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      Hepatitis C virus treatment for prevention among people who inject drugs: Modeling treatment scale-up in the age of direct-acting antivirals

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          Abstract

          Substantial reductions in hepatitis C virus (HCV) prevalence among people who inject drugs (PWID) cannot be achieved by harm reduction interventions such as needle exchange and opiate substitution therapy (OST) alone. Current HCV treatment is arduous and uptake is low, but new highly effective and tolerable interferon-free direct-acting antiviral (DAA) treatments could facilitate increased uptake. We projected the potential impact of DAA treatments on PWID HCV prevalence in three settings. A dynamic HCV transmission model was parameterized to three chronic HCV prevalence settings: Edinburgh, UK (25%); Melbourne, Australia (50%); and Vancouver, Canada (65%). Using realistic scenarios of future DAAs (90% sustained viral response, 12 weeks duration, available 2015), we projected the treatment rates required to reduce chronic HCV prevalence by half or three-quarters within 15 years. Current HCV treatment rates may have a minimal impact on prevalence in Melbourne and Vancouver (<2% relative reductions) but could reduce prevalence by 26% in 15 years in Edinburgh. Prevalence could halve within 15 years with treatment scale-up to 15, 40, or 76 per 1,000 PWID annually in Edinburgh, Melbourne, or Vancouver, respectively (2-, 13-, and 15-fold increases, respectively). Scale-up to 22, 54, or 98 per 1,000 PWID annually could reduce prevalence by three-quarters within 15 years. Less impact occurs with delayed scale-up, higher baseline prevalence, or shorter average injecting duration. Results are insensitive to risk heterogeneity or restricting treatment to PWID on OST. At existing HCV drug costs, halving chronic prevalence would require annual treatment budgets of US $3.2 million in Edinburgh and approximately $50 million in Melbourne and Vancouver. Conclusion: Interferon-free DAAs could enable increased HCV treatment uptake among PWID, which could have a major preventative impact. However, treatment costs may limit scale-up, and should be addressed. (H epatology 2013;58:1598–1609)

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          Boceprevir for untreated chronic HCV genotype 1 infection.

          Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).
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            Telaprevir for previously untreated chronic hepatitis C virus infection.

            In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).
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              HIV prevention, treatment, and care services for people who inject drugs: a systematic review of global, regional, and national coverage.

              Previous reviews have examined the existence of HIV prevention, treatment, and care services for injecting drug users (IDUs) worldwide, but they did not quantify the scale of coverage. We undertook a systematic review to estimate national, regional, and global coverage of HIV services in IDUs. We did a systematic search of peer-reviewed (Medline, BioMed Central), internet, and grey-literature databases for data published in 2004 or later. A multistage process of data requests and verification was undertaken, involving UN agencies and national experts. National data were obtained for the extent of provision of the following core interventions for IDUs: needle and syringe programmes (NSPs), opioid substitution therapy (OST) and other drug treatment, HIV testing and counselling, antiretroviral therapy (ART), and condom programmes. We calculated national, regional, and global coverage of NSPs, OST, and ART on the basis of available estimates of IDU population sizes. By 2009, NSPs had been implemented in 82 countries and OST in 70 countries; both interventions were available in 66 countries. Regional and national coverage varied substantially. Australasia (202 needle-syringes per IDU per year) had by far the greatest rate of needle-syringe distribution; Latin America and the Caribbean (0.3 needle-syringes per IDU per year), Middle East and north Africa (0.5 needle-syringes per IDU per year), and sub-Saharan Africa (0.1 needle-syringes per IDU per year) had the lowest rates. OST coverage varied from less than or equal to one recipient per 100 IDUs in central Asia, Latin America, and sub-Saharan Africa, to very high levels in western Europe (61 recipients per 100 IDUs). The number of IDUs receiving ART varied from less than one per 100 HIV-positive IDUs (Chile, Kenya, Pakistan, Russia, and Uzbekistan) to more than 100 per 100 HIV-positive IDUs in six European countries. Worldwide, an estimated two needle-syringes (range 1-4) were distributed per IDU per month, there were eight recipients (6-12) of OST per 100 IDUs, and four IDUs (range 2-18) received ART per 100 HIV-positive IDUs. Worldwide coverage of HIV prevention, treatment, and care services in IDU populations is very low. There is an urgent need to improve coverage of these services in this at-risk population. UN Office on Drugs and Crime; Australian National Drug and Alcohol Research Centre, University of New South Wales; and Australian National Health and Medical Research Council. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Hepatology
                Hepatology
                hep
                Hepatology (Baltimore, Md.)
                Blackwell publishing Ltd
                0270-9139
                1527-3350
                November 2013
                26 August 2013
                : 58
                : 5
                : 1598-1609
                Affiliations
                [1 ]School of Social and Community Medicine, University of Bristol Bristol, UK
                [2 ]Social and Mathematical Epidemiology Group, Department of Global Health and Development, London School of Hygiene and Tropical Medicine London, UK
                [3 ]Kirby Institute, University of New South Wales Sydney, Australia
                [4 ]Burnet Institute Melbourne, Australia
                [5 ]Health Protection Scotland Glasgow, UK
                [6 ]School of Health and Life Sciences, Glasgow Caledonian University Glasgow, UK
                [7 ]British Columbia Centre for Excellence in HIV/AIDS, University of British Columbia Vancouver, Canada
                [8 ]Blizard Institute, Queen Mary's University of London London, UK
                [9 ]Medical Research Institute, Ninewells Hospital, University of Dundee Dundee, UK
                Author notes
                Address reprint requests to: Natasha K. Martin, School of Social and Community Medicine, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS. E-mail: natasha.martin@ 123456bristol.ac.uk .

                The views expressed in this article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health.

                This work was produced under the terms of the postdoctoral research training fellowship (to N. K. M.) issued by the National Institute for Health Research (NIHR). P. V. was supported by Medical Research Council New Investigator Award G0801627. J. G. was supported by a National Health and Medical Research Council (NHMRC) Career Development Fellowship. M. Hellard was supported by an NHMRC Project Grant and the Victorian Operational Infrastructure Support Program. V. D. L. was supported by a National Institute on Drug Abuse Michael Smith Foundation for Health Research Scholar Award. G. J. D. was supported by a NHMRC Practitioner Research Fellowship. The Kirby Institute is funded by the Australian Government Department of Health and Ageing and is affiliated with the Faculty of Medicine, University of New South Wales. M. Hickman was supported by the NIHR School of Public Health Nationally Integrated Quantitative Understanding of Addiction Harm MRC addiction research cluster and The Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement, a UK Clinical Research Collaboration (UKCRC) Public Health Research Centre of Excellence. Funding was also received from the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council (grant RES-590-28-0005), the Medical Research Council, the Welsh Assembly Government, and the Wellcome Trust (grant WT087640MA) under the auspices of the UKCRC.

                Article
                10.1002/hep.26431
                3933734
                23553643
                2f0908a1-b96c-4cfa-aafa-87d2fe4734e8
                © 2013 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 January 2013
                : 24 March 2013
                Categories
                Viral Hepatitis

                Gastroenterology & Hepatology
                Gastroenterology & Hepatology

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