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.