From the Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK.
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IntroductionThe rapid increase in access to antiretroviral therapy in developing countries has brought with it new challenges. These include the unprecedented need for lifelong treatment for an infectious disease, and the pressure this will place on health services. The use of fixed dose combinations from generic manufacturers does not easily allow for individualization of dosage (e.g. with coadministered drugs for tuberculosis). Gaps in current knowledge that urgently need to be addressed are the effect of ethnicity, gender and body weight upon antiretroviral drug disposition, and defining interactions with other drugs, including antimalarial and antituberculosis drugs and traditional medicines.Malaria is widespread across areas of the world where resources are limited, and most of these areas also bear the brunt of the HIV pandemic. There are potentially many different ways in which both diseases interact, at political, social and public health levels, as well as emerging evidence for how one disease may affect the pathogenesis and outcome of the other. At a time when access to antiretroviral drugs is increasing, and new combinations of antimalarial drugs are being evaluated, it is important that potential interactions between therapies for these two infections are also reviewed.Pharmacology of antiretroviral drugsThat antiretroviral drugs have the ability to prolong survival and improve well-being of HIV-positive individuals is beyond question; yet their therapeutic effects may be limited by toxicity, pill burden, the need for strict adherence to treatment, emerging prevalence of resistance and the risk of developing adverse drug interactions. At least 19 drugs from three classes – nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI), are available for the oral treatment of HIV infection. Fusion inhibitors (enfuvirtide) are an additional class of parenterally administered drug.For most countries in Africa, preferred combinations are represented by the four ‘3 by 5’ regimens, which are made up of 2NRTI [zidovudine (ZDV) or stavudine (d4T) plus lamivudine (3TC)] plus an NNRTI [nevirapine (NVP) or efavirenz (EFV)]. Problems of cost, shelf life, storage and toxicity of PI drugs currently limits their availability and use, even with generic manufacture or discounting through United Nations drug-access initiatives. However, the emergence of NNRTI resistance will limit the useful therapeutic lifespan of NNRTI, and the use of PI in developing countries (currently available in many private clinics) is likely to grow.The pharmacology of antiretroviral drugs will be familiar to most readers and has been detailed in previous issues of this journal . A summary is provided for those unfamiliar with this topic (Table 1).AbsorptionNRTI [with the exception of didanosine (ddI)] and NNRTI are well absorbed. The absorption of PI drugs is improved with food, and this is especially important for nelfinavir where drug exposure is almost twice that when taken fasting. The absorption of PI is limited by metabolic degradation by cytochrome P450 enzymes (mainly the CYP 3A4 isoform) within the gut as well as the presence of drug efflux transporters (e.g. P-glycoprotein). Ritinavir (RTV) may be used to ‘boost’ the bioavailability of other PI such as saquinavir (SQV) or lopinavir (LPV), mainly through inhibition of gut CYP 3A4.DistributionSince HIV replicates within cells, drugs that target its replication must penetrate into infected cells and anatomical compartments such as the CNS and genital tract at sufficiently high concentrations to exert their effect; failure to do so results in the establishment of a sanctuary site. The tissue and intracellular accumulation of HIV drugs is determined primarily by their physicochemical characteristics (e.g.