August 17, 2006
Severe and potentially fatal toxicities have been observed in HIV treatment-naive patients who are initiating nevirapine (NVP, Viramune)-based highly active antiretroviral therapy (HAART) at a higher CD4+ cell count, which is defined as more than 250 cells/mm3 in women and as more than 400 cells/mm3 in men.
It is not known whether the same risk applies to patients who are beginning nevirapine following prior treatment exposure. Within the large EuroSIDA cohort, four groups were identified to attempt to address this issue: drug-naive and drug-experienced patients starting on nevirapine and having a CD4+ cell count above or below the thresholds defining risk for drug-associated toxicity.1
All cohort participants initiating therapy after Jan. 1, 1999 and for whom CD4+ cell count determinations were available in the previous six months were included in this evaluation. Among the patients with higher CD4+ cell counts, were 62 drug-naive individuals (median CD4+ cell count and HIV plasma viral load of 479 cells/mm3 and 4.43 log10 copies/mL, respectively) and 781 previously treated individuals (median CD4+ cell count and HIV plasma viral load of 561 cells/mm3 and 1.90 log10 copies/mL, respectively).
During 12 months of observation, 50% of drug-naive and 29% of treatment-experienced patients discontinued nevirapine due to toxicity. Among the patients with lower CD4+ cell counts (194 to 230 cells/mm3), the rate of discontinuation approached 27%, whether they were previously treated or not. The vast majority of treatment-limiting toxicities occurred during the first three months of therapy, especially in the higher CD4+ cell count groups. When treatment discontinuations in cohort participants receiving either efavirenz (EFV, Sustiva, Stocrin) or protease inhibitors were examined, no such predominance of early toxicity was noted. Further, there was only a 9% to 13% difference between drug-naive and treatment-experienced patients initiating therapy at higher CD4+ cell counts. This compares to a 42% reduction in non-naive patients initiating nevirapine at higher CD4+ cell counts.
There were four deaths among patients receiving nevirapine, all in women. Two of these deaths were due to malignancy (cervical carcinoma and non-Hodgkin's lymphoma) and one was due to an acute gastrointestinal hemorrhage. The fourth case, in a non-naive woman with a higher CD4+ cell count at the start of therapy, was due to hepatic disease. However, it occurred in the setting of hepatitis C-associated cirrhosis and its link to nevirapine use was uncertain.
These observational, non-randomized data suggest that, in patients with higher CD4+ cell counts, nevirapine-associated toxicity is less frequent when nevirapine is initiated in non-naive patients. In fact, in this group, toxicity closely parallels that observed in all patients with lower CD4+ cell counts -- including its increased incidence in the first three months of therapy. This suggests that it may be safe to start nevirapine as part of second-line therapy or as part of switch strategies regardless of the CD4+ cell count. However, it would still be prudent to exercise caution and to monitor patients extremely closely during the first weeks of therapy, if this strategy is employed. This is especially true of women, who appear to be at highest risk of fatal nevirapine-associated toxicity. In fact, it may still be prudent to avoid placing women who have CD4+ cell counts more than 250 cells/mm3 on nevirapine even if they are treatment-experienced unless no credible therapeutic alternative exists.
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