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Liver toxicity caused by nevirapine
  Editorial note from Jules Levin: Results from this study were initially presented at the Lipodystrophy workshop By Soriano in athens Oct 2001. The authors found nevirapine hepatotoxicity (elevated liver enzymes) was associated with higher nevirapine blood levels. They found that if a patient had HCV this also contributed to higher liver enzymes/hepatotoxicity. The one point, which may be crucual, not mentioned by the authors is what level of liver damage might be associated with elevated nevirapine blood levels. At the Lipodystrophy Wksp, Soriano suggested that only patients with advanced liver disease, perhaps cirrhosis, may suffer with harmful elevations in drug blood levels. We do not know at what level of liver damage (t.e., stage 3 biospy or cirrhosis, etc) may result in elevated drug blood levels. This deserves more research attention, and perhaps measuring drug blood levels with TDM (therapeutic drug monitoring) might be helpful in detecting the potential for liver toxicity. At Athens, Soriano also suggested that these observations may also apply to other drugs, not just nevirapine. Elevated liver enzymes may be more likely to occur in the patient with higher drug levels due to liver damage from hepatitis.
Daniel Gonzalez de Requenaa; Marina Nunezb; Inmaculada Jimenez-Nachera; Vincent Sorianob
AIDS 2002;16:290-291
Nevirapine plasma levels were measured in 70 HIV-infected patients, 33 of whom developed transaminase elevations. Higher nevirapine levels and hepatitis C virus infection were found to be independent predictors of liver toxicity. Moreover, in individuals with chronic hepatitis C, nevirapine concentrations greater than 6 g/ml were associated with a 92% risk of liver toxicity.
Therefore, monitoring nevirapine levels, especially in individuals with chronic hepatitis C, may be warranted.
A warning on the potential risk of liver toxicity caused by nevirapine has recently been released by health authorities. It specifically recommends the close monitoring of laboratory parameters during the first 12 weeks on therapy. Although transaminase elevations are a common side-effect using nevirapine, and grade 3-4 toxicity occurs in 8-17% of patients taking the drug, clinical hepatitis is rarely seen (< 2% of cases) [1,2].
Two mechanisms have been involved in nevirapine-associated liver toxicity. The first implies an immune-mediated mechanism, and accounts for cases of transaminase elevations seen in individuals, who are at the same time experiencing skin reactions, a few days to weeks after beginning nevi rapine-containing regimens. This hypersensitivity reaction seems to be more common in individuals who have high CD4 lymphocyte counts [3], which may explain the unexpectedly high rates and the severity of hepatotoxicity noted among immunocompetent HIV-negative patients who underwent post-exposure prophylaxis with nevirapine [4].
A second mechanism of nevirapine-related liver toxicity, which does not involve other organs, has a delayed onset, often several months, and might represent an intrinsic toxic effect of the drug. If this is the case, it should be predictable and perhaps dose-related. Supporting this hypothesis, a recent study [1] noted that the incidence of grade 3-4 liver toxicity increased over time in individuals treated with nevirapine, being 3.7, 9.7 and 20.1% at 3, 6 and 12 months, respectively.
As non-nucleoside reverse transcriptase inhibitors do not require intracellular phosphorylation to exert their blocking action on the HIV reverse transcriptase, the measurement of plasma drug levels may accurately predict their activity as well as their toxicity. This has been shown clearly for efavirenz [5], but no data are available on the potential relationship between nevirapine plasma levels and the risk of liver toxicity. Here we present the results of a study designed to assess the potential association between nevirapine plasma levels and the risk of transaminase elevations in individuals exposed to nevirapine for longer than 4 weeks.
In a case-control study, 70 patients taking nevirapine (200 mg twice a day) triple combinations were chosen and classified into two groups, one including subjects who developed any grade of hepatotoxicity, and a control group including subjects without transaminase elevations. The use of nucleoside analogues was comparable in both groups. Patients were stratified according to the presence of hepatitis C virus (HCV) antibodies. Blood samples were obtained 12 h after dose intake. The measurement of nevirapine plasma levels was performed using high-performance liquid chromatography, as described elsewhere [6].
The peak in transaminase levels among the 33 subjects of the first group occurred at a median time of 6.1 months after beginning nevirapine-based therapy. It was mild to moderate in 70% of patients; twenty-three of them were HCV-positive. The median (range) nevirapine plasma concentrations in subjects who developed transaminase elevations was significantly higher than in controls [6.25 g/ml (3.8-29) versus 5.2 g/ml (0.67-9.6); P = 0.025]. When HCV infection was also included in the analysis, both higher nevirapine plasma levels and HCV seropositivity were found to be independent factors predicting hepatic injury [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.2-2.6, P = 0.007 and OR 11.7, 95% CI 3.2-42.8, P = 0.0002, respectively]. Moreover, in subjects with chronic hepatitis C, nevirapine plasma levels above 6 g/ml were associated with a 92% risk of liver toxicity.
In summary, our preliminary findings support the theory that nevirapine-associated liver toxicity occurring after several months on therapy is not part of a systemic hypersensitivity reaction, and seems to correlate with higher plasma drug concentrations involving a dose-dependent mechanism. Chronic HCV infection acts as an independent predisposing factor for the development of nevirapine-related liver toxicity. Therefore, monitoring steady-state nevirapine plasma levels, especially in patients with chronic hepatitis C, may be warranted.
Daniel Gonzalez de Requenaa
Marina Nunezb
Inmaculada Jimenez-Nachera
Vincent Sorianob
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