Is the end of chronic hepatitis C virus infection in sight?

In this issue of the Journal, Dore outlines the astonishing recent progress in the treatment of hepatitis C virus (HCV) infection,1 largely triggered by the approval in 2011 by regulatory bodies, both overseas and in Australia, of the first two direct antiviral agents (DAAs) against HCV. These two agents, telaprevir and boceprevir, only target genotype 1 HCV and are used in combination with the current standard of care — pegylated interferon and ribavirin. This triple-therapy combination represents two main advances: an increase in sustained virological response (SVR) from 45% to 70%, and a shortened duration of treatment from 12 to 6 months in about 50% of patients. However, these benefits come with an increased side-effect profile compared with the current standard of care. In fact, the results from the current standard of care in Australia are also published in this issue of the Journal and reflect world’s best practice in treating patients with HCV infection.2

The development of new therapies has sparked significant enthusiasm among clinicians and patients alike; however, it is the potential flow-on from these first generation DAAs that has struck the imagination and has led to the provocative title of this editorial. Dore outlines the future, where combinations of DAAs without a pegylated interferon/ribavirin backbone are in rapid development. These include HCV polymerase inhibitors, NS5A inhibitors, as well as next-generation protease inhibitors. Already, we have proof-of-concept data that some of these combinations can lead to an SVR in 90% of patients after just 3 months of therapy.1 These combinations are aimed against all HCV genotypes and have minimal side effects. This progression parallels that of drug discovery and the development of therapeutic approaches in treating HIV infection. The major difference between HCV and HIV or hepatitis B virus is that HCV is an RNA virus and hence, like polio and hepatitis A virus, can be eliminated. Thus, SVR is actually thought to represent cure in the vast majority of cases, and short-duration rather than lifelong therapy is possible.

It seems likely that, within 5 years, we will have short-duration anti-HCV therapy with minimal side effects and cure rates above 90%. The challenge then will be how we can deliver such therapies to the 220 000 Australians with HCV infection. In another article in this issue of the Journal, Hellard and colleagues report that obtaining SVRs with current standard of care in the highest risk group for HCV infection in our community (ie, people who inject drugs) could theoretically reduce the overall prevalence of chronic HCV infection.3 However, the estimates in this study require a major increase of treatment uptake. Although there are data suggesting that this group can be treated successfully with the current standard of care, the number actually being treated is low. This does not just apply to this high-risk group; overall current treatment rates in Australia are quite low and it has been estimated that only 2% of all patients with chronic HCV actually receive antiviral therapy each year.4 A recent study found that the major barriers to treatment in a tertiary hospital setting were medical and mental health comorbidities.4

Interferon-free therapies will potentially see this barrier disappear, so that all patients referred to tertiary centres will be treated. However, this will still remain a small proportion of all HCV infections in our community. The challenge will be to introduce interferon-free therapies to regular primary practice, within methadone clinics, and into situations where people who inject drugs can obtain access. Short treatment duration, high cure rates and low toxicity will mean that all HCV-infected patients should eventually receive curative therapy.

The delivery of these therapies into these settings should reduce many barriers to treatment, such as geography and social circumstances. The lack of side effects will reduce consideration of comorbidities as an issue. Also, by moving HCV treatment from hospital clinics into the community, these new therapies will potentially reduce stigma and may stimulate increased testing and treatment of HCV infection.

What is the answer to the question posed by this editorial? Unfortunately, it is a sobering “not quite”. Apart from the actual challenges of delivering therapy to a large number of individuals, patients with cirrhosis may still progress and patients may still be susceptible to hepatocellular carcinoma development (although at a significantly reduced risk). Further, a recent study reports a continuing, although decreased, risk of liver-related mortality among patients with chronic HCV infection (even those without cirrhosis who have achieved an SVR) compared with the general community.5 The explanation for this observation remains obscure.

There are indeed challenges ahead, and these need to be met. This will require strategic planning in the health systems, education of the medical profession and delivery for high-risk populations. Only then will the “not quite” become a “yes”.