Sixth International Congress Drug Therapy in HIV Infection 17-21 November, 2002 Glasgow, UK

Background: Antiretroviral compounds from the NNRTI group have been associated with the occurrence of hepatic toxicity. However, large studies evaluating the comparative incidence of liver toxicity of nevirapine and efavirenz, especially in the subset of patients with HBV and/or HCV co-infection, are scarce and contraditory.

Methods: This comparative, retrospective cohort study evaluated the incidences of Grade 2 (G2) and ≥3 (G3) increases in AST, ALT (modified ACTG), at 3 (M3), 6 (M6), 9 (M9) and 12 (M12) months of treatment exposure to either nevirapine or efavirenz-based HAART regimens, as compared with pretreatment (PT) values, in 535 consecutive HIVpositive patients followed-up at a Lisbon Infectious Diseases clinic, having innitiated their medication between January and December 2000. The charts were also reviewed for drop-out rate, for shift in GGT, alkaline phosphatase (AP) and total bilirrubin (TBil) toxicity grading and for concomitant antiretroviral drugs.

Results: After excluding charts having PT evaluation collected more than 3 months before treatment, 475 charts were available for analysis: 313 were treated with nevirapine (Group A) and 162 with efavirenz (Group B). A total of 163 patients (Group HEP) had a positive test for either hepatitis C virus (HCV, N=152) and/or hepatitis B virus surface antigen (AgHBs, N=19). There were no significant differences between both treatment groups A and B in terms of age (median 38.9 years for A, 38.0 years for B), weight (median 65.5 kg for A, 64 kg for B), gender (male: 68.7% for A and 73.5% for B), risk for HIV infection (IVDU: 29.4% for A and 29.6% for B), AgHBs (6.4% for A, 11.7% for B, p=0,072), HCV+ (7.7% for A, 9.3% for B) and alcohol consumption (90.9% for A and 87.3% for B). Median PT viral load was 16451 copies/mL for A and 32074 copies/mL for B, and subsequently ≤ 500 copies/ mL for both treatments at all four time-points. Median CD4 increase from PT value at M12 was of 123 cells/mm³ for A and 162 cells/mm³ for B. Cumulative treatment discontinuation rates at M12 were 20.4% for A and 21.6% for B. No deaths due to hepatic failure were registered during this period. The observed frequencies of G3 and G2 ALT at any time-point were, respectively, 3.5% and 8.6% for A and 1.9% and 6.2% for B. For AST, values were 1.0% for A and 2.5% for B for any G3 and 1.9% for A and 6.8% for B for any G2 (p=0.007), with higher frequency of G2 AST for B at all 4 timepoints, statistically significant at M3 (A=1.1%, B=5.1%, p=0.043). In HEP Group, correspondent frequencies for G3 and G2 ALT, after correction for baseline values, were, respectively, 5.8% and 15.4% for A and 5.1% and 11.9% for B. For AST, frequencies of G3 at any time point were, respectively and after correction, 1.0% for A and 5.1 for B, with correspondent frequencies for G2 of 2.9% for A and 13.6% for B (p=0.009) and with statistical significance at M3 (p=0.038) and M6 (p=0.031) in patients with HCV co-infection.. In contrast, G1 and/or G2 GGT increases from PT were significantly more frequent for A at all time-points (p values of 0.020, 0.003, 0.021 and <0.001 for M3, M6, M9 and M12, respectively, Mann-Whitney test), and this difference was slightly less pronounced in HEP Group. No notable shifts from baseline were observed for either treatment at any time-point for AP and TBil. Logistic regression analyses for G2 AST at any time-point including hepatitis, concomitant NRTIs and alcohol consumption as co-variates showed odds ratios of 4.458 for efavirenz (95%CI: 0.966-20.576) and 1.485 for alcohol (95%CI: 0.462-1.955) in the HEP Group compared with 2.109 (95%CI:0.402-11.063) and 5.667 (95%CI:0.929-34.588), respectively, in non-HEP patients.

Conclusions: In this retrospective cohort, the frequency of serious increases in ALT and AST was low, comparable for nevirapine- and efavirenz-based regimens and consistent with previously published studies, although higher in patients with HBV and/or HCV. Higher comparative frequencies of G2 increases in ALT and AST in HBV and/or HCV patients support higher risk for toxicity in this population. Efavirenz was associated with significantly higher frequency of G2 AST at any time-point (of 13.6% in HBV and/or HCV patients), while nevirapine was associated with significantly higher risk for GGT increase, without risk increase in HBV and/or HCV patients.

Presenting author: Luis Caldeira

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1 Serviço de Doenças Infecciosas

2 Serviço de Farmácia e Terapêutica, Hospital Santa Maria, Lisboa

3 Escola Superior de Saúde Pública, Portugal

2002-11-17
PL12-2

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