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ID Week 2012: Hepatitis C
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Report written for NATAP by David H. Shepp, MD Associate Professor of Medicine Hofstra North Shore-LIJ School of Medicine North Shore University Hospital - Manhasset, NY
New Treatment Regimens for HIV/Hepatitis C Co-Infection. Between one third and one quarter of all HIV-infected individuals are co-infected with HCV. Progression of fibrosis is accelerated in co-infected patients, making the need for effective therapies great in this population. Cure rates with ribavirin and pegylated interferon are reduced. Limited data suggests improved responses to triple therapy with the first generation HCV protease inhibitors telaprevir or boceprevir, but at a cost of increased toxicity, regimen complexity and numerous drug-drug interactions. This treatment still leaves a cure inaccessible to many co-infected patients. Studies of new directly-acting antivirals (DAAs) suggest treatment will soon be much easier and more effective in mono-infected patients, but data in co-infected patients are extremely limited. Rodriguez-Torres et al. reported the results of a pilot study of 12 weeks of triple therapy with the HCV NS5B nucleotide polymerase inhibitor sofosbuvir (SOF), ribavirin and pegylated interferon in 23 co-infected patients [1]. Participants were HCV treatment-naive, non-cirrhotic and could be on antiretroviral therapy (ART) with tenofovir, emtricitabine and any of 5 commonly used 3rd agents. All HCV genotypes were permitted, but 15 were genotype 1a and four 1b. A cure (SVR12) was achieved in 91%. The 2 treatment failures included one relapse after completing therapy and one withdrawn consent after 6 weeks. Adverse effects were similar to those commonly seen with ribavirin and peginterferon or antiretroviral agents. This is a very small study but the results are dramatic for this group of predominantly genotype 1 patients. More data will will be needed to confirm these results, to identify optimal therapy for genotypes other than 1 and for cirrhotic patients. It is anticipated that SOF will be approved for clinical use by the end of 2103, making this regimen available for many co-infected patients in need of more effective therapy.
IDSA: Sofosbuvir and Peginterferon Alfa-2a/Ribavirin for Treatment-Naïve Genotype 1-4 HCV-Infected Patients Who Are Coinfected With HIV - (10/07/13)
New Regimens for Non-Genotype 1 HCV Mono-infection. Standard treatment for genotype 2 and 3 is ribavirin and peginterferon for 24 weeks because the currently available HCV protease inhibitors are less active against these genotypes. The combination of ribavirin and peginterferon with a DAA active against these genotypes may improve response rates, allow for shorter courses of therapy or both. Daclatasvir (DCV) is a potent NS5A inhibitor with activity against HCV genotypes 2 and 3. The COMMAND study compared triple therapy with DCV, ribavirin and peginterferon for 12 or 16 weeks to standard treatment for genotype 2 or 3 infection [2]. There were 151 treatment-naive participants enrolled, with approximately 25 patients with each genotype in each of the 3 treatment arms. Eighty-three percent in the two DCV arms had a protocol-defined response (HCV RNA <25 IU/mL at 4 weeks and undetectable at 10 weeks) and received the intended duration of triple therapy. The rest received 12 weeks of triple therapy and 12 weeks of ribavirin and peginterferon. For genotype 2, SVR24 rates for 12 and 16 weeks of triple therapy were 88% and 83%, respectively compared to 63 for standard treatment. For genotype 3 the corresponding SVR24 rates were 69%, 70% and 59%. In the DCV arms, virologic failure was mostly due to relapse, which was more common with genotype 3, underlying cirrhosis or the presence of baseline resistance polymorphisms in the NS5A gene. Adverse events were frequent but very similar with DCV triple therapy and standard treatment. This study suggests triple therapy with DCV modestly increases SVR rates with a 12 week treatment course compared to 24 weeks of ribavirin and peginterferon. Genotype 3 is harder to cure and may require other approaches to reduce relapse and improve overall responses. Studies of combinations of pangenotypic DAAs will be of interest for genotype 3, which is emerging as the new hard to treat genotype in the era of DAAs developed primarily to treat genotype 1.
IDSA: DACLATASVIR COMBINED WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN FOR 12 OR 16 WEEKS IN PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 2 OR 3 INFECTION: COMMAND GT 2/3 STUDY - (10/10/13)
Interferon-Free Regimens. Interferon has been a component of all treatment for hepatitis C (HCV) for more than 20 years. It also has been a major cause of limited treatment success because it causes numerous adverse events, requires injection and has variable activity against different HCV genotypes and in patients with different genetic backgrounds. Adding ribavirin to interferon improves responses, but contributes additional adverse effects, especially anemia, and increases pill burden. With the development of numerous investigational DAAs, treatment of HCV without either interferon or ribavirin will soon be possible. Everson et al. reported an interim analysis of an all oral DAA regimen consisting of DCV, a potent NS5A inhibitor, asunaprevir, a 2nd generation HCV protease inhibitor and one of two doses (75 or 150 mg bid) of BMS 791325, a non-nucleoside NS5B inhibitor given for either 12 or 24 weeks [3]. Sixty-six treatment-naive, HCV genotype 1 mono-infected patients were randomized into the four treatment arms. Three-quarters had genotype 1a. SVR12 was achieved in 89-94% with no apparent differences between the two doses of 791325 or the two durations of treatment. Only two viral breakthroughs and one relapse occurred. There were no grade 3/4 laboratory abnormalities and no patient discontinued for adverse effects.
IDSA: Interim Analysis of an Interferon (IFN)- and Ribavirin (RBV)-Free Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 in Treatment-Naive, Hepatitis C Virus Genotype 1-Infected Patients - (10/10/13)
One of the most promising interferon-free regimens is the two drug combination of the nucleotide NS5B polymerase inhibitor sofosbuvir (SOF) and DCV. In small, preliminary trials, this regimen produced high rates of SVR for all genotypes studied. Sulkowski et al. reported their experience using this regimen in one of the most difficult-to-treat patient groups, genotype 1 patients who failed triple therapy with ribavirin, peginterferon and a first generation HCV protease inhibitor, either telaprevir or boceprevir [4]. The 41 enrolled in the trial were a mixture of non-responder, relapser and breakthrough patients. Cirrhotics and those who failed prior therapy due to adverse events were not included. Eighty percent were genotype 1a and almost all had IL28B T alleles, factors that result in lower responses to many HCV regimens. All received SOF and DCV for 24 weeks. Additionally, participants were randomized to add or omit open label ribavirin. There were no discontinuations for adverse events and no virologic breakthroughs. One participant had missing data at post-treatment week 12. All others achieved SVR12. No grade 3/4 AST/ALT elevations and only 2 grade 3/4 adverse events of any kind were recorded. This very powerful regimen produced very high cure rates in difficult-to-treat patients with prior HCV protease failure and unfavorable HCV and IL28B genotypes. The addition of ribavirin did not appear to be necessary. Unfortunately, as it stands now, this combination will not be studied in large scale clinical trials. Instead, SOF will be studied with another NS5A inhibitor and DCV will be studied with other DAAs.
These studies show that very high rates of HCV cure are possible with certain combinations of 2 or 3 DAAs given for 12 to 24 weeks, even for hard to treat patients with genotype 1a or prior treatment failure. Interferon and ribavirin are not required and their elimination enhances safety and tolerability. Future clinical use of these very promising experimental regimens should greatly improve treatment and health outcomes in HCV-infected individuals.
Another exploratory study of an interferon-free regimen showed not all combinations will yield high SVR rates for all HCV genotypes. The SOUND-C3 study combined the 2nd generation HCV protease inhibitor faldaprevir, the non-nucleoside NS5B inhibitor deleobuvir and ribavirin to treat mono-infected patients with HCV genotype 1a and the IL28b CC genotype or genotype 1b (with any IL28B genotype) [5]. Sixteen weeks of treatment was highly effective for the 1b patients, failing to produce an SVR12 in only 1 of 20. However, it was much less effective for the 1a patients, leading to SVR in only 2 of 12. Viral rebound and relapse were both frequent in this latter group. Adverse effects led to discontinuation in 3 and hyperbilirubinemia was common due to inhibition of UTG1A1 by faldaprevir. This study highlights the important differences between genotype 1a and 1b infection in responsiveness to treatment. Genotype 1b responds readily to many two and three drug DAA combinations, but genotype 1a evolves resistance to many DAAs, leading to viral breakthrough or relapse. A combination of two low genetic barrier DAAs does not seem sufficient to suppress resistant variants. Adding ribavirin does not necessarily improve responses. Combinations of two potent DAAs including a high genetic barrier agent like sofosbuvir or three potent DAAs may be needed for optimal response in hard to treat HCV such as genotype 1a or 3.
IDSA: Optimization of an Interferon-free Hepatitis C Virus Therapy Regimen Containing the HCV NS3/4A Protease Inhibitor Faldaprevir, the Non-nucleoside NS5B Inhibitor Deleobuvir, and Ribavirin for Genotype-1b-infected Patients - (10/07/13)
Investigational interferon-free regimen demonstrates undetectable hepatitis C virus in all patients reaching end of treatment in ongoing Phase II trial: BI/Presidio Faldaprevir + PPI-668 + Deleobuvir - (10/10/13)
Health and Mortality in HCV-infected Individuals. With the impending approval of new DAAs, treatment of HCV will undergo dramatic changes, making a cure possible in many more patients. About half of the estimated 3-4 million cases in the US are undiagnosed. To improve diagnosis and facilitate linkage to care, the CDC and USPSTF have endorsed routine testing of all persons aged 45-65 ('baby boomers") who have the highest HCV prevalence in the US. Individuals with HCV infection suffer from both liver-related and non-liver related morbidity and mortality. Identifying more individuals through expanded testing and linkage to care could have profound effects on health outcome in HCV-infected individuals. Investigators from the New York City (NYC) Department of Health cross-matched reportable disease and vital statistics databases to identify premature death (at age <65) and cause of death among individuals with HCV, HIV/HCV co-infection or neither, who died in NYC between 2000 and 2011 [6]. The median age at death was 52, 59, and 78 for the HIV/HCV, HCV, and neither infection groups.
Two-thirds of deaths in the HCV mono-infection group and 95% in the co-infection group were premature. Compared to the group with neither infection, those with HCV mono-infection had an 8.7-and 3.5-fold increase in risk of death due to liver cancer and cirrhosis, respectively. Still, only a quarter of all deaths in the HCV mono-infection group were attributed to liver-related causes.
Cardiovascular disease and non-liver cancer were the most commonly reported causes of death. Drug-related deaths were increased in both the HCV and HIV/HCV groups. The HIV co-infected group had a 2.2-fold increased risk of death due to liver cancer, but not cirrhosis. However, competing mortality was extremely high in the co-infection group, as 53% of deaths were attributed to HIV/AIDS. In a related abstract, CDC investigators assessed mortality and cause of death from 2006-2010 in the Chronic Hepatitis Cohort Study, a cohort with almost 12,000 chronic HCV patients, comparing it to a large database of 12 million US death certificates [7]. All cause mortality was increased 12-fold and median age of death was 15 years younger in patients with HCV. As expected, liver-related causes of death were increased markedly (6-86-fold) in the hepatitis cohort, but many other causes, including circulatory, respiratory, digestive and genitourinary diseases, diabetes, trauma and mental health disorders were also significantly increased compared to the compared to the general population.
These studies document the high rate of premature mortality in HCV-infected individuals, and especially with HIV/HCV co-infection. Deaths due to liver disease are increased but premature deaths due to other causes still predominate. Programs to increase diagnosis and linkage to care, and the lure of simple new treatments that cure most infections will bring many new HCV-infected individuals into care. This will create a unique opportunity to reduce not only liver-related mortality but also to reduce premature deaths due to many other preventable and treatable conditions such as cardiovascular disease, chronic pulmonary disease, non-liver cancer diabetes and psychiatric illness and drug abuse.
IDSA: Hospitalization among Persons with Chronic Hepatitis C Virus Infection in the United States: The Chronic Hepatitis Cohort Study (CHeCS), 2006-2010 - (10/11/13)
IDSA:Mortality among Persons in Care with Hepatitis C Virus Infection-Chronic Hepatitis Cohort Study (CHeCS), 2006 -2010: HCV deaths grossly Underreported mortality rate 12 times higher than the general population, average age of death is 59 for HCV & 74 for general population, a 15 year difference - (10/11/13)
IDSA: Causes of Death among People with Hepatitis C in NYC, 2000-2011 - (10/10/13)
HCV at IDSA & ICAAC - 23 Reports - (10/11/13)
References.
1. Rodriguez-Torres M, Rodriguez-Orengo J, Gaggar A, et al. Sofosbuvir and Peginterferon alfa-2a/Ribavirin forTreatment-Naïve Genotype 1-4 HCV Infected Patients who are HIV Coinfected with HIV. ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 714.
2. Dore G, Lawitz E, Hezode C et al. Daclatasvir Combined With Peginterferon Alfa-2a and Ribavirin for 12 or 16 Weeks in Patients With Hepatitis C Virus Genotype 2 or 3 Infection: COMMAND GT 2/3 Study. ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 1827.
3. Everson GT, Sims KD, Rodriguez-Torres M, et al. Interim Analysis of an Interferon (IFN)- And Ribavirin (RBV)-Free Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 In Treatment-Naive, Hepatitis C Virus Genotype 1-Infected Patients. ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 1828.
4. Sulkowski M, Gardiner D, Rodriguez-Torres M, et al. Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) In Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC). ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 1357.
5. Mantry P, Schuchmann M, Lohse AW, et al. Optimization of an Interferon-free Hepatitis C Virus Treatment Regimen Containing the NS3/4A Protease Inhibitor Faldaprevir, the Non-nucleoside NS5B Inhibitor BI207127, and Ribavirin for Genotype 1b-infected Patients. ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 715.
6. Mahajan R, Xing J, Liu S,et al. Rates and Causes of Mortality among People in Care with Hepatitis C Virus Infection - Chronic Hepatitis Cohort Study (CHeCS), 2006- 2010. ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 1774.
7. Pinchoff J, Drobnik A, Fuld J, et al. Trends in HCV and Liver Related Causes of Death among People with HCV Infection in NYC, 2000 to 2010. ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 1777.
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