July 14, 2004
It is clear now that all but the most recently approved protease inhibitors (PIs) cause more gastrointestinal side effects and adverse effects on lipid profiles during treatment than the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz (EFV, Sustiva, Stocrin) and nevirapine (NVP, Viramune). Plus, of course, there is the greater pill burden of PIs compared with NNRTIs. So it's not a surprise that a growing number of patients with well-controlled HIV infection who are on a PI-containing regimen wish to change the PI to an NNRTI.
Randomized trials with antiretroviral treatment-naive patients have generally shown PI- and NNRTI-based regimens to have similar efficacies. But for the purpose stated above, it is useful to have specific information on the subset of patients who do well on a PI-containing regimen. This is a particular concern with respect to switching to nevirapine, as the rare but serious hepatotoxicity, at least in patients initiating antiretroviral treatment, seems more common in patients with higher CD4+ cell counts. In fact, in women, nevirapine should probably not be initiated if the CD4+ cell count is over 250; in men it should only be used with caution if the CD4+ cell count is over 400. But it is patients who have a higher CD4+ cell count and are doing well on a PI who are more likely to contemplate a switch to nevirapine, making the concern about hepatotoxicity more of a potential reservation. However, there is some basis for hope that the CD4+ cell count cutoffs for initiating therapy might not be applicable in patients switching therapy.
Details of This Study
Gorgolas et al assembled 160 NNRTI-naive patients who had been on a PI-containing regimen for at least 6 months and had undetectable HIV RNA over that interval. There was 1:1 randomization to continuance of the PI regimen or switching the PI to nevirapine. The outcomes were analyzed in 2 strata: baseline viral load >100,000 copies/mL and <100,000 copies/mL. The nadir CD4+ cell count for the studied patients was about 339 cells/mm3, with a mean CD4+ cell count of about 530 cells/mm3 at the time of randomization. Sixty percent had had a pretreatment viral load above 100,000 copies/mL.
After 48 weeks, there were no significant differences between the 2 arms with respect to the fraction still with undetectable HIV RNA, the percentage with virologic failure or the rise in CD4+ cell count. The patients switching to nevirapine were less likely to have elevated triglycerides and self-reported lipodystrophy, and had improved triglyceride levels. Four patients in the nevirapine group had enough liver toxicity to discontinue therapy, although it was reversible.
Significance for Patients and Clinicians
This study provides support for patients wanting to switch their PI to nevirapine. The evidence that there is no efficacy disadvantage to switching is strong. However, severe hepatotoxicity was rare enough that important differences could have been missed. The critical question remains: can patients switch to nevirapine with sufficient safety if their CD4+ cell counts are above the gender-specific cutoffs? For now, we should consider this as a relative contraindication.
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