Antiretroviral therapy drug resistance

Two classes of entry inhibitors have been developed. The first entry inhibitor approved as HIV therapy was enfuvirtide, a fusion inhibitor. In contrast with aU other antiretrovirals, this drug must be administered subcutaneously and twice a day, which represent important disadvantages to the patient. It is very potent and generally reserved for heavily antiretroviral-experienced patients with virologic failure. Unfortunately enfuvirtide shows a low genetic barrier for resistance (Fig. 2) and should be administered in combination with at least one other active drug. 

The use of potent combination antiretroviral therapy to suppress HIV replication to below the levels of detection of sensitive plasma HIV RNA assays limits the potential for selection of antiretroviral-resistant HIV variants, the major factor limiting the ability of antiretroviral drugs to inhibit virus replication and delay disease progression. 

Wainberg, M.A. and Friedland, G., Public health implications of antiretroviral therapy and HIV drug resistance, JAMA, 279,1977-1983,1998. 

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. ... 

Rifabutin is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, M avium-intracellulare, and M fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (eg, efavirenz)—drugs that also are cytochrome P450 substrates. 

After oral administration, lamivudine is rapidly absorbed, and its bioavailability is about 86%. Food slows down its absorption, and it is excreted unchanged in the urine. The drug crosses the placenta, and the transfer to placenta does not appear to be altered by zidovudine. Its concentrations are higher in the male genital tract in comparison with the circulation. In combination with other antiretroviral therapy, lamivudine is recommended for the treatment of HIV infection. It inhibits plasma HIV-1 RNA concentrations but resistance develops rapidly when used as monotherapy. 

Lipodystrophy, a syndrome characterized by fat redistribution, hyperglycemia/insulin resistance, and dyslipidemia, can be associated with long-term HIV infection or with highly active antiretroviral therapy (HAART). In 1035 patients, those who took stavudine were 1.35 times more likely to report lipodystrophy (1076). However, the study was retrospective, and other factors unrelated to specific drug therapy may have had a greater effect on the adjusted odds ratio. 

The advent of highly active antiretroviral therapy (HAART) to minimize the rapid development of viral resistance in the treatment of HIV infection may result in multiple drug interactions (110-113). Both the nonnucleoside reverse transcriptase inhibitors and the protease inhibitors are substrates and inhibitors of some CYP enzymes, and some act as inducers as well (110,111). The major effects are on the CYP3A isoforms, and this has been used to advantage to increase concentrations of some HIV drugs. For example, delavirdine is a mechanism-based irreversible inhibitor of CYP3A4, and thereby is used to increase exposure to protease inhibitors (114). Ritonavir is a protease inhibitor, but it is used primarily for its ability as a potent inhibitor of CYP3A4 to increase concentrations of other protease inhibitors (115). 

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