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EASL 2017: AbbVie Combination Cures Most People with Genotype 3 Hepatitis C

AbbVie's pangenotypic direct-acting antiviral combination of 2 drugs cured 95% of people with early-stage genotype 3 hepatitis C virus (HCV) infection, the hardest genotype to treat, according to results of the ENDURANCE-3 trial presented at the EASL International Liver Congress this week in Amsterdam.

[Produced in collaboration with infohep.org]

The AbbVie second-generation direct-acting antiviral combination consists of a protease inhibitor and an NS5A inhibitor. Glecaprevir is an HCV NS3/4A protease inhibitor active against all genotypes of HCV. Pibrentasvir is an NS5A inhibitor also active against all genotypes. They are available in a coformulation.

A pangenotypic combination should be similarly effective against all genotypes of HCV. To date, direct-acting antiviral combinations have tended to show somewhat lower efficacy in people with genotype 3, especially the hardest to treat -- those with cirrhosis and those with previous treatment experience.

The ENDURANCE-3 study was designed to test the combination of glecaprevir and pibrentasvir in people with HCV genotype 3 without cirrhosis. This is the population that liver specialists can expect to see more of in their clinics as genotype 3 patients with cirrhosis are prioritized for treatment and cured, said Graham Foster of Queen Mary University in London.

Genotype 3 is especially prevalent in South Asia and among South Asian populations in the U.K., but these patients tend to have more advanced disease. Genotype 3 is also found among people who inject drugs and plays a role in recent HCV outbreaks among injection drug users associated with epidemics of opioid use in North America and in Europe.

"Genotype 3 is spreading in the U.S. among young injectors, especially young men. For every patient that we treat and cure, that’s 10 of his friends who don’t get infected," said Foster.

ENDURANCE-3 was an international Phase 3 study. It recruited 505 previously untreated people without cirrhosis, who had genotype 3 infection. The study excluded people with HIV or hepatitis B coinfection. The study did not exclude people who tested positive for illicit drugs or who reported drug use, to ensure that the study population reflected real-life clinical conditions.

Participants in the first wave of recruitment were randomly assigned in a 2:1 ratio to receive either glecaprevir/pibrentasvir for 12 weeks (n = 233) or sofosbuvir (Sovaldi) and daclatasvir (Daklinza) for 12 weeks (n = 115). After results of a Phase 2 trial became public, a second wave of recruitment began, to an 8-week study arm in which 157 people were assigned to receive an 8-week course of glecaprevir/pibrentasvir.

Study participants mostly had mild or no fibrosis (stage F0/F1), ranging from 78% in the glecaprevir/pibrentasvir 8-week arm to 86% in the 12-week arm. Approximately two-thirds of participants had a history of injecting drugs, 85%-90% were white, and 45%-59% were male across study arms.

Results by intent-to-treat analysis showed that the 12-week glecaprevir/pibrentasvir regimen was non-inferior to sofosbuvir plus daclatasvir (95% vs 97% achieved a sustained virological response). The 8-week regimen was non-inferior to the 12-week regimen (95%), but showed a slightly higher frequency of viral relapse after treatment (5 relapses versus 3 in the 12-week arm and 1 in the sofosbuvir plus daclatasvir arm).

The majority of treatment failure, however, was due to loss to follow-up, non-compliance, or withdrawal for other reasons (7 in the 12-week arm, 2 in the 8-week arm, and 2 in the sofosbuvir plus daclatasvir arm).

Overall, 97% of patients who completed treatment and returned for follow-up were cured. Ten people experienced virological treatment failure, with no clear evidence that this was related to baseline NS5A polymorphisms.

Adverse events were mild, most commonly nausea, fatigue, and headache. Four patients discontinued treatment due to adverse events and a total of 10 patients experienced serious adverse events, but none was considered to be study drug-related.

Foster stressed that treating and preventing the spread of HCV genotype 3 in the future would depend much more on going out and looking for patients who are likely to be unaware of their infection and lacking any symptoms of liver damage.

4/21/17

Sources

G Foster, E Gane, A Asatryan, et al. ENDURANCE-3: Safety and efficacy of glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir in treatment-naïve HCV genotype 3-infected patients without cirrhosis. EASL International Liver Congress. Amsterdam, April 19-23, 2017. Abstract GS-007.

AbbVie. Eight Weeks of Treatment with AbbVie's Investigational, Pan-Genotypic Regimen of Glecaprevir/Pibrentasvir (G/P) Achieved High SVR(12) Rates in Challenging to Treat Genotype 3 Chronic Hepatitis C. Press release. April 21, 2017.