Liver fibrosis regression and progression during controlled hepatitis B virus infection among HIV-HBV patients treated with tenofovir disoproxil fumarate in France: a prospective cohort study

Abstract

Introduction: Long-term tenofovir disoproxil fumarate (TDF) use has been associated with significant regression of liver fibrosis during hepatitis B virus (HBV) mono-infection, yet little is known during HIV-HBV coinfection. The aim of this study was to evaluate the evolution of liver fibrosis and its determinants in TDF-treated coinfected patients.

Methods: In this prospective cohort study, 167 HIV-HBV-infected patients initiating TDF-containing antiretroviral therapy were included. Fibrosis was assessed using the FibroTest® at baseline and every six to twelve months. Risk factors for fibrosis progression (F0-F1-F2 to F3-F4) and regression (F3-F4 to F0-F1-F2) were evaluated.

Results: At baseline, 134 (80.2%) patients had detectable HBV-DNA (median = 4.93 log₁₀ IU/mL, IQR = 2.94-7.15) and 104 (62.3%) had hepatitis B "e" antigen-positive serology. Median follow-up was sixty months (IQR = 36-93). In the 47 (28.1%) patients with F3-F4 baseline fibrosis, 7/47 (14.9%) regressed to F0-F1-F2 at last follow-up visit. Fibrosis regression was significantly associated with higher CD4+ cell counts (P = 0.009) and lower fasting triglyceride levels (P = 0.007) at TDF-initiation. In the 120 (71.9%) patients with F0-F1-F2-baseline fibrosis, 20/120 (16.7%) progressed to F3-F4 at last follow-up visit. Fibrosis progression was associated with male gender (P = 0.01), older age (P = 0.001), from low/moderate HBV-endemic country (P = 0.007), lower nadir CD4+ cell count (P = 0.03), higher fasting glycaemia (P = 0.03) and anaemia (P = 0.004) at TDF-initiation. Control of HBV replication at end of follow-up was extensive (88.1%), while no HBV-related factors emerged as predictors of progression/regression. Incidence of severe liver-related events was low (n = 4, rate = 0.5/100 person-years).

Conclusion: Liver fibrosis levels are stable for most coinfected patients undergoing TDF, despite control of HBV replication. Nevertheless, a concerning amount of liver fibrosis progression did occur, which could be partly explained by metabolic abnormalities and past severe immunosuppression and requires further evaluation.

Keywords: hepatocellular carcinoma; immunosuppression; liver cirrhosis; liver fibrosis; noninvasive markers.

Figure 1.

Baseline liver fibrosis levels and HBV-related endpoints during tenofovir-containing antiretroviral therapy. Kaplan–Meier curves are used to depict time to HBV-related endpoints during tenofovir (TDF) containing ART, stratified on baseline none/mild/moderate liver fibrosis (F0–F1–F2) and fibrosis/cirrhosis (F3–F4). Time to undetectable HBV-DNA (<60 IU/mL) is represented in (a) among patients with detectable HBV-DNA at baseline. Time to HBeAg-seroclearance is represented in (b) among patients with HBeAg-positive serology at baseline.

Figure 2.

Liver fibrosis evolution during tenofovir-containing antiretroviral therapy. In (a), the distribution of liver fibrosis levels is provided at each yearly interval during tenofovir (TDF) containing ART. The number of patients continuing follow-up at the end of each interval is provided below. In (b), individual trajectories of FibroTest® scores in function of their METAVIR fibrosis equivalents are provided in grey lines for patients with