Elsevier

Journal of Infection

Volume 64, Issue 2, February 2012, Pages 204-211
Journal of Infection

Hepatic safety of efavirenz in HIV/hepatitis C virus-coinfected patients with advanced liver fibrosis

https://doi.org/10.1016/j.jinf.2011.10.016Get rights and content

Summary

Objective

To assess the frequency of severe liver toxicity in HIV/hepatitis C (HCV)-coinfected patients with advanced liver fibrosis receiving efavirenz (EFV)-based antiretroviral combinations.

Methods

One hundred and eighty-nine previously antiretroviral naïve, HIV/HCV-coinfected patients, who started a regimen including two nucleoside analogues plus EFV, and in whom the presence or absence of advanced liver fibrosis could be established, were retrospectively analyzed. Liver fibrosis was evaluated according to a stepwise algorithm including liver biopsy, transient elastography and FIB-4 index.

Results

Fifty-six patients had advanced fibrosis – 25 with cirrhosis – and 133 did not. Three (5.4%) subjects with and 9 (6.8%) (p = 0.717) without advanced fibrosis developed grade 3–4 transaminase elevation (TE). Grade 4 total bilirubin elevation was seen in 5 (8.9%) patients with advanced fibrosis and in 1 (0.8%) without it (p = 0.003). Liver events led to EFV discontinuation in 10 (5.3%) patients, 6 (10.7%) with and 4 (3%) without advanced fibrosis (p = 0.031).

Conclusions

The hepatic tolerability of EFV was good in HIV/HCV-coinfected patients with advanced liver fibrosis. The frequency of grade 3–4 TE was similar to that observed in patients without advanced fibrosis, there was no death attributable to liver failure caused by drug toxicity and the rate of EFV discontinuations due to liver events was low.

Introduction

Efavirenz (EFV) is the most commonly used non-nucleoside reverse transcriptase inhibitor (NNRTI) drug in HIV therapy in the developed world. Combinations including two nucleoside reverse transcriptase inhibitors (NRTI) plus EFV are considered as preferred strategies for naïve patients in most antiretroviral therapy guidelines.1, 2, 3, 4

Around 20% of HIV-infected patients worldwide are also coinfected with hepatitis C virus (HCV).5 Over 50% of these individuals show significant liver fibrosis, defined as a liver stiffness equal to or greater than 7.2 kPa measured by transient elastography, and 24% have liver cirrhosis.6

There are insufficient data on the use of EFV in patients with hepatic impairment.7 EFV metabolism is extensively mediated by the cytochrome P450. Consequently, plasma levels could theoretically be elevated in patients with liver damage, leading to an increased frequency of adverse events. Regarding to this, previous studies conducted in small populations have shown that plasma levels of EFV above 4000 ng/mL are observed more commonly in patients with HCV or hepatitis B coinfection.8 Likewise, plasma concentrations of this drug are significantly higher in patients with cirrhosis than in those without such a degree of liver damage.8, 9 Accordingly, another study performed in a cohort of patients with liver biopsy showed that the incidence of hepatotoxicity in 46 HIV/HCV-coinfected patients receiving EFV was significantly higher in those with advanced liver fibrosis, i.e., patients with liver cirrhosis or pre-cirrhosis.10 However, data on the safety and tolerability of EFV in larger cohorts of HIV/HCV-coinfected patients with advanced liver fibrosis are lacking.

The aim of the present study was to assess the frequency of severe liver toxicity in previously antiretroviral naïve HIV/HCV-coinfected patients with advanced liver fibrosis who started EFV in real life conditions.

Section snippets

Patients

The COINS Study was a retrospective, multicenter, cohort study aimed to compare the liver safety of combinations including two NRTI plus either EFV, nevirapine or one boosted protease inhibitor. It included 745 previously antiretroviral naïve HIV-infected patients, with chronic HCV infection, as defined by detectable plasma HCV-RNA, who started therapy in 26 centers in Spain from January 1, 2000 to June 30, 2006. All patients received the corresponding antiretroviral regimens at least for one

Characteristics of the population

Three hundred and twenty-three patients included in the COINS study received EFV. The presence or absence of advanced liver fibrosis could be determined in 189 patients, according to the algorithm used in this study (Figure 1), and these made up the population included in the present study. Fifty-six (30%) and 133 (70%) of patients showed advanced fibrosis and no advanced fibrosis, respectively. A diagnosis of liver cirrhosis was done in 25 patients, 13 by biopsy, 5 by transient elastography

Discussion

The results of this study show that severe adverse liver events are uncommon in antiretroviral naïve, HIV/HCV-coinfected patients with advanced liver fibrosis who start a drug combination including EFV. Indeed, no deaths attributable to liver toxicity were observed and the frequency of EFV discontinuations due to liver events was low. In addition, the incidence of grade 3–4 TE was also low and similar to that found in patients without advanced fibrosis, including the figure observed among

Acknowledgements

This study was supported by a grant from Bristol-Myers Squibb. The sponsor was involved in the study design, the collection, analysis and interpretation of data, in the writing of the manuscript and in the decision to submit the manuscript for publication. The authors wish to thank the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Red de SIDA of Spain for their support (ISCIII-RETIC RD06/006). JAP is the receptor of an intensification grant from the Fundaci€n Progreso y Salud

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