The Hepatitis C Revolution Part 2

Difficult-to-Treat Groups and Experimental Approaches

Prarthana Thiagarajan; Stephen D. Ryder


Curr Opin Infect Dis. 2015;28(6):572-575. 

In This Article

Abstract and Introduction


Purpose of review Novel direct-acting antiviral (DAA) agents are highly effective in the treatment of hepatitis C, achieving unprecedented rates of sustained virological response, a functional cure. However, a significant minority of patients belong to 'difficult-to-treat' groups, in which efficacy of DAAs appears less robust. The review article aims to discuss additional treatment strategies which may be employed in these patient cohorts, as well as evidence for the potential role of experimental DAAs.

Recent findings Patients with genotype 3 infection have consistently lower rates of virological clearance following DAA therapy when compared with other genotypes. However, in combination with sofosbuvir, the novel nonstructural protein 5A inhibitor daclatasvir has demonstrated high efficacy in the treatment of noncirrhotic genotype 3 infection. Recent data from phase 2 and 3 clinical studies support the use of currently approved DAA regimens in the treatment of patients with hepatitis C virus and human immunodeficiency virus (HIV) coinfection. Sustained virological response rates in coinfected patients are analogous to those observed in monoinfection, such that HIV infection itself does not pose a barrier to DAA efficacy. In posttransplant populations, DAAs have again shown great potential, with trial data validating use of sofosbuvir/ledipasvir.

Summary Unmet need persists in certain subsets of the hepatitis C patient population. The arrival on scene of novel DAAs is likely to further expand the repertoire of available therapy for these 'difficult-to-treat' groups.


Across all hepatitis C virus (HCV) genotypes, novel direct-acting antiviral (DAA) agents have demonstrated potential to enhance sustained virological response (SVR) rates above those achieved with interferon (IFN) and ribavirin (RBV) treatment, but significant challenges remain. Most agents are highly active against HCV genotype 1 infection but are less effective for genotype 3, where trials of DAA regimens show suboptimal SVR rates and high frequency of relapse.

Patients with HIV and HCV coinfection and posttransplant populations had lower cure rates with IFN-based therapies. In the United States and Europe, HCV remains the leading indication for liver transplantation,[1,2] and disease recurrence is almost universal after transplantation.[3] Patients with end-stage renal disease represent another group with more limited treatment options.

The advent of novel DAA agents with broader genotypic activity, greater antiviral potency, and higher barriers to resistance present an exciting opportunity to improve outcomes in these patient groups.