Deciding who should be treated for hepatitis C infection in a rapidly changing therapeutic landscape Stefan Z. Wiktor Global Hepatitis Programme, World Health Organization Allocating scarce health resources is ethically difficult. Different principles have been proposed to decide who should receive specific health interventions. These include prioritizing the sickest, maximizing utility by treating those who will benefit the most, or treating based on a person’s ‘social usefulness’1. In view of the recent improvements in the efficacy of medicines to treat hepatitis C infection and their high cost, these types of discussions are very relevant to the field of hepatitis C treatment. Until recently, treatment of persons with hepatitis C infection required 24-48 weeks of pegylated interferon and ribavirin which caused frequent, sometimes severe, adverse reactions and produced cure in between half and two-thirds of persons treated, depending on clinical stage and genotype. Because of these factors, treatment decisions were made in large part based on an assessment of whether the benefit of treatment outweighed the risk of adverse events. Consequently, treatment was reserved primarily for persons with advanced fibrosis and cirrhosis who were at highest risk of developing decompensated cirrhosis and hepatocellular carcinoma. The introduction of direct-acting antiviral (DAA) is changing this dynamic. The new drugs produce few side effects and result in cure for more than 90% of individuals, even those who are considered difficult to treat such as persons with cirrhosis. Based on the safety and efficacy of the new DAAs, in principle, all persons with chronic HCV infection could be considered for treatment. However, these medicines are extremely expensive, with costs sometimes exceeding $US 100,000 to treat a single patient. In view of this, restrictive eligibility criteria have been instituted by public and private health-insurance providers to minimize the budgetary impact of these expensive treatments2. The situation in low- and middle income countries (LMIC) is even more dire. Currently, very few persons in these countries receive treatment, and when the medicines are introduced, their use will be severely restricted because of their high cost. Guidance on who should be clinically prioritized for treatment is needed to help guide policy makers in how to allocate limited treatment slots. In this issue, Obach and colleagues have addressed this question through an effectiveness analysis comparing the impact on life-years saved (LYS) in three middle-income countries: Egypt, which has the highest HCV prevalence in the world and a large publicly funded HCV treatment program, and, Thailand and Côte d’Ivoire, two middle-income countries with lower HCV prevalence (2.2% and 3%, respectively) and nascent HCV treatment programs3. The authors compared the effectiveness of three different treatment-initiation scenarios: treating persons with Metavir stage F2-F4 (base case), compared with treating only those with F3 or F4 or those with F1-F4 stages. They found that in all three countries, treating persons with advanced disease (F3 and F4) was the most effective option. In Egypt, treating 45,000 patients per year with F3 and F4 disease over a twenty-year period would save 2,590,458 life-years, which represented a 6.7% increase over the base-case scenario. Treating
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27810 This article is protected by copyright. All rights reserved.
Hepatology
F1-F4 was the least effective scenario with 3.9% fewer LYS than the base case. The improvement in LYS of treating F3 and F4 compared with treating earlier stages of disease was also noted in Thailand (15.3% more LYS) and Cote d’Ivoire (11.0% more LYS). In a sensitivity analysis, these results remained unchanged even when a number of assumptions were varied widely. These results provide supportive evidence for the World Health Organization’s recommendations of prioritizing treatment for persons with F3-F4-stage disease4. The authors also modelled the impact of introducing a more efficacious, all-oral DAA regimen, which had a dramatic impact. Among persons with F3-F4 disease, in Egypt there was an estimated 69.3% increase in LYS with DAAs as compared with treating the same group with pegylated-interferonbased therapy. The increases in LYS were even greater in Thailand (82.8%) and Cote d’Ivoire (75.7%). This large increase is observed because of the higher comparative effectiveness of DAAs among cirrhotics relative to pegylated-interferon regimens. Some efforts are underway to improve access to the DAAs in resource-limited settings, including through donations provided by medicines manufacturers, and discounts and generic competition. Nevertheless, It is likely that for the next few years the DAAs will be in limited supply because of their high cost. Policy makers and clinicians will be faced with the challenge of whom to prioritize for treatment. These results in Obach’s paper will provide a useful framework for prioritization of treatment to achieve maximal impact. This analysis presupposes that an adequate number of patients with advanced HCV disease can be diagnosed and that their degree of fibrosis be correctly classified. For this to happen, persons need to be tested with an antibody test, chronic hepatitis C infection must be confirmed and genotyped with a nucleic acid test or antigen test, and they must be linked to care where fibrosis staging can be performed. There are barriers at each step of this cascade. In many low- and middle-income countries, there are no HCV testing policies and few testing sites; there are very few laboratories equipped to perform nucleic acid testing, and linkage to care frequently does not occur. Even In Egypt, with a high-profile treatment program, only 3.8% of persons know their HCV result, and this percentage is likely lower in many other LMICs5 Even in the United States, where approximately 50% of persons with HCV have been diagnosed, almost half of patients are lost to follow-up between the initial diagnosis and fibrosis assessment6 Another challenge for this prioritization strategy to work is that clinicians must have access to tests that can accurately stage the degree of liver fibrosis. In most resource constrained countries, liver biopsy is not an option because of the complex technical requirements, and ultrasound-based techniques such as transient elastography are not available because of the high cost of the equipment and maintenance. Thus, clinicians rely on serologic tests such as the APRI or FIB4 index, which are calculated based on widely available and inexpensive blood tests (platelet count and aminotransferase levels). These tests have a high specificity, thus producing few false positives but sensitivity is suboptimal such that, depending on the cut-off criterion, many patients with cirrhosis are not properly classified.7. This highlights the importance of regular evaluations of patients to assess fibrosis through repeat testing and the need for more accurate low-cost tests to accurately diagnose advanced fibrosis and cirrhosis. The approach proposed by Obach to prioritize treatment considers the utilitarian perspective of maximizing life years1. As such it only considered the mortality benefit of HCV therapy. However,
Hepatology This article is protected by copyright. All rights reserved.
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Hepatology
even at early stages of fibrosis, HCV infection can cause significant morbidity through extrahepatic manifestations and also can reduce quality of life8. Improvements in these outcomes accrue to patients at all stages of fibrosis but were not assessed in the analysis. An additional important benefit of HCV treatment is the prevention benefit -- persons who are cured of their HCV infection no longer transmit the infection to others. Mathematical modelling of treating persons who inject drugs and those who are frequent recipients of medical injections demonstrate that scaling up treatment in these groups, irrespective of fibrosis stage, can result in lower population prevalence of HCV9,10. For these benefits of hepatitis C treatment to be fully realized and for elimination of HCV to be possible, treatment will need to be simplified and made less expensive so that it can be dramatically expanded. The rapid progress in drug development makes this a possibility. What remains to be seen is whether the financial and political commitment will follow to make it a reality.
1
Persad G, Wertheimer A, Emanuel EJ. Principles for allocation of scarce medical interventions. Lancet 2009;373:423-431. 2
amFAR. Hepatitis C and Drug Pricing: The Need for a Better Balance. In. http://www.amfar.org/HCV-Drug-Pricing/; 2015. 3
Obach D, Yazdanpanah Y, Esmat G, Avihingsanon A, Dewedar S, Durier N, Attia A, et al. How to optimize HCV treatment impact on life years saved in resource-constrained countries. Hepatology 2015. 4
World Health Organization. Guidelines for screening, care, and treatment of persons with hepatitis C infection. Available from: http://apps.who.int/iris/bitstream/10665/111747/1/9789241548755_eng.pdf?ua=1&ua=1. Accessed 23 February 2015 5
El-Zanaty F, Way A. Egypt Demographic and Health Survey 2008. Department: Ministry of Health, Cairo, 2009. Available from: http://pdf.usaid.gov/pdf_docs/PNADO806.pdf. Accessed: 24 February 2015..
6
Yehia BR, Schranz AJ, Umscheid CA, Lo Re V. The treatment cascade for chronic hepatitis C virus infection in the United States: a systematic review and meta-analysis. PLoS One 2014;9:e101554. 7
Tsochatzis EA, Crossan C, Longworth L, Gurusamy K, Rodriguez-Peralvarez M, Mantzoukis K, O'Brien J, et al. Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis C. Hepatology 2014;60:832-843.
8
Spiegel BM, Younossi ZM, Hays RD, Revicki D, Robbins S, Kanwal F. Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment. Hepatology 2005;41:790800.
Hepatology This article is protected by copyright. All rights reserved.
Hepatology
9
Breban R, Arafa N, Leroy S, Mostafa A, Bakr I, Tondeur L, Abdel-Hamid M, et al. Effect of preventive and curative interventions on hepatitis C virus transmission in Egypt (ANRS 1211): a modelling study. Lancet Glob Health 2014;2:e541-549 10
Hellard M, Rolls DA, Sacks-Davis R, Robins G, Pattison P, Higgs P, Aitken C, et al. The impact of injecting networks on hepatitis C transmission and treatment in people who inject drugs. Hepatology 2014;60:1861-1870.
Hepatology This article is protected by copyright. All rights reserved.
Page 4 of 4
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27810 This article is protected by copyright. All rights reserved.
Hepatology
F1-F4 was the least effective scenario with 3.9% fewer LYS than the base case. The improvement in LYS of treating F3 and F4 compared with treating earlier stages of disease was also noted in Thailand (15.3% more LYS) and Cote d’Ivoire (11.0% more LYS). In a sensitivity analysis, these results remained unchanged even when a number of assumptions were varied widely. These results provide supportive evidence for the World Health Organization’s recommendations of prioritizing treatment for persons with F3-F4-stage disease4. The authors also modelled the impact of introducing a more efficacious, all-oral DAA regimen, which had a dramatic impact. Among persons with F3-F4 disease, in Egypt there was an estimated 69.3% increase in LYS with DAAs as compared with treating the same group with pegylated-interferonbased therapy. The increases in LYS were even greater in Thailand (82.8%) and Cote d’Ivoire (75.7%). This large increase is observed because of the higher comparative effectiveness of DAAs among cirrhotics relative to pegylated-interferon regimens. Some efforts are underway to improve access to the DAAs in resource-limited settings, including through donations provided by medicines manufacturers, and discounts and generic competition. Nevertheless, It is likely that for the next few years the DAAs will be in limited supply because of their high cost. Policy makers and clinicians will be faced with the challenge of whom to prioritize for treatment. These results in Obach’s paper will provide a useful framework for prioritization of treatment to achieve maximal impact. This analysis presupposes that an adequate number of patients with advanced HCV disease can be diagnosed and that their degree of fibrosis be correctly classified. For this to happen, persons need to be tested with an antibody test, chronic hepatitis C infection must be confirmed and genotyped with a nucleic acid test or antigen test, and they must be linked to care where fibrosis staging can be performed. There are barriers at each step of this cascade. In many low- and middle-income countries, there are no HCV testing policies and few testing sites; there are very few laboratories equipped to perform nucleic acid testing, and linkage to care frequently does not occur. Even In Egypt, with a high-profile treatment program, only 3.8% of persons know their HCV result, and this percentage is likely lower in many other LMICs5 Even in the United States, where approximately 50% of persons with HCV have been diagnosed, almost half of patients are lost to follow-up between the initial diagnosis and fibrosis assessment6 Another challenge for this prioritization strategy to work is that clinicians must have access to tests that can accurately stage the degree of liver fibrosis. In most resource constrained countries, liver biopsy is not an option because of the complex technical requirements, and ultrasound-based techniques such as transient elastography are not available because of the high cost of the equipment and maintenance. Thus, clinicians rely on serologic tests such as the APRI or FIB4 index, which are calculated based on widely available and inexpensive blood tests (platelet count and aminotransferase levels). These tests have a high specificity, thus producing few false positives but sensitivity is suboptimal such that, depending on the cut-off criterion, many patients with cirrhosis are not properly classified.7. This highlights the importance of regular evaluations of patients to assess fibrosis through repeat testing and the need for more accurate low-cost tests to accurately diagnose advanced fibrosis and cirrhosis. The approach proposed by Obach to prioritize treatment considers the utilitarian perspective of maximizing life years1. As such it only considered the mortality benefit of HCV therapy. However,
Hepatology This article is protected by copyright. All rights reserved.
Page 2 of 4
Page 3 of 4
Hepatology
even at early stages of fibrosis, HCV infection can cause significant morbidity through extrahepatic manifestations and also can reduce quality of life8. Improvements in these outcomes accrue to patients at all stages of fibrosis but were not assessed in the analysis. An additional important benefit of HCV treatment is the prevention benefit -- persons who are cured of their HCV infection no longer transmit the infection to others. Mathematical modelling of treating persons who inject drugs and those who are frequent recipients of medical injections demonstrate that scaling up treatment in these groups, irrespective of fibrosis stage, can result in lower population prevalence of HCV9,10. For these benefits of hepatitis C treatment to be fully realized and for elimination of HCV to be possible, treatment will need to be simplified and made less expensive so that it can be dramatically expanded. The rapid progress in drug development makes this a possibility. What remains to be seen is whether the financial and political commitment will follow to make it a reality.
1
Persad G, Wertheimer A, Emanuel EJ. Principles for allocation of scarce medical interventions. Lancet 2009;373:423-431. 2
amFAR. Hepatitis C and Drug Pricing: The Need for a Better Balance. In. http://www.amfar.org/HCV-Drug-Pricing/; 2015. 3
Obach D, Yazdanpanah Y, Esmat G, Avihingsanon A, Dewedar S, Durier N, Attia A, et al. How to optimize HCV treatment impact on life years saved in resource-constrained countries. Hepatology 2015. 4
World Health Organization. Guidelines for screening, care, and treatment of persons with hepatitis C infection. Available from: http://apps.who.int/iris/bitstream/10665/111747/1/9789241548755_eng.pdf?ua=1&ua=1. Accessed 23 February 2015 5
El-Zanaty F, Way A. Egypt Demographic and Health Survey 2008. Department: Ministry of Health, Cairo, 2009. Available from: http://pdf.usaid.gov/pdf_docs/PNADO806.pdf. Accessed: 24 February 2015..
6
Yehia BR, Schranz AJ, Umscheid CA, Lo Re V. The treatment cascade for chronic hepatitis C virus infection in the United States: a systematic review and meta-analysis. PLoS One 2014;9:e101554. 7
Tsochatzis EA, Crossan C, Longworth L, Gurusamy K, Rodriguez-Peralvarez M, Mantzoukis K, O'Brien J, et al. Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis C. Hepatology 2014;60:832-843.
8
Spiegel BM, Younossi ZM, Hays RD, Revicki D, Robbins S, Kanwal F. Impact of hepatitis C on health related quality of life: a systematic review and quantitative assessment. Hepatology 2005;41:790800.
Hepatology This article is protected by copyright. All rights reserved.
Hepatology
9
Breban R, Arafa N, Leroy S, Mostafa A, Bakr I, Tondeur L, Abdel-Hamid M, et al. Effect of preventive and curative interventions on hepatitis C virus transmission in Egypt (ANRS 1211): a modelling study. Lancet Glob Health 2014;2:e541-549 10
Hellard M, Rolls DA, Sacks-Davis R, Robins G, Pattison P, Higgs P, Aitken C, et al. The impact of injecting networks on hepatitis C transmission and treatment in people who inject drugs. Hepatology 2014;60:1861-1870.
Hepatology This article is protected by copyright. All rights reserved.
Page 4 of 4
