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EASL 2014: Researchers Look at Treatment as Prevention for Hepatitis C

Widespread hepatitis C treatment with effective new direct-acting antivirals could dramatically reduce hepatitis C virus (HCV) transmission, but making this work on a large scale will require efforts to scale up HCV screening and bring down drug costs, according to several presentations at the EASL International Liver Congress this month in London.

It was not until 30 years into the AIDS epidemic that the HPTN 052 study showed that early antiretroviral therapy reduced HIV transmission in serodiscordant heterosexual couples by 96%. More recently, researchers with the PARTNERS study reported at last month's Retrovirus conference that no transmissions occurred among mixed-status heterosexual couples that did not use condoms if the positive partner was on HIV treatment with suppressed viral load.

But lessons learned from HIV have enabled faster progression of advances in the hepatitis C arena. Next-generation DAAs combined in interferon-free regimens are now routinely curing 90% to 100% of participants in clinical trials, including traditionally difficult-to-treat groups such as people with liver cirrhosis or HIV/HCV coinfection.

Given these promising results, researchers are asking whether prompt and widespread treatment could reduce HCV transmission, especially among groups with high rates of incidence (new infections) and prevalence (total existing infections), such as people who inject drugs (PWID).

Traditionally, because injected interferon-based therapy was long (24 to 48 weeks) and arduous and cured less than half of treated patients, hepatitis C treatment was recommended only for people with moderate or worse liver disease. But with new interferon-free regimens that are well-tolerated and can cure most people in as little as 8 weeks, a growing number of experts think all people with HCV should be eligible for treatment.

The opening day of the Liver Congress featured a joint workshop by EASL and the International Network on Hepatitis in Substance Users that included a presentation by Gregory Dore on elimination of hepatitis C among PWID through treatment as prevention. (Dore and colleagues published a paper on the same topic in the October 1, 2013, issue of Clinical Infectious Diseases.)

Dore, with the Kirby Institute at the University of New South Wales in Sydney, defined elimination as reducing the incidence of infection to zero in a defined geographical area -- but requiring continued measures to prevent re-establishment of transmission -- versus eradication, or complete and permanent reduction of an infectious disease to zero new cases worldwide (as was accomplished for smallpox).

Since 60% of all existing HCV infections are among current and former injection drug users, and 80% of new HCV infections occur among current active injectors, controlling transmission in this group would have a major effect on overall incidence and prevalence.

"In contrast to HIV, HCV treatment is both curative and circumscribed in duration -- 2 features that hold great promise for the potential effectiveness of HCV treatment as prevention, particularly among PWID," Dore and colleagues concluded in their Clinical Infectious Diseases report.

The success of treatment-as-prevention for hepatitis C would depend on a number of parameters, including the size, chronic hepatitis C prevalence, and rate of treatment uptake in a local PWID population. These numbers can vary widely. Chronic hepatitis C prevalence, for example, ranges from 25% in Edinburgh, to 50% in Melbourne, to 65% in Vancouver.

In a poster at the Liver Congress and at a symposium sponsored by the European Liver Patients Association (ELPA), Natasha Martin from the University of Bristol described research she did with Dore and others modeling scale-up of treatment and harm reduction efforts such as needle exchange and opiate substitution in the age of direct-acting antivirals (also published in the November 2013 issue of Hepatology).

"Substantial reductions in hepatitis C virus prevalence among people who inject drugs cannot be achieved by harm reduction interventions such as needle exchange and opiate substitution therapy alone," they wrote in the published report.

At the current level of treatment uptake, new drugs with a cure rate of 90% could reduce prevalence by about 25% in Edinburgh in 15 years, but would only have a minimal impact in Melbourne and Vancouver. Scaling up treatment coverage to 15 or 76 patients per 1000 PWID in the population, respectively, could cut prevalence in half in Edinburgh and Vancouver within 15 years. If harm reduction coverage rose to 80%, however, treating 46 out of 1000 PWID in a high-prevalence city like Vancouver could reduce prevalence by 75% over 10 years.

"Individual level benefit favors treating the sickest patients first," Martin explained. "But on a population level, treating someone earlier may not immediately benefit them, but could prevent many new infections."

However, the cost of the next-generation DAAs is likely to be a barrier. At existing HCV drug costs, halving chronic hepatitis C prevalence would require estimated annual treatment budgets of $3 million in Edinburgh and $50 million in Vancouver, Martin's team concluded.

Dramatic reductions in hepatitis C prevalence among PWID can be achieved using a combination of expanded harm reduction and increased treatment in the coming interferon-free era, the researchers concluded, but treatment costs could limit scale-up. "This strategy is achievable, but I don’t know if it's affordable at current prices," Martin said.

The 2 next-generation DAAs approved so far -- Gilead Sciences sofosbuvir (Sovaldi) and Janssen's simeprevir (Olysio) -- run $84,000 and $66,000, respectively, for a 12-week course. Private insurers in the U.S. and national health programs in Europe will get discounts, but many public health experts say costs will still be too high given the large number of people with hepatitis C and the high proportion who are socioeconomically disadvantaged. Forthcoming new drugs from AbbVie, Bristol-Myers Squibb, and Merck may be priced lower to compete with the frontrunners, but it is unclear by how much.

In a related study presented in a session on public health at a Liver Congress, Anthony Cousien and colleagues used mathematical modeling to estimate the impact of treatment on HCV rates among injection drug users in France. They found that a combined strategy of increased HCV screening and diagnosis, improved linkage to care, and earlier treatment with new interferon-free therapies could potentially reducing prevalence from 40% to 10% over the next 10 years, as well as decreasing the long-term burden of advanced liver disease.

Thomas Berg from University Hospital Leipzig, also speaking at the ELPA symposium, underlined the importance of increased outreach and education to encourage increased diagnosis.

His estimates indicate that treating 20% of people with hepatitis C worldwide using drugs with a 50% cure rate would reduce prevalence by 10%. Even if the cure rate were 100% -- nearly achievable with some of the new DAA combos -- prevalence would fall by just 20%. "Only if you increase diagnosis will a higher cure rate lead to a large reduction in prevalence," he concluded. "There is a much higher reduction in mortality if you increase screening."

"Cost is the biggest obstacle of all," said ELPA's Ingo van Thiel, summing up the symposium. "Lowering the price [of treatment] will increase the political will for screening. [At current prices,] many governments are afraid to create new patients."

"It is likely that the incidence of HCV infection could be reduced to zero in defined geographical areas with continued interventions to prevent re-emergence of infection (e.g. needle and syringe programs and opioid substitution treatment), rather than a complete and permanent worldwide reduction to zero," Dore and Jason Grebely, also from the Kirby Institute, concluded in a commentary in the April 2014 issue of Antiviral Research. "As newer interferon-free DAA agents become available, HCV treatment as prevention may be an attractive option to reduce the future burden of HCV-related disease."

"HCV treatment as prevention is part of a larger challenge to expand access to HCV testing and care," they continued. "Both individual-level and population-based strategies will be required for a comprehensive approach for the control and eventual elimination of HCV transmission and disease. Cost-effectiveness evaluations are needed to determine how services can be optimally allocated. Future research in this area will help better understand the role of HCV treatment as prevention in the hope of eradicating HCV infection, or at least eliminating the virus in specific population groups such as PWID populations in many settings."

4/25/14

References

G Dore. Elimination of HCV infection among people who inject drugs through treatment as prevention: feasibility and future requirements. EASL-International Network on Hepatitis in Substance Users Joint Workshop. London, April 9, 2014.

MK Martin, M Hickman, SJ Hutchinson, et al. Can combination HCV prevention interventions in the DAA era result in dramatic reductions in HCV prevalence? A modeling analysis in settings with existing harm reduction. 49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract P1289.

A Cousien, VC Tran, M Jauffret-Roustide, et al. Impact of New DAA-containing Regimens on HCV Transmission among Injecting Drug Users (IDUs): a Model-based Analysis (ANRS 12376). 49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O89.

J Grebely, GV Matthews, AR Lloyd, and G Dore. Elimination of Hepatitis C Virus Infection Among People Who Inject Drugs Through Treatment as Prevention: Feasibility and Future Requirements. Clinical Infectious Diseases 57(7):1014-1020. October 1, 2013.

NK Martin, P Vickerman, J Grebely, et al. Hepatitis C Virus Treatment for Prevention Among People Who Inject Drugs: Modeling Treatment Scale-Up in the Age of Direct-Acting Antivirals. Hepatology 58(5):1598-1609. November 2013.

J Grebely and GJ Dore. Can Hepatitis C Virus Infection Be Eradicated in People Who Inject Drugs? (Commentary). Antiviral Research 104:62-72. April 2014.