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Reuters Health Information: Do direct-acting antivirals curb the long-term effects of chronic HCV infection?

Do direct-acting antivirals curb the long-term effects of chronic HCV infection?

Last Updated: 2017-10-05

By Marilynn Larkin

NEW YORK (Reuters Health) - After reviewing the evidence, researchers from the Cochrane Hepato-Biliary Group were unable to determine whether long-term treatment with direct-acting antivirals (DAAs) can affect hepatitis C-related morbidity, serious adverse events, health-related quality of life and all-cause mortality.

Dr. Christian Gluud, of Copenhagen University Hospital in Denmark, and colleagues analyzed data from 138 randomized trials (two still ongoing) involving 25,232 participants. Most were short-term, designed mainly to assess DAAs' effects on sustained viral response (SVR), according to the authors.

The trials, all at high risk of bias, evaluated 51 DAAs. Of the trials, 84 considered DAAs on the market or under development, and 57 concerned DAAs discontinued or withdrawn from the market.

More than two-thirds of the trials enrolled treatment-naive populations; the rest enrolled treated patients or both treatment-naive and treated individuals. Different trials focused on different HCV genotypes.

As reported in the Cochrane Database of Systematic Reviews, online September 18, the team stated they "could not reliably determine the effect of DAAs on the market or under development on (the) primary outcome of hepatitis C-related morbidity or all-cause mortality."

There were no data on HCV-related morbidity and only very low-quality evidence on mortality. The evidence suggesting that DAAs do not influence serious adverse events also was of very low quality.

DAAs on the market or under development may significantly reduce the risk of no SVR from 54.1% in untreated people to 23.8% in DAA users (relative risk, 0.44), according to the authors. Only one trial assessed DAAs' effects on quality of life.

No trials provided useful data on secondary outcomes such as ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, or hepatocellular carcinoma.

Further, the researchers said they lack sufficient evidence to understand how SVR affects long-term clinical outcomes and, therefore, that "SVR is still an outcome that needs proper validation in randomized clinical trials."

"One of the most important limitations of any systematic review is the nature of the evidence it can assemble," Dr. Gluud said in an email to Reuters Health. "Our confidence in the trials was limited because they were at high risk of bias (poor methodological quality) and (of) short duration."

"These factors limit what we can say about DAAs in the short and long run," he explained. "This is key to interpreting the evidence base because it cannot tell us with any great certainty about the long-term effects of DAAs on cure or complications of hepatitis C."

"Our results are consistent with the widely held belief that DAAs can eradicate hepatitis C virus from the blood after treatment (so-called sustained virological response)," he noted. "But the case for the value of SVR as a good predictor of long-term cure has still to be proven as we found no such evidence."

"We know that some patients who achieve 'sustained virological response' still have hepatitis C virus in different types of cells in the body, and the virus may reappear in their serum months or years later," he said.

"Furthermore, people can go on to develop manifestations of end-stage liver disease despite DAA intervention and SVR," Dr. Gluud observed. "From a patient's perspective, it may not matter whether the virus can be detected in the blood after six months when we do not have randomized evidence for long-term survival or hepatitis C-related complications."

"Based on theoretical considerations, DAAs may one day show clinical benefits or harms in patients with chronic hepatitis C," he continued. "We therefore need a higher standard of proof for their long-term effects because the reliability of the blood test to predict cure has not yet been tested in randomized trials with adequate follow-up."

"Decisions to use DAAs need also to take account of benefits and costs of treatment," he stated. "To illustrate this point, a 12-week course of treatment with sofosbuvir can cost as much as GBP 34,983, excluding value-added tax, (about US$46,000) in some countries."

"Our (group's) responsibilities are to assess the effects of all interventions for diseases of the liver and gallbladder," Dr. Gluud stressed, emphasizing the need to focus on patients' well-being and healthcare costs.

Dr. Thomas Schiano, medical director of both adult liver transplantation and intestinal transplantation at Mount Sinai Medical Center in New York City told Reuters Health the advent of DAAs has been just "short of miraculous in curing HCV in the great majority of patients who are treated with them."

"Previous interferon-based therapies were not very effective and had a lot of associated morbidity," he noted. "All major studies have shown that durable cure of HCV - SVR - leads to a decrease in all-cause mortality."

"Patients with cirrhosis, those having renal failure or HIV, and those patients who have received transplants used to be the most difficult populations to treat, and the DAAs have made treatment much more convenient and successful," Dr. Schiano said.

He noted that HCV cure rates are shortening liver-transplant waiting lists, adding "Pre-DAA, almost half of people undergoing liver transplantation for hepatocellular carcinoma (HCC) required re-transplantation within 10 years - this now has become a thing of the past."

Dr. Thomas Kerr, a hepatologist at UT Southwestern Medical Center in Texas, commented, "I think there is fairly good evidence that HCV eradication prevents long-term HCC complications (liver cancer, liver-related mortality)."

"These data take years to generate, and most of the benefits of HCV eradication were gathered prior to the era of DAAs," Dr. Kerr told Reuters Health by email. "The assumption is that, in time, the clinical benefits of HCV eradication using the newer medicines will mirror this, but it will take time to tell."

"Many people being treated for HCV - unless they were fully cirrhotic when treated - would not be expected to have HCV morbidity or mortality in the next five years," he noted. "Thus, clinical trials generally are only designed to show HCV eradication - defined as virus-negative 12 weeks after treatment) - and safety, and there are quite low rates of serious adverse events with current-generation medicines."

"Whether the current medicines give long-term clinical benefit and mortality reduction is an important question," Dr. Kerr said, noting the need for longer-term population studies and, eventually, a Cochrane Review of those studies.


Cochrane Database Syst Rev 2017.

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