Treatment of HIV infection / AIDS

The goal of treatment for HIV infection is to prolong the patient's life as much as possible and maintain its quality. Life expectancy without treatment in children is less than 6 months in 30% of cases; with therapy, 75% of children survive up to 6 years and 50% - up to 9 years.

It is necessary to conduct complex, strictly individualized therapy of patients with HIV infection, with careful selection of antiretroviral drugs, timely treatment of secondary diseases. The treatment plan is built taking into account the stage of the pathological process and the age of the patients.

Treatment is carried out in three directions:

• influence on the virus with the help of antiretroviral drugs (etiotropic);
• chemoprophylaxis of opportunistic infections;
• treatment of secondary diseases.

The basis for the prescription of antiretroviral drugs is the impact on the mechanisms of HIV replication, which are directly related to the periods of the virus's life activity.

There are four classes of antiretroviral drugs that inhibit viral replication at different stages of its life cycle. The first two classes include nucleoside and non-nucleoside reverse transcriptase inhibitors. These drugs disrupt the work of the viral enzyme, reverse transcriptase, which converts HIV RNA into DNA. The third class includes protease inhibitors, which act at the stage of assembling new viral particles, preventing the formation of full-fledged virions capable of infecting other host cells. Finally, the fourth class includes drugs that prevent the attachment of the virus to target cells - fusion inhibitors, interferons, interferon inducers - cycloferon (meglumine acridonacetate).

Monotherapy is used only as chemoprophylaxis of mother-to-child transmission of the virus in the first 6 weeks of life. In this case, chemoprophylaxis of a child born to an HIV-infected woman begins in the first 8-12 hours of life and is carried out with azidothymidine. The drug in syrup is given orally at a dose of 2 mg/kg every 6 hours. If it is impossible to take it orally, azidothymidine is administered intravenously at a rate of 1.6 mg/kg every 6 hours. Chemoprophylaxis can also be carried out with nevirapine in syrup during the first 72 hours of life at a rate of 2 mg/kg (if the mother did not receive chemoprophylaxis during pregnancy and/or childbirth - from the first day).

In all other cases, combinations of antiretroviral drugs of different classes should be used in the treatment of HIV-infected children. Preference is given to combined highly active (aggressive) therapy with three drugs, including various combinations of reverse transcriptase inhibitors and protease inhibitors.

Antiretroviral therapy is started in acute HIV infection in a manifest form, as well as in clinical manifestations of HIV infection (categories B, C according to CDC), regardless of age and viral load.

In addition to the development of clinical symptoms, high or rising HIV RNA levels and a rapid decline in the CD4+ T-lymphocyte percentage to levels consistent with moderate immunosuppression (immune category 2, CDC) may be indications for therapy. However, the HIV RNA level that could be considered an absolute indication for treatment in young children has not been determined.

The criterion for the effectiveness of therapy is an increase in CD4+ T-lymphocytes by at least 30% of the initial level after 4 months from the start of therapy in patients who have not previously received antiretroviral drugs, and a 10-fold decrease in viral load after 1-2 months of treatment. By 4 months, the viral load should decrease by at least 1000 times and by 6 months - to an undetectable level. As for the clinical criteria for the effectiveness of treatment, due to the slow dynamics of HIV infection, disease progression or the appearance of a secondary disease during the first 4-8 weeks of therapy is not always a sign of its inadequacy and cannot be sufficiently objective.

An equally important task in treating HIV-infected patients is the suppression of opportunistic flora that complicates the course of the underlying disease and threatens the patient's life. Antibacterial drugs, including various antibiotics, sulfonamides, etc., are widely used for this purpose.

Specific antiretroviral therapy is used to treat HIV infection. The goal of combined (highly active) antiretroviral therapy (HAART) of HIV infection is maximum suppression of viral replication to an undetectable level for the longest possible period, preservation or restoration of immune system functions, and prevention of disease progression and development of HIV infection complications (opportunistic infections).

A correctly selected first treatment regimen gives the best effect, and the child can be on it for many years. If the drugs are incorrectly selected, there is a need to change the therapy. With each subsequent change of drugs, the effectiveness of the antiretroviral therapy is reduced by 20-30%.

This is of particular importance in the treatment of HIV-infected children, since the number of antiretroviral drugs in pediatric practice is limited.

Currently, the following main recommendations for the treatment of children with HIV infection exist worldwide:

• "Recommendations for Antiviral Therapy for HIV Infection in Children" USA, Atlanta, CDC 03/24/2005;
• "Recommendations for antiviral therapy for HIV infection in children" PENTA, 2004 - European recommendations;
• "WHO Protocols for the CIS Countries on Providing Care and Treatment for HIV Infection and AIDS", March 2004.

Based on experience, the most progressive of the above are considered to be the American recommendations, based on the results of the most recent clinical studies. The European recommendations summarize the experience of treating HIV infection in children accumulated in European countries. The approaches to the tactics of treating HIV infection in the American and European recommendations are very similar.

An absolute indication for the initiation of HAART is clinical manifestations of HIV infection and/or severe immunodeficiency.

When deciding on the use of specific therapy, the doctor must take into account that HAART is prescribed to the child for life (continuous treatment), includes at least three drugs with a regimen of 2-3 times a day. Therefore, HAART should be prescribed only according to indications, taking into account the individual characteristics of each child and the course of HIV infection in each individual case.

Thus, HAART should be prescribed by a qualified specialist only for absolute indications, when the child's family is prepared to begin therapy. The key to the success of antiretroviral therapy is the desire of parents to treat their child and their strict compliance with the doctor's orders.

Unjustified prescription of HAART can significantly reduce the child's quality of life.

In children of the first year of life, the main criterion for prescribing therapy is the degree of immunosuppression. The level of viral load in infants is not an indication for prescribing HAART.

The amount of HIV RNA in infants is significantly higher than in older children and adults, and clinical manifestations of HIV infection can be quite meager. The level of HIV viral load is not a prognostic criterion for the course of the disease in children in the first year of life.

At the same time, severe immunodeficiency, regardless of the level of viral load, is a prognostically unfavorable sign and is an indication for the appointment of HAART.

Indications for HAART in children younger than 12 months (Guidelines for Antiretroviral Therapy for HIV Infection in Children, CDC 2005)

Clinical categories	CD4 lymphocytes	Viral load	Recommendations
Presence of symptoms (clinical categories A, B or C)	< 25% (immunological category 2 and pi 3)	Any	Treat
Asymptomatic stage (category I)	> 25% (immunological category 1)	Any	The possibility of therapy is being considered

Indications for initiation of HAART in children > 1 year

Category: Chinese	CD4 lymphocytes	Viral load	Recommendations
AIDS (clinical category C)	< 15% (immunological category 2 or 3)	Any	Treat
Presence of symptoms (clinical categories A, B or C)	15%-25% (immunological category 2)	> 100,000 copies/ml	The possibility of therapy is being considered
Asymptomatic stage (category N)	> 25% (immunological category I)	< 100,000 copies/ml	No need for therapy

In children over 1 year of age, when prescribing HAART, in addition to the degree of immunosuppression, the level of viral load is also taken into account. According to data from the USA and Europe, the risk of developing AIDS and death within a year in this age category increases sharply with a viral load level of more than 100,000 copies/ml.

Combination antiviral therapy for children with HIV has been administered since 1997.

Drug therapy for HIV infection includes basic therapy (which is determined by the stage of the disease and the level of CD4 lymphocytes), as well as therapy for secondary and concomitant diseases.

Currently, the main component of HIV treatment is antiretroviral therapy, which can help achieve a controlled course of the disease, i.e. a condition in which, despite the impossibility of a complete cure, it is possible to stop the progression of the disease. Antiretroviral therapy should be carried out for life, in a continuous course.

Conditions for prescribing HAART (PENTA guidelines for antiretroviral therapy, 2004)

Babies

1. Clinical
   • Start in all infants in CDC stage B or C (AIDS)
2. Surrogate markers
   • Start all infants with CD4 < 25-35%
   • It is recommended to start with a viral load > 1 million copies/ml

Children aged 1-3 years

1. Clinical
   • Start all children in stage C (AIDS)
2. Surrogate markers
   • Start all children with CD4 < 20%
   • It is recommended to start with a viral load > 250,000 copies/ml

Children aged 4-8 years

1. Clinical
   • Start all children in stage C (AIDS)
2. Surrogate markers
   • Start all children with CD4 < 15%
   • It is recommended to start with a viral load > 250,000 copies/ml

Children aged 9-12 years

1. Clinical
   • Start all children at stage C (AIDS)
2. Surrogate markers
   • Start all children with CD4 < 15%
   • It is recommended to start with a viral load > 250,000 copies/ml

Teenagers aged 13-17

1. Clinical
   • Start all children in stage C (AIDS)
2. Surrogate markers
   • Start for all adolescents with CD4 abs. count of 200-350 cells/ ^mm3

During the treatment, examinations are carried out to monitor its effectiveness and safety. These examinations are routinely carried out 4 and 12 weeks after the start of treatment, and subsequently every 12 weeks.

The following groups of antiretroviral drugs are used:

1. Drugs that block the process of reverse transcription (synthesis of viral DNA on the matrix of viral RNA) are reverse transcriptase inhibitors. Among them, two groups of drugs are distinguished:
   • nucleoside analogues (NRTIs) modified nucleoside molecules) that are incorporated into the synthesized DNA chain and stop its further assembly: azidothymidine (AZT), phosphazide (F-AZT), stavudine (d4T), didazonine (ddl), zalcitabine (ddC), lamivudine (ZTC), abzcavir (ABC), combivir;
   • non-nucleoside analogues (NNRTIs) that block the viral enzyme required for reverse transcription - reverse transcriptase: efavirenz (EFV), nevirapine (NVP).
2. Drugs that block the process of formation of complete HIV proteins and, ultimately, the assembly of new viruses - HIV protease inhibitors (PIs): saquinavir (SQV), indinavir (IDV), nelfinavir (NFV), ritonavir (RTV), lopinavir/ritonavir (LPV/RTV).
3. Drugs that act on the receptors used by the virus to penetrate the host cell are fusion inhibitors.

Many of these drugs are used in different dosage forms (including those intended for the treatment of young children). In addition, combination drugs containing two or more drugs in one tablet (capsule) have been registered.

The combination of two NRTI drugs is the basis of various antiretroviral therapy regimens.

For children, regimens that include 2 NRTIs and 1 PI or 2 NRTIs and 1 NNRT are recommended.

When choosing the optimal treatment regimen for a specific patient, the following is taken into account: the effectiveness and toxicity of the drugs, the possibility of combining them with each other, the patient's tolerance of the drugs, the convenience of taking the drugs - the brevity of the dose, the combination of antiretroviral drugs with drugs that are used (or may be used) to treat the patient's secondary and concomitant diseases.

Clinical and laboratory criteria are used to assess the effectiveness of HAART.

Of the laboratory criteria for assessing the effectiveness of treatment, the most informative are the level of CD4 lymphocytes and the concentration of HIV RNA.

With correctly selected HAART, a decrease in the level of HIV RNA by approximately 10 times is expected by 4-3 weeks after its start, and below the detection level (below 400 or 50 copies per ml) by 12-24 weeks of treatment. The number of CD4 lymphocytes also increases by 12-24 weeks from the start of HAART.

In the future, with effective HAART, the HIV RNA level should be below the detection level, but increases not exceeding 1000 copies/ml are possible. As the CD4 lymphocyte level increases, secondary diseases regress.

If HAART is ineffective and this is not due to violations of the drug regimen, taking antagonist drugs, etc., it is recommended to conduct a drug resistance test for the virus and prescribe a new treatment regimen based on the results of this test.

Forecast

Very severe. In clinically expressed forms, the mortality rate is about 50%. From diagnosis to death, it takes from 2-3 months to 2 years or more. In no case are normal immune functions restored spontaneously or under the influence of treatment. Among patients identified before 1982, about 90% have died by now. However, recently there have been reports of a more favorable prognosis, especially in the case of HIV type 2 infection. Patients with Kaposi's sarcoma have a better prognosis than patients with opportunistic infections. It is believed that patients with Kaposi's sarcoma have less damage to the immune system.

The prognosis in children is more serious than in adults. Children die from opportunistic infections and rarely from Kaposi's sarcoma and other blastomatosis.