AUTHOR ACCEPTED MANUSCRIPT FINAL PUBLICATION INFORMATION Mobilizing a Global Response to Hepatitis Lessons Learned from the HIV Movement The definitive version of the text was subsequently published in Global Public Health, 13(4), 2016-10-16 Published by Taylor and Francis and found at http://dx.doi.org/10.1080/17441692.2016.1233989 THE FINAL PUBLISHED VERSION OF THIS MANUSCRIPT IS AVAILABLE ON THE PUBLISHER’S PLATFORM This Author Accepted Manuscript is copyrighted by World Bank and published by Taylor and Francis. It is posted here by agreement between them. Changes resulting from the publishing process—such as editing, corrections, structural formatting, and other quality control mechanisms—may not be reflected in this version of the text. You may download, copy, and distribute this Author Accepted Manuscript for noncommercial purposes. 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(3) You must attribute this Author Accepted Manuscript in the following format: This is an Author Accepted Manuscript by Taaffe, Jessica; Wilson, David Mobilizing a Global Response to Hepatitis © World Bank, published in the Global Public Health13(4) 2016-10-16 CC BY-NC-ND 3.0 IGO http://creativecommons.org/ licenses/by-nc-nd/3.0/igo http://dx.doi.org/10.1080/17441692.2016.1233989 © 2018 World Bank Mobilizing a Global Response to Hepatitis: Lessons Learned from the HIV Movement Jessica Taaffe*^ and David Wilson* *World Bank, 1818 H Street, NW Washington DC ^Corresponding author Jessica.taaffe@gmail.com; 202-350-1641 dwilson@worldbank.org ; (202) 730-6898 ABSTRACT Hepatitis caused by hepatitis B and C virus (HBV and HCV) is increasingly becoming a significant global health threat, with widespread prevalence that may have severe disease and economic impacts in the future. Yet, preventative measures are not implemented universally and high costs of medicines limits treatment efforts. The global response to HIV/AIDS faced similar issues, but overcame them through a global movement that brought attention to the crisis and ultimately resulted in the creation and implementation of and access to better tools for HIV prevention and treatment. This also included effective policies and programs behind and supporting the movement. Such could be done for hepatitis, specifically using lessons from the HIV response. Here, we will discuss the current and potentially severe future burden of hepatitis globally, the challenges in addressing this epidemic, and how principles applied from the global HIV response can facilitate a successful and similar hepatitis movement. Keywords: viral hepatitis, Hepatitis C, Hepatitis B, hepatitis treatment, hepatitis prevention, HIV advocacy, hepatitis advocacy Word count: 5430 words Introduction Hepatitis B and C virus (HBV and HCV) infections are dangerously growing global epidemics. HBV has been referred to as a “silent killer,” and HCV has been called a “viral time bomb” by the WHO. Yet, not enough attention and action has been given to this disease, given its current disease burden and the substantial associated economic costs it may incur in the future. Preventative measures are not implemented universally, and affordable, accessible, and effective treatment is not readily available to all. Similar issues were faced in the history of the HIV/AIDS epidemic and there is growing interest in the lessons of HIV for other diseases (M. Rabkin, Fouad, & El- Sadr, 2016; Miriam Rabkin, Goosby, & El-Sadr, 2014). How the global health community mobilized to respond to HIV/AIDS, including overcoming these issues, is what makes it among the greatest success stories in public health and infectious disease history. Specifically, the successful response to global HIV/AIDS required not just the development of biomedical tools to combat the virus, but effective policies and programs promoting the scale-up and implementation of them. Lessons learned from the success of the global HIV/AIDS response can be applied to address hepatitis on a global scale. In this paper, we will discuss the potential disease and economic burden due to hepatitis and existing biomedical tools and public health strategies to treat and prevent HCV and HBV infection, including their costs. We will also discuss how hepatitis control can be strengthened, including through mobilizing a global response to respond to the epidemic, using HIV as an example. DISCUSSION Hepatitis B and C global epidemiology The burden of disease due to hepatitis caused by hepatitis B and C viruses (HBV and HCV) is alarming, especially since effective interventions exist to prevent and/or treat the infections (Table 1). Similarly, both infections are responsible for hundreds of thousands of deaths worldwide, and when accounting for all deaths related to these viruses, they rank as the 15th and 25th, respectively, top causes of death in the Global Burden of Disease Study (Lozano et al., 2012). In fact, estimated total deaths from hepatitis B and C (1.3 million) are not far behind estimated HIV deaths (1.5 million) in this same study. HBV affects an estimated 248 million people globally (Schweitzer, Horn, Mikolajczyk, Krause, & Ott, 2015) and in 2010, nearly 786,000 deaths were due to it (Lozano et al., 2012). The burden of HBV is largely concentrated in the African and Western Pacific region (8.83% and 5.26% seroprevalence), and seroprevalence as high as 22.38% was reported in South Sudan (Schweitzer et al., 2015). Based on anti-HCV antibody, an estimated 115 -185 million people globally have had or currently have active HCV infection (Gower, Estes, Blach, Razavi- Shearer, & Razavi, 2014; Mohd Hanafiah, Groeger, Flaxman, & Wiersma, 2013), and an estimated 500,000 deaths were due to HCV in 2010 (Lozano et al., 2012). An estimated 80 (64-103) million of HCV infections are viremic (RNA- positive), confirmed active, infections, with more than half of these infections are occurring in China, Pakistan, Nigeria, Egypt, India, and Russia (Gower et al., 2014). HBV and HCV prevalence, however, may be underestimates. Regional and global estimates frequently focus on the general population and exclude studies within specific demographics, from which a large number of new infections are occurring. Furthermore, HBV and HCV infections are often asymptomatic, and there are many chronically infected that are unaware of their infection status. Therefore, it is very likely that the burden of disease from hepatitis caused by HBV and HCV is larger than current estimates indicate. HBV and HCV share similar high-risk groups and transmission routes with HIV. In areas with high endemicity for HBV, the most common route of transmission is through vertical and childhood transmission, whereas in areas of low endemicity, injecting drug use or sexual transmission is largely responsible for the epidemic. Injecting drug use is also a main risk factor for HCV in developed countries with low prevalence and well-established blood screening programs, though unscreened parenteral transmission through unsafe medical practices, including unscreened blood transfusions, is more responsible for HCV transmission in developing countries (Alter, 2007). HCV and HBV can also be transmitted sexually, and the prevalence of these infections in men who have sex with men (MSM) are higher than the general population (Hahne et al., 2013; C. Wang et al., 2012), due to, but not exclusively, risk factors associated with injecting drug use and HIV co-infection. Migrant populations, especially if they originate from higher hepatitis prevalence countries, also have been shown to have higher HBV and HCV prevalence than the general population (Vriend et al., 2013). The potential severe disease and economic burden of hepatitis Progression to end-stage liver disease from initial HBV or HCV infection is long, unpredictable, and often asymptomatic. Those that do not recover from acute infection are at risk for HBV/HCV-related cirrhosis, hepatocellular cancer, and liver transplantation. Indeed, HBV and HCV are primary indications for liver transplants in Europe (Blachier, Leleu, Peck-Radosavljevic, Valla, & Roudot- Thoraval, 2013). The medical costs associated with treating hepatitis disease, especially end- stage, are substantial (Table 2). The median cost of a liver transplant in Europe, Asia Pacific, and the Americas (excluding the US) is $139,070, and the costs associated with cirrhosis and hepatocellular carcinoma (HCC) are also high; decompensated cirrhosis costs a median of $ 14,660, and HCC, $15,310 (El Khoury, Wallace, Klimack, & Razavi, 2012). Other HCV related sequelae and complications are similarly costly, as indicated in Table 1. The median costs of treating hepatitis-related complications in the US are comparable (El Khoury, Klimack, Wallace, & Razavi, 2012). Given the current high hepatitis prevalence, much of which is likely undiagnosed and untreated (and able to continue the transmission cycle), the future health and economic impact of viral hepatitis caused by HBV and HCV could be very severe. Existing biomedical tools to address hepatitis Like HIV, the biomedical tools to control HBV and HCV exist. HCV protease inhibitors (PIs) allow for more diversified and efficacious treatment options when incorporated into triple therapy regimens with peginterferon and ribavirin. And, the approval of sofosbuvir, an HCV nucleotide analog inhibitor, has been called a ‘game-changer,’ in combination with ribavirin, as the first all-oral, interferon-free HCV therapy, with high cure rates in just 12-weeks for some genotypes (Tucker, 2013). Finally, a large and diverse group of HCV drugs with different and synergistic mechanisms of action are in research and development, promising great potential for combination HCV therapy in the future. Chemotherapeutic options for HBV, on the other hand, are much more limited. Interferon-based treatment with antivirals can be used to suppress HBV replication and prevent progression to cirrhosis and HCC, but viral eradication is very rare and unrealistic in most cases. Antiviral resistance is major challenge in HBV therapy; with some drugs, resistance can occur in 29 – 80% of patients after 5 years of treatment (Zoulim, 2011). There is a great need for new and curative HBV drugs. The best prevention tool available against HBV is the existing vaccine. This vaccine is very effective, eliciting protective antibody responses in 95% of infants, children, and adults, and it provides long-time protection (Van Damme & Van Herck, 2007; Venters, Graham, & Cassidy, 2004). The vaccine also is 80-100% effective in protecting those having received the 3-part series against clinical infection and disease(Centers for Disease Control and Prevention, 2015). The vaccination schedule consists of the first two doses given a month apart, followed by the third 1 -12 months later. By 2013, 183 Member States had adopted universal infant vaccination programs, as per previous WHO recommendations, with global coverage at 81%. WHO now recommends that all infants receive the first dose at birth, within 24 hours of birth, but coverage for this earlier vaccination regimen is only at 38% global coverage (WHO, 2015b). Public health approaches to preventing and treating hepatitis B and C The biomedical tools to prevent and treat hepatitis B and C exist, and they are highly efficacious. Public health strategies to address hepatitis B and C epidemics must focus heavily on the use of these tools (Box 1), strategically using and implementing them among other wider public health interventions that reduce exposure to and increase the detection rate of infection. Control of hepatitis B can be achieved primarily through expanding universal vaccination, coupled with screening and treatment, as appropriate to epidemic context and resources. In highly and intermediately endemic countries, universal vaccination of infants is cost-effective (Tu et al., 2009). This approach targets prevention to the large number of infants and children that acquire hepatitis B vertically and horizontally. Universal vaccination coupled with treatment of perinatally-exposed infants with hepatitis B immunoglobin improves prevention but is much more costly. Universal vaccination alone has a protective efficacy of 70-80% against perinatal transmission(Beasley, 2009; Lo et al., 1985; Wong et al., 1984); the additional administration of hepatitis B immunoglobin to infants born from infected mothers increases protection efficacy against transmission to 95% (Beasley, 2009). This next-level approach is the most effective, though it requires logistical and financial resources to find, screen, and follow-up with infected pregnant women and administer hepatitis B immunoglobin to their infants. Thus, it is only being implemented by countries with the resources to do so, such as high and middle income countries in Europe and in the US. Some low-endemic and high income countries (Denmark, Finland, Iceland, Japan, Norway, Sweden, and the United Kingdom) have chosen a selective approach to vaccination, targeting high risk groups, including, but not limited to, IDU, MSM, healthcare workers, and perinatally exposed infants. Screening of pregnant women and hepatitis B immunoglobin administration to exposed infants is also carried out in these countries. This selective approach is considered most cost-effective in these countries where HBV seroprevalence is less than 1%. While not a primary form of prevention, identifying and treating chronically HBV- infected individuals would reduce their ability to pass on infection within the population. As many as 75% of people infected with HBV do not know they are infected. However, there are many challenges with a “Treatment as Prevention approach” for HBV – 1) treatment is lifelong, bringing challenges of adherence and drug resistance, and 2) treatment efforts are geared towards preventing liver disease, with a focus on starting treatment with life-threatening disease is imminent, rather than earlier in the infection. Hepatitis C prevention, on the other hand, should focus on “Treatment as Prevention.” Hepatitis C can be cured with existing drugs, thus reducing transmission potential within populations. To do so, HCV testing must be scaled- up to reach and capture the 75-90% of individuals(Hagan & Schinazi, 2013) that do not know they are infected with HCV. These efforts should particularly focus on and target high risk populations, such as injecting drug users (IDU), MSM, sex workers, people living with HIV, migrant populations from countries highly prevalent for HCV, and recipients of potentially contaminated blood transfusions. Once diagnosed, earlier treatment has individual and public health benefits. For the patient, earlier treatment can reduce the risk of HCV-related disease, and at the population level, it may reduce transmission and its associated costs (Attar & Van Thiel, 2016), as expanded treatment has done for HIV (Tanser, Barnighausen, Grapsa, Zaidi, & Newell, 2013; Vandormael, Newell, Barnighausen, & Tanser, 2014). Some modeling studies have shown that earlier HCV treatment is also cost-effective (Chahal et al., 2016; Leidner et al., 2015; Obach et al., 2014). However, the costs of newer HCV treatments are prohibitive in expanding access to effective therapy and recommending earlier treatment. Public health interventions to reduce exposure to HBV and HCV are also very important. For instance, blood products must be screened universally for these viruses to prevent transmission through this route. There are many effective and cost-effective strategies to screen blood for HBV and HCV, including nucleic acid amplification and antibody or antigen detection. However, logistical and cost constraints in resource-limited settings limit widespread implementation of blood screening procedures. Currently, 25 countries are unable to test for one or more of transfusion-transmissible infections (HIV, hepatitis B, hepatitis C and syphilis), and the presence of HBV and HCV in blood donations is higher in low and middle income countries than high-income countries. In high-income countries, median prevalence of HBV and of HCV in blood donations is 0.02%. In middle-income countries, that prevalence rises to 0.64 and 0.37%, respectively, and to 3.59 and 1.07% in low-income countries(WHO, 2015a). As they have been effective in reducing HIV transmission through injecting drug use(Abdul-Quader et al., 2013; Aspinall et al., 2014; Dutta, Wirtz, Baral, Beyrer, & Cleghorn, 2012), harm-reduction programs could be equally beneficial in reducing HBV and HCV transmission(Palmateer et al., 2014). Health education and behavior change programs, especially those targeting high-risk populations, are also necessary. Educating high-risk populations on their risk of viral hepatitis infection and disease may facilitate increased testing rates and promote safer behavior. Condom use should be promoted among those at risk for sexual transmission, such as MSM, sex workers, and partners of infected individuals, and needle-sharing should be discouraged among IDU. Parenteral transmission can be avoided by implementing safer needle use practices in healthcare facilities. Costs associated with treating and preventing hepatitis B and C A significant challenge to global hepatitis response is the expenses associated with using the biomedical tools to treat and prevent HBV and HCV. At $0.50 per dose, triple-dose HBV vaccination costs more than the other six childhood vaccines recommended by the WHO Expanded Programme on Immunization (EPI) combined. But, these costs are not prohibitive. By 2006, a higher proportion of low than high income countries offered HBV vaccination, and by 2009, Haiti and Somalia were the only low-income countries who did not provide it (Hepatitis B vaccine support). Treating HBV and HCV infection, on the other hand, is prohibitively costly, and costs greatly vary globally. The average wholesale cost of the medications in the US for one course of current treatment for genotype 1 HCV infection can exceed US$100,000, at extreme (Thomas, 2013), whereas in Egypt, a 48 week course of peginterferon and ribavirin treatment costs US$2000. A full treatment course of sofosbuvir, commercially sold as Sovaldi by Gilead on a tiered pricing system, costs $66,000-84,000 in the US and UK, and as low $2,000 in India and $900 in Egypt, one percent of the US cost (Scutti, 2014). These costs don’t include the price of other medicines required for dual or triple-therapy. Treating HBV is equally costly, and these drugs must be taken for long-term disease management rather than cure. Annually, average wholesale costs of HBV antivirals in the US range from US$5,000 (Lamivudine) – $13,000 (Adefovir), plus the added cost of interferon or peginterferon $8 - $35,000 (Hepatitis B Foundation). High cost of hepatitis medicines can be reduced Treating HIV also used to be very costly. Yet, extraordinary success was achieved in bringing down those costs; today the price of first-line HIV drugs are under $100 per person per year, a 99% reduction from costs in 2000 at $10,000 and above(Untangling the web of antiretroviral price reductions, 2013). Reasons for this sharp reduction includes availability of generic drugs, increased market competition and volume, and more efficient and cheaper manufacturing. These same tactics can be applied to reduce the price of HCV and HBV drugs, and Hill et al argues that within 15 years, HCV drug costs could be brought down to $100-250 for a full-treatment course (Hill, Khoo, Fortunak, Simmons, & Ford, 2014). Generic drugs are essential to bringing down HCV treatment costs, however, patents for many of the HCV drugs don’t expire until 2025. Thus, negotiations with patent-holders on voluntary licensing, access prices for LMIC countries, and mass production of low-cost drugs must be made now. As of August 2015, Gilead has already taken strides to do so with voluntary license agreements allowing 11 Indian manufacturers to produce sofosbuvir-based drugs generically for 101 LMIC income countries. However, depending on total infected estimate used, the coverage may only reach reach 56% of global infected population and does not include some key middle income countries, like China, which has the greatest burden of the disease (CHRONIC HEPATITIS C TREATMENT EXPANSION: Generic Manufacturing for Developing Countries, 2015; Medecins San Frontieres, 2015; RAJAGOPAL, 2015). Volume demand and purchasing facilitated reductions in HIV drugs costs, by driving competition and price reduction and improving process efficiencies. Clinton Health Access Initiative (CHAI) ensured lowest sustainable costs for some HIV drugs by purchasing from quality-assured generic pharmaceutical manufacturers in India and raw material manufacturers in China. CHAI also negotiated price-volume discounts through high volume purchasing, enabling them to set maximum prices at which suppliers could sell drugs to members of their Procurement Consortium. Similar price-volume agreements, including using a threshold, could be utilized for reducing the price of HCV drugs. For example, it could be negotiated that drugs cost full price until a certain number of units, and then they would be free. This strategy preserves the price of drugs but expands access. Importantly, global and national policies and legal approaches must be in place to support generic drug manufacturing. “Evergreening” (obtaining new/separate patents on different aspects of same medicines) must be prevented, and the use of compulsory licenses, as justified by World Trade Organization, can allow countries to manufacture generic versions of patented life-saving drugs they cannot afford. WHO can also greatly influence price reduction of HCV drugs. The inclusion of newer antiviral HCV drugs in 2015, including sofosbuvir, on the WHO Essential Medicines list may help with price negotiations, and WHO prequalification of HCV drugs can expedite access to quality generics. Strengthening the public health response for HBV and HCV Bringing down the costs of HCV medicines and making them affordable and accessible to the populations that need them is an essential step in the global response to viral hepatitis. However, other important actions must be taken in order to strengthen the overall public health response and framework with which to carry it out. For hepatitis B, the best strategy for control is increasing coverage of universal vaccination. Even though global coverage of the three-dose hepatitis B vaccine series is estimated at 82%, global coverage for the birth dose is estimated at 38% for the birth dose, leaving substantial room for improvement(WHO, 2015b). Coverage of the birth dose in the African region is especially poor, at an estimated 10%. As 90% of children infected with HBV will develop chronic hepatitis, catching them at the earliest possible time is crucial to reducing the burden of global hepatitis. Improving coverage of the hepatitis B birth dose requires addressing the barriers that make is difficult to deliver this immunization within 24 hours of birth. One, many births occur outside of healthcare facilities, and home births are associated with birth dose coverage (Centers for Disease Control and Prevention, 2007; Clements et al., 2006; Government of the People’s Republic of China, 2008; Liang et al., 2009; Ruff, Bravo, Gatchalian, & Bock, 2009; Zhou et al., 2009). Increasing access to skilled health care providers that can administer the vaccine can address this particular challenge. This includes within healthcare facilities and at home births. Similarly, enabling health workers to provide in-home vaccination, ideally within 24 hours of birth, has been shown to improve birth dose coverage among babies born away from health facilities(Murakami, Van Cuong, Huynh, & Hipgrave, 2008; Sobel et al., 2011; L. Wang et al., 2007). Stronger implementation and facilitation of birth dose policy in maternal and child health clinics is also necessary. More awareness for national policy or creation of local policies to implement the birth dose, including better understanding of whose responsibility it is to administer it (birth attendant or immunization nurse), could result in better birth dose coverage. Furthermore, simply having a stock of vaccine available in delivery rooms or postnatal wards will facilitate its timely administration. For hepatitis C control, expanded HCV screening and treatment would greatly impact the course of the epidemic. Currently, cost of treatment is the biggest barrier for individuals seeking it or governments that would provide it. Even though treatment at earlier stages of disease has been shown to be cost- effective at the patient level, upfront costs are still very large and at the population level may be more than a country is able or willing to spend. However, these cost-effective analyses do not take into consideration the effect of treatment as prevention, essentially reducing transmission and preventing new infections within the population. Therefore, even with its hefty costs, there is still strong rationale for investment in expanded HCV treatment for its public health benefits, which must be prioritized within national health programs. Expanded HCV screening is also important to maximize the individual and population benefits of treatment. In this context, individuals testing positive for HCV should be immediately linked to care and monitored for their treatment eligibility. Specifically, HCV testing should be expanded first in high risk populations, using epidemiologic information to assess which are those high risk populations in each context. Demand for HCV testing must be also created and encouraged within high risk populations. HCV awareness and education campaigns can facilitate this demand, and community-based testing initiatives like mobile testing or testing events can respond to it, in addition to expanded HCV testing capability in health facilities. Expanded HCV screening will also lead to more people knowing their HCV status, which may contribute to prevention efforts, as an HCV diagnosis may reduce risky behaviors, such as unprotected sex or shared needles. The opportunity to educate those negative for the infection about how to protect themselves from it also exists through screening. Blood donation screening is another critical arm of HBV and HCV prevention. However, carrying out high quality laboratory testing of blood donations is challenged by lack of technical expertise and infrastructure in low resource and remote settings. Many settings may be unable to perform high-throughput testing for antigen or antibody in blood donations or more sensitive nucleic acid testing. In these cases, pre-donation screening through rapid testing is a potential solution. Rapid tests exist for HBV and HCV, some even multiplexed together with HIV, and they are user-friendly and low cost. Though, quality assurance must be considered with the strategy, as lower-cost tests may perform poorly due to lack of evaluation or accreditation and poor testing procedure will lead to testing inaccuracy. Additionally, pre-donation screening will require paired counseling and treatment referral services for positive tests. Pre-donation screening through rapid testing is a feasible strategy to improve blood safety and hepatitis control in low resource settings. However, it may be more cost-effective in highly endemic areas where higher frequency of infection detection offsets the costs of tests, counseling, and quality assurance training. Similarly, the cost-effectiveness of nucleic acid testing should be considered in countries with high HBV or HCV prevalence and the capacity to carry out this more sensitive test. Nucleic acid testing captures infection before seroconversion, so there is an opportunity to detect individuals unaware of their infection and those that would not be detected by antibody based assays. Integration of HBV and HCV control strategies into other health programs is a way to facilitate their implementation into an existing public health framework. As HBV control should focus on immunization coverage, greater integration of HBV vaccination into maternal and child health programs would strengthen this response. HIV shares at risk populations with HBV and HCV, and co-infection with either hepatitis virus is associated with an increased risk for liver disease. Therefore, it makes sense to integrate HBV and HCV services into HIV programs, especially those targeting high risk populations. Approaches used by HIV programs and clinics to link patients to care and monitor them through treatment could equally be leveraged for HBV and HCV treatment. Finally, harm- reduction programs and services for IDU should include education on, screening, and treatment referral for HBV and HCV. Expansion of harm-reduction services could also reduce the number of new HBV and HCV infections from injecting drug use. Strengthening the public health response also requires political commitment and strong leadership to create and ensure implementation of hepatitis control policies. Countries with high HBV endemicity that have not already adopted universal newborn vaccination policy, should do so immediately and provide national guidance to support facilities to carry it out. Similarly, establishing a national blood transfusion safety and quality policy in the 44-60% low and middle income countries, respectively, that do not have one is greatly needed (WHO, 2015a). Additionally, financing the response to HBV and HCV epidemics will require government leadership and action. The development of an investment case can facilitate efforts to procure aid from donors and development partners. Making a strong investment case would also require collecting detailed epidemiological and programmatic data at national, regional, and local levels. Such information is crucial for implementing an effective and efficient national disease response and to continually measure progress in that response. A global movement for hepatitis must be created, using HIV/AIDS as an example Addressing hepatitis globally requires a strong movement to advocate for and effect change with regard to treatment/vaccination policy and practice. Global commitment to addressing hepatitis is growing, following a number of high level meetings, summits, and the daily work of viral hepatitis activists. The success of the HIV/AIDS response is widely recognized and celebrated, with detailed accounts of what made this movement successful (Colvin, 2014; Harrington, 2010; Hoen, Berger, Calmy, & Moon, 2011; Larson, Bertozzi, & Piot, 2011), particularly in how activism led achievements in reducing the price of HIV drugs, expanding access to treatment, and political commitment towards ending AIDS as a public health crisis. As such, much can be learned from it and applied towards building initial progress in the viral hepatitis response. The HIV/AIDS response was more than just a health response; it was a social movement, too, and it was framed as human right and linked to social justice, expanding the AIDS movement to wider movement for MSM, IDU, and SW rights. The impact of HIV infection goes beyond its effect on individual health – it extends to families, communities, and nations and affects their social structures, economies, development and collective health. Many of the same issues are shared in the viral hepatitis epidemic, as HBV/HCV high risk populations overlap with those in HIV and similar social and structural factors make these groups vulnerable to infection and limit access to treatment and care. Like the HIV response, the social issues and impact of hepatitis must be highlighted prominently. This effort will facilitate greater advocacy for the hepatitis response when the disease is not just seen as a medical problem, but also a social one. For instance, the Glasgow Declaration at the World Hepatitis Summit in 2015 stated, “universal access to prevention, diagnosis, care and treatment [for HBV and HCV] is a human right and promoting access to and affordability of these services is the responsibility of all stakeholders.” The HIV movement was immensely successful due to its diverse and comprehensive advocacy base. At first, a vanguard of disruptive AIDS activists (ACT UP), including a cadre of science and treatment literate patients, advocated for change and kept scientists and physicians accountable. The movement grew as a big tent coalition was built from a vast group of movement supporters, including patients, activists, rock stars, scientists, politicians, northern taxpayers and southern religious and community leaders. Finally, these efforts came to fruition when activists, scientists, researchers and regulators forged an alliance for greater scientific financing and faster regulatory approval. Science and activism was unified, as seldom done before or since. Hepatitis activists and informed supporters can respond similarly, building an equally diverse and comprehensive advocacy base. This contingency must also have equal global representation, so all stakeholders are able to share their own experiences and advocate for policies appropriate to their own epidemic. Activism is growing - there is an expanding collective of viral hepatitis activists and organizations that are pushing for expanded prevention and treatment and effective medicine options, many connected to each other through their membership through World Hepatitis Alliance. These groups must continue to bring awareness to the hepatitis epidemic through global and local social campaigns, High-Level Summits, lobbying, and recruitment of celebrities and politicians to champion their cause. Recently, the first European Union HCV Policy Summit in 2016 called for this same comprehensive response strategy. The Elimination Manifesto that was launched at the summit, with a commitment to make hepatitis C and its elimination in Europe a public health priority and addressed “through collaboration between individual citizens, civil society organizations, researchers, the private sector, local and national governments, European Union institutions”(Elimination Manifesto. Hepatitis C Elimination in Europe: “Our vision for a Hepatitis C-free Europe”, 2016). Finally, hepatitis scientists and physicians must support the movement and push for faster translation of research into products and policy. The Hepatitis movement must also aim big. Global solidarity and the concept of treatment as a universal right for ALL were fostered under the AIDS movement, undeterred by criticism of impracticality. Bold targets were set, and global accountability for targets were established. Campaigns like 3 x 5 (ARVs for 3 million people by 2005), 15 x 15 (ART for 15 million people by 2015), and now, 90-90-90 (90% of all people with HIV will know their HIV status, receive sustained ART, and achieve viral suppression by 2020) mobilized the global community into reaching these goals, and a global health architecture (PEPFAR and Global Fund for AIDS, Tuberculosis, and Malaria) was created to support their realization. Efforts in this direction are underway for hepatitis. The WHO Global Health Sector Strategy on Viral Hepatitis calls for a 1) 90% reduction in new cases of chronic hepatitis B and C, 2) 65% reduction in hepatitis B and C deaths, and 3) 80% of treatment eligible persons with chronic hepatitis B and C infections treated by 2030. The Strategy also calls for 90% coverage of HBV vaccination, including the birth dose, and HBV and HCV infections diagnosed, and it sets targets to increase harm reduction interventions and blood safety. While not as strong language as ending the AIDS epidemic, target 3.3 under Goal 3 among the Sustainable Development goals calls for combating hepatitis. The NOhep campaign (http://www.nohep.org/), however, launched on World Hepatitis Day 2016 by the World Hepatitis Alliance, does call for the elimination of viral hepatitis by 2030. Moving forward to meet these targets, there must be strong political and national commitment. Governments will need to develop and institute their own national strategies for hepatitis control and look for domestic sources of finance for hepatitis control, rather than relying on external donor aid. The Australian government is ambitiously pursuing to eliminate hepatitis C in the country within one generation by reducing the cost of and subsidizing new and more effective HCV treatment. Georgia and Egypt have also negotiated price reductions of HCV drugs and plan to expand their treatment programs. Uganda has developed a National Plan for the Control of Hepatitis, with $2.8 million allocated for hepatitis B prevention and treatment in 2015/16. Operationally, several things will ensure the success of a global hepatitis movement, as they did for the HIV movement, summarized in Table 3 and discussed in Ford et al (Ford et al., 2012): 1) Affordable drugs – made such through creative licensing mechanisms, use of generics, and volume purchasing. 2) Simplification of various aspects of the hepatitis response - international guidelines, care models, drug regimens, etc. 3) Task shifting - setting international guidelines for it, validation of different approaches for it (decentralization, low technology point-of-care diagnostics, etc) through operational research, and integration of hepatitis treatment into larger health service models 4) Patient and community participation – engaging the community to become more involved in treatment activities, including education and care. 5) Delivery – goals must be set, with a clear execution plan and accountability for doing so 6) Financing – investments must be made nationally and internationally, including new financial mechanisms to kick-start HCV treatment. Conclusion The current global burden of HCV and HBV is high, and its future health and economic impact requires action now. Addressing hepatitis globally, however, will require a strong global movement, much like the one that has been successful for HIV/AIDS. Such a movement can promote wider coverage and use of existing biomedical tools and public health strategies to combat hepatitis, and, equally important, advocate for policies that will result in more affordable hepatitis drugs. Scaling-up efforts now to vaccinate against or treat HBV and HCV will reduce future hepatitis disease and its associated medical costs, and it will also reduce HCV/HBV prevalence and transmission, leading to fewer infections in the future. Collectively, a global hepatitis movement can save millions of lives in the coming years, with similar success as that of the AIDS movement. REFERENCES Abdul-Quader, A. S., Feelemyer, J., Modi, S., Stein, E. S., Briceno, A., Semaan, S., . . . Des Jarlais, D. C. (2013). Effectiveness of structural-level needle/syringe programs to reduce HCV and HIV infection among people who inject drugs: a systematic review. AIDS and Behavior, 17(9), 2878-2892. doi: 10.1007/s10461-013-0593-y Alter, M. J. (2007). Epidemiology of hepatitis C virus infection. World Journal of Gastroenterology, 13(17), 2436-2441 Aspinall, E. J., Nambiar, D., Goldberg, D. J., Hickman, M., Weir, A., Van Velzen, E., . . . Hutchinson, S. J. (2014). Are needle and syringe programmes associated with a reduction in HIV transmission among people who inject drugs: a systematic review and meta-analysis. International Journal of Epidemiology, 43(1), 235- 248. doi: 10.1093/ije/dyt243 Attar, B. M., & Van Thiel, D. H. (2016). Hepatitis C virus: A time for decisions. Who should be treated and when? World Journal of Gastrointestinal Pharmacology and Therapeutics, 7(1), 33-40. doi: 10.4292/wjgpt.v7.i1.33 Beasley, R. P. (2009). Rocks along the road to the control of HBV and HCC. Annals of Epidemiology, 19(4), 231-234. doi: 10.1016/j.annepidem.2009.01.017 Blachier, M., Leleu, H., Peck-Radosavljevic, M., Valla, D. C., & Roudot-Thoraval, F. (2013). The burden of liver disease in Europe: a review of available epidemiological data. Journal of Hepatology, 58(3), 593-608. doi: 10.1016/j.jhep.2012.12.005 Centers for Disease Control and Prevention. (2007). Progress in hepatitis B prevention through universal infant vaccination — China, 1997–2006. MMWR Morbidity and Mortality Weekly Report, 56, 441–445 Centers for Disease Control and Prevention. (2015). In J. Hamborsky, A. Kroger & C. Wolfe (Eds.), Epidemiology and Prevention of Vaccine-Preventable Diseases (13th ed.). Washington D.C: Public Health Foundation. Chahal, H. S., Marseille, E. A., Tice, J. A., Pearson, S. D., Ollendorf, D. A., Fox, R. K., & Kahn, J. G. (2016). Cost-effectiveness of Early Treatment of Hepatitis C Virus Genotype 1 by Stage of Liver Fibrosis in a US Treatment-Naive Population. JAMA Intern Med, 176(1), 65-73. doi: 10.1001/jamainternmed.2015.6011 CHRONIC HEPATITIS C TREATMENT EXPANSION: Generic Manufacturing for Developing Countries. (2015). I. Gilead Scienceshttp://www.gilead.com/~/media/files/pdfs/other/hcvgenericagre ementfactsheet.pdf?la=en. Clements, C. J., Baoping, Y., Crouch, A., Hipgrave, D., Mansoor, O., Nelson, C. B., . . . Wiersma, S. (2006). Progress in the control of hepatitis B infection in the Western Pacific Region. Vaccine, 24(12), 1975-1982. doi: 10.1016/j.vaccine.2005.11.035 Colvin, C. J. (2014). Evidence and AIDS activism: HIV scale-up and the contemporary politics of knowledge in global public health. Glob Public Health, 9(1-2), 57- 72. doi: 10.1080/17441692.2014.881519 Dutta, A., Wirtz, A. L., Baral, S., Beyrer, C., & Cleghorn, F. R. (2012). Key harm reduction interventions and their impact on the reduction of risky behavior and HIV incidence among people who inject drugs in low-income and middle- income countries. Current Opinion in HIV and AIDS, 7(4), 362-368. doi: 10.1097/COH.0b013e328354a0b5 El Khoury, A. C., Klimack, W. K., Wallace, C., & Razavi, H. (2012). Economic burden of hepatitis C-associated diseases in the United States. Journal of Viral Hepatitis, 19(3), 153-160. doi: 10.1111/j.1365-2893.2011.01563.x El Khoury, A. C., Wallace, C., Klimack, W. K., & Razavi, H. (2012). Economic burden of hepatitis C-associated diseases: Europe, Asia Pacific, and the Americas. Journal of Medical Economics, 15(5), 887-896. doi: 10.3111/13696998.2012.681332 Elimination Manifesto. Hepatitis C Elimination in Europe: “Our vision for a Hepatitis C- free Europe”. (2016). Retrieved from http://www.hcvbrusselssummit.eu/elimination-manifesto Ford, N., Singh, K., Cooke, G. S., Mills, E. J., von Schoen-Angerer, T., Kamarulzaman, A., & du Cros, P. (2012). Expanding access to treatment for hepatitis C in resource-limited settings: lessons from HIV/AIDS. Clinical Infectious Diseases, 54(10), 1465-1472. doi: 10.1093/cid/cis227 Government of the People’s Republic of China. (2008). Annual Progress Report 2007, submitted to the Global Alliance for Vaccines and Immunization (GAVI) 2008. Geneva. Gower, E., Estes, C., Blach, S., Razavi-Shearer, K., & Razavi, H. (2014). Global epidemiology and genotype distribution of the hepatitis C virus infection. Journal of Hepatology, 61(1 Suppl), S45-57. doi: 10.1016/j.jhep.2014.07.027 Hagan, L. M., & Schinazi, R. F. (2013). Best strategies for global HCV eradication. Liver Int, 33 Suppl 1, 68-79. doi: 10.1111/liv.12063 Hahne, S. J., Veldhuijzen, I. K., Wiessing, L., Lim, T. A., Salminen, M., & Laar, M. (2013). Infection with hepatitis B and C virus in Europe: a systematic review of prevalence and cost-effectiveness of screening. BMC Infectious Diseases, 13, 181. doi: 10.1186/1471-2334-13-181 Harrington, M. (2010). From HIV to tuberculosis and back again: a tale of activism in 2 pandemics. Clinical Infectious Diseases, 50 Suppl 3, S260-266. doi: 10.1086/651500 Hepatitis B Foundation. In A. H. A. a. I. T. C. C. 2011 (Ed.). Hepatitis B vaccine support.). Retrieved from http://www.gavi.org/support/nvs/hepb/ Hill, A., Khoo, S., Fortunak, J., Simmons, B., & Ford, N. (2014). Minimum costs for producing hepatitis C direct-acting antivirals for use in large-scale treatment access programs in developing countries. Clinical Infectious Diseases, 58(7), 928-936. doi: 10.1093/cid/ciu012 Hoen, E., Berger, J., Calmy, A., & Moon, S. (2011). Driving a decade of change: HIV/AIDS, patents and access to medicines for all. Journal of the International AIDS Society, 14, 15. doi: 10.1186/1758-2652-14-15 Larson, H. J., Bertozzi, S., & Piot, P. (2011). Redesigning the AIDS response for long- term impact. Bulletin of the World Health Organization, 89(11), 846-852. doi: 10.2471/BLT.11.087114 Leidner, A. J., Chesson, H. W., Xu, F., Ward, J. W., Spradling, P. R., & Holmberg, S. D. (2015). Cost-effectiveness of hepatitis C treatment for patients in early stages of liver disease. Hepatology, 61(6), 1860-1869. doi: 10.1002/hep.27736 Liang, X., Bi, S., Yang, W., Wang, L., Cui, G., Cui, F., . . . Wang, Y. (2009). Evaluation of the impact of hepatitis B vaccination among children born during 1992-2005 in China. Journal of Infectious Diseases, 200(1), 39-47. doi: 10.1086/599332 Lo, K. J., Tsai, Y. T., Lee, S. D., Wu, T. C., Wang, J. Y., Chen, G. H., . . . et al. (1985). Immunoprophylaxis of infection with hepatitis B virus in infants born to hepatitis B surface antigen-positive carrier mothers. Journal of Infectious Diseases, 152(4), 817-822 Lozano, R., Naghavi, M., Foreman, K., Lim, S., Shibuya, K., Aboyans, V., . . . Memish, Z. A. (2012). Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet, 380(9859), 2095-2128. doi: 10.1016/S0140- 6736(12)61728-0 Medecins San Frontieres. (2015). Strategies to Secure Access to Generic Hepatitis C Medicines: Overcoming patent and regulatory barriers to secure access to generic hepatitis C medicines. http://www.msfaccess.org/sites/default/files/MSF_assets/HepC/Docs/Hep C_brief_OvercomingbarriersToAccess_ENG_2015.pdf. Mohd Hanafiah, K., Groeger, J., Flaxman, A. D., & Wiersma, S. T. (2013). Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology, 57(4), 1333-1342. doi: 10.1002/hep.26141 Murakami, H., Van Cuong, N., Huynh, L., & Hipgrave, D. B. (2008). Implementation of and costs associated with providing a birth-dose of hepatitis B vaccine in Viet Nam. Vaccine, 26(11), 1411-1419. doi: 10.1016/j.vaccine.2008.01.002 Obach, D., Deuffic-Burban, S., Esmat, G., Anwar, W. A., Dewedar, S., Canva, V., . . . Yazdanpanah, Y. (2014). Effectiveness and cost-effectiveness of immediate versus delayed treatment of hepatitis C virus-infected patients in a country with limited resources: the case of Egypt. Clinical Infectious Diseases, 58(8), 1064-1071. doi: 10.1093/cid/ciu066 Palmateer, N. E., Taylor, A., Goldberg, D. J., Munro, A., Aitken, C., Shepherd, S. J., . . . Hutchinson, S. J. (2014). Rapid decline in HCV incidence among people who inject drugs associated with national scale-up in coverage of a combination of harm reduction interventions. PloS One, 9(8), e104515. doi: 10.1371/journal.pone.0104515 Rabkin, M., Fouad, F. M., & El-Sadr, W. M. (2016). Addressing chronic diseases in protracted emergencies: Lessons from HIV for a new health imperative. Glob Public Health, 1-7. doi: 10.1080/17441692.2016.1176226 Rabkin, M., Goosby, E., & El-Sadr, W. M. (2014). Echoing the Lessons of HIV: How to serve milions with cardiovascular disease. Scientific American. RAJAGOPAL, D. (2015). Gilead adds ten new countries for Sovaldi access programmeDIVYA RAJAGOPAL. Ruff, T. A., Bravo, L., Gatchalian, S. R., & Bock, H. L. (2009). Priorities and challenges for hepatitis B control in the Philippines and the importance of a vaccine dose at birth. Southeast Asian Journal of Tropical Medicine and Public Health, 40(5), 972-990 Schweitzer, A., Horn, J., Mikolajczyk, R. T., Krause, G., & Ott, J. J. (2015). Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet, 386(10003), 1546- 1555. doi: 10.1016/S0140-6736(15)61412-X Scutti, S. (2014). Will New Hepatitis C Guidelines From WHO Help Make Sovaldi And Other New Drugs More Affordable? . Sobel, H. L., Mantaring, J. B., 3rd, Cuevas, F., Ducusin, J. V., Thorley, M., Hennessey, K. A., & Nyunt, U. S. (2011). Implementing a national policy for hepatitis B birth dose vaccination in Philippines: lessons for improved delivery. Vaccine, 29(5), 941-945. doi: 10.1016/j.vaccine.2010.11.047 Tanser, F., Barnighausen, T., Grapsa, E., Zaidi, J., & Newell, M. L. (2013). High coverage of ART associated with decline in risk of HIV acquisition in rural KwaZulu-Natal, South Africa. Science, 339(6122), 966-971. doi: 10.1126/science.1228160 Thomas, D. L. (2013). Global control of hepatitis C: where challenge meets opportunity. Nature Medicine, 19(7), 850-858. doi: 10.1038/nm.3184 Tu, H. A., Woerdenbag, H. J., Kane, S., Riewpaiboon, A., van Hulst, M., & Postma, M. J. (2009). Economic evaluations of hepatitis B vaccination for developing countries. Expert Rev Vaccines, 8(7), 907-920. doi: 10.1586/erv.09.53 Tucker, M. (2013). FDA Approves 'Game Changer' Hepatitis C Drug Sofosbuvir. Untangling the web of antiretroviral price reductions. (2013). http://www.msfaccess.org/content/untangling-web-antiretroviral-price- reductions-16th-edition. Van Damme, P., & Van Herck, K. (2007). A review of the long-term protection after hepatitis A and B vaccination. Travel Medicine and Infectious Disease, 5(2), 79-84. doi: 10.1016/j.tmaid.2006.04.004 Vandormael, A., Newell, M. L., Barnighausen, T., & Tanser, F. (2014). Use of antiretroviral therapy in households and risk of HIV acquisition in rural KwaZulu-Natal, South Africa, 2004-12: a prospective cohort study. Lancet Glob Health, 2(4), e209-215. doi: 10.1016/S2214-109X(14)70018-X Venters, C., Graham, W., & Cassidy, W. (2004). Recombivax-HB: perspectives past, present and future. Expert Rev Vaccines, 3(2), 119-129. doi: 10.1586/14760584.3.4.S119 Vriend, H. J., Van Veen, M. G., Prins, M., Urbanus, A. T., Boot, H. J., & Op De Coul, E. L. (2013). Hepatitis C virus prevalence in The Netherlands: migrants account for most infections. Epidemiology and Infection, 141(6), 1310-1317. doi: 10.1017/S0950268812001884 Wang, C., Wang, Y., Huang, X., Li, X., Zhang, T., Song, M., . . . Wang, W. (2012). Prevalence and factors associated with hepatitis B immunization and infection among men who have sex with men in Beijing, China. PloS One, 7(10), e48219. doi: 10.1371/journal.pone.0048219 Wang, L., Li, J., Chen, H., Li, F., Armstrong, G. L., Nelson, C., . . . Shapiro, C. N. (2007). Hepatitis B vaccination of newborn infants in rural China: evaluation of a village-based, out-of-cold-chain delivery strategy. Bulletin of the World Health Organization, 85(9), 688-694 WHO. (2015a). Blood safety and availability: Fact sheet N°279. Retrieved from http://www.who.int/mediacentre/factsheets/fs279/en/ WHO. (2015b). Global Immunization Data. http://www.who.int/immunization/monitoring_surveillance/Global_Immun ization_Data.pdf?ua=1. Wong, V. C., Ip, H. M., Reesink, H. W., Lelie, P. N., Reerink-Brongers, E. E., Yeung, C. Y., & Ma, H. K. (1984). Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis-B vaccine and hepatitis-B immunoglobulin. Double-blind randomised placebo-controlled study. Lancet, 1(8383), 921-926 Zhou, Y., Wang, H., Zheng, J., Zhu, X., Xia, W., & Hipgrave, D. B. (2009). Coverage of and influences on timely administration of hepatitis B vaccine birth dose in remote rural areas of the People's Republic of China. American Journal of Tropical Medicine and Hygiene, 81(5), 869-874. doi: 10.4269/ajtmh.2009.09- 0238 Zoulim, F. (2011). Hepatitis B virus resistance to antiviral drugs: where are we going? Liver Int, 31 Suppl 1, 111-116. doi: 10.1111/j.1478- 3231.2010.02399.x TABLES * Estimated in 2010, Lozano et al (Lozano et al., 2012) Table 1. Global hepatitis B and C epidemiology and biomedical tools available Public Health Strategies to Control Hepatitis B and C • Infant and child immunization, including birth dose* • Screening, especially high risk groups • Expanded and earlier treatment** • Blood donation screening • Harm reduction programs • Hepatitis awareness/health education campaigns • Integration of hepatitis prevention and treatment services into other health programs * Hepatitis B only ** Particularly for Hepatitis C Box 1. Public health strategies to control hepatitis B and C Table 2. Median costs of HCV-related sequelae in Europe, Asia, Pacific, and Americas (excluding US) (Source: El Khoury et al (El Khoury, Wallace, et al., 2012)) Table 3. Creating a global hepatitis movement using lessons from HIV response (Source: Ford et al (Ford et al., 2012))