CD4 count >250 not predictive of rash-associated hepatoxicity among women initiating nevirapine-based ART in Zambia, Thailand, and Kenya

Polly Clayden, HIV i-Base

Nevirapine (NVP)-containing HAART is the most frequently used regimen in resource-limited countries.

In 2004 Boehringer-Ingelheim, manufacturers of nevirapine (Viramune) performed a retrospective analysis of hepatoxicity events among 633 women receiving NVP within the company’s trials. This analysis revealed 11% women having hepatoxicity with pre-treatment CD4 count >250 cells/mm3 vs 0.9% with CD4 <250 cells/mm3. Following these results the company changed the Summary of Product Characteristics to include a caution that women with higher CD4 counts are at increased risk of hepatic toxicity.

The trials included in this analysis were conducted in Western Europe and North America. There are few data available from women initiating NVP-containing HAART in Africa and Asia. A poster from Anouk Kesselring which looked at this issue using data from several cohorts.

A poster from Philip Peters and coworkers from the CDC and centres in Zambia, Thailand and Kenya, showed findings from an evaluation of risk factors for rash-associated toxicity among women receiving NVP-containing ART between May 2005 and January 2007 in this multi-country cohort. This was a prospective observational study.

The investigators included 820 (497 Zambian, 192 Thai, and 131 Kenyan) treatment-naive women initiating NVP-containing ART in this analysis. Women received ART in accordance with national guidelines. NVP was initiated at half dose for the first two weeks of treatment.

Liver function tests (LFTs) were performed at 2, 4, 8, 16, and 24 weeks. Women also received a clinical evaluation for rash. Hepatoxicity was graded:

  • Grade 1 – mild (transaminase [AST or ALT] elevation 1.25 to 2.49 times the upper limit of normal [x ULN]), 50-99;
  • Grade 2 – moderate (2.5 to 4.99 x ULN), 100-199; and
  • Grade 3 – severe (>5.0 x ULN), >200.

Rash associated hepatoxicity (RAH) was defined as an ALT or AST elevation > grade 2 with concomitant rash. The investigators used multivariate analysis to identify variables associated with hepatoxicity and RAH.

At baseline women were a median age of 32 years (IQR 28-36) with a median CD4 count 149 cells/mm3 (IQR 83-215) and 86% had normal LFTs. The investigators reported that hepatotoxicity (> grade 2) occurred in 109 (13%) women and for 41 (5%) it was severe. In multivariate analysis abnormal baseline LFT was associated with severe hepatoxicity AOR 3.0 (95%CI 1.4-6.2).

RAH occurred in 27 (3%) women (Zambia 2%, Thailand 7%, Kenya 2%). Of these 8/123 (6.5%) women had a baseline CD4 <50 cells/mm3; 13/576 (2%) had a CD4 of 50 to 250 cells/mm3; and 6/121 (5%) women with a CD4 >250 cells/mm3.

RAH was also significantly associated with abnormal LFT at baseline, AOR 3.1 (95% CI 1.2- 8.2). Thai ethnicity AOR 4.5 (95%CI 1.8-11.4) was also associated with RAH.

Baseline CD4 >250 cells/mm3 was not associated with either severe hepatoxicity [AOR 1.1; 95%CI 0.4-2.7] or RAH [AOR 1.6; 95%CI 0.6-4.4]. When the investigators looked at the frequency of RAH and severe hepatoxicity stratified by CD4 count, women <50 cells/mm3 had the highest rates; 7% and 6.5% of RAH and severe hepatoxicity respectively. They also noted that there was an increased risk for RAH at CD4 >200 cells/mm3 vs 50-199 cells/mm3, p=0.004.

Three women (0.4%) died with symptoms suggestive of fatal hepatotoxicity, All 3 deaths had a baseline CD4 <100 cells/mm3 in women being treated for tuberculosis.

The investigators wrote: “Public health officials should be aware that limiting nevirapine use to women with a CD4 cell count <250 cells/mm3 may not limit hepatotoxicity.”


While restricting nevirapine use to men with CD4 count <400  cells/mm3 and women with CD4 count <250 cells/ mm3 will improve the safe use of this highly effective therapy, the introduction of nevirapine should always be with caution and careful monitoring.

As noted in this study, patients eligible for treatment with nevirapine, especially women, will have low CD4 counts and are therefore often at risk of opportunistic infections.

The case for using nevirapine in conjunction with other hepatotoxic therapies (eg common antituberculosis therapies) or in patients with abnormal LFTs, should always be carefully considered.

Gender and ethnic differences in drug handling are emerging as important factors andconclusions from studies based on selected populations cannot necessarily be generalised.


Peters et al. CD4 cell count >250 Cells/mm3 does not predict rash-associated hepatotoxicity among women initiating nevirapine-based ART in Zambia, Thailand, and Kenya. 16th CROI, February 2009, Montreal, Canada. Poster abstract 986.

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