CLINICAL DIAGNOSIS AND TREATMENT OF HIV INFECTION

Manual for Students, Interns, Residents, and Physicians in All Specialties

INTRODUCTION.............................................................................................................................................. 5 I. THE PRINCIPAL CHARACTERISTICS OF HIV INFECTION........................................................................5 II. THE DIAGNOSIS OF HIV INFECTION........................................................................................................ 7 1. Epidemiological Criteria Validating the Diagnosis of HIV Infection...........................................................7 2. Clinical Criteria for the Diagnosis of HIV Infection....................................................................................7 3. Laboratory Confirmation of the Diagnosis of HIV Infection.......................................................................8 3.1. Detection of HIV antibodies............................................................................................................... 8 3.1.1. Diagnostic approach to the determination of total HIV antibodies..............................................9 3.1.2. Immune blotting........................................................................................................................ 9 3.2. Other methods of laboratory confirmation of HIV infection..............................................................10 3.3. Nonspecific laboratory indicators of HIV infection...........................................................................10 3.4. The use of laboratory results in the diagnosis of HIV infection. ......................................................11 4. Determination of the Clinical Stage of HIV Infection...............................................................................11 5. Validation of a First-Time Clinical Diagnosis of HIV infection.................................................................14 6. Determination of Severity of the Course and Prognosis of HIV Infection ...............................................15 6.1. Clinical criteria of severity of the course and prognosis of HIV infection ........................................16 6.2. The use of laboratory criteria for assessing the severity of the course and prognosis of HIV infection.................................................................................................................................................. 16 6.2.1. Determination of the CD4 lymphocyte count............................................................................16 6.2.2. Quantifying the presence of HIV.............................................................................................. 17 6.2.3. Special features of the assessment of laboratory values in children........................................17 III. FOLLOW-UP CARE OF HIV-INFECTED INDIVIDUALS...........................................................................18 IV. THE TREATMENT OF HIV INFECTION................................................................................................... 20 1. Creation of protective psychological conditions for HIV-infected individuals..........................................20 2. The chemotherapy of HIV infection........................................................................................................ 21 2.1. Antiretroviral Therapy...................................................................................................................... 21 2.1.1. Indications for initiating antiretroviral therapy...........................................................................21 2.1.2. Evaluation to identify indications for antiretroviral therapy.....................................................23 2.1.3. Antiretroviral drugs and antiretroviral therapy regimens..........................................................24 2.2. Using Particular Antiretroviral Therapy Regimens...........................................................................25 2.2.1. Monotherapy with nucleoside analog reverse transcriptase inhibitors ..................................25 2.2.2. Bitherapy using two HIV reverse transcriptase inhibitors.........................................................26 2.2.3. Therapy with several antiretroviral drugs (high-intensity antiretroviral therapy) ......................27 2.3. Assessment of the Efficacy and Safety of Antiretroviral Therapy, Criteria for Discontinuation and Replacement of a Therapy Regimen, Prescription of Reserve Regimens.............................................28 2.4. Therapy Adjustment for Drug Intolerance........................................................................................ 29 2.5. Special Features of the Treatment of Pregnant Women With Antiretroviral Drugs..........................29 1

2.6. Special Features of the Chemotherapy of HIV Infection in Children...............................................30 3. Treatment of Opportunistic Diseases.................................................................................................... 32 V. CHEMOPROPHYLAXIS OF HIV INFECTION............................................................................................ 32 1. Chemoprophylaxis of Mother-to-Child Perinatal HIV Transmission........................................................32 2. Chemoprophylaxis of parenteral and sexual transmission ....................................................................34 VI. CHEMOPROPHYLAXIS OF SECONDARY (OPPORTUNISTIC) DISEASES IN HIV PATIENTS.............35 1. Chemoprophylaxis of Pneumocystis Pneumonia...................................................................................35 2. Chemoprophylaxis of Fungal Infections.................................................................................................. 35 3. Chemoprophylaxis of Mycobacterioses.................................................................................................. 36 4. Chemoprophylaxis of Cytomegalovirus Infection ...................................................................................37 Appendices..................................................................................................................................................... 38 Appendix No. 1.............................................................................................................................. 39 Russian Classification of HIV Infection (V. I. Pokrovsky, 2001).....................................................39 Appendix No. 2 ............................................................................................................................. 40 Patient's Quality of Life Assessment on the Karnovsky Scale ......................................................40 Appendix No. 3 ............................................................................................................................. 41 Schedule and Scope of Evaluation of the HIV Patient When Prescribing and Implementing Antiretroviral Therapy.................................................................................................................... 41 Appendix No. 4.............................................................................................................................. 42 Schedule and Scope of Evaluation of Children Born to HIV-Infected Mothers..............................42 Appendix No. 5.............................................................................................................................. 43 List of Drugs Registered in Russia, Most Frequently Used in the Treatment of HIV Patients........43 Appendix No. 6.............................................................................................................................. 45 Informed Consent for Therapy of HIV Infection.............................................................................45 Appendix No. 7.............................................................................................................................. 46 ANTIRETROVIRAL DRUGS.......................................................................................................... 46 Appendix No. 8.............................................................................................................................. 50 Options for Combining Antiretroviral Drugs...................................................................................50 Appendix No. 9.............................................................................................................................. 54 Main Side Effects of the Antiretroviral Drugs.................................................................................54 Appendix No. 10............................................................................................................................ 55 Interaction of Antiretroviral Drugs With Other Drugs........................................................................................................................... 55 Appendix No. 11............................................................................................................................ 57 Formulating Antiretroviral Therapy Regimens...............................................................................57 Appendix No. 12............................................................................................................................ 58 Indications for Antiretroviral Therapy............................................................................................. 58 Appendix No. 13............................................................................................................................ 59 Approach to Patient Management Depending on the Findings of Monitoring Studies at the Completion of a 12-Week Course of Monotherapy ................................................................................................................................. 59 Appendix No. 14............................................................................................................................ 60 Approach to Patient Management 2

Depending on the Findings of Monitoring Studies at the Completion of a 12-Week Course of Bitherapy With Two Reverse Transcriptase Inhibitors...................................................................60 Appendix No. 15............................................................................................................................ 61 Approach to Patient Management Depending on the Findings of Monitoring Studies at the Completion of a 12-Week Course of Highintensity Antiretroviral Therapy (Tritherapy)...................................................................................61 Appendix No. 16............................................................................................................................ 62 Replacement of Antiretroviral Therapy in Case of Inadequate Efficacy or Loss of Efficacy of Earlier Therapy.............................................................................................................................. 62 Appendix No. 17............................................................................................................................ 64 Antiretroviral Drug Replacement When Drug Intolerance Develops..............................................64 Appendix No. 18............................................................................................................................ 65 Antiretroviral Therapy in Pregnant Women....................................................................................65 Appendix No. 19............................................................................................................................ 67 The Use of Antiretroviral Drugs in Children*..................................................................................67 Appendix No. 20........................................................................................................................... 71 Treatment of Localized Candidiasis in HIV Patients......................................................................71 Appendix No. 21............................................................................................................................ 72 Treatment of Generalized Candidiasis, Candidial Meningitis, Cryptococcosis in HIV Patients...................................................................................................... 72 Appendix No. 22............................................................................................................................ 73 Treatment of Pneumocystis Pneumonia (PCP) in HIV Patients.....................................................73 Appendix No. 23............................................................................................................................ 74 Treatment of Herpes Virus Conditions in HIV Patients..................................................................74 Appendix No. 24............................................................................................................................ 75 Informed Consent for Chemoprophylaxis of HIV Transmission from Mother to Child During Pregnancy and Delivery ................................................................................................................ 75 Appendix No. 25............................................................................................................................ 76

STANDARD ABBREVIATIONS

AZT AAI VHB VHC HIV HIV infection HSV gp IB IHD PI EIA PGL NRTI NNRTI PCR AIDS P-AZT CMV 3TC ABC rDNA CMB ddC ddI d4T EFV FTV IDV NASBA NFV NVP p24Ag RT-PCR RTV SQV

Azothymidine (Thymazide, Retrovir, Zidovudine) Asymptomatic AIDS infection Viral hepatitis B Viral hepatitis C Human immunodeficiency virus HIV-induced infection Herpes simplex virus Glycoproteins Immune blotting Ischemic heart disease Protease inhibitors Enzyme immunoassay Persistent generalized lymphadenopathy Nucleoside reverse transcriptase inhibitor Non-nucleoside reverse transcriptase inhibitor Polymerase chain reaction Acquired immunodeficiency syndrome Phosphazide (Nikavir) Cytomegalovirus Lamivudine (Epivir) Abacavir (Ziagen) "DNA branching" reaction Combivir (AZT+3TC) Zalcitabine (Hivid) Didanosine (Videx) Stavudine (Zerit) Ifavirenz (Efavirenz) Fortovase Indinavir (Crixivin) Complete genome amplification Nelfinavir (Viracept) Nevirapine (Viramune) HIV p24 antigen Reverse transcriptase-PCR Ritonavir (Norvir) Saquinavir (Invirase, Fortovase)

INTRODUCTION
HIV infection is a protracted infectious disease resulting from infection with the human immunodeficiency virus. Immune system impairment in HIV infection is progressive, leading to the condition known as acquired immunodeficiency syndrome (AIDS), in which the patient develops opportunistic infections (severe forms of infections caused by opportunistic pathogens) as well as some oncological diseases. The infected individual remains a source of the infection throughout life. The untreated HIV infection progresses from 3 to 20 years and ends with the death of the infected individual. The diversity of clinical manifestations of HIV infection and of the opportunistic diseases associated with it, the protracted course of the disease and poor prognosis, and the high cost of diagnostic procedures and drugs demand the greatest improvement possible in diagnostic and treatment methods within the Russian Federation. This document aims to create a unified system of care for HIV-infected individuals, based on continuity and coordination of the efforts of physicians providing care to such persons. The document presents information regarding diagnostic systems and drugs approved for use in Russia on December 31, 2000.

I. THE PRINCIPAL CHARACTERISTICS OF HIV INFECTION

Agent. The human immunodeficiency virus (HIV) belongs to the lentivirus subfamily in the family of retroviruses. Two types of the virus, differing in genomic structure and serological characteristics, HIV-1 and HIV-2, are distinguished. The types are divided into subtypes designated by Latin letters. Prevalence. HIV infection is widespread and is ubiquitous. It is found more often in large population centers and among at-risk (vulnerable) groups; these include intravenous drug users; men who have sex with men; and people who change sexual partners frequently. However, in relation to the epidemic developing in Russia, HIV infection can also be found in areas where it had not been encountered previously, and in individuals who do not formally belong to at-risk population groups. Because of the particular features of its transmission, HIV infection is contracted primarily by young people. When HIVinfected male homosexuals or drug abusers predominate in an area, men predominate quantitatively among infected individuals. When the heterosexual population is involved in the epidemic process, the sex ratio among the infected population groups evens out. The source of HIV is an infected individual at all stages of the disease. The HIV transmission route. HIV transmission occurs during sexual contacts, through the transfusion of infected blood and blood products, through the use of HIV-contaminated medical instruments, and takes place from mother to infant during pregnancy and labor, as well as during breastfeeding, from an infected mother to the infant and from an infected infant to the nursing woman. Pathogenesis. HIV circulates in the internal body fluids of an infected individual as a viral particle, the virion, which carries the RNA of the virus. After the HIV virion attaches to CD4 receptors that are found on cells of the human immune system, HIV RNA penetrates the cell, where the formation of HIV DNA takes place under the influence of reverse transcriptase, with its subsequent incorporation into the cell genome. As a result, the 5

cell begins to produce new viral particles carrying HIV RNA. Assembly of the new viral particles and cleaving of viral proteins synthesized by the cell involve another HIV enzyme, a "protease." The viral particles formed attack new cells, killing them and disrupting their interaction with other cells, leading to progressive impairment of immunity. A large number of viral particles circulating in the blood increases the likehood of rapid reduction in the number of immune cells. The clear connection between disease progression and a fall in the patient's CD4 cell count leads to the view that a reduction in the number of these cells is the basic feature of the pathogenesis of the disease. The function of helper/inducer lymphocytes, which results in spontaneous activation of B-cells and the development of polyclonal hypergammaglobulinemia through the production of nonspecific immune globulins, is also impaired; the concentration of circulating immune complexes increases as a result. The immune abnormalities are responsible for a decline in resistance to secondary infections and neoplasms. In addition, the direct or mediated (autoimmune) cytopathic action of the virus may damage nervous system cells and various cells of the hemic, cardiovascular, musculoskeletal, endocrine and other systems. A broad spectrum of processes induced by secondary diseases associated with the advancing immune deficit are superimposed on the pathological and adaptive processes evoked by HIV. All these factors are responsible for the multiorgan impairments and the diverse clinical symptomatology. The Clinical Course of HIV Infection. Following an incubation period of 2 weeks to 6 months or longer, the period of initial clinical manifestations, lasting from several days up to 2 months, begins in 50-70% of cases; these take the form of a febrile state, possibly accompanied by lymph node enlargement, stomatitis, macular rash, pharyngitis, diarrhea, enlarged spleen, and occasionally signs and symptoms of encephalitis. An inapparent or mildly symptomatic onset of the disease may be seen in many cases; however, antibodies to HIV appear within 6 months of infection in the majority of HIV-infected individuals. The early clinical manifestations of HIV infection, with the exception of lymph node enlargement, resolve, and for several years thereafter there are no other clinical signs or symptoms of HIV infection in infected individuals. HIV activity persists and the CD4 count slowly falls during this period. Various opportunistic infections begin to appear in the patient when the body's defenses are sufficiently weakened; they become more conspicuous subsequently, as the CD4 count falls. The evolving opportunistic infections become lifethreatening when the count of these cells falls substantially, and without adequate treatment the patient will die. In addition to the somatic impairments, neuropsychological alterations develop in HIV-infected patients, first associated with awareness of a viral infection that threatens to ruin life plans (the danger of infecting sexual partners, possible social isolation, progression of a fatal disease), and later, with the appearance of the clinical signs and symptoms of various disorders. Prognosis. The average duration of the illness from the time of infection with HIV-1 to death is 11 years. Some patients die considerably earlier, some occasionally survive 15 years and longer. The disease progresses somewhat more slowly in the case of HIV-2 infection. Timely and properly managed treatment may add several years to the life span of infected individuals, as well as improve quality of life. The socioeconomic consequences of HIV infection. As HIV infection spreads appreciably, it may play a substantial role in population morbidity and mortality. Organizing medical care for patients requires substantial expenditures for diagnosis and treatment; therefore preventive and anti-epidemic measures are the most essential elements to counter the epidemic. 6

II. THE DIAGNOSIS OF HIV INFECTION

HIV infection is diagnosed through comprehensive assessment of the epidemiological data and clinical evaluation and laboratory study findings. The diagnosis of HIV infection involves two sequential stages: ascertainment of the diagnosis of HIV infection per se, that is, determination of the state of HIV infection, and establishment of a detailed clinical diagnosis, that is, characterizing the stage and course of the HIV infection, and its prognosis. Establishing the state of HIV infection is significant for implementation of anti-epidemic measures, and leads to important legal consequences. The success of subsequent anti-epidemic measures, for example, the prevention of transmission of HIV through donor blood, depends on timely ascertainment of the state of HIV infection or suspicion of infection. The clinical diagnosis of HIV infection is determined mainly for the purpose of providing medical care to the patient. Counseling the patient, which plays a significant therapeutic and anti-epidemic role, should come before the diagnosis of HIV infection is made. Counseling prepares the patient psychologically for the reporting of the HIV infection diagnosis, facilitates subsequent mutual understanding of patient and medical personnel, and is highly significant in preventing possible further spread of HIV.

1. Epidemiological Criteria Validating the Diagnosis of HIV Infection

Collection of the patient's epidemiological history and other epidemiological data is the first step in the diagnosis of HIV infection. The lack of epidemiological data can substantially hamper the diagnosis of HIV infection and impede the implementation of anti-epidemic measures. Epidemiological criteria can sometimes be decisive in making the diagnosis of HIV infection, but may also be of ancillary significance. Discovery of such infection risk factors as transfusion with donor blood obtained from an HIV-infected person in an individual under evaluation, or the delivery of an HIV-infected infant by a woman under evaluation, are criteria of a high likelihood of infection. There is a high likelihood of infection in the case of the delivery of a subject by an HIV-infected mother, of sexual contact with an HIV-infected person, or of shared parenteral drug use with an HIV-infected person. There is a definite risk of infection in the case of known parenteral procedures or injuries involving instruments that are probably contaminated by HIV (that is, in nosocomial and similar foci of HIV infection involving parenteral HIV transmission). There may be an appreciable risk of infection when the patient reports sexual relations or parenteral drug use that have occurred in areas where HIV is very prevalent in his or her population group. At the same time, sexual relations or drug use in areas with low HIV prevalence do not preclude the possibility of HIV infection. The absence of proven HIV infection risk factors may raise doubts about laboratory results. Laboratory studies should be repeated in such cases.

2. Clinical Criteria for the Diagnosis of HIV Infection

The clinical evaluation is an indispensable stage in the clinical diagnosis of HIV infection. Epidemiological 7

and laboratory data can be sufficient only to institute various anti-epidemic measures, but proper treatment of the patient cannot be arranged if a clinical evaluation cannot be done. The discovery that a patient has signs and symptoms of the disease (described below in section 4 of this chapter) that are especially characteristic of stages 4B, 4C, and 5 of HIV infection, for instance, Kaposi's sarcoma in a young person, is a reliable sign of the presence of HIV infection, unless other immunosuppressive factors are identified. Despite the fact that an asymptomatic course of HIV infection (stage 3) is seen occasionally, the absence of any clinical manifestations of this disease in a particular patient dictates both greater skepticism toward the laboratory findings and their comparison with the epidemiological data.

3. Laboratory Confirmation of the Diagnosis of HIV Infection

Various methods of detecting HIV and HIV antigens and genetic material are currently used for the laboratory diagnosis of HIV infection. These methods all differ in effectiveness, and require different equipment and varying levels of personnel training. The findings of these studies require competent interpretation. Diagnosis of HIV infection through detection of HIV antibodies remains the world's best studied, practically convenient, and most economical method. Other methods may be used as ancillary procedures in individual cases. 3.1. Detection of HIV antibodies Currently, detection of HIV antibodies with follow-up confirmation of their specificity by immune blotting is the standard procedure in Russia for the laboratory diagnosis of HIV Infection. HIV antibodies appear in 90-95% of infected individuals within 3 months following infection, in 5-9% within 6 months of infection, and later in 0.5-1%. The earliest detection of antibodies is 2 weeks after infection. There are two stages in the detection of HIV antibodies. In the first stage, the complete spectrum of antibodies to HIV antigens is identified using various assays: enzyme immunoassay, agglutination, combined, comb, filtration membrane, or diffusion membrane. In the second stage, antibodies to particular virus proteins are determined by immune blotting. Only those test systems authorized for use by the Russian Federation Ministry of Health may be utilized in this procedure. The diagnostic procedures must be done only in accordance with approved instructions for use of the respective assays. Three to five milliliters of blood are collected from the cubital vein in a clean, dry test tube. Umbilical blood can be taken from newborns. This material (whole blood) should not be stored more than 12 hours at room temperature, or more than 24 hours in a refrigerator at 4-8C. Hemolysis may affect the assay results. The serum is separated by centrifugation or by drawing the blood along the test tube wall by Pasteur pipette or glass rod. The separated serum is transferred to a clean (preferably sterile) test tube, vial, or plastic container, and can be stored in that form up to 7 days at a temperature of 4-8C. The safety rules cited in "Regulations for the Anti-epidemic Regime in the Laboratory Diagnosis of AIDS," N42-28/38-90 of July 5, 1990, must be observed in this procedure.

3.1.1. Diagnostic approach to the determination of total HIV antibodies When an initial positive result is obtained, the assay is repeated twice (with the same serum in the same test system). If even one positive result is then obtained (two positive results out of three EIA runs), the serum is sent to a reference laboratory. The reference laboratory re-tests the initial positive serum (that is, a serum which has given two positive results in the first test system) using EIA in a second (different) test system selected for confirmation. When a positive assay result is obtained in the second test system as well, the serum must be tested by IB. When a negative assay result is obtained in the second test system, the serum must be tested in a third test system. Should a negative assay result be obtained in both the second and third test systems, a finding of absence of HIV antibodies is issued. When a positive assay result is obtained in the third test system, the serum must also be sent for immune blotting. 3.1.2. Immune blotting This technique is based on the principle of detection of antibodies to particular virus proteins, immobilized on a nitrocellulose membrane. The HIV-1 virus envelope proteins (env), usually designated as glycoproteins ("gp [Cyrillic alphabet]" or "gp [Latin]") have molecular weights in kilodaltons (kd) of 160 kd, 120 kd, and 41 kd. The HIV-2 glycoproteins have weights of 140 kd, 105 kd, and 36 kd. The HIV-1 core proteins (gag), usually designated as "N [Latin]" or "P [Latin]" proteins, have molecular weights, respectively, of 55 kd, 24 kd, and 17 kd; those of HIV-2 are 55 kd, 26 kd, and 18 kd. HIV-1 enzymes (pol [Latin]) have molecular weights of 66 kd, 51 kd, and 31 kd; HIV-2 - 68 kd. Immune blotting results are interpreted as positive, negative, and doubtful. Tests is which antibodies to 2 or 3 HIV glycoproteins are detected are deemed positive (positive [Russian synonym]). Sera is which no antibodies to any HIV antigens (proteins) are detected are deemed negative (negative [Russian synonym]). Tests is which antibodies to 1 HIV glycoprotein and/or any HIV protein are detected are deemed doubtful (non-detectable or not interpretable). When a doubtful result is obtained with antibodies to core proteins (gag) in immune blotting with HIV-1 antigens, the study is done with HIV-2 antigens. When positive immune blotting results are obtained, a finding is made of the presence of HIV antibodies in the material assayed. When a negative IB assay result is obtained, a finding is made of the absence of HIV antibodies. When a non-detectable result is obtained (unless the p24 antigen is detected), repeat studies for HIV antibodies are done in 3 months, and with persistence of non-detectable results, in another 3 months. If the p24 antigen was detected, a repeat study is done 2 months after the first non-detectable result. If non-detectable results are obtained again 6 months after the first study, and the patient has not shown 9

infection risk factors or clinical symptoms of HIV infection, the result is deemed false-positive. (If epidemiological and clinical indications are present, the serological studies are repeated as ordered.) Immune blotting using recombinant virus-specific polypeptides, HIV Blot, is distinguished by the fact that it uses recombinant polypeptides, not the viral proteins themselves: analogs of HIV antigens (Env-1, Gag-1, Pol-1, Env-2). The recombinant polypeptide Env-1 directly detects antibodies to HIV-1 gp120 and gp41; the polypeptide Gag-1 detects antibodies to p17 and p24 antibodies [sic]; the polypeptide Pol1 detects antibodies to the p51 antigen; the polypeptide Env-2 detects antibodies to the HIV-2 gp110 and gp38 antigens. Sera reacting with Env-1 or Env-2 or with both (HIV-1/HIV-2 double infection) are deemed positive. A reaction just with Pol or Gag is regarded as a doubtful result, and in that case the follow-up steps are similar to those taken in case of doubtful (non-detectable) results with classical immune blotting using HIV lysate. The fact that HIV antibodies of maternal origin, which may subsequently disappear, are detected both in infected and non-infected children in the first 6 to 12 months of life is a special feature of the diagnostics of HIV infection in children born to HIV-infected mothers. Finding HIV antibodies in an infant at the age of 18 months and older is a criterion of the presence of HIV infection in that infant. The absence of HIV antibodies in an infant, born to an HIV-infected mother, at age 18 months argues against the presence of HIV infection in that infant. 3.2. Other methods of laboratory confirmation of HIV infection Isolation and identification of HIV culture is a reliable indicator of HIV infection; however, this method is not readily available, takes a long time, and requires highly qualified personnel and special equipment. Therefore the isolation of the virus and identification are only done for scientific purposes or in exceptionally hard-todiagnose cases. Test systems for detection of HIV genetic material of HIV antigens are currently authorized for use in Russia. These test systems may give positive reactions for HIV markers in the early stages of HIV infection. When positive results for HIV infection are found in these types of test systems, a search must be made for HIV antibodies. The standard diagnostic approach should be followed if antibodies are found. When the results of a search for HIV genetic or antigenic markers are positive and the results of a search for HIV antibodies are negative, the search for HIV antibodies must be repeated after 3 and 6 months. In children born to HIV-infected mothers, repeated detection of HIV genetic or antigenic markers in the first half year of life is a diagnostic criterion in favor of HIV infection, while repeated negative results are against the diagnosis of HIV infection. 3.3. Nonspecific laboratory indicators of HIV infection Abnormalities such as a fall in CD4 lymphocytes, an increase in the percentage of CD8 lymphocytes, an inversion of the CD4/CD8 ratio (if less than 1), increased beta-1-microglobin and neopterin, increased immunoglobulins, and others can be observed in HIV infection. These indicators are further evidence in favor of the diagnosis of HIV infection. However, these changes may be lacking during certain stages of HIV infection (see below), may vary individually in particular patients, and may be encountered in other diseases.

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3.4. The use of laboratory results in the diagnosis of HIV infection. The clinical diagnosis cannot be made on the basis of a laboratory workup alone. Epidemiological data and clinical evaluation results must be considered in order to reach a definitive diagnostic conclusion. The indicators of HIV infection found through laboratory studies may be used to implement anti-epidemic measures in accordance with Russian Federation Ministry of Health regulations.

4. Determination of the Clinical Stage of HIV Infection

The clinical staging of HIV infection is based on the Russian classification of HIV infection. The most recent version of this classification was proposed in 2001. It permits clinical and follow-up observation of HIVinfected individuals, prediction of the course of the disease, and determination of patient management approach and indications for prescription of drugs without special laboratory methods that are noteworthy for high cost and are therefore insufficiently accessible. The Russian classification of HIV infection (the 2001 version) is presented in appendix 1. Stage 1. The "incubation stage" extends from the time of infection to the appearance of the body's reaction in the form of the clinical manifestations of "acute infection" and/or the elaboration of antibodies. It usually lasts from 3 weeks to 3 months, but in isolated cases may even extend up to a year. Active HIV multiplication goes on during this period; however, there are no clinical manifestations, and HIV antibodies are not yet detected. HIV infection is diagnosed at this stage on the basis of epidemiological data, and must be confirmed in the laboratory through detection of the human immunodeficiency virus, its antigens, and HIV nucleic acids in the patient's serum. Stage 2. The "stage of primary manifestations." Active HIV replication continues in this period; however, the body's initial response to the introduction of this agent is in the form of the clinical manifestations and/or the elaboration of antibodies. The stage of early HIV infection can unfold in several forms. 2A The "asymptomatic stage," in which no clinical manifestations of HIV infection or opportunistic infections develop in association with the immune deficiency. The elaboration of antibodies is the only response to the introduction of HIV. 2B The stage of "acute HIV infection without secondary diseases" may develop with diverse clinical symptomatology. This generally includes fever, eruptions (urticarial, papular, petechial) on the skin and mucous membranes, lymph node enlargement, and pharyngitis. Enlargement of the liver and spleen and diarrhea may be observed. Occasionally so-called "aseptic meningitis" develops, manifested as a meningeal syndrome. Normal cerebrospinal fluid is usually obtained under increased pressure on lumbar puncture; slight lymphocytosis is seen from time to time. Such clinical symptomatology can be seen in many infectious diseases, especially the so-called "childhood diseases." For this reason acute HIV infection is sometimes called a "mononucleosis-like syndrome" or a "rubella-like syndrome." Wide-cytoplasm lymphocytes ("mononuclears") are seen in the blood of patients with acute HIV infection. These reinforce the resemblance of acute HIV infection and infectious mononucleosis. However, dramatic "mononucleosis-like " or "rubellalike" symptomatology is only seen in 15-30% of patients with acute HIV infection. One or two of the abovementioned symptoms, in any combination, are seen in the remainder. Autoimmune lesions may be seen in some patients. Overall, the acute clinical infection is observed in 50-90% of infected individuals in the first 3 11

months following the infection. As a rule, the beginning of the period of acute infection anticipates seroconversion, i.e., the appearance of HIV antibodies. Therefore, the patient's serum may not reveal antibodies to HIV proteins and glycoproteins when the initial clinical symptoms appear. A transient fall in the CD4 lymphocyte count is often observed at the acute infection stage. 2C "Acute HIV infection with secondary diseases." In 10-15% of cases, secondary diseases of varied etiology (sore throat, bacterial pneumonia, candidiasis, herpetic infections, and others) appear in patients with acute HIV infection who exhibit reduced CD4 lymphocyte count and resulting immune deficiency. As a rule, these occurrences are inconspicuous, short-lived, and respond well to therapy, but they can be severe (candidial esophagitis, pneumocystis pneumonia), and may even be fatal in rare instances. The clinical manifestations of acute HIV infection last from several days to several months, but it is usually 2 -3 weeks. Lymph node enlargement, which may persist throughout the entire illness, is an exception. The clinical manifestations of acute HIV infection may recur. An asymptomatic stage of initial HIV infection is more favorable prognostically. The more severe the acute infection, and especially if accompanied by secondary diseases, the greater the likelihood of rapid progression of the HIV infection. A protracted acute period of an HIV infection (persistence of clinical symptomatology beyond 14 days) is also considered unfavorable prognostically. The patient is considered to be in the stage of initial HIV infection for 1 year after the appearance of symptoms of the acute infection or seroconversion. In the overwhelming majority of patients, the stage of initial HIV infection proceeds to a latent stage, but in some it may bypass that stage, proceeding directly to the stage of secondary diseases. Stage 3. The "latent" stage. This stage is characterized by slow progression of the immune deficiency, compensated through modification of the immune response and excess reproduction of CD4 cells. Antibodies to HIV are found in the blood; the rate of virus replication slows as compared with the stage of primary manifestations. The only clinical manifestation of the disease is lymph node enlargement, which may also be absent. So-called "persistent generalized lymphadenopathy" (PGL) is characteristic of HIV infection. This is taken to mean enlargement of no fewer than 2 lymph nodes, in no fewer than 2 (not counting inguinal) non-interconnected groups; in adults, up to greater than 1 cm in size; in children, greater than 0.5 centimeters in diameter; persisting no fewer than 3 months. The lymph nodes in HIV patients are typically elastic, nontender, not adherent to the surrounding tissue; the overlying skin is unchanged. However, lymph node enlargement may also not be seen in HIV patients, or be observed but not meet the PGL criteria. Lymph node enlargement may be observed at later stages of HIV infection as well; however, in the latent stage, as already indicated, it is the only clinical manifestation. The latent stage may last from 2-3 up to 20 years and longer, 6-7 years on average. A gradual decline in CD4 lymphocyte count is observed in this period, at an average rate of 0.05-0.07x10 9/L per year. Stage 4. The stage of secondary diseases. Continuing HIV replication, leading to the death of CD4 cells and depletion of their population, results in the development of secondary (opportunistic) diseases, infectious and/or oncological, against the backdrop of the immune deficiency. The clinical manifestations of opportunistic diseases, along with the lymphadenopathy persisting in the majority of patients, in fact determine the clinical picture of the stage of secondary diseases. Stages 4A, 4B, and 4C are distinguished in relation to the severity of the secondary diseases.

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Stage 4 typically develops 6-10 years after infection. Bacterial, fungal, and viral lesions of the mucosae and cutaneous integuments and inflammatory diseases of the upper respiratory tracts are characteristic of this stage. Stage 4A usually develops in patients with a CD4 lymphocyte count of 0.35-0.5x109/L. Stage 4B (7-10 years after infection) skin lesions are more deep-seated and tend to a protracted course. Visceral lesions develop. In addition, localized Kaposi's sarcoma, moderately pronounced constitutional symptoms (weight loss, fever), and lesions of the peripheral nervous system can be seen. Stage 4B usually develops in patients with a CD4 lymphocyte count of 0.2-0.35x109/L. Stage 4C (after 10-12 years) is typified by the development of severe, life-threatening, and generalized secondary (opportunistic) diseases, as well as CNS impairment. Stage 4C usually unfolds in patients with a CD4 lymphocyte count below 0.2x109/L. Overall, the transition of HIV infection to the stage of secondary diseases is a manifestation of depletion of the body's defensive reserves. Virus replication accelerates, as does the rate of decline of the CD4 lymphocyte count. However, this process is still reversible (at least for some time). The clinical manifestations of the secondary diseases may disappear, either spontaneously or as a result of therapy. Therefore, phases of progression (in the absence of antiretroviral therapy, or with inadequately effective antiretroviral therapy) and remission (spontaneous, after previous antiretroviral therapy, or during antiretroviral therapy) are distinguished in the stage of secondary diseases. Stage 5. The terminal stage. The secondary diseases become irreversible in stage 5. Even adequately managed antiretroviral therapy and therapy of the secondary diseases are ineffective, and the patient dies within several months. A fall in the CD4 cell count below 0.05x109/L is typical for this stage. It should be noted that the clinical course of HIV infection is marked by great diversity. The data given on the duration of particular stages of the disease are averaged in nature and may vary substantially. The sequence of the progression of HIV infection through all stages of the disease is not obligatory. For example, should a patient develop pneumocystis pneumonia, the latent stage may proceed directly to stage 4C, bypassing stages 4A and 4B. Cases are known in which the latent stage has proceeded directly to the terminal stage. The duration of the HIV infection varies within wide limits. The most rapid progression of the disease described has been 28 weeks from the time of infection to death. On the other hand, cases are known in which the disease remained asymptomatic more than 20 years. As a rule, the older the age at which HIV infection is contracted, the more rapid its progression. Special features of the course of HIV infection in users of psychoactive substances. In users of psychoactive substances, who at the present time make up the overwhelming majority of HIV patients, the course of the illness has some specific features which may impede determination of the stage of the disease. In particular, in these individuals, the observed fungal and bacterial lesions of the skin and mucosae, as well as bacterial abscesses, phlegmons, pneumonias, sepsis, and septic endocarditis are usually not the consequence of HIV infection, and may develop even with a normal CD4 lymphocyte count. They may not, in and of themselves, be considered staging criteria in this group of patients. At the same time, the presence of these conditions fosters more rapid progression of HIV infection. Special features of the clinical picture of HIV infection in children. Overall, the course of HIV infection is similar in children and adults, and goes through the same stages. 13

However, there are certain differences. Lagging rates of psychomotor and physical development are the most common clinical manifestation of HIV infection in children. Recurring bacterial infections, as well as lymphoid interstitial pneumonitis, hyperplasia of the pulmonary lymph nodes, and encephalopathy are encountered in children more often than in adults. Kaposi's sarcoma is very rare. Thrombocytopenia, appearing clinically as a hemorrhagic syndrome which may be a cause of death in children, is frequently encountered. Anemia is also a fairly common symptom. HIV infection in children born to HIV-infected mothers, especially if intrauterine infection has taken place, is characterized by more rapid progression as compared with adults and children infected over the age of 1 year, and in comparison with children infected in the first year of life by other routes. On the other hand, the course of the disease is prognostically more favorable as a rule in children infected over the age of one year by comparison with adults.

5. Validation of a First-Time Clinical Diagnosis of HIV infection

When a patient is suspected of having HIV infection, he or she undergoes an initial evaluation to confirm the clinical diagnosis of HIV infection, determine the stage and phase of the disease, and to identify the patient's secondary and concurrent diseases in order to define the approach to further management. Counseling of the patient on issues relating to HIV infection must precede the initial evaluation. The purpose of counseling is to prepare the patient psychologically for appropriate understanding of the HIV infection diagnosis and for his or her adjustment to the prospect of life with the disease. The counseling is carried out by a specially trained professional. Following confirmation of the diagnosis of HIV infection, counseling is carried out by a professional with a higher medical education, preferably by the attending physician. At the initial evaluation, in addition to examination by the attending physician, which includes history-taking and physical examination, blood testing for HIV antibodies is recommended, if it has not been done earlier, or if more refined diagnosis is required. A complete blood count (including hemoglobin, erythrocytes, platelets, hematocrit, differential), blood biochemistries (bilirubin and its fractions, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, amylase or lipase, glucose, creatinine, urea), urinalysis, skin testing (tuberculin), blood testing for hepatitis B and C markers, stool testing for helminths and protozoa, chest x-ray, ultrasonography of the abdominal organs and kidneys, ECG, and specialist examinations (dermatologist, gynecologist, neurologist, otorhinolaryngologist, psychiatrist, ophthalmologist, dentist) are also done. Determination of the CD4 lymphocyte count and the amount of virus RNA in the blood (viral load) are done if possible. When the clinical diagnosis of HIV infection made for the first time in a given patient, it must first be validated on the basis of epidemiological, clinical, and available laboratory data, and the illness must then be staged with reference to its characteristic manifestations. The epidemiological diagnosis "Perinatal HIV Contact" is made in children born to HIV-infected mothers. A child with this diagnosis is observed up to 18 months of age; observation of the child is discontinued unless clinical and laboratory evidence in favor of HIV infection is found during that time. The diagnosis "HIV infection" in a child born to an HIV-infected mother may be made if the child is found to have clinical 14

(development of opportunistic diseases, especially in combination with lymphadenopathy) and/or laboratory (detection of HIV DNA or RNA in no fewer than three tests taken at an interval no shorter than 2 months) signs of HIV infection. The finding of HIV antibodies in a child in the first year of life does not constitute confirmation of HIV infection. Three negative HIV DNA results from blood samples taken at an interval no shorter than 2 months, provided the child's HIV antibodies have disappeared, and in the absence of clinical signs of the disease, makes it possible to discard the diagnosis at the age of 12 months. Examples: 1. HIV infection can be diagnosed on the basis of the epidemiological history (sexual contact with an HIV-infected individual), lymphadenopathy, and the presence of HIV antibodies (gp 41, 160). Taking into account the repeated episodes of herpes zoster, the currently observed fever, more than a month in duration, and the white film on the oral mucous membrane, it can be assumed that the patient is in the stage of secondary diseases (4B). Diagnosis: HIV infection, stage 4B. Recurrent herpes zoster by history. Oral thrush. The evaluation plan should be outlined next. 2. Diagnosis: HIV infection, based on the epidemiological history (parenteral drug use), generalized lymphadenopathy, and detection of HIV antibodies (gp 41, 120, 160). Considering the patient's pneumonia of unclear etiology, shortness of breath, and areas on the head and genitalia suggestive of Kaposi's sarcoma, HIV infection stage 4C can be diagnosed. Diagnosis: HIV infection, stage 4C, r/o Kaposi's sarcoma, r/o pneumocystis pneumonia. The evaluation plan should be outlined next. 3. The diagnosis of HIV infection, stage 2C (stage of primary manifestations with development of secondary diseases), can be made on the basis of the epidemiological history: blood transfusion 3 weeks before from an HIV-infected donor; fever accompanied by pharyngitis and macular rash on the trunk, candidial stomatitis. The evaluation plan should be outlined next. 4. Epidemiological data (sexual contacts with unknown partners) and repeated detection of antibodies to HIV glycoproteins, despite the absence of clinical manifestations, permit the diagnosis of HIV infection. Stage 3 (latent). 5. Based on the absence of epidemiological data suggesting infection of a 12-year-old girl, and the absence of clinical manifestations, the diagnosis of HIV infection is doubtful despite detection of antibodies to HIV proteins with molecular weights of 17 kd and 24 kd. Repeat testing for HIV antibodies in 3 months is recommended. 6. The epidemiological diagnosis "Perinatal HIV Contact" is discarded, based on the absence of clinical signs and symptoms of HIV infection and of laboratory evidence in its favor in a 2-year-old child born to an HIV-infected mother.

6. Determination of Severity of the Course and Prognosis of HIV Infection

After the diagnosis of HIV infection is made, further in-depth evaluation is carried out; the character of the course of the disease, the degree of immune impairment, the etiology, and the nature of the secondary diseases are determined more precisely; appropriate therapy is instituted accordingly.

15

6.1. Clinical criteria of severity of the course and prognosis of HIV infection The presence, severity, and frequency of clinical manifestations of HIV infection and secondary diseases are the clinical criteria used in assessing the severity of the course of the disease. The more often opportunistic diseases appear, the more severe they are, and the more poorly they respond to treatment, the worse the prognosis. It is also thought that the more severe the course of the stage of early HIV infection (stage 2), that is, if it has progressed as an acute infection, especially with manifestations of immune deficiency, the more rapidly the HIV infection will progress afterwards. It is recommended that the overall assessment of the patient's quality of life be based on the Karnovsky scale (appendix 2). Since the majority of HIV-infected patients are picked up in the asymptomatic period of the disease, the determination of indications for initiating specific treatment is one of the tasks of follow-up care. Various criteria for assessing the severity of the course of the disease and its prognosis are used for this purpose. The simplest way of determining the transition of the disease to a stage requiring treatment is the discovery of early secondary diseases (stage 4A). Follow-up care of HIV-infected individuals, including history-taking aimed at detecting signs of the appearance of opportunistic diseases between visits to the doctor as well as careful evaluation of the patient, is indicated in order to identify these conditions. The attending physician assesses the presence or disappearance of the various clinical manifestations as an index of change in the stage and character (phase) of the disease. The presence of manifestations of opportunistic diseases is a criterion for instituting antiretroviral therapy and treatment of a concurrent opportunistic disease. If laboratory testing is available, the physician has an opportunity to predict the appearance of opportunistic diseases on the basis of such signs as a fall in the CD4 cell count. A high blood content of HIV is a prognostic sign of more rapid progression of the disease. 6.2. The use of laboratory criteria for assessing the severity of the course and prognosis of HIV infection When the physician has the option of obtaining data from complex and expensive laboratory testing of the HIV-infected patient, the CD4 lymphocyte count and the blood viral load can be used to assess the probability of progression of the disease. These indicators can be used as criteria to justify the institution of therapy for HIV infection in the absence of clinical manifestations. 6.2.1. Determination of the CD4 lymphocyte count Measuring the CD4 lymphocyte count makes it possible to judge the depth of patient's evolving immune deficiency. The extent of the fall in the CD4 cell count may serve as a criterion of the probability of the emergence of various secondary diseases. Flow cytometry provides the most exact CD4 lymphocyte counts. The CD4 lymphocyte count in adult patients in the latent stage of the disease usually exceeds 0.5x109/L. A persistent fall in CD4 below this level results in a transition of the HIV infection to stage 4A, while a fall below 0.35109/L and 0.2x109/L leads to stage 4B and 4C, respectively. A fall below 0.5x109/L all the way down to a complete absence of CD4 cells is typical for stage 4. These are rough figures, however, since as a rule the drop in CD4 cell count somewhat anticipates progression of the disease. On the other hand, patients with a very low CD4 cell count, less than 0.2x109/L or even 0.1x109/L, sometimes live for several years. 16

The significance of the CD4 lymphocyte count also depends on the fact that this value helps determine the need not only for antiretroviral therapy, but for chemoprophylaxis of secondary diseases as well. Assessment of the changes in the CD4 lymphocyte count over time during treatment may also be a criterion of its efficacy. An increase in this count, or at least the absence of a significant (more than 30%) fall 4 weeks after the initiation of antiviral therapy, may point to its efficacy. If a fall in CD4 <0.2x109/L is found for the first time (except for stages 4C and 5), the study should be repeated in 2 weeks. In stage 4C, with a CD4 <0.2x109/L or one which is not known, a medical examination is done monthly. Since the CD4 lymphocyte count may fall temporarily for reasons unrelated to progression of the HIV infection, for instance as a result of an acute infectious disease or vaccination, the results of testing done within 4 weeks after such an episode cannot be regarded as criteria for instituting antiretroviral therapy (or evaluating its efficacy). A repeat evaluation is indicated in these cases. 6.2.2. Quantifying the presence of HIV The blood concentration of HIV RNA, the so-called "viral load," is currently considered one of the principal laboratory markers of progression of HIV infection. Increased viremia is the earliest indicator of incipient progression of the disease and an unfavorable prognostic sign. The HIV RNA concentration is measured in terms of the number of HIV RNA copies in a milliliter of blood. This is sometimes measured in decimal logarithms (log10). Since two RNA copies are contained in each human immunodeficiency virus, the number of viral particles in the blood is half the viral load. The viral load is used to determine indications for initiating antiretroviral therapy and to rapidly assess its efficacy. A viral load greater than 60,000 HIV RNA copies in a milliliter of blood indicates the need to initiate antiretroviral therapy. A no smaller than three-fold (by 0.5 log) difference in this value as compared with the preceding level is regarded as a significant change in the HIV RNA concentration. A three- to five-fold decrease in HIV RNA is observed as early as the 4th to 8th week with effective antiretroviral therapy. The HIV RNA level is not measurable in the majority of patients by the 12th to 16th week of treatment. Acute infectious diseases (not necessarily associated with HIV infection) and vaccination can temporarily increase the viral load. Therefore, testing results obtained within 4 weeks following such episodes cannot be considered criteria for instituting therapy. Repeat testing is indicated in such cases. 6.2.3. Special features of the assessment of laboratory values in children Special age-related features must be considered when assessing immunological findings in children below 6 years of age. Because of considerable individual fluctuations, changes in CD4 count can be regarded as reliable if they are confirmed by repeat testing at an interval of at least 1 week. A CD4 cell count over 1.5x10 9/L is an indicator of the absence of reduced immunity in children up to the age of one year. A decrease in the CD4 count below this level indicates the development of immune deficiency. In this case, the immune deficit is moderate if the CD4 count exceeds 0.75x109/L, and marked if CD4 <0.75x109/L. In children 1-5 years of age, a fall in the CD4 cell count below 1.0x109/L is a sign of moderate immune deficit, 17

and below 0.5x109/L, of marked immune deficiency. In children over 6 years of age, as in adults, a fall in the CD4 cell count below 0.5x109/L is a sign of moderate immune deficit, and below 0.2x109/L, of marked immune deficiency. Since the absolute values of the CD4 lymphocyte count in children up to the age of 6 years exhibit substantial age-related fluctuations, greater attention is paid to its percentage in their case than in the case of adults. A fall below 24% signifies a moderate decline in the percentage of CD4 cells, while a fall below 15% in the CD4 count signifies a marked decline. If the absolute and percentage values do not correspond when the degree of immune deficiency is evaluated, the percentage should be taken as the guide. Interpretation of the findings of the study of blood concentration of HIV RNA is also more difficult in children than in adults. This is especially so in children born to HIV-infected mothers with very high viremia. It should be noted that as a rule the HIV RNA level in these children falls even in the absence of treatment, by 0.6 log10 on average (approximately 4-fold) in the first year of life. It continues to fall in subsequent years (up to 5 years), approximately 2-fold per year. Individual fluctuations in HIV RNA concentration are considerably more pronounced in children than in adults. Up to 2 years of age, repeatedly recorded changes at least 5fold in magnitude are considered significant; above two years, those that are at least 3-fold.

III. FOLLOW-UP CARE OF HIV-INFECTED INDIVIDUALS

HIV-infected individuals should be evaluated periodically, that is, they should be in follow-up care. The purpose of follow-up care of HIV-infected patients is to provide timely medical assistance, including psychological support. Since patients are not always able to detect the signs of illness or psychological problems in themselves, it is advisable to identify them actively by means of periodic evaluations. Thus the purpose of planned evaluation of the HIV-infected individual in the period of follow-up care is the timely detection of the threat of progression of the disease and the institution of appropriate treatment. According to current law, evaluations of a patient within the framework of follow-up care must be done with his or her voluntary informed consent. HIV-infected individuals should be actively invited for periodic evaluations, but at the same time their right to refuse evaluation and treatment must not be infringed, nor equally their right to be followed in a medical facility of their choice. The following is done in the initial evaluation: Examination by the attending physician (counseling, history-taking, complete physical examination). Recording of secondary diseases, their change over time, and their course. Recording of concurrent diseases. Quality of life assessment on the Karnovsky scale (see appendix No. 2). Chest x-ray (if it has not been done in the past 6 months). Ultrasonography (USG) of the abdominal organs (liver, pancreas) and kidneys. Ophthalmology consult (eye grounds). 18

Otorhinolaryngology consult (hearing examination). Neurology consult. Dental consult. For women gynecology consult. Testing of serum or plasma for HIV antibodies by solid-phase enzyme immunoassay (EIA). (In case of a positive result, repeat immune blotting is done only if this study has not been done previously, or if it was in doubt.)

Complete blood count (hemoglobin, hematocrit, platelets, erythrocytes, leukocytes, differential, ESR).

Blood biochemistries (creatinine, urea, alanine aminotransferase - ALT, aspartate aminotransferase AST, alkaline phosphatase - AP, lactate dehydrogenase - LDH, bilirubin and its fractions, creatinine phosphokinase - CPK, amylase or lipase, glucose).

Urinalysis. Testing for viral hepatitis B and C markers. Serological testing for syphilis markers. Immunological evaluation (determination of the CD4 and CD8 lymphocyte count using flow cytometry, monoclonal antibodies).

Determination of blood HIV RNA level (if this resource is available).

Specialist consults may not be needed if the evaluation in question has been done by an attending physician qualified to do such. Other studies may also be done at the discretion of the attending physician when additional indications exist. If the evaluation establishes an HIV infection in stage 4C or the CD4 cell count is found to be below 0.2x109/L, examination of the brain by computed tomography (CT) or nuclear magnetic resonance imaging (NMRI) is recommended. The patient should then have repeat planned evaluations for timely identification of indications to initiate antiretroviral therapy, or if it has already begun, to adjust it. Planned evaluations of patients in stage 3 (latent) are done every 6 months; of patients in later stages of HIV infection, every 3 months. If it is known that the CD4 lymphocyte count is below 0.5x109/L, planned evaluations are done every 3 months. The scope of the repeat planned evaluations differs somewhat from the initial evaluation. Testing for HIV antibodies is not done; consults with narrow specialists, except dental, ophthalmological, and neurological, are done only when indicated; testing for viral hepatitis B and C and syphilis markers is done every 24 weeks. The scope of a repeat planned evaluation also depends on the stage of the disease and, if known, the CD4 cell count. For patients in stage 3 with a >0.5x109/L or unknown CD4 count, as well as for patients in stage 4A with a >0.5x109/L or unknown CD4 count, a chest x-ray and ultrasonography of the abdominal 19

organs are done once a year (48 weeks); in the remaining cases, twice a year (every 24 weeks). For these patients, neurological and dental consults are done every 24 weeks; in the remaining cases, every 12 weeks. When there are additional epidemiological and clinical indications suggesting the presence of secondary or concurrent diseases for which the scope of a planned evaluation is insufficient, additional studies may be done as the attending physician decides. Non-planned evaluations are done when signs of progression of HIV infection appear or when concomitant diseases develop. The schedule of evaluations of children born to HIV-infected mothers is given in appendix 4.

IV. THE TREATMENT OF HIV INFECTION

Considering the impossibility of complete cure of the HIV patient at the present time, the aim of treatment is the maximal prolongation of the patient's life and preservation of its quality. The main objectives are as follows: At the stage of primary manifestations (Stage 2) to attain the greatest reduction in severity and duration of the clinical manifestations observed at this stage of the disease and to shorten the period of marked viremia. At the latent stage of primary manifestations (Stage 3) and in the phase of remission of the secondary diseases (Stage 4) to prevent or delay the development of life-threatening conditions, and to support the preservation of the quality of life of infected individuals as long as possible. At the stage of secondary diseases (Stage 4) and in the phase of clinical progression to attain remission and restoration of quality of life and its long-term preservation, if possible, by means of rational therapy and prophylaxis of secondary diseases in combination with antiretroviral therapy. The following may be viewed as fundamental principles of the therapy of HIV infection: Creation of the required protective psychological conditions. Timely initiation of effective etiotropic (antiretroviral) therapy and prophylaxis of secondary diseases. Careful choice of drugs and selection of the required minimum. Timely treatment, requiring early diagnosis, of secondary diseases.

1. Creation of protective psychological conditions for HIV-infected individuals

Knowledge of the incurability of HIV infection and its fatal prognosis provokes severe emotional reactions in the HIV-infected individual, associated with sudden awareness of the inevitability of death. Prejudice toward those who are infected and ill is seen in the public consciousness, since in the majority of cases infection with HIV is regarded by society as a predictable result of amoral and antisocial behavior. When those around him (her) become aware that he (she) is infected, they react with rejection, which has an even more oppressive effect on his (her) mind. Infection with HIV entails serious emotional and social consequences, alters the individual's habitual behavior, and impacts on family relationships and legal status. Adaptation to 20

life with HIV infection implies a constant struggle against psychotraumatic experiences. As a result of this, the moment HIV infection is suspected, the patient is subjected to constant psychogenic stress; this requires measures to mitigate its medical and social consequences. The circle of individuals having access to personal information relating to the HIV-infected individual must be maximally restricted and steps must be taken for his (her) social adaptation. The patient's social adaptation, including psychological help, prevents aggressiveness toward society, the wish for "revenge by spreading AIDS"; it is a safeguard against the temptation to engage in prostitution or drug dealing to make up for financial losses due to the loss of livelihood. In the majority of cases, medical personnel cannot solve the material or personal problems of HIVinfected individuals, but can guard them against improper actions adversely affecting their mental state. Individual discussion as well as family psychotherapy are the most accessible forms of psychological help. The physician can use elements of explanatory and rational psychotherapy in discussion. Explanatory psychotherapy is effective in those cases in which the patient willingly listens to the physician's explanations aimed at correcting the patient's thinking and his (her) assessment of his disease state or the situation which caused the mental trauma. Rational psychotherapy is used in cases in which the patient does not agree with the physician regarding these matters. Logical persuasion is an essential feature of this method. Psychotherapeutic intervention that could have an activating effect on the patient and stimulate activity directed toward finding the best way out of the psychotraumatic situation, toward preparing him (her) for the inevitable reorganization of his (her) pattern of life, and toward adaptation to altered life prospects, is strongly indicated. In addition to the attending physician, professionals who have had special training in HIV counseling should be involved in the patient's psychosocial adaptation. Since it does not seem possible in the majority of cases to eliminate the psychotraumatic factors themselves, counseling is one of the most important methods for creating protective psychological conditions. Counseling and psychological support of HIV-infected individuals is implemented with their voluntary consent. It is recommended that psychological help be offered to patients during each planned and non-planned evaluation. Psychological support is then provided to particular individuals as indicated.

2. The chemotherapy of HIV infection

One of the special characteristics of HIV infection is the multiplicity of etiologies of, and organs affected by, the secondary diseases associated with it. For this reason, the therapy given to these patients must, as a rule, have multiple components. The list of vitally important drugs required for the treatment of HIV infection is given in appendix 5. Treatment with antiretroviral drugs, and the chemoprophylaxis and treatment of the secondary diseases, are among the principal lines of chemotherapy for HIV patients. 2.1. Antiretroviral Therapy 2.1.1. Indications for initiating antiretroviral therapy The indications for instituting antiretroviral therapy for the HIV patient and the approach to its administration are determined by the clinical stage of the disease. The blood CD4 lymphocyte count and RNA concentration 21

(viral load) may be criteria for initiating treatment (assuming these studies can be done), but the clinical course of the disease is the principal criterion. Clinical evidence, namely HIV infection in the stage of primary manifestations in a clinically expressed form (acute HIV infection, 2B, 2C) and the stage of secondary diseases (4b, 4C) in the phase of clinical progression, is an obligatory indication for the initiation of antiretroviral therapy. When antiretroviral therapy is instituted on the basis of clinical indications, it must be remembered that fungal and bacterial disorders (lesions of the skin and mucosae, abscesses, phlegmons, pneumonias, endocarditis, sepsis, etc.) in users of psychoactive substances are more often not the consequence of HIV infection, but the result of immune deficiency associated with the use of narcotics. In such cases instituting antiretroviral therapy is not rational. Laboratory indications for the administration of antiretroviral therapy are a fall in CD4 lymphocyte count below 0.3x109/L, or an increased blood HIV RNA concentration, the so-called "viral load," above 60,000 copies per mL. These values should be considered only if the patient did not have an illness accompanied by inflammatory processes or vaccinations in the month prior to their discovery. If laboratory indications for antiretroviral therapy have been found for the first time, a repeat study at an interval of at least 4 weeks must be done to determine the appropriateness of initiating therapy. Instituting antiretroviral therapy at the different stages of HIV infection: Therapy is not instituted in stage 1, with the exception of the first three days after possible infection, when preventive therapy is initiated (chemoprophylaxis of infection, see section V). Antiretroviral therapy is not given in stage 2, in the absence of clinical manifestations of acute HIV infection (stage 2A - asymptomatic seroconversion), except when it is known that the CD4 lymphocyte count is below 0.3x109/L or the HIV RNA concentration is greater than 100,000 per mL. Prescribing antiretroviral drugs is recommended in stage 2B (acute HIV infection without secondary diseases) or 2C (acute HIV infection with secondary diseases). In this case treatment consists of thymazide or phosphazide monotherapy or bitherapy. If in stage 2C the patient develops secondary diseases that are characteristic of stages 4B or 4C, highintensity therapy is recommended. A fall in the CD4 cell count below 0.2x10 9/L is also an indication for highintensity therapy in stage 2. The duration of monotherapy in stage 2 patients is at least 12 weeks; of highintensity therapy, at least 24 weeks. Therapy is instituted in stage 3 if it is known that the CD4 lymphocyte count is less than 0.3x10 9/L or the HIV RNA is greater than 60,000 per mL. Therapy is instituted in stage 4A in the stage of remission, as in stage 3, if it is known that the CD4 lymphocyte count is less than 0.3x10 9/L or the HIV RNA is greater than 60,000 per mL. Treatment is instituted in the stage of progression when the CD4 cell count is less than 0.3x10 9/L or HIV RNA is greater than 60,000 per mL. However, it is also recommended in this phase for patients whose secondary diseases are not amenable to treatment or who relapse and whose CD4 lymphocyte count and the HIV RNA concentration cannot be determined. Therapy is instituted in stage 4B in the phase of remission if it is known that the CD4 lymphocyte count is less than 0.3x109/L or the HIV RNA is greater than 60,000 per mL. It is instituted in the stage of progression regardless of the CD4 count and HIV RNA. 22

The indications for instituting antiretroviral therapy in stage 4C are the same as in stage 4B. Antiretroviral therapy is not given in stage 5. 2.1.2. Evaluation to identify indications for antiretroviral therapy A supplemental evaluation of the patient is carried out to identify indications for antiretroviral therapy. It accomplishes the following objectives: 1. 2. 3. Confirmation of the need for therapy. Determination of the patient's desire and readiness to be treated. Identifying data suggesting the presence of contraindications to it or to particular drugs.

A final decision is made on the basis of the data obtained regarding a given patient's need for antiretroviral therapy, and the approach to the therapy, its scope, and components are determined. Since the psychological preparation of the patient is the most important component of treatment success, he (she) is provided counseling regarding the anticipated efficacy, contraindications, and complications of the planned therapy. Women of childbearing age are informed of the possible effect of their therapy on the course of pregnancy and the development of the fetus. All information must be presented to the patient not only orally, but in writing as well. Treatment is done on a voluntary basis and presupposes the active participation of the patient; therefore, it is inadvisable to prescribe treatment to individuals who are unable to observe the drug regimen. The patient's written informed consent must be obtained before treatment is instituted (appendix 6). The approach to the evaluation to be done to confirm the need for specific therapy is determined by the preceding course of the illness and its stage. When clinical manifestations of acute HIV infection, 2B and 2C, are present, treatment is given in stage 2 (the stage of primary manifestations) regardless of HIV RNA concentration and CD4 lymphocyte count. Investigation of these parameters in this case is significant only for subsequent assessment of the efficacy of therapy. When the stage of primary manifestations unfolds in the form of asymptomatic seroconversion (2A), treatment is instituted if it is known that the CD4 lymphocyte count is below 0.3x10 9/L or the viral load is greater than 100,000 HIV RNA copies per mL. If a high viral load is the indication for instituting therapy in stage 3 (latent infection), 4A, and in the phase of remission in stages 4B and 4C , it should be studied again in 4 weeks when the preceding result was >30,000 copies/mL. If the indication is a low CD4 lymphocyte count, the study should also be repeated in 4 weeks if the result obtained differs from the preceding result by more than 30%. If indications for administering therapy have not been confirmed, planned re-evaluation is done in 12 weeks. Treatment is instituted in the phase of clinical progression of stages 4B and 4C regardless of the viral load and CD4 lymphocyte count. However, since the CD4 lymphocyte count may be of significance for subsequent assessment of the efficacy of therapy, this study is repeated in 2 weeks if available, if the results differ from the preceding study by more than 30%, and treatment is instituted only after that. The evaluation carried out for the purpose of identifying possible contraindications to therapy and its components (so-called "safety tests") includes the following: 23

Examination by the attending physician (including counseling, history-taking, complete physical examination, identification of concomitant diseases, recording of concurrent therapy).

Recording of secondary diseases and determination of the change in their course over time. Determination of the quality of life rating (appendix No. 2). Chest x-ray (if it has not been done in the past 6 months). USG of the abdominal organs (liver, pancreas) and kidneys (if it has not been done in the past 6 months). Ophthalmology consult (eye grounds). Otorhinolaryngology consult (hearing loss). Neurology consult. For women gynecology consult. Complete blood count (hemoglobin, hematocrit, platelets, erythrocytes, leukocytes, differential). Blood biochemistries - total proteins, cholesterol, creatinine, urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), lactate dehydrogenase (LDH), bilirubin and its fractions, creatinine phosphokinase (CPK), amylase or lipase, glucose).

Urinalysis. For women who are able to bear children, express test for pregnancy (at least three days before initiation of treatment).

Specialist consults may not be needed if the evaluation in question has been done by an attending physician qualified to do such. When deciding whether or not to institute therapy, consultation/counseling with a psychiatrist or psychologist is recommended to determine the patient's attitude toward therapy and his (her) ability to comply with the drug regimen. Other studies may also be done at the discretion of the attending physician when additional indications exist. While performing "safety tests," data obtained within 2 weeks prior to the initiation of treatment may be used. The chest x-ray and USG (data for the past 6 months may be used) as well as the express test for pregnancy, which must be done no later than three days before initiation of treatment, are the exception. The recording of "side effects" arising in the course of treatment is an important element in the management of patients receiving antiretroviral therapy. "Side effects" mean all changes in the patient's condition or in the results of his (her) physical, instrumental, or laboratory evaluation, regardless of whether or not, in the opinion of the patient or the physician, they are related to the therapy, since such a relationship may be identified later. When side effects appear, the patient may undergo a non-planned or additional evaluation to elucidate the underlying causes. 2.1.3. Antiretroviral drugs and antiretroviral therapy regimens HIV reverse transcriptase inhibitors and HIV protease inhibitors, used for specific antiretroviral therapy of HIV infection, as well as drugs of the interferon inducer group, which have nonspecific antiviral activity, are 24

currently employed as agents acting on HIV. As of the end of 2000, 13 antiretroviral drugs, including 7 HIV reverse transcriptase inhibitors of the nucleoside analog group, 2 non-nucleoside analog reverse transcriptase inhibitors, and 4 drugs of the HIV protease inhibitor group, were authorized for use in Russia (appendix 7). The antiretroviral drugs may be used as monotherapy (treatment with one drug, more commonly a reverse transcriptase inhibitor), bitherapy (using two drugs of the reverse transcriptase inhibitor group), and combined therapy (a combination of HIV reverse transcriptase inhibitors and HIV protease inhibitors). So-called "high-intensity antiretroviral therapy" (sometimes called "intensive," "highly aggressive," "heavy," or "combined" therapy) is the most effective regimen at the present time; it is usually given as tritherapy (using two reverse transcriptase inhibitors of the nucleoside analog group, and one drug of the nonnucleoside reverse transcriptase inhibitor group or a protease inhibitor). More intensive regimens are used when previous therapy has been ineffective. When deciding whether to institute high-intensity antiretroviral therapy, the improper use of which is associated with the formation of strains of the virus that are resistant to several drugs at the same time, social and psychological criteria - namely the patient's readiness and ability to fully pursue the instituted treatment and related evaluations, as well as medical criteria, must be considered. Timely institution and choice of optimally effective and tolerated regimen are extremely important for the success of antiretroviral therapy. A characterization of the antiretroviral drugs authorized for use in Russia is given in appendix 7; information on the possibility of combining the antiretroviral drugs with one another is given in appendix 8; information on their principal side effects is presented in appendix 9; and information on interaction with other drugs, in appendix 10. Recommendations for formulating antiretroviral therapy regimens are given in appendix 11. Since maximum avoidance of any interruptions of drug dosage is especially important for the success of antiretroviral therapy, the convenience of the drug dosage routine for the patient, as well as his (her) ability and desire to pursue treatment in strict accordance with the regimen prescribed, must be taken into account when selecting the therapeutic regimen. All else being equal, preference should be given to regimens requiring the least number of tablets (capsules) and avoiding the need to take medications during the work day. The cost of the drugs included in the therapeutic regimen and reliability of supply are of considerable importance. Therefore the choice of therapy regimens must be determined in keeping with the available resources. Institution of high-intensity antiretroviral therapy regimens is recommended at the present time, but if it is impossible to administer the most efficacious treatment regimens for any reason, a less intensive regimen is prescribed. 2.2. Using Particular Antiretroviral Therapy Regimens 2.2.1. Monotherapy with nucleoside analog reverse transcriptase inhibitors Monotherapy can be used in a protracted regimen when it is impossible for any reason to administer more 25

intensive treatment. Monotherapy can be given according to the following regimens: Thymazide (AZT), 0.1 g capsules, 2 capsules 3 times per day (0.6 g in 24 hours). Phosphazide (P-AZT), 0.2 g tablets, 2 tablets 2 times per day (0.8 g in 24 hours) or 1 tablet (0.2 g) 3 times per day (0.6 g in 24 hours). When monotherapy with thymazide or phosphazide cannot be carried out, d4T can be used. or in an extreme case, ddl. Even one of the changes listed below may be a criterion for replacement of therapy as insufficiently effective over the course of 12 weeks since its initiation: Clinical progression of HIV infection (shift to the phase of progression or to a later stage, the appearance of new secondary diseases) later than 4 weeks since the initiation of treatment. Drop in CD4 lymphocyte count greater than 30% of the initial (at the time of initiation of treatment) count (if this decline was not caused by bacterial or viral illness unrelated to HIV, or by inoculation). Absence of a reduction in the blood HIV RNA concentration after 4 weeks (if there was no bacterial or viral illness unrelated to HIV, or inoculation, during this time). A monitoring evaluation is carried out at the conclusion of the 12-week course (see appendix 13). If clinical signs of deterioration and progression of the disease are not found, a 3-month break in treatment is taken, after which a planned evaluation is carried out. When laboratory monitoring of treatment efficacy is available, absence of a drop in CD4 lymphocyte count and a decreased viral load may be indications for a planned treatment break. If clinical progression of HIV infection (progression of secondary diseases or the appearance of new ones, shift to the next stage of HIV infection), a drop in CD4 lymphocyte count, or the absence of a greater than three-fold fall in the amount of virus in the blood are discovered as a result of this evaluation, more intensive therapy must be instituted, or if this is not possible, an alternative drug. 2.2.2. Bitherapy using two HIV reverse transcriptase inhibitors Currently, one of the drugs working in activated cells (thymidine derivatives - AZT, P-AZT, d4T) and one of the drugs working in resting cells (derivatives of adenine - ddl, or of cytosine - ddC, 3TC) are employed for bitherapy using two drugs of the nucleoside analog reverse transcriptase inhibitor group. Here preference should be given to ddl, since it is recommended that ddC be prescribed only if prescribing the other drugs is impossible; the probability of resistance is greater in bitherapy using 3TC. Bitherapy may be instituted when previous monotherapy is insufficiently efficacious and high-intensity antiretroviral therapy is not possible for any reason. Criteria for replacement of the treatment regimen in bitherapy as insufficiently effective over the course of 12 weeks are: Clinical progression of HIV infection (shift to the phase of progression or to a later stage, the appearance of new secondary diseases) later than 4 weeks since the initiation of treatment. 26

Drop in CD4 lymphocyte count greater than 30% of the initial (at the time of initiation of treatment) count (if this decline was not caused by bacterial or viral illness unrelated to HIV, or by inoculation).

Absence of a reduction in the blood HIV RNA concentration after 4 weeks (if there was no bacterial or viral illness unrelated to HIV, or inoculation, during this time).

Possible results and approach to further management of the patient in the absence of changes in the course of the disease after a 12-week course are given in appendix 14. 2.2.3. Therapy with several antiretroviral drugs (high-intensity antiretroviral therapy) High-intensity antiretroviral therapy refers to the use of one drug from the protease inhibitor group or from the non-nucleoside analog reverse transcriptase inhibitor group in combination with two drugs from the nucleoside analog reverse transcriptase inhibitor group. The combination of nucleoside analog reverse transcriptase inhibitors for high-intensity antiretroviral therapy is selected according to the same principle as in the case of bitherapy. That is, one of the thymidine derivatives - AZT, P-AZT, d4T, and one of the nonthymidine derivative drugs - ddl or 3TC (if these cannot be prescribed - ddC), are selected. Other options for formulating antiretroviral therapy regimens are used less often, primarily in the form of alternative regimens. Their efficacy and safety are not as well studied. These are regimens using three nucleoside analog reverse transcriptase inhibitors (in this case, abacavir is used instead of a protease inhibitor or non-nucleoside analog reverse transcriptase inhibitor), or a combination of a protease inhibitor along with a non-nucleoside analog reverse transcriptase inhibitor and a nucleoside analog reverse transcriptase inhibitor. The simultaneous use of four or more antiretroviral drugs may serve as a high-intensity antiretroviral therapy option. This can be a combination of two reverse transcriptase inhibitors and two protease inhibitors, or the addition of one non-nucleoside analog reverse transcriptase inhibitor to the treatment regimen. Regimens using four and sometimes even five drugs are used almost exclusively as salvage regimens when previous therapy has been ineffective. Regimens using a combination of ritonavir and two protease inhibitors are an exception. High-intensity antiretroviral therapy is usually given in the form of tritherapy. The classical tritherapy regimen (combined therapy) includes two reverse transcriptase inhibitors and one HIV protease inhibitor. Regimens in which not one but two protease inhibitors are prescribed were first used in recent years; one of these is ritonavir, which is capable of increasing the concentration of the drugs in the blood, as well as slowing their excretion. As a result, the protease inhibitors are prescribed in smaller doses and at longer intervals. It is thought at the present time that this can increase the efficacy of therapy, improve its tolerability, and sometimes reduce its cost as well. in addition, high-intensity antiretroviral therapy regimens have recently appeared that include three reverse transcriptase inhibitors, one non-nucleoside and two nucleoside analogs. These regimens are generally less expensive, and they cause lipodystrophy less frequently. The possibility of interaction among the drugs included in a regimen must be borne in mind when selecting drugs to formulate high-intensity antiretroviral therapy regimens. In such a case it is sometimes necessary to change doses and drug dosage regimens. Thus, when nelfinavir and nevirapine are coadministered, the one-time dose of nelfinavir should be increased from 0.75 to 1.0 g, and the 24-hour dose from 2.25 to 3 g. Similarly, for the indinavir-ifavirenz combination, the one-time dose of indinavir is increased from 0.8 to 1.0 g, 27

and the 24-hour dose from 2.4 to 3 g. This increases the cost of therapy and the risk of side effects. Doses of protease inhibitors require especially drastic adjustment (but in this case in the direction of reduction) when they are combined with ritonavir (see appendix No. 7). The cost of treatment may be reduced in the process, and the risk of drug intolerance decreased as well. More detailed information on antiretroviral drugs of the various groups is given in appendix No. 7, and recommendations for formulating high-intensity antiretroviral therapy regimens are provided in appendix No. 11. The following regimen, which has undergone clinical testing in Russia, is recommended as first-line therapy: Phosphazide 0.4 g twice in 24-hours, didanozine 0.2 g twice in 24-hours, nevirapine 0.2 g twice in 24-hours (appendix No. 11). Criteria for replacement of the treatment regimen when high-intensity antiretroviral therapy is insufficiently effective over the course of 12 weeks are: Clinical progression of HIV infection (shift to the phase of progression or to a later stage, the appearance of new secondary diseases) later than 8 weeks since the initiation of treatment. Cases in which therapy was initiated at a CD4 lymphocyte count less than 0.2x109/L, or if it is known that a substantial drop in viral load was noted during treatment, are an exception. Drop in CD4 lymphocyte count greater than 30% of the initial (at the time of initiation of treatment) count (if this decline was not caused by bacterial or viral illness unrelated to HIV, or by inoculation). Absence of a reduction in the blood HIV RNA concentration greater than 0.5 log after 4-8 weeks, or greater than 1 log after 24 weeks (if there was no bacterial or viral illness unrelated to HIV, or inoculation, during this time). A monitoring evaluation is carried out at the conclusion of each 12-week course. Possible findings and approach to further management of the patient are given in appendix No. 16). 2.3. Assessment of the Efficacy and Safety of Antiretroviral Therapy, Criteria for Discontinuation and Replacement of a Therapy Regimen, Prescription of Reserve Regimens Planned evaluations, according to the schedule presented in appendix 3, are done in the course of treatment to assess the efficacy and safety of therapy for the purpose of its timely adjustment. Non-planned evaluations are done if side effects emerge to determine their relationship to the course of the HIV infection and to on-going therapy. Clinical and laboratory criteria are employed to assess the efficacy of antiretroviral therapy. The clinical criteria: progression of the HIV infection and the course of the secondary diseases are the most accessible indicators of the clinical efficacy of treatment for the practicing physician, and from the long-term perspective, the most objective. However, these are insufficiently reliable for short-term observation, due to the slow time course characteristic of HIV infection, the length of the incubation period of most opportunistic diseases, and the impossibility of rapid restoration of depressed immunity. For this reason, the progression of an existing, or the appearance of a new, secondary disease in the HIV patient on antiretroviral therapy in its first 4-8 weeks are not usually regarded as a sign of its inadequacy. 28

The viral load (the concentration of HIV nucleic acids, generally RNA) and the CD4 lymphocyte count are currently considered the most informative of the laboratory criteria for assessing treatment efficacy. With a good treatment effect, the HIV RNA concentration should fall approximately by a factor of 3.5-5 by its 4th-8th week, and more than 10-fold by its 12th-16th week, preferably to an non-detectable level. A significant increase in the absolute number of CD4 lymphocytes (no less than 30%) is observed. Re-testing is done if the HIV RNA concentration becomes detectable again after 6 months of treatment. Criteria for assessing the efficacy for particular antiretroviral therapy options (thymazide monotherapy, bitherapy with two reverse transcriptase inhibitors, high-intensity antiretroviral therapy) are given in section 2.2 and in appendices No. 13, No. 14, and No. 15. When the inefficacy of therapy confirmed, the treatment regimen is changed in light of the availability of antiretroviral drugs, according to a regimen indicated in appendix 16. 2.4. Therapy Adjustment for Drug Intolerance It is advisable when intolerance develops to one of the components of antiretroviral therapy to attempt to take corrective steps first without changing dose or drug dosage regimen. It is possible in the case of monotherapy and bitherapy to lower the dose and to discontinue a drug temporarily. In the case of highintensity antiretroviral therapy, especially if it has been possible to achieve a good effect, it is undesirable to lower the dose of one of the drugs or to discontinue it. Drug replacement should be carried out in view of the mechanism of action and the spectrum of the most commonly encountered toxic manifestations (appendix 9). Possible interaction with other drugs (not only antiretroviral) included in the patient's treatment regimen must also be taken into account (appendix 10). Drugs that the patient is not receiving currently, but which may be prescribed for him (her) shortly, must also not be overlooked. The antiretroviral drug replacement options recommended when intolerance develops are presented in appendix No. 17. If replacement is impossible for any reason, temporary discontinuation of all drugs in the antiretroviral therapy cocktail is advisable in the latent stage (stage 2) of primary manifestations or 4A and 4B, as well as in the remission phase of stage 4C, to avoid selection of resistant HIV strains. 2.5. Special Features of the Treatment of Pregnant Women With Antiretroviral Drugs When antiretroviral therapy is instituted during pregnancy, or when a woman who is already receiving antiretroviral therapy is found to be pregnant, she is counseled in order to explain the possible effect of treatment or refusal of it on her condition and on the health of the future infant. Indications for instituting therapy for HIV-infected pregnant women are the same as those for other patients (the chemoprophylaxis of HIV infection in the fetus is considered in section V). Therapy intensity is determined on the basis of the existing clinical, immunological, and virological indications and information on the particular features of the effect of drugs on the pregnant woman and the fetus. None of the antiretroviral drugs has thus far been shown to be safe for the fetus in well-controled clinical testing in humans in the first 12 weeks of pregnancy. However, such safety has been demonstrated in animal studies for ddl, P-AZT, ritonavir, saquinavir, and nelfinavir. For the other drugs, such studies have either not been conducted, or have demonstrated such a hazard (AZT, ddC, ifavirenz). Antiretroviral drugs' capacity to penetrate the placental barrier varies widely. It is 85% for AZT; 30-50% for 29

ddC; 50% for ddI; 76% for d4T; 100% for 3TC; and 100% for nevirapine. It is very low for indinavir and saquinavir, and has not been studied for nelfinavir and ifavirenz. The question of the advisability of immediate initiation of therapy, when the usual indications are discovered up to 14 weeks of pregnancy, must be resolved on the basis of the seriousness of the patient's condition, the viral load, the CD4 lymphocyte count, and the length of time before the end of the first trimester. If pregnancy has ensued during on-going treatment, the latter should continue if the patient is in the progression phase of stage 3C or has a CD4 lymphocyte count below 0.2x109/L. If necessary, modifications can be made to the therapeutic regimen by selecting drugs that are most suitable for pregnant women. In the remaining cases, the treatment course can be interrupted until the first trimester has elapsed. If the need to discontinue one of the therapy components arises (for instance, due to toxicity), it is better to terminate it temporarily in its entirety. When instituting antiretroviral therapy for pregnant women, regimens including indinavir should be avoided to the extent possible, since it is potentially toxic to the future infant. When previously instituted therapy is ongoing, indinavir should be changed to a different protease inhibitor. Regimens using ifavirenz should also be avoided. It is the most embryotoxic of the antiretroviral drugs in use today (can impair fetal development). If treatment must be instituted in the first 14 weeks of pregnancy, regimens that include phosphazide (P-AZT) and ddl are preferable, as the least hazardous drugs for the fetus in these periods of pregnancy. When previously instituted therapy is on-going, AZT or d4T should be replaced by phosphazide, and ddC or 3TC by ddl. Nelfinavir is preferred among the protease inhibitors. When choosing between AZT and d4T for pregnant women, AZT is preferred as a drug with proven capacity to reduce the risk of intrauterine infection of the fetus. If the patient is already receiving d4T, it should be replaced by AZT (if there are no contraindications to the latter). If, on the other hand, the patient continues for any reason to receive d4T right up to labor, chemoprophylaxis of HIV transmission during labor using AZT is recommended at its onset (absent life-threatening side effects associated with its use in the history) or nevirapine (see section V). When AZT is introduced, d4T must be discontinued. Pregnant women receiving antiretroviral therapy including a protease inhibitor should be instructed regarding the symptoms of hyperglycemia for self-monitoring purposes. Blood glucose levels should be determined at least once in 2 weeks. Any of the antiretroviral drugs registered in Russia may be used, even despite a potential hazard to the fetus, if there is no possibility of using a less dangerous drug in its place. Recommendations on prescription and management of antiretroviral therapy for pregnant women are summarized in appendix No. 18. 2.6. Special Features of the Chemotherapy of HIV Infection in Children When antiretroviral therapy is instituted for a child, the child as well as his (her) parents (or legal guardian) are counseled. Information on dosage and special features of the use of particular drugs in children are presented in appendix No. 19.

30

In addition to the development of opportunistic diseases, delay in the child's psychomotor development is also a clinical indication for instituting antiretroviral therapy in children. The clinical indications for instituting it are identical in children and adults. The general principles of prescription and management of antiretroviral therapy for children are similar to those for adults. It should just be noted that such manifestations of the disease as thrombocytopenia (asymptomatic, as well as accompanied by a hemorrhagic syndrome) and anemia are encountered more often in children than in adults. In the majority of cases, these conditions require not only appropriate pathogenetic therapy, but antiretroviral therapy as well. However, drugs that are capable of causing thrombocytopenia or anemia must not be used for such therapy. Signs of immune deficit in children are immunological indications for instituting therapy (see section II.6.2.3). A significant increase (taking age in to account) in viral load over time, is a virological indication, as is a repeatedly recorded high HIV RNA concentration, namely >100,000 copies per mL (5.0 log) in children up to 30 months of age, and 20,000 copies per mL (4.3 log) in older children. It is recommended that children up to 1 year of age with a definitive diagnosis of HIV infection be prescribed antiretroviral therapy regardless of the clinical, immunological, and virological data. When there is no immune deficit or it is moderate (see section II.6.2.3), or when data on CD4 are lacking, bitherapy is preferred for patients in stage 2A, 2B, or 3; but in stage 2C and 4, high-intensity antiretroviral therapy is preferred, regardless of the phase of the illness, immune status, or viral load. The selection of drugs and their combinations is made on the basis of the information presented in appendices 7-19. An antiretroviral drug is discontinued when side effects develop that threaten the health of the child. Drugs are replaced if clinical manifestations associated with HIV activity and the development of an immune deficit progress. The replacement of an antiretroviral drug or their combination in those cases in which appropriate laboratory studies can be carried out is recommended in the following situations: Progressive deterioration of psychomotor skills (not sooner than 6 weeks after the initiation of treatment). Progressive weight loss or lag in weight gain in relation to height increase, despite satisfactory nutrition (not sooner than 4 weeks after the initiation of treatment). The appearance of secondary diseases, previously absent or in remission (not sooner than 6 weeks after the initiation of treatment). Progression of the disease to a more severe stage (not sooner than 6 weeks after the initiation of treatment). When laboratory data are available, if the following are noted: Rapid and substantial drop in the absolute CD4 cell count (for example, three-fold over less than 6 months). A less than 10-fold reduction in viral load by 8-12 weeks of high-intensity antiretroviral therapy, or less 31

than 5-fold for bitherapy. Insufficient suppression of HIV replication 4-6 months after the initiation of treatment. Recurrent increases in HIV RNA after reduction to undetectable levels, unless associated with inoculation or an intercurrent illness. Substantial increase in plasma HIV RNA after a prolonged period of replication at low levels, unless associated with inoculation or an intercurrent illness (more than three-fold in children over 2 years of age and more than 5-fold in children less than 2 years of age).

3. Treatment of Opportunistic Diseases

Opportunistic diseases in HIV infection are treated with drugs authorized for use within the Russian Federation in accordance with the recommendations and instructions for their use. Maintenance therapy is given following the course of therapy for the acute manifestations of severe opportunistic diseases (chemoprophylaxis of recurrences). In addition, it is also recommended for frequent recurrences of nonsevere opportunistic diseases (localized candidiasis, herpes simplex). Treatment recommendations for the most prevalent diseases are given in appendices 20-23.

V. CHEMOPROPHYLAXIS OF HIV INFECTION

1. Chemoprophylaxis of Mother-to-Child Perinatal HIV Transmission
Mother-to-child HIV transmission is possible during pregnancy, labor, and breastfeeding. It is recommended that children born to an HIV-infected woman not be put to the breast nor fed with breast milk, in order to prevent infection of the infant through breastfeeding. If feeding is not possible without breast milk, it should be pasteurized. The use of chemoprophylaxis of HIV transmission from an infected woman to her infant during pregnancy and labor (assuming no subsequent breastfeeding with the infected woman's milk) substantially reduces the risk of infecting the infant (from 28-50% to 8%). This degree of efficacy along with adequate safety fro mother and fetus has been proven only for regimens using azidothymidine and nevirapine that are cited in these recommendations. Chemoprophylaxis of perinatal HIV transmission includes: Chemoprophylaxis during pregnancy. Chemoprophylaxis during labor. Chemoprophylaxis for the newborn.

The best results are obtained when all three components of chemoprophylaxis are implemented; however, if any of the components cannot be carried out (for example, due to late identification of HIV infection in the woman), this is not grounds for failure to carry out the next step. Counseling is provided, in the course of which she is informed of the aims of this measure, the probability of the birth of an infected infant when prophylaxis is carried out and when it is declined, and the possible side 32

effects of the drugs to be employed, (appendix 24). Chemoprophylaxis during pregnancy. Chemoprophylaxis of perinatal HIV transmission is instituted regardless of indications for antiretroviral therapy, assuming the pregnancy is at 14 weeks (earlier institution is not recommended due to the possible teratogenic effect). If HIV infection has been detected in a pregnant woman at later periods, chemoprophylaxis is initiated as early as possible (as soon as the diagnosis is established). Azidothymidine is prescribed by mouth at a dose of 0.2 g, 3 times a day (24-hour dose 0.6 g) throughout pregnancy. When AZT is tolerated poorly, P-AZT is prescribed in a 24-hour dose of 0.6 g (0.2 g, 3 times a day ). Chemoprophylaxis during labor. Several chemoprophylactic regimens have been worked out to reduce the risk of HIV transmission from mother to child during labor:: 1. Azidothymidine in the form of a solution for intravenous administration is prescribed at the onset of labor. It is given at a rate of 0.002 g/kg over the course of the first hour, and then (if required), 0.001 g/kg/hour until the completion of labor. 2. Azidothymidine by mouth - 0.3 g at the onset of labor. Then 0.3 g every 3 hours until the end of labor. 3. Nevirapine one 0.2 g tablet at the onset of labor (if the patient has been receiving azidothymidine during pregnancy, it is not discontinued before the completion of labor). 4. Phosphazide by mouth - 0.6 g at the onset of labor, then 0.4 g every 4 hours.

Chemoprophylaxis of HIV infection for the newborn. This step is initiated at the 8th hour after birth. Liquid oral forms of azidothymidine and nevirapine may be used. Azidothymidine is given by mouth in a syrup at a rate of 0.002 g/kg every 6 hours for 6 weeks. Nevirapine is given as a suspension, by mouth, at a rate of 0.002 g/kg once a day for 3 days. If it was not administered to an infant born to an HIV-infected mother during pregnancy and labor, and not started in the newborn period in the first three days postpartum, it is pointless to initiate chemoprophylaxis. Whether to give a woman antiretroviral therapy after delivery is decided on the basis of general indications. For purposes of the most effective prophylaxis of perinatal transmission of HIV infection when an HIVinfected pregnant woman is identified (if the pregnancy is to be maintained), notification in the form shown in appendix No. 25 must be forwarded, in case of the birth of an infant to an HIV-infected woman, by fax or telephone message to the Republic Clinical Hospital for Infectious Diseases, which is providing care to pregnant HIV-infected women and children born to HIV-infected mothers throughout the Russian Federation. Telephone (812) 464-93-29, fax (812) 4649360. Since it is felt that the risk of transplacental infection is especially great in the late stages of pregnancy, scheduled hospitalization of the patient at the 36th week and induction of labor or cesarean section are 33

recommended.

2. Chemoprophylaxis of parenteral and sexual transmission

Theoretically, the use of antiretroviral drugs in individuals who have been exposed to the risk of HIV infection may reduce this risk. Theoretically, the most efficacious drugs for this purpose should be the reverse transcriptase inhibitors, which, by contrast with the protease inhibitors, act before integration of the genetic material of the virus and of the host cell has taken place. Accordingly, in theory the non-nucleoside analog reverse transcriptase inhibitors, which do not require time for phosphorylation, should be the most efficacious. However, this problem is not well studied. Methods of preventing parenteral HIV infection have been worked out mainly in connection with prophylaxis for medical personnel injured by HIV-contaminated instruments. It is quite difficult to prove the effectiveness of these measures, considering the low probability of HIV infection, which is 0.09% in the case of contact of mucosa with HIV-contaminated blood, and 0.33% in the case of pricking by an instrument contaminated with HIV-positive blood. The efficacy of the following regimen of chemoprophylaxis has been proven (the risk of infection is reduced by 79%): azidothymidine (AZT) by mouth, 0.2 g, 3 times in 24 hours for 4 weeks. The efficacy of this regimen in reducing the probability of sexual HIV transmission has not been proven. Although the greater efficacy, as compared with AZT, of more intensive regimens for prophylaxis of HIV infection has not been proven, the use of one of the high-intensity therapy regimens for 4 weeks is recommended currently if a prick or cut by an instrument contaminated by an HIV-positive substance has occurred. Chemoprophylaxis must be initiated as early as possible (preferably within minutes of possible contamination) and combined with local treatment. Blood should expressed from the wound and the wound treated with iodine solution; mucosae that have come in contact with infected material should be washed (not rubbed!) and treated with antiseptic solutions (alcohol, boric acid, silver nitrate, etc.). Chemoprophylaxis is considered pointless if more than 72 hours have elapsed since the time of possible contamination. Counseling, in the course of which information is provided on the probability of infection given the patient's exposure to the risk factor, the efficacy of the chemoprophylaxis to be administered, and its possible side effects, is given when chemoprophylaxis is instituted. It should also be pointed out that the efficacy of chemoprophylaxis (reduction of risk of infection) has been proven only for prophylaxis of parenteral, not sexual, HIV transmission. Thus, the use of antiretroviral drugs for possible reduction of the risk of sexual contagion with HIV may be recommended not as a stand-alone method, but only in cases of "accident" during the use of a condom (tears, etc.). Since the effect of antiretroviral drugs on spermatogenesis has not been studied, prophylactic use of antiretroviral drugs should not be recommended to the sexual partner of an HIV-infected woman if they have sex without a condom in order to conceive a child.

34

VI. CHEMOPROPHYLAXIS OF SECONDARY (OPPORTUNISTIC) DISEASES IN HIV PATIENTS

The chemoprophylaxis (preventive therapy) of secondary diseases in HIV patients is done on the basis of epidemiological, clinical, and immunological indications. Issues relating to preventive chemotherapy are dealt with mainly in this section. The chemoprophylaxis of recurrences following therapy of the acute period (maintenance therapy) is described in detail in the manual on therapy of secondary diseases.

1. Chemoprophylaxis of Pneumocystis Pneumonia

Chemoprophylaxis of pneumocystis pneumonia is given to HIV patients with a CD4 lymphocyte count below 0.2x109/L (preventive therapy), and to patients who had previously had pneumocystis pneumonia (chemoprophylaxis of recurrences). When the CD4 count is not known, prophylaxis of pneumocystis pneumonia is given to patients in the progression phase of stage 4B, as well as to those with pulmonary pathology, and to all patients in stage 4C as well. Trimethoprim plus sulfamethoxazole (Biseptol, Septrim, Bactrim) is the first-line drug. Adult tablets contain 0.08 g of trimethoprim and 0.4 g of sulfamethoxazole; children's tablets contain 0.02 g and 0.1 g of these drugs, respectively. Adults are prescribed 2 tablets 3 days in a row each week for preventive therapy. Children are prescribed the drug in a reduced dose in the form of children's tablets or syrup. The drug is taken in the same 24-hour doses daily for prophylaxis of recurrences after completion of the course of treatment of the acute process. Dapsone, 0.05 g in 24 hours daily, may be used in case of Biseptol intolerance.

2. Chemoprophylaxis of Fungal Infections

Fungal disorders (primarily of candidial etiology) are among the most frequent and earliest secondary diseases in HIV patients. In the absence of prophylaxis and adequate treatment, they can cause the death even of a patient with a relatively moderate (for an HIV patient) immune deficiency. Preventive therapy of the fungal disorders is implemented when antibiotic therapy is given to HIV patients regardless of the stage of the disease and the CD4 lymphocyte count. In addition, when the CD4 lymphocyte count is below 0.05x109/L, preventive therapy is instituted regardless of the stage of the disease, even if antibiotic therapy is not being given. In stage 4, maintenance therapy is implemented after completion of treatment of the acute stage of recurrent localized fungal diseases, as well as of organ or generalized disorders. The following schedules of chemoprophylaxis of fungal disorders may be used in HIV patients (they can be used for both preventive therapy and maintenance therapy): No. 1: Nystatin, 2.0 g in 24 hours daily

35

No. 2: Nystatin, 4.0 g in 24 hours daily (not more than 10 days) No. 4: Fluconazole, 0.15 g once a week [Translator's note: sic - out of order] No. 3: Ketoconazole, 0.2 g daily [Translator's note: sic - out of order] No. 5: Fluconazole, 0.05 g daily No. 6: Fluconazole 0.1 g daily No. 7: Amphotericin B, 0.001 g/kg once a week IV No. 8: Itraconazole, 0.2 g daily

It is recommended that regimens with a lower number be prescribed initially, switching to the next in the absence or loss of effect. Side effects of the drugs and their interaction with other drugs must also be considered when choosing a prophylaxis regimen for a specific patient. In particular, if chemoprophylaxis of the mycoses impedes full-fledged antiretroviral therapy, preference is given to the latter. If the CD4 lymphocyte count is not known when antibiotic therapy is being given to an HIV patient, prophylaxis is initiated with regimen No. 1 in stages 3, 4A, and 4B, and with regimen No. 4 in stage 4C. If, regardless of the stage of the HIV infection, the CD4 count is not below 0.2x109/L, prophylaxis is initiated with regimen No. 1; if the CD4 count ranges from 0.05 to 0.2x109/L, it starts with regimen No. 4; if the CD4 count is below 0.05, with regimen No. 6. All patients with a CD4 count below 0.05x109/L, regardless of the stage of the HIV infection or the presence of antibacterial therapy, are prescribed regimen No. 6 (prophylaxis of cryptococcal meningitis). Should signs of a fungal infection appear against the backdrop of chemoprophylaxis, the drug is prescribed in curative doses.

3. Chemoprophylaxis of Mycobacterioses
Primary prophylaxis of tuberculosis in HIV patients is given: To individuals who have had contact with patients ill with open forms of tuberculosis, regardless of the stage of HIV infection and the CD4 lymphocyte count. To patients with an unknown CD4 lymphocyte count in stages 4B and 4C. To patients with a CD4 count <0.3109/L, regardless of the stage of HIV infection, if they have had contact with patients with active pulmonary tuberculosis (even if it has not been possible to isolate mycobacteria from the sputum of those patients). When a positive Mantoux reaction appears to 5 IU of tuberculin (area of induration greater than 5 mm), if this reaction had been negative previously. Given a positive Mantoux (area of induration greater than 5 mm), to patients in HIV infection stage 3 with an unknown CD4 count or with CD4 >0.5109/L, regardless of the stage of the disease. Given a positive Mantoux (area of induration greater than 5 mm), to patients in HIV infection stages 4A, 4B, and 4C, with an unknown CD4 count or with CD4 >0.5109/L, regardless of the stage of the disease. The following is prescribed for the prophylaxis of tuberculosis: isoniazid, 0.3 g in 24 hours, in combination 36

with pyridoxine (vitamin B6), 0.05 g in 24 hours. Rifampicin, 0.6 g in 24 hours, plus pyrazinamide, 20 mg/kg, for 2 months is an alternative treatment regimen in case of resistance to isoniazid. The duration of tuberculosis chemoprophylaxis is 12 weeks when instituted for epidemiological indications; when instituted in connection with tuberculin test conversion or its positivity, 12 months. Prophylaxis of atypical mycobacterioses is carried out regardless of the stage of HIV infection with CD4 <0.05109/L. azithromycin, 1.2 g per week, or rifabutin, 300 mg/day, are used.

4. Chemoprophylaxis of Cytomegalovirus Infection

PCR testing for CMV is done every 3 months in patients with a CD4 lymphocyte count below 0.05x109/L. Chemoprophylaxis of cytomegalovirus infection is instituted when CMV RNA, determined by PCR, is found in the blood, regardless of the stage and phase of HIV infection. Ganciclovir, 1.0 g, 3 times in 24 hours by mouth, is used.

37

Appendices

38

Appendix No. 1 Russian Classification of HIV Infection (V. I. Pokrovsky, 2001)

1. 2.

Incubation stage Stage of primary manifestations Course variants: A. Asymptomatic B. Acute HIV infection without secondary diseases. C. Acute HIV infection with secondary diseases.

3. 4.

Latent stage Stage of secondary diseases 4A. Weight loss less than 10%; fungal, viral, or bacterial lesions of the skin and mucous membranes; herpes zoster; recurrent pharyngitis, sinusitis. Phases: Progression (in the absence of antiretroviral therapy, or with antiretroviral therapy). Remission (spontaneous, after previous antiretroviral therapy, against the backdrop of antiretroviral therapy). 4B. Weight loss more than 10%: unexplained diarrhea or fever lasting more than one month; hairy leukoplakia; pulmonary tuberculosis; recurrent or persistent viral, bacterial, fungal, or protozoal pathology of the internal organs; recurrent or disseminated herpes zoster; localized Kaposi's sarcoma. Phases: Progression (in the absence of antiretroviral therapy, or with antiretroviral therapy). Remission (spontaneous, after previous antiretroviral therapy, against the backdrop of antiretroviral therapy). 4C. Cachexia; generalized bacterial, viral, fungal, protozoal, and parasitic diseases; pneumocystis pneumonia; esophageal, bronchial, and pulmonary candidiasis; extrapulmonary tuberculosis; atypical mycobacterioses; disseminated Kaposi's sarcoma; lesions of the central nervous system of varied etiology. Phases: Progression (in the absence of antiretroviral therapy, or with antiretroviral therapy). Remission (spontaneous, after previous antiretroviral therapy, against the backdrop of antiretroviral therapy).

5.

Terminal stage

39

Appendix No. 2 Patient's Quality of Life Assessment on the Karnovsky Scale

Assessment criteria No complaints or objective signs of disease. Minor signs of illness present. Maintenance of normal activity requires effort. Signs and symptoms of disease moderately prominent. Able to care for self maintained. Requires occasional assistance. Ability to care for self partially maintained, partly requires assistance. Frequent medical care required. Ability to care for self is lost. Medical care and assistance required constantly. Hospitalization required but no immediate threat of death. Severe illness, requiring hospitalization and active therapy. Rapidly progressing fatal disease. Death

Points 100 90 80 70 60 50 40 30 20 10 0

40

Appendix No. 3
Schedule and Scope of Evaluation of the HIV Patient When Prescribing and Implementing Antiretroviral Therapy
Procedure History Physical examination Determination of stage of disease Determination of quality of life index Recording of HIV-related diseases Ophthalmology consultation** Neurology consultation** ENT consultation** Gynecology consultation Chest x-ray Ultrasonography of organs of the abdominal cavity and true pelvis CD4 lymphocyte count HIV RNA concentration Complete blood count Blood biochemistries Urinalysis Testing for hepatitis B and C markers Express test for pregnancy Assessment of side effects Assessment of concurrent treatment Note: During selection, the results of tests obtained two weeks before the initiation of treatment may be used, with the exception of x-ray and ultrasonography (the results of the past 6 months may be used), as well as of pregnancy testing (done no later than 3 days before the initiation of treatment, provided contraception is used thereafter). Selectio Times (weeks) n* 2 4 8 + + + + + + + + + + + + + + + + + + + + + + + + + * * * + + + + + * * * + + + + + * + *

12 + + + + + + + + + + + + + + + + + +

Subsequently once every 4 weeks once every 12 weeks once every 12 weeks once every 12 weeks once every 12 weeks once every 12 weeks once every 12 weeks once every 12 weeks once every 12 weeks

+ + +

+ + + +

+*** + + +

once every 12 weeks once every 12 weeks once every 12 weeks once every 12 weeks once every 12 weeks once every 12 weeks Each visit Each visit

+ +

+ +

+ +

When drugs which are toxic to visual and auditory organs or the nervous system are used. Viral load testing is done at the 8th week if monitoring at the 4th week did not demonstrate its decline.

41

Appendix No. 4 Schedule and Scope of Evaluation of Children Born to HIV-Infected Mothers

Procedure Physical examination Anthropometric study Assessment of physical and psychomotor development Recording of HIV-related diseases CD4 lymphocyte count HIV DNA (if laboratory facility is available) HIV RNA (if laboratory facility is available) EIA, IB Complete blood count Blood biochemistries Urinalysis Serological testing for syphilis Testing for hepatitis B and C markers Serological testing for HSV, CMV, toxoplasmosis Cytological studies for CMV in saliva and urine Note:

At birth + + + +

Times (months) 1 + + + + + + 2 3 + + + + +* + +** 6 + + + + +* + +** +** +** +** + + + + + + + + + +** 9 + + + + 12 + + + + +* 15 + + + + +* 18 + + + + +* 24 + + + + +*

+ + + + + + + + + *

+ + + + * + + +

+** +*** + + + + + + + + + +

+ + + + + + +

* Testing done when clinical and laboratory indicators of HIV were present in previous evaluation, with the exception of detection of antibodies. ** When the result of previous testing for HIV DNA and RNA has been positive. *** When the result of previous testing has been negative.

42

Appendix No. 5 List of Drugs Registered in Russia, Most Frequently Used in the Treatment of HIV Patients
Drugs Abacavir (ABC) Azithromycin Azidothymidine (AZT) Amphotericin B Acyclovir Valacyclovir Ganciclovir Dapsone Didanosine (ddI) Ifavirenz (EFV) Stavudine (d4T) Zalcitabine (ddC) Isoniazid Normal human immunoglobulin Indinavir (IDV) Interferon Itraconazole Ketoconazole Lamivudine (3TC) Nevirapine (NVP) Nelfinavir (NFV) Nystatin Pyrazinamide Pyrimethamine Prospidine Ritonavir (RTV) Use Antiretroviral therapy Treatment and prophylaxis of atypical mycobacterioses, cryptosporidiosis. toxoplasmosis, bacterial infection Antiretroviral therapy Treatment of severe mycoses. Including with CNS involvement Treatment and prophylaxis of HSV infection Treatment and prophylaxis of HSV infection Treatment and prophylaxis of CMV infection Treatment and prophylaxis of pneumocystis pneumonia, prophylaxis of toxoplasmosis (reserve drug) Antiretroviral therapy Antiretroviral therapy Antiretroviral therapy Antiretroviral therapy Treatment and prophylaxis of tuberculosis Treatment of bacterial infections, prophylaxis of secondary diseases Antiretroviral therapy Treatment of Kaposi's sarcoma Treatment of severe mycoses Treatment of mycoses Antiretroviral therapy Antiretroviral therapy Antiretroviral therapy Treatment of mycoses Treatment of tuberculosis Treatment and prophylaxis of toxoplasmosis Treatment of Kaposi's sarcoma Antiretroviral therapy

43

Rifampicin Saquinavir (SQV) Streptomycin Trimethoprim Sulfamethoxazole Famciclovir Phosphazide (P-AZT) Fluconazole Ethambutol

Treatment and prophylaxis of mycobacterioses, treatment of bacterial infections Antiretroviral therapy Treatment of tuberculosis Treatment and prophylaxis of pneumocystosis, toxoplasmosis, bacterial infections Treatment and prophylaxis of HSV infection Antiretroviral therapy Treatment and prophylaxis of candidiasis (including severe forms and with CNS involvement), cryptococcosis Treatment of mycobacterioses

44

Appendix No. 6 Informed Consent for Therapy of HIV Infection

I (surname, name, patronymic in full) born 19____, hereby affirm my voluntary consent to chemotherapy of my HIV infection and/or the chemoprophylaxis of opportunistic diseases using the following drugs: I confirm that the reason this therapy is necessary has been explained to me, that the effect of the drugs to be prescribed has been explained, that I have received the patient information sheet, and that I have acquainetd myself with it; and that I have been given a contact telephone number through which I can, in case of need, get in touch with the physician treating me or the person covering for him. I am aware: That the treatment to be instituted for me is intended to suppress the multiplication of the human immunodeficiency virus (HIV) in the body and to prevent the development of secondary diseases associated with HIV infection. That it does not lead to complete cure of the HIV infection and does not completely preclude the possibility of other people being infected by me. That the treatment instituted for me can be discontinued at any time at my own volition or by decision of the attending physician, including as a result of my failure to observe the drug dose or examination schedule. Should treatment be discontinued by decision of the attending physician, the reasons for this decision must be explained to me. That the drugs to be prescribed for me are authorized for use in Russia. That, as with any drug, they can cause some side effects; information about these is given in the patient information sheet, which I have perused. To undergo medical examination to monitor treatment according to a set schedule, to complete the questionnaires required for this purpose, and to provide blood and urine for testing. To take the drugs prescribed for me strictly in accordance with the prescription of attending physician. To inform the attending physician of all irregularities of the treatment instituted for me or its interruption for any reason. To inform the attending physician of all changes in my state of health during the treatment and to do so immediately (within 24 hours) if I believe that these changes are related to taking the drugs prescribed for me. Not to take, without consulting the attending physician, any drugs not prescribed by him or her (even if they are prescribed by another physician on a non-emergency basis). If, however, taking these drugs is unavoidable (for example, in emergency situations), to inform the attending physician of this without fail.

I undertake:

Patient's signature: ________________________ Date: ________ Physician ____________________________ Date: ________ (Surname, first name, patronymic, legibly) (signature)

45

Appendix No. 7 ANTIRETROVIRAL DRUGS

Note: Basic information on the antiretroviral drugs authorized for use in the Russian Federation is given in this appendix; however, familiarity with the instructions for use before prescribing each drug is indispensable. Adult drug doses are indicated.

HIV Reverse Transcriptase Inhibitors (Nucleoside Analogs)

Thymidine Derivatives AZT, Azidothymidine, Zidovudine, ZDV Thymazide (Assotsiatsiya AZT) - capsules - 0.1 g Zidovudine, Retrovir (Glaxo-Wellcome) - capsules - 0.1 and 0.3 g, syrup for children (200 mL bottles, 0.01 g/mL, 2 g AZT in bottle), solution for IV injection (20 mL bottles of 0.01 g/mL solution, 0.2 g AZT in bottle) Usual dosage regimen of AZT drugs - 0.2 g, 3 times per day (0.6 g in 24 hours). The 24-hour dose is doubled for central nervous system impairment caused by HIV; it may be halved when poorly tolerated. Principal complications: nausea, anemia, granulocytopenia. Special features of use: AZT drugs must not be used together with P-AZT and d4T (mutual efficacy reduction)

P-AZT, Phosphazide Nikavir (Assotsiatsiya AZT) - tablets - 0.2 g. Usual dosage regimen - 0.2 g, 3 times per day (0.6 g in 24 hours) or 0.4 g, 2 times a day (0.8 g in 24 hours). Principal complications: nausea. Special features of use: Not used in combination with AZT and d4T (mutual efficacy reduction). Can be used for intolerance to AZT and resistance to AZT.

d4T, Stavudine Zerit (Bristol-Myers Squib) - capsules - 0.015 g, 0.2 g, 0.3 g, 0.4 g, oral solution - 1 mg/mL (200 mL). Usual dosage regimen for weight over 60 kg - 0.4 g, 2 times per day (0.8 g in 24 hours), for weight less than 60 kg - 0.3 g, 2 times per day (0.6 g in 24 hours). Principal complications: neuropathy, less often pancreatitis, hepatitis. Special features of use: Not used in combination with AZT and P-AZT (mutual efficacy reduction) and ddC (mutual toxicity enhancement). Can be used for intolerance to AZT and resistance to AZT.

46

Adenine Derivatives ddI, Didanozine Videx (Bristol-Myers Squibb) - chewable tablets - 0.025 g, 0.05 g, 0.1 g, 0.15 g, and powders 0.1 g, 0.167 g, 0.25 g. Usual dosage regimen of tablets: for weight >60 kg 0.2 g, 2 times per day or 0.4 g once per day (0.4 g in 24 hours), for weight <60 kg - 0.125 g, 2 times per day (0.25 g in 24 hours). Taken on an empty stomach. Alcohol substantially increases toxicity. Principal complications: pancreatitis, neuropathy, dyspepsia, hepatitis. Special features of use: For combined use with indinavir, ritonavir, delavirdine, use at an interval of at least 2 hours (impairs their absorption). Not used in combination with ddC (mutual toxicity enhancement).

Cytosine Derivatives ddC, Zalcitabine, Dideoxycytidine Hivid (Hoffman-LaRoche) - tablets - 0.000375 g and 0.00075 g. Usual dosage regimen - 0.00075 g, 3 times per day (0.00225 g in 24 hours). Principal complications: neuropathy, stomatitis, esophagitis, pancreatitis, hepatitis. Special features of use: Used as a second-line drug (when the use of ddI or 3TC is not possible). Not used in combination with d4T or ddI (mutual toxicity enhancement). Not used in combination with 3TC (mutual efficacy reduction). Not used together with magnesium- and aluminum-containing antacids.

3TC, Lamivudine Epivir (Glaxo-Wellcome)- tablets - 0.15 g, oral solution - 0.01 g/mL. Usual dosage regimen - 0.15 g, 2 times per day (0.3 g in 24 hours). Principal complications: rarely, headache, dyspepsia, insomnia, stomach ache. Special features of use: Not used in combination with ddC.

Guanine Derivatives Abacavir, ABC Ziagen (Glaxo Wellcome) - tablets - 0.3 g, oral suspension 0.02 g/mL. Usual dosage regimen 0.3 g, 2 times in 24 hours. Principal complications: Hypersensitivity reaction (usually appears in the first 6 weeks after the start of therapy; it may manifest in symptoms of intoxication (fever, fatigability, weakness), gastroenteritis (nausea, vomiting, diarrhea, stomach ache), skin eruptions (maculopapular, urticarial). Increased blood CPK, lymphopenia are possible. Special features of use: Since the hypersensitivity reaction can be very severe and even lead to death, patients must be warned about this, informed of the manifestations of this reaction, and about the fact that it is necessary to stop taking abacavir when its signs appear.

Combined Drugs Combivir (Glaxo-Wellcome) tablets. A tablet contains 0.3 g zidovudine and 0.15 g lamivudine. Usual dosage regimen: 1 tablet 2 times per day. Principal complications and special features of use - corresponds to the drugs contained in Combivir.

ANTIRETROVIRAL DRUGS HIV Reverse Transcriptase Inhibitors (Non-Nucleoside Analogs) 47

Ifavirenz, Efavirenz, EFV Stocrin (Merck Sharp & Dohme B.V.) capsules - 0.05 g, 0.1 g, 0.2 g. Usual dosage regimen - 0.6 g once in 24 hours, preferably at night. Principal complications: - mental disturbances (insomnia, drowsiness, impaired attention, rarely depersonalization, hallucinations), maculopapular rash, erythema multiforme, hepatotoxicity, embryotoxicity (developmental defects when used in the early stages of pregnancy), increased blood cholesterol. Special features of use: Use with caution in patients with diseases of the liver. Women of child-bearing age must use reliable contraception. When used in combination with with protease inhibitors, reduces their concentration. Therefore, coadministration with saquinavir is not recommended . For combined use with indinavir, the 2-hour dose of the latter must be increased up to 3.0 g. Adjustment of nelfinavir dose not required. Coadministration with rItonavir does not require dose adjustment, but does substantially increase toxicity and does require additional monitoring.

Nevirapine, Nevirapine, NVP Viramune (Boehringer Ingelheim) - tablets - 0.2 g, suspension 0.01 g/mL. Usual dosage regimen - 0.2 g once in 24 hours (24-hour dose 0.2 g) for 14 days, then 0.2 g, 2 times per day (24-hour dose 0.4 g). Principal complications - maculopapular rash, erythema multiforme, hives. Special features of use: should lesions on the mucosae, blisters, edema, arthralgia, fever, conjunctivitis, weakness appear, the use of nevirapine must be terminated. When combined with protease inhibitors, reduces their concentration. Therefore, coadministration with saquinavir is not recommended .

ANTIRETROVIRAL DRUGS HIV Protease Inhibitors

Saquinavir, Saquinavir, SQV Fortovase (Hoffman-La Roche) - soft gelatin capsules - 0.2 g. Usual dosage regimen 0.4 g, 2 times per day in combination with rItonavir. Without rItonavir, 1.2 g, 3 times per day or 1.8 g, 2 times per day (3.6 g in 24 hours) may be used when the use of other drugs is not possible. Principal complications - Nausea, stomach ache, diarrhea, headache, increased blood transaminases, disturbed lipid metabolism (hypercholesterolemia and hypertriglyceridemia, lipodystrophy). Special features of use: To improve absorption, take with fatty food or no later than two hours after it. Recommended for use with ritonavir 0.4 g, 2 times per day. Not used in combination with indinavir, ifavirenz, nevirapine.

48

Indinavir, IDV Crixivan (Merck Sharp & Dohme B.V.) - capsules - 0.2 g and 0.4 g. Usual dosage regimen - 0.8 g, 3 times per day (2.4 g in 24 hours). Principal complications - Nephrolithiasis, sometimes with hematuria (mainly in patients who ignore the recommendation to drink a large amount of fluids). Less commonly, asymptomatic increase in indirect bilirubin, headache, asthenia, impaired visual acuity, metallic taste, hyperglycemia, thrombocytopenia, disturbed lipid metabolism (hypercholesterolemia and hypertriglyceridemia, lipodystrophy). Special features of use: taken on an empty stomach or with a light meal. It is necessary to drink 1.5-2 L liquid a day to avoid the formation of kidney stones. In combination with ritonavir, 0.4-0.8 g, it is used 2 times per day. In combination with nelfinavir, 1.2 g, 2 times per day. In combination with ifavirenz, 1.0 g, 3 times per day. In combination with ddI, it is prescribed with an interval of at least 2 hours

Nelfinavir, Nelfinavir, NFV Viracept (Manufacturer- Agouron Pharmaceuticals, seller in Russia - Hoffman La Roche) tablets - 0.25 g. Usual dosage regimen 0.75 g, 3 times per day or 1.25 g, 2 times per day (2.25 g in 24 hours). Principal complications - diarrhea, meteorism, hyperglycemia, disturbed lipid metabolism (hypercholesterolemia and hypertriglyceridemia, lipodystrophy). Special features of use: Taken with meals or washed down with whole milk. Must not wash down with grapefruit juice. In combination with indinavir, is prescribed 1.25 g, 2 times per day; in combination with ritonavir, 0.50.75 g, 2 times per day. In combination with nevirapine, 1.0 g, 3 times per day.

Ritonavir, RTV Norvir (Abbott Laboratories) - capsules - 0.1 g, oral solution - 0.08 g/mL. Usual dosage regimen - 0.6 g, 2 times per day (1.2 g in 24 hours). On the first day, 0.3 g, 2 times per day, then the one-time dose is increased 0.1 g daily until it reaches 0.6 g. Principal complications - nausea, vomiting, anorexia, diarrhea, stomach ache, loss of taste, paresthesias, asthenia, headache fever, rash. Special features of use: Taken with food; it is recommended that the solution be mixed with chocolate or milk to improve taste. The Norvir solution must be stored at 2-8C; it can be stored at a temperature up to 25C for 30 days. For combined use with ddI, must be taken with an interval of 2 hours. It should be remembered that the oral solution contains ethyl alcohol. Primarily used with other HIV protease inhibitors. For combined use of ritonavir with other protease inhibitors, a substantial reduction of the dose of both drugs is required: Saquinavir 0.4 g, 2 times per day + Ritonavir 0.4 g, 2 times per day. Indinavir 0.4 g, 2 times per day + Ritonavir 0.4 g, 2 times per day. Indinavir 0.8 g, 2 times per day + Ritonavir 0.2 g, 2 times per day. Indinavir 0.8 g, 2 times per day + Ritonavir 0.1 g, 2 times per day. Nelfinavir 0.5 g, 2 times per day + Ritonavir 0.4 g, 2 times per day. Nelfinavir 0.75 g, 2 times per day + Ritonavir 0.4 g, 2 times per day. Saquinavir 1.0 g, 2 times per day + Ritonavir 0.1 g, 2 times per day. Saquinavir 1.6 g once per day + Ritonavir 0.1 g once per day.

49

Appendix No. 8 Options for Combining Antiretroviral Drugs

Drugs Possibility of Combination With Other Drugs Can be combined with: Synergism Azidothymidine Didanozine Zalcitabine Lamivudine Abacavir Ifavirenz Nevirapine Ritonavir Indinavir
Nelfinavir Saquinavir

Not combined with: Antagonism Phosphazide Stavudine Increased toxicity No synergism (or unproven)

Phosphazide

Didanozine Zalcitabine Lamivudine Abacavir Ifavirenz Nevirapine Ritonavir Indinavir

Nelfinavir Saquinavir

Azidothymidine Stavudine

Stavudine

Didanozine Lamivudine Abacavir Ifavirenz Nevirapine Ritonavir Indinavir

Nelfinavir Saquinavir

Azidothymidine Phosphazide

Zalcitabine

Didanozine

Azidothymidine Phosphazide Stavudine Lamivudine Abacavir Ifavirenz Nevirapine Ritonavir Indinavir

Nelfinavir Saquinavir

Zalcitabine

50

Drugs

Possibility of Combination With Other Drugs Can be combined with: Synergism Not combined with: Antagonism Increased toxicity
Lamivudine Didanozine Stavudine

No synergism (or unproven)

Zalcitabine

Azidothymidine Phosphazide Abacavir Ifavirenz Nevirapine Ritonavir Indinavir Nelfinavir Saquinavir Azidothymidine Phosphazide Stavudine Didanozine Abacavir Ifavirenz Nevirapine Ritonavir Indinavir Nelfinavir Saquinavir Azidothymidine Phosphazide Stavudine Didanozine Zalcitabine Lamivudine Ifavirenz Nevirapine Ritonavir Indinavir Nelfinavir Saquinavir Azidothymidine Phosphazide Stavudine Didanozine Zalcitabine Lamivudine Abacavir Ritonavir Indinavir Nelfinavir Saquinavir

Lamivudine

Zalcitabine

Abacavir

Ifavirenz

Nevirapine

51

Drugs

Possibility of Combination With Other Drugs Can be combined with: Synergism Not combined with: Antagonis m Increased toxicity No synergism (or unproven)
Ifavirenz

Nevirapine

Ritonavir

Indinavir

Nelfinavir

Azidothymidine Phosphazide Stavudine Didanozine Zalcitabine Lamivudine Abacavir Ritonavir Indinavir Nelfinavir Saquinavir Azidothymidine Phosphazide Stavudine Didanozine Zalcitabine Lamivudine Abacavir Nevirapine Ifavirenz Ritonavir Indinavir Nelfinavir Saquinavir Azidothymidine Phosphazide Stavudine Didanozine Zalcitabine Lamivudine Abacavir Nevirapine Ifavirenz Ritonavir Azidothymidine Phosphazide Stavudine Didanozine Zalcitabine Lamivudine Abacavir Nevirapine Ifavirenz Ritonavir Saquinavir

Nelfinavir Saquinavir

Indinavir

52

Drugs

Possibility of Combination With Other Drugs Can be combined with: Synergism Not combined with: Antagonis m Increased toxicity
Indinavir

No synergism (or unproven)

Saquinavir

Azidothymidine Phosphazide Stavudine Didanozine Zalcitabine Lamivudine Abacavir Nevirapine Ifavirenz Ritonavir Nelfinavir

53

Appendix No. 9 Main Side Effects of the Antiretroviral Drugs

Side Effects IDV NFV SQV RTV AZT d4T P-AZT ddI ddC 3TC ABC NVP EFV

Asthenia Headache Hypotension Sleep disturbances Impaired attention Mental disturbances Stomatitis Nausea, vomiting Rash Hepatotoxicity Diarrhea Pancreatitis Peripheral neuropathy Visual disturbances Embryotoxicity Hypersensitivity Erythema multiforme Anemia Neutropenia Thrombocytopenia Nephrolithiasis Hyperbilirubinemia Hyperglycemia Increased transaminases Increased risk of IHD Lipodystrophy

+ +

+ + +

+ + +

+ +

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ? + + + + + + + + + + +

- Side effects that are most significant for a given drug are highlighted by shading.

54

Appendix No. 10 Interaction of Antiretroviral Drugs With Other Drugs

IDV Ketoconazole, Nelfinavir, Ritonavir - increase IDV concentration. Ergot alkaloids, Ifavirenz, Nevirapine, Rifabutin, Rifampicin, Grapefruit Juice - decrease IDV concentration. ddI - decreases absorption of IDV when taken at an interval less than 2 hours.

NFV

Ergot alkaloids, Nevirapine, Rifabutin, Rifampicin, decrease NFV concentration. Norethindrone and other estradiol derivatives - NFV reduces their concentration. Indinavir, Saquinavir - mutual increase in concentration. Ritonovir increases NFV concentration.

SQV

Ketoconazole, Delavirdine, Nelfinavir, Ritonavir, Grapefruit Juice - decreased SQV concentration. Dexamethasone, Ifavirenz, Nevirapine, Rifampicin, Rifabutin, Phenobarbital - decreased SQV concentration. Ergot alkaloids competition. Amiodarone, astemizole, bepridil, bupropion, dihydroergotamine, itraconazole, ketoconazole, clozapine, meperidine, nimozide, piroxicam, propafenone, rifabutin, terfenadine, flecainide, quinidine, cisapride, encainide, ergotamine - ritonavir inhibits their metabolism by cytochrome P450. Aprazolam, diazepam, zolpidem, chlorazepate, triazolam, flurazepam, estazolam coadministration with ritonavir may induce muscle weakness and disturbed respiration. Phenobarbital, carbamazepine, dexamethasone, phenytoin, rifampin, rifabutin, nicotine (smoking) reduce ritonavir activity. Desipramine, clarithromycin, indinavir, nelfinavir, saquinivir dose must be reduced if coadministered with rItonavir. Oral contraceptives- ritonavir reduces efficacy. Theophylline - when coadministered with ritonavir, its dose must be increased. Disulfiram - combination with oral solution containing ethyl alcohol not recommended. Trimethaprim - its concentration increases when coadministered with ritonavir, but dose adjustment not required. Zidovudine - its concentration decreases when coadministered with ritonavir, but dose adjustment not required -Interferon, ddI, ddC, 3TC, Foscarnet - mutual reduction of activity against HIV. Ganciclovir, Ribavirin - decrease the antiretroviral activity of AZT. AZT, d4T - competition for phosphorylation and mutual reduction of antiretroviral activity. Adriamycin, -Interferon, Amphotericin B, Biseptol, Vinblastine, Vincristine, Ganciclovir. Dapsone, other sulfanylamides, Sulfadiazine - mutual enhancement of myelotoxicity. Probenicid - increases AZT concentration

RTV

AZT

55

P-AZT Ganciclovir, Ribavirin - decrease the antiretroviral activity of P-AZT. AZT, d4T competition for phosphorylation and mutual reduction of antiretroviral activity.

d4T

ddI, ddC, 3TC mutual enhancement of activity against HIV. AZT, Ganciclovir, Ribavirin, P-AZT - reduction of activity against HIV. (competition for phosphorylation). Vincristine, ddI, ddC, Isoniazid, Metranidozole, Ethambutol, Ethionamide - mutual enhancement of neurotoxicity. Dapsone, Delavirdine, Indinavir, Ketoconazole, Ritonavir, Tetracyclines, Fluoroquinolines must be taken at least 2 hours after taking ddI (impairs their absorption). Alcohol, Pentamidine, Ethambutol - mutual enhancement of pancreatotoxicity. Vincristine, ddC, d4T, Isoniazid, Ethambutol - mutual enhancement of neurotoxicity.

ddI

ddC

Vincristine, ddI, d4T, Isoniazid, Metranidozole, Ethambutol, Ethionamide mutual enhancment of neurotoxicity. 3TC competition for phosphorylation, and mutual reduction of antiretroviral activity.

3TC

Biseptol - increases the concentration 3TC. ddC competition for phosphorylation, and mutual reduction of antiretroviral activity.

ABC

Not found

EFV

Saquinavir, Indinavir EFV reduces their concentration. Ritonavir mutual toxicity enhancement (especially hepatotoxicity). Clarithromycin - EFV reduces its concentration, increased frequency of rash. Oral contraceptives- interaction with EFV insufficiently studied; therefore barrier methods of contraception recommended. Terfenadine, Astemizole, Cisapride, Midazolam NVP may inhibit their metabolism and increase toxicity. Saquinavir, Nelfinavir, Indinavir, Estradiol Derivatives - NVR reduces their concentration. Rifampin, Rifabutin, Oral contraceptives, Sedatives (triazolam, midazolam, and others), Oral Anticoagulants, digoxin, phenytoin, theophedrine - NVP may impair their metabolism, Increased toxicity possible; therefore, coadministration with caution.

NVR

Note: The underlined drugs are not recommended for coadministration. The underlined and italicized drugs are contraindicated for coadministration.

56

Appendix No. 11 Formulating Antiretroviral Therapy Regimens

To formulate a monotherapy regimen, select one drug from column 1. Select one drug from column 1 and 1 drug from column 2 to formulate a bitherapy regimen (the combination of d4T and ddC is not used). Select one drug from column 1, one drug from column 2, and one drug (or combination of drugs) from column 3 to formulate a high-intensity antiretroviral therapy regimen (the combination of d4T and ddC is not used). nucleoside analog HIV reverse transcriptase inhibitors, thymidine derivatives nucleoside analog HIV reverse transcriptase inhibitors, nonthymidine derivatives non-nucleoside analog HIV reverse transcriptase inhibitors and HIV protease inhibitors

Azidothymidine (AZT) Phosphazide (P-AZT)* Stavudine (d4T)**

Didanozine (ddI)* Lamivudine (3TC) Zalcitabine (ddC)*** Abacavir

Nevirapine* Ifavirenz Indinavir Nelfinavir Ritonavir **** Saquinavir + Ritonavir

Notes: * The P-AZT+ddI+NVP protocol has undergone clinical testing in Russia and is recommended as a firstline regimen. ** Stavudine (d4T) is not used in combination with ddC (mutually enhance neurotoxicity). *** Zalcitabine (ddC) is used as an alternative drug in case of intolerance to ddI or 3TC or their inefficacy. Not used in combination with d4T (mutually enhance neurotoxicity). **** Ritonavir is usually used in combination with other protease inhibitors, in which case the doses of the drugs must be adjusted. @ In alternative therapy regimens (when thymidine derivatives are not tolerated or efficacious), didanosine (ddI) may be used in their place.

57

Appendix No. 12 Indications for Antiretroviral Therapy

Indications Stage and phase of HIV infection 1 (incubation) 2A CD4 lymphocyte count (109/L) HIV RNA (103/mL) Presence of indications for therapy

regardless of count not known or >0.3

regardless of number not known or <100,000 >100,0000

(-) (-) (+) (+) (+) (-) (+) (+) (-) (+) (+) (-) (+) (-) (+) (+) (-) (+) (+) (+) (-) (+) (+) (+)

<0.3 2B, 2C 3 regardless of count not known or >0.3 <0.3

regardless of number regardless of number not known or <60000 >60000 regardless of number

4A (remission)

not known or >0.3

not known or <60000 >60000

<0.3 >0.5 4A (progression) 03-05 <0.3 not known or >0.3 4B (remission) <0.3 4B (progression) regardless of count 4C (remission) not known or >0.3

regardless of number not known or <60000 >60000 <30000 >30,000 or not known regardless of number not known or <60000 >60000 regardless of number regardless of number not known or <60000 >60,000

<0.3 4C (progression) regardless of count Symbols: (+) Prescribe antiretroviral therapy.

regardless of number regardless of number

(-) Do not prescribe antiretroviral therapy.

58

Appendix No. 13 Approach to Patient Management Depending on the Findings of Monitoring Studies at the Completion of a 12-Week Course of Monotherapy
Findings of monitoring study Clinical manifestations* Clinical progression absent CD4 ** 109/L Not known or not below initial HIV RNA*** (copies/mL) Not known or <30,000 >30,000. but below initial Not below initial Below initial Not known or not below initial Below initial Treatment break at 12 weeks, after which treatment is repeated, assuming the presence of indications. Continue treatment with the previous regimen another 12 weeks. Treatment is initiated using alternative drugs. Treatment is initiated using alternative drugs. Continue treatment with the previous regimen, repeat CD4 after 4 weeks. With the same result or further decrease, switch to treatment with alternative drug. Switch to more intensive therapy regimens, with prescription of alternative drug; when this is not possible continue treatment with an alternative drug. Switch to more intensive therapy regimens; when this is not possible continue treatment. Approach to patient management

Clinical progression present

Regardless of count

Not known or not below initial

Below initial Notes:

* Clinical changes, with the exception of transition to stage 3D are considered only if they appeared later than 4 weeks after initiation of therapy. ** *** of 3. **** A difference in CD4 count is considered if it is no less than 30%. A difference in HIV RNA is considered if one of the values differs from the other by at least a factor Value not known.

59

Appendix No. 14 Approach to Patient Management Depending on the Findings of Monitoring Studies at the Completion of a 12-Week Course of Bitherapy With Two Reverse Transcriptase Inhibitors
Findings of monitoring study Approach to patient management

Clinical manifestations*

CD4 ** 109/L

HIV RNA*** (copies/mL) Not known or below initial Not below initial Treatment continues with previous regimen Continue treatment with the previous regimen, repeat HIV RNA after 4 weeks. In the absence of a decrease, switch to alternative regimen. Continue treatment with the previous regimen, repeat CD4 after 4 weeks. In the absence of an increase, switch to alternative regimen. Treatment continues with previous regimen; if decrease continues, switch to alternative regimen after 12 weeks. Treatment continues with alternative bitherapy regimen. Treatment is initiated with alternative high-intensity therapy regimen; when this is not possible, with alternative bitherapy regimen. Continue treatment with the previous regimen; in the absence of clinical improvement over time for 12 weeks, switch to more intensive or alternative regimen. Continue treatment with the previous regimen; in the absence of clinical improvement over time for 12 weeks, switch to more intensive or alternative regimen. Treatment is initiated with alternative high-intensity therapy regimen; when this is not possible, with alternative bitherapy regimen.

Clinical Not below progression absent initial

Below initial

Not known

Below initial

Not below initial Clinical progression present. Not known or below initial Not known or above initial Below initial

Not below initial

Not known or below initial

Not below initial

Notes: * Clinical changes, with the exception of transition to stage 3C, are considered only if they appeared later than 4 weeks after initiation of therapy. ** *** of 3. **** A difference in CD4 count is considered if it is no less than 30%. A difference in HIV RNA is considered if one of the values differs from the other by at least a factor Value not known. 60

Appendix No. 15 Approach to Patient Management Depending on the Findings of Monitoring Studies at the Completion of a 12-Week Course of High-intensity Antiretroviral Therapy (Tritherapy)
Findings of monitoring study Clinical manifestations* Clinical progression absent CD4 ** 109/L HIV RNA*** (copies/mL) Continue treatment with previous regimen. Approach to patient management

Not known or Not known or not below below initial initial Not below initial

Continue treatment with previous regimen, repeat HIV RNA after 4 weeks. In the absence of decrease, switch to alternative regimen. Continue treatment with previous regimen, repeat CD4 after 4 weeks. With the same result or further decrease, switch to alternative regimen. Treatment continues with previous regimen. Repeat CD4 after 12 weeks. In the absence of further decrease, continue treatment with previous regimen; given further decrease, switch to alternative regimen. Switch to alternative regimen.

Below initial

Not known

Below initial

Not below initial Clinical progression present

Not known or Not known or not Switch to alternative regimen. not above below initial initial Below initial Continue treatment with previous regimen. Treat opportunistic diseases. In the absence of positive clinical changes over 4 weeks, switch to alternative regimen. Continue treatment with previous regimen. Treat opportunistic diseases. In the absence of positive clinical changes over 4 weeks, switch to alternative regimen. Continue treatment with previous regimen. Treat opportunistic diseases. Repeat HIV RNA after 2 weeks in the absence of a decrease or in the absence of positive clinical changes over 4 weeks, switch to alternative regimen.

Above initial Not known or below initial

Not below initial

Notes: * Clinical changes, with the exception of transition to stage 3C, are considered only if they appeared later than 4 weeks after initiation of therapy. ** A difference in CD4 count is considered if it is no less than 30%. *** A difference in HIV RNA is considered if one of the values differs from the other by at least a factor of 3. **** Value not known.

61

Appendix No. 16 Replacement of Antiretroviral Therapy in Case of Inadequate Efficacy or Loss of Efficacy of Earlier Therapy
1. General principle: Replacement of all drugs is recommended in case of inefficacy or loss of efficacy or earlier antiretroviral therapy. Substitution of one drug is not recommended. 2. Substitution of regimens of intensive antiretroviral therapy. Initial regimen Non-nucleoside reverse transcriptase inhibitor + 2 nucleoside analog reverse transcriptase inhibitors. Protease inhibitor + 2 nucleoside analog reverse transcriptase inhibitors. Alternative regimen 1 Protease inhibitor + 2 new nucleoside analog reverse transcriptase inhibitors. 2 protease inhibitors + 2 nucleoside analog reverse transcriptase inhibitors. Alternative regimen 2* 2 protease inhibitors + 2 nucleoside analog reverse transcriptase inhibitors. Non-nucleoside reverse transcriptase inhibitor + 2 nucleoside analog reverse transcriptase inhibitors. .

* Alternative regimen 2 is used in case of inefficacy of alternative regimen 1. 3. Substitution of antiretroviral drugs 3.1. Nucleoside analog reverse transcriptase inhibitors Drug received AZT Alternative drug 1. d4T (Most preferably) 2. ABC 3. P-AZT 1. d4T 2. AZT (Less preferably) 3. ABC 1. AZT 2. P-AZT 3. ABC 1. ddl 2. ABC 1. 3TC 2. ABC 3. ddC (Less preferably) 1. ddl 2. ABC

P-AZT

d4T

ddC ddI

3TC

3.2. Non-nucleoside reverse transcriptase inhibitors Drug received Nevirapine 1. Indinavir 2. Nelfinavir 3. Saquinavir 1. Indinavir 2. Nelfinavir 3. Saquinavir Alternative drug

Ifavirenz

62

3.3. Protease inhibitors Drug received Indinavir Alternative drugs or combinations of them 1. Nelfinavir + Saquinavir 2. Nelfinavir + Nevirapine 3. Nelfinavir + Ifavirenz 4. Nelfinavir + Ritonavir 5. Saquinavir + Ritonavir 6. Nelfinavir + Ritonavir 1. Indinavir + Nevirapine 2. Saquinavir + Ritonavir 3. Indinavir + Ritonavir 4. Indinavir + Ifavirenz 1. Indinavir + Ritonavir 2. Indinavir + Nevirapine 3. Indinavir + Ifavirenz 4. Nelfinavir + Ifavirenz 5. Nelfinavir + Nevirapine

Nelfinavir

Saquinavir

63

Appendix No. 17 Antiretroviral Drug Replacement When Drug Intolerance Develops

Initial drug AZT d4T ddI Toxic reaction Anemia, neutropenia, asthenia, insomnia, headache Peripheral neuropathy, pancreatitis Diarrhea, nausea Pancreatitis Peripheral neuropathy ddC Stomatitis Peripheral neuropathy 3TC Indinavir Nelfinavir Saquinavir No specific toxic reactions identified Nephrolithiasis, thrombocytopenia, visual disturbances, hyperbilirubinemia Diarrhea Headache, nausea, increased blood transaminases Diarrhea Nevirapine Rash, erythema multiforme, fever. Hepatotoxicity Ifavirenz Rash, erythema multiforme, fever. Hepatotoxicity Mental disturbances Nelfinavir, saquinivir, Stocrin, Viramune Indinavir, Stocrin, Viramune Nelfinavir, Viramune Indinavir, Stocrin, Viramune Indinavir, Nelfinavir, Saquinavir Indinavir, Nelfinavir, Saquinavir Indinavir, Nelfinavir, Saquinavir Nelfinavir, Saquinavir Indinavir, Nelfinavir, Saquinavir, Nevirapine Alternative drug d4T, P-AZT, less preferably - ddI AZT, P-AZT, less preferably - ddI ddC 3TC ddC, less preferably 3TC 3TC ddI, 3TC 3TC

64

Appendix No. 18 Antiretroviral Therapy in Pregnant Women

Period of Clinical stage and phase of the pregnancy (wk) disease (P - progression; R - remission) up to 8 2A, 2B, 2C CD4 (109/L) HIV RNA (in mL) >100,000 Regardless of count Not known or <100,000 2C (presence of secondary diseases corresponding to 4C) 3, 4A Regardless of count Regardless of number Not known or >0.1 >100,000 <100,000 or not known <0.1 R Not known or >0.1 Regardless of number >100,000 <100,000 or not known <0.1 4B P Not known or >0.1 Regardless of number >100,000 <100,000 or not known <0.1 Regardless of number >100,000 Done Not known <100,000 Not known R Not known or >0.1 >100,000 <100,000 or not known 4B <0.1 P 2A, 2B, 2C Regardless of number Done Done Not done Not done Done Done Not done * Antiretroviral therapy Done Not done Done Done Not done * Done Done Not done * Done Done Not done * Done

Regardless of count Regardless of number Regardless of count Regardless of number

65

Period of pregnancy (wk) 8-10

Clinical stage and phase of the disease (P - progression; R - remission) 2C (presence of secondary diseases corresponding to 4C) 3, 4A, 4B 4B R P

CD4 (109/L)

HIV RNA (in mL) Regardless of number Regardless of number Regardless of number Regardless of number

Antiretroviral therapy

Regardless of count Regardless of count Regardless of count Regardless of count

Done Not done Not done Done

11-13 >13

Not done before 14 weeks of pregnancy regardless of the presence of clinical and laboratory indications Done on the basis of the same indications as in the absence of pregnancy. The specific features of drug prescription for pregnant women are taken into account. If there had been indications for prescribing therapy, but it had been postponed, the issue of prescribing therapy is resolved again at the 14th week of pregnancy

Note:

66

Appendix No. 19 The Use of Antiretroviral Drugs in Children*

Drugs AZT (AZT) Special features of use and dosage Drug forms: Capsules - 0.1 g. Syrup for children - 0.01 g/mL. Solution for intravenous injection 0.01 g/mL. Newborns: By mouth - 0.002 g/kg body weight every 6 hours. Intravenously - 0.0015 g/kg every 6 hours. Children (up to 13 years): By mouth 0.01 g/kg in 24 hours. Intravenously 0.12 g/m 2 of body surface every 6 hours or (for continuous administration) 0.02 g/m2 over an hour. Adolescents: 0.2 g three times per day. Side effects: Most frequent - nausea, headache, suppression of hematopoiesis (anemia, granulocytopenia). Rarely - myopathy, myositis, hepatotoxicity. P-AZT Drug forms: Tablets - 0.2 g. Newborns: no data Children (up to 13 years): By mouth 0.01 g/kg in 24 hours. Adolescents: 0.2 g, 3 times per day or 0.4 g, 2 times per day. Side effects: Rarely - nausea. d4T Drug forms: Oral solution - 0.001 g/mL. Capsules - 0.015 g; 0.02 g; 0.03 g; 0.04 g. Newborns: in process of being worked out. Children (up to 13 years): For weight <30 kg, 0.001 g/kg body weight, every 12 hours. For weight 30 kg, 0.03 g, 2 times per day. Adolescents: For body weight 60 kg, 0.04 g two times per day. For body weight <60 kg, 0.03 g two times per day. Side effects: Most frequent - headache, skin eruptions, gastrointestinal disorders. Rare, but the most serious - peripheral neuropathy, pancreatitis. Rare - increased liver enzymes. ddI Drug forms: Pediatric powder for formulating oral solution - 0.01 g/mL. Chewable tablets - 0.025 g; 0.05 g; 0.1 g; 0.15 g. Powder for oral solution 0.1 g; 0.167 g; 0.25 g. Newborns: (less than 90 days of life) - 0.05 g/m2 of body surface, every 12 hours. Children (up to 13 years): 0.09 (up to 0.15) g/m2 of body surface, every 12 hours. Adolescents: For body weight 60 kg, 0.2 g two times per day. For body weight <60 kg, 0.125 g two times per day. Side effects: Most frequent - diarrhea, stomach ache, nausea, vomiting. Rare, but the most serious - peripheral neuropathy (dose-dependent), uremia, disturbed electrolyte balance. Rare - pancreatitis (dose-dependent, encountered less often in children than in adults), increased liver enzymes, retinal depigmentation.

67

Drugs ddC

Special features of use and dosage Drug forms: Tablets - 0.000375 g; 0.00075 g Newborns: - Not worked out. Children (up to 13 years): - Usual dose 0.00001 (from 0.000005) g/kg body weight, every 8 hours. Adolescents: - 0.00075 g three times per day. Side effects: Most frequent - headache weakness, gastrointestinal disorders. Rare, but more severe peripheral neuropathy, pancreatitis, hepatotoxicity, stomatitis with ulcerations, suppression of hematopoiesis, rash.

3TC

Drug forms: Oral solution - 0.01 g/mL. Tablets - 0.15 g. Newborns (less than 90 days of life) - 0.002 g/kg body weight, every 12 hours. Children (up to 13 years): 0.004 g/kg body weight, every 12 hours. Adolescents: For body weight >=50 kg, 0.15 g two times per day. For body weight <50 kg, 0.002 g/kg body weight, every 12 hours. Side effects: Most frequent headache weakness, diarrhea, stomach ache, nausea, vomiting, skin eruptions. Rare, but more severe - pancreatitis (observed in children, in the late stages of HIV infection, who have received massive concomitant therapy), peripheral neuropathy, decreased neutrophil count, increased liver enzymes

ABC

Drug forms: Tablets - 0.3 g. Newborns not worked out Children (up to 13 years): not worked out. Adolescents: 0.3 g two times per day. Side effects: Most frequent and severe: hypersensitivity reaction (usually appears in the first 6 weeks after the start of therapy); it may manifest in symptoms of intoxication (fever, fatigability, weakness), gastroenteritis (nausea, vomiting, diarrhea, stomach ache), skin eruptions (maculopapular, urticarial). Since the hypersensitivity reaction can be very severe and even lead to death, patients must be warned about this, informed of the manifestations of this reaction, and about the fact that it is necessary to stop taking abacavir when its signs appear. Increased blood CPK, lymphopenia are possible.

68

Drugs

Special features of use and dosage

Saquin Drug forms: Fortovase - capsules - 0.2 g. avir Newborns: not worked out. Children (up to 13 years): not worked out. Adolescents: Fortovase 1.2 g, 3 times per day or 1.8 g, 2 times per day Side effects: Most frequent - headache, diarrhea, abdominal discomfort, nausea, paresthesias, skin eruptions. Rare, but more severe - pancreatitis (observed in children, in the late stages of HIV infection, who have received massive concomitant therapy), peripheral neuropathy, decreased neutrophil count, increased liver enzymes.

Nelfina Drug forms: - Tablets - 0.25 g; powder for preparation of oral suspension, 0.05 g per measuring vir teaspoon division (0.2 g per teaspoon). Newborns: Worked out at a dose of 0.01 g/kg body weight 3 times per day. Children (up to 13 years): 0.02 0.03 g/kg body weight 3 times per day. Adolescents: 0.75 g, 3 times per day or 1.25 g, 2 times per day Side effects: Most frequent - diarrhea. Less common - asthenia, stomach ache, rash, exacerbation of chronic diseases of the liver. Rare - spontaneous episodes of bleeding in hemophiliacs, hyperglycemia, ketoacidosis, diabetes. Indinavi Drug forms: Capsules - 0.2 and 0.4 g. r Newborns: Not recommended due to danger of hyperbilirubinemia. Children (up to 13 years): Studied at a dose of 0.5 g/m2 of body surface 3 times per day. Adolescents: 0.8 g, 3 times per day. Side effects: Most frequent - nausea, headache stomach ache, dizziness, metallic taste, asymptomatic hyperbilirubinemia. Rare, but more severe - nephrolithiasis, exacerbation of chronic diseases of the liver. Rare - spontaneous episodes of bleeding in hemophiliacs, hyperglycemia, ketoacidosis, diabetes, hemolytic anemia.

69

Drugs

Special features of use and dosage

Ritonavi Drug forms: Capsules - 0.1 g, oral solution - 0.08 g/mL. r Newborns: Under investigation Children (up to 13 years): 0.35-0.4 g/m2 of body surface 2 times per day (starting dose 0.25 g/m2). Adolescents: 0.6 g, 2 times per day. Starting dose 0.3 g, 2 times per day, increases over 5 days. Side effects: Nausea, vomiting, anorexia, diarrhea, stomach ache, loss of taste, paresthesias, asthenia, headache fever, rash. Ifaviren Drug forms: Capsules - 0.05 g, 0.1 g, 0.2 g. z Newborns: Not studied. Children (from 3 up to 13 years): Prescribed once per day. For weight of 13-15 kg, 0.2 g; 15-20 kg, 0.25 g; 20-25 kg, 0.3 g; 2532.5 kg, 0.35 g; 32.5 - 40 kg, 0.4 g; >40 kg, 0.6 g. The action of the drug in children up to 3 years and less than 13 kg in weight has not been studied. Adolescents: 0.6 g once per day. Side effects: Most frequent - papulomacular rash, sleep disturbances, disturbed concentration. Rare, but more severe - erythema multiforme. Nevirapi Drug forms: Capsules - 0.2 g, suspension - 0.01 g/mL. ne Newborns: 0.005 g/kg once per day for 2 weeks, then 0.005 g/kg, 2 times per day. Not recommended due to danger of hyperbilirubinemia. Children (up to 13 years): Studied at a dose of 0.5 g/m2 of body surface 3 times per day. Adolescents: 0.8 g three times per day. Side effects: Most frequent - nausea, headache stomach ache, dizziness, metallic taste, asymptomatic hyperbilirubinemia. Rare, but more severe - nephrolithiasis, exacerbation of chronic diseases of the liver. Rare - spontaneous episodes of bleeding in hemophiliacs, hyperglycemia, ketoacidosis, diabetes, hemolytic anemia.

This table contains important but selective information on the drugs. Careful familiarization with instructions for use is indispensable when prescribing!

70

Appendix No. 20 Treatment of Localized Candidiasis in HIV Patients

Stomatitis. Vulvovaginitis First-line therapy Nystatin 500,000 AU, 5 times a day, p.o., at least 7 days Fluconazole 1.5 g once, p.o. (for vulvovaginitis) Fluconazole 0.20.4 g/day, p.o., at least 7 days Second-line therapy Ketoconazole 0.20.4 g/day, p.o., at least 7 days Amphoteracin B 0.00030.0005 g/kg/day, i.v., at least 7 days Maintenance therapy (administered for relapsing course) First-line maintenance therapy Nystatin 2.04.0 g/day (4.0 g/day, not more than 10 days), p.o. Fluconazole 0.15 g once a week Fluconazole 0.050.2 g/day, p.o. Second-line maintenance therapy Ketoconazole 0.2 g/day, p.o. Amphoteracin B 0.001 g/kg once a week i.v. Itraconazole 0.2 g/day Esophagitis. Bronchitis. Pneumonia (basic course for bronchitis. pneumonia, at least 21 days) Basic course of first-line therapy Ketoconazole 0.40.8 g/day, p.o., 1421 days, then 0.2 g/day Fluconazole 0.05-0.4 g/day, p.o. or i.v., 1421 days, then 0.05 g/day Basic course of second-line therapy Amphoteracin B 0.00030.0005 g/kg/day, i.v., 57 days, then ketoconazole Fluconazole, itraconazole up to 21 days Itraconazole 0.20.4 g/day, p.o., 1421 days First-line maintenance therapy Ketoconazole 0.2 g/day, p.o. Fluconazole 0.050.2 g/day, p.o. Second-line maintenance therapy Amphoteracin B 0.001 g/kg once a week Itraconazole 0.2 g/day p.o.

71

Appendix No. 21 Treatment of Generalized Candidiasis, Candidial Meningitis, Cryptococcosis in HIV Patients
Basic course of first-line therapy Amphoteracin B 0.0003-0.0005 g/kg/day, i.v., 10-14 days then Fluconazole 0.8 g/day, p.o., 2 days then Fluconazole 0.4 g/day, p.o., 810 weeks

Basic course of second-line therapy Fluconazole 0.4 g/day, p.o. or i.v. 2 days, then 0.4 g/day, p.o. or i.v., 610 weeks Itraconazole 0.6 g/day, p.o., 2 days, then 0.4 g/day, p.o. or i.v., 610 weeks

Maintenance therapy Fluconazole 0.20.4 g/day, p.o. Amphoteracin B 0.0006-0.001 g/kg 13 times per week Itraconazole 0.20.4 g/day

Maintenance therapy is administered for life for CNS involvement. Lumbar puncture and microbiological study of the spinal fluid are indicated in cryptococcosis and generalized candidiasis, even in the absence of symptoms of CNS involvement.

72

Appendix No. 22 Treatment of Pneumocystis Pneumonia (PCP) in HIV Patients

Basic course of first-line therapy Trimethoprim 0.020 g/kg/day Sulfamethoxazole 0.080 g/day Trade names - Septrin, Biseptol, Bactrim i.v. or p.o., 21 days. The 24-hour dose is taken in 3-4 doses

Basic course of second-line therapy Trimethoprim 0.015 g/kg/day, p.o., i.v. plus Dapsone 0.1 g/day, p.o., 21 days _____ Clindamycin 1.2 g/day, i.v. or p.o., plus Primaquine 0.03 g/day, p.o., 21 days Prescription of corticosteroids is indicated for patients with respiratory insufficiency (pO 2 <70 mm Hg): Prednisolone 0.08 g/day (0.04 x 2) for 5 days, then 0.04 g once per day for 5 days, then 0.02 g to the end of treatment. Maintenance therapy is administered when the course is completed Trimethoprim 0.08 g / Sulfamethoxazole 0.4 g (for children 0.02 g and 0.1 g), 2 tablets once per day.

73

Appendix No. 23 Treatment of Herpes Virus Conditions in HIV Patients

Herpes simplex First-line therapy Acyclovir 1.2 g/day p.o. at least 10 days Second-line therapy Acyclovir 0.0150.03 g/kg/day, i.v. or p.o. 4.0 g/day (0.8x5) at least 10 days Famcyclovir 250 mg, 3 times per day Valacyclovir 1 g, 2 times per day

Visceral herpes simplex or herpes zoster First-line therapy Acyclovir 0.03 g/kg/day, i.v. or p.o. 4.0 g/day (0.8 x 5) at least 10 days Famcyclovir 500 mg, 3 times per day or Valacyclovir 1 g, 3 times per day for 710 days Second-line therapy Acyclovir 0.036 g/kg/day, i.v. at least 10 days In disseminated, visceral, herpes zoster with impairment of the optic nerve or herpetic involvement of the CNS, treatment follows the second-line therapy regimen

CMV retinitis, generalized infection Ganciclovir 0.01 g/kg/day, i.v., 23 weeks, then 0.05 g/kg/day intravenously or 1.0 g, 3 times per day by mouth

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Appendix No. 24 Informed Consent for Chemoprophylaxis of HIV Transmission from Mother to
Child During Pregnancy and Delivery
I _______________________________________________________________ (Surname, name, patronymic in full) born in ______________ , hereby affirm my voluntary consent to the use of drugs to prevent the infection of my future child with the human immunodeficiency virus. I confirm that the reason this prophylaxis is necessary has been explained to me, that the effect of the drugs to be prescribed for me and my future child has been explained, that I have received the patient information sheet, and that I have acquainted myself with it. I am aware: That based on my state of health, I do not need treatment at the present time in connection with HIV infection, and that the drugs to be prescribed for me are needed exclusively to prevent the infection of my child with the human immunodeficiency virus (HIV) during pregnancy and delivery. That the drugs prescribed for me should suppress the replication (multiplication) of the virus in my body and to prevent its invasion of the body of my future child. That even if I absolutely observe all the rules for the use of the drugs, there is no total guarantee of prevention of infection of my future child. The risk of its being born infected in this case is 8%; however, if the chemoprophylaxis prescribed for me is not implemented or there are breaks in its implementation, the risk will increase up to 30%. That the chemoprophylaxis prescribed for me can be discontinued at any time at my own initiative. That if a threat to my health arises as a result of implementation of chemoprophylaxis, I will be informed of this in order that I may decide about the advisability of its further implementation. That if a threat to my health arises as a result of implementation of chemoprophylaxis, it may be terminated by decision of the attending physician. In that case, the reasons for this decision must be explained to me. That the drugs to be prescribed for me are authorized for use in Russia. That, as with any drug, they can cause some side effects; information about these is given in the patient information sheet, which I have perused. That I must not breastfeed my child after delivery, since this will increase the risk of its infection. I undertake: To undergo a medical evaluation to monitor the effect of the drugs prescribed for me according to a set schedule, to complete the questionnaires specified for this purpose, and to provide blood and urine for testing. To take the drugs prescribed for me strictly in accordance with the prescription of attending physician. To inform the attending physician of all breaks in the use of the drugs prescribed for me or its interruption for any reason. To inform the attending physician of all changes in my state of health during the treatment and to do so immediately (within 24 hours) if I believe that these changes are related to taking the drugs prescribed for me. Not to take, without consulting the attending physician, any drugs not prescribed by him or her (even if they are prescribed by another physician on a non-emergency basis). If, however, taking these drugs is unavoidable (for example, in emergency situations), to inform the attending physician of this without fail. Patient's signature: ____________________________________________Date: _________________ _________________ Physician _______________ ______________________________________Date: (Surname, first name, patronymic, legibly) (signature) 75

Appendix No. 25
This report is sent to the Republic Clinical Hospital for Infectious Diseases (188630, Saint Petersburg, Ust'Izhora village, 3 pr. 9 yanvarya, Russian Center for Pediatric AIDS), within 5 days by fax (812) 4649360, or by telephone message at (812) 464-93-29

Report on the birth of a child to an HIV-infected woman Facility, sending the report ______________________________________________________________

Data on mother Surname, first name, patronymic __________________________________________________________ Citizenship___________________________________________________________________________ Date of birth ____________ Stage of HIV infection ___________________________________________ Date of diagnosis of HIV infection _________________________________________________________

Data on child Surname, first name, patronymic __________________________________________________________ Date of birth ________________ Stage of HIV infection ________________________________________ Length _________ cm Developmental defects and diseases Weight ____________ kg Found Not found

If found, list ____________________________________________________________________________________ Report sent by ________________________________________________________________________ Position ____________________________________________________________________________________ Surname, first name, patronymic, legibly Date ________________ ================================================================================= For notes

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