Time for the Elimination of 70 Hepatitis C Virus as a Global Health Threat

John W. Ward1,2, Alan R. Hinman1, and Harvey J. Alter3 1Task Force for Global Health, Decatur, GA, USA 2Centers for Disease Control and Prevention, Atlanta, GA, USA 3Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA

INTRODUCTION in medicine, cure over 90% of people who complete treatment [7]. The HCV elimination goals provide the impetus for coun- Disease elimination and eradication, the ultimate goals of dis- tries to put in place their own comprehensive HCV prevention ease control, can achieve large health benefits and ensure global programs. The development of such programs is just beginning, health equity. HCV meets the benchmarks of a major public and the knowledge and experience gained from past elimination health problem whose elimination is feasible [1–3]. In 2016, the efforts (e.g. smallpox and polio) can be employed to success- World Health Organization released the Global Health Sector fully eliminate HCV. In this chapter, we will review the health Strategy on Viral Hepatitis 2016–2021: Towards Ending Viral burden of HCV infection, the process for development of HCV Hepatitis, which set goals to be achieved by 2030 that would elimination goals, the successes and challenges in the imple- indicate progress toward the elimination of hepatitis C virus mentation of interventions to reach these goals, field studies (HCV) as a public health threat. The goals are 90% reduction in illustrating the essential components of effective elimination global incidence and 65% reduction in global mortality by 2030 programs, and the key research that will accelerate progress [4]. If those goals were met, then estimated global HCV inci- toward elimination of HCV infection. dence would decrease from 1.75 million per year in 2015 to 175 000 per year in 2030; and global mortality would decrease from approximately 400 000 deaths with HCV as the underlying cause in 2015 to 140 000 per 100 000 population in 2030 [5]. In THE PUBLIC HEALTH PROBLEM 2015, the World Health Organization (WHO) estimated that 71 OF HCV INFECTION million people were infected with HCV globally. In 2016, the World Health Assembly (WHA) passed a resolution of endorse- Diseases must be of sufficient magnitude to warrant the prioriti- ment supporting the WHO goals and adding HCV to the select zation of resources for a dedicated elimination program. HCV is group of diseases targeted for global elimination [6]. a substantial public health problem globally: in 2015, an esti- Biologically, HCV is a virus that is easily transmitted via par- mated 71 million people (1% of the global population) were enteral exposures to contaminated blood with low infectivity infected with HCV [5]. HCV is present in almost all countries. through other routes. Global initiatives have greatly reduced However, HCV varies greatly at the national level, reflecting transmission in healthcare settings, increasing the proportion of differences in risk exposures and the importance of reliable data cases attributable to injection drug use. The latency from HCV to reveal local patterns of transmission and burden of disease. infection to onset of severe disease is several decades, providing First, based on genetic differences, HCV is classified into ample time for early diagnosis and treatment to prevent prema- seven genotypes which differ in frequency by country [7]. ture mortality. Tests for anti‐HCV and HCV RNA reliably detect Certain countries have high prevalence of HCV infection, HCV infection. New all‐oral therapies for HCV, a major advance including Mongolia (6.7%), Egypt (6.4%), Pakistan (3.8%),

The Liver: Biology and Pathobiology, Sixth Edition. Edited by Irwin M. Arias, Harvey J. Alter, James L. Boyer, David E. Cohen, David A. Shafritz, Snorri S. Thorgeirsson, and Allan W. Wolkoff. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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Russia (2.9%), and Romania (2.5%) [8]. Prevalence can also international call for action to apply this new prevention tool to vary at the sub‐national level. For example, in Egypt, a country more effectively prevent HCV transmission and disease. From of high prevalence, the prevalence is higher in Lower Egypt 2000 through 2010, HCV‐related mortality increased 10% glob- (8.2%) compared with Upper Egypt (2.2%) [9–11]. In the ally, whereas mortality from other infectious diseases, including United States, the estimated 1.67% anti‐HCV prevalence in HIV, malaria, and TB, declined during this time period [23]. In 2010 varied by state, ranging from a high of 3.34% (Oklahoma) 2010, 2014, and 2016, the WHA passed three resolutions recog- to a low of 0.71% (Illinois) [12]. nizing HCV and other forms of viral hepatitis as global public Globally, the population with highest prevalence of HCV health problems [2, 24, 25]. In 2010, the WHA called on WHO infection is persons who inject drugs (PWIDs). In 2017, of an and member states to take greater action to improve viral hepa- estimated 15.6 million people with a history of drug injection, titis prevention diagnosis and treatment. In 2011, the first‐gen- 8.1 million (52%) have been infected with HCV [13, 14]; 58% eration oral antiviral therapies that required continued use of of PWIDs with HCV have a history of incarceration. As a result, interferon‐based therapies for HCV infection were licensed in in 2012, an estimated 2.2 million incarcerated persons (26%) the United States by the US Food and Drug Administration have been infected with HCV [15]. In the United States, an esti- (FDA). In 2012, WHO released the first action plan to prevent mated 1.5 million people who are currently injecting drugs or viral hepatitis and began to assist countries with local preven- did so in the past are infected with HCV [14]. tion planning [26]. At the time, only 37% of 126 member coun- In 2010, an estimated 3.5 million people were infected with tries had national plans for viral hepatitis prevention [27]. HCV in the United States [16]. HCV is a leading cause of mor- In 2014, the WHA called for continued improvements in tality from infectious disease in the United States [17]. Deaths HCV prevention and emphasized the importance of prevention from HCV surpassed the number of deaths from HIV in 2007 measures to protect PWIDs [24]. Importantly, the WHA and in 2014, deaths from HCV exceeded the number of deaths requested WHO examine the feasibility of setting goals for from the 60 other reportable infectious diseases in the United elimination of HBV and HCV infection. In 2014, the first all‐ States [17, 18]. In 2016, a total of 18, 153 deaths (4.5 deaths/100 oral therapies for HCV infection were licensed in the United 000 population) were associated with HCV infection [19]. States by the FDA. In 2015, a total of 1.7 million new HCV infections occurred To respond to the WHA request, WHO convened numerous globally, with 40% attributed to unsafe injection in healthcare stakeholder consultations with member states, organizations in settings and about one‐third attributable to current injecting‐ the United Nations system, and other multilateral agencies, drug use [5]. Exposures in healthcare settings include receipt of donor and development agencies, civil society, nongovernmental unscreened blood and blood products from HCV‐infected organizations, scientific and technical institutions and networks, donors and procedures with nonsterile injection equipment and the private sector. WHO also commissioned models to esti- [5, 7]. The proportion of HCV attributable to healthcare and mate the impact of various prevention strategies on transmission­ injection drug use varies globally. Receipt of unscreened blood and burden of disease. While this process was underway in and poor infection control are the major modes of transmission 2015, the United Nations, in the Sustainable Development in low and middle income countries. PWIDs account for most Goals, called for a global response to combat viral hepatitis [28]. new infections in high and some middle income countries. In 2016, WHO released the WHO Global Health Sector Other routes of HCV transmission are less common. Children Strategy on Viral Hepatitis 2016–2021: Towards Ending Viral born to HCV‐infected mothers have a 6–14% risk of HCV Hepatitis [4]. In the global strategy, WHO set global targets for infection [20, 21]. Other incidental parenteral contacts with the elimination of HCV as a public health threat, defined as a 90% blood, intranasal inhalation of drugs, unregulated tattooing, and reduction in the incidence of HCV infection and a 65% reduction ritual scarification are associated with the spread of HCV [7]. in HCV‐related mortality by 2030. A discussion regarding setting Sexual transmission of HCV is rare except among certain and communicating elimination goals follows below. Countries ­populations of HIV‐infected men who have sex with men are encouraged to set more ambitious national goals based on the (MSM) [22]. Prevention is important in these populations. local assessment of burden of disease, the populations affected, However, achieving HCV elimination goals hinges on prevent- the capacity of clinical care and public health systems, and the ing the most common routes of transmission from unscreened resources available for mobilization. The 2016 WHA resolution blood and blood products and nonsterile injections in healthcare endorsed the strategy and elimination goals. WHO has set per- and community settings. formance targets for 2020 and 2030 for the key prevention inter- ventions, including HCV diagnosis and treatment (Figure 70.1). In parallel with global actions, steps were taken in the United States to strengthen the policy foundation for HCV pre- THE PROCESS FOR SETTING HCV vention. In 2010, the US Institute of Medicine (IOM) reported ELIMINATION GOALS findings from an expert panel that the national prevention capacity for HCV and other forms of viral hepatitis was inad- The development of the WHO strategy for HCV elimination fol- equate and recommended improvements in viral hepatitis sur- lowed a series of policies and actions globally. As new data veillance and prevention services [29]. The IOM called for the revealed mounting mortality from HCV infection, there were US government to draft a national action plan. In May 2011, progressively urgent calls for improvements in HCV prevention, the national action plan for viral hepatitis prevention was care, and treatment. The licensure and demonstrated effective- released by Assistant Secretary of Health Dr. Howard Koh ness of antiviral therapy in curing HCV infection added to the [30]. The national action plan was updated in 2014 and 2017

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Incidence of HCV infection Incidence rate (per 100 000) Total number (000)

WHO region Map key Best Uncertainty Best Uncertainty estimate interval estimate interval

African Region 31.0 22.5–54.4 309 222–544

Region of the Americas 6.4 5.9–7.0 63 59–69

Eastern Mediterranean Region 62.5 55.6–65.2 409 363–426

European Region 61.8 50.3–66.0 565 460–603

South-East Asia Region 14.8 12.5–26.9 287 243–524

Western Pacifc Region 6.0 5.6–6.6 111 104–124

Global 23.7 21.3–28.7 1 751 1 572–2 120

Figure 70.1 Incidence of HCV infection in the general population by WHO region, 2015. Reproduced from [5] with permission of the World Health Organization.

(https://www.hhs.gov/hepatitis/index.html). In 2017, the of controversy, that the annihilation of the Small Pox, the most National Academy of Sciences, formerly the IOM, released dreadful scourge of the human species, must be the final result of two reports recommending the global HCV elimination goals this practice” [32]. However, organized efforts to eradicate be adopted as national goals for the United States. The National ­diseases from humans did not begin until the early and mid‐­ Academies proposed a set of actions to build the prevention twentieth century. Yellow fever (1915–1977), yaws (1954–1967), and clinical capacity to achieve these goals [31]. malaria (1955–1969), and smallpox (1955–1980) were the first diseases targeted for eradication [32]. Of these, only smallpox has been eradicated as certified by the WHA in 1981 [33–35]. The successful campaign to eradicate smallpox sparked interest in tar- SETTING A GOAL FOR ELIMINATION geting other diseases for eradication, including dracunculiasis OF HCV AS A PUBLIC HEALTH THREAT (i.e. guinea worm) in 1986 and polio in 1988; both of these efforts are ongoing [1, 36]. The terms “eradication” and “elimination” are sometimes used The terms eradication and elimination both convey informa- interchangeably, as both convey information about the intended tion about the intended scope of disease control. Decades of scope of disease control. The concept of disease eradication origi- academic discussion including conferences in Berlin (1997) nated with Edward Jenner, who developed the first smallpox vac- Atlanta (1998), and Frankfurt (2010) [4, 36] resulted in general cine. Jenner wrote in 1801 “It now becomes too manifest to admit acceptance of standard definitions for disease eradication and

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elimination. Eradication is the permanent reduction to zero of support delivery of prevention and clinical services. Second, the worldwide incidence of infection caused by a specific agent numerical goals can be used to drive program planning, prior- as a result of deliberate efforts. Elimination of transmission itize resources, and monitor program performance. Lastly, in (also referred to as interruption of transmission) is the mean contrast to elimination programs for other infectious disease reduction to zero of the incidence of infection caused by a spe- agents that cause most morbidity at the time of infection, cific pathogen in a defined geographical area, with minimal risk WHO’s definition appropriately encompasses both HCV trans- of reintroduction, as a result of deliberate efforts. Continued mission and later disease as targets for elimination. The inter- actions to prevent re‐establishment of transmission may be ventions to prevent HCV transmission (e.g. clean injections, required [37]. De Serres et al. have pointed out that zero inci- safe blood supply) differ in large degree from the interventions dence is essentially unattainable in the absence of eradication necessary to eliminate the risk of mortality for those with because of the continued risk of importation with limited subse- chronic HCV infection (testing and treatment). quent spread [38]. In summary, WHO has set feasible targets for reductions in In practice, the term elimination has been used to describe HCV transmission and disease in the framework of the elimina- different targets – specific levels of control (e.g. reduction of tion of HCV as a public health threat. The WHA and the neonatal tetanus deaths to <1/100 000 live births in all districts International Task Force for Disease Eradication, two authorita- or reducing incidence of tuberculosis to <1/million population), tive bodies, have endorsed HCV joining the select group of dis- or interruption of measles transmission as manifested by no eases targeted for global elimination. However, the global chains of transmission lasting >1 year [39–43]. elimination goals are not necessarily final. HBV and HCV elim- There remain considerable differences in perspectives in the ination goals can be revised as program experience is accrued use of the term disease elimination. For example, the interna- and operational research is conducted. WHO encourages tional collaboration to eradicate measles prefers to use the national and local programs to develop numerical goals appro- term elimination for national and regional achievements and priate for their epidemiologic circumstances and health system preserve the term eradication for the global goal [2, 43, 44]. capacity. This flexibility fosters the accumulation of a wide Similarly, the global strategic framework to eliminate malaria body of experience from programs with ambitious goals for sets national and regional goals for cessation of transmission HCV elimination providing the evidence needed to revise global to achieve a global goal of a 90% reduction in incidence of goals. As progress is made, more stringent targets may be malaria by 2030 [45]. For the END‐TB campaign, the elimina- defined, potentially ultimately leading to an eradication goal. tion goal is reducing incidence to less than 1 per million popu- lations by 2035 [40–42]. In 1997, WHO introduced the concept of “elimination as a public health problem” as defined by achievement of measura- DETERMINANTS FOR SETTING ble global targets set by WHO in relation to a specific disease. FEASIBLE TARGETS FOR HCV When reached, continued actions are required to maintain the ELIMINATION targets and/or to advance the interruption of transmission. This concept of disease elimination is controversial and not as well Knowledge has been gleaned from other disease eradication and accepted as zero goals [36, 46]. First, there is an absence of a elimination programs, revealing the essential criteria to target a standard definition to designate a disease as a “public health disease for elimination [1, 2, 5, 33–36] (Table 70.1). problem.” Second, the targeted improvements in transmission HCV infection meets three biologic features for disease elim- or morbidity/mortality required to designate a disease as no ination. First, humans are essential in the life cycle of the agent: longer a “public health threat” can be perceived as arbi- HCV does not propagate in the environment, and intermediate trary. The definition may vary depending on circumstances, hosts are not involved in the replicative cycle of HCV. resources, etc. For some conditions (e.g. lymphatic filariasis,) Second, tests of high sensitivity and specificity are widely there is no specification of the level representing elimination; available to detect and diagnose HCV infection. Practical consequently, it may not be possible to know when elimination ­diagnostic tests are available to reliably detect past or current has been achieved [44]. HCV infection. Laboratory assays can detect antibodies to Resolution WHA69.22 of the 2016 WHA adopted the “global HCV ­cellular proteins within two weeks of HCV infection with health strategies on, respectively, HIV, viral hepatitis and sexu- a ­sensitivity and specificity of 97% and 99%, respectively ally transmitted infections, for the period 2016–2021” [4]. [47–49]. HCV antibody testing also is available as a point‐of‐care These strategies included a call for elimination of hepatitis B assay with equivalent performance as laboratory‐based testing. and C as a major public health threat by 2030. Specific targets Of HCV‐infected persons, 25–30% will clear infection spontane- set were 90% reduction (compared to 2015 levels) in new infec- ously; people cured of their infection continue to have HCV anti- tions and 65% reduction in deaths. Interim targets for 2020 were body detectable on serologic tests [7, 50]. Following a positive 30% reduction in infections and 10% reduction in deaths. test for HCV antibody, a second virologic test, typically for HCV Despite the imprecision of WHO’s general definition of HCV RNA, is necessary to diagnose current infection [51]. HCV RNA elimination as a public health threat, the hepatitis targets, as tests detect evidence of infection before antibody testing and the stated, serve several purposes. First, the elimination targets con- use of both tests improves detection of HCV in blood donations vey a sense of urgency, increasing awareness of the opportuni- and safety of the blood supply [52–54]. HCV RNA testing is ties for improving health through improved HCV prevention required for monitoring response to therapy, and document viro- and cure and helping to engage partners and build capacity to logic cure after completion of treatment. Point‐of‐care assays are

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Table 70.1 Criteria for setting feasible elimination goals for HCV rarely causes clinically significant disease [65]. Most HCV‐ Global public health importance related morbidity and mortality is caused by chronic HCV • 71 million persons with HCV infection infection, which can be clinically silent for decades before • 399 000 deaths ­causing cirrhosis, hepatocellular carcinoma (HCC), and other • Cause of one in five deaths from liver cancer extrahepatic manifestations (e.g. non‐Hodgkin’s lymphoma, Biologic feasibility • HCV requires humans for replication has no intermediate hosts and cryoglobulinemia, and renal disease) [7]. does not propagate in the environment • HCV infection is detectable by practical diagnostic tools with high sensitivity and specificity Technical feasibility • HCV modes of transmission are limited to parenteral contact • HCV‐related disease develops several decades after infection In the absence of a hepatitis C vaccine, multiple interventions Technical feasibility are effective in interrupting parenteral transmission of HCV in Prevent transmission the blood bank setting and related to unsafe injections in the • HCV testing and removal of HCV‐contaminated donations from the blood supply healthcare and community setting. The WHO has set perfor- • Universal precautions for infection control in healthcare settings mance indicators to monitor the implementation of key inter- • Adequate access to addiction treatment, sterile equipment and related ventions to eliminate HCV (Figure 70.2). services for persons who inject drugs • Test and cure HCV to reduce force of infection Prevent morbidity and mortality Donations screened with high‐quality tests • Test and cure HCV to stop disease progression Once a common mode of transmission, the strategies of rou- • Interventions are cost effective or cost saving tinely screening donors for HCV‐associated risks factors, HCV Global endorsement testing of donated blood, and removal of HCV‐contaminated • World Health Assembly • International Task Force for Disease Eradication blood donations from the blood supply, virtually eliminates transfusion‐associated HCV. In 1992, the United States and other countries began implementing these interventions [52– available to detect HCV in settings where laboratory testing is not 54, 74–83]; new generations of tests improve sensitivity and readily available [55, 56]. Assays to detect HCV core antigen are ­specificity. Over time, the risk of HCV infection among recipi- alternatives to HCV RNA testing [57–59]. ents of blood products fell from 7% to 10% (during the 1980s) Third, effective interventions are available that can stop to 1 per 1 000 000 donations in 2010 [67–71, 74–83]. HCV transmission and prevent morbidity and mortality. HCV is a antibody testing of donated blood is highly cost effective or cost bloodborne virus with constrained modes of transmission. saving [84]. The cost effectiveness of the addition of HCV RNA HCV does not penetrate intact skin, and there is no evidence of testing varies according to the prevalence and incidence of HCV vectorborne or airborne transmission. As a result, an HCV‐ in the donor population [84, 85]. infected person is estimated to transmit only two new infec- Because of financial issues and the lack of laboratory infra- tions over the course of their infection. This reproduction structure, HCV testing in blood banks was not immediately number (R0) of 1.2–2.9 for HCV is much less than the repro- adopted by all countries. Progressively, through the WHO Blood duction number for smallpox (4.5), a disease successfully Transfusion Safety Program (http://www.who.int/bloodsafety/ eradicated, or for polio (6.0) and measles (14.5), diseases suc- en/), PEPFAR support for blood safety (https://www.pepfar. cessfully eliminated in several regions of the world [60–62]. gov/documents/organization/83108.pdf), and regional efforts The final biologic characteristic that makes possible the (e.g. the Strengthening Laboratory Management Toward achievement of HCV elimination goals is the long latency Accreditation program in Africa) (https://slmta.org/), an increas- period from HCV infection to development of severe disease, ing number of countries have adopted routine HCV testing of which provides ample time for diagnosis and treatment to blood donations. By 2016, 174 of 175 countries responding to a ­prevent premature mortality [7, 63–73]. Acute HCV infection WHO survey reported having a policy in place for screening

HBV-Vaccination

HBV-PMTCT

Blood safety

Injection safety

Harm reduction

HBV–Diagnosis

HCV–Diagnosis

HBV–Treatment a 2015 baseline 2030 targets HCV–Treatment

0204060 80 100 Coverage (%)

Figure 70.2 Service coverage indicators for HCV elimination – the core interventions. PMTCT, prevention of mother‐to‐child transmission.

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donated blood for HCV [86]. Overall, 89% of donations are increasing the numbers of PWIDs tested, diagnosed, and cured screened following procedures to assure quality of testing. of their HCV infection can lower prevalence and force of However, the expansion of HCV antibody and RNA testing can infection, leading to >90% declines in incidence [100, 101]. reduce transmission to as low as 0.5 transmissions per million Because of reductions in both HCV transmission and disease, transfusions [83]. This testing is currently available in only a treatment of PWIDs for HCV is highly cost effective or cost quarter of the countries reporting routine HCV testing of the saving [102, 103]. blood supply. Efforts to optimize blood bank screening are Globally, in 2010, an estimated 27 sets of syringes and nee- ­particularly important for low‐income countries, where 1 in 100 dles were exchanged per user, per year, a rate far below the blood donors have evidence of HCV infection [86]. WHO targets of 200 and 300 of such exchanges for the years 2020 and 2030, respectively [13, 104, 105]. A study of PWIDs Reducing the proportion of unsafe injections in North America, Australia, and the Netherlands from 1985 through 2011 found an overall incidence rate of 22.6 per 100 The major risks for HCV transmission include reuse of injec- person‐years of observation (PYO), with declines in incidence tion devices and contamination of multidose vials [6, 87–92]. among PWIDs observed over this period from 24.6/100 PYO to The implementation of universal precautions for infection con- 18.8/100 PYO [97, 106]. The greatest declines in HCV inci- trol result in substantial declines in the prevalence of HCV dence were observed in Australia and the Netherlands, two among patients and healthcare workers [90, 91]. The steps countries that began in the 1980s to expand access to SSPs and toward universal precautions include setting up infection con- OST. In contrast, HCV risk behaviors and incidence among trol programs with staff, monitoring and responding to lapses PWID are high in North America, where access to SSPs and in infection control, educating clinicians in infection control, OST is limited. From 2010 through 2016, HCV incidence in the assuring reliable supplies of safe injection equipment, and United States has increased threefold, temporally associated using injection equipment that makes reuse impossible or with increases in the injection of prescription opioids and heroin extremely difficult [90–92]. Universal precautions to prevent [19]. Increases in HCV incidence are greatest in states with no HCV is cost saving [91]. or few SSPs [107]. In 2000, an estimated 2 000 000 (40%) of new HCV infections­ The recent rise in HCV transmission in the United States globally were attributed to exposures to unsafe injections [93]. might cause some to question the feasibility of reducing HCV Since that time, initiatives like WHO’s Safe Infection Global incidence by 90% from 2015 to 2030. This questioning is a Network have guided ministries of health and other stakehold- desired outcome of the disease elimination process [1, 2, 33–35]. ers to improve infection control. As a result of these initiatives, The sense of urgency created by setting limited elimination goal exposures to unsafe injections declined 88% from 2000 through leads to an examination of prevention capacity. Indeed the recent 2010, contributing to an 83% decline in the number of HCV rise in HCV transmission in the United States adds to the chal- infections attributed to unsafe injections [94]. In several regions lenges of reaching elimination targets. However, the new infec- of the world, 5% or less of injections involve reused syringes tions are not the result of changes in the virus or new modes of and needles [5, 94]. HCV transmission that increase spread of HCV. The new infec- In summary, the proportion of injections administered with tions in the United States are among PWIDs [19]. Evidence from nonsterile equipment has dramatically declined. Reducing this other countries demonstrate that strong prevention programs number even further requires enhanced community‐based efforts ­sustained over time result in low HCV incidence among this risk to educate patients about the availability of oral medications that population [106]; the availability of curative HCV therapies is are equally as effective as those administered via injection. A the new intervention that can further decrease transmission. The substantial number of patients in some parts of the world strongly ­incidence trends in the United States are the result of a poor HCV prefer and receive injectable medications despite availability of prevention infrastructure for this population. With sufficient oral equivalents, unnecessarily increasing HCV risk exposures improvements in prevention capacity, which are totally feasi- [9, 95]. This is particularly problematic in Egypt, where the prev- ble for a high‐income country such as the United States, alence of HCV infection among patients is high and health facili- HCV incidence will decline among PWIDs and elimination ties lack adequate infection control procedures [9]. goals can be achieved. Improving access to sterile syringes and needles for persons who inject drugs Increasing the proportion of infected persons diagnosed with HCV HCV transmission among PWIDs is preventable with imple- mentation of a combination of interventions, such as opioid sub- HCV testing is the essential step in a plan to reduce the preva- stitution therapy (OST), syringe service programs (SSPs), and lence of HCV and subsequent mortality. However, few silent HCV testing linked to therapy [96–101]. Based on a review of HCV carriers have been diagnosed with HCV, and even fewer published studies, adequate access to OST and SSP reduces have received treatment. WHO estimates that in 2015, a total of transmission risk by 50% and 23%, respectively, and together 71 million people were infected with HCV globally [6, 8, 104], by 71% [97, 98]. Syringe services are highly cost effective or of whom only 14 million (20%) have been diagnosed [104]. cost saving [98, 102, 103]. Reaching the HCV elimination goals will require diagnosing Although SSPs and OST reduce HCV incidence among 90% of HCV‐infected persons [1]. PWIDs, only antiviral therapy can lower HCV prevalence and The first step on the care continuum, HCV testing, must be risk for HCV‐related morbidity. Health models suggest that scaled up to potentiate increased access to treatment. National

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plans guided by local epidemiologic data must include policies INCREASING HCV TREATMENT prioritizing testing for populations at greatest risk (e.g. persons AND CURE AFTER DIAGNOSIS receiving unscreened blood donations and PWID) [5, 6]. The Centers for Disease Control (CDC), the United State Preventive Of HCV‐infected individuals who complete 8–12 weeks of Services Task Force (USPSTF), professional societies, and FDA‐approved antiviral therapies, more than >90% will achieve WHO recommend routine HCV testing of certain populations a sustained virologic response (SVR), with no evidence of HCV based on risk exposures, settings, and demographic charac- on testing 12–24 weeks after therapy [7, 133–137]. As of May teristics indicative of increased prevalence of HCV infection 2018, the FDA and the European Medicines Agency (EMA) [108–111]. HCV testing and treatment of PWIDs is highly together have approved 13 antivirals and several fixed‐dose cost effective or cost saving in low, middle, and high‐income combinations [126]. HCV therapies are safe, are active against ­countries [99, 112–117]. Similar returns on investment are seen all genotypes of HCV, and can effectively treat people with cir- for HCV testing and treatment of particular demographic sub- rhosis, HIV, and other previously hard‐to‐treat patients. HCV populations, including age and birth cohorts, PWIDs, and the treatment has a substantial impact on reducing the risks of HCV incarcerated. mortality. For patients with advanced liver disease, virologic In most countries, targeting multiple populations for HCV cure reduces the risk of mortality and HCC by 78% and 84%, testing is needed to fully capture the universe of persons at risk respectively [138–140]. In a large meta‐analysis, achievement for HCV infection. Testing of individuals for HCV based on risk of SVR reduces the risk of HCC and all‐cause mortality by 80% behaviors (e.g. recipients of unscreened blood, injection drug and 75%, respectively, compared with people who did not use) is a core strategy; HCV testing of incarcerated populations achieve SVR; virologic cure also results in a 56% decline in augments risk‐based testing. However, many people with expo- mortality from extrahepatic manifestations [140]. sures in the distant past do not recall drug‐use risk behaviors, or HCV testing and treatment is highly cost effective and cost are unaware of risks in healthcare settings or of perinatal trans- saving for many populations [141–147]. However, the economic mission [115, 118, 119]. benefits of HCV treatment are sensitive to the cost of HCV ther- High incidence of HCV in earlier decades has resulted in a apies. The original market prices of HCV medications (US$84 cohort of chronically infected individuals who are becoming 000–$96 000 per course) resulted in payers placing restrictive increasingly ill as their infection progresses, manifesting as criteria for approval of patients for therapy based the stage of chronic liver disease. Cohorts of older adults who have been liver fibrosis, the prescribing provider specialty, and level of infected for decades are at highest risk for severe liver dis- sobriety from alcohol and other drugs [141]. Since 2014, prices ease. In the United States, 81% of the 3.5 million people liv- of HCV medications have decreased and restrictions have been ing with HCV in 2010 were born during 1945–1965; of these, removed or loosened in some US states. The declines are result one in four has clinical evidence of severe fibrosis or cirrhosis of lawsuits by patients, competition with licensure of additional [118–120]. In other countries, different birth cohorts are dis- antiviral therapies, and data supporting shortening therapeutic proportionately affected by HCV based on different epidemi- courses from 8 to 12 weeks of treatment [142–144]. At a pricing ologic characteristics and different policies for controlling of less than $60 000 per curative course in 2015, HCV therapy risk (e.g. initiation of HCV screening in blood banks) [116, is cost saving in the United States [145]. 121, 122]. In the United States, the CDC and the USPSTF The initial market price of HCV medication also posed recommend a one‐time test for HCV for people born during ­challenges globally, resulting in many countries placing restric- 1945–1965 [109, 110]. Accordingly, a birth cohort strategy is tions on treatment. However, the costs of HCV therapies have one population‐based approach that is cost effective while declined globally. Over 100 countries can now access generic making HCV testing broadly available [123]. Other strategies medicines for US$200 (or less) per curative treatment [104]; the include testing all people in a particular setting, such as cor- prices to obtain generic HCV medications render HCV treat- rectional facilities, emergency departments, and all people ment cost saving in countries [146, 147]. In 2017, 62% of HCV‐ receiving inpatient services. Testing all adults for HCV can infected persons lived in countries where generic medicines are also be cost effective and readily implemented [124, 125]. In available [104]. 2018, WHO recommended routine HCV testing in settings The availability of new curative antiviral therapies has not yet with a ≥2% or ≥5% of HCV antibody seroprevalence in the resulted in large decreases in HCV globally. To reach the WHO general population [126]. 2030 goal, the number of cures must be large enough to reduce The release of a policy to guide HCV testing increases the global HCV prevalence by 7% annually [148]. In 2016, only 10 magnitude of HCV testing [123]. Evidence supports the use of countries, (the United States, Egypt, Japan, Australia, the certain strategies to implement policies and increase access to Netherlands, France, Spain, Germany, Iceland, and Qatar) had HCV testing for target populations. Reflex testing whereby treated ≥7% of their HCV‐infected population. Other countries specimens positive for HCV antibody are immediately tested have not made similar progress; 44 countries have treated <1% for HCV RNA improves diagnosis of current HCV infection of HCV‐infected persons during the same year. Indeed, given [127]. The ordering of HCV tests by clinicians is improved by continued increases in HCV incidence and low numbers of peo- professional education, and electronic reminders that prompt ple cured of HCV, the estimated size of the HCV‐infected popu- testing. The return of evaluation data can also motivate improve- lation is growing in Russia, other countries of Eastern Europe, ments in clinicians’ testing practices [128–131]. State‐based Central Asia, and sub‐Saharan Africa. By 2017, the global prev- mandates for HCV testing by clinicians also can be evaluated as alence of HCV‐infected population had declined by about 300 a means to increase testing [132]. 000 people to an estimated 69.55 million, representing a mere

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0.4% decline [148]. The estimated 2.1 million new HCV infec- Table 70.2 Essential components of an HCV elimination program tions annually in this analysis was also a factor in the small • Strategic data to assess HCV disease burden and health system capacity declines in HCV prevalence. • Plan of action with time‐limited numerical targets In the United States, 22–30% of HCV‐infected participants in • Civil/political support representing implementing partners and target populations national health surveys conducted in 2007–2014 reported • Capacity to deliver appropriate interventions to target populations receiving medications for HCV [149]. This number of HCV • Integration of services in existing health systems treatments will undoubtedly contribute to declines in the • Strategic data to monitor program performance and progress toward national prevalence of HCV infection. The 7% decline in HCV‐ elimination goals • Participation in operational research related mortality observed in 2016 reflects deaths averted among people cured of HCV infection [19]. This level of treat- ment suggests the United States is on track to achieve the elimi- plans [104]. Few have plans that include HCV elimination nation goals for HCV infection. For the United States to reach ­targets and plans to reach them. the national goals for HCV elimination, approximately 250 000 Civil and political support is as important as technical profi- people need to be treated each year [32]. However, to success- ciency in delivering HCV prevention, care and treatment ­services fully cure this number of infected people, large‐scale HCV test- [2, 32, 36, 46]. Political support increases program acceptance by ing and treatment programs must be implemented and sustained civil society at the national, state, or community level, increasing over time. the likelihood of the participation of target populations in the pro- As the price of HCV medications fall, the price of HCV test- gram. Political support also can assist with financing of elimina- ing represents an increasing portion of the total resources tion program activities, helping to assure sustainability of needed for HCV elimination. In some countries (e.g. Pakistan activities till elimination goals are reached. At the community and Egypt), the cost of testing is now equal to or slightly greater level, representatives of target populations can build trust through than the cost of treatment [10, 126, 150]. To improve access to assistance with education and outreach activities. this foundational and essential prevention tool and make pro- The capacity to implement elimination program activities can gress toward elimination goals, both HCV testing and treat- come from governmental and nongovernmental sources. Some ments must be affordable for individual patients and local nations have begun to support elimination programs. Disease programs. eradication and elimination programs at the national level also can be supported with resources from external organizations and coalitions. Gilead Sciences, has provided substantial resources for development of HCV programs [152–155]. The ESSENTIAL COMPONENTS OF HCV Global Fund to Fight AIDS, Tuberculosis and Malaria supports ELIMINATION PROGRAMS elimination activities for these disease [156]. The Rotary International support for polio eradication is essential to the suc- HCV elimination programs are in various stages of planning cess of that program [157]. The development of similar global and implementation at the national, sub‐national, facility, and coalitions is needed to place global HCV elimination on a sound risk population level. The experience gained from previous financial footing. disease eradication and elimination initiatives provide lessons Capacity to deliver appropriate interventions also can be built learned regarding the essential components of an HCV elimi- through integration within health systems. HCV testing and nation program (Table 70.2). First, surveillance data are treatment can be co‐localized in settings where people are needed to compile an epidemiologic profile of HCV transmis- accustomed to receiving care, improving the care cascade. An sion, burden of disease, and mortality. Information regarding additional benefit to integrating HCV elimination activities existing HCV community‐based activities, and clinical and within existing care systems includes ownership and empower- public health services programs informs program planning and ment of the community and providers; development of “local engagement of partners. The lack of a public health infrastruc- champions” facilitates adoption of HCV interventions in new ture as a foundation for HCV elimination programs is of con- settings and sustains these interventions over time. The WHO cern. Countries often lack public health surveillance and other strategic framework proposes to achieve HCV elimination by strategic information of sufficient quality to guide selection of aligning HCV prevention activities with related strategies for health outcome targets, inform program planning, and monitor HIV/AIDS, sexually transmitted diseases, safe injections, and program implementation. In 2016, only half of countries with blood safety [4]. national prevention plans had the data needed to estimate HCV When implemented within existing health systems, interven- prevalence [5]. tions associated with HCV elimination can benefit other preven- Second, a plan of action establishes time‐limited numerical tion initiatives. For instance, improved blood donor screening targets and guides program implementation. The plan prioritizes for HCV provides the platform to screen for other transfusion‐ activities, helps partners understand their roles, and provides a associated infections, improvements in infection control can basis for financial planning [10, 11, 151]. Numerical targets reduce other nosocomial infections, and the referral and training increase the accountability of program staff to reach program relationships cultivated between specialists and primary care goals. However, elimination plans are not yet in place for most professionals can be leveraged to improve the quality of care for countries. In 2017, 82 of 132 countries reported that viral hepa- other diseases. The secondary benefits of HCV elimination can titis plans were in place, compared with only 17 in 2012, yet build support for this effort, including cost sharing with other only 35% of these countries reported dedicated funding for such disease programs.

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Strategic information is needed to evaluate program activi- 80% reduction in incidence by 2025. To reach the goal, 75 of ties. The WHO performance indicators and similar data help 1000 infected PWIDs will need to be treated and cured per year; maintain the focus on program priorities, and identify successes a similar reduction in incidence would be reached by 2020 if the and gaps in service delivery. Importantly, reliable data regarding number of patients treated annually were increased to 188. HCV incidence, prevalence, and mortality are needed to moni- Iceland’s performance target is to treat most of the HCV‐posi- tor progress toward the elimination goals. Heath modeling tive people within the first 2 years of the program, with a third based on reliable data can estimate the benefits of program year dedicated to locating and treating those infected people activities to date (e.g. future deaths averted among the number who are difficult to find. of people cured of HCV infection to date) and estimate the ser- Overseen by two committees (one general and the other vices needed and related costs to achieve the elimination goals. research‐focused), the program is being implemented using a Lastly, it is important for elimination programs to partici- multidisciplinary team approach that includes physicians, pate in operational research. The prevention, care, and treat- nurses, and other healthcare professionals and engages settings ment needs of target populations change over time. Also new that provide psychosocial support services (including shelters issues arise as trends in HCV transmission and prevalence for the homeless) and correctional facilities. Key intervention change. Advances in technology can improve the feasibility of strategies are case registries to identify HCV‐infected persons elimination. Programs must remain dynamic, adaptable, and and those at risk for HCV infection, provider training, and out- open to change. reach to patients including reimbursement for travel. Point‐of‐ As a component of operational research, model programs care testing was offered in homeless shelters and other settings have a role in field testing program operations, and evaluating where PWIDs might be located. The care and treatment protocol interventions for a target population in a defined geographical was managed by specialists in addiction medicine, hematology, area or setting. For HCV, a variety of model programs are in and infectious disease. early stages of development at the national and sub‐national lev- During the first 15 months of the program, 557 people with els; programs have also been developed for specific settings and HCV were identified, and 526 started treatment [159]. The pro- populations (e.g. micro‐elimination). These model programs gram is on track to reach the national HCV elimination goal. help demonstrate the feasibility of HCV elimination and pro- The local coalition expressed concerns often voiced by disease vide operational experience in implementing the essential com- elimination programs, namely how to sustain political support ponents of HCV elimination programs. after external sources of funding come to an end.

Iceland Georgia Iceland’s demonstration project provides a model program for The country of Georgia is a low–middle income country with eliminating HCV in a high‐income, low‐prevalence country high HCV prevalence. In contrast to Iceland, risk populations [158, 159]. The focus of Iceland’s project was treating and cur- include PWIDs, blood transfusion recipients, and patients who ing HCV among PWIDs and reducing this population’s risk of have received unsafe injections in medical and dental care set- HCV transmission and reinfection. Essential features of tings [152, 156]. In April 2015, the Georgia Ministry of Health Iceland’s program include collection of strategic data to guide in collaboration with the US CDC and Gilead Sciences launched planning to reach national elimination targets, sound financing, an HCV testing and treatment program to eliminate HCV and the engagement of a local coalition of political leaders, (defined as a 90% reduction in HCV prevalence by 2020). With healthcare providers, and members of affected populations to technical assistance from the US CDC, a national HCV sero- implement appropriate interventions for the target population. logic survey was conducted revealing that 5.4% of the adult In December 2015, the country of Iceland set goals for the population was infected with HCV; men, people 30–59 years of elimination of HCV. Of the 340 000 people living in Iceland, age, PWIDs, and previous recipients of blood transfusions had an estimated 1100 (0.3%) (almost all of whom are PWIDs) the highest rates of HCV infection. In 2015, the country began a were infected with HCV at that time. Physicians caring for national HCV testing program in diverse settings; 470 890 indi- these patients engaged drug manufacturer Gilead Sciences to viduals were tested for HCV and over 10% were anti‐HCV posi- identify ways to eliminate HCV in the country. These discus- tive. HCV prevalence was greatest for PWIDs (45%). In April sions resulted in a pledge from the manufacturer to provide 2015, the HCV treatment program was launched following a financial support in the form of a donation of HCV medica- commitment of financial support by Gilead Sciences, which tions at no charge to the Icelandic health system. The public– agreed to donate HCV medications at no cost. A scale‐up of private partnership and plans for the demonstration project to sites providing HCV treatment in the country was initiated. eliminate HCV were approved by the Iceland Ministry of From April 2015 through December 2016, a total of 38 113 Health and by the directors of participating health facilities. (65%) of 58 223 people with positive HCV antibody test were Iceland’s governmental support of the project included pur- evaluated for treatment, 30 046 (79%) were confirmed as having chase of diagnostic tests and other services related to the chronic HCV infection, and 27 595 (91.8%) of those completing nationwide elimination campaign. the evaluation began treatment. Ninety‐eight percent of people HCV is a reportable condition to public health surveillance in who received all‐oral, interferon‐free therapies were cured of Iceland. The number of new (incident) HCV infections was HCV infection. The number testing positive for HCV and selected as the performance indicator and health outcome goal. receiving treatment declined in the last months of this time Based on data from health models, the program set a goal of an period, revealing the need for an expansion of testing and

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linkage to care services. A national HCV elimination plan was continued political and societal commitment to elimination, finalized in 2016 to guide expansion of clinical care to addi- availability of evaluation data, and conduct of operational tional primary care settings and safe injection services for research to drive programmatic change. Egypt’s elimination pro- PWIDs, and to make improvements in infection control within gram will likely evolve over time to meet current challenges. healthcare facilities and in blood donor screening and testing. In 2017, the HCV study team launched a scientific committee to Australia develop an operational research to provide data for expanding HCV testing, care, and treatment to primary care. Australia is another country with a national response to HCV that The benefits of the Georgia HCV program extend beyond predates the setting of global HCV elimination goals. HCV elimi- achieving the primary objective of reaching the elimination tar- nation in Australia illustrates many of the essential components of gets. Long‐lasting improvements to the health system have been a model HCV elimination program [160, 161]. The country first made that will have the additional benefits of a safer health sys- developed a plan for HCV prevention in 2000 and has made tem, stronger referral networks linking primary and specialty updates over time. Second, Australia has garnered involvement care providers, and improved services for PWIDs, all of which from diverse stakeholders representing public health, clinicians, can be used to tackle other public health issues. and civil society. Third, political commitment for HCV elimina- tion in Australia is robust: long‐standing political support and Egypt government funding have increased availability of SSPs and access to HCV testing, and as a result, the country was well posi- Egypt has one of the largest HCV‐infected populations in the tioned to set elimination goals even before availability of curative world. More than 6 million people in Egypt are living with HCV HCV therapies. Financing of HCV therapy was initially problem- infection, mostly resulting from poor infection control associated atic, limiting access to this intervention. However, cost‐related with a national, community‐based campaign against schistoso- barriers were addressed through negotiations involving the miasis conducted during 1950–1980 that required the injection of national government, civil society, and the pharmaceutical indus- medications [19, 11, 114, 151]. As a result, prevalence of HCV is try. The national government committed a budget of AUS$1 bil- highest for older adults, and this population is becoming progres- lion to purchase HCV medications in 2016–2020, and restrictions sively ill with HCV‐related disease over time. This large reservoir to HCV treatment based on stage of liver disease or history of of infected people and poor infection control contribute to 150 drug use were removed. A cap was placed on the amount of 000 new HCV infections annually. Egypt set targets for HCV national funds going to purchase HCV treatments per year so that elimination before the actions of the WHA and WHO led to as more patients are treated the cost per patient treated falls. Out‐ development of global HCV elimination goals. In 2006, the of‐pocket costs per patient were AUS$3–$7. Egyptian Ministry of Health created the National Committee for In 2016–2017, an estimated 69 000 people were treated for Control of Viral Hepatitis (NCCVH), headed by hepatitis experts HCV in Australia and 26% of the total HCV‐infected popula- from Egypt and other countries and charged with leading a tion has now received treatment. However, even with this solid national response to the HCV epidemic. The national goal and foundation of national planning, prevention infrastructure, and vision of the HCV management program in Egypt was to reduce national commitment to financing a HCV prevention and care HCV prevalence to <2% within 10 years and to approach disease program as well as HCV treatment, success in eliminating HCV elimination (prevalence <1%) by 2030. In 2011, a comprehensive in Australia is not assured. The number of people treated is national plan of action was developed to include all aspects of declining as the ones diagnosed in previous years are treated and HCV prevention, including improved infection control, blood cured, increasing the importance of continued HCV testing and bank screening procedures, and policies for HCV testing, care, linkage to care. Community education is needed to reach at‐risk and treatment. Egypt prioritized infection control, developing people who have not yet been diagnosed. Care models for collaborations with the WHO Safe Injection Campaign and estab- ­correctional establishments, indigenous populations, and other lishing infection control programs at healthcare facilities. specific settings are needed to co‐localize treatment. HCV pre- To encourage people to seek testing, a national media cam- vention services for PWIDs must continue. paign was launched to combat stigma for those with HCV. From Fortunately, Australia is one of the few countries that has both 2006 through 2017, a total of 60 HCV treatment centers were wide access to safe injection equipment (400 needle‐syringes opened across the country, a national patient registry was estab- distributed per PWID per year) and OST (40 per 100 PWIDs). lished, and testing and treatment services were made available As the number of people with HCV declines in Australia, contin- at low cost to patients [9–11]. Through this HCV treatment net- ued public attention and sustained political commitment will be work, approximately 1 million patients have received treatment. needed to achieve elimination goals. The specific targets for However, meeting Egypt’s 2030 goal requires that 350 000 peo- elimination help to sustain national commitment by focusing on ple be diagnosed and treated annually. the end‐goals that can be achieved rather than becoming com- These data reveal the necessity of scaling up testing policies placent with initial success. for broader segments of the population and addressing the finan- cial costs of testing, as the cost of diagnostic testing associated Cherokee Nation with the national program currently exceeds the cost of treat- ment. Other barriers to elimination revealed by the Egyptian pro- Elimination efforts by the Cherokee Nation of eastern Oklahoma gram are the low rate of follow‐up, which is needed to document in the United States illustrate a successful sub‐national program, cure. Despite challenges, Egypt’s program benefits from the exemplifying how elimination activities can be added in an

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iterative manner culminating in a comprehensive program treatment, including 11 000 PWIDs [164]. These estimates pro- [153]. Among racial and ethnic populations in the United States, vide benchmark data to guide delivery of prevention services rates of HCV mortality and incidence are highest for American and assess progress toward elimination goals. Indians and Alaskan Natives. The Cherokee Nation is the largest American Indian tribe and operates its own health system; all members of the tribe as well as other American Indians or Alaskan natives can receive clinical care services at no charge to SPECIFIC POPULATIONS AND SETTINGS: the patient. In recognition of HCV as a health disparity and in MICRO‐ELIMINATION response to the CDC recommendation for HCV testing of all people born 1945–1965, the Cherokee Nation health system Field studies of HCV elimination among specific populations implemented routine testing for this population. Electronic and settings, termed “micro‐elimination,” provide direct health prompts were added to the health information system, and clini- services and experience to scale up the program to reach the cal care providers were trained to provide both HCV testing and larger community. For HCV micro‐elimination projects, popu- care services. A case registry was created to monitor HCV test- lations are targeted based on their high prevalence of HCV and ing, diagnosis of HCV‐infected patients, and their receipt of opportunities to integrate HCV testing and treatment into exist- recommended services. Principal Chief Bill John Baker ing health services. expressed the civic support for the program “our hope is to elim- inate this disease entirely within the Cherokee population” Incarcerated populations [162]. Over a 33‐month period in 2012–2015, HCV testing increased sixfold, resulting in over 36% of patients in this Globally, an estimated 26% of incarcerated persons are infected 1945–1965 birth cohort being tested for HCV. Among the 16 with HCV [15]. To study implementation of an HCV elimination 772 patients tested for HCV antibody, 715 (4.3%) were anti- program in this setting, in March 2016, Lotus Glen Correctional body‐positive. Among these antibody‐positive patients, 488 Centre (LGCC), a high‐security correctional facility in Queensland, (68.3%) had a confirmatory HCV RNA test performed, of Australia housing 800 prisoners, launched an HCV elimination whom 388 (79.5%) were found to be chronically infected (HCV program [165]. HCV testing was provided for all prisoners on RNA positive). More than half (57.5%) with chronic HCV intake and for all prisoners with risks for HCV or a clinical presen- infection initiated treatment, of whom 89.6% achieved SVR tation suggestive of HCV‐related disease. All prisoners with labo- (the measure of HCV cure). ratory evidence of HCV infection were referred for treatment. The training of primary and mid‐level providers, including From March 2016 through December 2017, approximately 90% pharmacists, to provide HCV testing care and treatment services of new prison entrants were tested for HCV. A total of 125 patients greatly facilitated scale‐up of services in settings convenient for were found to have HCV and were assessed for HCV treatment. patients. Based on this initial success, the Cherokee Nation Of 66 prisoners who completed evaluation and treatment, 64 expanded routine HCV testing to include all adults, with the (97%) achieved virologic cure. With the documented cures tribal health system managing the costs of HCV testing care and among people who completed treatment and the number of cures treatment. In October 2015, the tribal leadership launched “The expected from those still receiving treatment, the prevalence of Path toward Elimination of HCV” program with the goal of HCV in the facility will have declined to 1.1%. The prison joined treating 85% of patients in the health system with HCV infec- forces with a regional project, “Cairns Hep C Free by 2020,” to tion over a 3‐year period. The health system expanded access to promote mutual treatment as prevention among the general com- HCV testing in dental, emergency care, and other services and munity and within LGCC. Lower community prevalence trans- co‐localized treatment in primary care settings. To reduce new lates to lower prevalence among future prison entrants. infections and identify people who do not access clinical care services, the elimination program is developing outreach testing People with HIV and harm‐reduction services for the community. People with HIV, particularly those with a history of injection drug use, can have higher HCV prevalence than other popula- San Francisco tions. People with HIV/HCV coinfection are at increased risk for Certain communities are responding to the call for elimination liver disease compared with other patients infected with HIV of HCV in the United States. One is End Hep C SF, a coalition alone [7]. Networks of clinical systems caring for people with of San Francisco Department of Public Health, University of HIV provide a feasible opportunity to integrate HCV testing and California San Francisco (UCSF), and community partners treatment services [166, 167]. Early results from studies of HIV/ [163]. In the absence of a national or state program, the coalition HCV‐infected people treated with all‐oral therapies reveal high aims to build the capacity to raise community awareness and rates of virologic cure (>95%) equivalent to data from clinical develop sites for testing and treatment in clinical and nonclini- trials. However, a large proportion of people remain to be treated, cal settings. To guide local planning, the coalition commis- and programmatic and strategic data are needed to track the suc- sioned a model based on local data, demonstrating that an cessful testing and cure of HCV [168]. Studies have shown that estimated 21 758 people (2.5% of the adult population) living in integrating HIV and HCV testing can improve acceptance of San Francisco have been infected with HCV. This exceeds the both interventions. Also, programs to eliminate HCV can be national HCV prevalence rate of 1.4%. A total of 16 408 people informed by best practices, including innovative approaches to are currently infected with HCV and in need of testing and testing, identified through the HIV operational research agenda.

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Other populations the gold standard for assessing the burden of HCV disease [11, 153, 169]. However, for many jurisdictions, stand‐alone surveys HCV elimination programs can be implemented for other for HCV alone are prohibitively expensive. Studies are needed ­populations with high HCV prevalence, including people with to assess whether surveys with less complex methodology and hemophilia and other blood‐clotting disorders. Of individuals requirements for testing of a smaller number of subjects will who received plasma‐derived clotting factor concentrates not provide comparable representative data. Another approach is to screened for HCV, 50–80% become infected with HCV [7, integrate HCV testing into large serologic surveys designed to 168]. The utilization of routine health services by these patients assess other infectious disease and health conditions. For exam- creates an opportunity to test and cure a population with high ple, the CDC recently assessed the reliability of HCV testing of prevalence for HCV infection [110]. dried blood spots often used in large health surveys [170]. The study found high sensitivity in the detection of HCV antibodies in stored dried blood spots but low sensitivity for detection of CLOSING EXISTING KNOWLEDGE HCV RNA. This suggests that it is best to use freshly prepared specimens to reliably detect HCV RNA in surveys. GAPS TO PROMOTE SUCCESSFUL Evaluations can inform development of standard definitions ELIMINATION for the performance indicators in the WHO global strategy and development of tools to collect this information from electronic Operational research health records. Other indicators can be considered. For exam- ple, the proportion of people positive for HCV antibody who Operational research is an essential component of disease elimi- have RNA will decline as a growing numbers of people in a nation programs. The operational research agenda is built on a populations are successfully treated [171]. This marker can be good monitoring and evaluation platform that identifies pro- evaluated as a performance indicator. Evaluations can also gram weaknesses and where changes in practice and techno- inform development of information technology tools to include logic innovations can improve performance and outcomes. In case registries of people diagnosed with HCV that allow for this regard, field trials, demonstration projects, and program monitoring of linkages to care and treatment and the outcomes evaluations are forms of operational research. Research can lead of such treatment [172]. The information obtained through case to new technologies that improve prevention, diagnosis, and registries can be used to identify people not responsive to treat- treatment. Examples of the operational research for HCV elimi- ment. Such information is critical, as treatment failures can sug- nation are listed in Table 70.3. gest the emergence of antiviral resistance. Health models based on available surveillance data can help Collection of strategic data estimate the burden of HCV disease, the impact of various interventions, and progress toward elimination goals [113, Collection of strategic information to guide and evaluate pro- 114, 124, 146]. Although more complete and accurate inputs gram performance and progress toward elimination goals is a for these models are needed, the Global Burden of Disease challenge. National or community‐based serologic surveys are provides estimates of HCV burden of mortality for over 190 countries (http://www.healthdata.org/gbd). Models can also Table 70.3 Operational research agenda for HCV elimination guide development of financing strategies for HCV testing and Strategic information treatment. • Serologic surveys to estimate disease burden • Case registries to monitor HCV testing, care and treatment outcomes Models of HCV testing, care, and treatment • Public health data to monitor progress toward elimination targets‐ incidence, mortality in diverse settings • Laboratory data to detect networks of transmission and emergence of antiviral resistance Research is needed to improve the HCV test and cure cascade by • Health models of cost effectiveness of interventions increasing the proportion of HCV‐infected people tested and Models of care aware of their infection status, referred for care and treatment, • Tools to facilitate HCV testing, linkage to care and treatment cured of HCV, and receiving services to prevent reinfection. • HCV test, care and treat procedures simplified for integration in primary care settings HCV testing is the necessary first step in the treatment and cure • HCV test, care and treat procedures for new populations (e.g. TB, of HCV‐infected people. Rates of testing currently are low due to pregnant women, children) multiple barriers that can be reduced or eliminated through oper- • HCV cure as prevention strategies for persons who inject drugs (PWID) ational research. The effectiveness of HCV testing can be • Delivery of comprehensive prevention services for PWID improved by implementing interventions in settings that serve New technologies people at high risk. Previous evaluations have identified emer- • A single test to detect current HCV infection gency departments as settings where large numbers of people • Point‐of‐care tests to diagnose current infection and monitor response with previously undiagnosed HCV infection can be found. Yet to therapy • HCV vaccine research is needed to determine how to link people from this set- Civic engagement ting into care [173]. Correctional facilities have large numbers of • Community involvement in program planning and implementation HCV‐infected people. Models of testing, care and treatment • Social marketing strategies culturally appropriate for the community financing and delivery, together with the governmental leader- • Education to address stigma and create demand for program services ship to prioritize the delivery of these services are needed [174].

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The complexity of interferon‐based therapies required man- Next‐generation sequencing can detect the relatedness of agement by hepatologists and other specialists. Yet the devel- HCV quasispecies among patient populations, identifying cases opment of all‐oral therapeutic options, which are short in with similar genetic sequences indicative of shared patterns of duration, have relatively few serious adverse events, and have transmission [178]. Studies are needed to determine how to high cure rates creates opportunities to co‐localize HCV treat- deploy this new technology. Current experience demonstrates ment into primary settings. Research is needed to guide this HCV genetic sequencing can map social networks of HCV process. Care models that simplify HCV testing and treatment transmission in communities [179]. New interventions trials can increase the feasibility of primary care clinicians and mid‐level evaluate how next‐generation sequencing can guide delivery of providers delivering HCV treatment services [144, 171]. For HCV treatment services to people in social networks, document example, the HCV elimination program in the Cherokee Nation elimination of HCV transmission, and detect the reintroduction provides evidence that HCV therapies can be managed by phar- of HCV after elimination is achieved. macists [153]. Therapies for HCV infection are highly effective. Therapeutic Studies are also needed to support integration of HCV treat- failures are relatively few, and the emergence of antiviral resist- ment into other clinical programs. For example, in some coun- ance is not a major barrier to the elimination of HCV disease tries, the prevalence of HCV is high among patients in treatment [111]. However, elimination programs need to remain vigilant for HIV or active TB; evidence is needed to inform the modifi- and collect data to monitor the emergence of antiviral resist- cation of clinical practices to include provision of HCV testing ance, as this phenomenon has been documented among people and treatment. Short courses of therapy can increase the accept- who have experienced treatment failure. ability of treatment for some patients [175]. A better under- standing of strategies that can facilitate co‐localization of testing and treatment in primary care settings can greatly benefit New prevention tools for persons patients in rural and other areas where specialty care is not rou- who inject drugs tinely available, along with settings serving marginalized popu- With improvements in blood safety and infection control, suc- lations (e.g. incarcerated and migrant populations). cess in the elimination of HCV transmission will depend on the Studies also can improve testing strategies targeted to effectiveness of HCV prevention among PWIDs. A review of PWIDs [176]. Research is needed to identify strategies for data from multiple studies suggests access to programs provid- quickly detecting new or repeat infections to prevent transmis- ing treatment for opioid addiction and those providing safe drug sion. Finally, data are needed to inform strategies for improving preparation and injection equipment lowers HCV transmission HCV testing among pregnant women and infants of HCV‐ risks, with adequate access to both interventions the optimal infected mothers. strategy. However, studies are needed to determine how best to Data can guide the integration of HCV treatment in programs deliver these services as part of a comprehensive program. providing drug treatment services. The Patient‐Centered Drug‐use behaviors, social circumstances of drug users, and Outcomes Research Institute is supporting an eight‐site study in access to clinical services vary. Addiction treatments are needed the United States of HCV treatment of PWIDs in drug treatment for methamphetamines and other illicit drugs. [177]. Available data suggest people currently injecting drugs Studies are needed to ensure strategies for delivery of preven- and HIV‐infected MSM are at highest risk for reinfection. New tion interventions are appropriate and effective for PWIDs in an studies can guide case management of these populations and areas targeted for HCV elimination. Theoretical models suggest deliver services (e.g. access to drug treatment and social support that combining HCV treatment with these risk‐reduction meas- services) that minimize reinfection risks and sustain cure. ures will optimize HCV prevention for PWIDs [97, 98, 180, 181]. Treatment as prevention is a well‐accepted method for New technologies for testing and treatment interrupting transmission of HIV. The curative therapies availa- ble for HCV potentially increase the impact of this strategy by Innovations in testing technologies can also reduce barriers to decreasing the prevalence of HCV in a risk population and low- HCV diagnosis. The current two‐step process required for HCV ering the force of infection, resulting in declines in HCV inci- testing is complicated and as such may result in substantial dence. Several research questions remain to be answered to numbers completing only part of the testing process and remain- determine how to most effectively reduce prevalence and impact ing undiagnosed. The development of precise and affordable of HCV infection among PWIDs: virologic detection assays available as front‐line tests will greatly simplify the testing process and expand the settings • How many and what percentage of HCV‐infected PWIDs where testing can be made available [156]. For example, evalu- must be treated in a given time? ations of an HCV core antigen assay, a serologic test available at • Is it advantageous to treat PWIDs as they are identified by lower cost than HCV RNA testing, found that the assay results routine HCV testing? were comparable to the results of HCV polymerase chain reac- • What is the effectiveness of strategies that encourage PWIDs tion (PCR) testing [59–61]. Point‐of‐care testing compounds in care to refer their injecting partner(s) for treatment? the advantages of virologic detection assays. At least one point‐ • Can broad HCV testing including next‐generation sequencing of‐care test for HCV has been licensed for use in Europe [57, be deployed to first map the social network of PWIDs, fol- 58]. Improvements in test technologies to differentiate acute lowed by large‐scale implementation of a coordinated HCV from chronic HCV infection would help identify patients with test‐and‐treat program to reduce prevalence as quickly as recent infection or reinfection. possible?

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• What combination of services is needed to protect individuals CONCLUSION cured of their HCV infection from returning to injection behaviors that can lead to HCV reinfection? HCV is a major public health problem. Rising global HCV mor- Prevention research also can guide the use of HCV therapies as tality rates despite availability of curative therapies has prompted antiviral prophylaxis to interrupt mother‐to‐child transmission and a global call for elimination of this life‐threatening disease. also sexual transmission, particularly among HIV‐infected MSM. Clinical studies demonstrate over 90% of HCV infections can be cured, and if initiated early in the course of disease, treatment virtually eliminates HCV‐related mortality. New infections can Development of a hepatitis C vaccine be limited through continued improvements in public health and A safe and effective vaccine could help prevent new HCV infec- clinical interventions. The greatest remaining challenges are tions and could be particularly important in preventing trans- providing prevention services for PWIDs and implementing mission among PWIDs [181–184], the population at greatest large‐scale HCV testing programs to identify and link to care risk for new infection. An effective vaccine could reduce the risk persons living with this silent infection. As elimination chal- of HCV transmission if it were routinely provided to people lenges are met and lessons learned, HCV elimination programs before the onset of high‐risk behaviors. Health models suggest will strengthen existing health systems and help inform other even a hepatitis C vaccine of low efficacy could be a cost‐effec- disease control and elimination efforts. The journey toward the tive approach to prevention of HCV among PWIDs [181]. elimination of HCV has just begun, and program development People tend to begin drug injection behaviors as young adults, and operational research are nascent. Partnerships with global and the incidence of HCV is highest (26 per 100 person‐years of and local organizations are needed to build the capacity to observation) for new injectors [14]. Therefore, to optimize the deliver the highly effective interventions available to eliminate impact of such an intervention, an HCV vaccine would need to HCV. Programs must learn by doing and conduct the opera- be administered during early adolescence, before the start of tional research needed to capitalize on technologic innovations injection behaviors. Research to this point has failed to identify and existing models of care. By building prevention capacity a promising candidate. The lone clinical trial in progress is a and working together, HCV transmission and disease can be study of a prime/boost strategy using a chimpanzee adenoviral eliminated. (prime) and modified vaccinia virus Ankara (boost) vectors to induce HCV‐specific T cell responses. The study assessed the safety and effectiveness of the candidate vaccine in reducing HCV incidence among PWIDs [183]. The study found the vac- REFERENCES cine candidate not to be effective at preventing chronic HCV infection in adults [184]. Although not successful, a concerted 1. Dowdle, W.R. The principles of disease elimination and eradication. Bull World Health Organ, 1998;76(Suppl 2):22–5. and coordinated research effort by the public and private sectors 2. Cochi, S.L. and Dowdle, W.R. Introduction, in Disease Eradication in the is needed to assure future studies of other vaccine candidates. 21st Century: Implications for Global Health (Eds. S.L. Cochi and W.R. Dowdle), MIT Press, Cambridge, MA, 2010, pp. 33–61. 3. Hinman, A.R. Prospects for disease eradication or elimination. N Y State J A Coalition for Global Hepatitis Elimination Med, 1984;84(10):502–6. Many disease elimination efforts are supported by a technical hub 4. Global Health Sector Strategy on Viral Hepatitis 2016–2021: Towards Ending Viral Hepatitis, WHO/HIV/2016.06, World Health Organization, 2016. http:// of readily available information and access to expert assistance. www.who.int/hepatitis/strategy2016–2021/ghss‐hep/en/ (Accessed Jul 15, Examples include HIV (http://www.differentiatedservicedelivery. 2018). org/home), neglected tropical diseases (http://www.ntdsupport. 5. WHO. Global Hepatitis Report, 2017. World Health Organization, Geneva, org/), and malaria (http://allianceformalariaprevention.com/). http://www.who.int/hepatitis/publications/global‐hepatitis‐report2017/en/ The success of HCV elimination programs hinges on availability (Accessed Jul 17, 2018). 6. Draft Global Health Sector Strategies. Viral Hepatitis, 2016–2021, Sixty‐ of such a resource, as these programs are early in development and Ninth World Health Assembly. http://apps.who.int/gb/ebwha/pdf_files/ individual efforts tend to be relatively isolated. Program leaders WHA69/A69_32‐en.pdf?ua=1 (Accessed Jun 18, 2018). have varying levels of experience and training to analyze epide- 7. Ward, J.W. and Holtzman, D.A. Hepatitis C, in Zakim and Boyer’s miologic information and prepare scientific reports. Results of Hepatology: A Textbook of Liver Disease, 7th edn (Eds. T.D. Boyer, M.P. operational research, when available, are often presented or pub- Manns, A.J. Sanyal, and N. Terrault), Elsevier Health Sciences, London, 2017, pp. 428–45. lished in multiple locations over time, complicating and delaying 8. Polaris Observatory HCV Collaborators. Global prevalence and genotype access to this information. HBV and HCV elimination programs distribution of hepatitis C virus infection in 2015: a modelling study. Lancet have limited access to technical experts that can facilitate their Gastroenterol Hepatol, 2017;2(3):161–76. work and help overcome barriers to implementation. Guided by 9. Talaat, M., El‐Oun, S., Kandeel, A. et al. Overview of injection practices in experience of elimination programs for other diseases, the Task two governorates in Egypt. Trop Med Inter Health, 2003;8:234–41. 10. El Kassas, M., Elbaz, T., Elsharkawy, A., Omar, H., and Esmat, G. HCV, Force for Global Health launched in July 2019 the Coalition for prevention, treatment and key barriers to elimination. Expert Rev Anti Infect Global Hepatitis Elimination as a community of practice to Ther, 2018;16(4):345–50. obtain consensus on elimination goals, bring implementing pro- 11. Gomaa, A., Allam, N., Elsharkawy, A. et al. Hepatitis C infection in Egypt: grams together to share knowledge and experience, provide tech- prevalence, impact and management strategies. Hepat Med, 2017;15(9): 17–25. nical assistance to overcome barriers, generate new knowledge 12. Hall, E.W., Rosenberg, E.S., and Sullivan, P.S. Estimates of state‐level through research, and advocate for viral hepatitis elimination and chronic hepatitis C virus infection, stratified by race and sex, United States, the resources to achieve it (www.globalhepatitiselimination.org). 2010. BMC Infect Dis, 2018;18(1):224.

0004435662.INDD 948 10/05/2019 10:59:16 70: Time for the Elimination of Hepatitis C Virus as a Global Health Threat 949

13. Degenhardt, L., Peacock, A., Colledge, S., et al. Global prevalence of inject- 37. WHO. 89th Meeting of the Strategic and Technical Advisory Group for ing drug use and sociodemographic characteristics and prevalence of HIV, Neglected Tropical Diseases, 2015. http://www.who.int (Accessed Jun 15, HBV, and HCV in people who inject drugs: a multistage systematic review. 2018). Lancet Glob Health, 2017;5(12):e1192–207. 38. De Serres G1, Gay, N.J., and Farrington, C.P. Epidemiology of transmissible 14. Midgard, H., Weir, A., and Palmateer, N. HCV epidemiology in high‐risk diseases after elimination. Am J Epidemiol, 2000;151(11):1039–48. groups and the risk of reinfection. J Hepatol, 2016;65(1 Suppl):S33–S45. 39. WHO. Maternal and neonatal tetanus elimination (MNTE). http://www.who. 15. Larney, S., Kopinski, H., Beckwith, C.G. et al. Incidence and prevalence of int/immunization/diseases/MNTE_initiative/en/ (Accessed Aug 6, 2017). hepatitis C in prisons and other closed settings: results of a systematic review 40. Uplekar, M., Weil, D., Lönnroth, K. et al. WHO’s new end TB strategy. and meta‐analysis. Hepatology, 2013;58(4):1215–24. Lancet, 2015;385:1799–801. 16. Edlin, B.R., Eckhardt, B.J., Shu, M.A., Holmberg, S.D., and Swan, T. 41. WHO. Implementing the end TB strategy: the essentials. http://www.who. Toward a more accurate estimate of the prevalence of hepatitis C in the int/tb/publications/2015/The_Essentials_to_End_TB/en/ United States. Hepatology, 2015;62(5):1353–63. 42. Lönnroth, K., Migliori, G.B., Abubakar, I. et al. Towards tuberculosis elimi- 17. Ly, K.N., Hughes, E.M., Jiles, R.B., and Holmberg, S.D. Rising mortality nation: an action framework for low‐incidence countries. Eur Respir J, associated with hepatitis C virus in the United States, 2003–2013. Clin Infect 2015;45:928–52. Dis, 2016;62(10):1287–8. 43. WHO. Measles fact sheet. Updated 2018. http://www.who.int/news‐room/ 18. Ly, K.N., Xing, J., Klevens, R.M. et al. The increasing burden of mortality fact‐sheets/detail/measles (Accessed Jul 15, 2018). from viral hepatitis in the United States between 1999 and 2007. Ann Intern 44. WHO. Global Programme to Eliminate Lymphatic Filariasis. http://www. Med, 2012;156(4):271–8. who.int/lymphatic_filariasis/elimination‐programme/en/ (Accessed Jul 15, 19. CDC. Viral Hepatitis Surveillance 2016. CDC, Atlanta, GA. https://www. 2018. cdc.gov/hepatitis/statistics/index.htm (Accessed Jul 15, 2018). 45. WHO. A Framework for Malaria Elimination. World Health Organization, 20. Mast, E.E., Hwang, L.Y., Seto, D.S. et al. Risk factors for perinatal transmis- Geneva, Switzerland, 2017. sion of hepatitis C virus (HCV) and the natural history of HCV infection 46. Jacobsen, J. The role of research, in Disease Eradication in the 21st Century: acquired in infancy. J Infect Dis, 2005;192(11):1880–9. Implications for Global Health (Eds. S.L. Cochi and W.R. Dowdle), The 21. Benova, L., Mohamoud, Y.A., Calvert, C., and Abu‐Raddad, L.J. Vertical MIT Press, Cambridge, MA, 2010, pp. 152–3. transmission of hepatitis C virus: systematic review and meta‐analysis. Clin 47. Kamili, S., Drobeniuc, J., Araujo, A.C., and Hayden, T.M. Laboratory diag- Infect Dis, 2014;59:765–73. nostics for hepatitis C virus infection. Clin Infect Dis, 2012;55(Suppl 22. Jin, F., Matthews, G.V., and Grulich, A.E. Sexual transmission of hepatitis C 1):S43–8. virus among gay and bisexual men: a systematic review. Sex Health, 48. Barrera, J.M., Francis, B., Ercilla, G. et al. Improved detection of anti‐HCV 2017;14(1):28–41. in post‐transfusion hepatitis by a third‐generation ELISA. Vox Sang, 23. GBD 2016 Causes of Death Collaborators. Global, regional, and national 1995;68:15–18. age‐sex specific mortality for 264 causes of death, 1980–2016: a systematic 49. Gretch, D.R. Diagnostic tests for hepatitis C. Hepatology, 1997;26(3 Suppl. analysis for the Global Burden of Disease Study 2016. Lancet, 2017; 1):43S–7S. 390(10100):1151–210. 50. Micallef, J.M., Kaldor, J.M., and Dore, G.J. Spontaneous viral clearance fol- 24. Hepatitis. WHA 67.6, 67th World Health Assembly, May 2014. http://apps. lowing acute hepatitis C infection: a systematic review of longitudinal stud- who.int/gb/ebwha/pdf_files/WHA67/A67_R6‐en.pdf?ua=1 (Accessed Jun ies. J Viral Hepat, 2006;13:34–41. 18, 2018). 51. CDC. Testing for HCV infection: an update of guidance for clinicians and 25. Viral hepatitis. Resolution WHA 63.18, 63rd World Health Assembly, 2010. laboratorians. MMWR, 2013;62(18):362–5. http://apps.who.int/gb/ebwha/pdf_files/WHA63/A63_R18‐en.pdf 52. Food and Drug Administration, HHS. Requirements for testing human blood (Accessed Jul 15, 2018). donors for evidence of infection due to communicable disease agents. Final 26. World Health Organization. Prevention and Control of Viral Hepatitis rule. Fed Regist, 2001;66(112):31146–65. Infection: Framework for Global Action 2012. http://www.who.int/hepatitis/ 53. CDC. Public Health Service inter‐agency guidelines for screening donors of publications/Framework/en/ (Accessed Jun 18, 2018). blood, plasma, organs, tissues, and semen for evidence of hepatitis B and 27. World Health Organization. Global Policy Report on the Prevention and hepatitis C. MMWR Recomm Rep, 1991;40(RR‐4):1–17. Control of Viral Hepatitis in WHO Member States. http://www.who.int/hiv/ 54. Christensen, P.B., Groenbaek, K., and Krarup, H.B. Transfusion‐acquired pub/hepatitis/global_report/en/ (Accessed Jul 15, 2018). hepatitis C: the Danish lookback experience. The Danish HCV [hepatitis C 28. United Nations General Assembly resolution A/RES/70/1, Transforming our virus] Lookback Group. Transfusion, 1999;39(2):188–93. World: the 2030 Agenda for Sustainable Development, http://www.un.org/ga/ 55. Llibre, A., Shimakawa, Y., Mottez, E. et al. Development and clinical valida- search/view_doc.asp?symbol=A/RES/70/1&Lang=E (Accessed Jun 18, 2018). tion of the Genedrive point‐of‐care test for qualitative detection of hepatitis 29. Institute of Medicine (US) Committee on the Prevention and Control of Viral C virus. Gut, 2018;67(11):2017–24. Hepatitis Infection. Hepatitis and Liver Cancer A National Strategy for 56. Lamoury, F.M.J., Bajis, S., Hajarizadeh, B. et al. Evaluation of the Xpert Prevention and Control of Hepatitis B and C (Eds. H.M. Colvin and A.E. HCV viral load finger‐stick point‐of‐care assay. J Infect Dis, 2018;217(12): Mitchell), National Academies Press, Washington DC, 2010. 1889–96. 30. US Department of Health and Human Services. Combating the Silent 57. Aoyagi, K., Ohue, C., Iida, K. et al. Development of a simple and highly Epidemic of Viral Hepatitis: Action Plan for the Prevention, Care & sensitive enzyme immunoassay for hepatitis C virus core antigen. J Clin Treatment of Viral Hepatitis. https://www.hhs.gov/sites/default/files/action‐ Microbiol, 1999;37:1802–8. plan‐viral‐hepatitis‐2011.pdf 58. Leary, T.P., Gutierrez, R.A., Muerhoff, A.S. et al. A chemiluminescent, mag- 31. National Academies of Sciences et al. A National Strategy for the Elimination netic particle‐based immunoassay for the detection of hepatitis C virus core of Hepatitis B and C: Phase Two Report (Eds. B.I. Strom and G.J. Buckley), antigen in human serum or plasma. J Med Virol, 2006;78:1436–40. National Academies Press, Washington DC, 2017. 59. Mixson‐Hayden, T., Dawson, G.J., Teshale, E. et al. Performance of 32. Hall, R.G. Political and social determinants of disease, in Disease Eradication ARCHITECT HCV core antigen test with specimens from US plasma in the 21st century: Implications for Global Health (Eds. S.L. Cochi and W.R. donors and injecting drug users. J Clin Virol, 2015;66:15–18. Dowdle), The MIT Press, Cambridge, MA, 2010, pp. 152–3. 60. van den Driessche, P. Reproduction numbers of infectious disease models. 33. WHO. Archives of the Smallpox Eradication Programme. http://www.who. Infect Dis Model, 2017;2(3):288–303. int/archives/fonds_collections/bytitle/fonds_6/en/ (Accessed Jun 15, 2018). 61. Pybus, O.G., Charleston, M.A., Gupta, S. et al. The epidemic behavior of the 34. Foege, W.H. Confronting emerging infections: lessons from the smallpox hepatitis C virus. Science, 2001;292(5525):2323–5. eradication campaign. Emerg Infect Dis, 1998;4(3):412–13. 62. Shy, R. and Cui, Y. Global analysis of a mathematical model for hepatitis C 35. Okwo‐Bele, J.M. and Cherian, T. Expanded programme on immunization: a virus transmissions. Virus Res, 2016;17:8–17. lasting legacy of smallpox eradication. Vaccine, 2011;29(Suppl 4):D74–9. 63. Alter, M.J. Epidemiology of hepatitis C. Hepatology, 1997;26(Suppl 36. CDC. Global Disease Elimination and Eradication as Public Health 3):62S–5S. Strategies. Proceedings of a Conference, Atlanta, Georgia, USA, 23–25 64. Seeff, L.B. The history of the “natural history” of hepatitis C (1968–2009). February 1998. MMWR Suppl 1999;48:1–208. Liver Int, 2009;29(Suppl 1):89–99.

0004435662.INDD 949 10/05/2019 10:59:16 950 THE LIVER: REFERENCES

65. Harris, H.E., Ramsay, M.E., Andrews, N. et al. Clinical course of hepatitis C Multicenter Study. The Universitaires Cliniques St‐Luc (UCL) virus during the first decade of infection: cohort study. Br Med J, Collaborative Group. Kidney Int, 1998;53(4):1022–5. 2002;324(7335):450–3. 91. Dziekan, G., Chisholm, D., Johns, B., Rovira, J., and Hutin, Y.J. The cost‐ 66. Tong, M.J., el‐Farra, N.S., Reikes, A.R. et al. Clinical outcomes after trans- effectiveness of policies for the safe and appropriate use of injection in fusion‐associated hepatitis C. N Engl J Med, 1995;332:1463–6. healthcare settings. Bull World Health Organ, 2003;81(4):277–85. 67. Datz, C., Cramp, M., Haas, T. et al. The natural course of hepatitis C virus 92. WHO. Some strategies to reduce risk, in World Health Report 2002: infection 18 years after an epidemic outbreak of non‐A, non‐B hepatitis in a Reducing Risks, Promoting Healthy Life, World Health Organization, plasmapheresis centre. Gut, 1999;44(4):563–7. Geneva, 2002, pp. 101–44. 68. Wiese, M., Fischer, J., Löbermann, M. et al. Evaluation of liver disease pro- 93. Hauri, AM1, Armstrong, G.L., and Hutin, Y.J. The global burden of disease gression in the German hepatitis C virus (1b)‐contaminated anti‐D cohort at attributable to contaminated injections given in health care settings. Int J 35 years after infection. Hepatology, 2014;59:49–57. STD AIDS, 2004;15(1):7–16. 69. Yano, M., Kumada, H., Kage, H. et al. The long‐term pathological evolution 94. Pepin, J., Abou Chakra, C.N., Pepin, E., and Nault, V. Evolution of the of chronic hepatitis C. Hepatology, 1996;23:1334–40. global burden of unsafe medical injections, 2000–2010. PLoS One, 70. Goodgame, N.J., Shaheen, J., Galanko, H.B., and El‐Serag. The risk of end 2013;e80948. stage liver disease and hepatocellular carcinoma among persons infected 95. Janjua, N.Z., Butt, Z.A., Mahmood, B., and Altaf, A. Towards safe injection with hepatitis C virus: publication bias? Am J Gastroenterol, 2001;98: practices for prevention of hepatitis C transmission in South Asia: chal- 2535–42. lenges and progress. World J Gastroenterol, 2016;22(25): 5837–52. 71. Degos, F., Christidis, C., Ganne‐Carrie, N. et al. Hepatitis C virus related 96. Alter, H.J. The dominant role of non‐A, non‐B in the pathogenesis of post‐ cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut, transfusion hepatitis: a clinical assessment. Clin Gastroenterol, 1980;9: 2000;47(1):131–6. 150–70. 72. Westbrook, R.H., Dusheiko, G. Natural history of hepatitis C. J Hepatol, 97. Platt, L., Reed, J., Minozzi, S. et al. Effectiveness of needle/syringe pro- 2014;61(1 Suppl):S58–68. grammes and opiate substitution therapy in preventing HCV transmission 73. Thein, H.H., Yi, Q., Dore, G.J., and Krahn, M.D. Estimation of stage‐specific among people who inject drugs. Cochrane Database Syst Rev, 2016; fibrosis progression rates in chronic hepatitis C virus infection: a meta‐anal- 2016(1):pii: CD012021. ysis and meta‐regression. Hepatology, 2008;48:418–31. 98. Platt, L., Sweeney, S., Ward, Z. et al. Assessing the impact and cost‐effec- 74. Glynn, S.A., Kleinman, S.H., and Schreiber, G.B. Trends in incidence and tiveness of needle and syringe provision and opioid substitution therapy on prevalence of major transfusion‐transmissible viral infections in US blood hepatitis C transmission among people who inject drugs in the UK: an donors, 1991 to 1996. Retrovirus Epidemiology Donor Study (REDS). analysis of pooled data sets and economic modelling. Public Health Res, JAMA, 2000;284(2):229–35. 2017;5(5). 75. Zou, S., Stramer, S.L., and Dodd, R.Y. Donor testing and risk: current preva- 99. Martin, N.K., Vickerman, P., Grebely, J. et al. Hepatitis C virus treatment for lence, incidence, and residual risk of transfusion‐transmissible agents in US prevention among people who inject drugs: modeling treatment scale‐up in allogeneic donations. Transfus Med Rev, 2012;26(2):119–28. the age of direct‐acting antivirals. Hepatology, 2013;58(5):1598–609. 76. Prince, A.M., Brotman, B., Grady, G.F. et al. Long‐incubation post‐transfu- 100. Fraser, H., Martin, N.K., Brummer‐Korvenkontio, H. et al. Model projec- sion hepatitis without serological evidence of exposure to hepatitis B virus. tions on the impact of HCV treatment in the prevention of HCV transmission Lancet 1974;2:241–6. among people who inject drugs in Europe. J Hepatol, 2018;68(3):402–11. 77. Alter, H. Discovery of non‐A, non‐B hepatitis and identification of its etiol- 101. Fraser, H., Zibbell, J., and Hoerger, T. Scaling‐up HCV prevention and ogy. Am J Med, 1999;107(6):16–20. treatment interventions in rural United States‐model projections for tack- 78. Alter, H.J. and Purcell Dienstag, J.L. Non‐A, non‐B hepatitis. I. Recognition, ling an increasing epidemic. Addiction, 2018;113(1):173–82. epidemiology, and clinical features. Gastroenterology, 1983;85:439–62. 102. Cousien, A., Tran, V.C., Deuffic‐Burban, S. et al. Effectiveness and cost‐ 79. Dienstag, J.L. and Alter, H.J. Non‐A, non‐B hepatitis: evolving epidemio- effectiveness of interventions targeting harm reduction and chronic hepati- logic and clinical perspective. Semin Liver Dis, 1986;6(1):67–81. tis C cascade of care in people who inject drugs: the case of France. J Viral 80. Prati, D. Transmission of viral hepatitis by blood and blood derivatives: cur- Hepat, 2018;25(10):1197–207. rent risks, past heritage. Dig Liver Dis, 2002;34:812–17. 103. Cousien, A., Tran, V.C., Deuffic‐Burban, S. et al. Hepatitis c treatment as 81. Allain, J.P. Transfusion risks of yesterday and today. Transf Clin Biol, prevention of viral transmission and liver‐related morbidity in persons who 2003;10:1–5. inject drugs. Hepatology, 2015;63:1090–101. 82. Dodd, R.Y., Notari, E.P., and Stramer, S.L. Current prevalence and incidence 104. Hutin, Y.J., Bulterys, M., and Hirnschall, G.O. How far are we from viral of infectious disease markers and estimated window‐period risk in the hepatitis elimination service coverage targets? J Int AIDS Soc, American Red Cross blood donor population. Transfusion, 2002;42:975–9. 2018;21(Suppl 2):e25050. 83. Preiksaitis, J.K. and Rivet, C. A history of the evolution of hepatitis C testing 105. Larney, S., Peacock, A., Leung, J. et al. Global, regional, and country‐level of blood donors: implications for the Canadian blood supply system. coverage of interventions to prevent and manage HIV and hepatitis C Transfusion, 1995;35(4):348–52. among people who inject drugs: a systematic review. Lancet Glob Health, 84. Custer, B., Janssen, M.P., Hubben, G., Vermeulen, M., and van Hulst, M. 2017;5(12):e1208–20. Development of a web‐based application and multi‐country analysis frame- 106. Morris, M.D., Shiboski, S., Bruneau, J. et al. Geographic differences in work for assessing interdicted infections and cost‐utility of screening temporal incidence trends of hepatitis C virus infection among people who donated blood for HIV, HCV and HBV. Vox Sang, 2017;112(6):526–34. inject drugs: the InC3 Collaboration. Clin Infect Dis, 2017;64(7):860–9. 85. Janssen, M.P., van Hulst, M., and Custer, B. ABO RBDM Health Economics 107. Canary, L., Hariri, S., Campbell, C. et al. Geographic disparities in aAccess and Outcomes Working Group & Collaborators. An assessment of differ- to syringe services programs among young persons with hepatitis C virus ences in costs and health benefits of serology and NAT screening of dona- infection in the United States. Clin Infect Dis, 2017;65(3):514–17. tions for blood transfusion in different Western countries. Vox Sang, 108. CDC. Recommendations for prevention and control of hepatitis C virus 2017;112(6):518–25. (HCV) infection and HCV‐related chronic disease. MMWR, 1998;47(RR‐19). 86. WHO. Global database on blood safety, 2017. http://www.who.int/ 109. Moyer, V.A.; US Preventive Services Task Force. Screening for hepatitis C bloodsafety/global_database/en/ virus infection in adults. US Preventive Services Task Force recommenda- 87. Wenzel, R.P. and Edmond, M.B. Patient‐to‐patient transmission of hepatitis tion statement. Ann Intern Med, 2013;159(5):349–57. C virus. Ann Intern Med, 2005;142: 940–1. 110. WHO. Guidelines on hepatitis B and C testing – policy brief. http://www. 88. Krause, G., Trepka, M.J., Whisenhunt, R.S. et al. Nosocomial transmission who.int/ (Accessed Jul 15, 2018). of hepatitis C virus associated with the use of multi‐dose saline vials. Infect 111. AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD‐IDSA Control Hosp Epidemiol, 2003;24:122–7. recommendations for testing, managing, and treating adults infected with 89. Moyer, L.A. and Alter, M.J. Hepatitis C virus in the hemodialysis setting: a hepatitis C virus. https://www.hcvguidelines.org/ (Accessed Jun 18, 2018). review with recommendations for control. Semin Dialysis, 1994;7:124–7. 112. Cacoub, P., Desbois, A.C., Comarmond, C., and Saadoun, D. Impact of 90. Jadoul, M., Cornu, C., and van Ypersele de Strihou, C. Universal precautions sustained virological response on the extrahepatic manifestations of chronic prevent hepatitis C virus transmission: a 54 month follow‐up of the Belgian hepatitis C: a meta‐analysis. Gut, 2018;67(11):2025–34.

0004435662.INDD 950 10/05/2019 10:59:16 70: Time for the Elimination of Hepatitis C Virus as a Global Health Threat 951

113. Younossi, Z.M., Tanaka, A., Eguchi, Y. et al. Treatment of hepatitis C virus 137. Zepatier (elbasvir, grazoprevir). Merck Sharp & Dohme, Whitehouse leads to economic gains related to reduction in cases of hepatocellular Station, NJ, 2016 (package insert). ­carcinoma and decompensated cirrhosis in Japan. J Viral Hepat, 2018; 138. Backus, L.I., Belperio, P.S., Shahoumian, T.A., and Mole, L.A. Impact of 25(8):945–51. sustained virologic response with direct‐acting antiviral treatment on mor- 114. Elsisi, G.H., Aburawash, A., and Waked, E. Cost‐effectiveness analysis of tality in patients with advanced liver disease. Hepatology, 2018;68(3): new HCV treatments in Egyptian cirrhotic and non‐cirrhotic patients: a 827–38. societal perspective. Value Health Reg Issues, 2017;13:7–15. 139. Backus, L.I., Boothroyd, D.B., Phillips, B.R. et al. A sustained virologic 115. Rein, D.B., Smith, B.D., Wittenborn, J.S. et al. The cost‐effectiveness of response reduces risk of all‐cause mortality in patients with hepatitis C. birth‐cohort screening for hepatitis C antibody in, US primary care settings. Clin Gastroenterol Hepatol, 2011;9(6):509–16. Ann Intern Med, 2012;156(4):263–70. 140. Cacoub, P., Desbois, A.C., Comarmond, C., and Saadoun, D. Impact of 116. Morgan, J.R., Servidone, M., Easterbrook, P., and Linas, B.P. Economic sustained virological response on the extrahepatic manifestations of chronic evaluation of HCV testing approaches in low and middle income countries. hepatitis C: a meta‐analysis. Gut, 2018;67(11):2025–34. BMC Infect Dis, 2017;17(Suppl 1):697. 141. Ward, J.W. and Mermin, J.H. Simple, effective, but out of reach? Public 117. Coward, S., Leggett, L., Kaplan, G.G., and Clement, F. Cost‐effectiveness health implications of HCV Drugs. N Engl J Med, 2015;373(27):2678–80. of screening for hepatitis C virus: a systematic review of economic evalua- 142. Tumber, M.B. Restricted access: state Medicaid coverage of Sofosbuvir tions. BMJ Open, 2016;6(9):e011821. hepatitis C treatment. J Leg Med, 2017;37(1–2):21–64. 118. Smith, B.D., Morgan, R.L., Beckett, G.A. et al. Hepatitis C virus testing of 143. Campbell, C.A., Canary, L., Smith, N. et al. State HCV incidence and poli- persons born during 1945–1965: recommendations from the Centers for cies related to HCV preventive and treatment services for persons who Disease Control and Prevention. Ann Intern Med, 2012;157(11):817–22. inject drugs – United States, 2015–2016. MMWR, 2017;66(18):465–9. 119. Selvapatt, N., Ward, T., Harrison, L. et al. The cost impact of outreach test- 144. Kapadia, S.N., Johnston, C.D., Marks, K.M., Schackman, B.R., and Martin, ing and treatment for hepatitis C in an urban drug treatment unit. Liver Int, E.G. Strategies for improving hepatitis C treatment access in the United 2017;37(3):345–53. States: State officials address high drug prices, stigma, and building treat- 120. Klevens, R.M., Canary, L., Huang, X. et al. The burden of hepatitis C infec- ment capacity. J Public Health Manag Pract, 2018, Jun 20. tion‐related liver fibrosis in the United States. Clin Infect Dis, 2016; 145. Chhatwal, J., He, T., Hur, C., and Lopez‐Olivo, M.A. Direct‐acting antiviral 63(8):1049–55. agents for patients with hepatitis C virus genotype 1 infection are cost‐sav- 121. Ethgen, O., Sanchez Gonzalez, Y., Jeanblanc, G. et al. Public health impact ing. Clin Gastroenterol Hepatol, 2017;15(6):827–37. of comprehensive hepatitis C screening and treatment in the French baby‐ 146. Aggarwal, R., Chen, Q., Goel, A. et al. Cost‐effectiveness of hepatitis C boomer population. J Med Econ, 2017;20(2):162–70. treatment using generic direct‐acting antivirals available in India. PLoS 122. Alfaleh, F.Z., Nugrahini, N., Matičič, M. et al. Strategies to manage hepa- One, 2017;12(5):e0176503. titis C virus infection disease burden – volume 3. J Viral Hepat, 147. Assefa, Y., Hill, P.S., Ulikpan, A., and Williams, O.D. Access to medicines 2015;22(Suppl 4):42–65. and hepatitis C in Africa: can tiered pricing and voluntary licencing assure 123. Barocas, J.A., Wang, J., White, L.F. et al. Hepatitis C testing increased universal access, health equity and fairness? Global Health, 2017;13(1):73. among baby boomers following the 2012 change to CDC testing recom- 148. Hill, A.M., Nath, S., and Simmons, B. The road to elimination of hepatitis mendations. Health Aff (Millwood), 2017;36(12):2142–50. C: analysis of cures versus new infections in 91 countries. Virus Erad, 124. Barocas, J.A., Tasillo, A., Eftekhari Yazdi, G. et al. Population level outcomes 2017;3(3):117–23. and cost‐effectiveness of expanding the recommendation for age‐based hepa- 149. Foster, M.A., Barker, L., Jiles, R., and Holmberg, S. Awareness of infection titis C testing in the United States. Clin Infect Dis, 2018;67(4):549–56. and medical follow‐up among persons testing positive for hepatitis C 125. Eckman, M.H., Ward, J.W., and Sherman, K.E. Cost‐effectiveness of uni- virus – National Health and Nutrition Examination Survey, 2001–2014. versal screening for hepatitis C in the era of direct‐acting, pangenotypic Open Forum Infect Dis, 2016;3(Suppl 1):1787. treatment regimens. Clin Gastroenterol Hepatol, 2019;17(5):930–9.e9. 150. El‐Akel, W., El‐Sayed, M.H., El Kassas, M. et al. National treatment pro- 126. WHO. Guidelines for the care and treatment of persons diagnosed with gramme of hepatitis C in Egypt: hepatitis C virus model of care. J Viral chronic hepatitis C virus infection, 2018. www.who.int (Accessed Aug 5, Hepat, 2017;24(4):262–7. 2018). 151. WHO. Manual for the development and assessment of national viral hepa- 127. Kapadia, S.N., Johnston, C.D., and Marks, K.M., Hepatitis C management titis plans: a provisional document. www.who.int (Accessed Jul 15, 2018). simplification from test to cure: a framework for primary care providers. 152. Gilead Sciences. HCV Elimination. https://www.gilead.com/responsibility/ Clin Ther 2018;40(8):1234–45. hcv%20elimination (Accessed Jul 30, 2018). 128. Miller, L.S., Rollin, F., Fluker, S.‐A. et al. High‐yield birth‐cohort hepatitis 153. Mera, J., Vellozzi, C., Hariri, S. et al. Identification and clinical manage- C virus screening and linkage to care among underserved African ment of persons with chronic hepatitis C virus infection – Cherokee Nation, Americans, Atlanta, Georgia, 2012–2013. Public Health Rep, 2016; 2012–2015. MMWR, 2016;65(18):461–6. 131(Suppl 2):84–90. 154. Nasrullah, M., Sergeenko, D., Gamkrelidze, A., and Averhoff, F. HCV 129. Spradling, P.R., Tong, X., Rupp, L.B., and Moorman, A.C. Trends in HCV elimination – lessons learned from a small Eurasian country, Georgia. Nat RNA testing among HCV antibody‐positive persons in care, 2003–2010. Rev Gastroenterol Hepatol, 2017;14(8):447–8. Clin Infect Dis, 2014;59(7):976–81. 155. Progress reports: Report by the Director‐General, Seventy‐first World 130. Zhou, K., Fitzpatrick, T., Walsh, N. et al. Interventions to optimise the care Health Assembly. May 11, 2018. http://apps.who.int/gb/ebwha/pdf_files/ continuum for chronic viral hepatitis: a systematic review and meta‐analy- WHA71/A71_41Rev1‐en.pdf (Accessed Jul 15, 2018). ses. Lancet Infect Dis, 2016;16(12):1409–22. 156. Richter, L.M., Lönnroth, K., Desmond, C. et al. Economic support to 131. Trinh, J. and Turner, N. Improving adherence to hepatitis C screening patients in HIV and TB grants in rounds 7 and 10 from the Global Fund to guidelines. BMJ Open Qual, 2018;7(2):e000108. Fight AIDS, Tuberculosis and Malaria. PLoS One, 2014;9(1):e86225. 132. Flanigan, C.A., Leung, S.J., Rowe, K.A. et al. Evaluation of the impact of 157. Patel, M. and Cochi, S. Addressing the challenges and opportunities of the mandating health care providers to offer hepatitis C virus screening to all polio endgame: lessons for the future. J Infect Dis, 2017;216(Suppl persons born during 1945–1965 – New York, 2014. MMWR, 2017;66(38): 1):S1–S8. 1023–6. 158. Scott, N., Ólafsson, S., and Gottfreðsson, M. Modelling the elimination of 133. Zeuzem, S., Foster, G.R., Wang, S. et al. Glecaprevir‐pibrentasvir for 8 or hepatitis C as a public health threat in Iceland: A goal attainable by 2020. J 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med, 2018; Hepatol, 2018;68(5):932–9. 378(4):354–69. 159. Ólafsson, S., Tyrfingsson, T., Runarsdottir, V. Treatment as prevention for 134. Harvoni (ledipasvir and sofosbuvir). Gilead Sciences, Foster City, CA, hepatitis C (TraP Hep C) – a nationwide elimination programme in Iceland 2015 (package insert). using direct‐acting antiviral agents. J Intern Med, 2018;283(5):500–7. 135. Epclusa (sofosbuvir and velpatasvir). Gilead Sciences, Foster City, CA, 160. Dore, G.J. and Hajarizadeh, B. Elimination of hepatitis C virus in Australia: 2015 (package insert). laying the foundation. Infect Dis Clin North Am, 2018;32(2):269–79. 136. Viekira Pak (ombitasvir, paritaprevir, ritonavir, dasabuvir). AbbVie, North 161. Haridy, J., Wigg, A., Muller, K. et al. Real‐world outcomes of unrestricted Chicago, IL, 2015 (package insert). direct‐acting antiviral treatment for hepatitis C in Australia: The South

0004435662.INDD 951 10/05/2019 10:59:16 952 THE LIVER: REFERENCES

Australian statewide experience. J Viral Hepat, 2018, Jun 11. doi: 10.1111/ 173. Galbraith, J.W., Franco, R.A., Donnelly, J.P. et al. Unrecognized chronic jvh.12943 hepatitis C virus infection among baby boomers in the emergency depart- 162. Cherokee Nation conducts study to eliminate hepatitis C among Natives. ment. Hepatology, 2015;61(3):776–82. Cherokee Nation news release, Nov 3, 2015. http://www.cherokee.org 174. Sterling, R.K., Cherian, R., Lewis, S. et al. Treatment of HCV in the depart- (Accessed Jul 15, 2018). ment of corrections in the era of oral medications. J Correct Health Care, 163. End Hep C., S.F. End Hep C SF Strategic Plan, 2017–2019. San Francisco, 2018;24(2):127–36. CA, 2017. http://www.endhepcsf.org/ (Accessed Aug 12, 2018). 175. Lau, G., Benhamou, Y., Chen, G. et al. Efficacy and safety of 3‐week 164. Facente, S.N., Grebe, E., Burk, K., and Morris, M.D. Estimated hepatitis C response‐guided triple direct‐acting antiviral therapy for chronic hepatitis C prevalence and key population sizes in San Francisco: a foundation for infection: a phase 2, open‐label, proof‐of‐concept study. Lancet Gastroenterol elimination. PLoS One, 2018;13(4). Hepatol, 2016;1(2):97–104. 165. Bartlett, S.R., Fox, P., Cabatingan, H., and Jaros, A. Demonstration of near‐ 176. Martinello, M., Dore, G.J., Matthews, G.V., and Grebely, J. Strategies to elimination of hepatitis C virus among a prison population: the Lotus Glen reduce hepatitis C virus reinfection in people who inject drugs. Infect Dis Correctional Centre hepatitis C treatment project. Clin Infect Dis, 2018, Clin North Am, 2018;32(2):371–93. Mar 12. doi: 10.1093/cid/ciy210 177. Patient‐centered hepatitis C virus care for people who inject drugs – The 166. Clement, M.E., Collins, L.F., Wilder, J.M. et al. Hepatitis C virus elimina- HERO study. Patient‐Centered Outcomes Research Institute. www.pcori. tion in the human immunodeficiency virus‐coinfected population: leverag- org (Accessed Aug 1, 2018). ing the existing human immunodeficiency virus infrastructure. Infect Dis 178. Longmire, A.G., Sims, S., Rytsareva, I. et al. GHOST: global hepatitis out- Clin North Am, 2018;32(2):407–23. break and surveillance technology. BMC Genomics, 2017;18(Suppl 10):916. 167. Sacks‐Davis, R., Pedrana, A.E., Scott, N., Doyle, J.S., and Hellard, M.E. 179. Peters, P.J., Pontones, P., Hoover, K.W. et al. HIV Infection linked to injec- Eliminating HIV/HCV co‐infection in gay and bisexual men: is it achieva- tion use of Oxymorphone in Indiana, 2014–2015. N Engl J Med, ble through scaling up treatment? Expert Rev Anti Infect Ther, 2018; 2016;375(3):229–39. 16(5):411–22. 180. Fraser, H., Zibbell, J., Hoerger, T. et al. Scaling‐up HCV prevention and 168. Rumi, M.G., Di Marco, V., and Colombo, M. Management of HCV‐related treatment interventions in rural United States‐model projections for tack- liver disease in hemophilia and thalassemia. Semin Liver Dis, 2018; ling an increasing epidemic. Addiction, 2018;113(1):173–82. 38(2):112–20. 181. Liang, T.J. and Ward, J.W. Hepatitis C in injection‐drug users – a hidden 169. WHO. Technical considerations and case definitions to improve surveillance danger of the opioid epidemic. N Engl J Med, 2018;378(13):1169–71. for viral hepatitis. Technical report. www.who.int (Accessed Jul 30, 2018). 182. Page, K., Cox, A., and Lum, P.J. Opioids, hepatitis C virus infection, and 170. Tejada‐Strop, A., Drobeniuc, J., Mixson‐Hayden, T. et al. Disparate detec- the missing vaccine. Am J Public Health, 2018;108(2):156–7. tion outcomes for anti‐HCV IgG and HCV RNA in dried blood spots. J 183. Stone, J., Martin, N.K., Hickman, M. et al. The potential impact of a hepa- Virol Methods, 2015;212:66–70. titis C vaccine for people who inject drugs: is a vaccine needed in the age 171. Thomas, D.L. Global control of hepatitis C: where challenge meets oppor- of direct‐acting antivirals? PLoS One, 2016;11(5):e0156213. tunity. Nat Med, 2013;19(7):850–8. 184. National Institutes of Health. Trial evaluating experimental hepatitis C vac- 172. Belperio, P.S., Chartier, M., Gonzalez, R. et al. Hepatitis C care in the cine concludes. Press release, May 29, 2019. https://www.niaid.nih.gov/ Department of Veterans Affairs: building a foundation for success. Infect news-events/trial-evaluating-experimental-hepatitis-c-vaccine-concludes Dis Clin North Am, 2018;32(2):281–92. (Accessed June 15, 2019).

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