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Clinical HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa
Gilead Sciences, Inc.
Duke University Medical Center, Durham, North Carolina
Case Western Reserve University, University Hospital of Cleveland, Cleveland, Ohio
In their response to our article [1], Leith et al. [2] from Boehringer Ingelheim (BI) Pharmaceuticals, the manufacturer of nevirapine, argue against our overall conclusion. Briefly, we observed a high incidence of hepatotoxicity (17%) in a large randomized, prospective, controlled trial that included nevirapine as part of combination antiretroviral therapy. On the basis of a multiple regression analysis, we concluded that women with a body mass index (BMI) <18.5 and low albumin levels had a markedly increased risk of developing nevirapine-associated hepatotoxicity, but we did not identify a correlation between the occurrence of hepatotoxicity and high CD4 cell counts, as had been reported by BI.
The analysis completed by BI concluded that the major predictive factor for nevirapine-associated hepatotoxicity was baseline CD4 cell count (>250 cells/mm3 in women and >400 cells/mm3 in men). The data used to derive these results were from 9 randomized controlled trials that primarily enrolled male patients (80%); 63% of the patients were white, 19% were black, and 61% had baseline CD4 cell counts <200 cells/mm3. By comparison, the group of patients treated with nevirapine in the FTC-302 study was primarily female (60%); 78% of the patients were black, and 12% were white. Seventeen percent of the women had baseline CD4 cell counts <250 cells/mm3, and 56% of the men had baseline CD4 cell counts <400 cells/mm3. The population in the FTC-302 study allowed for the assessment of other possible factors associated with hepatotoxicity that were not assessed in previous studies. In our study, we used a definition that was based solely on liver enzymes rather than on symptomatic hepatic adverse events. We observed 53 cases of early hepatotoxicity, 42 in women and 11 in men. Six of the 42 women had baseline CD4 cell counts <250 cells/mm3, and 6 of the 11 men had baseline CD4 cell counts <400 cells/mm3. In our study, immune status at baseline was not predictive of hepatotoxicity, but a BMI <18.5 and a serum albumin level <35 g/L were strong risk factors for the emergence of hepatotoxicity. In the FTC-302 study, 80% of the hepatotoxicity events were detected before week 12, with 34% of these events resolving in spite of continuation of nevirapine treatment.
In the double-blind, placebo-controlled trial FTC-302, contrary to the statement by Leith et al. [2] regarding the monitoring for the appearance of rash or hepatotoxicity, patients were monitored at day 7, day 14, and day 28 (week 4) for adverse events, with laboratory evaluations (including assessment of alanine aminotransferase and aspartate aminotransferase levels) beginning at the week 4 visit. This monitoring schedule was more stringent than that prescribed in the guidance information at the time the study was initiated and did not allow for the prevention of liver failure in 2 patients.
As described in our article [1], a population pharmacokinetics study of nevirapine conducted by De Maat et al. demonstrated a decreased clearance of nevirapine in subjects with lower weight or who were of black race [3]. A recent pharmacogenomic study of nevirapine and hepatotoxicity in patients in FTC-302 found that the risk of hepatotoxicity while taking nevirapine was strongly associated with a multiple drug resistance protein 1 (MDR1) polymorphism that differs in frequency between ethnic populations [4]. Although the BI analysis found a correlation between baseline CD4 cell count and reported toxicities, our analysis and others [5] found no such correlation between CD4 cell count and hepatotoxicity. In conclusion, factors other than, or in addition to, CD4 cell count must play a role in nevirapine-associated hepatotoxicity.
References
1. Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 2005; 191:8259. First citation in article
2. Leith J, Piliero P, Storfer S, Mayers D, Hinzmann R. Appropriate use of nevirapine for long-term therapy . J Infect Dis 2005; 192:5456 (in this issue). First citation in article
3. De Maat MM, Huitema AD, Mulder JW, Meenhorst PL, Van Gorp EC, Beijen JH. Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1 infected individuals. Br J Clin Pharmacol 2002; 54:37885. First citation in article
4. Haas DW, Bartlett J, Andersen J, et al. Pharmacogenetics of nevirapine and hepatotoxicity: NWCS220, an ACTG collaborative study [abstract 833]. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections (Boston). Alexandria, VA: Foundation for Retrovirology and Human Health, 2005:374. First citation in article
5. Phanuphak N, Apornpong T, Intarasuk S, Teeratakulpisarn S, Phanuphak P. Toxicities from nevirapine in HIV-infected males and females with various CD4 cell counts [abstract 21]. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections (Boston). Alexandria, VA: Foundation for Retrovirology and Human Health, 2005:72. First citation in article