US study provides 'real world' evidence about which patients with hepatitis C should be prioritised for therapy

For patients with hepatitis C virus (HCV) mono-infection, baseline fibrosis stage is strongly predictive of the medium-term risk of serious liver disease and death, investigators from the United States report in the online edition of Clinical Infectious Diseases. After five years of follow-up, over a third of patients with F4 stage liver fibrosis at baseline had developed hepatic decompensation or liver cancer. This compared to a progression rate of just 2% among patients with F0/F1 stage disease at baseline.

“We observed significant progression to liver failure and death among patients with advanced liver fibrosis or cirrhosis in the absence of successful treatment,” write the authors. “Our results emphasise that effective treatment is urgently needed in these groups of patients.”

Patients with HCV infection are at risk of developing liver fibrosis and cirrhosis, leading to hepatic decompensation, liver cancer and early death. Curative oral HCV therapy has recently become available. Current US guidelines recommend that patients with liver cirrhosis or advanced fibrosis have the highest priority for therapy, followed by individuals with less advanced fibrosis who have co-infections or co-morbidities.

Modern HCV therapy is expensive and access to some regimens is limited according to disease stage. Real-world evidence is needed to inform ongoing debates about which patients should be prioritised for therapy. Investigators from the Chronic Hepatitis Cohort Study (CHeCS) therefore designed a study describing rates of progression of liver disease and all-cause mortality over five years among 2,799 patients with HCV mono-infection according to their baseline liver fibrosis stage (Metavir F0/1 – F4).

Fibrosis stage was determined by liver biopsy. The risk of progression to serious liver disease in the absence of effective therapy after one, two and five years of follow-up was reported.

Patients were biopsied between 2001-2012. At baseline 11% were at stage F0, 26% at F1, 30% at F2, 18% at F3 and 15% at F4. The overall mean age at baseline was 51 years. However, this differed according to fibrosis stage (F0/1 = 48 years vs. F4 = 53 years, p < 0.001). The proportion of males increased as fibrosis stage advanced (53% in F0/1 vs. 69% in F4). As expected for the US, over two-thirds of patients had genotype 1 infection.

During follow-up, 54% of patients received HCV therapy and 24% had two or more attempted courses of treatment.

The risk of serious liver disease doubled with each increase in baseline fibrosis stage. No patient with F0/F1 stage progressed to liver cancer. In contrast, progression rates among patients with F4 disease were 9% to liver cancer, 27% developed decompensated liver disease, 5% had a liver transplant and approximately a quarter had died by the end of follow-up.

The one-year risk of liver cancer increased from 0.1% for patients with baseline F0/1 fibrosis, to 1.6% for individuals with stage F4 fibrosis at baseline. Two-year incidence of liver cancer was 0.3% for those with stage F2 at the start of the study and 6% for individuals with baseline F4 fibrosis. Patients with baseline F4 fibrosis experienced the highest five-year rate of decompensated liver disease (34% vs. 19% F3 vs. 4% F2 vs. 2% F1/0). Incidence of decompensation was similar over five years between patients with F0/1 and F2 stage fibrosis at baseline.

Five years after biopsy, all cause mortality rates were 32% in stage F4, 14% in stage F3, 7% in F2 and 7% in F1/0.

The strongest factors associated with the development of decompensated liver disease or liver cancer were baseline fibrosis stage F3 (aHR = 4.2) or F4 (aHR = 7.2) and a platelet count below normal (aHR = 3.45).

“This natural history study provides ‘real-world’ data about the probability, time to and risk factors for HCV-related morbidity and mortality,” conclude the investigators. “These timely data can help evidence-based decision making by clinicians and policy makers about HCV management, and can help inform the debate regarding the comparative benefits and harm of treating HCV patients at the time of diagnosis versus waiting to treat only those patients who show early signs of progression of liver disease (e.g. F2) or other manifestations of infection.”