DAA treatment reduces the risk of death and liver cancer in people with hepatitis C

Treatment with direct-acting antivirals (DAAs) reduced the risk of death, liver cancer and death from liver-related causes in French people with hepatitis C, according to results of one of the largest studies to date of the impact of the drugs.

The findings are published in advance online by The Lancet this week.

DAA treatment for hepatitis C was introduced from 2012, and the most effective regimens deliver almost universal cure rates. Many countries are now moving to implement testing and treatment programmes designed to eliminate hepatitis C as a significant cause of illness and death by 2030, by seeking to diagnose and treat everyone with the infection.

Glossary

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

antiviral

A drug that acts against a virus or viruses.

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

decompensated cirrhosis

The later stage of cirrhosis, during which the liver cannot perform some vital functions and complications occur. 

exclusion criteria

Defines who cannot take part in a research study. Eligibility criteria may include disease type and stage, other medical conditions, previous treatment history, age, and gender. For example, many trials exclude women who are pregnant, to avoid any possible danger to a baby, or people who are taking a drug that might interact with the treatment being studied.

However, a systematic review by the Cochrane Collaboration concluded that trials of DAAs did not provide enough evidence to conclude that curing hepatitis C reduced risks of death or clinical illness.

The review was strongly criticised by liver experts, including the American Association for the Study of Liver Diseases, for the short follow-up period of the studies selected and the lack of statistical power to detect differences in death rates in relatively small studies.

French researchers set out to assess the impact of treatment on mortality and morbidity in a large cohort followed over several years.

ANRS Co22 Hepather is a large cohort of French patients followed prospectively to evaluate the impact of DAAs in people with chronic hepatitis C. The cohort began to follow patients after the introduction of the first generation of DAAs in August 2012.

The study excluded cohort participants with hepatitis B, with a history of hepatocellular carcinoma or decompensated cirrhosis, liver transplant recipients, and people who received pegylated interferon as part of their hepatitis C treatment after cohort entry. A total of 10,166 people were eligible for inclusion in the analysis, of which 3045 had cirrhosis at the time of enrolment.

The study compared the mortality and health of people treated with DAAs (7344 people) and people who remained untreated in the cohort between 2012 and 2015 (2551 people).

There were no significant differences in current alcohol use, route of hepatitis C virus (HCV) acquisition, or degree of cirrhosis as measured by MELD score, between treated and untreated people, but treated participants were significantly older (57 vs 54 years), were more likely to be overweight or obese, more likely to have a history of previous treatment (57% vs 39%), more likely to have genotypes 1 or 3, more likely to have cirrhosis (42% vs 10%) and to have poorer liver function and more advanced fibrosis as measured by median APRI and FIB-4 scores (all p < 0.001).

Treated participants were also more likely to have diabetes, hypertension, low platelet count, elevated ALT and AST, and elevated alpha-fetoprotein (p < 0.001).

The median follow-up time was 33.4 months. During this period, 129 people in the treatment group died (48 of liver-related causes), an incidence of 0.95 per 100 person-years. The incidence of death in the untreated participants was 0.70 per 100 person-years, but after adjustment for cirrhosis and other demographic and HCV-related variables, treated people had a lower risk of death.

Treatment reduced the risk of death by 52% (HR 0.48, 95% CI 0.33-0.70) and reduced the risk of liver-related death by 61% (HR 0.39, 95% CI 0.21-0.71).

Treatment also reduced the risk of hepatocellular carcinoma by 34% (HR 0.66, 0.40-0.93).

The effect of treatment on mortality was only evident in people with cirrhosis and did not affect mortality or rates of liver cancer in people with less advanced disease, in part because the number of reported deaths and cases of liver cancer or liver-related death were so low in people without cirrhosis.

When the researchers looked at the relationship between sustained virological response (SVR) and mortality as opposed to exposure to treatment, they found that SVR was associated with a reduced risk of all outcomes apart from decompensated cirrhosis. Seventy-six per cent of participants who received treatment achieved SVR. Lack of SVR more than doubled the risk of developing hepatocellular carcinoma (aHR .2.23, 1.37-3.64).

The study investigators note that cirrhosis was not confirmed by biopsy in all cases and people with decompensated cirrhosis were excluded from the study, potentially leading to an underestimation of the effect of treatment on mortality.

In an accompanying Comment article, Jacinta Holmes, Stephanie Rutledge and Raymond Chung say “these findings firmly counter those of a Cochrane review of direct-acting antiviral treatment trials that could neither confirm or reject if direct-acting antivirals had an effect on long-term HCV-related morbidity and mortality. They also provide the best evidence to date to support guidance documents that recommend direct-acting antiviral treatment for all patients with chronic HCV infection.”

References

Carrat F et al. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet, advanced online publication, 11 February 2019.