Review Article

Safety and Tolerability of Direct-acting Anti-viral Agents in the New Era of Hepatitis C Therapy

D. Banerjee; K. R. Reddy


Aliment Pharmacol Ther. 2016;43(6):674-696. 

In This Article

Evolution of Treatment

Since the early 1990s, standard interferon-based therapy via subcutaneous injection served as the standard of care (SOC) for patients with chronic hepatitis C; this therapy had a dismal cure rate of just 6% and was accompanied by serious side effects that frequently led to treatment discontinuation.[12] By the start of the millennium, pegylated interferon (peg-IFN) co-administered with a guanosine analogue called ribavirin (RBV) took the place of standard interferon as a safer and better tolerated regimen, and was routinely used to treat patients regardless of HCV genotype.[4,8,9] Progress was limited, however, as this dual therapy still produced a considerable AE profile and suboptimal response rates in patients infected with HCV genotype 1, the most common genotype in the USA and Europe.[8,13]

The advent and subsequent approval of oral DAAs ushered in a new era of HCV treatment. In contrast to the nonspecific nature of interferon-based therapy, DAAs directly target various component proteins involved in the replication of HCV in the host.[14] The main classes of DAAs are NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors. The initial protease inhibitors approved for HCV therapy, telaprevir and boceprevir, led to an increase in efficacy when combined with peg-IFN and RBV, but also produced novel AEs in addition to side effects commonly associated with peg-IFN and RBV.[15,16]

The next wave of approvals included the protease inhibitor, simeprevir, and the first NS5B nucleotide polymerase inhibitor, sofosbuvir.[17–19] Either simeprevir or sofosbuvir along with peg-IFN and RBV were indicated for therapy in patients with genotype 1 HCV infection, but again were accompanied by AEs related to the use of interferon and ribavirin.[20–26] These approvals were closely followed by several well tolerated interferon-free regimens, including sofosbuvir plus simeprevir, 3D regimen (paritaprevir/ritonavir/ombitasvir co-administered with dasabuvir with or without ribavirin), and ledipasvir plus sofosbuvir with the possible need for ribavirin in difficult-to-treat populations.[27–36] These combination therapies offered significant advantages, including higher cure rates, shorter treatment duration, and less severe side effects.[5,22–25,37–41] The last few years have witnessed an expansion within the classes of DAAs, with several new anti-virals currently populating the HCV drug development pipeline. Although great strides have been made for HCV therapy in this era of DAAs, many challenges remain; among these are drug–drug interactions, high-pill burden and strict dosing schedule, significant cost barrier, safety in all populations, variability in regimen and dosing duration across patient genotypes, and the development of viral resistance.[42–48]