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1
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Garbuzenko DV. [The role of antiviral therapy in the management of patients with liver cirrhosis associated with chronic HBV and HCV infection]. Vopr Virusol 2021; 66:331-339. [PMID: 34738448 DOI: 10.36233/0507-4088-70] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 11/04/2021] [Indexed: 12/12/2022]
Abstract
The formation of the liver cirrhosis (LC) is an unfavorable event of the natural history of chronic liver diseases being accompanied by complications that often cause a fatal outcome. The study of the effectiveness of drugs that affect various etiopathogenetic mechanisms of this condition is an urgent problem of modern hepatology.The aim of the review was to show the role of antiviral therapy (AVT) in the management of patients with LC associated with chronic HBV (hepatitis B virus) and HCV (hepatitis C virus) infection.PubMed database, Google Scholar search engine, Cochrane Systematic Reviews, eLIBRARY.RU electronic scientific library, as well as the reference lists of articles were used to search for scientific articles. The relevant objectives of the review of the publications were identified for the period since 2000 up to 2021 by the search queries as following: «liver cirrhosis», «liver fibrosis», «chronic HBV infection», «chronic HCV infection», «portal hypertension», «treatment». The inclusion criteria were restricted to the management of patients with LC associated with chronic HBV and HCV infection.Current guidelines recommend indefinite treatment of patients with HBV-associated LC with nucleos(t)ide analogues regardless of serum HBV DNA levels, while the modern concept of using direct-acting antiviral drug combinations has become the standard treatment for HCV-associated cirrhosis. Studies have shown the ability of AVT to inhibit and reverse fibrotic processes in LC associated with chronic HBV and HCV infection. It has also been reported that HBV/HCV eradication prior to orthotopic liver transplantation improves long-term overall survival.This, in turn, can reduce the severity of portal hypertension and decrease the risk of associated complications, as well as normalize liver function. Thus, ensuring the availability of drugs for those in need of AVT will not only help prevent the development of LC, but also improve the quality of life and increase its expectancy of patients suffering from this disease.
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Affiliation(s)
- D V Garbuzenko
- FSBEI HE «South Ural State Medical University» of the Ministry of the Health of Russia
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2
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KASL clinical practice guidelines for liver cirrhosis: Ascites and related complications. Clin Mol Hepatol 2018; 24:230-277. [PMID: 29991196 PMCID: PMC6166105 DOI: 10.3350/cmh.2018.1005] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 04/06/2018] [Indexed: 02/07/2023] Open
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Abstract
Treatment with direct-acting antiviral agents has revolutionized the approach to hepatitis C. We are now able to obtain high sustained virological response (SVR) rates, even in the historically difficult-to-treat patient populations. SVR translates into improved clinical outcomes, particularly overall and liver-related mortality, and benefits are more striking in patients with cirrhosis. A 2.5- to 5-fold risk reduction in the incidence of hepatocellular carcinoma and improvement in complications derived from portal hypertension have been reported as well. It is hypothesized that the benefits from SVR occur largely due to regression of fibrosis, which arises from the halt on the fibrogenic stimuli and activation of extracellular matrix reabsorption signals. Non-invasive markers of fibrosis are being utilized to assess regression, but it is still unclear how accurate they are in this clinical scenario. Interventions aiming to improve liver wellness and screening for cirrhosis-related complications should continue to be the norm after SVR.
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Weiler N, Zeuzem S, Welker MW. Concise review: Interferon-free treatment of hepatitis C virus-associated cirrhosis and liver graft infection. World J Gastroenterol 2016; 22:9044-9056. [PMID: 27895394 PMCID: PMC5107588 DOI: 10.3748/wjg.v22.i41.9044] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 08/09/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.
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5
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Mesquita F, Santos ME, Benzaken A, Corrêa RG, Cattapan E, Sereno LS, Naveira MCM. The Brazilian comprehensive response to hepatitis C: from strategic thinking to access to interferon-free therapy. BMC Public Health 2016; 16:1132. [PMID: 27806712 PMCID: PMC5094040 DOI: 10.1186/s12889-016-3784-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 10/19/2016] [Indexed: 11/21/2022] Open
Abstract
Background Hepatitis C affects over 185 million people around the world. This silent disease is responsible for up to 700,000 deaths per year. Despite the scientific revolution in diagnosis and treatment, hepatitis C control remains a huge challenge due to the cost of effective medications. In response to the global outcry of hepatitis epidemic and the need to improve the nation’s public health response, the Ministry of Health of Brazil revolutionized hepatitis C treatment by incorporating highly effective drugs that can be accessed through sustainable and universal means. Discussion This paper describes the unique process of implementing evidence-informed policy to respond to hepatitis C epidemic through the update of hepatitis C treatment in Brazil based on the estimate of disease prevalence, current international guidelines, and the cost-effectiveness impact in the Brazilian Unified Health System. Through a debate of an experience report, the authors underlie the strategic plan implemented according to the situation analysis that emphasized the need to improve its current response over a relatively short-term period. The comprehensive response is detailed comprising three main objectives: improve treatment outcomes by evaluating and incorporating new and effective medications at a sustainable price; elaborate on clinical guidelines to treat hepatitis C patients; and develop awareness and diagnosis campaigns targeted at the population of interest. In this scenario, Brazil was able to obtain an unprecedented discount for a high-medium income country; provided treatment to more than 7000 individuals in the last 2 months of 2015; and expects to treat 38,000 new patients in 2016. Summary The remarkable process applied in Brazil was developed according to epidemiological data and scientific evidence, and it was motivated by the engagement of the country in the Sustainable Development Goals, which may inspire other developing countries to identify ways to achieve these goals by 2030.
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Affiliation(s)
- Fabio Mesquita
- Department of STI, AIDS and Viral Hepatitis, Secretariat of Health Surveillance, Ministry of Health, Setor Administrativo Federal Sul 02-Bloco F-Ed. Premium Torre I, Brasília, 70070-600, Federal District, Brazil
| | - Melina Erica Santos
- Department of STI, AIDS and Viral Hepatitis, Secretariat of Health Surveillance, Ministry of Health, Setor Administrativo Federal Sul 02-Bloco F-Ed. Premium Torre I, Brasília, 70070-600, Federal District, Brazil
| | - Adele Benzaken
- Department of STI, AIDS and Viral Hepatitis, Secretariat of Health Surveillance, Ministry of Health, Setor Administrativo Federal Sul 02-Bloco F-Ed. Premium Torre I, Brasília, 70070-600, Federal District, Brazil
| | - Renato Girade Corrêa
- Department of STI, AIDS and Viral Hepatitis, Secretariat of Health Surveillance, Ministry of Health, Setor Administrativo Federal Sul 02-Bloco F-Ed. Premium Torre I, Brasília, 70070-600, Federal District, Brazil
| | - Elisa Cattapan
- Department of STI, AIDS and Viral Hepatitis, Secretariat of Health Surveillance, Ministry of Health, Setor Administrativo Federal Sul 02-Bloco F-Ed. Premium Torre I, Brasília, 70070-600, Federal District, Brazil
| | - Leandro Soares Sereno
- Pan American Health Organization, World Health Organization, Avenida das Nações-Setor de Embaixadas Norte, Lote 19, Brasília, 70312-970, Federal District, Brazil
| | - Marcelo Contardo Moscoso Naveira
- Department of STI, AIDS and Viral Hepatitis, Secretariat of Health Surveillance, Ministry of Health, Setor Administrativo Federal Sul 02-Bloco F-Ed. Premium Torre I, Brasília, 70070-600, Federal District, Brazil.
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6
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Hathorn E, Elsharkawy AM. Management of hepatitis C genotype 4 in the directly acting antivirals era. BMJ Open Gastroenterol 2016; 3:e000112. [PMID: 27752338 PMCID: PMC5051320 DOI: 10.1136/bmjgast-2016-000112] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 08/10/2016] [Accepted: 09/07/2016] [Indexed: 12/14/2022] Open
Abstract
Genotype 4 chronic hepatitis C (G4 HCV) accounts for 13% of worldwide HCV infections; with 10 million people infected with the virus across the world. Up to the end of 2013, the only treatment option for G4 HCV was treatment with pegylated interferon and ribavirin for 24-48 weeks. Since late 2013, treatment of G4 HCV has been transformed by the licensing of many directly acting antiviral agents (DAA). It is an exciting time to be involved in the management of HCV generally and G4 particularly. Interferon-free DAA regimens are now a reality for G4 HCV. This review will highlight these developments and discuss the data behind the use of these drugs. It will also highlight future regimens that are likely to be available over the coming years.
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Affiliation(s)
- Emma Hathorn
- Liver Unit , University Hospitals Birmingham NHS Foundation Trust , Birmingham , UK
| | - Ahmed M Elsharkawy
- Liver Unit , University Hospitals Birmingham NHS Foundation Trust , Birmingham , UK
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7
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Optimum timing of treatment for hepatitis C infection relative to liver transplantation. Lancet Gastroenterol Hepatol 2016; 1:165-172. [PMID: 28404073 DOI: 10.1016/s2468-1253(16)30008-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 06/03/2016] [Accepted: 06/03/2016] [Indexed: 12/19/2022]
Abstract
The approval of direct-acting antiviral agents that may be given orally in an interferon-free regimen has greatly changed the landscape of treatment for hepatitis C virus (HCV) infection, especially for patients with the most severe disease, who have decompensated cirrhosis, or who are waiting for or have undergone liver transplantation. Treatment with interferon proved to be ineffective and poorly tolerated because of high risks of infection and transplant rejection. The availability of new drugs poses new questions about the optimum time to give treatment to prevent HCV recurrence, taking into account efficacy, tolerance, and drug-drug interactions. Treatment is acceptable before and after transplantation, but the two strategies have subtle differences. In this Review, we present the available data on the treatment of HCV infection before and after transplantation, and discuss new challenges for practice.
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8
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Omata M, Kanda T, Wei L, Yu ML, Chuang WL, Ibrahim A, Lesmana CRA, Sollano J, Kumar M, Jindal A, Sharma BC, Hamid SS, Dokmeci AK, Mamun-Al-Mahtab, McCaughan GW, Wasim J, Crawford DHG, Kao JH, Yokosuka O, Lau GKK, Sarin SK. APASL consensus statements and recommendation on treatment of hepatitis C. Hepatol Int 2016; 10:702-726. [PMID: 27130427 PMCID: PMC5003907 DOI: 10.1007/s12072-016-9717-6] [Citation(s) in RCA: 153] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 02/18/2016] [Indexed: 12/18/2022]
Abstract
The Asian-Pacific Association for the Study of the Liver (APASL) convened an international working party on the "APASL consensus statements and recommendation on management of hepatitis C" in March, 2015, in order to revise "APASL consensus statements and management algorithms for hepatitis C virus infection (Hepatol Int 6:409-435, 2012)". The working party consisted of expert hepatologists from the Asian-Pacific region gathered at Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed and debated to draft a revision. Participants of the consensus meeting assessed the quality of cited studies. Finalized recommendations on treatment of hepatitis C are presented in this review.
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Affiliation(s)
- Masao Omata
- Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-Shi, Yamanashi, 400-8506, Japan.
- The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Tatsuo Kanda
- Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Lai Wei
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
| | - Ming-Lung Yu
- Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Wang-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Alaaeldin Ibrahim
- GI/Liver Division, Department of Internal Medicine, University of Benha, Benha, Egypt
| | | | - Jose Sollano
- University Santo Tomas Hospital, Manila, Philippines
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Saeed S Hamid
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - A Kadir Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Mamun-Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, 1000, Bangladesh
| | - Geofferey W McCaughan
- Centenary Institute, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia
| | - Jafri Wasim
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Darrell H G Crawford
- School of Medicine, University of Queensland, Woolloongabba, QLD, 4102, Australia
| | - Jia-Horng Kao
- National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Osamu Yokosuka
- Graduate School of Medicine, Chiba University, Chiba, Japan
| | - George K K Lau
- The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, China
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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9
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Stasi C, Silvestri C, Voller F, Cipriani F. The epidemiological changes of HCV and HBV infections in the era of new antiviral therapies and the anti-HBV vaccine. J Infect Public Health 2016; 9:389-395. [PMID: 26148849 DOI: 10.1016/j.jiph.2015.05.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Revised: 04/24/2015] [Accepted: 05/16/2015] [Indexed: 12/14/2022] Open
Abstract
The World Health Organization (WHO) resolution adopted in 2010 recognized viral hepatitis as a global health problem. In April 2014, for the first time, the WHO produced guidelines for the screening, care and treatment of persons with hepatitis C infections. In May 2014, a follow-up resolution urged WHO Member States to develop and implement a national strategy for the prevention, diagnosis and treatment of viral hepatitis based on the local epidemiological context. Although blood donor screening, which began in the early 1990s, has reduced the spread of the virus in the population, the WHO estimates that 150 million people are chronically infected with hepatitis C virus (HCV) and are at an increased risk of developing liver cirrhosis and hepatocellular carcinoma. In addition, 3-4 million people are infected each year. HCV treatment is currently evolving rapidly, and several drugs are in various stages of development. With regard to the hepatitis B virus (HBV), in March 2015, the WHO published the first guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection, which were designed to complement the recent guidelines on HCV. Although the introduction of an effective vaccine against the hepatitis B virus has reduced the prevalence and health and economic impact of hepatitis in industrialized countries, the WHO estimates that more than 2 billion people are HBV-infected and 350 million people are chronic carriers.
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Affiliation(s)
- Cristina Stasi
- Health Agency of Tuscany, 50141 Firenze, Italy; Department of Experimental and Clinical Medicine, University of Florence, 50134 Firenze, Italy.
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Mangia A, Arleo A, Copetti M, Miscio M, Piazzolla V, Santoro R, Squillante MM. The combination of daclatasvir and sofosbuvir for curing genotype 2 patients who cannot tolerate ribavirin. Liver Int 2016; 36:971-6. [PMID: 26786792 DOI: 10.1111/liv.13069] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 01/10/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND The current standard-of-care for treatment of HCV genotype 2 (GT-2) patients is the combination of sofosbuvir (SOF) with weight-based ribavirin (RBV). Patients with HCV GT-2 infection and ribavirin contraindications require the use of SOF plus NS5A inhibitor daclatasvir (DCV) which is not reimbursed everywhere. METHODS We conducted an open-label observational, prospective study on a subgroup of GT-2 patients either naïve or treatment experienced (TE) with contraindications to the use of RBV. Patients with cirrhosis of Child-Pugh-Turcotte (CPT) class A and B or advanced fibrosis with comorbidities were included. They were assigned to receive 12 or 24 weeks of SOF/DCV. The primary end point of the study was sustained virological response (SVR) defined as HCV RNA levels <12 IU/ml, 12 weeks post treatment. RESULTS Out of 106 patients with GT-2 who received treatment at our unit from July 2014 to June 2015, 20 (18.8%) patients, whose treatment could not be deferred, were ribavirin intolerant; 19 received SOF/DCV combination for 12 or 24 weeks. The majority of the patients was men, 58% had cirrhosis, and 58% were TE. All treated patients achieved SVR regardless of treatment duration. The most common adverse events (AEs) were fatigue, headache and nausea. No discontinuations due to AEs were observed. Two patients had oesophageal bleeding but continued treatment and achieved SVR; one patient developed HCC 12 weeks post treatment, but remained HCV RNA undetectable. CONCLUSIONS This study supports the use of SOF/DCV for 12 weeks in non-cirrhotics or 24 weeks in cirrhotic GT-2 patients who cannot tolerate RBV, including those with decompensated disease.
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Affiliation(s)
- Alessandra Mangia
- Liver Unit, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy
| | - Andrea Arleo
- Liver Unit, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy
| | - Massimiliano Copetti
- Biostatic Unit, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy
| | - Maria Miscio
- Liver Unit, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy
| | - Valeria Piazzolla
- Liver Unit, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy
| | - Rosanna Santoro
- Liver Unit, IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy
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11
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Abstract
PURPOSE OF REVIEW The aim of this review was to define the implication of hepatitis C virus (HCV) eradication in patients with cirrhosis. RECENT FINDINGS Sustained virologic response (SVR) is associated with a favourable outcome in patients with cirrhosis especially in the presence of regression of cirrhosis but also with extrahepatic outcomes regarding health-related quality of life, risk of diabetes, risk of cardiovascular diseases and control of HIV replication by antiretroviral therapy. In patients with decompensated cirrhosis identifying the point of no return where viral eradication is not followed by clinical improvement is extremely relevant. A strict follow-up is needed in order to early diagnose HCC and signs of liver dysfunction, even after SVR, not only in patients with histological diagnosis of cirrhosis but also in those with advanced disease identified by liver stiffness measurements or by noninvasive methods. SUMMARY Eradication of HCV is associated with regression or 'freezing' of cirrhosis even if it is still unknown the point of no return where this has no benefit for the patient. Nevertheless, in patients with cirrhosis, follow-up should be pursued after eradication of HCV. In addition, HCV eradication has several extrahepatic benefits.
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12
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Abstract
BACKGROUND Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-associated liver cirrhosis is a major indication for liver transplantation. This concise review gives an overview about current interferon (IFN)-free treatment options before and after liver transplantation in HBV- or HCV-associated liver disease. METHODS A PubMed database search using the terms hepatitis B, hepatitis C, cirrhosis, and liver transplantation was performed to identify significant clinical studies as well as national and international guidelines. RESULTS Studies investigating IFN-free treatment in patients with decompensated HBV as well as in HCV-associated cirrhosis are scarce. Hepatic recompensation during antiviral therapy seems more frequent in patients with HBV than in those with HCV-associated cirrhosis. Graft hepatitis B or C is characterized by an accelerated and unfavorable course. Graft infection prophylaxis is safe and efficacious in HBV-related liver transplantation. Eradication of HCV prior to liver transplantation prevents HCV graft infection, and IFN-free treatment of established HCV graft infection is safe and associated with high sustained virologic response rates. CONCLUSION Patients with HBV-associated cirrhosis should be treated prior to liver transplantation, and receive a continuing graft infection prophylaxis thereafter. Patients with HCV-associated decompensated cirrhosis may be considered as candidates for antiviral therapy prior to liver transplantation or may be treated subsequently.
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Affiliation(s)
- Martin-Walter Welker
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
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13
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Treatment of hepatitis C in patients with cirrhosis: remaining challenges for direct-acting antiviral therapy. Drugs 2016; 75:823-34. [PMID: 25943281 DOI: 10.1007/s40265-015-0401-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis C virus (HCV) infection is a major global health concern, resulting in significant morbidity and mortality. Treatment using interferon-based therapy in patients with HCV-related cirrhosis has been problematic due to toxicity and poor tolerability. Furthermore, interferon therapy is contraindicated in those with advanced cirrhosis or clinical decompensation, who are arguably the group most in need of viral eradication. The arrival of the direct-acting antiviral (DAA) era has resulted in the development of well-tolerated and highly effective interferon-free drug regimens that promise to dramatically change the therapeutic landscape for those with advanced HCV-related liver disease, including patients with clinical decompensation or pre-liver transplantation. Many successful DAA combinations have emerged; however, a number of challenges remain including the establishment of the optimal treatment duration, the ideal combination of drug classes and determining the role of ribavirin. Moreover, the identification of treatment-experienced patients with genotype 3 HCV cirrhosis as a difficult-to-treat subgroup is a significant impediment to overcome, as are those who have failed prior DAA therapy. Despite these barriers, the ongoing prolific development of safe and effective DAA combinations indicates the future is optimistic for the ultimate goal of HCV eradication.
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14
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Giannini EG, Savarino V. An independent validation of the mortality score for the short-term prognostic prediction in patients with chronic HCV infection and advanced liver disease. Gut 2016; 65:183-4. [PMID: 25804633 DOI: 10.1136/gutjnl-2015-309440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Accepted: 03/07/2015] [Indexed: 12/08/2022]
Affiliation(s)
- Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, IRCCS-Azienda Ospedaliera Universitaria San Martino-IST, University of Genoa, Genoa, Italy
| | - Vincenzo Savarino
- Gastroenterology Unit, Department of Internal Medicine, IRCCS-Azienda Ospedaliera Universitaria San Martino-IST, University of Genoa, Genoa, Italy
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Bruno S, Boccaccio V, Russo ML, Maisonneuve P. Is the benefit of treating patients with cirrhosis proven? Liver Int 2016; 36 Suppl 1:21-7. [PMID: 26725893 DOI: 10.1111/liv.13013] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 11/02/2015] [Indexed: 01/16/2023]
Abstract
Hepatitis C virus (HCV)-related cirrhosis is an extremely heterogeneous pathological condition with a wide spectrum of clinical manifestations, ranging from pre-clinical to compensated and decompensated stages, each of which is characterized by a different clinical outcome. To measure the benefit of a sustained virological response (SVR) with interferon (IFN)-based therapy, several studies have been performed in patients with compensated disease, while only a few have been performed in decompensated disease. Nevertheless, these studies have certain methodological weaknesses that may limit the accuracy of results. Access to new, more effective and safe direct acting antivirals (DAAs) has significantly changed these outcomes, with SVR rates that were not seen previously, making antiviral treatment available to patients with end-stage liver disease. However, the clinical benefit of treating patients with late stage disease is still poorly understood and must be investigated. The existence of a point of no return beyond which a SVR is not beneficial has not yet been determined. All of these issues are discussed in this review.
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Affiliation(s)
- Savino Bruno
- Department of Internal Medicine, Humanitas University Medicine, Rozzano, Italy.,Department of Internal Medicine, Humanitas Research Hospital, Rozzano, Italy
| | - Vincenzo Boccaccio
- Department of Internal Medicine, Humanitas Research Hospital, Rozzano, Italy
| | - Maria Luisa Russo
- Department of Internal Medicine, Humanitas Research Hospital, Rozzano, Italy
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
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16
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Ohkoshi S, Hirono H, Yamagiwa S. Direct antiviral agent treatment of decompensated hepatitis C virus-induced liver cirrhosis. World J Gastrointest Pharmacol Ther 2015; 6:114-119. [PMID: 26558145 PMCID: PMC4635151 DOI: 10.4292/wjgpt.v6.i4.114] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 07/15/2015] [Accepted: 09/10/2015] [Indexed: 02/06/2023] Open
Abstract
Recently, direct antiviral agents (DAAs) have been increasingly used for the treatment of chronic hepatitis C virus (HCV) infections, replacing interferon-based regimens that have severe adverse effects and low tolerability. The constant supply of new DAAs makes shorter treatment periods with enhanced safety possible. The efficacy of DAAs for treatment of compensated liver cirrhosis (LC) is not less than that for treatment of non-cirrhotic conditions. These clinical advantages have been useful in pre- and post-liver transplantation (LT) settings. Moreover, DAAs can be used to treat decompensated HCV-induced LC in elderly patients or those with severe complications otherwise having poor prognosis. Although encouraging clinical data are beginning to appear, the actual efficacy of DAAs for suppressing disease progression, allowing delisting for LT and, most importantly, improving prognosis of patients with decompensated HCV-LC remains unknown. Case-control studies to examine the short- or long-term effects of DAAs for treatment of decompensated HCV-LC are urgently need.
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Saxena V, Terrault N. Current Management of Hepatitis C Virus: Regimens for Peri-Liver Transplant Patients. Clin Liver Dis 2015; 19:669-88, vi. [PMID: 26466655 PMCID: PMC8115933 DOI: 10.1016/j.cld.2015.06.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C virus (HCV) infection currently remains the leading indication for liver transplant in the United States. However, recurrent HCV infection after transplant is universal in those who enter transplant with viremia resulting in reduced posttransplant graft and patient survival rates, caused in large part by progressive recurrent HCV disease. Therefore, successful treatment of HCV in the peri-transplant period, either before or after transplant, is paramount in ensuring improved posttransplant outcomes. This article reviews the experience to date treating HCV in wait-listed patients and liver transplant recipients and the unique challenges encountered when treating this population.
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Affiliation(s)
- Varun Saxena
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Norah Terrault
- Division of Gastroenterology and Hepatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
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12 weeks of interferon-based therapy is feasible in patients with hepatitis C-related cirrhosis and thrombocytopenia: A post hoc analysis of eltrombopag studies. Dig Liver Dis 2015; 47:864-8. [PMID: 26187555 DOI: 10.1016/j.dld.2015.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 05/29/2015] [Accepted: 06/21/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND A 24-48-week course of interferon-based therapy poorly tolerated in hepatitis C virus (HCV) cirrhosis patients with thrombocytopenia. Aim of the study was to identify patients at low-risk of liver-related complications over a 12-week course of interferon-based therapy. METHODS We assessed the rate of complications and death during the first 12 weeks of interferon-based therapy in HCV cirrhotics with thrombocytopenia (platelets ≤75×10(9)/L) enrolled in the ENABLE-1 and -2 phase 3 randomised controlled trials. RESULTS Overall, among 1441 patients, 89 complications (6.9%) and 10 deaths (0.7%) were observed within the first 12 weeks of therapy. At univariate analysis baseline albumin levels and Model for End Stage Liver Disease (MELD) score (≤35 g /L, p<0.001, and ≥10, p<0.001, respectively) were the only predictors associated with occurrence of complications and death. Of the 1026 patients with serum albumin >35 g/L (71.2%), one patient died (0.1%) and 17 experienced liver-related complications (1.7%). Among 667 patients with serum albumin >35 g/L and MELD score <10, no deaths occurred and 4 experienced liver-related complications (0.6%). CONCLUSION Among HCV cirrhotic patients with thrombocytopenia, albumin levels and MELD score can identify patients who may safely receive a 12-week course of interferon-based therapy with a low risk of complications.
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Ferenci P, Kozbial K, Mandorfer M, Hofer H. HCV targeting of patients with cirrhosis. J Hepatol 2015; 63:1015-1022. [PMID: 26100497 DOI: 10.1016/j.jhep.2015.06.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 06/09/2015] [Accepted: 06/10/2015] [Indexed: 12/15/2022]
Abstract
Interferon (IFN)-free treatments are now the treatment of choice for patients with chronic hepatitis C. Previously difficult to treat patients by IFN-containing treatments can now be treated safely by IFN-free therapies. More than 90% of hepatitis C genotype 1 and 4 patients with compensated cirrhosis or after orthotopic liver transplantation (OLT) can be cured by sofosbuvir combined with simeprevir, daclatasvir or ledipasvir, or by the paritaprevir/ritona-vir/ombitasvir/±dasabuvir (3D) combination. Addition of ribavirin confers to a minimal, if any, benefit to increase SVR. The need for ribavirin is controversial and remains to be studied. The optimal length of treatment is still unknown, and an individual approach may be needed. Most patients require only 12weeks of therapy. The safety of these drugs is not fully explored in patients with decompensated cirrhosis (Child-Pugh C), who should not be treated with protease inhibitors. In cirrhosis hepatitis C virus eradication does not necessarily mean a cure of the disease and patients regularly require follow-up. Drug-drug interactions with immunosuppressant in patients after OLT are easier to manage but still require attention. Better drugs are needed for genotype 3 patients.
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Affiliation(s)
- Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Karin Kozbial
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Harald Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Beinhardt S, Peck-Radosavljevic M, Hofer H, Ferenci P. Interferon-free antiviral treatment of chronic hepatitis C in the transplant setting. Transpl Int 2015; 28:1011-1024. [PMID: 25864369 DOI: 10.1111/tri.12577] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 03/03/2015] [Accepted: 04/02/2015] [Indexed: 12/16/2022]
Abstract
Interferon-based regimens with first-generation protease inhibitors have a limited efficacy and an unfavorable safety profile. Combination therapies with two or more second-generation direct-acting antivirals plus/minus ribavirin revolutionized treatment strategies in patients chronically infected with hepatitis C virus. In this rapidly evolving era, patients in the transplant setting benefit from interferon-free treatment regimens. Scientific societies can barely keep up with this development, making it necessary to update the clinical guidelines by the American and European Associations for the Study of Liver Diseases within short periods. This review presents and discusses the currently available data of the use of interferon-free treatment in the setting of liver transplantation. However, costs, different reimbursement strategies, and health-care options cannot be answered by guidelines and recommendations from scientific societies. Further investigator-initiated trials are needed to individualize treatment concepts.
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Affiliation(s)
- Sandra Beinhardt
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Harald Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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21
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Puri P, Anand AC, Saraswat VA, Acharya SK, Dhiman RK, Sarin SK, Singh SP, Chawla YK, Aggarwal R, Amarapurkar D, Arora A, Dixit VK, Sood A, Shah S, Duseja A, Kapoor D, Shalimar, Madan K, Pande G, Nagral A, Kar P, Koshy A, Puri AS, Eapen C, Thareja S. Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection in 2015. J Clin Exp Hepatol 2015; 5:221-38. [PMID: 26628840 PMCID: PMC4632106 DOI: 10.1016/j.jceh.2015.09.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 09/17/2015] [Indexed: 12/12/2022] Open
Abstract
Overall prevalence of HCV infection in India has been estimated to be approximately 1.3% in the general population. Recent introduction of sofosbuvir in India at a relatively affordable price has led to great optimism about prospects of cure for these patients. This drug is likely to form the backbone of current and future treatment regimes for HCV infection, displacing pegylated interferon. Availability of directly acting antiviral drugs (DAAs) has necessitated revision of INASL guidelines for the treatment of HCV published in 2014, as has happened across the world. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. Since only one DAA, sofosbuvir, is available in India, only two sofosbuvir-based regimes are possible: either dual drug therapy in combination with ribavirin alone for 6 months or triple drug therapy in combination with ribavirin and pegylated interferon for 3 months. The utility of these regimes in various situations has been discussed. Availability of a few other newer DAAs, expected in 2016, is expected to lead to more widespread use of these agents. Current guidance will be updated once newer DAAs, newer evidence with DAAs and 'real-life experience' with use of DAAs accumulate in India.
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Key Words
- ALT, alanine aminotransferase
- ANC, absolute neutrophil count
- AST, aspartate aminotransferase
- CH-C, chronic hepatitis C
- CTP, Child-Turcotte Pugh
- DAA, directly acting antiviral agents
- EIA, enzyme immunoassay
- ESRD, end stage renal disease
- EVR, early virological response
- HCV
- HCV, hepatitis C virus
- HIV, human immunodeficiency virus
- IFN-α, interferon alfa
- INASL, Indian National Association for Study of the Liver
- PCR, polymerase chain reaction
- Peg-IFNα, pegylated interferon alfa
- RBV, ribavirin
- RVR, rapid virological response
- SOC, standard of care
- SVR, sustained virological response
- Sof, sofosbuvir
- ULN, upper limit of normal
- anti-HCV, antibody to HCV
- antiviral therapy
- chronic hepatitis
- hepatitis C virus
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Affiliation(s)
- Pankaj Puri
- Department of Internal Medicine, Armed Forces Medical College, Pune 411040, India
| | - Anil C. Anand
- Department of Gastroenterology and Hepatology, Indraprastha Apollo Hospital, New Delhi 110076, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Subrat K. Acharya
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Shiv K. Sarin
- Institute of Liver and Biliary Sciences, VasantKunj, New Delhi 110070, India
| | - Shivaram P. Singh
- Department of Gastroenterology, SCB Medical College, Cuttack 753007, India
| | - Yogesh K. Chawla
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | | | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Vinod K. Dixit
- Department of Gastroenterology, Banaras Hindu University, Varanasi 221005, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College, Ludhiana 141001, India
| | - Samir Shah
- Department of Gastroenterology, Global Hospital, Mumbai 400078, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Dharmesh Kapoor
- Department of Gastroenterology, Global Hospital, Hyderabad 500004, India
| | - Shalimar
- Department of Gastroenterology, Artemis Hospital, Gurgaon 122001, India
| | - Kaushal Madan
- Department of Gastroenterology, Artemis Hospital, Gurgaon 122001, India
| | - Gaurav Pande
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Aabha Nagral
- Department of Gastroenterology, Jaslok Hospital, Mumbai 400026, India
| | - Premashis Kar
- Department of Gastroenterology, LNJP Hospital, and Maulana Azad Medical College, New Delhi 110002, India
| | - Abraham Koshy
- Department of Hepatology, Lakeshore Hospital, Cochin 682304, India
| | - Amarender S. Puri
- Department of Gastroenterology, GB Pant Hospital, New Delhi 110002, India
| | - C.E. Eapen
- Department of Gastroenterology, Christian Medical College, Vellore 632004, India
| | - Sandeep Thareja
- Department of Gastroenterology, Army Hospital (R & R), New Delhi 110010, India
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22
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Interferon-free therapy for hepatitis C: The hurdles amid a golden era. Dig Liver Dis 2015; 47:727-33. [PMID: 25937625 DOI: 10.1016/j.dld.2015.04.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 04/02/2015] [Indexed: 12/11/2022]
Abstract
The long awaited all-oral therapy for hepatitis C virus infection has officially been inaugurated by the registration of the hepatitis C nucleotide inhibitor sofosbuvir in a combination regimen with ribavirin. More recently, the oral array to treat hepatitis C has been enriched by the arrival of the NS5A inhibitors ledipasvir (also in a single formulation with sofosbuvir, Harvoni(®)) and daclatasvir; the protease inhibitor simeprevir, and the Viekirax(®)+Exviera™ regimen based on the ritonavir boosted protease inhibitor paritaprevir; the NS5A inhibitor ombitasvir, and the non-nucleoside inhibitor dasabuvir. Owing to the budget-breaking price of the newer oral medicines, the Italian National Health System elected to restrict reimbursement of oral anti-hepatitis C therapy to patients with advanced liver disease or transplanted organs, and those who are interferon unable, only. While this therapeutic strategy harmonizes with principles of distributive justice, at the same time it fuelled the argument of its doubtful cost-effectiveness, owing to the National Health System's reimbursement of the sole sofosbuvir+ribavirin regimen, which has suboptimal efficacy against the prevalent hepatitis C virus genotype 1b. As a consequence, we are left with a number of uncertainties regarding the optimal treatment modality for certain subgroups of hepatitis C patients, and the clinical benefits provided by hepatitis C virus clearance in patients with advanced liver disease.
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Mandorfer M, Kozbial K, Freissmuth C, Schwabl P, Stättermayer AF, Reiberger T, Beinhardt S, Schwarzer R, Trauner M, Ferlitsch A, Hofer H, Peck-Radosavljevic M, Ferenci P. Interferon-free regimens for chronic hepatitis C overcome the effects of portal hypertension on virological responses. Aliment Pharmacol Ther 2015; 42:707-718. [PMID: 26179884 DOI: 10.1111/apt.13315] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 03/14/2015] [Accepted: 06/22/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Portal hypertension is the strongest predictor of virological response to pegylated interferon (IFN)/ribavirin in patients with chronic hepatitis C (CHC)-related cirrhosis. AIM To investigate the effects of portal pressure assessed by hepatic venous pressure gradient (HVPG) measurement on virological responses in patients treated with IFN-free regimens outside of clinical trials. METHODS Fifty-six patients with CHC and cirrhosis who underwent HVPG measurement before starting an IFN-free therapy were retrospectively studied. Patients were treated with sofosbuvir in combination with daclatasvir (n = 32), ribavirin (n = 12) or simeprevir (n = 11), or the combination of simeprevir/daclatasvir (n = 1), for 12-24 weeks. RESULTS Hepatic venous pressure gradient values ≥10 mmHg and ≥16 mmHg were observed in 41 (73%) and 31 (55%) patients respectively. The distributions of treatment regimens and durations were comparable between patients with or without portal hypertension. Patients with portal hypertension had lower platelet counts and albumin levels, while bilirubin levels, INR, MELD and Child-Pugh scores were higher than in patients without portal hypertension. Importantly, rates of on-treatment virological response and viral kinetics, as well as the rates of sustained virological response 12 weeks after the end of therapy [96% (54/56)] were not affected by portal hypertension. Anti-viral therapy improved liver stiffness, platelet count, serum albumin and bilirubin levels, as well as prothrombin time. CONCLUSIONS This is the first study to demonstrate that IFN-free regimens overcome the negative effect of portal hypertension on virological responses and viral kinetics. Improvements in liver stiffness and platelet count might reflect an anti-portal hypertensive effect of IFN-free treatments.
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Affiliation(s)
- M Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - K Kozbial
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - C Freissmuth
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - P Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - A F Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - T Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - S Beinhardt
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - R Schwarzer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - M Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - A Ferlitsch
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - H Hofer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - M Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - P Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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Cholongitas E, Pipili C, Papatheodoridis G. Interferon-free regimens for the treatment of hepatitis C virus in liver transplant candidates or recipients. World J Gastroenterol 2015; 21:9526-33. [PMID: 26327760 PMCID: PMC4548113 DOI: 10.3748/wjg.v21.i32.9526] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Revised: 05/27/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
The goal of therapy in chronic hepatitis C virus (HCV) infection is sustained virological response (SVR) which reflects HCV eradication. Treatment against HCV has dramatically improved with the recent availability of direct-acting antivirals (DAAs) including sofosbuvir, simeprevir, daclatasvir, ledipasvir/sofosbuvir, paritaprevir/ombitasvir and dasabuvir. Carefully selected combinations of these DAAs offer the potential for highly effective all-oral safe regimens even for patients with decompensated cirrhosis or liver transplant (LT) recipients. Like all current protease inhibitors, simeprevir and paritaprevir should not be used in patients with Child C cirrhosis, while sofosbuvir and ledipasvir/sofosbuvir should not be given in patients with severe renal impairment and glomerular filtration rate less than 30 mL/min. Drug-drug interactions may still occur with the current DAAs particularly in post-LT patients, in whom simeprevir should not be co-administered with cyclosporine and dose adjustments of calcineurin inhibitors are required in case of regimens including the ritonavir boosted paritaprevir. Phase II clinical trials and real life cohort studies have shown that sofosbuvir based combinations are safe and can achieve improvements of clinical status, high SVR rates and even prevention of post-LT HCV recurrence in patients with decompensated cirrhosis or LT-candidates. In the post-LT setting, sofosbuvir based regimens and the combination of paritaprevir/ombitasvir and dasabuvir have been reported to be safe and achieve high SVR rates, similar to those in non-transplant patients, being effective even in cases with cholestatic fibrosing hepatitis. Ongoing clinical trials and rapidly emerging real life data will further clarify the safety and efficacy of the new regimens in these settings.
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25
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Bailly F, Pradat P, Virlogeux V, Zoulim F. Antiviral Therapy in Patients with Hepatitis C Virus-Induced Cirrhosis. Dig Dis 2015; 33:613-23. [PMID: 26159282 DOI: 10.1159/000375359] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Opportunities to treat infection with hepatitis C virus (HCV) are evolving rapidly. From the introduction of interferon (IFN)-α monotherapy in the early 1990s to the approval of telaprevir- and boceprevir-based triple therapies with pegylated (PEG)-IFN-α and ribavirin (RBV) in 2011, the chances of curing patients infected with HCV genotype 1 have improved dramatically to reach approximately 70%. Significant further improvements that may cure virtually all HCV patients with an all-oral, IFN-free regimen are becoming progressively available. Key Messages: Historically, a PEG-IFN/RBV combination therapy of patients with liver cirrhosis was associated with lower virological rates and a worse safety profile. The advent of the first protease inhibitor-based triple therapy was long expected, but the promise fell rapidly because of the numerous side effects and the requirement for intensive clinical management in cirrhotic patients. The newer direct-acting antivirals (DAAs) target the viral polymerase with either nucleos(t)ide analogues or nonnucleosidic inhibitors, the viral protease and the viral NS5A protein. Several clinical trials have now shown that a combination of sofosbuvir (nucleosidic polymerase inhibitor) with daclatasvir or ledipasvir (NS5A inhibitors), or sofosbuvir with simeprevir (protease inhibitor), or a combination of ABT-450 (protease inhibitor) with ritonavir (ABT-450/r), the nonnucleosidic polymerase inhibitor ABT-333 and the NS5A inhibitor ABT-267, can achieve a sustained virological response in up to 95% of naive patients or previously treated patients, even in those who failed prior treatment with first-generation protease inhibitors. The best treatment regimens enable the achievement of comparable results even in cirrhotics, while other regimens still require RBV or a longer treatment duration to achieve optimal results. This improved risk/benefit ratio justifies early access programs of IFN-free regimens for cirrhotic patients. The remaining difficult-to-treat patients are cirrhotics infected with HCV genotype 3 and those with decompensated cirrhosis, for whom novel DAA combinations should be evaluated in clinical trials. CONCLUSIONS As new DAAs are becoming available in early access treatment programs, treatment strategy studies are being performed to optimize treatment regimens with respect to the choice of DAAs and treatment duration, based on viral genotypes, prior treatment response and the presence of liver cirrhosis. In the near future, this should allow: (i) a decrease in the complications of HCV-induced cirrhosis, (ii) liver transplantations to be performed in virally cured patients, and (iii) the rescue of patients in the worst clinical situation (decompensated cirrhosis and HCV recurrence on liver graft).
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Affiliation(s)
- François Bailly
- Hepatology Department, Hospices Civils de Lyon, Lyon, France
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27
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Cortesi PA, Mantovani LG, Ciaccio A, Rota M, Mazzarelli C, Cesana G, Strazzabosco M, Belli LS. Cost-Effectiveness of New Direct-Acting Antivirals to Prevent Post-Liver Transplant Recurrent Hepatitis. Am J Transplant 2015; 15:1817-26. [PMID: 26086300 PMCID: PMC4946849 DOI: 10.1111/ajt.13320] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 01/02/2015] [Accepted: 01/14/2015] [Indexed: 01/25/2023]
Abstract
Preliminary studies on HCV-cirrhotics listed for transplant suggest that sofosbuvir in combination with ribavirin is very effective in promoting viral clearance and preventing disease recurrence. Unfortunately, the high cost of such treatment (€46 500 per 12 weeks of treatment) makes its cost-effectiveness questionable. A semi-Markov model was developed to assess the cost-effectiveness of sofosbuvir/ribavirin treatment in cirrhotic patients without HCC (HCV-CIRRH) and with HCC (HCV-HCC) listed for transplant. In the base-case analysis, the incremental cost-effectiveness ratio for 24 weeks of sofosbuvir/ribavirin was €44 875 per quality-adjusted life-year gained in HCV-CIRRH and €60 380 in HCV-HCC patients. Both results were above the willingness to pay threshold of €37 000 per quality-adjusted life-year. Our data also show that in order to remain cost-effective (with a 24-week treatment), any novel interferon-free treatment endowed with ideal efficacy should cost less than €67 224 or €95 712 in HCV-cirrhotics with and without HCC, respectively. The results shows that sofosbuvir/ribavirin therapy, given to patients listed for transplant, is not cost-effective at current prices despite being very effective, and new, more effective treatments will have little economic margins to remain cost-effective. New interferon-free combinations have the potential to revolutionize the treatment and prognosis of HCV-positive patients listed for transplant; however, without sustainable prices, this revolution is unlikely to happen.
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Affiliation(s)
- P. A. Cortesi
- Research Centre on Public Health (CESP), University of Milan-Bicocca, Monza, Italy
| | - L. G. Mantovani
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Naples, Italy
| | - A. Ciaccio
- Department of Surgical and Interdisciplinary Medicine, University of Milan-Bicocca, Monza, Italy
| | - M. Rota
- Department of Health Sciences, Centre of Biostatistics for Clinical Epidemiology, University of Milan-Bicocca, Monza, Italy
| | - C. Mazzarelli
- Department of Hepatology and Liver Unit, Niguarda Hospital, Milan, Italy
| | - G. Cesana
- Research Centre on Public Health (CESP), University of Milan-Bicocca, Monza, Italy
| | - M. Strazzabosco
- Department of Surgical and Interdisciplinary Medicine, University of Milan-Bicocca, Monza, Italy
- Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - L. S. Belli
- Department of Hepatology and Liver Unit, Niguarda Hospital, Milan, Italy
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Pipili C, Cholongitas E. Treatment of chronic hepatitis C in liver transplant candidates and recipients: Where do we stand? World J Hepatol 2015; 7:1606-16. [PMID: 26140081 PMCID: PMC4483543 DOI: 10.4254/wjh.v7.i12.1606] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 05/18/2015] [Accepted: 06/01/2015] [Indexed: 02/06/2023] Open
Abstract
The first generation direct antiviral agents (DAAs) highlighted substantial prognosis improvement among liver transplant (LT) candidates and recipients with recurrent hepatitis C virus (HCV) infection. During 2014, second generation DAAs are associated with high sustained virological response rates (> 95%), shortened duration courses and relatively few toxicities. In keeping with the currently available data, patients with decompensated cirrhosis awaiting LT is preferable to be treated with interferon-free, new generation DAAs, with or without ribavirin combinations. Although data about the safety of new DAAs combinations in this patient population are limited, sofosbuvir and daclatasvir pharmacokinetics do not appear to change significantly in moderate or severe liver impairment, while other new DAAs (simeprevir, asunaprevir) seem to be contraindicated in patients with severe liver impairment (Child-Pugh class C). On the other hand, sofosbuvir should not be given in patients with glomerular filtration rate ≤ 30 mL/min, but ongoing trials will clarify better this issue. With the objective that newer antiviral combinations will yield safer and more efficient manipulation of HCV recurrence post-transplant, the European Association for the Study of the Liver has recently updated its recommendations towards this direction. Nevertheless the new antivirals' high cost may be the biggest challenge to their implementation worldwide.
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Affiliation(s)
- Chrysoula Pipili
- Chrysoula Pipili, Division of Nephrology, Royal Infirmary of Edinburgh, Scotland EH16 4SA, United Kingdom
| | - Evangelos Cholongitas
- Chrysoula Pipili, Division of Nephrology, Royal Infirmary of Edinburgh, Scotland EH16 4SA, United Kingdom
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29
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Abstract
OBJECTIVE To provide an understanding of the detrimental impact of cirrhosis and its complications, strengths and weaknesses of current treatment options for the management of these complications, and new developments in this rapidly changing field. RESEARCH DESIGN AND METHODS Relevant publications were identified via PubMed and Cochrane databases, with additional references obtained by reviewing bibliographies from selected articles. RESULTS Cirrhosis, a progressive liver disease, is characterized by fibrosis caused by chronic liver injury. Liver fibrosis impairs hepatic function and causes structural changes that result in portal hypertension. Most patients with cirrhosis remain asymptomatic until they develop decompensated cirrhosis. At this stage, patients experience complications associated with portal hypertension (i.e., the abnormal increase in portal vein pressure), including ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), hepatorenal syndrome, portopulmonary hypertension, or variceal bleeding. In addition, intestinal microbial translocation in patients with cirrhosis might also cause SBP and HE. Because the survival rate for patients with cirrhosis substantially decreases once complications develop, the key goals in treating patients with cirrhosis include both managing the underlying liver disease and preventing and treating related complications. In patients with compensated cirrhosis, the management strategy is to prevent variceal bleeding and other complications that can lead to decompensated cirrhosis. Patients with decompensated cirrhosis are typically referred for liver transplantation, and the main focus of pre-transplant management is to eliminate the cause of cirrhosis (e.g., excess alcohol consumption, hepatitis virus) and prevent the recurrence of each decompensating complication. CONCLUSIONS Although substantial progress has been made to prevent the complications and mortality associated with cirrhosis, liver transplantation in combination with resolution of the etiology of cirrhosis remains the only curative option for most patients. Emerging therapies such as anti-fibrotic agents hold promise in potentially halting or reversing the progression of cirrhosis, even in patients with decompensated cirrhosis.
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Affiliation(s)
- Fred F Poordad
- The Texas Liver Institute, University of Texas Health Science Center , San Antonio, TX , USA
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van der Meer AJ. Achieving sustained virological response: what's the impact on further hepatitis C virus-related disease? Expert Rev Gastroenterol Hepatol 2015; 9:559-66. [PMID: 25579804 DOI: 10.1586/17474124.2015.1001366] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Continuous hepatic inflammation as a result of chronic infection with the hepatitis C virus may lead to the development of fibrosis and eventually cirrhosis. At the stage of cirrhosis, patients are at elevated risk of liver failure and hepatocellular carcinoma, two complications that shorten their life expectancy. Survival may be further impaired by the extra-hepatic manifestations of chronic hepatitis C virus infection, such as diabetes mellitus and lymphoma. Sustained virological response (SVR) following antiviral therapy has been associated with regression of hepatic fibrosis as well as with a reduction in portal pressure, both important markers of liver disease severity. Long-term follow-up studies indicated that SVR was related not only to a reduced occurrence of solid clinical end points, including liver failure and hepatocellular carcinoma, but also cardiovascular events and malignant lymphomas. Together, these findings may explain the recently observed improved overall survival among patients who attained SVR, even in the case of advanced liver disease.
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Affiliation(s)
- Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, 's Gravendijkwal 230, Room Ha 206, 3015 CE Rotterdam, The Netherlands
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31
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Gitto S, Belli LS, Vukotic R, Lorenzini S, Airoldi A, Cicero AFG, Vangeli M, Brodosi L, Panno AM, Di Donato R, Cescon M, Grazi GL, De Carlis L, Pinna AD, Bernardi M, Andreone P. Hepatitis C virus recurrence after liver transplantation: a 10-year evaluation. World J Gastroenterol 2015; 21:3912-3920. [PMID: 25852276 PMCID: PMC4385538 DOI: 10.3748/wjg.v21.i13.3912] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 10/10/2014] [Accepted: 11/18/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the predictors of 10-year survival of patients with hepatitis C recurrence. METHODS Data from 358 patients transplanted between 1989 and 2010 in two Italian transplant centers and with evidence of hepatitis C recurrence were analyzed. A χ(2), Fisher's exact test and Kruskal Wallis' test were used for categorical and continuous variables, respectively. Survival analysis was performed at 10 years after transplant using the Kaplan-Meier method, and a log-rank test was used to compare groups. A P level less than 0.05 was considered significant for all tests. Multivariate analysis of the predictive role of different variables on 10-year survival was performed by a stepwise Cox logistic regression. RESULTS The ten-year survival of the entire population was 61.2%. Five groups of patients were identified according to the virological response or lack of a response to antiviral treatment and, among those who were not treated, according to the clinical status (mild hepatitis C recurrence, "too sick to be treated" and patients with comorbidities contraindicating the treatment). While the 10-year survival of treated and untreated patients was not different (59.1% vs 64.7%, P = 0.192), patients with a sustained virological response had a higher 10-year survival rate than both the "non-responders" (84.7% vs 39.8%, P < 0.0001) and too sick to be treated (84.7% vs 0%, P < 0.0001). Sustained virological responders had a survival rate comparable to patients untreated with mild recurrence (84.7% vs 89.3%). A sustained virological response and young donor age were independent predictors of 10-year survival. CONCLUSION Sustained virological response significantly increased long-term survival. Awaiting the interferon-free regimen global availability, antiviral treatment might be questionable in selected subjects with mild hepatitis C recurrence.
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32
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Burgess S, Partovi N, Yoshida EM, Erb SR, Azalgara VM, Hussaini T. Drug Interactions With Direct-Acting Antivirals for Hepatitis C: Implications for HIV and Transplant Patients. Ann Pharmacother 2015; 49:674-87. [PMID: 25770114 DOI: 10.1177/1060028015576180] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Review pharmacokinetics of new direct-acting antivirals (DAAs) for hepatitis C (HCV) infection and interactions with concomitant immunosuppressant and antiretroviral therapies (ART). DATA SOURCES MEDLINE (1948-January 2015), EMBASE (1964-January 2015), International Pharmaceutical Abstracts (1970-January 2015), Google, and Google Scholar were searched combining the terms simeprevir, sofosbuvir, ledipasvir, daclatasvir, paritaprevir, ABT-450, ombitasvir, dasabuvir, pharmacokinetics, drug interaction, drug metabolism, HIV, antiretroviral, immunosuppressant, transplant. Articles, conference proceedings, abstracts, and product monographs were reviewed. STUDY SELECTION AND DATA EXTRACTION Literature on pharmacokinetic or pharmacodynamic interactions with DAAs and immunosuppressants or ART was considered for inclusion. Pertinent information was extracted and summarized in the review. In the absence of data, pharmacokinetic and pharmacodynamic principles were used to predict the likelihood of interactions. DATA SYNTHESIS DAA pharmacokinetics are reviewed and drug interaction data are presented with provision of management strategies. Fixed-dose combination paritaprevir/ritonavir/ombitasvir plus dasabuvir is most susceptible to drug interactions with immunosuppressants and ART mainly due to the influence of ritonavir on multiple enzymes. Simeprevir is also prone to drug interactions because of cytochrome P450(CYP) 3A4, CYP1A2, P-glycoprotein, and OATP1 involvement and is not recommended for use in combination with several HIV antiretrovirals (ARVs). Close therapeutic drug monitoring of calcineurin inhibitors is required with concomitant simeprevir. Few clinically significant interactions are expected with sofosbuvir or ledipasvir. Limited data suggest that daclatasvir may be coadministered with immunosuppressants but requires dose adjustments with certain ARVs. CONCLUSIONS None of the DAAs are completely free of drug interactions. Awareness and management of drug interactions is critical to optimize outcomes and minimize adverse effects in these patient populations.
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Affiliation(s)
- Sarah Burgess
- University of British Columbia, Vancouver, BC, Canada
| | - Nilufar Partovi
- University of British Columbia, Vancouver, BC, Canada Vancouver General Hospital, Vancouver, BC, Canada
| | - Eric M Yoshida
- University of British Columbia, Vancouver, BC, Canada Vancouver General Hospital, Vancouver, BC, Canada
| | - Siegfried R Erb
- University of British Columbia, Vancouver, BC, Canada Vancouver General Hospital, Vancouver, BC, Canada
| | - Vladimir Marquez Azalgara
- University of British Columbia, Vancouver, BC, Canada Vancouver General Hospital, Vancouver, BC, Canada
| | - Trana Hussaini
- University of British Columbia, Vancouver, BC, Canada Vancouver General Hospital, Vancouver, BC, Canada
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33
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Gentile I, Buonomo AR, Zappulo E, Borgia G. Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world? Expert Rev Anti Infect Ther 2015; 12:763-73. [PMID: 24918116 DOI: 10.1586/14787210.2014.929497] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
About 2% of the world's population is estimated to be chronically infected with hepatitis C virus (HCV). These chronic carriers are at risk of developing liver cirrhosis and its complications. Successful treatment of HCV infection is associated with improved quality of life and increased survival. Antiviral approaches were formerly based on interferon and therefore all patients with a contraindication to interferon were excluded from treatment (e.g., patients with decompensated disease, severe impairment of other organs). Very recently, interferon-free combinations have become available for genotypes 2 and 3. This review focuses on the most recently reported data on the various interferon-free combinations used (namely, sofosbuvir-based combinations, the ABT-450/ombitasvir/dasabuvir/ribavirin combination, the daclatasvir/asunaprevir combination, and the MK-5172/MK-8742 combination). All these combinations yielded amazing results in terms of efficacy (90-100%), tolerability and safety. If the problem of the high cost is overcome, interferon-free therapies will lead to what has long been a chimera, namely, an HCV-free world.
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Affiliation(s)
- Ivan Gentile
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", via S. Pansini 5, I-80131 Naples, Italy
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34
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D'Ambrosio R, Aghemo A, Colombo M. Assessing safety and efficacy of sofosbuvir for the treatment of hepatitis C. Expert Opin Drug Saf 2015; 14:473-84. [PMID: 25645644 DOI: 10.1517/14740338.2015.1009035] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION IFN-free regimens with direct antiviral agents (DAAs) against hepatitis C virus (HCV) are likely to greatly expand patients' access and response to hepatitis C therapy, while safety and tolerability of treatments seem substantially improved. Sofosbuvir (SOF), a NS5B nucleotide polymerase inhibitor with pan-genotypic activity and a high-barrier to resistance, has been approved by FDA and EMA in an all oral combination therapy for chronic hepatitis C with ribavirin (RBV) alone, or in combination with either pegylated interferon/RBV or other DAAs. AREAS COVERED This paper provides an overview of SOF-based therapy in chronic hepatitis C as it emerges from the published clinical trials. Data on special populations are included (i.e., decompensated patients, patients on liver transplant waiting lists, patients with renal impairment). The data has been analyzed according to the different HCV-genotypes and comprehensively covers both safety and efficacy treatment profiles. EXPERT OPINION Clinical trials have highlighted the safety and efficacy of SOF-based regimens, leading to the rapid approval of this therapy and its incorporation in the recommendations of the international societies on treatment of HCV infection. However, additional data are still needed to optimize both combination therapies' efficacy and duration in some categories of patients who have been under-represented in the registration trials.
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Affiliation(s)
- Roberta D'Ambrosio
- Università degli Studi di Milano, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milano, Via F. Sforza 35, 20122 Milan , Italy +39 0255035432 ; +39 0250320410 ;
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35
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Aspinall EJ, Hutchinson SJ, Janjua NZ, Grebely J, Yu A, Alavi M, Amin J, Goldberg DJ, Innes H, Law M, Walter SR, Krajden M, Dore GJ. Trends in mortality after diagnosis of hepatitis C virus infection: an international comparison and implications for monitoring the population impact of treatment. J Hepatol 2015; 62:269-77. [PMID: 25200903 DOI: 10.1016/j.jhep.2014.09.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 08/01/2014] [Accepted: 09/01/2014] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIMS People living with hepatitis C virus (HCV) are at increased risk of all-cause and liver-related mortality, although successful treatment has been shown to reduce this risk. The aim of this study was to provide baseline data on trends in cause-specific mortality and to establish an international surveillance system for evaluating the population level impact of HCV treatments. METHODS Population level HCV diagnosis databases from Scotland (1997-2010), Australia (New South Wales [NSW]) (1997-2006), and Canada (British Columbia [BC]) (1997-2003) were linked to corresponding death registries using record linkage. For each region, age-adjusted cause-specific mortality rates were calculated, and trends in annual age-adjusted liver-related mortality were plotted. RESULTS Of 105,138 individuals diagnosed with HCV (21,810 in Scotland, 58,484 in NSW, and 24,844 in BC), there were 7275 deaths (2572 in Scotland, 2655 in NSW, and 2048 in BC). Liver-related deaths accounted for 26% of deaths in Scotland, 21% in NSW, and 22% in BC. Temporal trends in age-adjusted liver related mortality were stable in Scotland (males p=0.4; females p=0.2) and NSW (males p=0.9; females p=0.9), while there was an increase in BC (males p=0.002; females p=0.04). CONCLUSIONS The risk of liver-related mortality after a diagnosis of HCV has remained stable or increased over time across three regions with well-established diagnosis databases, highlighting that HCV treatment programmes to-date have had minimal impact on population level HCV-related liver disease. With more effective therapies on the horizon, and greater uptake of treatment anticipated, the potential of future therapeutic strategies to reduce HCV-related mortality is considerable.
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Affiliation(s)
- Esther J Aspinall
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK; Health Protection Scotland, National Services Scotland, Glasgow, UK; The Kirby Institute, University of New South Wales, Sydney, Australia.
| | - Sharon J Hutchinson
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK; Health Protection Scotland, National Services Scotland, Glasgow, UK
| | - Naveed Z Janjua
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jason Grebely
- The Kirby Institute, University of New South Wales, Sydney, Australia
| | - Amanda Yu
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Maryam Alavi
- The Kirby Institute, University of New South Wales, Sydney, Australia
| | - Janaki Amin
- The Kirby Institute, University of New South Wales, Sydney, Australia
| | - David J Goldberg
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK; Health Protection Scotland, National Services Scotland, Glasgow, UK
| | - Hamish Innes
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK; Health Protection Scotland, National Services Scotland, Glasgow, UK
| | - Matthew Law
- The Kirby Institute, University of New South Wales, Sydney, Australia
| | - Scott R Walter
- The Kirby Institute, University of New South Wales, Sydney, Australia; The Australian Institute of Health Innovation, University of New South Wales, Sydney, Australia
| | - Mel Krajden
- British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada; School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Gregory J Dore
- The Kirby Institute, University of New South Wales, Sydney, Australia
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36
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Abstract
Optimal therapy for patients with hepatitis C virus (HCV) genotype 4 (HCV-4) infection is changing rapidly, and the possibility of a total cure is near. The standard of care has been combination pegylated interferon (PEG-IFN)-ribavirin (RBV), with modest response rates and considerable adverse events. Since the introduction of sofosbuvir (SOF), simeprevir (SIM), and daclatasvir (DCV), the duration of treatment has been significantly shortened and response rates have increased. The recommended treatment for IFN-eligible patients is PEG-IFN/RBV plus SOF, SIM or DCV. In IFN ineligible patients, the optimal regimen is a 24-week course of SOF/RBV, or a 12-week course of SOF-SIM or SOF-DCV with or without RBV. The pipeline for patients with chronic HCV is highly active. IFN-free combinations with paritaprevir-ombitasvir, SOF-ledipasvir, or DCV-asunaprevir (ASV)-beclabuvir (BMS-791325) for 12 weeks or less with close to 100% cure rates will soon become the optimal therapy.
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Affiliation(s)
- Wael Abdel-Razek
- Hepatology Department, National Liver Institute, Menoufiya University, Menoufiya, Egypt
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37
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Gallegos-Orozco JF, Charlton MR. Treatment of HCV prior to liver transplantation to prevent HCV recurrence - wise or wasteful? Liver Int 2015; 35:9-11. [PMID: 25412996 DOI: 10.1111/liv.12742] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Juan F Gallegos-Orozco
- Division of Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, USA
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38
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Coilly A, Roche B, Duclos-Vallée JC, Samuel D. Optimal therapy in hepatitis C virus liver transplant patients with direct acting antivirals. Liver Int 2015; 35 Suppl 1:44-50. [PMID: 25377540 DOI: 10.1111/liv.12728] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatitis C virus (HCV) end stage liver disease is a main indication for liver transplantation (LT). Recurrent HCV always occurs when patients are transplanted with a detectable viral load, leading to cirrhosis in 20-30% of patients within 5 years. Achieving a sustained virological response (SVR) with antiviral treatment is the only way to improve patient and graft survival. Dual therapy based on pegylated interferon and ribavirin (PEG-IFN/RBV) was the standard of care for many years with limited efficacy and a poor safety profile. The addition of first generation NS3/4 protease inhibitors (PI) improved SVR rates from 30 to 50-60%. But the occurrence of serious adverse events and drug-drug interactions with calcineurin inhibitors have both been limiting factors for their use during LT. The preliminary results of the use of second generation direct acting antivirals (DAA) in transplant patients showed better efficacy with an SVR rate >70%. The pre- and post-transplantation safety profile is good. Although fewer drug-drug interactions are expected, some new DAA still interact with immunosuppressive drugs. Certain questions such as the use of RBV or the optimal duration of therapy have still not been resolved but should be answered by the many ongoing studies in the coming year.
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Affiliation(s)
- Audrey Coilly
- AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; Univ. Paris-Sud, UMR-S 785, Villejuif, France; Inserm, Unité 785, Villejuif, France; Hepatinov, Villejuif, France
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39
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Price JC, Terrault NA. Sofosbuvir and ribavirin use in wait-listed patients with hepatitis C should be selective. Liver Int 2015; 35:7-8. [PMID: 25183500 DOI: 10.1111/liv.12679] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Affiliation(s)
- Jennifer C Price
- Department of Medicine, University of California, San Francisco, CA, USA
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40
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Lens S, Mariño Z, Forns X. Efficacy of new direct acting antivirals in transplant recipients and patients with advanced disease. Dig Liver Dis 2014; 46 Suppl 5:S197-205. [PMID: 25458782 DOI: 10.1016/j.dld.2014.10.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 10/06/2014] [Indexed: 12/11/2022]
Abstract
The development of new direct acting antivirals constitutes a clinical revolution in the field of hepatitis C therapy and, most probably, in the history of Hepatology. Difficult-to-treat patients, such as cirrhotics or patients in the peri-transplant setting, will clearly benefit from these therapies, particularly from interferon-free all-oral combinations. However, despite the substantial improvement of the hepatitis C drug market, access to these therapies will likely be different around the world due to economic restrictions. This review aims to clarify the current stage of different antiviral strategies (with or without interferon) in these difficult populations by analysing specific efficacy and safety results in patients with cirrhosis, patients on the waiting list for liver transplantation and recipients with hepatitis C recurrence after liver transplantation. Hitherto, some important challenges still remain unanswered in these patients and will need to be assessed in clinical practice, such as the evaluation of safety and efficacy in advanced cirrhotic patients with portal hypertension, the impact (if any) of viral clearance on clinical outcomes in patients with decompensated liver disease, the role of ribavirin in all-oral combinations, the relevance of the development of multi-drug viral resistant strains and the drug-drug interaction profiles of these drugs, especially after liver transplantation.
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Affiliation(s)
- Sabela Lens
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Zoe Mariño
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain.
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41
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Farnik H, Ferreirós N, Labocha S, Geisslinger G, Zeuzem S, Sarrazin C, Vermehren J. Role of telaprevir plasma levels for predicting response to antiviral therapy in patients with hepatitis C virus genotype 1 infection. Scand J Gastroenterol 2014; 49:1473-9. [PMID: 25384840 DOI: 10.3109/00365521.2014.978363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Telaprevir (TVR)-based triple therapy has substantially improved cure rates of hepatitis C virus (HCV) genotype 1 infection but side effects are frequent and often severe. Therefore, response predictors are needed for early identification of patients not responding to TVR-based triple therapy. MATERIAL AND METHODS Forty-five patients (mean age: 54 ± 13 years; male gender: 60%; treatment-experienced: 82%; cirrhosis: 58%) with HCV genotype 1 infection were treated with a TVR-based triple-therapy regimen. TVR plasma levels were analyzed by liquid chromatography electrospray-ionization-tandem mass spectrometry at weeks 2, 4, 8, and 12 of antiviral therapy. On-treatment HCV RNA response was assessed at weeks 4, 12, and 24 by real-time polymerase chain reaction. RESULTS An extended rapid virological response (eRVR) and sustained virological response (SVR) was achieved in 21 of 45 patients (47%) and 36 of 45 (80%) patients, respectively. Mean ± standard deviation TVR plasma levels at week 2 were 3.4 ± 0.2 log10 ng/ml and did not differ over time (when assessed at weeks 4, 8, and 12). TVR plasma levels at week 2 were significantly higher in patients who achieved an eRVR compared to those who did not achieve eRVR (3.5 ± 0.1 vs. 3.3 ± 0.2 log10 ng/ml; p = 0.003) but were neither associated with SVR nor with treatment-related anemia. CONCLUSION TVR plasma levels are associated with on-treatment response but not with overall treatment efficacy. Given the high overall response rates to TVR-based triple therapy, our data suggest that TVR trough levels may not be a useful predictor of treatment response, and routine drug-level monitoring is not required.
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Affiliation(s)
- Harald Farnik
- Medizinische Klinik 1, Universitätsklinikum Frankfurt , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany
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42
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Abdel-Razek W, Waked I. Optimal Management of HCV Genotype 4. CURRENT HEPATOLOGY REPORTS 2014; 13:286-294. [DOI: 10.1007/s11901-014-0243-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Gambato M, Lens S, Navasa M, Forns X. Treatment options in patients with decompensated cirrhosis, pre- and post-transplantation. J Hepatol 2014; 61:S120-31. [PMID: 25443340 DOI: 10.1016/j.jhep.2014.07.020] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2014] [Revised: 07/03/2014] [Accepted: 07/11/2014] [Indexed: 12/21/2022]
Abstract
Interferon-based treatments have a poor safety profile and limited efficacy in patients with advanced liver disease and in patients with hepatitis C (HCV) recurrence after liver transplantation (LT). Despite the recent approval of the first interferon-free regimen, which will be followed by several other interferon-free combinations in 2014 and 2015, data in patients with advanced cirrhosis and hepatitis C after LT are still limited. One study has already proven the concept that graft HCV infection can be prevented in a significant proportion of patients by treating them with sofosbuvir and ribavirin while awaiting LT. Two interferon-free regimens have also demonstrated a high efficacy in patients with hepatitis C recurrence after transplantation. Before these treatment strategies can be implemented in clinical practice, a few issues need to be addressed: (1) safety and efficacy of new antivirals in patients with decompensated cirrhosis, (2) the impact of viral clearance on liver function, (3) the potential consequences of virological failure (and the selection of multi-drug resistant HCV strains) in patients with decompensated cirrhosis or with severe hepatitis C recurrence after LT, and (4) drug-drug interactions (DDI) profiles. Finally, in the transplant setting it is also relevant to learn which strategy is most cost-effective in minimizing the negative impact of hepatitis C: preventing graft infection by treating patients before transplantation or treating hepatitis C recurrence after LT.
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Affiliation(s)
- Martina Gambato
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain
| | - Sabela Lens
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain
| | - Miquel Navasa
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain
| | - Xavier Forns
- Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Spain.
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