HIV infection and AIDS

HIV infection is an infection caused by the human immunodeficiency virus (HIV infection). HIV infection is a slowly progressing anthroponotic disease with contact transmission, characterized by damage to the immune system with the development of AIDS. Clinical manifestations of AIDS leading to the death of an infected person are opportunistic (secondary) infections, malignant neoplasms and autoimmune processes.

HIV infection is caused by one of two retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair the cellular immune response, thereby increasing the risk of certain infections and tumors. Initially, infection may manifest itself as a nonspecific febrile fever. The likelihood of subsequent manifestations depends on the degree of immunodeficiency and is proportional to the level of CD4+ lymphocytes. Manifestations vary from asymptomatic course to acquired immunodeficiency syndrome (AIDS), which is manifested by severe opportunistic infections or tumors. Diagnosis of HIV infection is made by detection of antigens or antibodies. The goal of HIV treatment is to suppress HIV replication with a combination of drugs that inhibit the activity of viral enzymes.

ICD-10 codes

• 820. A disease caused by the human immunodeficiency virus (HIV), manifested in the form of infectious and parasitic diseases.
• 821. A disease caused by the human immunodeficiency virus (HIV), manifested in the form of malignant neoplasms.
• 822. Disease caused by human immunodeficiency virus (HIV), manifested in the form of other specified diseases.
• 823. A disease caused by the human immunodeficiency virus (HIV) that manifests itself in other conditions.
• 824. Disease caused by human immunodeficiency virus (HIV), unspecified.
• Z21. Asymptomatic infectious status caused by human immunodeficiency virus (HIV)

Epidemiology of HIV infection and AIDS

HIV is transmitted through contact with human body fluids: blood, seminal fluid, vaginal secretions, breast milk, saliva, secreted from wounds or lesions of the skin and mucous membranes that contain free virions or infected cells. The higher the concentration of virions, which can be very high during primary HIV infection, even if it is asymptomatic, the more likely the virus will be transmitted. Transmission through saliva or droplets produced by coughing and sneezing is possible, but very unlikely. HIV is not transmitted through normal contact or even through close non-sexual contact at work, school, or home. Infection occurs through direct transmission of physiological fluids during sexual contact, the use of sharp household items contaminated with blood, during childbirth, breastfeeding, and medical procedures (blood transfusions, the use of contaminated instruments).

Some sexual practices, such as fellatio and cunnilingus, have a relatively low risk of transmitting the virus, but are not completely safe. The risk of HIV transmission does not increase significantly with swallowing semen or vaginal secretions. However, if there are open wounds on the lips, the risk of HIV transmission increases. Sexual techniques that cause trauma to the mucous membranes (eg, sexual intercourse) have a very high risk. The highest risk of HIV transmission is anal sex. Inflammation of the mucous membranes facilitates transmission of the virus; STIs such as gonorrhea, chlamydia, trichomoniasis, as well as those that cause ulceration of the mucous membranes (chancroid, herpes, syphilis) increase the risk of HIV transmission.

HIV is transmitted from mother to child transplacentally or through the birth canal in 30-50% of cases. HIV is passed into breast milk, and 75% of previously uninfected infants at risk can be infected through breastfeeding.

The infection of large numbers of women of childbearing age has led to an increase in cases of AIDS in children.

The risk of HIV transmission following a skin injury with a medical instrument contaminated with infected blood is on average 1/300 without specific treatment; immediate antiretroviral therapy probably reduces this risk to 1/1500. The risk of transmission is higher if the wound is deep or if blood has been inoculated (eg, by a contaminated needle). The risk of transmission from infected health care workers, provided that appropriate precautions are taken to prevent infection of patients, is not fully understood but appears to be minimal. In the 1980s, one dentist infected six or more of his patients with HIV through an unknown route. However, extensive studies of patients treated by HIV-infected physicians, including surgeons, have found several other causes.

[ 1 ], [ 2 ], [ 3 ], [ 4 ]

Risk of HIV transmission through different types of sexual activity

In the absence of wounds

There is no risk of HIV transmission

• friendly kiss petting and massage
• use of individual sex devices
• (during masturbation by a partner, without sperm and vaginal secretions)
• bathing and showering together
• contact of feces or urine with intact skin

Theoretically very low risk of HIV transmission

If there are wounds

• wet kiss
• oral sex for a man (with/without ejaculation, without/with swallowing sperm)
• oral sex to a woman (with/without barrier)
• oral-anal contact
• digital stimulation of the vagina or anus with or without gloves
• use of non-individual disinfected sex devices

Low risk of HIV transmission

• vaginal or anal intercourse (with proper use of a condom)
• use of non-individual and non-disinfected sex devices

High risk of HIV transmission

• vaginal or anal intercourse (with/without ejaculation, without or with an incorrectly used condom)

Although donor screening has minimized the risk of transmission of the virus through blood transfusions, there still remains a small risk because screening tests may be negative in the early stages of HIV infection.

HIV is divided into two epidemiologically distinct groups. The first group includes predominantly male homosexuals and persons who have had contact with contaminated blood (intravenous drug users using unsterile needles; blood recipients before effective donor screening methods were introduced). This group predominates in the USA and Europe. In the second group, heterosexual transmission predominates (infection rates among men and women are approximately equal).

This group predominates in Africa, South America and South Asia. In some countries (e.g. Brazil, Thailand) there is no predominant transmission route. In countries where heterosexual transmission predominates, HIV infection spreads along trade and transport routes, as well as economic migration routes first to cities and only then to rural areas. In Africa, especially in southern Africa, the HIV epidemic has claimed the lives of millions of young people. Factors that predetermine this situation are poverty, poor education, an imperfect health care system, and the lack of effective drugs.

Many opportunistic infections are reactivations of latent infections, so the same epidemiologic factors that activate latent diseases also increase the risk of developing specific opportunistic infections. Toxoplasmosis and tuberculosis are common in the general population in most developing countries, as are coccidioidomycosis in the southwestern United States and histoplasmosis in the Midwestern United States. In the United States and Europe, herpes simplex virus type 8, which causes Kaposi's sarcoma, is common among gay and bisexual men but is virtually uncommon among other categories of HIV-infected individuals. Indeed, more than 90% of HIV-infected individuals in the United States who developed Kaposi's sarcoma were in this risk group.

What causes HIV infection and AIDS?

HIV infection is caused by retroviruses. Retroviruses are RNA-containing viruses, some of which cause diseases in humans. They differ from other viruses in their replication mechanism, by reverse transcription of DNA copies, which are then integrated into the host cell genome.

Infection with human T-lymphotropic virus type 1 or 2 causes T-cell leukemia and lymphoma, lymphadenopathy, hepatosplenomegaly, skin lesions, and, rarely, immunodeficiency. Some immunocompromised patients develop infections similar to those that occur in AIDS. HTLV-1 can also cause myelopathy. HTLV-1 can be transmitted through sexual contact and blood. In most cases, the virus is transmitted from mother to child through breastfeeding.

AIDS is an HIV infection that results in any of the disorders listed in categories B, C or a decrease in the number of CD4 lymphocytes (T-helpers) less than 200 per 1 μl. The disorders listed in categories B, C are severe opportunistic infections, certain tumors such as Kaposi's sarcoma and non-Hodgkin's lymphoma, which are caused by a decrease in the cellular immune response, and pathology of the nervous system.

HIV-1 causes most cases in the Western Hemisphere, Europe, Asia, Central, Southern, and East Africa. HIV-2 is common in parts of West Africa and is less virulent than HIV-1. In some areas of West Africa, both types of the virus are common, meaning that a person can be infected with both HIV-1 and HIV-2 at the same time.

HIV-1 first appeared among farmers in Central Africa in the first half of the 20th century, when the virus, which had previously circulated only among chimpanzees, first infected humans. The virus began to spread globally in the late 1970s, and AIDS was first diagnosed in 1981. Currently, more than 40 million people are infected worldwide. Three million patients die annually, and 14,000 people become infected every day. 95% of HIV-infected people live in developing countries, half of whom are women, and 1/7 are children under 15 years of age.

What happens with HIV infection?

HIV attaches to and penetrates host T cells by interacting with CD4 molecules and chemokine receptors. Once inside the host cell, the viral RNA and enzymes are activated. Viral replication begins with the synthesis of proviral DNA by reverse transcriptase, an RNA-dependent DNA polymerase. During this copying, numerous errors occur due to frequent mutations. The proviral DNA enters the nucleus of the host cell and integrates into its DNA. This process is called integration. With each cell division, the integrated proviral DNA is duplicated along with the host cell DNA. Proviral DNA serves as the basis for the transcription of viral RNA, as well as for the translation of viral proteins, including the viral envelope glycoproteins dr40 and dr120. Viral proteins assemble into HIV virions on the inner side of the cell membrane and then bud off from the cell. Thousands of virions are formed in each cell. Another HIV enzyme, protease, breaks down viral proteins, converting the virion into an active form.

Over 98% of HIV virions circulating in plasma are formed in infected CD4 lymphocytes. The population of infected CD4+ lymphocytes is a reservoir of the virus and causes reactivation of HIV infection (e.g., when antiretroviral therapy is interrupted). The half-life of virions in plasma is about 6 hours. On average, 10 ⁸ to 10 ⁹ virions are formed and destroyed per day in severe HIV infection. Given the rapid replication of the virus, as well as the high frequency of errors in reverse transcription caused by mutations, the risk of developing resistance to therapy and the body's immune response increases.

The main consequence of HIV infection is the suppression of the immune system, namely the loss of CD4+ T-lymphocytes, which determine cellular immunity and, to a lesser extent, humoral immunity. Depletion of CD4+ lymphocytes is due to the direct cytotoxic effect of the virus, cellular immune cytotoxicity, and damage to the thymus, which results in a decrease in lymphocyte formation. The half-life of infected CD4+ lymphocytes is about 2 days. The degree of decrease in CD4+ lymphocytes correlates with the viral load. For example, in the prodromal or primary HIV infection period, the viral load is maximum (>106 copies/ml), and accordingly, the number of CD4+ lymphocytes quickly decreases. The normal level of CD4+ lymphocytes is 750 cells/μl. To maintain an adequate immune response, the level of CD4+ lymphocytes must be above 500 cells/μl.

The concentration of HIV virions in plasma stabilizes at a certain level (set point), which varies widely among patients (on average 4-5 x 1010/ml). It is determined by nucleic acid amplification and is recorded as the number of HIV RNA copies in 1 ml of plasma. The higher the set point, the faster the level of CD4+ lymphocytes falls to values at which immunity is impaired (<200 cells/μl) and, as a consequence, AIDS develops. With each 3-fold increase in viral load (0.5 log ¹⁰ ) in patients not receiving antiretroviral therapy (ART), the risk of developing AIDS and death over the next 2-3 years increases by almost 50% unless ART is started.

Humoral immunity is also affected. B cells (producing antibodies) hyperplasia occurs in the lymph nodes, which leads to lymphadenopathy and increased synthesis of antibodies to previously known antigens, often resulting in hyperglobulinemia. The total number of antibodies (especially IgG and IgA), as well as the titer of antibodies against "old" antigens (for example, against cytomegalovirus) can be unusually high, while the reaction to "new antigens" is impaired or absent altogether. The response to immune stimulation decreases along with a decrease in the level of CD4+ lymphocytes.

Antibodies to HIV can be detected several weeks after infection. However, antibodies cannot eliminate the infection due to the formation of mutant forms of HIV that are not controlled by the antibodies circulating in the patient's body.

The risk and severity of opportunistic infections, AIDS and AIDS-associated tumors are determined by two factors: the level of CD4+ lymphocytes and the patient's sensitivity to potential opportunistic microorganisms. For example, the risk of developing Pneumocystis pneumonia, toxoplasmic encephalitis, cryptococcal meningitis occurs at a CD4+ lymphocyte level of about 200 cells/μl, and the risk of developing infections caused by Mycobacterium avium or cytomegalovirus - at a level of 50 cells/μl. Without treatment, the risk of progression of HIV infection to AIDS is -2% per year in the first 2-3 years after infection, and 5-6% per year thereafter. In any case, AIDS develops.

HIV affects not only lymphocytes, but also dendritic cells of the skin, macrophages, microglia of the brain, cardiomyocytes, renal cells, causing diseases in the corresponding systems. HIV virions in some systems, such as the nervous (brain and cerebrospinal fluid) and reproductive (sperm), are genetically different from those circulating in blood plasma. In these tissues, the concentration of the virus and its stability may differ from those in blood plasma.

What are the symptoms of HIV infection and AIDS?

Primary HIV infection may be asymptomatic or cause transient non-specific symptoms of HIV infection (acute retroviral syndrome). Acute retroviral syndrome usually begins 1-4 weeks after infection and lasts from 3 to 14 days. It occurs with fever, weakness, rash, arthralgia, generalized lymphadenopathy, and sometimes aseptic meningitis develops. These symptoms of HIV infection are often mistaken for infectious mononucleosis or non-specific manifestations of symptoms of a respiratory viral infection.

Most patients experience a period of months to years during which symptoms of HIV infection are virtually absent, mild, intermittent, and nonspecific. These symptoms of HIV infection are subsequently explained by the development of other manifestations of HIV or opportunistic infections. The most common symptoms are asymptomatic generalized lymphadenopathy, oral candidiasis, herpes zoster, diarrhea, weakness, and fever. Some patients develop and progress to exhaustion. Asymptomatic mild cytopenia (leukopenia, anemia, thrombocytopenia) is common.

Ultimately, when the CD4+ lymphocyte count falls below 200 cells/mm3, symptoms of HIV infection become more severe and one or more often several AIDS-defining illnesses (categories B, C in Table 192-1) develop. Detection of infections with Mycobacterium spp, Pneumocystis jiroveci (formerly P. carinn), Cryptococcus neoformans, or other fungal infections is critical. Other infections are nonspecific but suggestive of AIDS because of unusual severity or recurrence. These include herpes zoster, herpes simplex, vaginal candidiasis, and recurrent salmonella sepsis. Some patients develop tumors (eg, Kaposi sarcoma, B-cell lymphomas), which are more common, more severe, or have an uncertain prognosis in HIV-infected patients. Some patients may experience dysfunction of the nervous system.

Clinical groups of HIV infection

Category A

• Asymptomatic course
• Symptoms of acute primary HIV infection
• Persistent generalized lymphadenopathy
• Cryptosporodiosis, chronic gastrointestinal tract infection (>1 month)
• CMV infection (without damage to the liver, spleen, lymph nodes)

Category B

• Bacterial angiomatosis
• Cytomegalovirus retinitis (with loss of vision)
• Oropharyngeal candidiasis
• Vulvovaginal candidiasis: persistent, frequent, difficult to treat
• Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
• General symptoms - fever >38.5 °C or diarrhea lasting more than 1 month
• Hairy leukoplakia of the oral cavity
• Herpes zoster - at least 2 proven episodes of infection or involvement of more than 1 dermatome
• Autoimmune thrombocytopenic purpura
• Listeriosis
• Inflammatory diseases of the pelvic organs, especially if complicated by tubo-ovarian abscess
• Peripheral neuropathy
• HIV-associated encephalopathy
• Herpes simplex: chronic rash (lasting more than 1 month) or bronchitis, pneumonitis, esophagitis
• Disseminated or extrapulmonary histoplasmosis
• Isosporiasis (chronic gastrointestinal tract disease >1 month)
• Kaposi's sarcoma
• Burkitt's lymphoma
• Immunoblastic lymphoma
• Primary CNS lymphoma
• Disseminated or extrapulmonary lesions caused by Mycobacterium avium or Mycobacterium kansasii
• Pulmonary and extrapulmonary lesions caused by Mycobacterium tuberculosis
• Disseminated or extrapulmonary lesions caused by Mycobacterium species other or unspecified

Category C

• Candidiasis of the bronchi, trachea, lungs
• Esophageal candidiasis
• Invasive cervical cancer
• Disseminated or extrapulmonary coccidioidomycosis
• Extrapulmonary cryptococcosis
• Pneumocystis pneumonia (formerly P. carinii)
• Recurrent pneumonia
• Progressive multifocal leukoencephalopathy
• Recurrent salmonella septicemia
• Toxoplasmosis of the brain
• HIV-induced cachexia

The most common neurological syndromes in HIV infection

• AIDS dementia
• Cryptococcal meningitis
• Cytomegalovirus encephalitis
• Primary CNS lymphoma
• Progressive multifocal leukoencephalopathy
• Tuberculous meningitis or focal encephalitis
• Toxoplasmosis encephalitis

[ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ], [ 11 ]

Tumors Common in HIV-Infected Patients

Kaposi's sarcoma, non-Hodgkin's lymphoma, cervical cancer are AIDS-indicating neoplasms in HIV-infected patients. Other tumors: Hodgkin's lymphoma (especially mixed-cell and lymphopenic subtypes), primary CNS lymphoma, anal cancer, testicular cancer, melanoma and other skin tumors, lung cancer are more common and are characterized by a more severe course. Leiomyosarcoma is a rare complication of HIV infection in children.

Non-Hodgkin's lymphoma

The incidence of non-Hodgkin's lymphoma in HIV-infected patients increases 50-200 times. Most of these are B-cell aggressive histologically highly differentiated lymphomas. In this disease, extranodal structures such as the red bone marrow, gastrointestinal tract and other organs that are rarely affected in non-HIV-associated non-Hodgkin's lymphoma are involved in the process - the central nervous system and body cavities (pleural, pericardial and abdominal).

The disease usually presents with rapid enlargement of lymph nodes or extranodal masses or systemic manifestations such as weight loss, night sweats, and fever. Diagnosis is by biopsy with histologic and immunochemical examination of tumor cells. Abnormal lymphocytes in the blood or unexplained cytopenias indicate bone marrow involvement and require bone marrow biopsy. Tumor staging may require CSF examination and CT or MRI of the chest, abdomen, and any other suspected tumor sites. Prognosis is poor with CD4+ lymphocyte count <100 cells/μL, age over 35 years, poor functional status, bone marrow involvement, history of opportunistic infections, and well-differentiated histologic subtype of lymphoma.

Non-Hodgkin lymphoma is treated with systemic polychemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone), usually in combination with antiretroviral drugs, blood growth factors, prophylactic antibiotics, and antifungals. Therapy may be limited by the development of severe myelosuppression, especially when a combination of myelosuppressive antineoplastic and antiretroviral drugs is used. Another possible treatment option is the use of intravenous anti-CD20 monoclonal antibodies (rituximab), which are effective in the treatment of non-Hodgkin lymphoma in patients without HIV infection. Radiation therapy shrinks large tumors and reduces pain and bleeding.

Primary central nervous system lymphoma

Primary CNS lymphomas develop in HIV-infected patients with a higher frequency than in the general population. The tumor consists of moderately and highly differentiated malignant B cells originating from CNS tissue. It manifests itself with the following symptoms: headache, epileptic seizures, neurological defects (paralysis of cranial nerves), changes in mental status.

Acute therapy includes prevention of cerebral edema and radiation therapy of the brain. The tumor is usually sensitive to radiation therapy, but the average survival time does not exceed 6 months. The role of antitumor chemotherapy is unknown. Life expectancy is increased with the use of HAART.

Cervical cancer

Cervical cancer in HIV-infected patients is difficult to treat. HIV-infected women have an increased incidence of human papillomavirus, persistence of its oncogenic subtypes (types 16, 18, 31, 33, 35 and 39), and cervical intraepithelial dysplasia (CIDD) (frequency reaches 60%), but they do not have a significant increase in the incidence of cervical cancer. Cervical cancer in these women is more severe, more difficult to treat, and has a higher recurrence rate after cure. Generally recognized risk factors in HIV-infected patients are: infection with human papillomavirus subtypes 16 or 18, CD4+ lymphocyte count <200 cells/μl, age over 34 years. HIV infection does not worsen the course of CIDD and cervical cancer. To monitor the progression of the process, it is important to frequently take smears according to Papanicolaou. Conducting HAART can cause the cessation of papillomavirus infection, regression of cervical cancer, but its effect on cervical cancer has not been studied.

[ 12 ], [ 13 ], [ 14 ]

Squamous cell carcinoma of the anus and vulva

Squamous cell carcinoma of the anus and vulva is caused by the human papillomavirus and is more common in HIV-infected patients. The high incidence of this pathology in HIV-infected patients is believed to be due to the high incidence of high-risk behavior, i.e. anal intercourse, rather than HIV itself. Anal dysplasia is common, which can make squamous cell carcinoma of the anus very aggressive. Treatment includes surgical excision of the tumor, radiation therapy, and combination modal chemotherapy with mitomycin or cisplatin plus 5-fluorouracil.

How are HIV and AIDS diagnosed?

HIV screening tests (to detect antibodies) are periodically recommended for people at risk. People at very high risk, especially those who are sexually active, have multiple sexual partners, and do not practice safe sex, should be tested every 6 months. This testing is anonymous, available, and often free, at many public and private institutions around the world.

HIV infection is suspected in patients with persistent unexplained generalized lymphadenopathy or any of the conditions listed in categories B or C. HIV infection should also be suspected in high-risk patients with nonspecific symptoms that may represent acute primary HIV infection. Once the diagnosis of HIV infection is established, the disease stage should be determined by plasma viral load and CD4+ lymphocyte count. The CD4+ lymphocyte count is calculated from the white blood cell count, the percentage of lymphocytes, and the percentage of lymphocytes that have CD4. The normal CD4+ lymphocyte count in adults is 750±250 cells/μl. HIV antibody testing is sensitive and specific except during the first few weeks after infection. The enzyme-linked immunosorbent assay (ELISA) - an HIV antibody test - is highly sensitive, but can sometimes give false-positive results. That is why a positive ELISA test result must be confirmed by a more specific test such as the Western blot. New rapid tests for blood and saliva are produced quickly, do not require technically complex manipulations and equipment, and allow testing in a variety of settings and immediate communication of the result to the patient. Positive results from these tests must be confirmed by standard blood tests.

If HIV infection is suspected despite the absence of antibodies in the blood (during the first few weeks after infection), plasma can be tested for HIV RNA. The nucleic acid amplification tests used are sensitive and specific. Detection of HIV p24 antigen by ELISA is less specific and sensitive than direct detection of HIV in blood. Determination of HIV RNA concentration (virions) requires sophisticated methods such as reverse transcription PCR (RT-PCR) or brush DNA testing, which are sensitive to very low levels of HIV RNA. Quantification of HIV RNA in plasma is used to determine prognosis and monitor treatment efficacy. The level of HIV in plasma, or viral load, reflects replication activity. A high set point level (a relatively stable viral load level that remains at the same level as during primary infection) indicates a high risk of a decrease in the level of CD4+ lymphocytes and the development of opportunistic infections even in patients without clinical manifestations, as well as in immunocompetent patients (patients with a CD4+ lymphocyte level > 500 cells/μl).

HIV infection is divided into stages based on clinical manifestations (in order of increasing severity - categories A, B, C) and the number of CD4+ lymphocytes (>500, 200-499, <200 cells/μl). The clinical category is assigned based on the most severe condition that the patient has had or has. Thus, the patient cannot be transferred to a lower clinical category.

The diagnosis of various opportunistic infections, tumors, and other syndromes that develop in HIV-infected patients is described in most guidelines. Most of the questions are unique to HIV infection.

Hematological abnormalities are common and bone marrow aspiration and biopsy may be very useful in elucidating some syndromes (eg, cytopenias, lymphoma, cancer). They are also helpful in diagnosing disseminated infections caused by MAC, Mycobacterium tuberculosis, Cryptococcus, Histoplasma, human parvovirus B19, Pneumocystis jiroveci (formerly P. carinii), and Leishmania. Most patients have normoregenerative or hyperregenerative bone marrow despite peripheral cytopenias reflecting peripheral destruction of formed elements of the blood. Iron levels are usually normal or elevated, reflecting the anemia of chronic disease (impaired iron reutilization). Mild to moderate plasmacytosis, lymphoid aggregates, large numbers of histiocytes, and dysplastic changes in hematopoietic cells are common.
Contrast-enhanced CT or MRI is often required for diagnosis of HIV-associated neurological syndromes.

How is HIV infection and AIDS treated?

The goal of HAART is maximal suppression of viral replication. Complete suppression of replication to undetectable levels is possible if patients take the drugs >95% of the time. However, achieving such compliance is difficult. Partial suppression of replication (failure to reduce plasma HIV RNA levels to undetectable levels) indicates HIV resistance and a high probability of failure of subsequent treatment. After initiation of HAART, some patients experience a deterioration in their clinical condition despite an increase in the number of CD4+ lymphocytes. This occurs due to the immune system's reaction to previously subclinical opportunistic infections or to microbial antigens remaining after their successful treatment. These reactions can be severe and are called immune resurgence inflammatory syndromes (IRIS).

The effectiveness of HAART is assessed by the level of viral RNA in the plasma after 4-8 weeks in the first months, and then after 3-4 months. With successful therapy, HIV RNA ceases to be detected within 3-6 months. An increase in the viral load is the earliest sign of treatment failure. If treatment is ineffective, by studying sensitivity (resistance) to drugs, it is possible to establish the sensitivity of the dominant HIV variant to all available drugs for adequate treatment adjustment.

The increasing number of patients receiving inadequate treatment regimens contributes to the formation of mutant forms of HIV that have higher drug resistance but are similar to wild-type HIV and exhibit less ability to reduce CD4+ lymphocyte levels.

Drugs in three of the five classes inhibit reverse transcriptase by blocking its RNA-dependent or DNA-dependent polymerase activity. Nucleoside reverse transcriptase inhibitors (NRTIs) are phosphorylated and converted into active metabolites that compete for incorporation into viral DNA. They competitively inhibit HIV reverse transcriptase and stop DNA strand synthesis. Nucleotide reverse transcriptase inhibitors inhibit it in the same way as nucleoside ones, but, unlike the latter, do not require preliminary phosphorylation. Non-nucleoside reverse transcriptase inhibitors directly bind the enzyme itself. Protease inhibitors inhibit viral protease, which is critical for the maturation of daughter HIV virions upon exit from the host cell. Fusion inhibitors block the binding of HIV to CD4+ lymphocyte receptors, which is necessary for the virus to enter cells.

A combination of 3-4 drugs from different classes is usually required to completely suppress wild-type HIV replication. Antiretroviral therapy is selected taking into account concomitant diseases (e.g., liver dysfunction) and other drugs used by the patient (to prevent drug interactions). To achieve maximum agreement between the doctor and the patient, it is necessary to use available and well-tolerated therapy regimens, as well as to use drugs once a day (preferably) or twice a day. Expert recommendations on the initiation, selection, change, and termination of therapy, as well as the specifics of treatment for women and children, are regularly updated and presented at www. aidsinfo. nih. gov/guidelines.
When antiretroviral drugs interact with each other, their effectiveness can increase synergistically. For example, a subtherapeutic dose of ritonavir (100 mg) can be combined with any other drug from the protease inhibitor class (lopinavir, amprenavir, indinavir, atazonavir, tipronavir). Ritonavir inhibits the liver enzymes that metabolize other protease inhibitors, thereby increasing their concentration and effectiveness. Another example is the combination of lamivudine (3TC) and zidovudine (ZDV). When these drugs are used as monotherapy, resistance develops rapidly. However, the mutation that causes resistance to 3TC also increases the sensitivity of HIV to ZDV. Thus, the two drugs are synergistic.

However, interactions between antiretroviral drugs may also lead to a decrease in the effectiveness of each of them. One drug may accelerate the elimination of another (by inducing liver enzymes of the cytochrome P-450 system responsible for elimination). A second, poorly understood mechanism of interaction of some NRTIs (zidovudine and stavudine) is a decrease in antiviral activity without accelerating the elimination of the drug.

Combining drugs often increases the risk of side effects compared to monotherapy with the same drugs. One possible reason for this is the metabolism of protease inhibitors in the liver in the cytochrome P-450 system, which inhibits the metabolism (and, accordingly, increases the concentration) of other drugs. Another mechanism is the summation of drug toxicity: the combination of NRTIs such as d4T and ddl increases the likelihood of developing undesirable metabolic effects and peripheral neuropathy. Given that many drugs can interact with antiretroviral drugs, it is always necessary to check their compatibility before starting to use a new drug. In addition, it should be said that grapefruit juice and St. John's wort decoction reduce the activity of some antiretroviral drugs and, therefore, should be excluded.

Side effects: severe anemia, pancreatitis, hepatitis, impaired glucose tolerance - may be detected by blood tests even before the first clinical manifestations appear. Patients should be examined regularly (clinically and with appropriate laboratory tests), especially when a new drug is prescribed or when unclear symptoms appear.

Metabolic disorders include the interrelated syndromes of fat redistribution, hyperlipidemia, and insulin resistance. Redistribution of subcutaneous fat from the face and distal extremities to the trunk and abdomen is common. This causes disfigurement and stress in patients. Cosmetic therapy with collagen or polyactic acid injections has a beneficial effect. Hyperlipidemia and hyperglycemia due to insulin resistance and nonalcoholic steatohepatitis may be accompanied by lipodystrophy. Drugs of all classes can cause these metabolic disorders. Some drugs, such as ritonavir or d4T, tend to increase lipid levels, while others, such as atazanavir, have minimal effect on lipid levels.

There are probably multiple mechanisms that lead to metabolic disorders. One of them is mitochondrial toxicity. The risk of developing mitochondrial toxicity and, accordingly, metabolic disorders varies depending on the drug class (highest for NRTIs and PIs) and within each class: for example, among NRTIs, the highest risk is with d4T. These disorders are dose-dependent and usually appear in the first 1-2 years of treatment. Remote disorders and optimal therapy for metabolic disorders have not been studied. Lipid-lowering agents (statins) and drugs that increase cell sensitivity to insulin (glitazones) can be used.

Bone complications of HAART include asymptomatic osteopenia and osteoporosis, which are common among patients with metabolic disorders. Rarely, avascular necrosis of large joints (hip, shoulder) develops, accompanied by severe pain and joint dysfunction. The causes of bone complications are poorly understood.

Interruption of HAART is relatively safe, provided that all drugs are stopped simultaneously. Interruption of therapy may be necessary for surgical treatment or when drug toxicity is refractory to therapy or requires management. After interruption of therapy to identify the toxic drug, the same drugs are given as monotherapy for several days, which is safe for most drugs. An exception is abacavir: patients who have had fever and rash on initial administration of abacavir may develop severe and even fatal hypersensitivity reactions when re-exposed to it.

Lifelong care

Although new treatments have greatly increased the hopes of survival for people with HIV, many patients deteriorate and die. Death from HIV infection is rarely sudden. Patients usually have time to consider their intentions. However, intentions should be recorded as early as possible in the form of a durable power of attorney for care with clear instructions for lifelong care. All legal documents, including powers of attorney and a will, should be in place. These documents are especially important for homosexual patients because of the complete lack of protection for inheritance and other rights (including visitation and decision-making) of the partner.

When patients are dying, doctors must prescribe painkillers, drugs to relieve anorexia, anxiety, and all other symptoms of stress. The significant weight loss in patients in the last stages of AIDS makes good skin care especially important. Comprehensive hospice support is a good option for people dying of AIDS. However, hospices are still supported only by individual donations and the help of all those who are willing and able to help, so their support is still provided at home.

How is HIV infection and AIDS prevented?

HIV vaccines are very difficult to develop due to the high variability of HIV surface proteins, which allows for a wide variety of HIV antigenic variants. Despite this, a large number of potential vaccines are in various stages of research to prevent or improve infection.

Prevention of HIV transmission

Educating people is very effective. It has significantly reduced the prevalence of infection in some countries, notably Thailand and Uganda. Given that sexual contact is the primary cause of infection, education aimed at eliminating unsafe sex practices is the most appropriate measure. Even if both partners are known to be HIV-negative and have never been unfaithful, safe sex is still essential. Condoms provide the best protection, but oil-based lubricants can damage latex, increasing the risk of condom breakage. ART for HIV-infected people reduces the risk of sexual transmission, but the extent of the reduction is unknown.

Safe sex remains appropriate to protect both HIV-infected individuals and their partners. For example, unprotected sexual contact between HIV-infected individuals can result in the transmission of resistant or more virulent strains of HIV, as well as other viruses (CMV, Epstein-Barr virus, HSV, hepatitis B virus) that cause severe illness in patients with AIDS.

Intravenous drug users should be warned about the risks of using unsterile needles and syringes. Warning may be more effective when combined with the provision of sterile needles and syringes, drug dependence treatment, and rehabilitation.

Anonymous HIV testing with the option of a pre- or post-test consultation with a specialist should be available to all. Pregnant women who test positive are advised of the risk of transmission of the virus from mother to fetus. The risk is reduced by two-thirds with monotherapy with ZDV or nevirapine, and perhaps even more with a combination of two or three drugs. Treatment may be toxic to the mother or fetus and cannot reliably prevent transmission. Some women choose to terminate their pregnancy for these or other reasons.

In parts of the world where blood and organ donations are routinely screened using modern methods (ELISA), the risk of HIV transmission through blood transfusion probably ranges between 1:10,000 and 1:100,000 transfusions. Transmission is still possible because antibody tests can be false negative early in infection. Blood screening for both antibodies and p24 antigen has now been introduced in the United States and may further reduce the risk of transmission. To further reduce the risk of HIV transmission, people with risk factors for HIV infection, even those who do not yet have HIV antibodies in their blood, are asked not to donate blood or organs.

To prevent HIV transmission from patients, healthcare workers should wear gloves in situations where contact with the patient's mucous membranes or body fluids is possible, and should know how to avoid pricks and cuts. Social workers caring for patients at home should wear gloves if there is a possibility of contact with body fluids. Surfaces or instruments contaminated with blood or other body fluids should be washed and disinfected. Effective disinfectants include heat, peroxides, alcohols, phenols, and hypochlorite (bleach). Isolation of HIV-infected patients is not necessary, except when indicated due to opportunistic infections (e.g., tuberculosis). An agreement on measures to prevent transmission of the virus from HIV-infected healthcare workers to patients has not yet been reached.

Post-exposure prophylaxis of HIV infection

Preventive treatment of HIV infection is indicated for penetrating wounds with HIV-infected blood entering the wound (usually with piercing objects) or with massive contact of HIV-infected blood with mucous membranes (eyes, mouth). The risk of infection due to skin damage exceeds 0.3%, and after contact with mucous membranes is about 0.09%. The risk increases proportionally depending on the amount of biological material (higher with visibly contaminated objects, damage with hollow sharp objects), the depth of damage and the viral load in the blood that entered. Currently, a combination of 2 NRTIs (ZDV and ZTC) or 3 drugs (NRTI + PI or NNRTI; nevirapine is not used, as it causes hepatitis (rare, but with a severe course)) for 1 month is recommended to reduce the risk of infection. The choice of combination depends on the degree of risk due to the type of contact. ZDV monotherapy may reduce the risk of transmission following sharps injuries by about 80%, although there is no conclusive evidence to support this.

Prevention of opportunistic infections

Effective chemoprophylaxis of HIV infection is available for many opportunistic infections. It reduces the incidence of diseases caused by P. jiroveci, Candida, Cryptococcus and MAC. In patients with immune resurgence during therapy, restoration of the number of CD4+ lymphocytes above the threshold values for >3 months, prophylaxis can be discontinued.

Patients with CD4+ lymphocyte counts <200 cells/mm3 should receive primary prophylaxis against P. jiroveci pneumonia and toxoplasmic encephalitis. A combination of trimethoprim and sulfamethoxazole, given daily or 3 times a week, is highly effective. Side effects can be minimized by giving the drug 3 times a week or by gradually increasing the dose. Some patients who do not tolerate trimethoprim-sulfamethoxazole tolerate dapsone (100 mg once daily) well. For the small proportion of patients who develop bothersome side effects (fever, neutropenia, rash) during treatment with these drugs, aerosolized pentamidine (300 mg once daily) or atovaquone (1500 mg once daily) can be used.

Patients with CD4+ lymphocyte counts <75 cells/mm3 should receive primary prophylaxis against MAC dissemination with azithromycin, clarithromycin, or rifabutin. Azithromycin is preferred because it can be given as two 600-mg tablets weekly and provides protection (70%) comparable to that provided by daily clarithromycin. In addition, it does not interact with other drugs. Patients suspected of having latent TB (with any CD4+ lymphocyte count) should be treated with rifampin or rifabutin plus pyrazinamide daily for 2 months or isoniazid daily for 9 months to prevent reactivation.

For primary prevention of fungal infections (esophageal candidiasis, cryptococcal meningitis and pneumonia), fluconazole per os is successfully used daily (100-200 mg once a day) or weekly (400 mg). However, it should not be used frequently due to the high cost of the prophylactic course, good diagnostics and treatment of this pathology.

Secondary prophylaxis with fluconazole is prescribed to patients who have developed oral, vaginal, or esophageal candidiasis or cryptococcal infections. History of histoplasmosis is an indication for prophylaxis with itraconazole. Patients with latent toxoplasmosis who have serum antibodies (IgG) to Toxoplasma gondii are prescribed trimethoprim-sulfamethoxazole (in the same doses as for the prophylaxis of Pneumocystis pneumonia) to prevent reactivation of the process and subsequent toxoplasmic encephalitis. Latent infection is less common in the United States (approximately 15% of adults) compared with Europe and most developed countries. Secondary prophylaxis is also indicated for patients with previous Pneumocystis pneumonia, HSV infection, and possibly aspergillosis.

What is the prognosis for HIV infection and AIDS?

As mentioned above, the risk of developing AIDS and/or death is determined by the number of CD4+ lymphocytes in the short term and the level of HIV RNA in the blood plasma in the long term. For every threefold (0.5 log10) increase in the viral load, mortality over the next 2-3 years increases by 50%. If HIV infection is effectively treated, this leads to an increase in the number of CD4+ lymphocytes, and the level of HIV RNA in the plasma falls very rapidly. HIV-associated morbidity and mortality are rare when the number of CD4+ lymphocytes is >500 cells/μl, low at 200-499 cells/μl, moderate at 50-200 cells/μl and high when the number of CD4+ lymphocytes falls to less than 50 in 1 μl.

Since adequate antiviral therapy for HIV infection can cause significant and prolonged side effects, it should not be prescribed to all patients. Current indications for initiating antiviral therapy for HIV infection are CD4+ lymphocyte count <350 cells/μl and HIV RNA level in plasma >55,000 copies/ml. The use of conventional combinations of antiretroviral drugs for the treatment of HIV infection (highly active antiretroviral therapy - HAART) is aimed at reducing the HIV RNA level in plasma and increasing the CD4+ lymphocyte count (immune revival or restoration). A decrease in the CD4+ lymphocyte count and an increase in the HIV RNA level compared to these values before treatment reduce the likelihood of the effectiveness of the prescribed therapy. However, some improvement is also possible in patients with severe immunosuppression. An increase in the CD4+ lymphocyte count means a corresponding decrease in the risk of opportunistic infections, other complications and death. With the restoration of immunity, even conditions that are not specifically treated (e.g., HIV-induced cognitive dysfunction) or those that were previously considered incurable (e.g., progressive multifocal leukoencephalopathy) may improve. The prognosis of tumors (e.g., lymphoma, Kaposi's sarcoma) and opportunistic infections also improves. Vaccines that could improve immunity to HIV in infected patients have been studied for many years, but they are not yet effective.