Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection

There are 3 groups of drugs available for the treatment of patients with HI V disease. These are the nucleoside reverse transcriptase inhibitors ('nucl eoside analogues') [zidovudine, didanosine, zalcitabine, lamivudine and aba cavir]; the non-nucleoside reverse transcriptase inhibitors (nevirapine, de lavirdine and efavirenz); and the protease inhibitors (saquinavir, ritonavi r, indinavir, nelfinavir and amprenavir). The preferred initial regimen sho uld reduce and maintain plasma HIV RNA below the level of detection. Presen tly, the regimen of choice consists of 2 nucleoside analogues plus a protea se inhibitor with high in vivo efficacy. An alternative combination consist s of 2 nucleoside analogues plus a non-nucleoside reverse transcriptase inh ibitor. Drug interactions are one of the major problems associated with the se multidrug regimens. Changes in plasma concentrations of the nucleoside analogues are unlikely t o be of clinical relevance as drug effect is mainly dependent on the rate a nd extent of intracellular phosphorylation. Combinations of zidovudine plus stavudine, and probably zalcitabine plus lamivudine, should be avoided as competition for phosphorylating enzymes may occur. The antiviral efficacy o f some nucleoside analogues, e.g. stavudine, may be compromised by prior tr eatment with other nucleosides (e.g. zidovudine). However, these data need to be clarified in further studies. It is unlikely that administration of o ther antiretrovirals will influence the activity of nucleoside analogues. Protease inhibitors are metabolised by hepatic cytochrome P450 (CYP) 3A4. C ombination protease inhibitor therapy can result in drug interactions media ted by enzyme inhibition. Ritonavir is the most potent inhibitor, saquinavi r the least. The protease inhibitors also interact with the non-nucleoside reverse transcriptase inhibitors. Nevirapine and efavirenz induce drug meta bolising enzymes and may reduce plasma concentrations of protease inhibitor s. A study in healthy volunteers showed that nelfinavir concentrations are increased by combination with efavirenz. Delavirdine inhibits drug metaboli sing enzymes and increases the plasma concentration of coadministered prote ase inhibitors. The nucleoside analogues would not be expected to interact with the protease inhibitors. Apart from the ability of didanosine to reduce the area under the concentra tion-time curve of delavirdine, there are no reports of clinically signific ant interactions of other antiretrovirals with the non-nucleoside reverse t ranscriptase inhibitors. Triple therapy is the current standard of care for patients with HIV diseas e. However, studies of quadruple therapy are already under way. Drug intera ctions are likely to remain one of the major considerations when selecting a therapeutic regimen for patients with HIV.