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

Hepatology

Volume 58, Issue 5, pages 1598–1609, November 2013

Viral Hepatitis

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Natasha K. Martin^1,2,*, Peter Vickerman²,  Jason Grebely³, Margaret Hellard⁴,  Sharon J. Hutchinson^5,6, Viviane D. Lima⁷,  Graham R. Foster⁸, John F. Dillon⁹, David J. Goldberg⁵, Gregory J. Dore³, Matthew Hickman¹

Article first published online: 26 AUG 2013

DOI: 10.1002/hep.26431

© 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.

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.

Potential conflict of interest: N. K. M. has received an honorarium for speaking at a conference sponsored by Janssen. J. G. owns stock in Gilead and is a member of an advisory board for Merck. S. J. H. has received honoraria for speaking at conferences sponsored by MSD and Janssen and consults for Janssen. G. R. F. has received funding from Roche, Novartis, Janssen, Gilead, Bristol-Meyers Squibb, Boehringer Ingelheim, Idenix, Abbott, and Merck for consultancy and lectures. D. J. G. is a member of advisory boards and undertakes consultancy for Merck and Janssen. G. J. D. is a consultant/advisor and has received research grants from Roche, Merck, Janssen, Gilead, Bristol-Myers Squibb, and Abbott.

See Editorial on Page 1523

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. (Hepatology 2013;58:1598–1609)

The global burden of hepatitis C virus (HCV) infection continues to rise.[1, 2] The core of the HCV epidemic in the developed world occurs among people who inject drugs (PWID), who comprise the majority of new (80%) and existing (60%) cases.[1] Globally, HCV seroprevalence (>60% in most countries)[3] and incidence (5%-40% annually)[4, 5] remains high among PWID. Prevention strategies, such as needle and syringe programs (NSP) and opiate substitution therapy (OST), can reduce HCV transmission and have maintained low levels of human immunodeficiency virus (HIV) infection in many settings, but they are insufficient to achieve substantial reductions in HCV prevalence.[6-9] This is partly because high HCV prevalence and long injecting duration among PWID in many settings combine such that the intervention coverage required for major prevalence reductions is unobtainable and unsustainable.[9] Given that there is no HCV vaccine, alternative strategies for HCV prevention are urgently needed.

In HIV, the demonstration that antiretroviral therapy given to HIV-infected individuals can prevent secondary transmission has generated considerable excitement[10] and suggests that we may have reached a tipping point for preventing HIV transmission.[11] In contrast to HIV, HCV is curable and therapy is finite. Therefore, HCV treatment as prevention may provide even greater opportunity for preventing onward HCV transmission and directly reducing HCV chronic prevalence.

Mathematical modeling studies have suggested HCV treatment for PWID could be an effective[12-16] and cost-effective[17] intervention to prevent HCV transmission. However, these studies only considered treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV). The feasibility of expanding this treatment regimen as a strategy for treatment as prevention is limited, given the poor tolerability and limited uptake of PEG-IFN+RBV therapy, particularly among PWID.[18, 19] However, therapeutic options for HCV are evolving rapidly. Preliminary data from IFN-free direct-acting antiviral (DAA) therapy phase 2 trials indicates that in the near future, regimens will be available with markedly reduced toxicity, high efficacy (>90% cure), improved dosing schedules (once or twice-daily), and shortened treatment duration (6-24 weeks).[20-22] Such advances indicate that a HCV treatment as prevention strategy among PWID may be feasible in the very near future.

We project the potential impact of DAA therapy on HCV prevalence in three international settings with varied prevalence.

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Antiretroviral Treatment IS Prevention

Medscape HIV/AIDS

Benjamin Young, MD, PhD

Jun 14, 2013

It is well established that antiretroviral treatment (ART) can prevent HIV/AIDS-related morbidity and mortality in HIV-infected individuals. Published in 2011, the landmark HPTN 052 study confirmed that ART (and an undetectable plasma viral load) can virtually eliminate the risk for transmission of HIV to sexual partners.^[1] These and other advances in our understanding of how the use of ART can work to prevent new HIV infection are changing the lexicon of HIV medicine.

The notion of treatment as prevention (TasP) is now firmly established in language of World Health Organization and US Department of Health and Human Services treatment guidelines as components of counseling and testing of serodiscordant couples. Indeed, expansion of access to treatment and earlier initiation of treatment can even be viewed not only as a strategy to reduce the burden of HIV disease, but also as a way to reduce new HIV infections in some resource-limited settings,^[2] although much additional research and debate is needed to ascertain the feasibility and challenges of scaling up this approach worldwide at the level of communities or nations.

Giving medications to HIV-uninfected individuals to reduce risk for infection dates to the earliest days of ART, when postexposure prophylaxis strategies were introduced. Several recent reports, including the iPrEx study,^[3] demonstrated the feasibility of preexposure prophylaxis (PrEP), or the use of ART to prevent HIV infection before exposure in at-risk individuals. Together, these data led to approval by the US Food and Drug Administration of oral tenofovir/emtricitabine for PrEP and the release of interim guidance on PrEP by the Centers for Disease Control and Prevention.^[4]

However, enthusiasm for PrEP has been tempered by appreciation of the critical role of adherence to PrEP. Two large studies -- FEM-PrEP and VOICE -- were halted early because of lack of efficacy, at least in part driven by suboptimal adherence to medication.^[5] Many other investigations continue into strategies to address these limitations, such as alternative dosing strategies and newer medications with long half-lives.

Appreciating the rapid pace of investigations into these issues, in 2012 the International Association of Providers of AIDS Care (IAPAC) convened an international summit in London to review the scientific literature and to bring together global thought leaders for the purpose of generating discussion and clarifying areas of consensus and controversy.

The Consensus Statement of the summit, published in the current issue of the Journal of the International Association of Providers of AIDS Care, summarizes of the state of the science from the perspective of a diverse panel of experts representing healthcare providers, researchers, policy-makers, pharmaceutical companies, governmental and nongovernmental agencies, and advocacy groups.^[6]

The advisory committee concluded that the current evidence for TasP's effectiveness justifies ART use in persons who wish to start treatment early. However, the committee noted that additional research is needed to evaluate the effectiveness and cost-effectiveness of TasP, particularly at the national level, and that effective deployment of TasP requires efforts to scale up HIV testing and improving the cascade of engagement in HIV care.

In addition, the advisory committee acknowledged the considerable challenges for the implementation of successful PrEP programs, including financial constraints, the need to identify and reach at-risk populations, and the importance of training a cadre of healthcare providers in this new discipline. Nevertheless, the committee agreed that the current evidence on the effectiveness and safety of daily oral PrEP supports its use in high-risk groups. The committee also recommended that PrEP be part of a comprehensive risk-reduction package and that safety monitoring and adherence counseling are required.

In short, antiretroviral treatment is prevention. For persons already infected with HIV, ART prevents disease progression and death; for those recently exposed to HIV and for those at risk for HIV infection, postexposure prophylaxis and PrEP can prevent the establishment of infection. At its best, ART can reduce the burden of the HIV/AIDS epidemic and perhaps portend the beginning of an AIDS-free generation. There will be tremendous additional challenges in finding the political will to accomplish this goal and in defining an optimal way forward.

I look forward to seeing how much further the community has traveled down this pathway when we reconvene at the second International Summit on Controlling the HIV Epidemic with Antiretrovirals, in London, in September 2013.

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