Nevirapine hepatotoxicity

In a retrospective analysis of 221 patients with prior viral suppression who were switched to nevirapine, hepatotoxicity, defined as liver aminotransferase activities five times above the upper limit of the reference range, was detected in 6.7% of those with high CD4 cell counts and 13% of those with low counts [95 j. Hepatotoxicity was mild, reversible on withdrawal, and more likely to occur after 6 months of nevirapine therapy. 

Kochar R, Nevah Ml, Lukens FJ, Fallon MB, Machicao VI. Vanishing bile duct syndrome in human immunodeficiency virus nevirapine hepatotoxicity revisited. World J Gastroenterol 2010 16 (26) 3335-8. 

Nevirapine in place of efavirenz in selected populations (due to a more frequent incidence of hepatotoxicity, nevirapine should only be used in patients with low to moderate CD4+ T-cell counts less than or equal to 250 cells/mm3 for females, less than or equal to 400 cells/mm3 for males)... 

Nevirapine is a non-nucleoside reverse transcriptase inhibitor used to treat HIV-infected patients that causes mild to severe skin rash and even Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in a substantial proportion (16%) of patients. Nevirapine also induces hepatotoxicity. These adverse clinical symptoms may also occur in non-HIV subjects taking the drug as postoperative prophylaxis [15]. 

Severe, life-threatening, and, in some cases, fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in patients treated with nevirapine (see Warnings). 

Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy role of hepatitis C and B infections. Hepatology 2002 35(l) 182-9. 

In 77 HIV-positive subjects randomized to switch from protease inhibitors to nevirapine or efavirenz or to continue taking protease inhibitors, quality of life significantly improved among those who switched (3). Lipid profiles improved in those who took nevirapine but gamma-glutamyltransferase and alanine aminotransferase activities increased significantly and one patient interrupted treatment because of hepatotoxicity. 

In a prospective study of the incidence of severe hepatotoxicity in 312 patients taking nevirapine, hepatitis C and hepatitis B viruses were detected in 43% (9). There was severe hepatotoxicity in 16%, but only 32% of episodes were detected during the first 12 weeks of therapy. The risk was significantly greater among those with chronic viral hepatitis (69% of cases) and those taking concurrent protease inhibitors (82% of cases). However, 84% of patients with chronic hepatitis C or hepatitis B did not have severe hepatotoxicity. 

The incidence of NNRTI-induced hepatotoxicity in HIV-infected patients and the effect of co-infection with hepatitis B or hepatitis C virus have been studied in 272 patients (8). The NNRTIs used were delavirdine (n = 40), efavirenz (n = 91), and nevirapine (n = 141). 

There were mild to moderate rises in serum aspartate transaminase or alanine transaminase in 81 patients and large rises in three patients, one of whom was taking efavirenz and two nevirapine. Hepatitis B or hepatitis C virus infection did not significantly increase the risk of hepatotoxicity. The authors concluded that NNRTIs cause little hepatotoxicity, despite the presence of co-infection with hepatitis B or hepatitis C viruses. 

Nevirapine (NVP), a nonnucleoside reverse transcriptase inhibitor, is widely used for the treatment of human immunodeficiency virus (HIV) infections. It is the main option for the first-line treatment of HIV-1, together with two nucleoside reverse transcriptase inhibitors, in countries with limited resources. NVP is associated with two serious clinically restrictive side effects skin reactions and hepatotoxicity. Severe, life threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure, has been reported in HIV-infected patients taking NVP (DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents 2008). For this reason, NVP is given a black box warning for hepatotoxicity, and concern has been raised over NVP-based treatment. 

Clarke S, Harrington P, Condon C et al (2000) Late onset hepatitis and prolonged deterioration in hepatic function associated with nevirapine therapy. Int J STD AIDS 11 336-337 Clawson GA (1989) Mechanisms of carbon tetrachloride hepatotoxicity. Pathol Immunopathol Res 8 104-112... 

Saiuie I, Mommeja-Marin H, Hinkle J et al (2005) Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 191 825-829 Sarich TC, Zhou T, Adams SP et al (1995) A model of isoniazid-induced hepatotoxicity in rabbits. J Pharmacol Toxicol Methods 34 109-116... 

De Maat MM, Mathot RA, Veldkamp AI, Huitma AD, Mulder JW, Meenhorst PL, Van Gorp EC, earlier H, Beijnen JH (2002) Hepatotoxicity following nevirapine-containing regimens in HIV-1-infected individuals. Pharmacol Res 46 295-300 De Maat MM, ter Heine R, Mulder JW, Meenhorst PL, Mairuhu AT, van Gorp EC, Huitema AD, Beijnen JH (2003) Incidence and risk factors for nevirapine-associated rash. Eur J Clin Pharmacol 59 457-462... 

Nevirapine 45 h single dose 25-30 h multiple doses Chronic Hepatotoxicity, rash. ... 

Cozza KL, Swanton EJ, Humphreys CW. Hepatotoxicity with combination of valproic acid, ritonavir, and nevirapine a case report. Psychosomatics (2000) 41,452-3. 

Efavirenz levels were not altered by valproic acid in one study in mV-positive patients, and valproic acid levels were not different to those in a control group not taking efavirenz. However, one patient had a marked decrease in valproate levels after starting efavirenz. A case of hepatotoxicity has occurred in a patient taking valproic acid with nevirapine and saquinavir/ritonavir. 

A case of valproate-associated hepatotoxicity occurred in a 51-year-old man about 3 weeks after he started nevirapine 200 mg twice daily, saquinavir/ritonavir 400/400 mg twice daily, and stavudine. Serum valproic acid levels remained therapeutic. ... 

Liver In 1809 HIV-infected adults who took nevirapine-based antiretroviral drug therapy the cumulative proportion of early hepatotoxicity was 1.0-2.0%, an incidence rate of 3.6-7.6 per 100 person-years [94 ]. The median time to hepatotoxicity was 32 days. At 12 weeks, only 8% of patients had alanine aminotransferase monitoring at all the times recommended by national guidelines. There was no association between early hepatotoxicity and age, sex, baseline CD4 count, concurrent tuberculosis infection, prior participation in a prevention of mother-to-child-transmission program, or baseline weight. There was no association between early hepatotoxicity and mortality. 

In 330 HIV-positive, of whom 267 received nevirapine-based antiretroviral therapy and 63 received efavirdine-based therapy there was a significant difference in the rates of hepatotoxicity 133 (50%) of the patients on nevirapine had at least one episode of a rise on alanine aminotransferase activity over a median follow-up period of 21 months, or 285 cases per 1000 person-years [96 ]. A baseline rise in activity (OR = 14) and hepatitis C co-infection (OR=3) were susceptibility factors, and a high CD4-I- cell count was protective. 

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