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Infection With Hepatitis C Virus Genotype 3 Is an Independent Risk Factor for End-Stage Liver Disease, Hepatocellular Carcinoma, and Liver-Related Death
Mc Mahon BJ, et al.
Clin Gastroenterol Hepatol 2017;15 :431-437.

Background & Aims: Few studies have examined factors associated with disease progression in hepatitis C virus (HCV) infection. We examined the association of 11 risk factors with adverse outcomes in a population-based prospective cohort observational study of Alaska Native/American Indian persons with chronic HCV infection.

Methods: We collected data from a population-based cohort study of liver-related adverse outcomes of infection in American Indian/Alaska Native persons with chronic HCV living in Alaska, recruited from 1995 through 2012. We calculated adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for end-stage liver disease (ESLD; presence of ascites, esophageal varices, hepatic encephalopathy, or coagulopathy), hepatocellular carcinoma (HCC), and liver-related death using a Cox proportional hazards model.

Results: We enrolled 1080 participants followed up for 11,171 person-years (mean, 10.3 person-years); 66%, 19%, and 14% were infected with HCV genotypes 1, 2, and 3, respectively. On multivariate analysis, persons infected with HCV genotype 3 had a significantly increased risk of developing all 3 adverse outcomes. Their aHR for ESLD was 2.1 (95% CI, 1.5–3.0), their aHR for HCC was 3.1 (95% CI, 1.4–6.6), and their aHR for liver-related death was 2.4 (95% CI, 1.5–4.0) compared with genotype 1. Heavy alcohol use was an age-adjusted risk factor for ESLD (aHR, 2.2; 95% CI, 1.6–3.2), and liver-related death (aHR, 2.9; 95% CI, 1.8–4.6). Obesity was a risk factor for ESLD (aHR, 1.4; 95% CI, 1.0–1.9), and diabetes was a risk factor for ESLD (aHR, 1.5; 95% CI, 1.1–2.2). Male sex was a risk factor for HCC (aHR, 3.6; 95% CI, 1.6–8.2).

Conclusions: In a population-based cohort study of American Indian/Alaska Native persons with chronic HCV infection, we found those infected with HCV genotype 3 to be at high risk for ESLD, HCC, and liver-related death.

Expert's Commentary

Although global distributions of HCV genotypes vary across geographical areas, genotype 3 is common worldwide, accounting to around 30% of infected patients in Northern Europe or in Asia. Compared with other genotypes, genotype 3 infection, which is highly prevalent in South East Asia and in drug users, has been associated with viral steatosis (Livingston SE, et al. Factors associated with the progression of fibrosis on liver biopsy in Alaska Native and American Indian persons with chronic hepatitis C. Can J Gastroenterol 2010;24:445–451), increased risk of fibrosis progression (Bochud PY, et al. Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C. J Hepatol. 2009;51:655-666), resulting in more severe disease (Larsen C, et al. Hepatitis C virus genotype 3 and the risk of severe liver disease in a large population of drug users in France. J Med Virol. 2010;82:1647-1654), and development of hepatocellular carcinoma in cirrhotic patients in several retrospective studies (Nkontchou G, et al. HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis. J Viral Hepatol. 2011;18:516-22).

The main originality of the study by Mac Mahon et al. is to provide a prospective confirmation in American Indian/Alaska Native persons with chronic HCV living in Alaska (who are not different than the “general” HCV-infected US population) that HCV genotype 3 is significantly associated with a more severe liver disease (than HCV genotype 1) since two thirds had progressed to advanced fibrosis, 48% to end-stage liver disease (ESLD), 24% had died or had received a liver transplant, and almost 1 in 10 developed hepatocellular carcinoma (HCC).

In addition other well-know predictors were confirmed to be associated with adverse outcomes: older age at enrolment, heavy alcohol use, obesity and type 2 diabetes mellitus increased risk for developing ESLD, and male gender increased by more than 3 fold the risk of HCC. Persons with heavy alcohol use were at increased risk for liver-related death (aHR, 2.9; 95% CI, 1.8–4.6).

This confirmation of a more severe pathobiology of genotype 3 is important in daily practice since genotype 3-infected patients should be considered as priority patients for the new therapies. In addition, at the time of highly efficacious and well-tolerated direct acting antivirals, the genotype 3 remains the most difficult HCV genotype to treat, especially in treatment-experienced cirrhotic patients. The new pangenotype oral antivirals will likely modify the outcome of these HCV genotype 3-infected patients.

Pr Stanislas Pol
Université Paris Descartes; Hepatology Department, Cochin hospital, APHP
INSERM U-818 and UMS-20, Institut Pasteur, Paris, France