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Re-treatment of hepatitis C is highly effective after the first combination fails

Keith Alcorn
24 June 2022

Two combinations proved highly effective in curing hepatitis C in people who had experienced the failure of a previous combination containing an NS5A inhibitor, studies in Europe and New Zealand show.

The findings, presented at the International Liver Congress this week, provide reassurance that the vast majority of people with hepatitis C who experience the failure of their first treatment combination can be cured with a follow-up course of treatment, without the need for adding the potentially toxic drug ribavirin.

Re-treatment after failure of a direct-acting antiviral combination that contains an NS5A inhibitor (daclatasvir, ledipasvir, elbasvir, pibrentasvir or velpatasvir) may be challenging if resistance to the NS5A inhibitor emerges as a result of treatment failure.


decompensated cirrhosis

The later stage of cirrhosis, during which the liver cannot perform some vital functions and complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.

European and US guidelines recommend 12 weeks of treatment with voxilaprevir/velpatasvir/sofosbuvir (Vosevi) or 12 weeks of glecaprevir/pibrentasvir (Maviret) plus sofosbuvir (Sovaldi), with or without ribavirin. However, each recommendation is based on small numbers of treated patients and the added value of using ribavirin as an extra drug in these cases of treatment failure is uncertain.

An international study looked at real-world responses to the three-drug combination voxilaprevir/velpatasvir/sofosbuvir (Vosevi) in people who had experienced the failure of at least one previous regimen. The study recruited all patients re-treated with this combination at 153 liver clinics in Austria, Belgium, Germany and Switzerland between May 2015 and November 2020.

The study recruited 458 participants with a median age of 55 years, 79% male, predominantly genotype 1 (54%) or genotype 3 (39%). Participants received Vosevi for 12 weeks; 4% received ribavirin too.

Of those recruited, 427 were evaluable. Of these, 26 relapsed after the completion of treatment, a cure rate of 94%.

Treatment failure occurred more frequently in people with genotype 3 infection and those with hepatocellular carcinoma but the effectiveness of treatment was not affected by baseline hepatitis C RNA level, previous DAA regimen or the presence of cirrhosis. The presence of resistance mutations did not compromise the effectiveness of treatment.

Another study, carried out in New Zealand, looked at responses to re-treatment with glecaprevir and pibrentasvir (Maviret) and generic sofosbuvir for 16 weeks in people whose first regimen had failed and who had NS5A resistance mutations. The study excluded people with decompensated cirrhosis or hepatocellular carcinoma, as well as people with post-transplant hepatitis C.

Vosevi is not available and Sovaldi is not approved for re-treatment of hepatitis C in New Zealand, so the study investigators added generic sofosbuvir, supplied by Pharco in Egypt, to glecaprevir/pibrentasvir.

The study recruited 66 participants, 54% with previous failure of a glecaprevir/pibrentasvir regimen, 38% with failure of ombitasvir, paritaprevir, dasabuvir and ritonavir, and the remainder with failure of grazoprevir/elbasvir, ledipasvir/sofosbuvir or sofosbuvir/velpatasvir. Six patients had experienced failure of more than one regimen. Thirty-nine per cent had multiple NS5A resistance mutations.

Fifty-one had completed treatment and had post-treatment HCV RNA results available. Fifty of 51 had been cured (98%).

Two study participants were lost to follow-up and three interrupted treatment during the study. Dr Gane said that the biggest challenge to curing people who had experienced first-line failure was social factors and non-adherence, not drug resistance. “The most common reason for DAA treatment failure now is non-virologic,” he concluded. Rather than worrying about drug resistance, or whether to add ribavirin, adherence and loss to follow-up were the problems that need to be addressed.

He said the study findings emphasised the need for wrap-around support for people undergoing hepatitis C treatment, including psychosocial interventions, daily dispensing for people who are using drugs or receiving opioid substitution therapy and outreach teams who can deliver medication and follow-up people in the community.


Graf C et al. Effectiveness of voxilaprevir/velpatasvir/sofosbuvir in hepatitis C patients previously treated with direct-acting antiviral agents. International Liver Congress, London, abstract OS003, 2022.

Gane E et al. Glecaprevir/pibrentasvir and sofosbuvir for 16 weeks without ribavirin is safe and highly effective retreatment for patients who have failed an NS5A inhibitor-containing antiviral regimen. International Liver Congress, London, abstract OS004, 2022.