Nevirapine‐associated hepatotoxicity was not predicted by CD4 count ≥250 cells/μL among women in Zambia, Thailand and Kenya

Abstract

ObjectiveThe aim of the study was to determine risk factors for developing severe hepatotoxicity (grade 3 or 4 hepatotoxicity) and rash-associated hepatotoxicity (rash with ! grade 2 hepatotoxicity) among women initiating nevirapine-based antiretroviral therapy (ART). MethodsThe Non-Nucleoside Reverse Transcriptase Inhibitor Response Study was a prospective cohort study carried out in Zambia, Thailand and Kenya. Between May 2005 and January 2007, we enrolled antiretroviral-naïve HIV-infected women initiating nevirapine-based ART. At enrolment and at weeks 2, 4, 8, 16 and 24, participants had serum alanine transferase (ALT) and aspartate transaminase (AST) measured and were evaluated clinically for hepatitis and rash. ResultsNevirapine-based ART was initiated in 820 women and baseline ALT or AST results were abnormal ( ! grade 1) in 113 (14%) women. After initiating nevirapine-based ART, severe hepatotoxicity occurred in 41 (5%) women and rash-associated hepatotoxicity occurred in 27 (3%) women. In a multivariate logistic regression model, severe hepatotoxicity and rash-associated hepatotoxicity were both associated with baseline abnormal ( ! grade 1) ALT or AST results, but not with a baseline CD4 cell count ! 250 cells/mL. Three participants (0.4%) died with symptoms suggestive of fatal hepatotoxicity; all three women had baseline CD4 count o100 cells/mL and were receiving anti-tuberculosis therapy. ConclusionAmong women taking nevirapine-based ART, severe hepatotoxicity and rash-associated hepatotoxicity were predicted by abnormal baseline ALT or AST results, but not by a CD4 count ! 250 cells/mL. In resource-limited settings where transaminase testing is available, testing should focus on early time-points and on women with abnormal baseline ALT or AST results.

HLA Class I restricted CD8+ and Class II restricted CD4+ T cells are implicated in the pathogenesis of nevirapine hypersensitivity

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Objectives: This study sought to examine nevirapine hypersensitivity (NVP HSR) phenotypes and their relationship with differing major histocompatibility complex (MHC) Class I and Class II alleles and the associated CD4 þ and CD8 þ T-cell NVPspecific responses and their durability over time.

Methods: A retrospective cohort study compared HIV-positive patients with NVP HSR, defined by fever and hepatitis and/or rash, with those tolerant of NVP for more than 3 months. This is consistent with the decreased incidence of rash in patients with a low CD4 þ T-cell count [3][4][5][6][7][8][9].

Cellular studies examined NVP-specific CD4 þ and CD8 þ T-cell responses by interferon-gamma (IFNg) ELISpot assay and intracellular cytokine staining (ICS).…”

Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women

“…Some prior studies have reported increased risks of hepatotoxicity and rash for women with CD4 >250 cells/mm 3 [44, 45], while others have not. [4, 46-50] Of note, for participants with pretreatment CD4>200 cells/mm 3 but entry CD4<200 cells/mm 3 ; we believe these CD4 counts are accurate despite the intra-patient variability, since CD4 testing was performed in monitored labs that successfully met the requirements of the DAIDS Immunology Quality Assurance program. Furthermore, considerable intra-subject CD4 count variability (as much as 200 cells/mm 3 obtained a few weeks apart) has been reported previously.…”

Association of Nevirapine Levels with Rash or Hepatotoxicity Among HIV-Infected Thai Women

“…Some studies have supported an association between risk for hepatotoxicity and CD4 cell count ≥250 cells/µL in women [26,27] but others have not [14,28]. We have previously demonstrated from the parent study of this sub-study that among women taking nevirapine-based ART, severe hepatotoxicity and rash-associated hepatotoxicity were predicted by abnormal baseline ALT or AST results but not by a CD4 count ≥250 cells/µL [14]. Co-infection with viral hepatitis B or C has also been associated with hepatotoxicity from antiretroviral therapy in some [29,30] but not all studies [30,31].…”

“…At enrollment and at weeks 2, 4, 8, 16, and 24, participants had serum alanine transaminase (ALT) and aspartate transaminase (AST) measured and were evaluated clinically for signs and symptoms of hepatitis and rash. We graded adverse events including hepatotoxicity and rash according to the National Institutes of Health’s Division of AIDS guidelines as previously reported [14,15]. …”