Antiretroviral drugs

The clinical effectiveness of antiretroviral therapy has improved markedly over the last few years. Since 1996 in the developed world there have been dramatic falls in the incidence of new AIDS cases and AIDS-associated deaths.

Figure 9.9 Immune reconstitution of disease: MAC lymphadenitis in a patient recently starting HAART

Box 9.5 Antiretroviral regimens

1.

2.

Antiretroviral regimens for the initial treatment of chronic infection in adults (2001). Choice would depend upon efficacy, tolerability, adherence and resistance profile of the regimen. Treatment guidelines are constantly reviewed and updated.

There are several potential targets for antiretroviral drugs in the viral replication cycle. Three classes of antiretroviral drugs are currently used in combination for the treatment of HIV infection, which target the activity of two viral enzymes. New therapeutic agents are constantly being evaluated.

Reverse transcriptase inhibitors

The first drugs made available for clinical use were inhibitors of the HIV reverse transcriptase enzyme. Before the virus can be integrated into the host cell genome DNA, a copy of the viral RNA has to be formed (pro-viral DNA). This is regulated by the specific HIV DNA polymerase: reverse transcriptase (RT). If a DNA copy is not formed, the viral RNA genome becomes susceptable to destruction by cellular enzymes.

The nucleoside reverse transcriptase inhibitors (NRTIs) are both competitive inhibitors of RT and DNA chain terminators. The normal 2¹ deoxynucleosides which are substrates for DNA synthesis link to form a chain by phosphodiester linkages bridging the 5^l and 3^l positions on the five carbon sugar molecule.

Genotypic mutations at various codons in the RT gene result in decreased susceptability of HIV to inhibition by the NRTIs. Several NRTIs 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 (NNRTIs) are a group of structually diverse agents which bind to RT 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. As monotherapy, rapid emergence of resistant strains associated with single point mutations of the RT gene, high-level phenotype resistance and loss of antiviral effect occurs. The drugs therefore need to be combined with other antiretroviral agents, usually two NRTIs, to achieve and maintain an effective long-term treatment response.

Protease inhibitors

The protease inhibitors bind competitively to the substrate site of the viral protease enzyme. 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.

Figure 9.10 Mechanism of action of nucleoside reverse transcriptase inhibitors

Figure 9.11 MAC infection causing multiple cutaneous pustular lesions in a severely immunosuppressed patient after initiating HAART