In this issue Rachel Jordan and colleagues have provided a meta-analysis of published controlled clinical trials, which provide significant information relevant to the initial treatment of established HIV infection in adults and adolescents (p 757).1 Their analyses are based on a large number of well conducted clinical trials. The data largely confirm earlier observations, often from relatively small studies, which have shown that dual nucleoside antiretroviral regimens are significantly more effective than single nucleoside therapy, and that three drug antiretroviral regimens are significantly better than two drug regimens for initial therapy of HIV infection.
The conclusions of the meta-analysis are entirely consistent with current consensus recommendations that initial therapy for established HIV infection in adults and adolescents should include a combination of three potent antiretroviral drugs.2–4 Since the major biological factor in failure of antiretroviral therapy is the development of viral mutations which confer resistance to specific antiretroviral agents, a two drug regimen has a more durable effect than a single drug regimen, simply because more viral mutations are required to confer resistance to the two antiretroviral drugs. Similarly, resistance to a potent three drug regimen generally takes longer to develop than resistance to a two drug regimen. Clinically relevant resistance may take several years to develop when the patient consistently adheres to a three drug regimen which is successful in decreasing the plasma HIV RNA to less than 50 copies per ml.5 An additional benefit from a potent three drug regimen appears to be that the viral strains resistant to three antiretroviral agents often exhibit less fitness and virulence than the original wild type virus.
Since antiretroviral naive patients who are adherent to three drug regimens often show effective suppression of HIV RNA levels for several years, it has been difficult to show that a regimen containing four or more drugs is better than a three drug regimen. However, a sound scientific rationale exists for using an initial four drug regimen that includes two protease inhibitors, in which a low dose of ritonavir is used to provide a pharmacokinetic boost to the effectiveness of the second protease inhibitor.
By inhibiting enzymes of the cytochrome P450 system, ritonavir may enhance intestinal absorption (for example, indinavir) or inhibit hepatic metabolism (for example, saquinavir, lopinavir) of certain other protease inhibitors. The low dose ritonavir thus enhances the blood concentration of the second protease inhibitor and thereby decreases the patient's likelihood of developing viral resistance to the second drug. A significant booster effect occurs when ritonavir is given with indinavir, saquinavir, lopinavir, or amprenavir; the effects are greatest with saquinavir, in which a 20 fold increase in the area under the curve may be achieved,6 and lopinavir, where an up to 100 fold increase in the area under the curve can be obtained.7
Other advantages of the coadministration of low dose ritonavir and a second protease inhibitor are that the higher and more prolonged blood concentrations of the second protease inhibitor permit twice daily dosing in all cases. In addition, coadministration eliminates the food restrictions that have been a requirement for giving certain protease inhibitors.
In the case of the combination of ritonavir and saquinavir, the duration of therapeutic saquinavir blood concentrations has been sufficient to justify controlled clinical trials of this combination as a component of once daily, four drug regimens. Data are not yet sufficient to determine long term effectiveness of such regimens.
The meta-analysis presented by Jordan et al provides a solid background against which further changes in therapeutic recommendations can be measured. The meta-analysis, however, deals only with antiretroviral regimens used for initial treatment of established HIV infection in adults and adolescents. It has no direct bearing on the treatment of primary (acute) HIV infection8 or on the possible use of four or more antiretroviral agents when an initial regimen has failed because of the development of resistance.9
Papers p 757
References
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