Received: 19 June 2017  |  Accepted: 3 July 2017 DOI: 10.1111/jvh.12759 S U P P L E M E N T A R T I C L E Strategies to manage hepatitis C virus infection disease burden—Volume 4 D. S. Chen1,† | W. Hamoudi2,3,† | B. Mustapha4,† | J. Layden5,† | A. Nersesov6,† | T. Reic7,† |  V. Garcia8,† | C. Rios9,† | L. Mateva10,† | O. Njoya11,† | S. A. Al-Busafi12,† |  M. K. Abdelmageed13 | M. Abdulla14,† | D. Adda15,16 | O. Akin17,† | A. Al Baqali18 |  N. Al Dweik19 | K. Al Ejji19 | I. Al ghazzawi20,† | S. Al Kaabi19 | K. Al Naamani21,† |  J. Al Qamish22,† | M. Al Sadadi14 | J. Al Salman14 | M. AlBadri19 | H. E. Al-Romaihi23 |  W. Ampofo24 | K. Antonov10 | C. Anyaike17 | F. Arome25 | A. Bane26,27,† | S. Blach28,*  |  M. M. Borodo29,30 | S. M. Brandon28 | B. Bright31 | M. T. Butt19 | I. Cardenas32,† |  H. L. Y. Chan33,34,† | C. J. Chen35,† | P. J. Chen36 | R. N. Chien37 | W. L. Chuang38 |  D. Cuellar39 | M. Derbala19,† | A. A. Elbardiny23 | C. Estes28 | E. Farag23 | J. Fung40,† |  I. Gamkrelidze28 | J. Genov41 | Z. Ghandour42 | M. Ghuloom14 | B. Gomez43 | J. Gunter28 |  J. Habeeb14 | O. Hajelssedig19 | S. M. Himatt23,† | I. Hrstic44 | C. C. Hu37 | C. F. Huang38 |  Y. T. Hui45 | R. Jahis46 | D. Jelev10 | A. K. John19 | K. S. Kaliaskarova47,48,† | Y. Kamel19,49 |  J. H. Kao50 | J. Khamis14 | H. Khattabi51 | I. Khoudri52 | A. Konysbekova53,54 | I. Kotzev55 |  M. S. Lai56 | W. C. Lao57 | M. H. Lee58 | O. Lesi59,60 | M. Li61 | A. Lo34 | C. K. Loo62 |  B. Lukšić63 | A. Maaroufi52,† | A. O. Malu64 | R. Mitova41 | R. Mohamed65,† |  M. Morović66 | K. Murphy28 | H. Nde28 | E. Ngige17 | R. Njouom67,† | D. Nonković68 |  S. Obekpa25,64 | S. Oguche69,70,71 | E. E. Okolo72 | O. Omede17,† | C. Omuemu73 |  P. Ondoa74,75 | O. Opare-Sem76,† | S. Owusu-Ofori77,† | R. O. Phillips76,† |  Y. N. Prokopenko48 | H. Razavi28 | D. Razavi-Shearer28 | K. Razavi-Shearer28 |  B. Redae27,78,† | T. Rinke de Wit79 | S. Robbins28 | L. R. Roberts80 | S. J. Sanad42 | M. Sharma19 | M. Simonova81,† | T. H. Su50 | K. Sultan19 | S. S. Tan82,† | K. Tchernev83 |  O. T. Y. Tsang84 | S. Tsang85 | C. Tzeuton86 | S. Ugoeze87 | B. Uzochukwu88 | R. Vi48,89 |  A. Vince90,† | H. U. Wani19 | V. W. S. Wong33,91 | A. Workneh92,93 | R. Yacoub19 |  K. I. Yesmembetov94 | M. Youbi52 | M. F. Yuen95 | J. D. Schmelzer28 Abbreviations: DAA, direct-acting antiviral agent; G, Genotype; GHSS, Global Health Sector Strategy on viral hepatitis; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IDU, injection drug use; Peg-IFN, Pegylated interferon; RBV, ribavirin; SVR, sustained viral response; WHO, World Health Organization. †Denotes senior authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2017 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd. 44  |  wileyonlinelibrary.com/journal/jvh J Viral Hepat. 2017;24(Suppl. 2):44–63. CHEN Et al      |  45 1Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan 2Department of Gastroenterology & Hepatology, Al Bashir Hospital, Amman, Jordan 3Jordan Ministry of Health, Amman, Jordan 4IBN SINA Hospital, Rabat, Morocco 5Department of Public Health Sciences, Loyola University Chicago, Chicago, IL, USA 6National Research Institute of Cardiology and Internal Diseases, Almaty, Kazakhstan 7European Liver Patients Association, Sint-Truiden, Belgium 8Ministry of Public Health, Santo Domingo, Dominican Republic 9Department of Health Promotion and Disease Prevention, Ministry of Health and Social Protection, Bogota, Colombia 10University Hospital “St. Ivan Rilski”, Sofia, Bulgaria 11Research Laboratory on Viral Hepatitis & Health Communication, Faculty of Medicine, University of Yaoundé, Yaoundé, Cameroon 12Division of Gastroenterology, Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman 13Hamad Medical Corporation, Doha, Qatar 14Salmaniya Medical Complex, Manama, Bahrain 15Civil Society Network on Hepatitis, Abuja, Nigeria 16Chagro-Care Trust (CCT), Jalingo, Nigeria 17Federal Ministry of Health, Abuja, Nigeria 18Al Kindi Specialised Hospital, Manama, Bahrain 19Division of Gastroenterology, Department of Medicine, Hamad Medical Corporation, Doha, Qatar 20GI and Hepatology Department, Jordan Royal Medical Services, Amman, Jordan 21Division of Gastroenterology and Hepatology, Department of Medicine, Armed Forces Hospital, Muscat, Oman 22Gastroenterolgy Clinic, IBN Al-Nafees Hospital, Manama, Bahrain 23Ministry of Public Health Qatar, Doha, Qatar 24Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana 25Advocacy for the Prevention of Hepatitis in Nigeria, Jos, Nigeria 26Gastroenterology and Hepatology, Addis Ababa University Medical School, Addis Ababa, Ethiopia 27Ethiopian Gastroenterological Association, Addis Ababa, Ethiopia 28Center for Disease Analysis (CDA), Lafayette, CO, USA 29Aminu Kano Teaching Hospital, Kano, Nigeria 30Bayero University, Kano, Nigeria 31LiveWell Initiative (LWI), Lagos, Nigeria 32Communicable Diseases Division, Ministry of Health and Social Protection, Bogota, Colombia 33Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China 34Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China 35Academia Sinica, Taipei, Taiwan 36National Taiwan University, Taipei, Taiwan 37Liver Research Unit, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan 38Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan 39Department of Epidemiology and Demography, Ministry of Health and Social Protection, Bogota, Colombia 40Department of Medicine, The University of Hong Kong, Hong Kong, China 41University Hospital “Queen Joanna”, Sofia, Bulgaria 42BDF Hospital, Royal Medical Services, Riffa, Bahrain 43Pan American Health Organization, Washington, DC, USA 44General Hospital Pula, Pula, Croatia 45Department of Medicine, Queen Elizabeth Hospital, Hong Kong, China 46Disease Control Division, Ministry of Health, Putrajaya, Malaysia 47Ministry of Healthcare and Social Development of the Republic of Kazakhstan, Astana, Kazakhstan 48Republican Coordination Center for Hepatology and Gastroenterology, Astana, Kazakhstan 49Department of Medicine, Miniya University, Minya, Egypt 50Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 51Eastern Mediterranean Regional Office, World Health Organization, Cairo, Egypt 46  |     CHEN Et al 52Department of Epidemiology and Disease Control, Ministry of Health, Rabat, Morocco 53Republican Diagnostic Center, Astana, Kazakhstan 54University Medical Center, Astana, Kazakhstan 55University Hospital “St. Marina”, Varna, Bulgaria 56Department of Medicine, North District Hospital, Hong Kong, China 57Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China 58Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 59University of Lagos, Lagos, Nigeria 60Lagos University Teaching Hospital, Lagos, Nigeria 61Division of Gastroenterology and Hepatology, Department of Medicine and Geriatrics, Tuen Mun Hospital, Hong Kong, China 62Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong, China 63Clinical Department of Infectious Diseases, Split University Hospital and Split University Medical School, Split, Croatia 64Benue State University Teaching Hospital, Makurdi, Nigeria 65University of Malaya Medical Centre, Kuala Lumpur, Malaysia 66Department of Infectious Diseases, Zadar General Hospital, Zadar, Croatia 67Virology Department, Centre Pasteur of Cameroon, Yaounde, Cameroon 68Department of Epidemiology, Institute of Public Health, Split, Croatia 69Department of Pediatrics, University of Jos, Jos, Nigeria 70Department of Medicine, University of Jos, Jos, Nigeria 71Jos University Teaching Hospital, Jos, Nigeria 72Beacon Youth Initiative, Lafia, Nigeria 73University of Benin, Benin City, Nigeria 74Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands 75African Society of Laboratory Medicine, Addis Ababa, Ethiopia 76Kwame Nkrumah University of Science and Technology, Kumasi, Ghana 77Komfo Anokye Teaching Hospital, Kumasi, Ghana 78St. Paul’s Hospital Millennium College, Addis Ababa, Ethiopia 79PharmAccess Foundation, Department of Global Health, University of Amsterdam, Amsterdam, The Netherlands 80Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA 81Clinic of Gastroenterology, Military Medical Academy, Sofia, Bulgaria 82Department of Hepatology, Selayang Hospital, Selangor, Malaysia 83“Sofiamed” Hospital, Sofia, Bulgaria 84Department of Medicine and Geriatrics, Princess Margaret Hospital Authority, Hong Kong, SAR China 85Department of Medicine, Tseung Kwan O Hospital, Hong Kong, China 86Faculty of Medicine and Pharmaceutical Sciences, University of Douala, Douala, Cameroon 87Federal Medical Centre, Jalingo, Nigeria 88Institute of Public Health, University of Nigeria, Nsukka, Nigeria 89International HepatoTransplant Group, Astana, Kazakhstan 90Medical School University of Zagreb, University Hospital of Infectious Diseases Zagreb, Zagreb, Croatia 91State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China 92Non-Communicable Diseases Programme, World Health Organization, Addis Ababa, Ethiopia 93Federal Ministry of Health, Addis Ababa, Ethiopia 94National Scientific Center of Oncology and Transplantation, Astana, Kazakhstan 95Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China Correspondence Sarah Blach, Center for Disease Analysis, Summary Lafayette, CO, USA. The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 17 countries in Email: sarah.blach@centerforda.com Africa, Asia, Europe, Latin America and the Middle East, and interventions for achieving Funding information the Global Health Sector Strategy on viral hepatitis targets—“WHO Targets” (65% Polaris Observatory; Gilead Sciences; AbbVie CHEN Et al      |  47 reduction in HCV- related deaths, 90% reduction in new infections and 90% of infec- tions diagnosed by 2030) were considered. Scaling up treatment and diagnosis rates over time would be required to achieve these targets in all but one country, even with the introduction of high SVR therapies. The scenarios developed to achieve the WHO Targets in all countries studied assumed the implementation of national policies to pre- vent new infections and to diagnose current infections through screening. K E Y W O R D S diagnosis, disease burden, elimination, epidemiology, hepatitis C virus, hepatitis C, incidence, mortality, prevalence, scenarios, strategy, treatment 1  | INTRODUCTION were treated with DAAs compared to those treated with Peg- IFN/ RBV, when these data were available. If a country exclusively treated Although the number of new hepatitis C virus (HCV) infections has patients using oral DAAs, this was reflected in a higher average SVR declined in recent years, liver- related morbidity and mortality are on for each genotype.5 the rise due to an ageing infected population.1 The availability of more The future number of treated patients was limited by the num- efficacious treatment options has the potential to influence the treat- ber of diagnosed, eligible and unrestricted cases. Restrictions were ment paradigm at a country level. In the light of these new treatments defined implicitly (by physician’s practice) and/or explicitly (by treat- and the possibility of elimination, the World Health Organization’s 69th ment guidelines) and could be modified in the model by changing the World Health Assembly approved the Global Health Sector Strategy upper and lower end of patient’s age and the stage of fibrosis (≥F4, (GHSS) on viral hepatitis.2 The strategy includes a set of targets for ≥F3, ≥F2, ≥F1 or ≥F0). While age restrictions were applied to all gen- countries to achieve including a diagnosis rate of 90% of total infec- otypes, the restrictions by the stage of liver disease were applied to tions, a 90% decrease in new infections and a 65% decrease in liver- specific genotypes. Patients with decompensated cirrhosis, irrespec- related mortality by 2030. tive of genotype, were considered ineligible for any treatment that in- In this study, a modelling approach was used to forecast the future volved Peg- IFN. The fibrotic stages eligible for treatment are shown in disease burden and to develop a “WHO target” scenario for each coun- Figures 1-17. When the number of treated patients was greater than try to meet the GHSS targets. The findings are not meant to prescribe those diagnosed, eligible and unrestricted, the number of newly diag- specific strategies for implementation but rather to serve as “what- if” nosed cases was increased or the treatment restrictions were relaxed. scenarios to support long- term strategic planning efforts to reduce the The focus of the analysis was to highlight how many cases have to be disease burden associated with HCV. diagnosed to achieve a strategy rather than to forecast the screening capacity in a country. When treatment data for 2015 were not avail- able, it was assumed that the number of treated patients in 2015 was 2  | METHODOLOGY equal to the number of treated patients in 2014. In this analysis, two strategies were considered; base and WHO Previous publications have provided technical details of the model target. In the base strategy, all assumptions (the number of acute cases, used to forecast HCV disease burden.3,4 An interactive model inter- treated patients, per cent of patients eligible for treatment, treatment face allowed for the adjustment of several parameters: the number restrictions, the number of newly diagnosed patients and the average of patients treated, the proportion of cases eligible for treatment, the SVR by genotype) were projected to remain constant after 2015. While extent of treatment restrictions, the average sustained viral response it is unlikely that the treatment paradigm will remain completely un- (SVR) by genotype, the number of newly diagnosed individuals and the changed over the years, this scenario serves as a reference to compare number of new infections at five different points in time. against. The base scenario for each country was described in detail pre- A variety of therapies were available in 2015, including direct- viously.4 The WHO target scenario achieves WHO GHSS targets of a acting antivirals (DAAs) with or without pegylated interferon (Peg- 90% reduction in new infections and a 65% reduction in liver- related IFN) and/or ribavirin (RBV), dual therapy (Peg- IFN/RBV) and triple mortality by 2030. To meet these targets, screening and treatment therapy regimens using protease inhibitors. Over the last few years, were expanded across all genotypes and treatment restrictions were many countries have experienced a period of transition in which a changed in future years. combination of low and high SVR therapies was used. This was rep- Figures 1-17 detail the scenario inputs, including SVR, fibrosis resented in the model by changing the average SVR parameter. The stage and medical eligibility by age and genotype, as well as the num- average SVR for each genotype in 2015 was determined using a ber of patients that must be diagnosed and treated to meet the WHO weighted average based on the proportion of treated patients that targets. 48  |     CHEN Et al F IGURE  1 Bahrain model inputs, by year F IGURE  2 Bulgaria model inputs, by year F IGURE  3 Cameroon model inputs, by year F IGURE  4 Colombia model inputs, by year CHEN Et al      |  49 F IGURE  5 Croatia model inputs, by year F IGURE  6 Dominican Republic model inputs, by year F IGURE  7 Ethiopia model inputs, by year F IGURE  8 Ghana model inputs, by year 50  |     CHEN Et al F IGURE  9 Hong Kong model inputs, by year F IGURE  10  Jordan model inputs, by year F IGURE  11 Kazakhstan model inputs, by year F IGURE  12 Malaysia model inputs, by year CHEN Et al      |  51 F IGURE  13 Morocco model inputs, by year F IGURE  14 Nigeria model inputs, by year F IGURE  15 Oman model inputs, by year F IGURE  16 Qatar model inputs, by year 52  |     CHEN Et al F IGURE  17 Taiwan model inputs, by year Total Infected Cases (Viremic) - Bahrain Liver-related Deaths - Bahrain 18,000 140 16,000 120 14,000 100 12,000 10,000 80 8,000 60 6,000 40 4,000 2,000 20 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Bahrain All Cirrhosis - Bahrain 120 3,500 100 3,000 2,500 80 2,000 60 1,500 40 1,000 20 500 - - Base Case WHO Target Base Case WHO Target Total Infected Cases (Viremic) - Bulgaria Liver-related Deaths - Bulgaria 100,000 700 90,000 600 80,000 70,000 500 60,000 400 50,000 40,000 300 30,000 200 20,000 10,000 100 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Bulgaria All Cirrhosis - Bulgaria 600 14,000 500 12,000 10,000 400 8,000 300 6,000 200 4,000 100 2,000 - - Base Case WHO Target Base Case WHO Target F IGURE  18 Change in HCV morbidity and mortality, by scenario, 2015- 2030 In all instances, viremic infections represented current HCV or chronic (HCC) referred to the total number of viremic HCV- related HCC cases, HCV infections. The term viremic was used throughout this study to high- rather than new cases. Additionally, all reductions by disease stage were light the presence of HCV virus. The term incidence was used for new HCV assumed to occur among the viremic HCV population, that is the effects of infections and not newly diagnosed infections. Hepatocellular carcinoma non- HCV- related liver disease were not considered in this analysis. CHEN Et al      |  53 Total Infected Cases (Viremic) - Cameroon Liver-related Deaths - Cameroon 180,000 1,200 160,000 1,000 140,000 120,000 800 100,000 600 80,000 60,000 400 40,000 200 20,000 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Cameroon All Cirrhosis - Cameroon 1,200 25,000 1,000 20,000 800 15,000 600 10,000 400 200 5,000 - - Base Case WHO Target Base Case WHO Target Total Infected Cases (Viremic) - Colombia Liver-related Deaths - Colombia 450,000 4,000 400,000 3,500 350,000 3,000 300,000 2,500 250,000 2,000 200,000 150,000 1,500 100,000 1,000 50,000 500 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Colombia All Cirrhosis - Colombia 3,500 80,000 3,000 70,000 2,500 60,000 50,000 2,000 40,000 1,500 30,000 1,000 20,000 500 10,000 - - Base Case WHO Target Base Case WHO Target F IGURE  18  (Continued) 2.1 | Birth cohort effect countries would also reduce cases of compensated and decompen- sated cirrhosis and HCC by 45%- 85% by 2030. The birth cohort The age distribution of each country was gathered from published effect in the HCV- infected population is shown in Figure 19. Each data and reported previously.6 The disease progression model was bar represents the range of birth years, with the value on each bar used to age the HCV- infected population after taking into account showing the percentage of the total infected population who were mortality and SVR.4 For this analysis, the median age in each 5- year born between the years shown. Country- specific scenario results age cohort was selected and converted to a birth year. A range of birth are discussed below. years was selected that accounted for approximately 70% (or more) of the total HCV- infected population using the 2015 HCV population 4 3.1 | Bahraindistribution. An aggressive treatment and diagnosis strategy to achieve the WHO targets would result in 14 200 fewer viremic individuals in 2030, an 3  | RESULTS 85% reduction as compared to 2015. Doing so would require the num- ber annually treated to increase from 50 in 2015 to 1610 by 2025 and The results of the analyses are summarized in Figure 18. In meet- the number annually diagnosed to expand from 280 in 2015 to 1170 ing the WHO target of a 65% reduction in liver- related deaths, by 2025. 54  |     CHEN Et al Total Infected Cases (Viremic) - Croatia Liver-related Deaths - Croatia 30,000 250 25,000 200 20,000 150 15,000 100 10,000 5,000 50 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Croatia All Cirrhosis - Croatia 250 6,000 5,000 200 4,000 150 3,000 100 2,000 1,000 50 - - Base Case WHO Target Total Infected Cases (Viremic) - Dominican Republic Liver-related Deaths - Dominican Republic 80,000 600 70,000 500 60,000 50,000 400 40,000 300 30,000 200 20,000 10,000 100 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Dominican Republic All Cirrhosis - Dominican Republic 500 12,000 450 400 10,000 350 8,000 300 250 6,000 200 150 4,000 100 2,000 50 - - Base Case WHO Target Base Case WHO Target F IGURE  18  (Continued) 3.2 | Bulgaria introduction of DAAs in 2016, which increased the average SVR to 90%. Achieving the WHO targets with an aggressive treatment strategy would result in 75 600 fewer viremic individuals in 2030, an 80% 3.4 | Colombia reduction as compared to 2015. Annual number treated would need to expand from 720 in 2015 to 6000 in 2025. An increase in annual Utilizing an aggressive treatment and diagnosis strategy, there would number diagnosed would be required from 1200 in 2015 to 6100 in be a 95% reduction in the total number of viremic individuals, repre- 2025. This scenario assumed an increase in average SVR to 95% with senting 364 000 fewer viremic individuals in 2030, relative to 2015. the adoption of DAAs in 2017. Achieving the WHO targets would require an increase in annual num- ber treated from 1000 in 2015 to 33 600 by 2025 and the annual 3.3 | Cameroon number diagnosed from 3190 in 2015 to 57 400 by 2025. An increase in SVR to 90% due to the adoption of DAAs in 2016 was assumed. With an aggressive treatment strategy, there would be 122 000 fewer viremic individuals in 2030, a 75% reduction as compared to 3.5 | Croatia the 2015 base case. To reach the WHO targets, treatment would need to be expanded from fewer than 1000 patients treated in 2015 Utilizing an aggressive treatment and diagnosis strategy, there would to 9500 by 2025. Similarly, the number of diagnosed patients would be a 95% reduction in the total number of viremic individuals, repre- need to increase to 10 500 by 2025. This scenario incorporates the senting 25 300 fewer viremic individuals in 2030, relative to 2015. To CHEN Et al      |  55 Total Infected Cases (Viremic) - Ethiopia Liver-related Deaths - Ethiopia 700,000 4,500 600,000 4,000 3,500 500,000 3,000 400,000 2,500 300,000 2,000 1,500 200,000 1,000 100,000 500 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Ethiopia All Cirrhosis - Ethiopia 4,500 100,000 4,000 90,000 3,500 80,000 3,000 70,000 60,000 2,500 50,000 2,000 40,000 1,500 30,000 1,000 20,000 500 10,000 - - Base Case WHO Target Base Case WHO Target Total Infected Cases (Viremic) - Ghana Liver-related Deaths - Ghana 500,000 2,500 450,000 400,000 2,000 350,000 300,000 1,500 250,000 200,000 1,000 150,000 100,000 500 50,000 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Ghana All Cirrhosis - Ghana 2,500 60,000 2,000 50,000 40,000 1,500 30,000 1,000 20,000 500 10,000 - - Base Case WHO Target Base Case WHO Target F IGURE  18  (Continued) achieve the WHO targets, Croatia would need to increase the annual cases annually diagnosed would also need to be increased from 1990 number treated from 150 in 2015 to 2970 by 2025 and the annual in 2015 to 49 700 in 2025. number diagnosed from 150 in 2015 to 2310 by 2025. 3.8 | Ghana 3.6 | Dominican Republic With an aggressive treatment strategy, there would be 270 300 fewer If the WHO targets are met, there would be 63 200 fewer viremic indi- viremic individuals in 2030, a 70% reduction compared to the base viduals in 2030, a 90% reduction as compared to the base case. Reaching case. Achieving the WHO targets would require a treatment expan- the WHO targets would require treatment to expand from 270 annually sion from 20 annually treated in 2015 to almost 35 000 by 2025 and treated in 2015 to 7000 by 2025. Diagnosis would also need to expand an increase in cases annually diagnosed from 2770 in 2015 to 35 000 from 690 cases diagnosed annually in 2015 to 6500 by 2025. in 2025. This scenario assumed an increase in SVR to 90% starting in 2015 due to the arrival of DAAs. 3.7 | Ethiopia 3.9 | Hong Kong With treatment more than doubling annually, there would be 566 000 fewer viremic individuals in 2030, an 85% reduction from 2015. To With an aggressive treatment and diagnosis strategy, there would be achieve the WHO targets, an expansion of annual number treated 13 500 fewer viremic individuals in 2030 than in 2015, a 90% reduc- would be required, from 2000 in 2015 to 65 000 by 2025. Number of tion. This strategy would achieve the WHO targets by increasing the 56  |     CHEN Et al Total Infected Cases (Viremic) - Hong Kong Liver-related Deaths - Hong Kong 16,000 160 14,000 140 12,000 120 10,000 100 8,000 80 6,000 60 4,000 40 2,000 20 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Hong Kong All Cirrhosis - Hong Kong 140 3,500 120 3,000 100 2,500 80 2,000 60 1,500 40 1,000 20 500 - - Base Case WHO Target Base Case WHO Target Total Infected Cases (Viremic) - Jordan Liver-related Deaths - Jordan 30,000 200 180 25,000 160 20,000 140 120 15,000 100 80 10,000 60 5,000 40 20 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Jordan All Cirrhosis - Jordan 180 4,500 160 4,000 140 3,500 120 3,000 100 2,500 80 2,000 60 1,500 40 1,000 20 500 - - Base Case WHO Target Base Case WHO Target F IGURE  18  (Continued) annual number treated and diagnosed to 1000 and 1480 by 2025 and The analysis also found that a scale- up of treatment would require an 2018, respectively. increase in annual number diagnosed (from 4000 to 25 000 by 2021) to avoid running out of patients to treat. 3.10 | Jordan 3.12 | Malaysia With an aggressive treatment and diagnosis strategy, there would be 21 500 fewer viremic individuals in 2030, an 85% reduction as com- With an aggressive treatment strategy, there would be 373 000 fewer pared to 2015. Increasing the annual number treated to 1900 and the viremic individuals in 2030, a 95% reduction as compared to the base annual number diagnosed to 1570 by 2025 would result in meeting case. This strategy would achieve the WHO targets by increasing the the WHO targets. annual number treated and diagnosed to 41 000 and 35 100, respec- tively, by 2026. 3.11 | Kazakhstan 3.13 | Morocco With an aggressive treatment and diagnosis strategy, there would be 260 000 fewer viremic individuals in 2030, an 80% reduction as com- With an aggressive treatment strategy, there would be 299 000 fewer pared to 2015. Increasing annual number treated from 1750 in 2015 viremic individuals in 2030, a 95% reduction as compared to 2015. to 26 000 by 2023 would be required to achieve the WHO targets. Achieving the WHO targets would require a scale- up of number CHEN Et al      |  57 Total Infected Cases (Viremic) - Kazakhstan Liver-related Deaths - Kazakhstan 350,000 1,600 300,000 1,400 250,000 1,200 1,000 200,000 800 150,000 600 100,000 400 50,000 200 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Kazakhstan All Cirrhosis - Kazakhstan 1,600 35,000 1,400 30,000 1,200 25,000 1,000 20,000 800 15,000 600 400 10,000 200 5,000 - - Base Case WHO Target Base Case WHO Target Total Infected Cases (Viremic) - Malaysia Liver-related Deaths - Malaysia 450,000 3,500 400,000 3,000 350,000 2,500 300,000 250,000 2,000 200,000 1,500 150,000 1,000 100,000 50,000 500 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Malaysia All Cirrhosis - Malaysia 3,500 70,000 3,000 60,000 2,500 50,000 2,000 40,000 1,500 30,000 1,000 20,000 500 10,000 - - Base Case WHO Target Base Case WHO Target F IGURE  18  (Continued) annually treated from 3000 patients in 2015 to 33 100 patients by compared to 2015. The estimated number of patients annually 2025. The analysis also found that a scale- up of treatment would re- treated in 2015 would need to be increased to 1150 by 2025 (from quire an increase in annual number diagnosed (from 3100 to 30 500 by 70 in 2015) in order to achieve the WHO targets. This scale- up of 2025) to avoid running out of patients to treat. treatment would require an increase in annual number diagnosed from 230 in 2015 to 1000 by 2018 to avoid running out of patients 3.14 | Nigeria to treat. With an aggressive treatment strategy, there would be 1 804 000 fewer 3.16 | Qatar viremic individuals in 2030, a 70% reduction compared to the base case. To achieve the WHO targets, the number annually treated would need to The current treatment paradigm in Qatar was projected to achieve the increase from 300 in 2015 to 180 000 by 2030 and the number annually WHO target by 2030. There would be 1190 fewer viremic individuals diagnosed from 1300 in 2015 to 195 000 by 2025. This scenario assumed in 2030, a 90% reduction as compared to 2015. There would be fewer an increase in SVR to 90% starting in 2016 with the arrival of DAAs. than 600 total viremic cases by the year 2020. 3.15 | Oman 3.17 | Taiwan An aggressive treatment and diagnosis strategy would result in With an aggressive treatment and diagnosis strategy, there would 13 600 fewer viremic individuals in 2030, an 85% reduction as be 440 000 fewer viremic individuals in 2030 than in 2015, an 85% 58  |     CHEN Et al Total Infected Cases (Viremic) - Morocco Liver-related Deaths - Morocco 350,000 2,500 300,000 2,000 250,000 200,000 1,500 150,000 1,000 100,000 500 50,000 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Morocco All Cirrhosis - Morocco 2,000 45,000 1,800 40,000 1,600 35,000 1,400 30,000 1,200 25,000 1,000 20,000 800 600 15,000 400 10,000 200 5,000 - - Base Case WHO Target Base Case WHO Target Total Infected Cases (Viremic) - Nigeria Liver-related Deaths - Nigeria 3,000,000 12,000 2,500,000 10,000 2,000,000 8,000 1,500,000 6,000 1,000,000 4,000 500,000 2,000 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Nigeria All Cirrhosis - Nigeria 12,000 250,000 10,000 200,000 8,000 150,000 6,000 100,000 4,000 2,000 50,000 - - Base Case WHO Target Base Case WHO Target F IGURE  18  (Continued) reduction. This strategy would achieve the WHO targets by increas- Using today’s treatment paradigm, HCV- related morbidity and ing the annual number treated and diagnosed to 30 000 and 18 500, mortality is expected to increase through 2030 in most countries, with respectively, by 2025. the exception of Qatar and Taiwan.1 Additionally, in four countries (Ethiopia, Ghana, Jordan and Oman) the total number of HCV- infected individuals is expected to increase. 4  | DISCUSSION As part of this analysis, a WHO target scenario was developed to meet the GHSS targets for 2030: a 65% reduction in HCV- related mor- With the introduction of highly efficacious therapies for HCV treat- tality, a 90% reduction in new cases and 90% of all cases receiving ment, 2015 and 2016 were critical transition years for some countries, a diagnosis. In developing these scenarios, the future SVR as well as as health officials planned and began to implement new treatment medical eligibility, age range and number treated and diagnosed annu- strategies (ie, Hong Kong and Qatar). For other countries considered ally were modified to achieve the desired reduction in mortality. The in this analysis, discussions are underway to make HCV treatment ac- number diagnosed annually was further modified to achieve 90% di- cessible in the future (ie, Ghana and Bulgaria). This analysis suggests agnosed by 2030. The reduction in new infections was directly input that achieving WHO targets for the elimination of HCV is possible with into the scenarios. Therefore, it is assumed that factors both inside the a multifaceted approach that increases screening, expands treatment scope of the model (eg, treatment expansion and reduction in total access to F1 and F0 patients and gradually scales up the number of infection) and outside the scope of the model (prevention efforts such treated patients annually. as education and needle programs) account for the reduction in new CHEN Et al      |  59 Total Infected Cases (Viremic) - Oman Liver-related Deaths - Oman 18,000 140 16,000 120 14,000 100 12,000 10,000 80 8,000 60 6,000 40 4,000 2,000 20 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Oman All Cirrhosis - Oman 12,000 250,000 10,000 200,000 8,000 150,000 6,000 100,000 4,000 2,000 50,000 - - Base Case WHO Target Base Case WHO Target Total Infected Cases (Viremic) - Qatar Liver-related Deaths - Qatar 1,400 6 1,200 5 1,000 4 800 3 600 2 400 200 1 - - Base Case/WHO Target Base Case/WHO Target Total HCC Cases - Qatar All Cirrhosis - Qatar 6 140 5 120 100 4 80 3 60 2 40 1 20 - - Base Case/WHO Target Base Case/WHO Target F IGURE  18  (Continued) Total Infected Cases (Viremic) - Taiwan Liver-related Deaths - Taiwan 600,000 7,000 500,000 6,000 5,000 400,000 4,000 300,000 3,000 200,000 2,000 100,000 1,000 - - Base Case WHO Target Base Case WHO Target Total HCC Cases - Taiwan All Cirrhosis - Taiwan 7,000 140,000 6,000 120,000 5,000 100,000 4,000 80,000 3,000 60,000 2,000 40,000 1,000 20,000 - - Base Case WHO Target Base Case WHO Target F IGURE  18  (Continued) 60  |     CHEN Et al Bahrain 77% Bulgaria 75% Cameroon 75% Colombia 74% Croatia 73% Dominican Republic 75% Ethiopia 71% Ghana 74% Hong Kong 73% Jordan 70% Kazakhstan 74% Malaysia 75% Morocco 77% Nigeria 75% Oman 73% Qatar 74% Taiwan 71% 1925 1935 1945 1955 1965 1975 1985 1995 2005 2015 F IGURE  19 Distribution of HCV- infected population by birth year cohort infections. The feasibility of achieving the WHO targets varies by coun- The strategy to achieve the WHO targets is most effective when try due to the heterogeneity in baseline disease projections over the treatment is restricted to more advanced patients (≥F3) in the first next 15 years. For example, under the base case assumptions, liver- several years before expanding to all fibrosis stages and older patients. related mortality is projected to decline in a few countries while most However, because 77% of all infections in Bahrain are among those other countries are projected to see increases in the number of deaths, aged 32- 57 years, targeting this younger population would be more some to a very large degree. Factors that influence this include the age effective for diagnosing cases and reducing the overall infection rate. of the infected population and the strength of the current treatment paradigm. 4.2 | Bulgaria A key observation of this analysis was that increased treatment coverage and SVR in patients who were >F2 had the largest impact Under the current treatment structure, in which an estimated 0.8% in reducing morbidity and mortality. However, treatment of F0- F1 pa- of the infected population receives treatment annually, the preva- tients was necessary to achieve reductions in total cases and prevent lence of chronic HCV was projected to decrease by 18%. An ageing ongoing transmission. The WHO target scenarios were most effective infected population contributed to the projected decline in prevalence. when following a strategy of prioritizing treatment in >F2 patients in Achieving the WHO targets, in addition to increasing treatment and the first few years before expanding treatment to all. The exception diagnosis, would require an expansion of the treated population to in- was in countries where the number of diagnosed and treated patients clude F1 and F0 cases and higher SVRs with the adoption of DAAs in was so low to begin with that there were too few patients diagnosed 2017. with advanced disease. This strategy did have a major drawback. The HCV- infected population is ageing, and not treating early- stage 4.3 | Cameroon patients meant that patients would continue to advance to higher fi- brosis stages, cirrhosis and HCC. Thus, the lower rates of advanced In this analysis, it was found that the adoption of higher SVR liver- related disease and mortality would not be sustained without therapies would have a small impact on the burden of advanced additional intervention. Even in a scenario where all infections are ag- disease. These therapies will have to be combined with an aggres- gressively targeted, the age of the infected population is one of the sive treatment strategy to achieve a 75% reduction in total viremic key variables for not being able to feasibly achieve zero infections in a infections. country. Another challenge to achieving the WHO targets and/or com- The strategies modelled here required increases in the diagnosed plete eradication is immigration in today’s mobile society. The models population, as it was estimated that less than 10% of the viremic in- take into account the assumption that some new cases always entered fected population was living with a diagnosis. This input has some the country through immigration. The long- term goals of the WHO tar- uncertainty, however, as it was estimated through expert input in the gets will require a global effort to eliminate the virus across borders. absence of a national registry. 4.1 | Bahrain 4.4 | Colombia Under the current treatment structure, the prevalence of chronic HCV The HCV prevalence in Colombia is comparable to many countries in is projected to decrease by 5% by 2030, which is relatively static given the Americas. Under the current treatment paradigm, HCV infections that new DAAs are already available. The estimated number of patients will decline by 20% by 2030. However, the most costly stages of the currently treated (50 annually) is low due to patients waiting on DAA disease burden, including cirrhosis, decompensated cirrhosis and HCC, therapies and the ramp up of DAA availability. are expected to increase 45%- 70%. Currently, Colombia allows the CHEN Et al      |  61 treatment of all fibrosis stages, thus is in a unique position to save on 4.9 | Hong Kong screening costs. To meet WHO 2030 targets, large increases in treatment, diagnosis Under the current treatment strategy, the number of viremic infec- and prevention would be necessary. However, 74% of all viremic indi- tions is expected to decline by 18% by 2030. However, advanced viduals were born between 1953 and 1988 making targeted screening liver- related morbidity and mortality will continue to increase. This is and treatment a feasible way to address the disease burden. By focus- likely explained by the older age distribution of the infected popula- ing on the older patients in this age cohort, there would be faster and tion; over half of all infections are among those older than 47 years. larger decreases observed in the later stages of the disease and the The higher rate of mortality in the older ages likely more than off- WHO targets could be met more quickly. sets the incidence of new infection. Modelling the increased use of high SVR therapies, however, showed an 80%- 85% reduction in 4.5 | Croatia cases of cirrhosis, decompensated cirrhosis and HCC by 2030. It is important to note that focusing on targeting treatment in the older Under the current treatment structure, the prevalence of chronic HCV infected population would be imperative to the effectiveness of such was projected to decrease by 6000 patients, a 25% decline compared an intervention. to 2015. A low incidence rate (4.5 per 100 000) and an ageing infected population contribute to the projected decline in prevalence. Achieving 4.10 | Jordan the WHO targets, in addition to increased number of cases treated and diagnosed, would require treatment to expand to F1 and F0 cases. It is Under the current treatment strategy, the number of viremic infections assumed that Croatia will adopt new DAAs leading to a 90% average is expected to increase 7% by 2030 and then remain stable into the SVR for treatment in 2017. future. This is likely a result of a moderate incidence rate (8.3 per 100 k) that is partially offset by a treatment rate of 0.6%. Modelling the use 4.6 | Dominican Republic of increased SVR therapies, however, showed a 65% reduction in cases of cirrhosis, decompensated cirrhosis and HCC. It is important to note Under the current treatment structure, the prevalence of chronic that this intervention would be most effective when targeted screen- HCV is projected to decrease by 15%, but advanced liver disease and ing at patients aged 32- 57 years, as this group accounts for greater liver- related mortality are projected to increase by 85%- 100%. Large than 70% of all infections. increases in treatment must be paired with increased diagnosis rates to reduce the disease burden. Additionally, to prevent new infections, 4.11 | Kazakhstan treatment must eventually be expanded to F1 and F0 patients. Under the current treatment structure, the prevalence of chronic HCV 4.7 | Ethiopia is projected to remain relatively static, decreasing by 3% by 2030. Liver- related morbidity and mortality, however, were projected to in- Under the current treatment structure, the prevalence of chronic HCV crease by 60%- 65% by 2030. Subsequently, the strategy to achieve was projected to minimally increase. A low treatment rate (0.3%) con- the WHO targets is most effective when treatment is restricted to tributes to the projected minimal change. In this analysis, it was found more advanced patients (≥F2) in the first several years and made avail- that the adoption of higher SVR therapies among patients with fibrosis able to older patients. (≥F1) would have no impact on the burden of advanced disease with- out increasing the number of patient treated. 4.12 | Malaysia Treatment in Ethiopia is limited; it was estimated that approximately 10 000 patients were treated over the course of 5 years. However, cur- Under the current treatment strategy, the number of viremic infections rent therapies are expensive for many patients throughout the country, is expected to decline by 11% by 2030. However, advanced fibrosis which is a barrier to increasing the number of patients treated in the and liver- related morbidity and mortality were projected to increase future. by 100% compared to 2015. While the overall prevalence will decline due to low incidence, those who are currently infected will continue 4.8 | Ghana to advance to liver- related morbidity. Modelling the increased use of high SVR therapies with expansion of treatment and diagnosis would Under the current treatment structure, the prevalence of chronic thus be most effective when restricted to patients with F2 and higher HCV between 2015 and 2030 was projected to increase by 12%. The fibrosis in the initial years. WHO target strategy modelled here required a sharp increase in the diagnosed population, as it was estimated that only 7% of the viremic 4.13 | Morocco infected population was living with a diagnosis. This input has some uncertainty, however, as it was estimated through expert consensus in Under the current treatment structure, the prevalence of chronic HCV the absence of a national registry. was projected to slightly decrease by 9% from 2015 to 2030. However, 62  |     CHEN Et al advanced liver- related morbidity and mortality were projected to in- HCV infection may be associated with extra hepatic diseases7,8 sug- crease at a higher rate (30%- 35%) over that same time. gesting that the benefits of such a strategy may extend beyond the The strategy to achieve the WHO targets is thus most effective hepatic disease burden. when treatment is restricted to more advanced patients (≥F2) at first and made available to older patients before expanding to all patients. 4.18 | Utility of HCV screening 4.14 | Nigeria As shown previously, 4,6 diagnosis remains low in many countries. In all countries except Qatar, the diagnosis rate was increased in future Under the current treatment structure, the prevalence of chronic HCV years in developing the WHO target scenarios in the models. This was was projected to decrease by 10% from 2015 to 2030. However, ad- required to both provide a sufficient patient pool for treatment as well vanced liver- related morbidity and mortality were projected to increase as to achieve the WHO target of diagnosing 90% of all cases by 2030. by 1%- 3% over that same time. The WHO target strategy modelled However, it is not clear if the number of newly diagnosed patients can here required an increase in the diagnosed population, as it was esti- realistically be increased without a focused screening strategy and with mated that just about 5% of the viremic infected population was living the current medical infrastructure in each country. with a diagnosis. This input has some uncertainty, however, as it was One way to more efficiently identify cases, as recommended by the estimated through expert input in the absence of a national registry. U.S. Centers for Disease Control and Prevention, is to screen the birth cohorts with a higher prevalence rate.9-11 A birth cohort analysis was 4.15 | Oman conducted for each country, and the results are shown in Figure 19. The analysis identified specific age ranges accounting for over 70% of the Under the current treatment structure, the prevalence of chronic HCV infected population. The cohort ranges in the countries analysed varied is projected to remain relatively static, increasing by only 3% by 2030. from 20 years (Croatia and Jordan) to 45 years (Nigeria), likely due to The strategy to achieve the WHO targets is most effective when treat- variations in risk factors. The ranges tended to be wider when nosoco- ment is restricted to more advanced patients (≥F2) in the first several mial infection was identified as a risk factor (eg, blood transfusions from years and made available to older patients before expanding treatment unscreened blood). In countries where IDU was identified as a key risk to all patient population segments. And because >70% of all infections factor, the birth cohort range often skewed towards younger ages. Age in Oman are among those aged 32- 57 years, targeting these younger distributions within each country’s total populations might also account patients for screening would more efficiently identify patients. for some of the variation in the range and age of the birth cohorts. The birth year cohorts for these countries provide an efficient mechanism 4.16 | Qatar for identifying new patients as part of a national screening strategy. Under the current treatment strategy, the number of viremic infections 4.19 | Limitations is expected to greatly decrease by 2030, eventually leading to elimi- nation. This is likely a result of a high treatment rate with new DAAs There were several limitations of this study. SVR rates for current among nationals with HCV (13% in 2015). In fact, the current treat- treatment protocols were often based on clinical data from centres ment and diagnosis rates were projected to achieve the WHO targets. highly adept at and experienced in treating patients and limiting ad- It is important to note that nationals make up only a small percentage verse events. SVR rates observed outside of these ideal settings could of the country’s population and of the infected population in Qatar. be lower,12 resulting in a greater need to increase annual treatment Incidence will likely not drop in the national population even as most rates than what is reported here in order to achieve the WHO target patients become cured. Interventions that target the immigrant popu- scenarios. In addition, there is uncertainty around HCV prevalence es- lation as well would be necessary to achieve the WHO targets across timates identified for each country.4 Therefore, the required actions to the total population. achieve the WHO targets may be more or less pronounced if this anal- ysis under- or over- estimated the true prevalence. 4.17 | Taiwan Another limitation was that increases in treatment rate, diagnosis rate, eligibility and SVR in developing the WHO target scenarios were Under the current treatment strategy, the number of viremic infec- assumed to be implemented immediately. In reality, the market entry tions is expected to decline by 45% by 2030. Advanced liver- related of new therapies, adoption of policies and implementation of national morbidity and mortality were also projected to show modest declines disease management strategies would take several years to actualize. between 5%- 17% compared to 2015. This is likely explained by the However, time sensitivity analyses examining the impact of accelerat- combination of the advanced age of the patient population (>70% be- ing or delaying initiating strategies consistently demonstrated that the tween 42- 72 years), the relatively high treatment rate (1.5% annually) WHO targets were more likely to be met and more efficiently achieved and the relatively low incidence rate (13 new cases per 100 000 peo- when the strategies were implemented sooner than later. ple). It is important to note that expanding treatment to the older ages A final limitation of this analysis is that disease progression was was critical to achieving these targets. There is evidence showing that considered to halt once patients were cured. In reality, it has been CHEN Et al      |  63 shown that the risks for advancing to liver- related morbidity and mor- S. Kaliaskarova, Y. Kamel, J. H. Kao, J. Khamis, H. Khattabi, I. Khoudri, A. tality can persist even after achieving SVR, though at significantly lower Konysbekova, I. Kotzev, M. S. Lai, W. C. Lao, M. H. Lee, O. Lesi, M. Li, A. rates.13 Therefore, the model could underestimate the rate of increased Lo, C. K. Loo, B. Lukšić, A. Maaroufi, A. O. Malu, R. Mitova, R. Mohamed, treatment and diagnosis needed to achieve the WHO target of a 65% M. Morović, E. Ngige, R. Njouom, D. Nonković, S. Obekpa, S. Oguche, E. reduction in liver- related mortality. However, any underestimation is E. Okolo, O. Omede, C. Omuemu, P. Ondoa, O. Opare- Sem, S. Owusu- likely to be minimal, as the bulk of this reduction is due to the decrease Ofori, R. O. Phillips, Y. N. Prokopenko, B. Redae, T. Rinke de Wit, S. J. in early- stage chronic infections, which are at very low risk of progress- Sanad, M. Sharma, M. Simonova, T. H. Su, K. Sultan, S. S. Tan, O. T. Y. ing to advanced liver disease once cured. Tsang, C. Tzeuton, S. Ugoeze, B. Uzochukwu, R. Vi, A. Vince, H. U. Wani, A. 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