French study finds unusual level of nevirapine toxicities

A French study has found high rates of discontinuation amongst people taking nevirapine due to side-effects, even when medication to control adverse events was prescribed. Rates of discontinuation, particularly for gastrointestinal side-effects were much higher in this study than in the Dutch ATHENA study published earlier this year.

In a retrospective investigation published in the 15th November 2002 edition of Clinical Infectious Diseases, researchers analysed the medical records of 137 people enrolled in the southern French Aquitaine Cohort who were treated with nevirapine as part of first-line of subsequent HAART regimens between September 1997 and May 1999.

To be included in the study people had to have received at least one dose of nevirapine. Signs of clinical intolerance (skin disorders and digestive and constitutional problems) and biological side-effects (changes in alanine aminotransferase [ALT] a key marker of liver function, and triglyceride and cholesterol levels) were assessed every three months.

The study population included 99 men, 58 (42%) of whom were gay and 44 (27%) were injecting drug users. HIV and hepatitis B coinfection was diagnosed in 16% of trial participants, coinfection with HIV and hepatitis C in 25% and coinfection with HIV and both hepatitis B ad hepatitis C in 7%. Before starting nevirapine, 121 of the study sample had previously been treated with HAART. Of these, 37 (31%) switched only one drug to nevirapine; 27 made this switch in order to simplify their regimen or because of concerns about the side-effects of protease inhibitor therapy when their viral load was suppressed (below 500 copies/mL). Most people (72%) were taking nevirapine with two NRTIs (typically 3TC and d4T), although 20% were taking nevirapine with a single NRTI and a protease inhibitor.

Baseline investigations included CD4 and viral load as well as cholesterol and triglyceride levels.

To help prevent the rash frequently seen with nevirapine therapy, antihistamines were prescribed to 25 patients (18%), corticosteroids to nineteen people (14%) and both drugs to three people (2%). After an average follow-up of eleven months, nevirapine associated side-effects were reported by a third of the study population. Rash and other skin disorders were most frequently reported (23% of the cohort), although a further fifteen people reported digestive problems, musculoskeletal events or constitutional problems.In total, 29 people (21%) discontinued because of nevirapine-associated side-effects, but the investigators point out that most discontinuations were due to less severely side-effects with only only three discontinuations for severe or moderately severe physical adverse effects.

Data from the Dutch ATHENA cohort, previously reported on aidsmap found that changing to a nevirapine-based regimen rather a protease inhibitor was protective of having to make further changes. Of particular note was the low incidence of further treatment changes because of gastrointestinal problems in people switching to nevirapine: 22 people out of 100 were given nevirapine after complaining of gastric problems on their first PI-based regimen and of these only one had to make a subsequent treatment change because of the recurrence or continuation of toxicity

In the French study, providing antihistamines or steroids when commencing treatment did not prevent nevirapine related side-effects from developing. In addition, the occurrence of side-effects was found to be unrelated to any “epidemiological, clinical, biological, or theraputic factors”.

Blood tests also revealed that nevirapine was causing biological side-effects. Of particular note was the increase in ALT levels observed in people coinfected with HIV and hepatitis B/hepatitis C or HIV and hepatitis B and C. What’s more, abnormally high total cholesterol levels were detected in 39.2% of patients compared to 22.6% at baseline. However, no significant changes in triglyceride levels were detected. Data regarding HDL and LDL cholesterol were unavailable, which the investigators admitt is a weakness of their study.

The investigators observed that “in our cohort of patients…adverse events associated with nevirapine use were more common than has been reported in most previously published controlled clinical trials” adding, “even the incidence of cutaneous intolerance seems to be much higher than reported” in other investigations. The study authors believe that their trial adds further evidence to the case against providing drugs like antihistamines to prevent nevirapine-associated side-effects.

Regarding the evidence for nevirapine related liver toxicity, the French researchers suggest that “the risk of hepatotoxicity increased steadily over time, which indicates a direct toxicity of nevirapine on hepatocytes” and the investigators recommend the “cautious use” of the drug in people coinfected with HIV and hepatitis B and/or hepatitis C.

The study concludes with a caution about the metabolic impact of nevirapine with the study authors saying that this “is still debatable” and should be monitored in both HAART experienced and naïve individuals starting nevirapine therapy.