Re-treatment of HCV Following DAA Failure

-Introduction Oral drugs, termed collectively as 'Direct-acting anti-viral agents' (DAAs), are the standard-of-care for HCV treatment. In India, four DAAs, namely sofosbuvir (SOF), daclatasvir (DCV), ledipasvir (LDV) and velpatasvir (VEL), are marketed. Initially, people were treated using SOF in combination with ribavirin with or without pegylated-interferon (Peg-IFN). Thereafter, HCV treatment was switched to use of two DAAs with or without ribavirin and discontinuation of Peg-IFN. All these combinations of DAAs have obtained excellent rates of cure - defined as undetectable HCV RNA at 12 weeks after stopping DAA-based HCV, also referred to as sustained virological response at week 12 (SVR12).

Though DAAs-based anti-HCV treatment has shown generally excellent results, globally some patients fail to achieve SVR12. The rate of such failure is higher in patients with advanced liver disease and HCV genotype 3 infections. In India, genotype 3 is the most prevalent HCV genotype (~65%), followed by genotype 1 (~30%).

Data on management of the people who relapse after DAA treatment are extremely limited, and no guidelines exist regarding retreatment options for them. Hence, physician need to re-treat such people with the best combination available in a given situation.

• Objective To study the re-treatment response in people with chronic HCV infection and relapsed to prior DAA based treatment
• Rationale for the proposed treatment regimens

Overall, investigators attempted to tried to combine drugs to give the best chance of virus clearance to those with prior treatment failure by following the following principles, as have emerged from the experience worldwide:

1. Prolongation of treatment duration to 24 weeks if previous treatment was for 12 weeks
2. Addition of pegylated interferon (previous standard of care for HCV, and which acts by a different mechanism) if person has previously failed 24 weeks of dual-DAA treatment
3. Addition of ribavirin, if it appears that the participant can tolerate this drug.
4. Use of sofosbuvir (a NS5b inhibitor) as the backbone of re-treatment, since drug resistance to this drug is the least common
5. Use of a pangenotypic drug (velpatasvir) if the previous treatment was with a genotype-specific NS5a inhibitor (daclatasvir or ledipasvir)
6. Use of genotype-specific drug (daclatasvir or ledipasvir) if the previous treatment was with a pan-genotypic NS5a inhibitor (velpatasvir)

• Methods Relevant clinical, laboratory and treatment details will be recorded in pre-defined data collection form, used for monitoring patients with HCV infection as part of their clinical care. Treatment outcome will be categorized as successful (SVR12), treatment failure (any detectable HCV RNA at the end of pre-defined 12-24 weeks treatment duration) or relapse (HCV RNA negative at the end of treatment, but positive at 12 weeks after stopping treatment). The data will be analyzed for the entire group and for specific subgroups, such as: (i) those without cirrhosis; (ii) those with compensated cirrhosis; (iii) those with decompensated cirrhosis
• Blood specimen collection If possible, a 5 ml blood specimen will be collected before starting anti-HCV retreatment from all the participants. If the HCV retreatment also fails, then a repeat 5 ml blood specimen will be collected for virological studies.
• Follow-up plan During anti-HCV treatment: HCV RNA will be tested at 4-week intervals starting from week 4 till RNA reports are negative, and then at the end of treatment and 12 weeks after stopping treatment.
• Sample size Considering usual clinical load, investigators expect to treat around 1000-1200 DAA treatment naive people with chronic HCV infection between during the study period. considering a 5% relapse rate, HCV relapse is expected in about 50 people.