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


The last few years have witnessed the development of several direct-acting anti-viral agents that has led to a new treatment paradigm for HCV-infected patients. Landmark clinical trials have demonstrated that NS3/4A protease inhibitors, NS5A inhibitors and NS5B inhibitors used in combination with each other greatly attenuate AEs associated with peg-IFN and RBV dual therapy and shorten the duration of treatment by as much as fourfold. Side effects unique to different DAAs have been enumerated in Table 5.

Simeprevir is generally well tolerated by patients, is a photosensitiser, but consequent adverse skin reactions rarely lead to withdrawal from therapy. In addition, elevated bilirubin levels, often of the unconjugated type, routinely return to baseline following completion of simeprevir triple therapy in most patients. The 3D regimen is generally well tolerated by both treatment-naïve and treatment-experienced patients. Hyperbilirubinaemia, presumably due to transient elevated unconjugated (indirect) bilirubin, has been most frequently reported alongside reversible increases in aminotransferase levels. Elevated bilirubin has a higher incidence in treatment-experienced patients with Child–Pugh class A cirrhosis compared to patients without cirrhosis, but rarely leads to treatment cessation. The most frequent use of asunaprevir is in combination with daclatasvir, which has a favourable AE profile in patients with genotype 1 HCV infection. Drawbacks of asunaprevir include risk of elevated liver enzymes and other limitations characteristic of PIs. No AEs unique to daclatasvir have been reported in clinical trials, but dose modifications may be required due to drug–drug interactions, based on the use of concomitant therapies. Ledipasvir co-administered with sofosbuvir is generally well tolerated, and results of clinical trials implicate a diminishing role of ribavirin with this regimen. Those on additional ribavirin have an increased incidence and severity of AEs without any concomitant increase in efficacy. While sofosbuvir possesses pangenotypic activity, has a high barrier to resistance, and is very effective in a variety of combination therapies, no dosage recommendation has been established for its use in those with severe renal impairment. Preliminary results of elbasvir and grazoprevir are promising, as this regimen was effective and tolerable with no unique AEs reported regardless of treatment duration or setting of compensated cirrhosis.

Altogether, data collated from several phase II and III clinical trials show that various DAA therapies are well tolerated in both treatment-naïve and treatment-experienced patients with compensated or decompensated cirrhosis, with no more than 10% of patients undergoing treatment experiencing SAEs (Table 6a, Table 6b, Table 6c, Table 6d, Table 6e and Table 6f, Figure 1).

Figure 1.

Visual representation of the risk of SAEs attributed to each DAA regimen evaluated in phase II/III clinical trials. Risk of SAEs measured by percent of patients who have experienced SAEs while receiving treatment. Findings are limited to treatment-naïve and treatment-experienced populations, and those without cirrhosis or with compensated cirrhosis; data is not generalisable for special populations. Some SAEs reported were not deemed regimen-related. 1: SIM 150 mg q.d., PR; 2: SIM 150 mg q.d., SOF 400 mg q.d.; 3: OBV 25 mg q.d., PTV 150 mg q.d., ritonavir 100 mg q.d., DSV 250 mg b.d., RBV b.d.; 4: SIM 100 mg q.d., PR; 5: OBV 25 mg q.d., PTV 150 mg q.d., ritonavir 100 mg q.d., with or without RBV; 6: DCV 60 mg q.d., ASV 100 mg b.d.; 7: DCV 60 mg q.d., SOF 400 mg q.d.; 8: DCV 60 mg q.d., SOF 400 mg q.d., with or without RBV; 9: DCV 30 mg b.d., ASV 200 mg b.d., BCV 75 mg b.d.; 10: SOF 400 mg q.d., PR; 11: SOF 400 mg q.d., RBV; 12: LDV 90 mg q.d., SOF 400 mg q.d., with or without RBV

The safety of DAAs has yet to be extensively assessed in special populations, including pregnant women, those with advanced-stage liver disease, children, patients post-transplantation, and those who have failed DAA therapy. Further clinical trials and real-world data are likely to shed light on the newer AEs, and their frequency, that have thus far not been observed in clinical trials where patients are often well selected. Attempts are also being made to eliminate ribavirin from HCV therapy due to its dose-limiting toxicity.[138]