Developments in the treatment of HCV genotype 3 infection

ABSTRACT

Introduction: Unlike other hepatitis C virus (HCV) genotypes (GTs), patients infected with GT3 are associated with an increased risk of accelerated liver disease progression. Although early immuno-modulator therapies yielded moderate sustained virologic response (SVR) rates, treatment of GT3 patients has proven more challenging in the era of direct-acting antivirals (DAAs).

Areas covered: The review provides an overview of the evolution of therapies against GT3 since the approval of the first immunomodulatory agent nearly 30 years ago.

Expert opinion: A greater choice of treatment options is now available for HCV GT3-infected patients. In treatment-naïve patients with or without compensated cirrhosis, SVR rates are comparably high approaching 100% irrespective of treatment option. For treatment-experienced patients, choosing the right therapy is important, especially for those with advanced liver disease. For the few patients who fail with multiple persistent highly resistant DAA substitutions, retreatment options are limited. Additional real-world treatment comparisons are required to confirm differences in SVR in these more difficult-to-treat patients. This also includes patients infected with GT3 subtypes such as GT3b where multiple DAA-resistant substitutions occur naturally. In the absence of new drugs with non-overlapping drug-resistant profiles, an interferon-based therapy may still be beneficial in select patient populations with high-level multiple DAA-resistant substitutions.

KEYWORDS:

• Daclatasvir
• direct-acting antivirals
• HCV genotype 3
• interferon
• NS5A
• pibrentasvir
• resistance
• sofosbuvir
• sustained virologic response
• velpatasvir

Article highlights

• Over 30 years ago, the first proof-of-concept study assessing treatment options for patients with HCV infection was reported. Over the last five years, treatment options, administration and treatment duration, safety and tolerability, and sustained virologic response (SVR) rates have significantly improved for patients with HCV genotype (GT)3 infection.

• Multiple direct-acting antiviral (DAA)-based therapies are now approved for treating patients with GT3 infection yielding ≥90% SVR irrespective of patient population.

• Real-world and clinical GT3 data are generally in agreement although differences in SVR may vary depending on geographic location.

• Response rates in patients with the most prevalent GT3 subtype a are approaching 100% in the absence or presence of fibrosis or cirrhosis of the liver for most of the approved DAA-based therapies. Early diagnosis and treatment yield optimal response rates.

• Patients with preexisting GT3 NS5A polymorphisms such as A30K and Y93H may have lower response rates depending on the approved NS5A-based therapy, especially when combined with negative predictive factors such as treatment-experience and cirrhosis.

• For the few HCV GT3 patients not achieving SVR with approved NS5A-based regimens, DAA-only retreatment options are limited. Additional real-world retreatment studies will increase our understanding of response rates to multiple high-level NS5A drug-resistant substitutions in patients with and without liver cirrhosis. Inclusion of pegIFN may be beneficial for treating select highly DAA-resistant populations.

• Minimal efficacy data are available for GT3 subtypes harboring NS5A-A30K-L31M (genotypes 3b, 3g, 3k). In China, GT3b is more predominant than GT3a. SVR rates in HCV GT3b patients with cirrhosis have been sub-optimal even with next-generation therapies. Further studies are highly recommended to explore SVR rates achieved by HCV GT3b patients with prior treatment-experience and/or liver cirrhosis and treated with approved DAA-based regimens.

Acknowledgments

Thank you to the HCV teams at Bristol-Myers Squibb who played significant roles in the discovery, development and advancement of medicines for the treatment of patients infected with HCV. It was an honor working with so many dedicated scientists over the years aspiring to make a difference in the lives of patients with this chronic infection.

Declaration of interest

F McPhee is an employee of Bristol-Myers Squibb. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.