Reverse transcriptase antiretroviral agents

Hertogs K, de Bethune MP, Miller V, Ivens T, Schel P, Van Cauwenberge A, Van Den Eynde C, Van Gerwen V, Azijn H, Van Houtte M, Peelers F, Staszewski S, Conant M, Bloor S, Kemp S, Larder B, Pauwels R (1998) A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs. Antimicrob Agents Chemother 42 269-276... 

There are currently six major antiretroviral drug families (Table 5). Nucleoside reverse transcriptase inhibitors (NRTI) are nucleoside analogs (discussed in more detail in chapter by De Clercq and Neyts, this volume) and were the first approved antiretroviral agents. They include drugs such as AZT, didanosine (ddl), stavudine (d4T), abacavir (ABC), and lamivudine (3TC), the latest used at doses of 300 mg daily as anti-HIV agent (lOOmg/day is the dosing approved for treatment of HBV... 

Data from Panel on Clinical Practices for the Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. 2006, http/AMM/vAIDSinfo.NIH.gov Anderson PL, Kakuda TN, Lichtenstein KA. The cellular pharmacology of nucleoside- and nudeotide-andogue reverse-transcriptase inhibitors and its relationship to dinical toxdties. din Infect Dis 2004 38 743-753 and produd information for agents... 

Zidovudine, azidothymidine, AZT (Retrovir, Combivir) Antiretroviral agent Inhibits HIV replication by blocking reverse transcriptase... 

The development of antiretroviral therapy has been a major challenge since the discovery of the human inununodeficiency virus (HIV). Early successes with nucleoside and non-nucleoside reverse transcriptase (RT) inhibitors, as well as the development of protease inhibitors have facilitated, in recent years, a highly active antiretroviral therapy (HAART), where a combination of drugs is simultaneously administered. In spite of significant improvements in the morbidity and mortality of HIV-infected patients, the rapid appearance of resistant HIV-variants, as well as adverse effects and high cost of contemporary drugs necessitate the continuous development of independent classes of anti-HIV agents. ... 

HIV infection In combination with other antiretroviral agents (such as nonnucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults. 

This class of antiretrovirals may be considered the most potent therapeutic agents for HIV to date. Protease inhibitors are used in combination regimens and combinations of reverse-transcriptase inhibitors and protease inhibitors have been proven most effective to decrease viral load and prolong survival. However, the protease inhibitors generally show poor penetration into the CNS and thus have no effect on aids dementia. The present Pis available for the treatment of HIV are indinavir, ritonavir, nel-finavir, saquinavir and (fos)amprenavir, atazanavir and lopinavir (in combination with ritonavir as ritonavir improves the bioavailability of lopinavir by inhibiting its metabolism in the liver by CYP3A). 

Single agents are seldom used to treat HIV infection. Instead, multidrug therapy is used to counteract the rapid mutation rate of HIV and to minimize drug toxicity. Highly active antiretroviral therapy (HAART) uses combinations of reverse transcriptase inhibitors and protease inhibitors (Table 51.1). In this system, drugs working by different mechanisms produce a sequential blockade of steps required for viral reproduction. It is... 

Treatment of human immunodeficiency virus (HIV) infections has been radically modified during the past two years by the introduction of powerful antiretroviral drugs, and by the development of methods to determine the viral burden in plasma. The introduction of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors has made this breakthrough possible. However, the long-term therapeutic benefits and safety profiles of these agents are still being evaluated. 

Antiretroviral agents currently in use include inhibitors of reverse transcriptase, HIV protease, and fusion inhibitors. Several other compounds are in development including... 

All of the classical antiretroviral agents are 2. .2 -didcoxy-nucleoside analogues. These compounds. share a common mechanism of action in inhibiting the reverse transcriptase of HIV. Because reverse transcriptase acts early in the viral infection sequence, inhihitors of the enzyme block acute infection of cells but are only weakly active in chronically infected ones. Even though the reverse tran.scripta.se inhihitors share a common mechanism of action, their phamtaeo-logical and toxicological profiles differ dramatically. 

Highly Active Antiretroviral Therapy (HAART) HAART slows or inhibits reverse transcriptase and protease enzymes by using several antiretroviral agents. HAART decreases the viral load. The viral load measures the amount of virus in the body. A decreased viral load causes an increase in CD4+ T cells and results in the immune system being able to identify, neutralize, and destroy non-self-cells. HAART therapy must be adhered to because the virus can become resistant to the antiretroviral agents. The patient must also adhere to nutritional therapy and avoid infections. 

Indications Management of HIV Infections in combination with at least two other antiretroviral agents Category Antiretroviral Nucleotide analog reverse transcriptase inhibitor Half-life 12.0-14.4 hours... 

Abacavir is an antiretroviral/nucleoside reverse transcriptase inhibitor. It is used in the treatment of HIV-1 in combination with other antiretroviral agents. Abacavir is converted inside cells to an active metabolite, carbovir 5 -triphosphate, which is a potent inhibitor of the HIV-1 reverse transcriptase. 

Delavirdine is an antiretroviral/nonnucleoside reverse transcriptase inhibitor that inhibits replication of HlV-1 infection by interfering with DNA synthesis. Delavirdine is indicated in treatment of HfV-l infection in combination with appropriate antiretroviral agents when therapy is warranted. 

Lamivudine is a nucleoside reverse transcriptase inhibitor, which inhibits replication of HIV and hepatitis B virus (HBV). HIV infection Epivir is used in combination with other antiretroviral agents for the treatment of HIV infection. Chronic hepatitis B Epivir-HBV is used in the treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation. 

Nevirapine is a nonnucleoside reverse-transcriptase inhibitor that inhibits replication of retroviruses, including HIV. In combination with other antiretroviral agents it is used for treatment of HIV-1 infection. 

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