Treatment of hepatitis C with new fixed dose combinations

The advent of oral direct-acting antivirals (DAA) has revolutionized the hepatitis C virus (HCV) therapeutic landscape providing cure rates over 90%. However, a subset of patients remains at higher risk for treatment failure, including those infected with: i) genotype 3 and cirrhosis; ii) resistance-associated substitutions (RAS) occurring either as natural polymorphisms or selected after prior DAA failure; and iii) poor drug adherence associated with social disabilities (homeless, psychiatric illnesses, injection drug use, alcoholism, etc.). Whereas discovery of new DAA with increased antiviral activity across all genotypes and over RAS may enhance efficacy, development of fixed dose combinations (FDC) may be the best way to improve drug adherence in difficult-to-treat HCV populations. Areas covered: Three FDC regimens are in the last steps of clinical development for treating hepatitis C. Two distinct nucleotide analogues that inhibit the HCV polymerase, sofosbuvir and uprifosbuvir, are part of the FDC from Gilead and Merck, respectively. The AbbVie dual FDC does not include a polymerase inhibitor. All three new FDC include second-generation NS3 protease inhibitors and NS5A inhibitors active across all HCV genotypes and over common RAS. Expert opinion: Hepatitis C cure rates over 95% are expected with all three next-coming DAA, even in the most difficult-to-treat and/or cure patient populations. These regimens would be particularly needed for the growing number of prior DAA failures. Co-formulations and 8-week shorter treatment lengths will help to overcome drug adherence challenges in certain populations.