ABC of AIDS: Antiretroviral drugs

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Abstract
Reverse transcriptase inhibitors The first drugs made available for clinical use were inhibitors of the HIV reverse transcriptase. Before the virus can be integrated into the host cell genome DNA, a copy of the viral RNA has to be formed (proviral DNA). This is regulated by the specific HIV DNA polymerase: reverse transcriptase. If a DNA copy is not formed, the viral RNA genome becomes susceptible to destruction by cellular enzymes. The nucleoside reverse transcriptase inhibitors are both competitive inhibitors of reverse transcriptase and DNA chain terminators. The normal 2' deoxynucleosides which are substrates for DNA synthesis link to form a chain by phosphodiester linkages bridging the 5' and 3' positions on the five carbon sugar molecule. The 2', 3'-dideoxynucleoside analogues are formed by the replacement of the 3'-hydroxy group by an azido (zidovudine), hydrogen, or other group. These nucleoside analogues as substrates will bind to the active site of the HIV reverse transcriptase and will be added to the growing HIV proviral DNA chain. However, once inserted, the normal 5' to 3' links will not occur, resulting in HIV proviral DNA chain termination. Genotypic mutations at various codons in the reverse transcriptase gene result in decreased susceptibility of HIV to inhibition by the nucleoside reverse transcriptase inhibitors. Several nucleoside reverse transcriptase inhibitors are currently licensed for the treatment of HIV infection in combination regimens, and newer agents with better tolerability and resistance profiles are under evaluation. The non-nucleoside reverse transcriptase inhibitors are a group of structually diverse agents which bind to reverse transcriptase at a site distant to the active site resulting in confirmational changes at the active site and inhibition of enzyme activity. These agents show high antiviral activity in vitro and have relatively low toxicity. They are also highly specific, inhibiting the reverse transcriptase of HIV-1 but not HIV-2. In monotherapy, rapid emergence of resistant strains associated with single point mutations of the reverse transcriptase gene, high level phenotype resistance and loss of antiviral effect occurs. The drugs therefore need to be combined with other antiretroviral agents, usually two nucleoside reverse transcriptase inhibitors, to achieve and maintain an effective long term treatment response. Antiretroviral regimens 2 nucleoside reverse transcriptase inhibitors, eg, zidovudine or stavudine + lamivudine or didanosine Plus either 1 non-nucleoside reverse transcriptase inhibitor: nevirapine or efavirenz or 1 protease inhibitor: indinavir, nelfinavir or saquinavir soft gel or 2 protease inhibitors, eg, ritonavir + saquinavir 3 nucleoside reverse transcriptase inhibitors: zidovudine + lamivudine + abacavir Recommended antiretroviral regimens for the initial treatment of chronic infection in adults (2001). Choice will depend on efficacy, tolerability, adherence, and resistance profile of regimen. Treatment guidelines are constantly reviewed and updated. Protease inhibitors The protease inhibitors bind competitively to the substrate site of the viral protease. This enzyme is responsible for the post-translational processing and cleavage of a large structural core protein during budding from the infected cell. Inhibition results in the production of immature virus particles. Their potent anti-HIV activity and introduction to clinical use from 1996 was one of the main reasons for the observed substantial falls in morbidity and mortality associated with HIV infection in the developed world. However, tolerability, relatively high pill burden, and poor adherence were frequent problems with the initial protease inhibitor containing regimens. Specific genotypic mutations in the protease gene can result in high levels of phenotype resistance to individual protease inhibitors and cross resistance. New protease inhibitors are under evaluation.

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