From the Journals

Liver cancer risk lower after sustained response to DAAs

Publish date: July 18, 2017

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Do direct-acting antivirals benefit or harm patients with hepatitis C?

The availability of direct-acting antivirals (DAAs) has revolutionized treatment of hepatitis C. Sustained virologic response (SVR) can be routinely achieved in more than 95% of patients – except in those with decompensated cirrhosis – with a 12-week course of these oral drugs, which have minimal adverse effects. Thus, guidelines recommend that all patients with hepatitis C should be treated with DAAs.1 It was a shock to the medical community when the recent Cochrane review concluded there was insufficient evidence to confirm or reject an effect of DAA therapy on HCV-related morbidity or all-cause mortality.2 The authors cautioned that the lack of valid evidence for DAAs’ effectiveness and the possibility of potential harm should be considered before treating people with hepatitis C with DAAs. Their conclusion was in part based on their rejection of SVR as a valid surrogate for clinical outcome. Previous studies of interferon-based therapies showed that SVR was associated with improvement in liver histology, decreased risk of hepatocellular carcinoma (HCC), and mortality.

Dr. Anna S. Lok

DAAs have only been available for a few years, yet increasingly, data show that SVR achieved with DAAs has beneficial effects similar to those seen with interferon-based therapies. The most dramatic benefit is observed in patients with decompensated cirrhosis, in whom improvement in liver function and reversal of cirrhosis complications can occur within a few months of treatment, allowing some of these patients to be taken off the transplant waiting list.3 A potential concern for harm was raised by several studies suggesting DAAs may increase the risk of HCC, but these studies involved small numbers of patients. The recent study by Kanwal et al. with 22,500 patients treated with DAAs showed the incidence of HCC in patients who achieved SVR after DAA therapy was 72% lower than those who did not achieve SVR.4 They also found that patients treated in the DAA era were older and more likely to have cirrhosis and comorbidities that increase the risk of HCC, compared with those treated in the interferon era, highlighting the pitfalls of comparison with historical data. This large study did not find any evidence of harm but rather benefits of DAAs and support for early, rather than late, initiation of treatment.

Treatment of hepatitis C with DAAs represents one out of a handful of cases in which we can claim that a cure for a chronic disease is possible; however, treatment must be initiated early before advanced fibrosis or cirrhosis to prevent a persistent, though greatly reduced, risk of HCC. Physicians managing patients with hepatitis C should make treatment decisions based on evidence from the entire literature – which supports claims of the DAA treatment’s benefits and refutes allegations of its harmfulness – and should not be swayed by the misguided conclusions of the Cochrane review.

References

1. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Accessed on July 2, 2017.
2. Jakobsen J.C., Nielsen E.E., Feinberg J., et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev. 2017 Jun 6;6:CD012143.
3. Curry M.P., O’Leary J.G., Bzowej N., et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618-28.
4. Kanwal F., Kramer J., Asch S.M., et al. Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents. Gastroenterology. 2017 Jun 19. pii: S0016-5085(17)35797.

Anna S. Lok, MD, AGAF, FAASLD, is the Alice Lohrman Andrews Research Professor in Hepatology in the department of internal medicine at the University of Michigan Health System in Ann Arbor. She has received research grants from Bristol-Myers Squibb and Gilead through the University of Michigan.

FROM GASTROENTEROLOGY

Individuals with hepatitis C infection who achieved a sustained virologic response (SVR) to treatment with direct-acting antivirals had a significantly lower risk of hepatocellular carcinoma (HCC), a new study suggests.

A retrospective cohort study of 22,500 U.S. veterans with hepatitis C who had been treated with direct-acting antivirals (DAAs) found those with an SVR had a 72% lower risk of HCC, compared with those who did not achieve that response (hazard ratio, 0.28; 95% confidence interval, 0.22-0.36; P less than .0001), even after adjusting for demographics as well as clinical and health utilization factors.

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The study showed the incidence of HCC among patients with SVR was 0.90/100 person-years, compared with 3.45/100 person-years in those without (Gastroenterology. 2017 Jun 19. doi: 10.1053/j.gastro.2017.06.012).

“These data show that successful eradication of HCV [hepatitis C virus] confers a benefit in DAA-treated patients,” wrote Fasiha Kanwal, MD, from the Michael E. DeBakey Veterans Affairs Medical Center in Houston and her coauthors. “Although a few recent studies have raised concerns that DAA might accelerate the risk of HCC in some patients early in the course of treatment, we did not find any factors that differentiated patients with HCC that developed during DAA treatment.”

The results highlighted the importance of early treatment with antivirals, beginning well before the patients showed signs of progressing to advanced fibrosis or cirrhosis, the investigators noted.

“Delaying treatment until patients progress to cirrhosis might be associated with substantial downstream costs incurred as part of lifelong HCC surveillance and/or management of HCC,” they wrote.

Sustained virologic response to DAAs also was associated with a longer time to diagnosis, and patients who didn’t achieve it showed higher rates of cancer much earlier. The most common antivirals used were sofosbuvir (75.2%; 51.1% in combination with ledipasvir), the combination of paritaprevir/ritonavir (23.3%), daclatasvir-based treatments (0.8%), and simeprevir (0.7%).

While the patients achieved SVR that showed similarly beneficial effects on HCC risk in patients with or without cirrhosis, the authors also noted that patients with cirrhosis had a nearly fivefold greater risk of developing cancer than did those without (HR, 4.73; 95% CI, 3.34-6.68). Similarly, patients with a fibrosis score (FIB-4) greater than 3.25 had a sixfold higher risk of HCC, compared with those with a value of 1.45 or lower.

Researchers commented that, at this level of risk, surveillance for HCC in these patients may be cost effective.

“Based on these data, HCC surveillance or risk modification may be needed for all patients who have progressed to cirrhosis or advanced fibrosis (as indicated by high FIB-4) at the time of SVR,” they wrote.

Alcohol use was also associated with a significantly higher annual incidence of HCC (HR, 1.56; 95% CI, 1.11-2.18).

Among the study cohort, 39% had cirrhosis, 29.7% had advanced fibrosis, and nearly one-quarter had previously been treated for hepatitis C infection. More than 40% also had diabetes, 61.4% reported alcohol use, and 54.2% had a history of drug use.

“DAAs offer a chance of cure for all patients with HCV, including patients with advanced cirrhosis, older patients, and those with alcohol use – all characteristics independently associated with risk of HCC in HCV,” the authors explained. “These data show the treated population has changed significantly in the DAA era to include many patients with other HCC risk factors; these differences likely explain why the newer cohorts of DAA-treated patients face higher absolute HCC risk than expected, based on historic data.”

The study was partly supported by the Department of Veteran Affairs’ Center for Innovations in Quality, Effectiveness, and Safety at the Michael E. DeBakey VA Medical Center. No conflicts of interest were declared.

Liver cancer risk lower after sustained response to DAAs

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