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

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An eight-week course of grazoprevir/pibrentasvir (Zepatier) achieved a high cure rate in people recently infected with hepatitis C, but a six-week course of sofosbuvir/velpatasvir (Epclusa) in recently infected people resulted in an inferior cure rate compared to standard treatment, two recent studies show.

Both studies tested shorter durations of treatment predominantly in people with HIV and hepatitis C co-infection, as the incidence of new hepatitis C infection and reinfection in HIV-positive gay and bisexual men makes treatment of acute infection a priority for hepatitis C elimination 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).

Glossary

acute infection

The very first few weeks of infection, until the body has created antibodies against the infection. During acute HIV infection, HIV is highly infectious because the virus is multiplying at a very rapid rate. The symptoms of acute HIV infection can include fever, rash, chills, headache, fatigue, nausea, diarrhoea, sore throat, night sweats, appetite loss, mouth ulcers, swollen lymph nodes, muscle and joint aches – all of them symptoms of an acute inflammation (immune reaction).

reinfection

In HIV, synonym for superinfection. In hepatitis C, used when someone who has been cured of the virus is infected with hepatitis C again.

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

viral rebound

When a person on antiretroviral therapy (ART) has persistent, detectable levels of HIV in the blood after a period of undetectable levels. Causes of viral rebound can include drug resistance, poor adherence to an HIV treatment regimen or interrupting treatment.

virologic response

Reduction in viral replication in response to treatment, especially achievement of an undetectable viral load.

 

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.

Short-course treatment with grazoprevir/elbasvir

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 non-randomised study recruited 30 people who had tested positive for hepatitis C RNA or antibody less than six months after a negative 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 had co-infection with HIV, all were taking antiretroviral therapy and 26 of 28 had an undetectable HIV 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 hepatitis C drugs and low levels of HIV drugs at week 4 of the study, undetectable hepatitis C 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 retreated.

The researchers concluded that their data support the use of grazoprevir/elbasvir for immediate treatment in order to reduce hepatitis C transmission in gay and bisexual men.

Short-course treatment with sofosbuvir/velpatasvir

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. Study sites were in North America, western Europe and Australia.

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 there was a smaller number of injecting drug users (21%). 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's 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 different 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 with 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.

References

Boyd A et al. Grazoprevir /elbasvir for the immediate treatment of recently acquired HCV genotype 1 or 4 infection in MSM. Journal of Antimicrobial Chemotherapy, online ahead of print, dkaa091, April 2020.

http://doi. 10.1093/jac/dkaa091

Matthews G et al. Inferiority of short duration sofosbuvir-velpatasvir for recent HCV (REACT study). Coneference on Retroviruses and Opportunistic Infections, abstract 121, 2020.

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