levels of anxiety and depression in general medical practice. It demonstrates high discriminant validity for two distinct disorders: anxiety and depression.

Hospital Anxiety and Depression Scale (HADS) – Key Benefits:

1. A reliable self-assessment scale measuring the degree of anxiety and depression.

2. Speed. Only 14 questions. Completion takes 2 to 5 minutes.

3. Simplicity. Easy to complete, easy to score, and easy to interpret.

4. Prevalence. The scale is available in 115 languages, making it suitable for international studies.

Content: The Hospital Anxiety and Depression Scale consists of 14 items, each accompanied by 4 response options reflecting the increasing severity of symptoms.

The questionnaire form is given to the patient for self-completion along with instructions. The scale comprises 14 statements divided into 2 subscales: "Anxiety" (7 statements) and "Depression" (7 statements). Each statement has 4 response options reflecting the severity of the feature, coded in order of increasing symptom severity from 0 (none) to 3 (maximum severity).

Scoring Key: The levels of depression and anxiety are evaluated independently of each other. Separate scores are calculated for the questions assessing depression and those assessing anxiety.

Notes: Initially, the Hospital Anxiety and Depression Scale (HADS; Zigmond A.S., Snaith R.P.) was developed to detect states of depression, anxiety, and emotional distress among patients receiving treatment for various somatic illnesses. According to the authors' design (Zigmond & Snaith, 1983), this would help identify the contribution of mood disorders (especially anxiety and depression) to the development and treatment of the underlying condition. Currently, this scale is the most widely used worldwide for the primary detection of depression and anxiety in general medical practice. The HADS scale has been validated in Russia (Russian version by A.V. Andryushchenko, M.Y. Drobizhev, A.V. Dobrovolsky, 2003).

The HADS scale for determining anxiety and depression levels is easy for patients to complete and does not require much time for administration and interpretation. The scale is designed to help the physician better understand the patient's emotional state and well-being. For a more in-depth diagnosis of the patient's emotional state, it is recommended to use: the Hamilton Anxiety Rating Scale (HARS) and the Hamilton Depression Rating Scale (HDRS).

Practical Recommendations for the Patient: The scale should be completed independently within 10–15 minutes, without discussing it with anyone. All items must be answered. Each HADS statement has four response options. Select and check the response that best describes your state over the past 7 days. Do not spend too much time thinking about an answer. Your first reaction is usually the most accurate.

Hospital Anxiety and Depression Scale (HADS)

Scientists believe that emotions play a major role in the onset of most diseases. If your doctor learns more about your feelings, they will be able to help you better. This questionnaire is designed to help your doctor understand how you feel. Do not pay attention to the numbers. Read each statement carefully and check the response that best corresponds to how you felt last week. Do not deliberate too long over each statement; your first reaction is always the most accurate.

Part I (Assessment of ANXIETY level)

1. I feel tense or 'wound up'

3 - most of the time

2 - a lot of the time

1 - from time to time, occasionally

0 - not at all

2. I get a sort of frightened feeling as if something awful is about to happen

3 - very definitely and quite severely

2 - yes, but not too badly

1 - a little, but it doesn't worry me

0 - not at all

3. Worrying thoughts go through my mind

3 - a great deal of the time

2 - a lot of the time

1 - from time to time, but not too often

0 - only occasionally

4. I can sit at ease and feel relaxed

0 - definitely

1 - usually

2 - Only occasionally

3 - not at all

5. I get a sort of frightened feeling like 'butterflies' in the stomach

0 - not at all

1 - occasionally

2 - a lot of the time

3 - very often

6. I feel restless as I have to be on the move

3 - very much indeed

2 - quite a lot

1 - Not very much

0 - not at all

7. I get sudden feelings of panic

3 - very often

2 - quite a lot

1 - not very often

0 - not at all

Total score ________

Part II (Assessment of DEPRESSION level)

1. I still enjoy the things I used to enjoy

0 - definitely

1 - probably as much

2 - Only a little

3 — not at all

2. I can laugh and see the funny side of things

0 - definitely

1 - probably as much

2 - Only a little

3 — not at all

3. I feel cheerful

3 — not at all

2 — very rarely

1 - occasionally

0 — almost all the time

4. I feel as if I am slowed down

3 — almost all the time

2 - a lot of the time

1 - occasionally

0 — not at all

5. I have lost all interest in my appearance

3 - very much indeed

2 — I do not take as much care of it as I should

1 — I may take a little less care than I used to

0 — I take just as much care as ever

6. I look forward with enjoyment to things

0 — as much as I ever did

1 — rather less than I used to

2 — definitely less than I used to

3 — hardly at all

7. I can enjoy a good book or radio or television program

0 — as much as I ever could

1 - occasionally

2 — rather less than I used to

3 — definitely not so much now

Total score ________