Antiretroviral drugs

Antiretroviral drugs should be started by the patient based on clinical and laboratory indications.

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What is the role of hydroxyurea?

Hydroxyurea is of great interest and research will continue to evaluate its potential role as an adjuvant in antiviral therapy. Hydroxyurea has been used as a component of various highly active antiretroviral therapy (HAART) regimens, particularly those containing didanosine (ddl), with which it has synergistic anti-HIV activity.

This new approach to antiretroviral therapy develops selective inhibition of cellular ribonucleotide reductase by hydroxyurea. Inhibition of ribonucleoside reductase significantly reduces intracellular DNTP pools. For example, although hydroxyurea is not a primary antiretroviral agent, it inhibits HIV replication indirectly by blocking reverse transcriptase, which depends on intracellular DNTP as a substrate.

Several clinical studies demonstrate the in vitro and in vivo efficacy of hydroxyurea in suppressing HIV replication when used in combination with ddl and other nucleoside reverse transcriptase inhibitors. Studies also suggest that hydroxyurea's ability to limit CD4+ T-lymphocyte target cell numbers may also contribute to its in vivo activity in combination with antiretrovirals.

Preliminary studies indicate that hydroxyurea-containing regimens robustly inhibit viral replication when initiated during primary HIV seroconversion (see below). At least one patient in a small series had a very low proviral reservoir in peripheral blood when treated with hydroxyurea, ddl, and protease inhibitors and maintained an undetectable viral load after stopping HAART. Another series reported that two patients taking ddl and hydroxyurea alone had a withdrawal syndrome after stopping treatment. A third series, however, found that plasma HIV RNA rapidly returned to high levels after stopping HAART with or without hydroxyurea during primary HIV infection. However, one patient in this study had fewer than 50 copies of HIV RNA per ml of plasma 46 weeks after stopping HAART. This case suggests that early therapy may occasionally induce "remission" of HIV replication.

It would also be worthwhile to investigate the potential effects of hydroxyurea on the HIV reservoir in patients who have achieved undetectable plasma RNA levels on HAART. Hydroxyurea is a relatively small molecule that can penetrate the blood-brain barrier and thus is also able to cross the blood-testes barrier.

In addition, these antiretroviral drugs may significantly inhibit the process of partial reverse transcription within the full-length reverse transcriptase, a step necessary for viral integration into the host genome. If reverse transcriptase is normally retained in some reproductive tract cellular reservoirs, as in other cellular pools, hydroxyurea may further delay reverse transcription and reduce proviral integration in reproductive tract cells. This hypothesis suggests that hydroxyurea may be a prime candidate for reducing or abolishing HIV proviral reservoirs and replicating virus.

Recent studies have evaluated hydroxyurea, ddl, and protease inhibitors during acute HIV infection. This regimen resulted in undetectable viremia (in clinical trials) and significantly reduced latently infected CD4+ T cells in some of these patients. Other studies have shown, however, that HAART without hydroxyurea in HIV infection also allows a greater proportion of patients to achieve undetectable viral RNA in plasma and may reduce the latent T cell reservoir. A similar approach using the nucleoside analogue abacavir and the lymphocyte proliferation inhibitor mycophenolic acid may also modify residual HIV replication.

One of the methods of immunotherapy during a break in HAART is the PANDAs method, which includes hydroxyuria, which does not cause HIV mutation, and compensatory ddl, which does. Thus, intermittent HAART therapy is controlled. The authors (Lor F. et al., 2002) noted an increase in the level of interferon. This method of action can be compared with a "therapeutic" vaccine, which, as a specific antigen, induces T-cells.

Auto-vaccination

• patients without therapy due to high viral load without HIV immune response
• against the background of HAART, the HIV level below the threshold cannot stimulate HIV-specific immunity
• patients during a break from HAART may increase their immune response due to the booster effect
• Panda induces a specific immune response because the HIV count is above the threshold level that can elicit a cellular immune response, but the viral load is below the threshold level.

Non-nucleoside reverse transcriptase inhibitors

(NNRTIs) are a new class of drugs that stop HIV replication. These antiretroviral drugs act at the same stages of the process as the nucleoside RT inhibitors, but in a different way. They do not insert themselves into the growing DNA chain, but attach directly to reverse transcriptase, near its catalytic site, preventing the conversion of HIV RNA to DNA. Each drug in this class has a unique structure, but all of them inhibit the replication of HIV-1 only, but are not active against HIV-2.

The fundamental limitation of the use of MPIOTs as monotherapy is associated with the rapid development of viral resistance; the formation of cross-resistance of the virus to various NNRTIs (but not to nucleoside RT inhibitors) is possible, which is associated with the occurrence of mutations in RT. NNRTIs are synergistic with most nucleoside analogues and protease inhibitors, which allows them to be more effectively used in combination therapy.

Currently, three NMIOTs are used in global practice for the treatment of HIV infection: delavirdine, pevirapine, efavirepc (stocrip).

Delavirdine (Rcscriptor, Upjohn) - antiretroviral drugs, available in tablets of 100 mg, daily dose is 1200 mg (400 mg x 3); 51% of the drug is excreted in the urine, 44% in the feces.

Delavirdine is metabolized by the cytochrome P450 system, inhibiting its enzymes. Since the metabolism of many common drugs is also associated with the cytochrome system, delavirdine has a pronounced drug interaction, for example, with phenobarbital, cimetidine, ranitidine, cizanrine, etc. When delavirdine and ddl are taken simultaneously, plasma concentrations of both substances decrease, so delavirdine should be taken one hour before or after taking ddl. On the contrary, co-administration of delavirdine and indinavir or saquinavir increases the plasma level of protease inhibitors, so it is recommended to reduce the doses of these drugs when used together with delavirdip. It is not recommended to use rifabutin and rifampin together with delavirdip.

The most characteristic manifestation of delavirdine toxicity is rash.

Nevirapine (Viramune, Boehringer Ingelheim) - dosage form - 200 mg tablets and oral suspension. Nevirapine directly binds to reverse transcriptase, causing destruction of the catalytic site of the enzyme, and blocks RNA- and DNA-dependent polymerase activity. Nevirapine does not compete with nucleoside triphosphates. Antiretroviral drugs penetrate into all organs and tissues, including the placenta and central nervous system. Taken according to the scheme: the first 14 days - 200 mg x 1 time per day, then 200 mg 2 times per day. Metabolized by the cytochrome P450 system. inducing its enzymes; 80% of the substance is excreted in the urine. 10% - with feces.

It is known that ionotherapy to nevirapine quickly forms resistant strains of HIV, therefore it is recommended to use these antiretroviral drugs only in combination therapy with antiretroviral drugs. There are data on the combined use of nevirapine ddl or with AZT/ddl in children with symptomatic HIV infection. The results of the study showed that in general, combination therapy was well tolerated, however, sometimes patients receiving nevirapine were forced to interrupt treatment due to severe skin rashes. Clinical trials are being conducted to further study the effectiveness of nevirapine in preventing perinatal HIV infection.

Viramune (nevirapine) is highly effective in both initial and maintenance antiretroviral combination therapy. It is very important that viramune is highly effective both in patients with developed resistance to protease inhibitors and in patients with intolerance to this group of drugs. It should be noted that these antiretroviral drugs, normalizing fat metabolism, reduce the side effects of protease inhibitors.

Viramun is well tolerated by patients with long-term use, there is experience of use for more than 7 years:

• The spectrum of adverse effects is predictable.
• Does not affect mental status and does not cause lipodystrophy.
• The daily dose for maintenance combination therapy is 2 tablets once or 2 times one tablet per day.
• The intake does not depend on the intake and nature of food.
• Viramune is highly effective in initial and maintenance antiretroviral combination therapy in children and adults, with both low and high viral load; highly effective and most cost-effective in preventing perinatal transmission of HIV-1 infection; effective in patients with developed resistance to protease inhibitors; does not have cross-resistance to protease inhibitors and nucleoside reverse transcriptase inhibitors.

Viramun® has a unique bioavailability - more than 90%; quickly penetrates into all organs and tissues, including the placenta, nervous system and breast milk.

Wide possibilities of combination in regimens with almost all antiretroviral drugs and drugs for the treatment of opportunistic infections.

In studies conducted by P. Barreiro et al., 2000, the efficacy and safety of switching from protease inhibitors to nevirapine in patients with a viral load of less than 50 cells per ml were assessed. Of the 138 patients observed who had such a viral load and who received treatment regimens including protease inhibitors for 6 months, 104 were transferred to nevirapine, and 34 continued to receive the previous treatment. The authors concluded that replacing protease inhibitors with nevirapine is safe both virologically and immunologically, provides a significant improvement in quality of life and improves body shape changes associated with lipodystrophy in half of the patients at 6 months of admission, although the level of serum lipid disorders remains unchanged. In another study, performed by RuizL. et al., 2001, found that a PI-linked regimen including nevirapine was an effective alternative for patients. Nevirapine-based tritherapy achieved sustained control of HIV RNA levels and improved immunological response after 48 weeks of observation in patients. Switching to nevirapine significantly improved the lipid profile in group A, although there were no differences between the groups at the end of the study.

Nevirapine is highly effective and cost-effective in preventing vertical transmission of HIV from mother to fetus. The cost of a course of treatment is approximately 100 times cheaper than other treatment regimens (see below). At the same time, the frequency of HIV transmission is reduced by 3-4 times. These antiretroviral drugs do not have cross-resistance with protease inhibitors and nucleoside analogues, and are well tolerated with long-term use.

The interaction of nevirapine with nucleoside analogues (azidothymidine, videx or hivid), as well as with protease inhibitors (saquinavir and indinavir) does not require dosage adjustment.

When nevirapine is used in combination with protease inhibitors, oral contraceptives, rifabutin, rifampicin, plasma concentrations of these substances are reduced, therefore careful monitoring is necessary.

At the 7th Conference on Retroviruses and Opportunistic Infections (San Francisco, 2000), the advisability of a combination of nevirapine and combivir was reported. It was shown that the combivir/nevirapine combination has significantly higher activity than the regimen containing combivir and nelfinavir. In patients receiving the combivir and nevirapine combination, after 6 months from the start of therapy, the viral load level was significantly reduced, down to undetectable, and the CD cell level increased. In this case, treatment was prescribed to patients with an initial viral load of more than 1500 copies of RNA per ml even before the development of AIDS. It should be noted that 39% of those treated were injection drug addicts and had not received antiretroviral treatment before this therapy. Compared with patients receiving nelfinavir with combivir, the nevirapine+combivir combination had fewer side effects and it was less often necessary to cancel it due to its better tolerability. However, according to generally accepted data, nelfinavir, unlike nevirapine, has less pronounced side effects. In view of this, it is possible to recommend 2 schemes alternatively or sequentially.

Other NNRTIs are in the clinical trials stage, among them niclovirides are non-competitive antiretroviral drugs, HIV-1 inhibitors, unique in structure, have the same mechanism of action for all NNRTIs, and are characterized by the rapid development of viral resistance.

DuPont-Merk has developed a new non-nucleoside reverse transcriptase inhibitor, efavirenz (Sustiva, DMP-266, Stocrin), which has a long half-life (40-55 hours), making a single dose of 600 Mr/cyT possible (AIDS Clinical Care, 1998). Efavirenz is currently approved for use in Russia.

These antiretroviral drugs were introduced in 1998. In combination with two reverse transcriptase inhibitors, efavirenz has been shown to be more effective than protease inhibitors and nevirapine. Efavirenz inhibits HIV more rapidly and for a longer period of time, up to 144 weeks.

The advantage of using efavirenz over other drugs is its long half-life (48 hours). Efavirenz is well tolerated. The initial side effect on the central nervous system is significantly reduced after the first few weeks of treatment. J. van Lunzen (2002) suggests a new form of the drug - 600 mg in one tablet, which is taken once a day, instead of 3 tablets of 200 mg. This facilitates the intake and reduces the forgetfulness factor, thereby improving adherence to therapy.

A special study (Montana trial, ANRS 091) proposes a combination of a new drug - emitricitabine (emitricitabine) 200 mg, ddl -400 mg and efavirenz 600 mg once. All medications are given before bedtime. In this case, in 95% of patients after 48 weeks, the level of viral load decreased, and the level of CD4 T-lymphocytes increased by 209 cells.

Domestic antiretroviral drugs

Domestic azidothymidine (timazid) is produced in capsules of 0.1 g and is recommended for use in situations where the use of regrovir, zidovudine (Glaxo Wellcome) is indicated. One of the most effective domestic drugs is phosphazide, which is produced by the "AZT Association" under the commercial name nikavir (5'-H-phosphonate sodium salt of azidothymidine), tablets of 0.2 g. Nikavir belongs to the class of HIV reverse transcriptase inhibitors. Antiretroviral drugs are protected not only by Russian, but also by foreign patents.

Nikavir is similar to azidothymidine (Thimazid, Retrovir), which is widely used for the treatment of HIV infection, in its chemical structure, mechanism of action, antiviral activity, however, it is significantly less toxic to the body (6-8 times), and also has a prolonged effect, that is, it remains in the blood longer at a therapeutic concentration, which makes it possible to assume a once-daily regimen.

At the preclinical testing stage, it was also shown that the bioavailability and bioequivalence of nikavir are comparable to azidothymidine: it does not have a mutagenic, DNA-damaging, carcinogenic or allergenic effect. Adverse effects on the development of pregnancy were noted only when using 20-fold therapeutic doses (with the use of 10-fold therapeutic doses, it was not noted).

The results of the trials showed high therapeutic efficacy of nikavir in patients taking antiretroviral drugs both as monotherapy and as part of combination therapy. An increase in the level of CD4 lymphocytes by an average of 2-3 times, a decrease in the median level of HIV RNA (viral load) by an average of 3-4 times (more than 0.5 log / l.) were observed in the vast majority of patients (73.2%) taking nikavir. The positive therapeutic effect (restoration of the immune status and a decrease in the risk of developing opportunistic diseases) was stable at all studied daily doses: from 0.4 g to 1.2 g in 2-3 doses.

The standard recommended regimen is to take Nikavir 0.4 g twice a day. For children: 0.01-0.02 g per kilogram of weight in 2 doses. It is recommended to take antiretroviral drugs before meals and wash them down with a glass of water. In case of central nervous system lesions by a retrovirus, the drug is prescribed in a daily dose of 1.2 g. In case of severe side effects (unlikely), the daily dose is reduced to 0.4 g in adults and to 0.005 g per kilogram of weight in children. The course of treatment is unlimited, if necessary, in intermittent courses for at least three months.

Nikavir is well tolerated not only by adults but also by children. Side effects common to other antiretroviral drugs, such as nausea, vomiting, headaches, diarrhea, myalgia, anemia, thrombocytopenia, neutropenia were practically not observed in patients throughout the entire period of Nikavir use. In addition, the results of studies show the possibility of using Nikavir for patients who developed intolerance to azidothymidine (retrovir, thymazid) during previous therapy. No development of resistance to Nikavir was noted with long-term (more than a year) use. Low toxicity of the drug opens up prospects for its use as a preventive measure for the risk of HIV infection.

In view of the above, there is every reason to consider Nikavir a promising drug for the treatment of HIV infection, which has significant advantages over similar drugs currently used in global clinical practice, and the creation of Nikavir is an undoubted achievement of domestic science and technology.

Domestic antiretroviral drugs "Nikavir" are 2-3 times cheaper than foreign ones ("Retrovir", "Abacavir". "Epivir" Glaxo Wellcome lnc, "Videx", "Zerit" Bristol-Myers Squit Corn and others).

The results of using nikavir in a three-component combination antiretroviral therapy with reverse transcriptase inhibitors: nikavir, videx and non-nucleoside inhibitor viramune in 25 adult patients turned out to be very effective and was not accompanied by any side effects. In recent years, the number of antiretroviral agents has been constantly increasing, the treatment of HIV-positive individuals has become complex and continues to improve. When prescribing antiretroviral therapy, patients with asymptomatic and symptomatic HIV infection are distinguished, and among the latter - the category of people with an advanced stage of the disease. Approaches to prescribing antiretroviral therapy in the acute phase of the disease, as well as the basic principles for changing ineffective regimens or their individual components are considered separately.

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Reverse transcriptase inhibitors - nucleoside analogues

Nucleoside analogues have slightly altered structures of natural nucleosides - thymidine, cytidine, adenosine or guanosine. Intracellularly, under the action of cellular enzymes, these antiretroviral drugs are converted into active triphosphate forms, which HIV reverse transcriptase mistakenly uses instead of natural nucleoside triphosphates to extend the DNA chain. However, differences in the structure of analogues and natural nucleosides make it impossible to attach the next nucleotide in the growing chain of viral DNA, which leads to its termination.

The most studied antiretroviral drug included in the complex of antiviral agents is azidothymidine.

Azidothymidine (3'-azido,2'3'-dideoxythymidine, AZT, zidovudine, retrovir; Glaxo-Smithklein) - synthetic antiretroviral drugs, analogs of the natural nucleoside thymidine - was proposed for the treatment of patients with HIV infection in 1985 and for a long time was one of the most effective antiviral agents.

In Russia, AZT is produced under the commercial name timazid. The second domestic nucleoside analogue, phosphazid, is also a derivative of azidothymidine and is also approved for widespread use.

Inside the cell, AZT is phosphorylated to its active metabolite AZT triphosphate, which competitively inhibits the addition of thymidine to the growing DNA chain by RT. By replacing thymidine triphosphate, AZT triphosphate blocks the addition of the next nucleotide to the DNA chain because its 3'-azido group cannot form a phosphodiester bond.

AZT is a selective inhibitor of HIV-1 and HIV-2 replication in CD4 T-lymphocytes, macrophages, monocytes, and has the ability to penetrate the central nervous system through the blood-brain barrier.

AZT is recommended for the treatment of all HIV-positive adults and adolescents with CD4 lymphocyte counts less than 500/mm3, as well as children with HIV infection. In recent years, AZT has been widely used for the chemoprophylaxis of perinatal HIV infection.

These antiretroviral drugs are well absorbed when taken orally (up to 60%). The half-life from the cell is approximately 3 hours. Accumulated experience has shown that the optimal dose for adults is 600 mg per day: 200 mg x 3 times or 300 mg x 2 times per day, but, depending on the stage of HIV infection, tolerance, it can be reduced to 300 mg / day. According to most European researchers, a dose of AZT of 500 mg per day can also be considered optimal. AZT is excreted by the kidneys, so in patients with chronic renal failure, the doses should be reduced.

For children, antiretroviral drugs are prescribed at a rate of 90-180 mg/m2 of body surface every 6 hours.

Studies have shown that AZT significantly slows HIV replication and progression of HIV infection in patients with asymptomatic and symptomatic HIV infection and improves quality of life by reducing the severity of opportunistic infections and neurological dysfunctions. At the same time, the number of CD4 T cells in the body increases and the level of viral load decreases.

The side effects of AZT are mainly related to the need for high doses and toxicity to the bone marrow. Among them are anemia, leukopenia and other symptoms - fatigue, rashes, headaches, myopathy, nausea, insomnia.

Resistance to AZT develops in most patients with long-term use (more than 6 months). To reduce the development of resistant strains, it is recommended to use AZT in combination with other antiretroviral drugs.

Currently, along with AZT, other nucleoside antiretroviral drugs and analogues are used in the treatment of HIV infection - didanosine, zalcitabine, stavudine, lamivudine, abacavir and combivir.

Didanosine (2',3'-dideoxyinosine, ddl, videx; Bristol-Myers Squibb) is a synthetic antiretroviral drug, an analog of the purine nucleoside deoxyadenosine, and was the second antiretroviral agent approved for the treatment of HIV infection in 1991.

After penetrating the cell, didanosine is converted by cellular enzymes into active dideoxyadenosine triphosphate, exhibiting pronounced anti-HIV-1 and anti-HIV-2 activity.

Initially, ddl was used in adult patients with symptomatic HIV infection in combination with previously initiated AZT therapy, later it was used in combination with other antiviral agents, as well as monotherapy. Recommended doses for adults: over 60 kg body weight - 200 mg x 2 times a day, less than 60 kg - 125 mg x 2 times a day, for children - 90 - 150 mg / m2 of body surface every 12 hours.

Currently, it is proposed to prescribe ddl (videx) once a day at 400 mg for adults and 180-240 mg/kg per day for children.

The efficacy of newly initiated ddl monotherapy for HIV infection is approximately the same as AZT monotherapy. However, according to Spruance SL et al., in patients receiving AZT monotherapy, switching to ddl monotherapy was more effective than continuing AZT. According to Englund J. et al., ddl, either alone or in combination with AZT, was more effective than AZT alone in the treatment of HIV infection in children.

Data have been obtained that in vitro didanosine (as well as cytidine analogues - zalcitabine and lamivudine) is more active against non-activated peripheral blood mononuclear cells than in activated cells, in contrast to zidovudine and stavudine, so it is rational to use combinations.

The most serious side effects of ddl are pancreatitis, up to the development of pancreatic necrosis with a fatal outcome, as well as peripheral neuropathies, their frequency increases with increasing dose. Among other negative manifestations, there are renal dysfunction, changes in liver tests. The appearance of symptoms such as nausea, abdominal pain, increased amylase or lipase are an indication for a break in ddl therapy until pancreatitis is excluded.

Antiretroviral drugs such as dapsone, ketoconazole should be taken 2 hours before ddl as ddl tablets may inhibit gastric absorption of dapsone and ketoconazole. Caution should be exercised when oral ganciclovir is co-administered with ddl as it increases the risk of pancreatitis.

The development of ddl-resistant HIV strains occurs with long-term use. Studies have shown that the ddI/AZT combination does not prevent the development of viral resistance (Scrip World Pharmaceutical News, 1998), and decreased sensitivity to AZT occurs with equal frequency in patients receiving AZT therapy or the A3T/ddl combination.

Zalcitabine (2',3'-dideoxycytidine, ddC, hyvid; Hoffmann-La Roche) is a pyrimidine analogue of the nucleoside cytidine in which the hydroxyl group at the cytidine position is replaced by a hydrogen atom. After conversion to the active 5'-triphosphate by cellular kinases, it becomes a competitive inhibitor of reverse transcriptase.

DdC was approved for use in combination with AZT in patients who had not previously received antiretroviral therapy, and as monotherapy to replace AZT in individuals with progressive HIV infection or with AZT intolerance. Studies have shown that the combination of zalcitabine and zidovudine significantly increased the CD4+ cell count by more than 50% from baseline, and reduced the incidence of AIDS-defining conditions and deaths in previously untreated HIV-infected patients and in patients receiving antiviral therapy. The duration of therapy averaged 143 weeks (AIDS Clinical Trials Group Study Team, 1996).

However, although large clinical trials have demonstrated good therapeutic effects with the combined use of ddC and AZT, it is currently recommended to use ddC in triple therapy including a protease inhibitor.

The recommended dose for adults and adolescents is 0.75 mg x 3 times a day, for children under 13 years old 0.005-0.01 mg/kg body weight every 8 hours.

Common side effects include headache, weakness, and gastrointestinal disorders. These antiretroviral drugs have the most characteristic complications - peripheral neuropathies, which occur in patients with advanced HIV infection in about 1/3 of cases. Pancreatitis develops in 1% of people receiving ddC. Rare complications include liver steatosis, ulcers of the oral cavity or esophagus, and cardiomyopathy.

Drug interactions: the combined use of ddC with some drugs (chloramphenicol, dapsone, didanosine, isoniazid, metronidazole, ribavirin, vincristine, etc.) increases the risk of peripheral neuropathies. Intravenous administration of pentamidine can cause pancreatitis, so its use simultaneously with ddC is not recommended.

Resistance to ddC develops within approximately one year of treatment. Concomitant use of ddC with AZT does not prevent the development of resistance. Cross-resistance with other nucleoside analogues (ddl, d4T, 3TC) is possible (AmFAR's AIDS/HIV treatment directory, 1997).

Stavudine (2'3'-didehydro-2',3'-deoxythymidine, d4T, zerit; Bristol-Myers Squibb) is an antiretroviral drug, an analog of the natural nucleoside thymidine. It is active against HIV-1 and HIV-2. Stavudine is phosphorylated to stavudine-5'-triphosphate by cellular kinases and inhibits viral replication in two ways: by inhibiting reverse transcriptase and by interrupting the forming DNA chain.

It is not recommended to use stavudine together with zidovudine (AZT), because they compete for the same cellular enzymes. However, zerit can be successfully used in cases where zidovudine therapy is not indicated or needs to be replaced. The therapeutic effect of stavudine is enhanced when it is prescribed together with didanosine, lamivudine and protease inhibitors. Zerit has the property of penetrating the central nervous system, preventing the development of HIV dementia.

Doses for adults and adolescents: over 60 kg of weight - 40 mg x 2 times a day, 30 - 60 kg of weight - 30 mg x 2 times a day.

Recently, these antiretroviral drugs have been approved for use in HIV infection in children at a dose of 1 mg/kg body weight every 12 hours for children weighing less than 30 kg.

Side effects of zerit include sleep disturbances, skin rashes, headaches, and gastrointestinal disorders. A rare but most severe manifestation of toxicity is dose-dependent peripheral neuropathy. Sometimes, liver enzymes are elevated.

Cases of d4T resistance were rare.

Zerit and Videx have been approved by the FDA as first-line treatment for HIV infection.

According to S. Moreno (2002), resistance to d4T develops more slowly than to AZT. Currently, three main side effects associated with lipid metabolism disorders are distinguished: lipoatrophy, lipodystrophy and lipohypertrophy. One study showed significant differences between d4T and AZT in patients with lipoatrophy but without hypertrophy, another study showed a similar frequency of lipodystrophy occurring during treatment with d4T and AZT. The once-daily d4T (100 mg per tablet) (Zerit PRC) is convenient and optimal for adherence and can improve clinical outcomes.

Lamivudine (2',3'-dideoxy-3'-tacitidine, 3TC, Epivir; GlaxoSmithKline) has been used in HIV infection since 1995. Intracellularly, these antiretrovirals are phosphorylated to the active 5'-triphosphate with a cellular half-life of 10.5 to 15.5 hours. The active L-TP competes with natural deoxycytidine triphosphate for attachment to the growing chain of proviral DNA, thereby inhibiting HIV RT.

Antiretroviral drugs have high bioavailability when taken orally (86%), are excreted by the kidneys, taken at 150 mg twice a day (for adults and adolescents weighing over 50 kg), children under 13 years of age are prescribed 4 mg/kg of weight every 12 hours.

Synergism of lamivudine and retrovir action has been established. With combined therapy, the emergence of chemotherapy-resistant HIV strains is delayed. A good antiviral effect has also been noted when using ZTS in combination with d4T and protease inhibitors. Lamivudine is successfully used to treat not only HIV infection, but also chronic viral hepatitis B. The advantage of lamivudine over other reverse transcriptase inhibitors is the ability to use it twice a day, which significantly facilitates the implementation of combined therapy.

The use of AZT/ZTS and AZT/ZTS/indinavir combinations in HIV infection in children is being studied.

Lamivudine has minimal toxicity. When taking it, symptoms such as headache, nausea, diarrhea, neuropathy, neutropenia, and anemia may occur.

It is known that resistance to ART was formed in patients who took antiretroviral drugs for more than 12 weeks.

GlaxoSmithKline also produces combined antiretroviral drugs - Combivir, one tablet of which contains two nucleoside analogues - Retrovir (zidovudine) - 300 mg and Epivir (lamivudine) - 150 mg. Combivir is taken 1 tablet twice a day, which significantly simplifies the implementation of combined therapy. Antiretroviral drugs are well combined with other drugs and exhibit maximum suppressive properties in triple therapy, recommended for HIV-positive patients starting antiviral therapy, or who have already received other antiretroviral drugs. Combivir clearly slows the progression of HIV disease and reduces mortality.

The most common side effects of Combivir are headache (35%), nausea (33%), fatigue/malaise (27%), nasal signs and symptoms (20%), as well as manifestations directly related to its component zidovudine, such as neutropenia, anemia, and, with long-term use, myopathy.

Combivir is not recommended for use in children under 12 years of age, patients weighing less than 110 pounds (approximately 50 kg), or patients with kidney failure.

Azidothymidine (retrovir), hivid (zalcitabine), videx (didanosine), lamivudine (epivir), stavudine (zerit), combivir are approved for use in our country.

Another new drug from the group of nucleoside analogues, abacavir, has currently undergone clinical trials.

Abacavir or Ziagen (GlaxoSmithKline) - antiretroviral drugs, analogs of natural guanosine, has unique intracellular phosphorylation pathways, which distinguishes it from previous nucleoside analogs. It is taken at a dose of 300 mg x 2 times a day. It has good bioavailability when taken orally, is able to penetrate the central nervous system.

Studies have shown that when used alone, abacavir significantly reduced viral load levels, and when used in combination with AZT and 3TC, as well as with protease inhibitors (ritonavir, indinavir, fortovase, nelfinavir, amprenavir), viral load levels became undetectable. Clinical studies have shown that patients on ddl or d4T therapy responded better to the addition of abacavir than those receiving AZT or AZT/3TC.

Abacavir is generally well tolerated. When using it, allergic reactions (2-5%), neutropenia, skin rashes, nausea, headaches or abdominal pain, diarrhea sometimes occurred, but untimely identified hypersensitivity reactions can lead to serious consequences or even death of the patient. Clinical trials have not revealed any cross-interaction of abacavir with other antiretroviral drugs.

Rare cases of resistant HIV strains have been reported with abacavir monotherapy for 12-24 weeks, however, AZT or 3TC therapy may cause cross-resistance to abacavir.

Adefovir dipivoxil (Preveon, Gilead Sciences) is the first antiretroviral drug of the nucleotide analogue, which already contains a monophosphate group (adenosine monophosphate), which facilitates further stages of phosphorylation, which makes it more active against a wide range of cells, especially resting ones. Adefovir has a long half-life in the cell, which allows the use of antiretroviral drugs once a day at a dose of 1200 mg. It is excreted by the kidneys. The interactions of adefovir with other antiviral agents have not been sufficiently studied to date. It has been established that adefovir exhibits activity against other viral agents, such as hepatitis B virus and cytomegalovirus (CMV), which makes it promising for use in patients with HIV infection with viral hepatitis B and CMV infection.

New antiretroviral drugs from GlaxoSmithKline have been developed and prepared for clinical testing: Trizivir, which includes 300 mg of retrovir, 150 mg of epivir and 300 mg of abacavir, and is recommended for use at 1 tablet 2 times a day.

The introduction of another of the most powerful nucleoside reverse transcriptase inhibitors, abacavir, into Combivir will help overcome the development of resistance to Retrovir and Epivir.

Experience with combinations of two nucleoside analogues has shown that, in general, combination nucleoside therapy (AZT/ddl, AZT/ddC or AZT/3TC) is more effective than mono-AZT or ddl therapy, but nucleoside analogues have disadvantages: HIV reverse transcriptase quickly mutates and becomes insensitive to drugs, which in turn can cause side effects, so it is necessary to use nucleoside reverse transcriptase inhibitors with inhibitors of other HIV enzymes, in particular, C protease inhibitors.