CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

Session S-9 Symposium

Room 6E

4:00 pm– 6:00 pm HCV: New Frontiers and Controversies 179 Pathogenesis of Acute HCV Infection Ashwin Balagopal

Johns Hopkins University School of Medicine, Baltimore, MD, US Hepatitis C virus (HCV) infects 170 million people worldwide; most persons who are acutely infected will develop chronic infection, while 25% of people will spontaneously clear the virus. Because of common routes of transmission, HIV-1/HCV co-infection is highly prevalent. In HIV-1/HCV co-infection, the likelihood of spontaneous clearance is worsened. While we do not fully understand the mechanisms underlying spontaneous clearance versus viral persistence, recent progress has uncovered a number of contributing factors: persons at highest risk for developing chronic HCV infection are older, male, and of African descent. The racial predisposition is partly explained by recently discovered genetic markers in the Interferon Lambda ( IFNL ) gene locus, which are among the most strongly predictive genetic markers of susceptibility to an infectious disease. There has been some progress in identifying the cause underlying the IFNL cluster of genes, although questions still remain. Notable defects have also been found in cytotoxic T cells and NK cells that may contribute to HCV persistence. When studying hepatitis C under the microscope, we have seen evidence of clustered infection of hepatocytes, strongly suggesting that local processes foster hepatitis C propagation. Several clinical controversies have emerged in the management of acute HCV infection. Although public health measures have been effective at attenuating the incidence of acute HCV transmission in urban centers, there is evidence that increased rates of injection drug use in non-urban and rural settings has resulted in emerging outbreaks in these settings. There has also been evidence of outbreaks of acute HCV among HIV-1 infected men who have sex with men. With respect to treatment in the era of direct-acting antivirals, there has been discussion about whether universal treatment should be recommended: currently, AASLD/IDSA guidelines continue to support a period of monitoring patients for spontaneous clearance. However, as therapies evolve, it is likely that more patients will be treated during the acute period. 180 HCV Treatment as Prevention: Challenges and Opportunities Gregory Dore University of New South Wales, Sydney, Australia Major recent advances in hepatitis C virus (HCV) therapeutic development, with highly curative well tolerated all oral regimens now available have raised the prospect that treatment could provide considerable prevention impact. Mathematical modelling has demonstrated that rapid scale-up of interferon-free direct acting antiviral (DAA) therapy among people who inject drugs (PWID) to levels of 4-8% treated per annumwould lead to near elimination of HCV within 20 in settings with a chronic HCV prevalence of 25-50%. Concerted efforts in several areas are required to enhance the feasibility of HCV treatment as prevention. HCV therapeutic regimens with pangenotypic activity, single daily dosing and short duration (4-6 weeks) would be optimum. HCV screening rates need to be increased, particularly among PWID and HIV-infected men who have sex with men (MSM). HCV treatment infrastructure needs to be broadened to provide access through community-based clinics, drug and alcohol services, harm reduction facilities, and prisons. Community engagement including peer-based worker involvement in HCV screening, disease assessment and treatment delivery programs needs to be developed. Finally, drug price reform and public health advocacy will be instrumental to enable levels of HCV treatment coverage among marginalised populations that would provide major prevention impacts. Two major Australian HCV treatment as prevention initiatives will be described. The SToP-C project is evaluating HCV treatment as prevention in the prison system in New South Wales. A surveillance phase will monitor HCV incidence in four prisons (two maximum security, two medium security), followed by rapid scale-up of interferon-free DAA therapy with ongoing monitoring of HCV transmission. The CEASE project is evaluating HCV treatment as prevention within the HIV-infected population, predominantly MSM. Components include characterisation of the HIV/HCV population through an observational database (CEASE-d), surveillance for newly acquired HCV and modelling (CEASE-m), education of HIV prescribers in HCV management (CEASE-e) and scale-up of HCV treatment (CEASE-t). 181 HCV Therapeutics: It’s the Virus, Stupid Mark Sulkowski Johns Hopkins University School of Medicine, Baltimore, MD, US In 1986, Hoofnagle and coworkers reported the initial use of recombinant interferon alfa to treat patients with non-A, non-B hepatitis, demonstrating improvement in serum ALT levels in most patients. Over the ensuing decade, hepatitis C virus was identified cause of non-A, non-B hepatitis and molecular techniques were applied to test HCV RNA response during therapy, and it became apparent that the majority of persons treated with interferon alfa did not achieve HCV eradication (Sustained Virologic Response, SVR). Further, the poor safety and tolerability of interferon alfa prohibited treatment of many HCV-infected patients. In 1995, several studies demonstrated that the addition of the guanosine nucleoside analogue ribavirin to interferon led to higher SVR rates despite the lack of HCV RNA reduction with ribavirin monotherapy. In 2003, the first report of a potent direct acting antiviral (DAA), an inhibitor of the HCV NS3/4A protease known as BILN 2061, was published, and, in 2011, two HCV NS3/4A protease inhibitors, telaprevir and boceprevir, entered clinical practice as part of “triple therapy” with interferon/ribavirin, and, while toxicity limited their effectiveness, the DAA era was launched. In 2012, proof of HCV eradication by the interferon-free, combination of a HCV NS3/4A protease inhibitor and a NS5A inhibitor was published. In 2015, multiple, interferon-free, combinations of DAAs targeting HCV nonstructural proteins (e.g.,NS3/4A protease, NS5B polymerase and NS5A) have been approved by regulatory authorities. Remarkably, 12 weeks of treatment with these DAA regimens can deliver high rates of HCV cure (> 95%) with minimal adverse effects in diverse range of patients including those with HIV coinfection and decompensated liver disease. In this era, historical barriers to HCV cure linked to the necessity for interferon alfa have been overcome. In their place, new challenges have emerged including the cure of persons with HCV genotype 3 infection and those with advanced liver disease among whom SVR rates are lower than observed in other patient groups as well as the specter of HCV drug resistance in persons who fail to achieve HCV eradication following treatment. However, the greatest challenge will be the need to rapidly translate these remarkable advances in HCV therapeutics to the large global community of persons chronically infected with hepatitis C to prevent the development of life-threatening complications of HCV disease. 182 HCV Therapeutics: Big Sticks With Big Stickers Marion G. Peters University of California San Francisco, San Francisco, CA, US The new all oral direct acting antiviral agents (DAA) for HCV have permanently changed the treatment landscape for patients with Hepatitis C (HCV). Because of better tolerability, fewer side effects and shorter length of therapy, the majority of HCV patients are now eligible for treatment and most patients who know they have HCV are eager to be treated. However these drugs are expensive. Health care systems throughout the world are trying to determine how and to whom to provide HCV therapy. While those with severe disease clearly are in greatest need, recent data has revealed benefits in morbidity and mortality even in those without severe fibrosis. In addition, extrahepatic benefits accrue with

Oral Abstracts

195

CROI 2015