Genotype 3 HCV: The Next Hurdle in Hepatitis C Therapy

Genotype 3 HCV: The Next Hurdle in Hepatitis C Therapy

 Graham R. Foster, FRCP, PhD - 6/14/2013  More from this author

Source - Clinical Care Opinions

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The emerging wave of new direct-acting antivirals almost seems an embarrassment of riches as we learn of improving efficacies, reduced adverse event profiles, and simpler treatment regimens seemingly by the day. Much as was seen in HIV during the mid- to late-1990s, the excitement grows with treatment efficacies reaching 90% or better at hand. Indeed, clinical studies have crossed that threshold for patients infected with genotype 2 HCV treated with daclatasvir plus peginterferon and ribavirin or sofosbuvir plus ribavirin alone. Our patients infected with genotypes 1, 4, 5, and 6 also have a very real expectation of reaching that goal very soon.

Stumbling Over a Divergent Step
However, genotype 3 remains stubbornly different, challenging the high expectations for a pangenotypic HCV cure. A substantial departure from the other HCV genotypes, genotype 3 presents a unique diagnostic and treatment challenge with treatment success rates substantially lower than those of other HCV genotypes. The FUSION trial of sofosbuvir plus ribavirin for 12 or 16 weeks in treatment-experienced patients reported that 94% of HCV genotype 2–infected patients treated for 16 weeks achieved SVR12 vs only 62% of those infected with genotype 3. Similarly, treatment-naive patients in the FISSION trial of sofosbuvir plus ribavirin for 12 weeks experienced SVR12 rates of 97% if they were infected with HCV genotype 2, but only 56% if infected with HCV genotype 3.

Steatosis and fibrosis are commonly associated with genotype 3 infection, which may challenge the latest noninvasive hepatic imaging devices and may render their results less reliable for this viral strain making it harder to diagnose cirrhosis in this population. Cirrhosis and/or intrahepatic fat may be, at least in part, responsible for the persistently low rates of SVR associated with genotype 3. It is unclear whether intrahepatic fat sequestration by the replicating virus reduces access to direct acting anti-viral agents thereby reducing the efficacy of these drugs and further work to examine the mechanisms underlying treatment failure with this genotype is urgently required.

Where to From Here?
So what do we do for our genotype 3–infected patients who do not respond to treatment with peginterferon and [ribavirin]? Fundamental questions of management strategy, such as retreatment duration, remain unanswered. In general, the data are equivocal. For example, the recent N-CORE study showed little or no difference in treating genotype 2/3 patients with peginterferon and [ribavirin] for 24 vs 48 weeks if they failed to achieve RVR.

For Genotype 3 and investigational agents, we’ve seen instances where promising initial data provided hope that an effective agent was on the way, but these data often are derived from studies in small numbers of patients and given the enormous diversity of genotype 3 small studies may not provide an accurate reflection of response rates in larger studies. Pangenotypic efficacy is a claim that many agents would like to make. However, because of the unique characteristics of genotype 3, I remain highly skeptical that we will see an anti-HCV agent with truly pangenotypic potent activity any time soon.

As my colleague Norah Terrault, MD, MPH, pointed out recently, genotype 3 is the “stress test” for new drugs entering the HCV arena. It’s likely to remain a stressor both for patients infected with it and the clinicians charged with treating it for the foreseeable future.

Your Thoughts?
I’m interested to hear your own perspectives regarding the management of patients with genotype 3, now and in the future. What do you currently do with patients who fail to respond to standard peginterferon/ribavirin? Were you aware of the challenges this genotype is presenting in clinical trials of direct-acting antivirals? If you are deferring treatment in the hope of better options, and do you have specific future options in mind?

Topics: HCV - Treatment