Original article
Hepatic safety of maraviroc in HIV-1-infected patients with hepatitis C and/or B co-infection. The Maraviroc Cohort Spanish GroupSeguridad hepática de maraviroc en pacienes coinfectados con VIH y hepatitis C y/o B. Grupo español de la cohorte de Maraviroc

https://doi.org/10.1016/j.eimc.2016.02.029Get rights and content

Abstract

Introduction

Limited data is available regarding the hepatic safety of maraviroc in patients co-infected with HIV and HCV and/or HBV. Our objective was to compare the hepatic safety profile and fibrosis progression in HIV-mono-infected patients and co-infected with HCV and/or HBV treated with maraviroc.

Methods

Retrospective multicentre cohort study of HIV-infected patients receiving treatment with a maraviroc-containing regimen in 27 hospitals in Spain.

Results

A total of 667 patients were analyzed, of whom 313 were co-infected with HCV (n = 282), HBV (n = 14), or both (n = 17). Maraviroc main indications were salvage therapy (52%) and drug toxicity (20%). Grade 3–4 hypertransaminasaemia (AST/ALT >5 times ULN) per 100 patient-years of maraviroc exposure, was 5.84 (95% CI, 4.04–8.16) and 1.23 (95% CI, 0.56–2.33) in co-infected and HIV-mono-infected patients, respectively (incidence rate ratio, 4.77; 95% CI, 2.35–10.5). However, the degree of aminotransferase abnormalities remained stable throughout the study in both groups, and no significant between-group differences were seen in the cumulative proportion of patients showing an increase in AST/ALT levels greater than 3.5 times baseline levels. No between-group differences were seen in liver fibrosis over time. With a maraviroc median exposure of 20 months (IQR, 12–41), two patients (0.3%) discontinued maraviroc because of grade 4 hepatitis, and other 2 died due to complications associated to end-stage-liver disease.

Conclusions

Maraviroc-containing regimens showed a low incidence of hepatitis in a large Spanish cohort of HIV-infected patients, including more than 300 patients co-infected with HCV and/or HBV. Co-infection did not influence the maximum liver enzyme level or the fibrosis progression throughout the study.

Resumen

Introducción

La seguridad hepática del maraviroc en pacientes coinfectados por VIH y VHC y/o VHB es poco conocida. Nuestro objetivo es comparar el riesgo de hepatitis y la progresión de la fibrosis hepática en pacientes monoinfectados por VIH y coinfectados por VHC y/o VHB, tratados con maraviroc.

Métodos

Estudio de cohortes, retrospectivo, en pacientes infectados por VIH, tratados con maraviroc en 27 hospitales españoles.

Resultados

Analizamos 667 pacientes, 313 coinfectados por VHC (n = 282), VHB (n = 14) o ambos (n = 17). El rescate (52%), y la toxicidad farmacológica (20%) fueron las principales indicaciones de tratamiento con maraviroc. La incidencia de hipertransaminasemia de grado 3–4 (AST o ALT >5 veces el LSN), por 100 paciente-años de exposición a maraviroc, fue 5,84 (IC 95%, 4,04–8,16) y 1,23 (IC 95%, 0,56–2,33) en coinfectados y monoinfectados por VIH, respectivamente (razón de tasas, 4,77; IC95%, 2,35–10,5). No se observaron diferencias en la proporción acumulada de pacientes con elevación de AST o ALT mayor de 3,5 veces respecto al valor basal, ni en la progresión de la fibrosis hepática entre ambos grupos. Tras una mediana de tratamiento de 20 meses (AIC, 12–41), dos pacientes (0,3%) discontinuaron el maraviroc por hepatitis de grado 4, y dos pacientes fallecieron por enfermedad hepática.

Conclusiones

En una cohorte española de pacientes infectados por VIH que incluye más de 300 pacientes coinfectados por VHC y/o VHB, maraviroc mostró una baja incidencia de hepatitis. La coinfección no afectó al grado de elevación de las transaminasas ni a la progresión de la fibrosis hepática.

Introduction

Approximately 1–8% of HIV-infected patients develop severe hepatitis, mostly grade 3 or 4 elevations in aminotransferases, during the first year of antiretroviral therapy (ART).1 Coinfection with either hepatitis B (HBV) or hepatitis C (HCV) has been frequently reported as a major risk factor for liver toxicity after initiation of ART.1

Although the incidence of severe liver toxicity is lower with currently recommended regimens, and the majority of cases involve asymptomatic liver enzyme elevations2, 3, 4, 5 some cases of severe liver disease have been still reported3 and ART-related hepatotoxicity is a concern in the management of HIV-infected subjects, mainly in those coinfected with HCV and/or HBV.

Initial concerns were raised in regard with the hepatic safety of CCR5 antagonists, following the description of severe cases of hepatotoxicity with aplaviroc.6 Maraviroc (MRV), the first and only CCR5 antagonist approved so far for ART, has shown a favorable safety profile both in patients enrolled in clinical trials and in the expanded access program.7 However, very limited data is available regarding the hepatic safety of maraviroc in patients co-infected with HCV and/or HBV,8 and the package insert for maraviroc includes some specific warnings in regard with the potential risk of hepatotoxicity.9

On the other hand, development of progressive liver disease is one of the principal comorbidities in HIV infected patients coinfected with HCV and/or HBV, and complications associated to end-stage liver disease remain a major cause of morbidity and mortality among coinfected patients.10 In chronic hepatitis, the CCR5/RANTES pathway appears to be involved in the inflammatory response, a critical step in the promotion of hepatic fibrosis, metabolic liver disease and the development of hepatocellular carcinoma.11

Preclinical data, obtained from different animal models of liver injury, have shown that blocking the CCR5 activation pathway could play a protective role on liver fibrosis progression12, 13 hepatocellular carcinoma development,14, 15 and in protecting against the development of non-alcoholic fatty liver disease (NAFLD).16

The primary outcome of this substudy was to compare the liver safety profile of maraviroc-containing ART in a large heterogeneous cohort of patients coinfected or not with HBV and/or HCV, in real-life conditions. As a secondary outcome we studied the impact of maraviroc treatment on liver fibrosis progression by analyzing changes in FIB-4 index over time.

Section snippets

Study design and follow-up

Demographic and clinical data from all maraviroc-treated subjects in 27 centers across Spain were retrospectively collected in an observational multicenter cohort study. Complete study design and data on efficacy and overall safety have been reported elsewhere.17 Briefly, all HIV-1 infected adults receiving a first dose of maraviroc and with at least one follow-up visit were recruited. Data obtained from every 3–6 months scheduled visits until the last follow-up control were entered into a web

Patient characteristics

Baseline characteristics of 667 patients analyzed are summarized in Table 1. Of them, 313 (46.9%) were co-infected either with HCV (n = 282; 42.2%) or HBV (n = 14; 2.1%) or both HBV and HCV (n = 17; 2.5%). Median age was 45 years; 74% were men; main route of infection was IDU (80.5%) in coinfected and sexual intercourse (84.8%) in HIV-monoinfected patients. Salvage therapy was the indication for the maraviroc-containing regimen in more than half of patients in both groups. Maraviroc dose ranged from

Discussion

In the present study, including more than 300 patients coinfected with HCV and/or HBV, only 2 patients (0.3%) discontinued maraviroc because of severe hepatitis. In regard with the impact of HCV or HBV coinfection on the risk of hepatitis, the incidence of grade 3–4 hypertransaminasemia, was 5-fold higher in coinfected patients. Notwithstanding, the relative risk in coinfected patients was inferior to 2-fold in the analysis adjusted by baseline levels, when defining grade 3–4 as ASLT/ALT

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgment

ViiV Healthcare supported the study with an unrestricted grant.

References (25)

  • F. Marra et al.

    Roles for chemokines in liver disease

    Gastroenterology

    (2014)
  • View full text