Antiretroviral drugs

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

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]

What is the role of hydroxyurea?

Hydroxyurea is of great interest, so studies will continue to assess its potential role as an antiviral therapy assistant. Hydroxyurea has been used as a component of various modes of highly active antiretroviral therapy (HAART), especially those containing didanosine (ddl), with which it has a synergistic anti-HIV effect.

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

Some clinical studies demonstrate in vitro and in vivo the efficacy of hydroxyurea to suppress HIV replication when used in combination with ddl and other nucleoside reverse transcriptase inhibitors. Studies also suggest that the ability of hydroxyurea to limit the number of CD4 + T-lymphocytes of target cells can also contribute to the activity of this drug in vivo in combination with antiretroviral drugs.

Preliminary studies show that regimens containing hydroxyurea substantially inhibit viral replication if they start in the period of primary HIV seroconversion (see below). At least one patient from a small group had a very low provisional reservoir in the peripheral blood when treated with hydroxyurea, ddl and protease inhibitors and maintained an undetectable viral load after stopping HAART. In another group, it was reported that two patients taking only ddl and hydroxyurea had a withdrawal syndrome after discontinuation of treatment. The third group, however, found that HIV RNA in plasma quickly returned to a high level after the cessation of HAART with or without hydroxyurea during primary HIV infection. However, one patient in this study had fewer than 50 copies of HIV RNA in ml of plasma for 46 weeks after cessation of HAART. This case suggests that early therapy may occasionally induce a "remission" of HIV replication.

It also makes sense to investigate the potential effect of hydroxyurea on the HIV reservoir in patients who achieved an undetectable plasma RNA level on HAART. Hydroxyurea is a relatively small molecule that can penetrate the blood-brain barrier and is thus also capable of crossing the blood-testes barrier.

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

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

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

Autovaccination

• patients without therapy due to high viral load without HIV immune response
• on the background of HAART below the threshold, the level of HIV can not stimulate specific HIV immunity
• patients during the interruption of HAART can, due to the booster effect, increase the immune response
• The panda causes a specific immune response, since the number of HIV is above a threshold level that can increase the cellular immune response, but the viral load is below the threshold level.

Non-nucleoside reverse transcriptase inhibitors

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

The principal limitation of the use of MPIEN as monotherapy is associated with the rapid development of viral resistance, it is possible to form cross-resistance of the virus to various NNRTIs (but not to nucleoside RT inhibitors), which is associated with the occurrence of mutations in RT. NNRTIs are synergistic with most nucleoside analogs and protease inhibitors. Which allows more rapid use of them in combination therapy.

Currently, three NMIOT-delavirdine, peviapine, efavirep (stokryp) are used in the world practice for the therapy of HIV infection.

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

Delavirdine is metabolized by the cytochrome P450 system, suppressing its enzymes. Since the metabolism of many of the most common drugs is also associated with the cytochrome system, delavirdine has a pronounced drug interaction, for example, with phenobarbital, cimetidine, ranitidine, cisanrin, etc. With simultaneous administration of delavirdine and ddl, plasma concentrations of both one substance and the other decrease, therefore Delavirdine should be taken one hour before or after taking ddl. In contrast, 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 combined with delavirdip. It is not recommended to use rifabutin and rifampiain together with delavirdine.

The most typical manifestation of toxicity of delavirdine is a rash.

Nevirapine (Viramune, Behringer Ingelheim) - dosage form - tablets 200 mg and suspension for oral administration. Nevirapine directly combines with reverse trapscriptase, 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 all organs and tissues, including the placenta and the central nervous system. It is taken according to the scheme: the first 14 days - 200 mg x once a day, then 200 mg 2 times a 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 with ionotherapy to nevirapine, resistant strains of HIV are rapidly being formed, therefore it is recommended to use these antiretroviral drugs only in complex therapy with antiretroviral drugs. There is evidence of the combined use of nevirapine ddl or AZT / ddl in children with symptomatic HIV infection. The results of the study showed that overall the combination therapy was well distorted, however, sometimes patients receiving nevirapine had to interrupt treatment because of severe skin rashes. Clinical studies are underway but further study of the efficacy of nevirapine in the prevention of perinatal HIV infection.

Viramune (nevirapine) is highly effective in both primary and in supporting 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, by normalizing fat metabolism, reduce the side effects of protease inhibitors.

Viramune is well tolerated by patients with prolonged use, there is experience of use for more than 7 years:

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

Viramune ® 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 the schemes with almost all antiretroviral drugs and preparations for the treatment of opportunistic infections.

In studies conducted by P.Barreiro et al., 2000, the efficacy and safety of the transition from protease inhibitors to nevirapine in patients with a viral load of less than 50 cells / ml was evaluated. Of 138 observed patients 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 previous treatment. The authors concluded that the replacement of the protease inhibitors with nevirapine is safe both virologically and immunologically, it provides a significant improvement in the quality of life and in half of the patients improves body shape changes associated with lipodystrophy at the 6th month of admission, although the level of serum lipid abnormalities remains unchanged . In another study, performed by RuizL. Et al., 2001, found that PI-related treatment regimens including nevirapine proved to be an effective alternative for patients. Neuropine-based neuromuscular tritherapy achieved controlled HIV RNA levels and improved immunological response after 48 weeks of follow-up in patients. Switching to nevirapine significantly improved the lipid profile in group A, although there was no difference between the groups at the end of the study.

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

The interaction of nevirapine with the analogues of nucleosides (azidothymidine, videox or chivid), as well as with protease inhibitors (saquinavir and indinavir) does not require correction of the dosing regimen.

With the combined use of nevirapine with protease inhibitors, oral contraceptives, rifabutin, rifampicin, plasma concentrations of these substances decrease, and careful monitoring is therefore required.

At the 7th Conference, on retroviruses and opportunistic infections (San Francisco, 2000), it was reported about the advisability of combining nevirapine with a combivir. Combivir / nevirapine has been shown to have significantly greater activity than the regimen containing combivir and nelfinavir. In patients who received a combination of combination virovir and nevirapine, 6 months after the start of therapy, the level of viral load was reduced substantially, up to undetectable and the level of CD cells increased. In this case, patients were prescribed treatment with initial viral load greater than 1500 copies of RNA in ml before the development of AIDS. It should be noted that 39% of those treated were injecting drug users and had not received antiretroviral therapy prior to this therapy. Compared with patients who received nelfinavir with a combination, in patients the combination of nevirapine + combivir less often gave side effects and rarely had to be canceled because of its better tolerability. However, according to generally accepted data, nelfinavir in contrast to nevirapine has less pronounced side effects of the action. In view of this, it is possible to recommend 2 schemes alternatively or sequentially.

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

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

These antiretroviral drugs were introduced in 1998. In combination with two reverse transcriptase inhibitors, efavirenz was more effective than protease inhibitors and nevirapine. Efavirenz is faster and longer inhibits HIV up to 144 weeks.

The advantage of using efavirenz before other drugs is its long half-life (48 hours). Efavirenz is well tolerated. The initial side effect on the CNS is markedly reduced after the first few weeks of treatment. J.van Lunzen (2002) offers 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 reception and reduces the factor of forgetfulness, thereby improving adherence to therapy.

In a special study (Montana trial, ANRS 091), a new drug - emitricitabine (emitricitabine) 200 mg, ddl -400 mg and efavirenz 600 mg once is proposed in combination. All medications are given before bedtime. 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 (thymazide) is available in capsules of 0.1 g and is recommended for use in situations where the use of regrovir, zidovudine (Glaxo Welcam) is indicated. One of the most effective domestic drugs is phosphazide, which is produced by the "Association AZT" under the commercial name niacavir (5'-H-phosphonate sodium salt of azidothymidine), tablets 0.2 g. Nicavir belongs to the class of HIV reverse transcriptase inhibitors. Antiretroviral drugs are protected not only by Russian, but also by foreign patents.

Nikavir is close to azidothymidine (Timazid, Retrovir), widely used for the treatment of HIV infection, in its chemical structure, mechanism of action, antiviral activity, however, it is much less toxic to the body (6-8 times), and also has a prolonged action, that is longer persists in the blood in the therapeutic concentration, which makes it possible to assume a pattern of its administration once a day.

At the stage of preclinical trials, it was also shown that the bioavailability and bioequivalence of the nicavir are comparable to azidothymidine: it does not have a mutagenic. DNA-damaging, carcinogenic and allergicidal effect. Adverse effect on the development of the fetus during pregnancy was noted only with the use of 20-fold therapeutic vines (10-fold therapeutic doses were not observed).

The results of the tests showed the high therapeutic efficacy of nicavir in patients who used antiretroviral drugs both in monotherapy and in combination therapy. An increase in CD4-lymphocyte levels by an average of 2-3 times, a median decrease in the level of HIV RNA (viral load) was 3-4 times higher (by more than 0.5 log / l in the vast majority of patients (73.2% ), who took nicavir.The positive therapeutic effect (restoration of the immune status and reduction of the threat of development of opportunistic diseases) was stable in all studied daily doses: from 0.4 g to 1.2 g in 2-3 doses.

As a standard, a regimen for the administration of niacavir to 0.4 g twice daily is recommended. For children: 0,01-0,02 g per kilogram of weight in 2 divided doses. It is recommended to take antiretroviral drugs before meals and drink with a glass of water. When the central nervous system is affected by a retrovirus, the drug is prescribed at a daily dose of 1.2 g. With severe side effects (unlikely), the daily dose is reduced to 0.4 g in adults and up to 0.005 g per kilogram of body weight in children. The course of treatment - unlimited, if necessary intermittent courses for at least three months.

Nicavir is well tolerated not only by adults, but also by children. Common side effects for other antiretroviral drugs, such as nausea, vomiting, headaches, diarrhea, myalgia, anemia, thrombocytopenia, neutropenia, were virtually nonexistent in patients throughout the entire duration of administration of the nicavir. In addition, the results of studies show the possibility of using nicavir for patients who developed an intolerance to azidothymidine (retrovir, thymazide) in the course of previous therapy. There was no development of resistance to nicavir for a long (more than a year) admission. The low toxicity of the drug opens the prospect of using it as a preventive agent in the risk of HIV infection.

In view of the foregoing, there is every reason to consider nicavir a promising drug for the therapy of HIV infection, which have serious advantages over similar drugs currently used in world 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 the use of Nicavir in a three-component combination antiretroviral therapy using reverse transcriptase inhibitors: niacavir, videks and a non-nucleoside Viramune inhibitor in 25 adult patients proved to be very effective and not accompanied by any side effects. In recent years, the number of antiretroviral drugs is constantly increasing, the treatment of HIV-positive individuals is becoming complex and continues to improve. When appointing antiretroviral therapy, patients with asymptomatic and symptomatic HIV infection are allocated, and among the latter, the category of persons with advanced disease. The approaches to the appointment of antiretroviral therapy in the acute phase of the disease, as well as the basic principles for changing ineffective regimes or their individual components, are considered separately.

[12], [13], [14], [15], [16], [17], [18], [19], [20]

Inhibitors of reverse transcriptase - analogues of nucleosides

Nucleoside analogs have a slightly altered structure 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 the HIV reverse transcriptase mistakenly uses instead of natural nucleoside triphosphates to extend the DNA strand. However, differences in the structure of analogs 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 a complex of antiviral agents is azidothymidine.

Azidothymidine (3'-azido, 2'3'-dideoxythymidine, AZT, zidovudine, retrovir, Glaxo-Smithklein) - synthetic antiretroviral drugs, analogues of 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 commercially available as thymazide. The second domestic nucleoside analogue phosphazide is also a derivative of azidothymidine, it is also approved for wide application.

Inside the cell, AZT is phosphorylated, becoming an active metabolite AZT triphosphate, which competitively inhibits the addition of thymidine to the growing DNA chain, carried out by RT. By replacing thymidine triphosphate, AZT triphosphate blocks the addition of the next nucleotide to the DNA strand, since its 3'-azido group can not 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 CNS through the blood-brain barrier.

AZT is recommended for the treatment of all HIV-positive adults and adolescents with a C04-lymphocyte count of less than 500 / mm3, as well as children with HIV infection. In recent years, AZT is widely used for the purpose of chemoprophylaxis of perinatal HIV infection.

These antiretroviral drugs are well absorbed when taken orally (up to 60%). The half-life of the cell is approximately 3 hours. The 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 a day, but, depending on the stage of HIV infection, tolerability can be reduced to 300 mg / day. According to most European researchers, the dose of AZT 500 mg per day can also be considered as optimal. AZT is excreted by the kidneys, therefore, in patients with chronic renal failure, doses should be reduced.

Children are given antiretroviral drugs at a rate of 90-180 mg / m2 body surface every 6 hours.

Studies have shown that AZT clearly slows the replication of HIV and the progression of HIV infection in patients with asymptomatic and symptomatic HIV infection and improves the quality of life, reducing the severity of opportunistic infections and neurological dysfunctions. In this case, the body increases the number of CD4 T cells and reduces the level of viral load.

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

Resistance to AZT is formed in the majority of patients with long-term admission (more than 6 months). To reduce the production of resistant strains, the use of AZT in combination with other antiretroviral drugs is recommended.

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

Didanosine (2 ', 3'-dideoxyinosine, ddl, videks, Bristol-Myers Squibb) - synthetic antiretroviral drugs, purine nucleoside analogues of deoxyadenosine was the second antiretroviral agent approved for HIV therapy in 1991.

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

Initially ddl was used in adult patients with symptomatic HIV infection in combination with AZT-therapy, which was started earlier, later it was used in combination with other antiviral agents, as well as as monotherapy. Recommended doses for adults: more than 60 kg of body weight - 200 mgx2 times a day, less than 60 kg - 125 mg x 2 times a day, for children 90-150 mg / m2 body surface every 12 hours.

Currently, ddl (vidix) is suggested to prescribe once a day for 400 mg of adults and 180-240 mg / kg per day for children.

The effectiveness of the first begun ddl-monotherapy of HIV infection is about the same as AZT-monotherapy. However, according to Spruance SL et al. In patients receiving AZT-monotherapy, the transition to ddl-monotherapy was more effective than continued use of AZT. According to Englund J. Et al., Ddl, either alone or in combination with AZT. Was more effective than one AZT in the treatment of HIV infection in children.

Data have been obtained that in vitro didanosine (as well as cytidine analogs - 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 are violations of kidney function, changes in liver tests. The appearance of symptoms such as nausea, abdominal pain, increased amylase or lipase are indications for a break in ddl therapy before pancreatitis is excluded.

Antiretroviral drugs such as dapsone, ketoconazole should be taken 2 hours before ddl, since ddl tablets can inhibit gastric absorption of dapsone and ketoconazole. Caution should be exercised when combined oral ganciclovir with ddl, as this increases the risk of pancreatitis.

Development of ddl-resistant strains of HIV occurs with prolonged admission. Studies have shown that the combination of ddI / AZT does not prevent the onset of viral resistance (Scrip World Pharmaceutical News, 1998), the decrease in sensitivity to AZT develops with the same frequency in patients receiving AZT therapy or a combination of A3T / ddl.

Zalcitabine (2 ', 3'-dideoxycytidine, ddC, quid; Hoffmann-La Roche) is a pyrimidine analogue of the cytidine nucleoside in which the hydroxyl group of the y position is replaced by a hydrogen atom. After conversion into the active 5'-triphosphate under the action of 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 for the replacement of AZT in people with progressive HIV infection or with AZT intolerance. In studies it was shown that when the combination of zalcitabine and zidovudine significantly increased the content of CD4 + cells by more than 50% of the initial, decreased the incidence of conditions determining the diagnosis of AIDS and death 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 extensive clinical trials have demonstrated a good therapeutic effect when combined with 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 daily, children under 13 years 0.005-0.01 mg / kg body weight every 8 hours.

Frequent side effects are headache, weakness, gastrointestinal disorders. These antiretroviral drugs have the most characteristic complications - peripheral neuropathies, which occur in patients with advanced HIV infection in approximately 1/3 of the cases. 1% of people receiving ddC develop pancreatitis. Rarely encountered complications - steatosis of the liver, ulcers of the oral cavity or esophagus, cardiomyopathy.

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

Resistance to ddC develops approximately in one year of treatment. Sharing ddC with AZT does not prevent the development of resistance. Cross-resistance is possible with other nucleoside analogs (ddl, d4T, ZTS) (AmFAR's AIDS / HIV treatment directory, 1997).

Stavudip (2'3'-didehydro-2 ', 3'-deoxythymidine, d4T, zerit, Bristol-Myers Squibb) - antiretroviral drugs, analogues of natural nucleosidatymidine. It is active against HIV-1 and HIV-2. Stavudine is phosphorylated into stavudine-5'-triphosphate by cellular kinases and inhibits viral replication in two ways: by inhibiting reverse transcriptase and by interrupting the emerging DNA strand.

It is not recommended to use stavudine in conjunction with zidovudine (AZT), t. They compete for the same cellular enzymes. However, zerite can be successfully used in cases when zidovudine therapy is not indicated or it must be replaced. The therapeutic effect of stavudine is enhanced when it is administered together with didanosine, lamivudine and protease inhibitors. Zerit has the ability to penetrate the central nervous system, preventing the development of HIV-dementia.

Doses for adults and adolescents: more than 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 every 12 hours with a child weighing less than 30 kg.

Among the side effects of zeritis, there are violations of sleep, skin rashes, headaches, digestive disorders. A rare, but most severe manifestation of toxicity is dose-dependent peripheral neuropathy. Sometimes there is an increase in the level of hepatic enzymes.

The occurrence of d4T - resistance was rare.

Zerit and videix were approved by the FDA as first-line therapy for HIV infection.

According to S. Moreno (2002), resistance to d4T develops more slowly than to AZT. Currently, there are three main side effects associated with impaired lipid metabolism: 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 in the treatment of d4T and AZT. The d4T form for taking 1 time per day (100 mg per tablet) (zerit PRC) is convenient and is optimal for adherence and can improve clinical outcomes.

Lamivudine (2 ', 3'-dideoxy-3'-taacitidine, ZTS, epivir; GlaxoSmithKline) has been used in HIV infection since 1995. Intracellularly, these antiretroviral drugs are phosphorylated into an active 5'-triphosphate with a half-life of 10.5 to 15.5 hours from the cell. Active L-TP competes with natural deoxycytidine triphosphate for its attachment to the growing strand of proviral DNA, thereby inhibiting HIV OV.

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

The synergism of lamivudine and retrovir has been established. When combined therapy is delayed the emergence of chemotherapy-resistant strains of HIV. A good antiviral effect was also observed 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 compared with other reverse transcriptase inhibitors is the possibility of using 2 times a day, which greatly facilitates the implementation of combination therapy.

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

The toxicity of lamivudine is minimal. When he is admitted, symptoms such as headache, nausea, diarrhea, neuropathy, neutropenia, anemia can be noted.

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

GlaxoSmithKline also produces combined antiretroviral drugs - a combination of which one tablet contains two nucleoside retrovir analogues (zidovudine) - 300 mg and epivir (lamivudine) - 150 mg. Combivir is taken for 1 tab. Twice a day, which greatly simplifies the conduct of combination therapy. Antiretroviral drugs combine well with other drugs and show maximum suppressive properties in triple therapy, recommended for HIV-positive patients who start 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 the combivir are headache (35%), nausea (33%), fatigue / malaise (27%), nasal symptoms and symptoms (20%), and manifestations associated with zidovudine alone. As neutropenia, anemia, with prolonged use - myopathy.

Combivir is not recommended for children under 12 years of age, patients who weigh less than 110 pounds (about 50 kg), patients with renal insufficiency.

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

At present, another new drug from the group of nucleoside analogues, abacavir, has been clinically tested.

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

Studies have shown that with monotherapy abacavir significantly reduced the level of viral load, and in combination with AZT and ZTS, as well as with protease inhibitors (ritonavir, indinavir, fortovaz, nelfinavir, amprenavir), the level of viral load became undetectable. Clinical studies have shown that patients on ddl- or d4T-therapy respond better to the addition of abacavir than those receiving AZT or AZT / ZTS.

Tolerability of abacavir is generally good. When it was used, there were sometimes allergic reactions (2-5%), neutropenia, skin rashes, nausea, headache or abdominal pain, diarrhea, but untimely identified hypersensitivity reactions can lead to serious consequences or even death of the patient. The conducted clinical trials did not reveal any cross-interaction of abacavir with other antiretroviral drugs.

When monotherapy with abacavir for 12-24 weeks, rare cases of the formation of resistant HIV strains were noted, however, AZT-therapy or ZTS-therapy can cause cross resistance to abacavir.

Preveon, Gilead Sciences are the first antiretroviral preparations of a nucleotide analogue already containing a monophosphate group (adenosine monophosphate), which facilitates further phosphorylation steps, 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 studied to date. Adefovir has been shown to be active 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.

Developed and prepared for clinical approbation are new antiretroviral drugs from GlaxoSmithKline-Trizivir, which includes 300 mgtrovir, 150 mg epivir and 300 mg abacavir, is recommended for use in 1 table. 2 times a day.

The introduction of one of the most powerful nucleoside reverse transcriptase inhibitors, abacavir, into the compound is able to overcome the formation of resistance to retrovirus and epivir.

The use of combinations of two nucleoside analogs has shown that, in general, combined nucleoside therapy (AZT / ddl, AZT / ddC or AZT / ZTS) is more effective than mono AZT or ddl therapy, however, the nucleoside analogs have drawbacks: grnskriptaza HIV rapidly mutates and becomes unaffected by 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, protease inhibitors.