Hepatitis C: Treatment triumphs

The story of hepatitis C began in the 1970s, when it was recognized that something other than hepatitis A or hepatitis B infections was causing liver inflammation following blood transfusions,. In 1989, the troublemaker was identified as a small RNA virus, named hepatitis C (HCV). Although there are now effective diagnostic procedures that allow a safe blood supply in most developed countries, intravenous drug abuse continues to lead to new infections. An estimated 185 million people are chronically infected with HCV and are at risk of developing life-threatening liver diseases, including cirrhosis and cancer. But a recent series of clinical trials, reported in the New England Journal of Medicine demonstrate drastic increases in the effectiveness of anti-HCV drugs.

Historically, HCV-infected patients have been treated by intravenous injections with type I interferons - secreted cellular proteins that elicit potent antiviral responses. The success rates for interferon-based regimens improved from single digits in the 1970s to around 50% by 2002, accomplished by increasing dose, lengthening treatment, chemically stabilizing the interferon (by PEGylation) and adding ribavirin, an RNA-nucleoside analogue. Ribavirin has poor anti-HCV activity when used alone but significantly increased treatment success when combined with interferon (by mechanisms that are still unsettled). However, this treatment required a 24- or 48-week course and was plagued by awful side effects, including nausea, depression and anaemia. Hence, the goal remained to develop highly effective, orally administered and well-tolerated regimens that work for all patient groups.

Two enzymes encoded by HCV that are essential for viral replication - a serine protease (NS3-4A) and an RNA polymerase (NS5B) - are attractive drug targets. In the 2000s, inhibitors of these enzymes and of another non-enzymatic but essential HCV protein (NS5A), referred to as direct acting antivirals (DAAs), emerged as the lead targets for HCV drug development. In late 2011, two NS3-4A protease inhibitors were approved for human use in combination with PEGylated interferon and ribavirin, raising treatment success to more than 70% for patients with HCV genotype 1 (there are six highly divergent and variable genotypes of the virus).

However, euphoria over this advance was short-lived. Patients with advanced disease were treated but many others were not, owing to the additional, often severe, side effects of this drug combination and the emergence of viral resistance. In the meantime, and continuing into the present, dozens of new compounds were being tested in the clinic. In 2013, more-potent DAAs, in combination with PEGylated interferon and ribavirin, were approved, as was the first all-oral regimen, consisting of a NS5B-targeting DAA combined with ribavirin alone.

The recent clinical studies present the next wave of interferon-free, all-oral, DAA-based regimens, which are likely to be approved in the near future for HCV treatment. Without delving into details and trade names, several key points about these trials emerge. First, they include multiple all-oral combinations that can achieve success rates of more than 95%. 'Success' for HCV treatment means no detectable virus 12 weeks after stopping treatment. Unlike drug treatments for hepatitis B and HIV, most HCV researchers believe that this endpoint represents a durable cure that lowers the risk of progressive liver disease. Second, these treatments are effective in patients who are in greatest need and are most difficult to treat - those with advanced fibrosis and cirrhosis, those who are co-infected with HIV, and even liver-transplant candidates and recipients. Also noteworthy is that the new drug combinations promise shorter treatment times (12 weeks and possibly even less) and minimal side effects; as a result, fewer people are expected to discontinue their treatment.

So from a mystery virus and a 5% treatment-success rate, we have come to an era of cure rates of more than 95% . Game over, right? Not quite. What about viral resistance to the drugs? With nearly 200 million infected individuals, 6 diverse viral genotypes and around 1 trillion viral variants being generated per day per infected person, it is likely that HCV will have some tricks up its sleeve to develop resistance. However, some of the new DAAs, in particular sofosbuvir, which targets the active site of NS5B, have an extremely high barrier to resistance, and there have been only rare glimpses of resistant variants in clinical observations with multiple viral genotypes. Combining potent DAAs, each with lower resistance barriers, can still be highly effective at avoiding the build-up of resistance. Nonetheless, resistance will undoubtedly occur and should be taken into account to guide treatment decisions. The current drugs are also less effective against genotype 3 HCV, which is common in South Asia, although pan-genotype drugs are in development.