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Abstract and Introduction
Abstract
The impact of antiretroviral drug exposure and associated lipodystrophy and/or insulin resistance (IR) on advanced liver fibrosis in HIV/HCV-coinfected patients is not fully documented. We determined the prevalence of advanced liver fibrosis (defined by hepatic stiffness ≥9.5 kPa) and associated factors, focusing on the impact of highly active antiretroviral therapy and its major adverse effects (lipodystrophy and IR), in 671 HIV/HCV-coinfected patients included in the ANRS CO13 HEPAVIH cohort. One hundred ninety patients (28.3%) had advanced liver fibrosis. In univariate analysis, advanced liver fibrosis was significantly associated with male sex, higher body mass index, HCV infection through intravenous drug use, a lower absolute CD4 cell count, a longer history of antiretroviral treatment, longer durations of protease inhibitors, non-nucleoside reverse transcriptase inhibitors and NRTI exposure, lipodystrophy, diabetes, and a high homeostasis model assessment method (HOMA) value. The only antiretroviral drugs associated with advanced liver fibrosis were efavirenz, stavudine and didanosine. In multivariate analysis, male sex (OR 2.0, 95% CI 1.1–3.5; P = 0.018), HCV infection through intravenous drug use (OR 2.0, 95% CI 1.1–3.6; P = 0.018), lipodystrophy (OR 2.0, 95% CI 1.2–3.3; P = 0.01), median didanosine exposure longer than 5 months (OR 1.7, 95% CI 1.0–2.8; P = 0.04) and a high HOMA value (OR 1.1, 95% CI 1.0–1.2; P = 0.005) remained significantly associated with advanced liver fibrosis. Mitochondrial toxicity and IR thus appear to play a key role in liver damage associated with HIV/HCV-coinfection, and this should be taken into account when selecting and optimizing antiretroviral therapy. Antiretroviral drugs with strong mitochondrial toxicity (e.g. didanosine) or a major effect on glucose metabolism should be avoided.
Introduction
Compared to isolated HCV infection, concurrent infection by HIV and HCV results in more rapid progression toward cirrhosis and liver failure. This progression is not linear over time and may occur after only a few years. Significant fibrosis has been linked to a low CD4 cell count, a longer estimated duration of HCV infection, daily alcohol intake, a higher necro-inflammation score, steatosis, uncontrolled HIV replication and late initiation of antiretroviral therapy after diagnosis of HIV infection. The effect of highly active antiretroviral therapy (HAART) on liver fibrosis is controversial. Recent studies suggest that cytotoxic CD8 T cell accumulation and associated release of inflammatory mediators may augment liver damage (mainly fibrosis) in HIV/HCV-coinfected patients. The protective effect of HAART on liver damage could thus be linked to an attenuation of inflammation. However, the beneficial impact of antiretroviral therapy on fibrosis progression might be offset by its hepatic toxicity. The aim of this study, conducted more than 10 years after the advent of HAART, was to identify factors associated with advanced liver fibrosis, as measured by transient elastometry (TE), in a large cohort of HIV/HCV-coinfected patients, focusing on the impact of HAART and its major adverse effects [lipodystrophy and insulin resistance (IR)].
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