Roxane Laboratories has issued a new warning to US doctors about liver toxicity related to nevirapine treatment.
The company has advised that during the first 12 weeks of nevirapine treatment, patients should receive "intensive clinical and laboratory monitoring, including liver function tests".
It is suggested that during the first 12 weeks of treatment, it may be advisable to monitor liver function at baseline, prior to dose escalation (usually after 14 days), and again two weeks later, with monthly monitoring thereafter.
The company also warns that although the majority of hepatic events have occurred during the first 12 weeks of treatment, approximately one-third of reported cases have occurred after the first 12 weeks of nevirapine treatment have passed.
Physical symptoms of hepatotoxicity may not always be immediately recognisable, and people taking nevirapine should look out for symptoms that include:
- Nausea
- Loss of appetite
- Fatigue
- Liver tenderness or swelling
- Malaise
- Yellowing of the whites of the eyes
- Dark greenish/brown urine
- Yellowing of the skin (jaundice)
- Greyish or white stools
If these symptoms of hepatitis develop, nevirapine should be stopped and should not be resumed when the symptoms go away.
The European Agency for the Evaluation of Medicinal Products issued a warning in April about the need for careful monitoring during the first eight weeks of nevirapine treatment. The US warning is based on further analysis of clinical trials and reports of adverse events made to the manufacturer and the US Food and Drug Administration.
How often does liver toxicity occur?
A recent study of patients starting HAART at the University of Amsterdam Academic Medical Centre has shown that the risk of serious liver toxicity is associated with elevated liver enzymes at baseline (ALT/AST), or a history of chronic hepatitis B or C infection (Lange).
A review of liver enzyme elevations in the South African study comparing FTC or 3TC in combination with nevirapine and d4T found a 15% incidence of grade 3 or 4 hepatotoxicities, two of which resulted in death. Women were significantly more likely to experience severe toxicity, and the high proportion of women in this study (59%) may have led to the higher overall incidence compared with other studies of nevirapine.
In this study the onset of liver enzyme elevations tended to occur during the first 8 weeks of therapy, usually at the time when the nevirapine dose was increased from 200mg to 400mg. Only 3 of the 36 individuals who developed serious liver toxicity had hepatitis B or C, but the sole patient with hepatitis B died of liver failure, along with one other (Sanne).
A 2249-person international study of two nucleoside analogues plus nevirapine or placebo found that 2.8% of the nevirapine group developed hepatitis, compared to 1.4% of the placebo group, but there was no significant difference in the proportion of patients in each arm who developed transaminase elevations more than five times higher than the upper limit of normal (Cahn).
Finally, Spanish doctors reviewed the incidence of liver enzyme elevations in 610 patients who started nevirapine in Barcelona. After nine months follow-up, 2% (n=13) had stopped nevirapine due to liver toxicity. Six of the thirteen who discontinued due to liver toxicity had hepatitis C and had already been diagnosed with chronic liver disease. Overall, 20% of those who received nevirapine for 12 months had greater than threefold elevations in liver enzymes (ALT or AST), with the proportion increasing as time went on. The authors of this study concluded that frequent testing of liver enzymes during the first two months of therapy was probably not justified, despite the European warning issued in April (Martinez).
References
Cahn P, Johnson M, Nusrat R, et al. Hepatic safety with nevirapine (NVP) and two nucleosides in patients with advanced HIV infection, from a placebo controlled clinical endpoint trial (1090). Fifth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract PL8.6, 2000.
Lange JMA. Perspectives on the safety profiles of antiretroviral drugs. Fifth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract CS3.4, 2000.
Martinez E et al. Nevirapine-induced liver toxicity: a prospective cohort study. Fifth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract PL8.5, 2000.
Sanne I, et al. Severe liver toxicity in patients receiving two nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor. Fifth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract PL9.3, 2000.