Appropriate use of nevirapine for long-term therapy.

To the Editor—The recent article by Sanne et al. [1] described possible risk factors associated with hepatic adverse events that can occur while nevirapine is being taken in a clinical trial. We are concerned about several key issues either overlooked or minimized in the article. It is important to understand that the preliminary results of the FTC-302 study provided the impetus for Boehringer Ingelheim (BI) to conduct a comprehensive analysis of hepatotoxicity in all large BI controlled and uncontrolled studies. This analysis resulted in warnings that female sex and higher CD4 cell count at the initiation of therapy increases the risk of hepatotoxicity, particularly during the first 6 weeks of treatment. This information has been widely communicated through changes to the prescribing information and through BI communications to physicians. Most recently, BI has recommended against the initiation of nevirapine treatment in women with CD4 cell counts 1250 cells/mm or in men with CD4 cell counts 1400 cells/ mm unless the benefit outweighs the risk (see http://www.fda.gov/cder/drug/ advisory/Nevirapine.htm). As shown in figure 1, there is a clear demarcation in the risk of developing nevirapine-associated symptomatic hepatitis at the CD4 cell count cutoffs mentioned above. In our comprehensive analyses, the frequency of patients with symptomatic hepatic events in the lower CD4 cell count groups (women with counts ! 250 cells/ mm and men with counts ! 400 cells/ mm) was significantly reduced and was consistent with frequencies found in association with other antiretrovirals, including efavirenz (1%–2%). We are concerned that, because study FTC-302 excluded patients with CD4 cell counts ! 200 cells/mm, the major predictive factor of hepatic events was removed from consideration, therein biasing the authors’ conclusion that a low body mass index (BMI) is predictive of nevirapine hepatotoxicity. Additionally, there was only a small number of patients with BMIs ! 18.5 (4.4% of total), and these accounted for only a small proportion of patients with hepatotoxicity (11.3%). This result suggests that there were other explanations for the high rate of hepatic events observed in this study, including the mean CD4 cell count of 406 cells/mm in patients with early events and coadministration of other potentially hepatotoxic medications, including stavudine. Thus, the conclusion that BMI is predictive of nevirapine-associated hepatotoxicity may be spurious, because of a combination of study design, statistical artifact, and the involvement of other factors that were not assessed in the article. It is also important to emphasize that patients were not monitored for the appearance of rash or hepatotoxicity until after 4 weeks of treatment. This is insufficient, according to current recommendations, especially given that the majority of these events occur during the first 6 weeks of treatment. Likewise, prompt discontinuation of nevirapine is recommended after the onset of grade 3 or 4 rash or constitutional symptoms suggestive of hepatitis. It is possible that recommended monitoring and more-rapid discontinuation of trial medications would have lessened the severity of reactions in some patients in FTC-302. Although BI has initiated a toxicogenomics program to study the complex relationship between nevirapine and hypersensitivity reactions, we believe that, by making the relatively simple recommendation based on CD4 cell count, there will be a significant reduction in the incidence of nevirapine-associated adverse events. By working to improve nevirapine safety within the standard guidelines for treatment initiation, an important option for