People with undetectable viral load who switch from current treatment to nevirapine when they have a CD4 count above the recommended threshold for starting the drug are no more likely to develop hepatotoxicity than women with CD4 cell counts below 250 cells/mm3 or men with CD4 counts below 400 cells/mm3. The findings were presented in two studies at the Forty-Sixth Interscience Conference on Antimicrobial Agents and Chemotherapy in San Francisco on Thursday.
Nevirapine has been shown to pose a risk for liver toxicity for treatment-naïve individuals who are starting a first antiretroviral regimen at relatively high CD4 counts.
The degree of risk is different for men and women: men with CD4 counts above 400 cells/mm3, and women with CD4s above 250 cells/mm3, are most at risk for liver toxicity (hepatotoxicity). However, the risk has been unclear for those who are already virologically suppressed on a non-nevirapine-containing regimen, who switch to one that contains nevirapine, and who have CD4 cell counts above these levels.
Spanish researchers conducted a ‘meta-analysis’ that pooled the results of four existing studies. To be eligible for inclusion in the meta-analysis, studies had to have switched participants from a successful combination to one containing nevirapine while their viral load was still undetectable, and then observed participants for at least three months after switching. Studies were only selected if they included at least 50 participants.
The studies were:
- A one year study in patients who switched to nevirapine from a protease inhibitor (Ruiz 2001) (n=84)
- A randomised study of prednisone as a preventive treatment against nevirapine-associated rash (Montaner 2003) (n=70)
- A large randomised comparative study of switching from a protease inhibitor to either nevirapine, abacavir or efavirenz (the NEFA study) (Martinez 2003) (n=155)
- A study of cetirizine as a preventive treatment against nevirapine-associated rash (Knobel 2004). (n=183)
A total of 410 trial participants were entered into the analysis. Of these, 277 were deemed ‘high-CD4’: females with CD4 cell counts of 250 cells/mm3 or higher, and men with counts of 400 cells/mm3, or higher. The remaining 133 participants were ‘low-CD4’.
Occurrences of liver toxicity (after the treatment switch) were then examined in both groups. The researchers defined hepatotoxicity as happening if: (a) liver enzymes (ALAT or ASAT) increased from normal levels to above 200 units/L, or (b) increased by a factor of 3 or more if they were abnormally high to begin with.
The study showed a 2% risk of hepatotoxicity in the low-CD4 group, and a 4% risk in the high-CD4 group. However, the statistical difference between the two groups was not significant, and the overall results showed essentially no difference in risk between the low- and high-CD4 groups. The only clear risk factor for hepatoxicity was having elevated liver enzymes at the beginning of the study. There were no deaths, and only a very few patients (1%) developed liver inflammation (hepatitis).
The authors concluded that their analysis found no evidence of an increased risk of hepatotoxicity for women with CD4 counts above 250 or men with CD4 counts above 400 who switch to nevirapine when they already have undetectable viral load as a result of previous antiretroviral treatment.
A second study, conducted at a single treatment centre in Munich, Germany, looked at that centre’s experience of hepatotoxicity in treatment-naïve and treatment-experienced patients from 1996 to 2005. They defined hepatotoxicity as an ALT five times the upper limit of normal.
Their analysis included 507 patients (397 male, 110 female) with a median baseline CD4 count of 219 cells/mm3 in women and 270 cells/mm3 in men. Forty per cent of women had a CD4 count over 250 cells/mm3 and 27% of men had a CD4 count over 400 cells/mm3.
The study evaluated 817 patient-years of nevirapine treatment with a median observation time on nevirapine of 21 months. At the time of analysis 58% had discontinued nevirapine treatment, 20% due to treatment failure, 6.7% due to rash and 7.5% due to liver enzyme elevations. Other reasons for discontinuation were not stated.
Of the 38 patients who discontinued due to liver enzyme elevations, 20 of 38 discontinued due to ALT more than five times the upper limit of normal, after a median of 3.6 months on nevirapine. Two patients had acute hepatitis A or B, whilst the remainder discontinued due to smaller liver enzyme increases.
Among men 3.9% experienced grade 3 or 4 ALT elevations, compared to 6.3% of women. There was no significant difference by CD4 count in the risk of grade 3 or 4 ALT elevation for either men or women, and the only independent risk factors by multivariate analysis were hepatitis B or C coinfection (odds ratio 3.92), or elevated ALT levels at baseline (OR 4.84). A prior AIDS diagnosis, a CD4 count above 250 or being new to treatment did not increase the risk.
De Lazzari E et al. Risk of hepatotoxicity in virologically suppressed HIV patients switching to nevirapine according to gender and CD4 count. 46th ICAAC, San Francisco, abstract H-1064, 2006.
Wolf E et al. No increased risk for females or high CD4 count in a single-centre HIV cohort. 46th ICAAC, San Francisco, abstract H-1063, 2006.