Short-course treatment for recent hepatitis C: some courses may be too short

An eight-week course of grazoprevir/elbasvir (Zepatier) achieved a high cure rate in people recently infected with hepatitis C, but another study found that a six-week course of sofosbuvir/velpatasvir (Epclusa) resulted in an inferior cure rate compared to standard treatment.

Both studies tested shorter durations of treatment predominantly in people co-infected with HIV and hepatitis, as the incidence of new hepatitis C infections and reinfections in HIV-positive gay and bisexual men makes treatment of acute infection a priority for hepatitis C control in this population.

Short-course treatment for acute hepatitis C infection remains experimental. The AASLD Hepatitis C treatment guidelines say that as of November 2019, there isn’t enough evidence to recommend any short-course regimen and that acute infection should be treated in the same way as chronic infection. The only eight-week pangenotypic regimen approved for chronic hepatitis C treatment is glecaprevir/pibrentasvir (Maviret).

Short-course treatment for hepatitis C may improve adherence and should prove more cost-effective than standard-duration treatment in acute infection. It’s unclear if shortening the duration of treatment also reduces the risk of onward transmission.

Two recent pilot studies reported on short-course treatment.

The French SAHIV study evaluated an eight-week course of treatment with grazoprevir/elbasvir in recently infected gay and bisexual men. Grazoprevir/elbasvir is approved for chronic genotype 1 or 4 infection as a 12-week course of once-daily treatment. A study in the Netherlands and Belgium has shown that an eight-week regimen achieved a 94% cure rate in co-infected men.

The study recruited 30 people who had tested positive for HCV RNA or antibody less than six months after a negative HCV test or less than six months after a potential exposure and less than 12 months after a previous negative test, including ten people who had been reinfected.

All were male. Twenty-three reported probable exposure through sex, six through nasal drug use and five through injecting drugs. Two had unknown exposure routes.

Twenty-eight out of 30 were co-infected with HIV, all were taking antiretroviral therapy and 26 of 28 had an undetectable viral load at enrolment.

Twenty-eight out of 30 who completed treatment achieved a sustained virologic response (91%). One participant committed suicide and one participant experienced viral rebound after completing treatment. This participant had undetectable levels of HCV drugs and low levels of HIV drugs at week 4 of the study, undetectable HCV RNA levels after completing treatment and experienced viral rebound 12 weeks after completion of treatment. Resistance to the study medication was detected.

Adherence to grazoprevir/elbasvir was similar to antiretroviral adherence during the study; 7% of participants reported missing a dose of hepatitis C treatment in the past four days at the week 8 study visit.

No serious drug-related adverse effects were reported by study participants and the most common side-effects were diarrhoea, insomnia and fatigue.

Three participants subsequently became reinfected within a year of completing treatment and were successfully re-treated.

A second study of treatment in acute or recent infection found that six weeks of treatment with sofosbuvir/velpatasvir (Epclusa) resulted in an inferior cure rate in people recently infected with hepatitis C when compared to a 12-week treatment course.

A six-week course of sofosbuvir/ledipasvir (Harvoni) has been shown to be an effective treatment for acute hepatitis C genotype 1 infection in two single-arm studies but no randomised comparison of short-course versus standard-course pangenotypic treatment has reported findings.

The REACT study was designed to test whether sofosbuvir-velpatasvir was an effective treatment. The study enrolled people who inject drugs and people with HIV who had been infected with hepatitis C less than 12 months previously.

All study participants received six weeks of treatment with sofosbuvir/velptasvir and were then randomised to stop treatment or continue for a further six weeks.

Ninety-three people were randomised to the short-course arm and 99 to the 12-week arm. The study population was almost entirely male (96%), predominantly white (83%), just over two-thirds were HIV positive (70%), the predominant route of exposure to hepatitis C was sex between men (72%) and 21% were injecting drug users. Thirty-seven per cent were undergoing treatment due to reinfection.

Participants had been infected with hepatitis C for a median of 25 weeks at study entry, predominantly with genotype 1 (65%), 3 (17%) or 4 (16%).

The study Data and Safety Monitoring Board stopped the study at the second scheduled review of the data in May 2019 due to an unacceptably high rate of virological relapse in the short-course arm. Eighty-two per cent in the short-course arm achieved a sustained virologic response compared to 91% in the 12-week arm (p = 0.063). Although there was no difference in the proportions with undetectable viraemia at the end of treatment, nine people in the short-course arm and two in the 12-week arm experienced viral rebound, despite excellent adherence in those who experienced rebound. Those who experienced rebound tended to have higher baseline viral load, but numbers were insufficient for an analysis of predictors of rebound.

There was no substantive difference in deaths, loss to follow-up or reinfection in the two study arms.

The reason for the higher rate of virological rebound in the short-course arm is unclear. Only one person who experienced rebound had sub-optimal adherence. It is possible that the combination of a nucleotide analogue (sofosbuvir) and NS5A inhibitor (velpatasvir) may not induce sufficiently rapid viral load reduction to permit a six-week treatment course.