Hepatitis C: Down but Not Out

Within the past 4 years, no fewer than 10 potent, orally available antiviral drugs have received U.S. Food and Drug Administration (FDA) approval as therapy for chronic hepatitis C virus (HCV) infection. These small molecules are directed at 1 of 3 HCV targets: NS3/4A protease (-previrs [simeprevir, paritaprevir, and grazoprevir]), NS5B RNA polymerase (-buvirs [sofosbuvir and dasabuvir]), or NS5A polypeptide (-asvirs [daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir]). Most important, combinations of 2 or 3 of these agents have proven highly effective in inducing a sustained virologic response (SVR), with persistent loss of HCV RNA from serum. Long-term follow-up of patients who have achieved SVR shows resolution of the accompanying liver disease and permanent loss of HCV RNA from both serum and the liver, suggesting a cure of the chronic viral infection. These new all-oral regimens typically have SVR rates of 95% or more with only 8 to 12 weeks of treatment and minimal adverse effects; in contrast, previous interferon-based regimens yielded rates of 50% to 60%, but only in highly selected patients and after 48 weeks of poorly tolerated treatment with serious adverse effects and significant contraindications. The new antiviral regimens have transformed management of chronic HCV infection. Falade-Nwulia and colleagues provide a systematic review of 42 published clinical trials of these 10 agents in all 6 HCV genotypes and in cohorts with and without cirrhosis, previous treatment, HIV co-infection, and liver transplantation (1). Few of the studies were placebo-controlled, and none provided head-to-head comparisons with the existing standard of care or even with each other. Regardless, response rates were close enough to 100% that comparisons would not be informative. Furthermore, the nonresponse rates were based on a strict intention-to-treat analysis that judged participants who were lost to follow-up or did not return at the prearranged time as nonresponders. Thus, virologic nonresponse (documented failure to clear HCV RNA during therapy or relapse of viremia within 12 weeks of stopping) was often only 1% to 2%. These findings provide hope that HCV infection is now a fully treatable condition that, with sufficient efforts, can be eliminated as an important medical problem in the United States. Amid the optimism about HCV therapy, however, a few caveats need to be mentioned. First, the response rates were close to, but not equal to, 100%. A conservative estimate is that 2% to 5% of patients will have virologic failure or relapse, and the rate will likely be higher for patients with cirrhosis or genotype 3 infection (1). Although this rate is low, it equates to tens of thousands of persons who might remain infected despite therapy, potentially harboring antiviral resistance-associated variants. Fortunately, more rigorous antiviral regimens are being developed that hold material promise. These regimens are likely to include 3 or 4 oral agents with broad specificity against HCV variants, perhaps given for longer periods. Results of clinical trials of these salvage regimens are eagerly awaited. The second caveat is more serious: problems of access to care. Chronic HCV infection is often clinically silent, and many persons remain unaware of their infection until cirrhosis or end-stage liver disease arises. Screening for HCV infection is simple but has yet to become part of routine medical care. Recently, public health messages (2) and television commercials have raised awareness of the benefits of screening, but reaching the populations most likely to harbor HCV will be a challenge. Compounding this problem are the costs of these therapies. The current market prices for available oral regimens in the United States range from $55000 to more than $150000 (3). Even with negotiated price discounts, these therapies will remain a considerable burden both to private insurers and to our already fragile public budgets for health care funding. The third caveat concerns serious adverse events during therapy. The all-oral regimens are associated with few and only mild adverse effects. In the placebo-controlled trials, common adverse events, such as headache and nausea, were no more frequent with treatment than with placebo (4, 5). Nevertheless, rare but serious adverse events have been reported. Chief among these have been reactivation of hepatitis B virus (HBV) in patients with inactive or resolved HBV infection (6) and sudden hepatic decompensation in patients with preexisting cirrhosis (7). Of note, these adverse outcomes seem to be shared by all of the oral regimens and may relate to successful eradication of HCV infection rather than drug toxicity. At least 2 dozen instances of HBV reactivation have been reported during oral antiviral therapy. This led the FDA to append a black box warning and recommendation for screening for hepatitis B surface antigen and antibody to hepatitis B core antigen before starting therapy, followed by monitoring HBV DNA levels during treatment in patients with reactivation (8). Sudden hepatic decompensation during or shortly after successful HCV therapy is a second unexpected and unexplained adverse event; it indicates that patients with clinically apparent cirrhosis should be monitored carefully during treatment, particularly during the first few weeks, and antiviral therapy should be discontinued promptly if signs of decompensation (jaundice, ascites, or hepatic encephalopathy) arise. Both of these complications are rare, and neither is a reason to withhold treatment. Finally, the word cure may imply that further concern or follow-up is not needed. Clearance of HCV infection is an exciting and gratifying outcome for both patients and physicians but does not guarantee against long-term complications. Follow-up of patients who achieved SVR after antiviral therapy has shown that subsequent survival is excellent but lower than that of age- and sex-matched control patients (9). The excess mortality in SVR cohorts is largely due to hepatocellular carcinoma, the most dire and dreaded consequence of chronic liver disease of any cause. Indeed, in recent studies, this disorder has been reported to arise within the first year after HCV eradication (10). For these reasons, patients with HCV infection and cirrhosis (or even advanced fibrosis) deserve continued follow-up with imaging and blood tests focusing on early detection of this carcinoma after successful therapy. The optimal means of surveillance and the appropriate intervals and duration of monitoring are currently not clear. These issues are a high priority for future research in this now easily treated disease. Hepatitis C is down but not out.