Aiming at the Global Elimination of Viral Hepatitis: Challenges Along the Care Continuum

Aiming at the Global Elimination of Viral Hepatitis: Challenges Along the Care Continuum Open Forum Infectious Diseases MAJOR ARTICLE Aiming at the Global Elimination of Viral Hepatitis: Challenges Along the Care Continuum 1 2,3 4 5 6 2 7 Alastair Heffernan, Ella Barber, Nicola A. Cook, Asmaa I. Gomaa, Yolande X. Harley, Christopher R. Jones, Aaron G. Lim, 4,8 1,4 4,9 10 11 11 5 Zameer Mohamed, Shevanthi Nayagam, Gibril Ndow, Rajiv Shah, Mark W. Sonderup, C. Wendy Spearman, Imam Waked, 2,12,13 4 Robert J. Wilkinson, and Simon D. Taylor-Robinson 1 2 Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, London, UK; Division of Infectious Diseases, Faculty of Medicine, Imperial College London, London, 3 4 5 UK; Médecins Sans Frontières, London, UK; Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; Hepatology Department, National Liver Institute, 6 7 Menoufiya University, Shebeen El-Kom, Egypt; Research Office, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Population Health Sciences, Bristol Medical 8 9 School, University of Bristol, Bristol, UK; Liver and Antiviral Unit, Imperial College Healthcare NHS Trust, St. Mary’s Hospital, London, UK; Hepatitis Unit, Disease Control and Elimination, MRC 10 11 Unit, Banjul, The Gambia; Infectious Diseases Department, Nottingham University Hospitals NHS Trust, Nottingham, UK; Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Tuberculosis Laboratory, The Francis Crick Institute, London, UK A recent international workshop, organized by the authors, analyzed the obstacles facing the ambitious goal of eliminating viral hepatitis globally. We identified several policy areas critical to reaching elimination targets. These include providing hepatitis B birth- dose vaccination to all infants within 24 hours of birth, preventing the transmission of blood-borne viruses through the expansion of national hemovigilance schemes, implementing the lessons learned from the HIV epidemic regarding safe medical practices to elim- inate iatrogenic infection, adopting point-of-care testing to improve coverage of diagnosis, and providing free or ao ff rdable hepatitis C treatment to all. We introduce Egypt as a case study for rapid testing and treatment scale-up: this country oer ff s valuable insights to policy makers internationally, not only regarding how hepatitis C interventions can be expeditiously scaled-up, but also as a guide for how to tackle the problems encountered with such ambitious testing and treatment programs. Keywords. elimination; hepatitis care continuum; policy; viral hepatitis. Viral hepatitis was responsible for 1.3 million deaths globally in before elimination will be reached. We focused on those areas in 2015 and is now the seventh leading cause of mortality, rising which improvements are possible (using tools currently avail- from the 10th cause in 1990 [1, 2]. The full burden of disease able) and on those aspects of treatment and care where the encompasses not only mortality, but also reduced quality of life impact of changes in policy or strategy is potentially greatest. for patients (through cirrhosis and associated complications), This viewpoint is a distillation of these discussions and is written financial costs of care for individuals and health care systems with the aim of informing policy at this critical moment in the alike, and economic costs to society as a whole. Despite this formation of national and international viral hepatitis programs. burden, viral hepatitis has only in recent years received the HBV BIRTH-DOSE VACCINATION: CONFRONTING attention it merits. Now, with a World Health Organization LOST OPPORTUNITIES (WHO) elimination strategy published [1], the international Scaling-up of infant vaccination has already had demonstrable community is at last focused on tackling the twin epidemics of impacts on global HBV prevalence [5]. Infant vaccination hepatitis B virus (HBV) and hepatitis C virus (HCV). alone, however, does not prevent mother-to-child transmission At a recent conference (the first “Chronic Viral Hepatitis in (PMTCT). As the risk of chronic hepatitis B (CHB) infection is Africa” conference, Egypt), clinicians and researchers from across as high as 90% if infected perinatally [6], effective PMTCT is the globe discussed the challenges of reaching WHO elimination crucial to reducing incidence. targets. Considering the hepatitis care continuum (Figure 1) [3, 4], A key component of a comprehensive PMTCT strategy is we identified several key areas in which progress must be made birth-dose vaccination. Modeling studies have suggested that an 80% global scale-up of birth-dose vaccination plus infant Received 6 September 2017; editorial decision 2 November 2017; accepted 16 November 2017. vaccination, compared with scaling-up of infant vaccination Correspondence: C. W. Spearman, Division of Hepatology, Department of Medicine, Faculty alone, could avert 18.7 million new chronic infections over the of Health Sciences, University of K Floor, Old Main Main Building, Groote Schuur Hospital, Observatory, Cape Town, 7925, South Africa (wendy.spearman@uct.ac.za). next 15 years, highlighting its importance as a PMTCT tool [7]. Open Forum Infectious Diseases Monovalent HBV vaccine is inexpensive (US$0.20 per dose), © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases and birth-dose vaccination is likely to be cost-effective [8]. Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits Despite such evidence, global HBV birth-dose vaccine cover- unrestricted reuse, distribution, and reproduction in any medium, provided the original work age remains low, at 39% [9]. Moreover, vaccines are oen admini ft s- is properly cited. DOI: 10.1093/ofid/ofx252 tered beyond 24 hours of birth [10], when they are less effective in Aiming at Elimination of Viral Hepatitis • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx252/4638518 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Reached by prevention services Tested Aware of status Populations Enrolled in care within the care Initiated continuum for treatment viral hepatitis Treatment completed (HCV) or maintained (HBV) Achieved cure (HCV) or viral suppression (HBV) Care continuum Prevention Screening and Linkage to Care Treatments for viral hepatitis Current challenges 1) Provision of HBV birth-dose 3) Adoption of point-of-care testing 5) Maintenance of treatment for all vaccination within 24 hours of to expand diagnostic coverage cirrhotic HBV-infected patients within the care birth to prevent mother-tochild and strengthen linkage to care. indefinitely to minimize risk of continuum for transmission. disease progression. viral hepatitis, 4) Integration of screening into with reference to existing care delivery models for 6) Procurement of aˆordable 2) Expansion of hemovigilance achieving WHO schemes and safe injection at-risk populations to increase directacting antiviral agents to elimination practices to reduce iatrogenic their access to and engagement enable universal access to with viral hepatitis care. treatment for HCV. targets transmission. Figure  1. Overview of the WHO care continuum for viral hepatitis and the associated challenges encountered when aiming toward WHO elimination targets, adapted fromn Zhou et al. [3]. Populations within the care continuum for viral hepatitis are as defined within the Global Health Sector Strategy on Viral Hepatitis [4]. Abbreviations: HBV = hepatitis B virus; HCV = hepatitis C virus; WHO = World Health Organization. PMTCT [11, 12]. There are several reasons for this low coverage: the HCV from blood is 2.5 per 1000 units transfused, compared with monovalent vaccine is not funded by agencies like GAVI, as the cost 1 per 2–3 million units in high-income countries [24]. In add- of the vaccine falls below their funding threshold [13]; there are sig- ition, the reuse of injection equipment, inadequate sterilization nificant costs for vaccine delivery [14]; cultural factors may reduce procedures, lack of universal precautions, sharps injuries, and access to health care by women in the postpartum period [15]; and inadequate medical waste management systems all contribute hepatitis B interventions are rarely a public health priority [16], with to the burden of viral hepatitis. To reach WHO targets by 2030, only 9 countries in sub-Saharan Africa, for example, incorporating all blood donations should be screened for HIV, HCV, HBV, birth-dose vaccination into their national policies by 2015 [10, 17]. and syphilis in a quality-assured manner, and 90% of injections Innovative approaches exist to improve timely birth-dose should be administered using a safety-engineered device [25]. vaccination administration, including increasing the number er Th e are several options for reducing risk of transfu- of health staff–attended births [18], ensuring coordination sion-transmissible infections (TTIs). Centralized blood trans- between immunization and maternal health services [19], fusion services targeting low-risk, regular, voluntary blood expanding vaccine management systems [19], using prefilled donors should be developed and integrated into health care sys- injectable vaccines for home births [20], promoting awareness tems [26]. Although more expensive than replacement donor of the need for timely HBV vaccination [21], and simplifying systems [27], voluntary blood donors represent a safer, more the supply chain by, for example, using heat-sensitive labels to sustainable approach [28] and should contribute at least 80% of allow storage of vaccine outside the cold chain [22, 23]. all donations to transfusion services [29]. All donations should A substantial scale-up in birth-dose vaccination coverage is be screened for TTIs, with external quality assurance, using pivotal to reaching WHO 2030 elimination targets [1]. This is highly sensitive and specific assays [30, 31]. National hemovigi- long overdue, and acceleration of efforts requires a combination lance systems supported by local transfusion committees enable of political engagement by governments, financial commit- ongoing surveillance for transfusion-related complications [32], ment, and strategic planning to help countries reach these goals. but in low- and middle-income countries (LMICs), only 28% operate hemovigilance systems [33]. Blood safety programs IATROGENIC TRANSMISSION: A COST -EFFECTIVE can be cost-effective [34], but cost-effectiveness varies, and APPROACH TO CURBING TRANSMISSION this should inform program design: adding antigen-antibody Blood and injection safety are fundamental to national viral hep- combination tests to reduce the serologically negative window atitis programs [1]. In Africa, for example, the risk of acquiring period can be cost-effective [35], whereas TTI predonation 2 • OFID • Heffernan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx252/4638518 by Ed 'DeepDyve' Gillespie user on 16 March 2018 screening using rapid diagnostic tests (RDTs) is not considered suggest a role for DBS testing in marginalized populations un- to be cost-effective [36]. likely to present at centralized testing facilities [54]. Improving injection safety is also key to reducing iatrogenic e de Th velopment and validation of RDTs has become a transmission: in 2010, approximately 1.7 million new cases of HBV research priority. The WHO has prequalified 2 HCV RDTs: and up to 315 000 new cases of HCV were attributable to unsafe SDBioline (SDBioline, Gyeonggi-do, Republic of Korea) and injections [37]. Such infections can be avoided through the use of Oraquick (OraSure Technologies Inc., Bethlehem, PA) [55, 56], safety-engineered devices that protect health care workers from an oral fluid-based point-of-care (POC) test with a comparable hazardous occupational exposures to bodily fluids [38], needle/ performance to third-generation enzyme immunoassays (EIAs) sharps hygiene and safe disposal, and a ban on needle reuse [39]. [57]. POC testing has been shown to improve HIV linkage to Such measures must be delivered alongside education of health care in LMIC and to be cost-effective [58-60, S61]. Combination care workers in universal precautions and safe waste management RDTs for HIV, HBV, and HCV have also been shown to increase systems. National policies for safe and appropriate use of injec- uptake and receipt of results relative to laboratory testing [S62]. tions are, furthermore, highly cost-effective [40]. Global bodies Finally, the adoption of pangenotypic DAA regimens may must take the lead in promoting and financing blood screening eliminate the requirement for genotype testing entirely [53]. All and injection safety initiatives to ensure that these cheap and ef- such developments can simplify and strengthen the diagnosis fective interventions are implemented worldwide. and treatment cascade, removing potential causes of LTFU, and will be crucial in reaching diagnosis and treatment targets. DIAGNOSTICS FOR HCV: TACKLING THE Active implementation of ao ff rdable POC testing at the primary BOTTLENECK care level will be essential to upscale identification and linkage The advent of highly efficacious direct-acting antiviral (DAA) to care of infected individuals. treatment has revolutionized the therapeutic landscape for PROVIDING CARE: ACCESSING HARD-TO-REACH chronic HCV infection, but less attention has been paid to screen- HCV-INFECTED POPULATIONS ing and diagnosis. Given the nature of the infection, asymptom- atic HCV-infected individuals are unlikely to seek health care In most countries, anti-HCV prevalence is well below 10% in the [41]. Consequently, WHO targets of 90% of active infections general population [S63] but significantly greater in high-risk pop- diagnosed by 2030 [1] are aspirational, outstripping the diagnosis ulations. The most studied population is PWID, in which anti-HCV coverage achieved even in those countries that have been most prevalence can exceed 90% [S64], but men who have sex with men successful in identifying infected individuals, such as France, (MSM) and other recreational drug users are increasingly being Australia, and Sweden [42]. Currently, a 2-step process for diag- recognized as significant at-risk populations [S65, S66]. Such popu- nosing active HCV infection is usually required: a serological test lations are often difficult to reach for a variety of reasons, including to screen for exposure, followed by an HCV RNA nucleic acid stigma and the possibility of prosecution [S67, S68]. Programs spe- test (NAT) to confirm viremia [43]. This 2-step process inevitably cifically designed to address epidemics within these populations are leads to patient loss to follow-up (LTFU) [44–46]. Furthermore, critical to the success of disease burden reduction efforts. in LMIC, NAT is economically challenging, and the specialized Qualitative [S69,  S70] and quantitative [S71–S73] research laboratory staff and equipment are often not available [47, 48]. has shown that PWID are interested in engaging with health care Alternatively, serum HCV core antigen quantification services for HCV testing and treatment; there is clear evidence of (HCVcAg) can be used as a surrogate marker for HCV viremia. successful treatment outcomes in this group [S74], yet treatment Testing HCVcAg is a relatively low cost (as low as US$10 per in PWID remains suboptimal [S75,S76]. Health care provider sample [49]), fully automated, and a commercially available assay concerns can act as barriers to HCV treatment. Such concerns that can be performed on the Abbott ARCHITECT platform, may include the presence of comorbidities, the belief that there making it an attractive test for resource-limited settings [49, 50]. will be adherence issues, and difficulties managing side effects Employing HCVcAg testing while still dependent on a central- [S77]. From a patient perspective, there are several factors that ized testing facility can “uncouple” the sample collection from the may reduce the likelihood of accessing HCV treatment, includ- testing site through the use of dried blood spot (DBS) samples ing negative experiences within health care systems [S78, S79], [51, 52]: While whole blood and plasma samples require prompt low literacy rates [S80,  S81], inadequate communication with transport to the laboratory or refrigeration, DBS samples can be health care providers regarding the nature of the disease and stored at room temperature for several weeks [53]. The robust- treatment options [S79], and social factors such as discrimin- ness of this sample storage technique makes it ideal for decen- ation, the threat of stigmatization, and criminalization [S81]. tralizing testing, which is attractive for resource-limited settings Reviews of treatment models in high-income countries suggest [43]. Though testing DBS samples for HCVcAg has been shown that effective approaches to improving rates of HCV diagnosis to have reduced sensitivity compared with using serum samples and treatment integrate HCV services into addiction care units [52, 54], the low cost and uncoupling of sample and testing site [S82]. Focusing on treatment of addiction [S83] and encouraging Aiming at Elimination of Viral Hepatitis • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx252/4638518 by Ed 'DeepDyve' Gillespie user on 16 March 2018 positive feedback between health care staff and PWID [S84] While there is consensus that cirrhotics require lifelong treat- improve outcomes. Such multidisciplinary approaches reduce ment, the safety of stopping therapy in noncirrhotic patients noncompliance even among homeless or active illicit drug users remains less clear. Most international guidelines recommend dis- [S85]. Similar approaches can be utilized in general practitioner continuation of therapy for noncirrhotic HBeAg-positive indi- services; a study in the United Kingdom demonstrated how spe- viduals who show evidence of HBeAg loss and seroconversion cialist nurses seconded to primary care facilities can oer s ff creen- to antibody to HBeAg (anti-HBe), undetectable HBV DNA, and ing to at-risk individuals, considerably improving HCV detection who complete at least 12 months of consolidation therapy [S94]. [S86]. An alternative approach may be treatment as prevention: Discontinuation is only recommended when ALT and HBV Modeling suggests that it may be effective at curbing transmis- DNA levels can be monitored, as a high proportion relapse aer ft sion in both PWID [S87] and MSM [S88]. stopping treatment [S94,  S97], placing an additional financial In LMIC, many patients, in addition to those discussed above, strain on health care systems. Antiviral therapy can be stopped in are hard to reach through lack of health care services. In such noncirrhotic HBeAg-negative individuals at least 12 months fol- scenarios, HCV screening could be integrated into existing lowing loss of HBsAg and achieving anti-HBs status [S98]. This care delivery models for HIV and tuberculosis (TB) [S89, S90]. needs to be accompanied by sustained virological suppression and Success of HIV treatment roll-out oer ff s valuable lessons [43]: normalization of ALT, with off-treatment monitoring for relapse. Community-based testing improves uptake among high–CD4 With only a small proportion of patients achieving HBsAg loss, count individuals compared with facility-based approaches and with the need for regular monitoring for reactivation and [S91], and we propose that the impressive improvements in HIV a fl res aer ces ft sation of antiviral therapy in both HBeAg-positive case finding could be replicated for HCV using similar methods. and -negative individuals, we believe it is advisable at present to treat all patients indefinitely [S98]. e Th additional financial bur - TREATING HBV INFECTION: SETTING GLOBAL den that such lifelong treatment imposes, however, as well as STANDARDS TO SIMPLIFY CARE challenges to maintaining people in the cascade of care, must be Achieving ambitious WHO testing and treatment targets for acknowledged when adopting this approach. HBV requires careful consideration of the challenges of scale-up; An additional complication is access to treatment in LMICs: discussion should focus on simplified models of care and meth- despite generic tenofovir costing less than US$50 per annum ods of wide-scale testing and treatment, particularly in LMICs. and being accessible to HIV-HBV co-infected individuals as Treatment for CHB targets individuals with, or at risk for, part of antiretroviral therapy, many HBV-monoinfected indi- advanced liver disease, and aims to suppress virus replication, halt viduals cannot access antiviral therapy or have to pay out of disease progression, prevent complications, and avert HBV-related pocket. National health care systems need to ensure funded, deaths [S92–S94]. Several antiviral agents approved for the treat- sustainable access to antiviral therapy for HBV-mono-infected ment of CHB are available in developed countries, with regional individuals, implemented in concert with diagnosis scale-up guidelines outlining a continuum of care and recommendations on strategies. who to treat, how to treat, and when to stop treatment [S95–S96]. Treatment programs need to be accompanied by wide-scale es Th e documents, while based on evidence of drug efficacy and HBV testing, particularly in LMICs, where screening rates are benefits of treatment, are not adapted for use in countries where low. Community-based testing and treatment for chronic HBV CHB is endemic and HBV-related mortality is highest [2]. WHO infection has been shown to be feasible: In The Gambia, the guidelines for the prevention and treatment of CHB attempt to Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) address this unmet need [S94]. Tenofovir is the recommended study showed that POC HBV tests perform well in African com- antiviral in resource-limited settings, with entecavir recommended munity settings [S99], and subsequently demonstrated that com- in children aged 2–11 years. The guidelines encourage the use of munity-based screening could achieve high coverage and good clinical parameters (clinical diagnosis of cirrhosis) and/or nonin- linkage to care [S100] while remaining cost-effective [S101]. vasive tests (APRI score > 2) to assess severity of liver disease. THE COST OF DIRECT-ACTING ANTIVIRALS FOR WHO guidelines suggest that treatment should be targeted at HCV: HOW PROGRESS CAN BE MADE those with the highest risk of disease progression, based on the detection of persistently raised alanine aminotransferase (ALT), A 12-week DAA course costs in excess of US$70 000 in the and HBV DNA levels greater than 20 000 IU/mL in those older United States today [S102]. With an estimated 71 million active than age 30 years [S94]. All cirrhotics should be treated regard- HCV infections globally [1], such prices render any program less of ALT levels, HBeAg status, or HBV DNA levels. The sim- aimed at global HCV elimination unrealistic. In 2016, the WHO plicity of administration of these antivirals, their tolerability reported a range of approaches adopted by several countries to and safety profiles, and their high barrier to resistance make demonstrate how barriers to treatment can be overcome [S103]. them ideal for long-term use in regions where close monitoring In LMICs where patents have not been filed or remain under and management of adverse effects may not be feasible. examination, a market for low-cost, generic versions of patented 4 • OFID • Heffernan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx252/4638518 by Ed 'DeepDyve' Gillespie user on 16 March 2018 drugs can be created. Sofosbuvir is not patented in Egypt, and a example to policy makers, not only as an exemplar of how viral 28-day supply currently costs under US$30 [S104]. India has used hepatitis interventions can be scaled-up quickly and intensively, this approach to facilitate production of generics, but a recent but also as a guide for how to tackle the problems that may be decision to grant a patent to Gilead for Sofosbuvir may damage faced with such ambitious interventions. India’s role as an HCV generics producer [S105]. Pharmaceutical Recommendations companies have, in places, awarded voluntary license agreements Egypt demonstrates what can be accomplished with regards to to permit local companies to produce generics. As of August 2015, HCV diagnosis and treatment, given sufficient political will, Gilead had 11 such agreements with Indian companies [S106]. state coordination, and investment. Across the world, efforts Additionally, the originator company of Daclatasvir has signed an to address viral hepatitis, both HBV and HCV, should focus agreement with the Medicines Patent Pool to enable sublicensing on providing universal HBV birth-dose vaccination within 24 to multiple generic manufacturers in 112 LMICs [S103]. Many hours of birth, establishing hemovigilance schemes to prevent middle-income countries are viewed as having market potential transmission of blood-borne viruses, providing nonreusable and are excluded from these agreements, including China, Brazil, syringes and educating health staff in injection safety, adopt- and Thailand [S106]. More generally, complexities of volun- ing new diagnostic technologies to expand access to screen- tary licensing fragment the market, ensuring that pricing power ing, specializing intervention efforts for vulnerable high-risk remains in the hands of pharmaceutical companies [S107]. This groups to reduce transmission where it is highest, treating all problem can be circumvented by development of new therapies: HBV-infected patients indefinitely to minimize potential harm e Dr Th ugs for Neglected Diseases Initiative (DNDi) has obtained caused by discontinuation, and collaborating across the contin- the license for a new HCV DAA, ravidasvir. This has allowed it to ent to drive down HCV drug costs to ensure that, once treat- begin production of the drug through an Egyptian firm, Pharco ment has been accessed, it is affordable. Pharmaceuticals, without the need to maximize prot [S108]. fi Supplementary Data High-income countries can bulk purchase to reduce costs; Supplementary materials are available at Open Forum Infectious Diseases online. no country has attempted this more ambitiously than Australia. Consisting of data provided by the authors to benefit the reader, the posted e g Th overnment agreed to a AU$1 billion (US$0.73 billion) materials are not copyedited and are the sole responsibility of the authors, so program to treat 62 000 individuals, corresponding to per-treat- questions or comments should be addressed to the corresponding author. ment costs of around US$12 000 [S109]. The true novelty of the Australian approach is that if expenditure exceeds up-front cost, Acknowledgments e a Th uthors are grateful to the Newton Fund, the British Council, the the price of drugs decreases, potentially to 0 [S109]. Australia Mosharafa Foundation, the Science and Technology Development Fund, has, in effect, created a subscription system, paying a fixed and the South African National Research Foundation for facilitating the amount and treating as many Australians as it can. workshop and for funding the conference at which this work was started. What ultimately unites these approaches is their customized Author contributions. I.W., A.I.G., C.W.S., M.W.S., Y.X.H., R.J.W., N.C., and S.T.R.  organized the conference and conceived the article, along with its nature; some countries have had success in reducing prices, but principal themes. A.H., A.G.L., C.R.J., E.B., G.N., I.W ., R.S., S.N., and Z.M. wrote others risk being left behind. A unified approach must be taken the initial draft. All authors critically reviewed the manuscript. A.H., S.T.R., to ensure that high-quality, low-cost drugs are available regard- C.W.S., Y.X.H., R.J.W., and M.W.S. edited and formatted the final submission. Potential conifl cts of interest. All authors: no reported conflicts of less of location. Pooled procurement is one method for achieving interest. All authors have submitted the ICMJE Form for Disclosure of this, an approach pioneered by the Global Fund to tackle the HIV, Potential Conflicts of Interest. 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Open Forum Infectious Diseases MAJOR ARTICLE Aiming at the Global Elimination of Viral Hepatitis: Challenges Along the Care Continuum 1 2,3 4 5 6 2 7 Alastair Heffernan, Ella Barber, Nicola A. Cook, Asmaa I. Gomaa, Yolande X. Harley, Christopher R. Jones, Aaron G. Lim, 4,8 1,4 4,9 10 11 11 5 Zameer Mohamed, Shevanthi Nayagam, Gibril Ndow, Rajiv Shah, Mark W. Sonderup, C. Wendy Spearman, Imam Waked, 2,12,13 4 Robert J. Wilkinson, and Simon D. Taylor-Robinson 1 2 Department of Infectious Disease Epidemiology, Faculty of Medicine, Imperial College London, London, UK; Division of Infectious Diseases, Faculty of Medicine, Imperial College London, London, 3 4 5 UK; Médecins Sans Frontières, London, UK; Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; Hepatology Department, National Liver Institute, 6 7 Menoufiya University, Shebeen El-Kom, Egypt; Research Office, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Population Health Sciences, Bristol Medical 8 9 School, University of Bristol, Bristol, UK; Liver and Antiviral Unit, Imperial College Healthcare NHS Trust, St. Mary’s Hospital, London, UK; Hepatitis Unit, Disease Control and Elimination, MRC 10 11 Unit, Banjul, The Gambia; Infectious Diseases Department, Nottingham University Hospitals NHS Trust, Nottingham, UK; Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; Tuberculosis Laboratory, The Francis Crick Institute, London, UK A recent international workshop, organized by the authors, analyzed the obstacles facing the ambitious goal of eliminating viral hepatitis globally. We identified several policy areas critical to reaching elimination targets. These include providing hepatitis B birth- dose vaccination to all infants within 24 hours of birth, preventing the transmission of blood-borne viruses through the expansion of national hemovigilance schemes, implementing the lessons learned from the HIV epidemic regarding safe medical practices to elim- inate iatrogenic infection, adopting point-of-care testing to improve coverage of diagnosis, and providing free or ao ff rdable hepatitis C treatment to all. We introduce Egypt as a case study for rapid testing and treatment scale-up: this country oer ff s valuable insights to policy makers internationally, not only regarding how hepatitis C interventions can be expeditiously scaled-up, but also as a guide for how to tackle the problems encountered with such ambitious testing and treatment programs. Keywords. elimination; hepatitis care continuum; policy; viral hepatitis. Viral hepatitis was responsible for 1.3 million deaths globally in before elimination will be reached. We focused on those areas in 2015 and is now the seventh leading cause of mortality, rising which improvements are possible (using tools currently avail- from the 10th cause in 1990 [1, 2]. The full burden of disease able) and on those aspects of treatment and care where the encompasses not only mortality, but also reduced quality of life impact of changes in policy or strategy is potentially greatest. for patients (through cirrhosis and associated complications), This viewpoint is a distillation of these discussions and is written financial costs of care for individuals and health care systems with the aim of informing policy at this critical moment in the alike, and economic costs to society as a whole. Despite this formation of national and international viral hepatitis programs. burden, viral hepatitis has only in recent years received the HBV BIRTH-DOSE VACCINATION: CONFRONTING attention it merits. Now, with a World Health Organization LOST OPPORTUNITIES (WHO) elimination strategy published [1], the international Scaling-up of infant vaccination has already had demonstrable community is at last focused on tackling the twin epidemics of impacts on global HBV prevalence [5]. Infant vaccination hepatitis B virus (HBV) and hepatitis C virus (HCV). alone, however, does not prevent mother-to-child transmission At a recent conference (the first “Chronic Viral Hepatitis in (PMTCT). As the risk of chronic hepatitis B (CHB) infection is Africa” conference, Egypt), clinicians and researchers from across as high as 90% if infected perinatally [6], effective PMTCT is the globe discussed the challenges of reaching WHO elimination crucial to reducing incidence. targets. Considering the hepatitis care continuum (Figure 1) [3, 4], A key component of a comprehensive PMTCT strategy is we identified several key areas in which progress must be made birth-dose vaccination. Modeling studies have suggested that an 80% global scale-up of birth-dose vaccination plus infant Received 6 September 2017; editorial decision 2 November 2017; accepted 16 November 2017. vaccination, compared with scaling-up of infant vaccination Correspondence: C. W. Spearman, Division of Hepatology, Department of Medicine, Faculty alone, could avert 18.7 million new chronic infections over the of Health Sciences, University of K Floor, Old Main Main Building, Groote Schuur Hospital, Observatory, Cape Town, 7925, South Africa (wendy.spearman@uct.ac.za). next 15 years, highlighting its importance as a PMTCT tool [7]. Open Forum Infectious Diseases Monovalent HBV vaccine is inexpensive (US$0.20 per dose), © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases and birth-dose vaccination is likely to be cost-effective [8]. Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits Despite such evidence, global HBV birth-dose vaccine cover- unrestricted reuse, distribution, and reproduction in any medium, provided the original work age remains low, at 39% [9]. Moreover, vaccines are oen admini ft s- is properly cited. DOI: 10.1093/ofid/ofx252 tered beyond 24 hours of birth [10], when they are less effective in Aiming at Elimination of Viral Hepatitis • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx252/4638518 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Reached by prevention services Tested Aware of status Populations Enrolled in care within the care Initiated continuum for treatment viral hepatitis Treatment completed (HCV) or maintained (HBV) Achieved cure (HCV) or viral suppression (HBV) Care continuum Prevention Screening and Linkage to Care Treatments for viral hepatitis Current challenges 1) Provision of HBV birth-dose 3) Adoption of point-of-care testing 5) Maintenance of treatment for all vaccination within 24 hours of to expand diagnostic coverage cirrhotic HBV-infected patients within the care birth to prevent mother-tochild and strengthen linkage to care. indefinitely to minimize risk of continuum for transmission. disease progression. viral hepatitis, 4) Integration of screening into with reference to existing care delivery models for 6) Procurement of aˆordable 2) Expansion of hemovigilance achieving WHO schemes and safe injection at-risk populations to increase directacting antiviral agents to elimination practices to reduce iatrogenic their access to and engagement enable universal access to with viral hepatitis care. treatment for HCV. targets transmission. Figure  1. Overview of the WHO care continuum for viral hepatitis and the associated challenges encountered when aiming toward WHO elimination targets, adapted fromn Zhou et al. [3]. Populations within the care continuum for viral hepatitis are as defined within the Global Health Sector Strategy on Viral Hepatitis [4]. Abbreviations: HBV = hepatitis B virus; HCV = hepatitis C virus; WHO = World Health Organization. PMTCT [11, 12]. There are several reasons for this low coverage: the HCV from blood is 2.5 per 1000 units transfused, compared with monovalent vaccine is not funded by agencies like GAVI, as the cost 1 per 2–3 million units in high-income countries [24]. In add- of the vaccine falls below their funding threshold [13]; there are sig- ition, the reuse of injection equipment, inadequate sterilization nificant costs for vaccine delivery [14]; cultural factors may reduce procedures, lack of universal precautions, sharps injuries, and access to health care by women in the postpartum period [15]; and inadequate medical waste management systems all contribute hepatitis B interventions are rarely a public health priority [16], with to the burden of viral hepatitis. To reach WHO targets by 2030, only 9 countries in sub-Saharan Africa, for example, incorporating all blood donations should be screened for HIV, HCV, HBV, birth-dose vaccination into their national policies by 2015 [10, 17]. and syphilis in a quality-assured manner, and 90% of injections Innovative approaches exist to improve timely birth-dose should be administered using a safety-engineered device [25]. vaccination administration, including increasing the number er Th e are several options for reducing risk of transfu- of health staff–attended births [18], ensuring coordination sion-transmissible infections (TTIs). Centralized blood trans- between immunization and maternal health services [19], fusion services targeting low-risk, regular, voluntary blood expanding vaccine management systems [19], using prefilled donors should be developed and integrated into health care sys- injectable vaccines for home births [20], promoting awareness tems [26]. Although more expensive than replacement donor of the need for timely HBV vaccination [21], and simplifying systems [27], voluntary blood donors represent a safer, more the supply chain by, for example, using heat-sensitive labels to sustainable approach [28] and should contribute at least 80% of allow storage of vaccine outside the cold chain [22, 23]. all donations to transfusion services [29]. All donations should A substantial scale-up in birth-dose vaccination coverage is be screened for TTIs, with external quality assurance, using pivotal to reaching WHO 2030 elimination targets [1]. This is highly sensitive and specific assays [30, 31]. National hemovigi- long overdue, and acceleration of efforts requires a combination lance systems supported by local transfusion committees enable of political engagement by governments, financial commit- ongoing surveillance for transfusion-related complications [32], ment, and strategic planning to help countries reach these goals. but in low- and middle-income countries (LMICs), only 28% operate hemovigilance systems [33]. Blood safety programs IATROGENIC TRANSMISSION: A COST -EFFECTIVE can be cost-effective [34], but cost-effectiveness varies, and APPROACH TO CURBING TRANSMISSION this should inform program design: adding antigen-antibody Blood and injection safety are fundamental to national viral hep- combination tests to reduce the serologically negative window atitis programs [1]. In Africa, for example, the risk of acquiring period can be cost-effective [35], whereas TTI predonation 2 • OFID • Heffernan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx252/4638518 by Ed 'DeepDyve' Gillespie user on 16 March 2018 screening using rapid diagnostic tests (RDTs) is not considered suggest a role for DBS testing in marginalized populations un- to be cost-effective [36]. likely to present at centralized testing facilities [54]. Improving injection safety is also key to reducing iatrogenic e de Th velopment and validation of RDTs has become a transmission: in 2010, approximately 1.7 million new cases of HBV research priority. The WHO has prequalified 2 HCV RDTs: and up to 315 000 new cases of HCV were attributable to unsafe SDBioline (SDBioline, Gyeonggi-do, Republic of Korea) and injections [37]. Such infections can be avoided through the use of Oraquick (OraSure Technologies Inc., Bethlehem, PA) [55, 56], safety-engineered devices that protect health care workers from an oral fluid-based point-of-care (POC) test with a comparable hazardous occupational exposures to bodily fluids [38], needle/ performance to third-generation enzyme immunoassays (EIAs) sharps hygiene and safe disposal, and a ban on needle reuse [39]. [57]. POC testing has been shown to improve HIV linkage to Such measures must be delivered alongside education of health care in LMIC and to be cost-effective [58-60, S61]. Combination care workers in universal precautions and safe waste management RDTs for HIV, HBV, and HCV have also been shown to increase systems. National policies for safe and appropriate use of injec- uptake and receipt of results relative to laboratory testing [S62]. tions are, furthermore, highly cost-effective [40]. Global bodies Finally, the adoption of pangenotypic DAA regimens may must take the lead in promoting and financing blood screening eliminate the requirement for genotype testing entirely [53]. All and injection safety initiatives to ensure that these cheap and ef- such developments can simplify and strengthen the diagnosis fective interventions are implemented worldwide. and treatment cascade, removing potential causes of LTFU, and will be crucial in reaching diagnosis and treatment targets. DIAGNOSTICS FOR HCV: TACKLING THE Active implementation of ao ff rdable POC testing at the primary BOTTLENECK care level will be essential to upscale identification and linkage The advent of highly efficacious direct-acting antiviral (DAA) to care of infected individuals. treatment has revolutionized the therapeutic landscape for PROVIDING CARE: ACCESSING HARD-TO-REACH chronic HCV infection, but less attention has been paid to screen- HCV-INFECTED POPULATIONS ing and diagnosis. Given the nature of the infection, asymptom- atic HCV-infected individuals are unlikely to seek health care In most countries, anti-HCV prevalence is well below 10% in the [41]. Consequently, WHO targets of 90% of active infections general population [S63] but significantly greater in high-risk pop- diagnosed by 2030 [1] are aspirational, outstripping the diagnosis ulations. The most studied population is PWID, in which anti-HCV coverage achieved even in those countries that have been most prevalence can exceed 90% [S64], but men who have sex with men successful in identifying infected individuals, such as France, (MSM) and other recreational drug users are increasingly being Australia, and Sweden [42]. Currently, a 2-step process for diag- recognized as significant at-risk populations [S65, S66]. Such popu- nosing active HCV infection is usually required: a serological test lations are often difficult to reach for a variety of reasons, including to screen for exposure, followed by an HCV RNA nucleic acid stigma and the possibility of prosecution [S67, S68]. Programs spe- test (NAT) to confirm viremia [43]. This 2-step process inevitably cifically designed to address epidemics within these populations are leads to patient loss to follow-up (LTFU) [44–46]. Furthermore, critical to the success of disease burden reduction efforts. in LMIC, NAT is economically challenging, and the specialized Qualitative [S69,  S70] and quantitative [S71–S73] research laboratory staff and equipment are often not available [47, 48]. has shown that PWID are interested in engaging with health care Alternatively, serum HCV core antigen quantification services for HCV testing and treatment; there is clear evidence of (HCVcAg) can be used as a surrogate marker for HCV viremia. successful treatment outcomes in this group [S74], yet treatment Testing HCVcAg is a relatively low cost (as low as US$10 per in PWID remains suboptimal [S75,S76]. Health care provider sample [49]), fully automated, and a commercially available assay concerns can act as barriers to HCV treatment. Such concerns that can be performed on the Abbott ARCHITECT platform, may include the presence of comorbidities, the belief that there making it an attractive test for resource-limited settings [49, 50]. will be adherence issues, and difficulties managing side effects Employing HCVcAg testing while still dependent on a central- [S77]. From a patient perspective, there are several factors that ized testing facility can “uncouple” the sample collection from the may reduce the likelihood of accessing HCV treatment, includ- testing site through the use of dried blood spot (DBS) samples ing negative experiences within health care systems [S78, S79], [51, 52]: While whole blood and plasma samples require prompt low literacy rates [S80,  S81], inadequate communication with transport to the laboratory or refrigeration, DBS samples can be health care providers regarding the nature of the disease and stored at room temperature for several weeks [53]. The robust- treatment options [S79], and social factors such as discrimin- ness of this sample storage technique makes it ideal for decen- ation, the threat of stigmatization, and criminalization [S81]. tralizing testing, which is attractive for resource-limited settings Reviews of treatment models in high-income countries suggest [43]. Though testing DBS samples for HCVcAg has been shown that effective approaches to improving rates of HCV diagnosis to have reduced sensitivity compared with using serum samples and treatment integrate HCV services into addiction care units [52, 54], the low cost and uncoupling of sample and testing site [S82]. Focusing on treatment of addiction [S83] and encouraging Aiming at Elimination of Viral Hepatitis • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx252/4638518 by Ed 'DeepDyve' Gillespie user on 16 March 2018 positive feedback between health care staff and PWID [S84] While there is consensus that cirrhotics require lifelong treat- improve outcomes. Such multidisciplinary approaches reduce ment, the safety of stopping therapy in noncirrhotic patients noncompliance even among homeless or active illicit drug users remains less clear. Most international guidelines recommend dis- [S85]. Similar approaches can be utilized in general practitioner continuation of therapy for noncirrhotic HBeAg-positive indi- services; a study in the United Kingdom demonstrated how spe- viduals who show evidence of HBeAg loss and seroconversion cialist nurses seconded to primary care facilities can oer s ff creen- to antibody to HBeAg (anti-HBe), undetectable HBV DNA, and ing to at-risk individuals, considerably improving HCV detection who complete at least 12 months of consolidation therapy [S94]. [S86]. An alternative approach may be treatment as prevention: Discontinuation is only recommended when ALT and HBV Modeling suggests that it may be effective at curbing transmis- DNA levels can be monitored, as a high proportion relapse aer ft sion in both PWID [S87] and MSM [S88]. stopping treatment [S94,  S97], placing an additional financial In LMIC, many patients, in addition to those discussed above, strain on health care systems. Antiviral therapy can be stopped in are hard to reach through lack of health care services. In such noncirrhotic HBeAg-negative individuals at least 12 months fol- scenarios, HCV screening could be integrated into existing lowing loss of HBsAg and achieving anti-HBs status [S98]. This care delivery models for HIV and tuberculosis (TB) [S89, S90]. needs to be accompanied by sustained virological suppression and Success of HIV treatment roll-out oer ff s valuable lessons [43]: normalization of ALT, with off-treatment monitoring for relapse. Community-based testing improves uptake among high–CD4 With only a small proportion of patients achieving HBsAg loss, count individuals compared with facility-based approaches and with the need for regular monitoring for reactivation and [S91], and we propose that the impressive improvements in HIV a fl res aer ces ft sation of antiviral therapy in both HBeAg-positive case finding could be replicated for HCV using similar methods. and -negative individuals, we believe it is advisable at present to treat all patients indefinitely [S98]. e Th additional financial bur - TREATING HBV INFECTION: SETTING GLOBAL den that such lifelong treatment imposes, however, as well as STANDARDS TO SIMPLIFY CARE challenges to maintaining people in the cascade of care, must be Achieving ambitious WHO testing and treatment targets for acknowledged when adopting this approach. HBV requires careful consideration of the challenges of scale-up; An additional complication is access to treatment in LMICs: discussion should focus on simplified models of care and meth- despite generic tenofovir costing less than US$50 per annum ods of wide-scale testing and treatment, particularly in LMICs. and being accessible to HIV-HBV co-infected individuals as Treatment for CHB targets individuals with, or at risk for, part of antiretroviral therapy, many HBV-monoinfected indi- advanced liver disease, and aims to suppress virus replication, halt viduals cannot access antiviral therapy or have to pay out of disease progression, prevent complications, and avert HBV-related pocket. National health care systems need to ensure funded, deaths [S92–S94]. Several antiviral agents approved for the treat- sustainable access to antiviral therapy for HBV-mono-infected ment of CHB are available in developed countries, with regional individuals, implemented in concert with diagnosis scale-up guidelines outlining a continuum of care and recommendations on strategies. who to treat, how to treat, and when to stop treatment [S95–S96]. Treatment programs need to be accompanied by wide-scale es Th e documents, while based on evidence of drug efficacy and HBV testing, particularly in LMICs, where screening rates are benefits of treatment, are not adapted for use in countries where low. Community-based testing and treatment for chronic HBV CHB is endemic and HBV-related mortality is highest [2]. WHO infection has been shown to be feasible: In The Gambia, the guidelines for the prevention and treatment of CHB attempt to Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) address this unmet need [S94]. Tenofovir is the recommended study showed that POC HBV tests perform well in African com- antiviral in resource-limited settings, with entecavir recommended munity settings [S99], and subsequently demonstrated that com- in children aged 2–11 years. The guidelines encourage the use of munity-based screening could achieve high coverage and good clinical parameters (clinical diagnosis of cirrhosis) and/or nonin- linkage to care [S100] while remaining cost-effective [S101]. vasive tests (APRI score > 2) to assess severity of liver disease. THE COST OF DIRECT-ACTING ANTIVIRALS FOR WHO guidelines suggest that treatment should be targeted at HCV: HOW PROGRESS CAN BE MADE those with the highest risk of disease progression, based on the detection of persistently raised alanine aminotransferase (ALT), A 12-week DAA course costs in excess of US$70 000 in the and HBV DNA levels greater than 20 000 IU/mL in those older United States today [S102]. With an estimated 71 million active than age 30 years [S94]. All cirrhotics should be treated regard- HCV infections globally [1], such prices render any program less of ALT levels, HBeAg status, or HBV DNA levels. The sim- aimed at global HCV elimination unrealistic. In 2016, the WHO plicity of administration of these antivirals, their tolerability reported a range of approaches adopted by several countries to and safety profiles, and their high barrier to resistance make demonstrate how barriers to treatment can be overcome [S103]. them ideal for long-term use in regions where close monitoring In LMICs where patents have not been filed or remain under and management of adverse effects may not be feasible. examination, a market for low-cost, generic versions of patented 4 • OFID • Heffernan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx252/4638518 by Ed 'DeepDyve' Gillespie user on 16 March 2018 drugs can be created. Sofosbuvir is not patented in Egypt, and a example to policy makers, not only as an exemplar of how viral 28-day supply currently costs under US$30 [S104]. India has used hepatitis interventions can be scaled-up quickly and intensively, this approach to facilitate production of generics, but a recent but also as a guide for how to tackle the problems that may be decision to grant a patent to Gilead for Sofosbuvir may damage faced with such ambitious interventions. India’s role as an HCV generics producer [S105]. Pharmaceutical Recommendations companies have, in places, awarded voluntary license agreements Egypt demonstrates what can be accomplished with regards to to permit local companies to produce generics. As of August 2015, HCV diagnosis and treatment, given sufficient political will, Gilead had 11 such agreements with Indian companies [S106]. state coordination, and investment. Across the world, efforts Additionally, the originator company of Daclatasvir has signed an to address viral hepatitis, both HBV and HCV, should focus agreement with the Medicines Patent Pool to enable sublicensing on providing universal HBV birth-dose vaccination within 24 to multiple generic manufacturers in 112 LMICs [S103]. Many hours of birth, establishing hemovigilance schemes to prevent middle-income countries are viewed as having market potential transmission of blood-borne viruses, providing nonreusable and are excluded from these agreements, including China, Brazil, syringes and educating health staff in injection safety, adopt- and Thailand [S106]. More generally, complexities of volun- ing new diagnostic technologies to expand access to screen- tary licensing fragment the market, ensuring that pricing power ing, specializing intervention efforts for vulnerable high-risk remains in the hands of pharmaceutical companies [S107]. This groups to reduce transmission where it is highest, treating all problem can be circumvented by development of new therapies: HBV-infected patients indefinitely to minimize potential harm e Dr Th ugs for Neglected Diseases Initiative (DNDi) has obtained caused by discontinuation, and collaborating across the contin- the license for a new HCV DAA, ravidasvir. This has allowed it to ent to drive down HCV drug costs to ensure that, once treat- begin production of the drug through an Egyptian firm, Pharco ment has been accessed, it is affordable. Pharmaceuticals, without the need to maximize prot [S108]. fi Supplementary Data High-income countries can bulk purchase to reduce costs; Supplementary materials are available at Open Forum Infectious Diseases online. no country has attempted this more ambitiously than Australia. Consisting of data provided by the authors to benefit the reader, the posted e g Th overnment agreed to a AU$1 billion (US$0.73 billion) materials are not copyedited and are the sole responsibility of the authors, so program to treat 62 000 individuals, corresponding to per-treat- questions or comments should be addressed to the corresponding author. ment costs of around US$12 000 [S109]. The true novelty of the Australian approach is that if expenditure exceeds up-front cost, Acknowledgments e a Th uthors are grateful to the Newton Fund, the British Council, the the price of drugs decreases, potentially to 0 [S109]. Australia Mosharafa Foundation, the Science and Technology Development Fund, has, in effect, created a subscription system, paying a fixed and the South African National Research Foundation for facilitating the amount and treating as many Australians as it can. workshop and for funding the conference at which this work was started. What ultimately unites these approaches is their customized Author contributions. I.W., A.I.G., C.W.S., M.W.S., Y.X.H., R.J.W., N.C., and S.T.R.  organized the conference and conceived the article, along with its nature; some countries have had success in reducing prices, but principal themes. A.H., A.G.L., C.R.J., E.B., G.N., I.W ., R.S., S.N., and Z.M. wrote others risk being left behind. A unified approach must be taken the initial draft. All authors critically reviewed the manuscript. A.H., S.T.R., to ensure that high-quality, low-cost drugs are available regard- C.W.S., Y.X.H., R.J.W., and M.W.S. edited and formatted the final submission. Potential conifl cts of interest. All authors: no reported conflicts of less of location. Pooled procurement is one method for achieving interest. All authors have submitted the ICMJE Form for Disclosure of this, an approach pioneered by the Global Fund to tackle the HIV, Potential Conflicts of Interest. 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J Int AIDS Soc 2013; 16:18518. 6 • OFID • Heffernan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx252/4638518 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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