INHSU 2016: HCV Treatment Effective and May Work as Prevention for People Who Inject Drugs

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Hepatitis C treatment for people who inject drugs is as safe and effective as it is for non-drug-users -- with cure rates exceeding 90% -- and treating enough of this population could reduce transmission or even bring a halt to local epidemics, according to presentations at the 5th International Symposium on Hepatitis Care in Substance Users (INHSU 2016) last week in Oslo.

Hepatitis C virus (HCV) is easily transmitted through shared drug injection equipment, and current and former injection drug users have high rates of infection. But many providers and insurers have considered people who inject drugs to be poor candidates for treatment, concerned that they would not stick to their regimens.

Graham Foster from Queen Mary University of London presented a state-of-the-art lecture on treatment of HCV infection, Gregory Dore from the Kirby Institute at the University of New South Wales spoke on hepatitis C treatment trials for injection drug users, and Matthew Hickman from the University of Bristol spoke on HCV treatment as prevention. This was followed by a debate on whether people who inject drugs should be prioritized for hepatitis C treatment.

HCV Treatment Today

For HCV genotype 1 -- the most common type in the U.S. and Europe -- there are 2 main strategies using direct-acting antivirals: use the HCV NB5S polymerase inhibitor sofosbuvir (Sovaldi) with whatever you have at hand, or combine a potent HCV protease inhibitor with 1 or 2 other drugs.

Gilead Sciences' sofosbuvir/ledipasvir (Harvoni) has the advantage of being a once-daily single tablet regimen. It cures more than 95% of non-cirrhotic genotype 1 patients in 8 weeks with virtually no side effects, and a similar proportion of patients with cirrhosis in 12 weeks in combination with ribavirin.

HCV protease inhibitor regimens include AbbVie's paritaprevir-based "3D" regimen (sold as Viekira XR, Viekira Pak, or Viekirax/Exviera) and Merck's grazoprevir/elbasvir coformulation (Zepatier). An investigational AbbVie regimen containing the protease inhibitor ABT493 plus ABT530 looks promising so far and could bring more competition -- and lower prices -- to the market.

Both approved protease inhibitor regimens have sustained virological response rates similar to those of the sofosbuvir combination. The AbbVie regimen used to be more complex, requiring multiple pills and twice-daily dosing, but the U.S. Food and Drug Administration recently approved a once-daily extended release version.

The caveat with the AbbVie regimen -- and probably all protease inhibitors, Foster suggested -- is that if a person has or has ever had decompensated cirrhosis, these drugs can lead to worse liver disease and potentially death.

"It's really almost too good to be true," Foster said. "You apply these drugs, your patients get cured." He acknowledged, however, that things aren't always that simple, as there are some issues of drug interactions and resistance that must be considered.

HCV genotype 3 is a "pussycat" and easy to treat in people without cirrhosis, but becomes harder to treat in cirrhotics, he noted. The recently approved sofosbuvir/velpatasvir coformulation (Epclusa) is effective against genotype 3 -- and all HCV genotypes -- and does not require ribavirin.

"We're not quite there yet" with genotype 3, Foster concluded, and it's important to treat these patients early, while they have milder liver disease, "so you won't end up with harder-to-treat cirrhotics."

Treatment failure with the new direct-acting antivirals in genotype 1 patients "is so rare that unless you look for it, you won't see it," Foster said. In the old days of interferon-based therapy, 90% efficacy for genotype 3 "would have looked pretty good, but today it's not good enough."

In daily clinical practice, a provider likely won't see the difference between 95% and 98% efficacy. However, Foster stressed, "if we're going to eliminate hepatitis C, we need 98% -- 90% efficacy will blow chances of elimination. To hit the 98% SVR rates we dream of, we need to make sure the right the drugs are given to the right people in the right way."

Treatment for People Who Inject Drugs

People who inject drugs have typically been excluded from clinical trials of new hepatitis C therapies, but some recent studies of direct-acting antivirals have enrolled people using opioid substitution therapy (OST) to manage their addiction.

Dore noted the rapid evolution of hepatitis C treatment and said the new interferon-free regimens are "highly suited to people who inject drugs," given their high cure rates, easy dosing, and good tolerability.

Dore reviewed recently published results from the Phase 3 C-EDGE CO-STAR trial, the first study specifically designed for people who inject drugs. This international study enrolled 301 previously untreated chronic hepatitis C patients on OST with HCV genotypes 1, 4, or 6. They were treated with grazoprevir/elbasvir for 12 weeks either immediately or after a delay.

Treatment was well-tolerated and cured most study participants, with a 93%-94% response rate for genotype 1 and 92% for genotype 4, but falling to just 20% for the small number of genotype 6 patients. During post-treatment follow-up, 6 participants were apparently reinfected with HCV after achieving viral suppression; counting them as sustained responders pushed the cure rate up to 94% overall and 60% for genotype 6. Adherence matched that of non-drug users in other C-EDGE trials even though many participants continued to use illicit drugs during the study.

Recently published ad hoc analyses of the Phase 3 ION trials testing sofosbuvir/ledipasvir and ASTRAL trials evaluating sofosbuvir/velpatasvir likewise found that people on OST, including those who continued to use illicit drugs, maintained good adherence and had high sustained response rates comparable to those of non-drug users in the trials. People on OST also did as well as participants overall in a study of paritaprevir-based therapy.

Dore noted the need for studies of treatment for active injection drug users, including follow-up analysis of reinfection after being cured, which could compromise the ability of treatment to curb hepatitis C epidemics.

The SIMPLIFY trial is now treating current injectors and people on OST (genotypes 1-6) using sofosbuvir/velpatasvir. The D3FEAT study, which just started enrollment, is evaluating the paritaprevir-based "3D" regimen in current injectors and people on OST (genotype 1). These studies, conducted by the international ACTIVATE network, will continue following participants for 3 years.

HCV Treatment as Prevention

Effective treatment eliminates HCV from the body so it cannot be transmitted, and treating enough people therefore has the potential to eliminate hepatitis C as a public health threat.

Hickman discussed evidence showing that while primary prevention approaches such as syringe provision and OST can reduce HCV transmission, they alone cannot end the hepatitis C epidemic.

Modeling research conducted by Natasha Martin and colleagues has shown that scaling up hepatitis C treatment for people who inject drugs can have a prevention benefit, but its magnitude depends on HCV prevalence in a given population and liver disease stage at the time of treatment.

The lower the prevalence -- that is, the more drug injectors who remain susceptible to HCV infection -- the greater the benefit of treatment as prevention. Treating patients with advanced liver disease, who tend to be older and in networks with people who are already infected, could have a major effect on liver disease morbidity and mortality, but not so much on transmission. However, treating younger, healthier people with mild or moderate liver disease could eliminate the virus among those most likely to transmit it.

"Relatively modest scale-ups of hepatitis C treatment can have a major impact on hepatitis C epidemics," Hickman concluded. "HCV treatment as prevention is a real possibility -- we have to scale up treatment and cannot rely on primary prevention."

Who To Prioritize for Treatment?

These presentations set the stage for a debate about whether people who inject drugs should be prioritized for hepatitis C treatment. AASLD and EASL guidelines state that almost everyone living with hepatitis C should be considered eligible for treatment -- and specifically say that drug users should not be excluded. But the high cost of the new drugs and a shortage of knowledgeable providers mean that, in practice, some people will be treated first.

In his talk Hickman noted that treating people with mild liver disease does not have much impact on liver cancer or liver-related death, so if they are prioritized it would be for other reasons, such as prevention. But so far there is no observed evidence yet that HCV treatment works as prevention.

Foster said that if treatment is focused on cirrhotics, "you get a lot of bang for your buck," but this raises the risk that politicians who set budgets will only want to treat the sickest patients.

In order to make the case for treating people with milder disease -- especially a politically unpopular group like injection drug users -- we need data to show the benefits of treating everyone, he stressed. "Unless we can show a reduction in incidence, we won't get the funding."

Anne Øvrehus from Odense University Hospital in Denmark and Martin Kåberg from the Karolinska Institute in Sweden argued that we should provide treatment for everyone with hepatitis C.

"It's a deadly disease and now we have a cure," Kåberg said. "It is not only a personal tragedy if people get cirrhosis or liver cancer, it's a sign that the health system doesn’t work. To withhold treatment for a treatable disease is not fair."

Øvrehus noted that incidence and mortality due to HIV did not start to turn around until effective treatment became widespread. "Just as condoms didn't do it for HIV, safe injecting and harm reduction wont do it for HCV," she said.

On the other side, Sharon Hutchinson from Glasgow Caledonian University argued that until drug prices come down -- and they will inevitably come down -- we should focus on diagnosing and treating people with serious liver disease.

Treating a few people who inject drugs will not make a difference in terms of curbing the epidemic, and in a few years prices should come down and we will have empirical evidence we need to make a much stronger case for treating active drug injectors.

"We have time later to drive down transmission, but we don't have time to treat people with severe liver disease," she said.

Speaking from the audience, Margaret Hellard from the Burnet Institute said that the cost of treatment is down to $300 in Egypt, and the community should stop talking and get on to country negotiations about drug prices and parallel importing of generic drugs.

Foster concluded that if we wait a couple years we could expand treatment to people who inject drugs for less money -- but "this dilemma just goes away if we can get [HCV] drugs at more affordable prices."

9/16/16

References

G Foster. Treatment of HCV Infection in 2016. 5th International Symposium on Hepatitis Care in Substance Users (INHSU 2016). Oslo, September 7-9, 2016.

G Dore. HCV Treatment Trials Among PWID. 5th International Symposium on Hepatitis Care in Substance Users (INHSU 2016). Oslo, September 7-9, 2016.

M Hickman. HCV Treatment as Prevention. 5th International Symposium on Hepatitis Care in Substance Users (INHSU 2016). Oslo, September 7-9, 2016.

ALH Øvrehus, I Birkemose, JH Hansen, et al. Treatment Evaluation and Uptake among Persons with Chronic Hepatitis C on Opium Substitution Therapy. Is Treatment as Prevention Realistic? 5th International Symposium on Hepatitis Care in Substance Users (INHSU 2016). Oslo, September 7-9, 2016. See abstract and presentation.