affordability of antiviral Therapy in asia-Pacific Countries and its impact on Public Health Outcomes
Prowpanga Udompap, M.D.,*
,†Tawesak Tanwandee, M.D.,
†and Rino Gani, M.D.
‡In 2015, the World Health Organization (WHO) esti- mated that viral hepatitis claimed 1.3 million lives globally, surpassing that of human immunodeficiency virus (HIV;
1.1 million deaths).1 The Asia-Pacific region has the largest share of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections.2 The majority of countries in this regions are low- to middle-income countries where investment in hep- atitis care is not a priority and poverty contributes to a lack of patient and public involvement. Unsurprisingly, despite the highly effective antivirals that make chronic hepatitis B (CHB) manageable and chronic hepatitis C (CHC) curable, affordability of these lifesaving antivirals in this region re- mains a principal issue.
In this article, we discuss the affordability of antivirals and the mechanisms Asia-Pacific countries use to increase access to treatment for viral hepatitis and the potential public health outcomes.
reiMBUrseMenT sYsTeM: a KeY TO sUCCess
The most common measure in Asia-Pacific countries to help patients access treatment is the reimbursement pro- gram. This program enables the national provision of med- ications, including nucleoside/nucleotide analogues (NAs) and direct-acting antivirals (DAAs), making the government
Abbreviations: CHB, chronic hepatitis B; CHC, chronic hepatitis C; DAA, direct-acting antiviral; ETV, entecavir; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IFN, interferon; LAM, lamivudine; NA, nucleoside/nucleotide analogue; NLEM, National List of Essential Medicines; PEG-IFN, pegylated interferon; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization.
From the * Department of Medicine, University of Minnesota, Minneapolis, MN; † Division of Gastroenterology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; and ‡ Hepatobiliary Division, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
Potential conflict of interest: Nothing to disclose.
Received March 13, 2020; accepted April 22, 2020.
View this article online at wileyonlinelibrary.com
© 2021 by the American Association for the Study of Liver Diseases
fully responsible for medication expenditure, as well as on-treatment laboratory monitoring. The reimbursement policy is commonly issued by the central government. It is usually accompanied by a list of reimbursable drugs, so-called National List of Essential Medicines (NLEM), to control access and to cover the cost of medications. Each country has its own committees that include experts and other stakeholders to determine the medications on NLEM and the tests for monitoring response based on the cost- effectiveness data of each medication and each test.
HePaTiTis B
Not all patients with CHB require treatment. Indications for treatment depend on the disease activity and severity.
Pegylated interferons (PEG-IFNs) and NAs are two types of medications approved for CHB therapy. NAs are usu- ally a preferred option because they can be administered orally with negligible adverse effects and are much less ex- pensive. The high genetic barrier NAs, including tenofovir disoproxil fumarate (TDF), entecavir (ETV), and tenofovir alafenamide (TAF), are the first-line treatment options rec- ommended in multiple liver societies’ guidelines.3-5 One major downside of NA therapy is the duration of treat- ment, which is usually indefinite, leading to a substantial economic burden.
Although the patents on TDF and ETV have now expired and low-cost generic medications are available worldwide, the costs of generic medications remain higher when com- pared with the income of patients in need. Once NAs are approved to be reimbursable, patients would no longer be responsible for the cost, and more patients would be able to receive the treatment. In addition, the reimbursement system was also proved to have a positive effect on antivi- ral utilization and adherence.6
Asia-Pacific countries encompass a spectrum of reim- bursement policy coverage for CHB treatment, from full to almost none. The reimbursement policies in Australia, Japan, South Korea, and New Zealand cover more than 90% of their populations, whereas the policy in Bangladesh covers less than 1% of the population. In addition to non- universal reimbursement coverage, there are other eligibil- ity criteria for antivirals that vary from country to country.
Most countries’ criteria are based on specific clinical/lab- oratory parameters, but some are based on physicians’
opinions (e.g., Bangladesh, India, Philippines, Singapore, and Vietnam), for which the physicians could make a case
for each patient to be eligible for antivirals. However, the choice of antivirals still has to be made from the NLEM.7
Although all countries in this region have both low and high genetic barrier NAs listed in their NLEM, limitations remain.8 In Thailand, only government servants can access TDF or ETV as an initial treatment option. Patients in the general public are started on lamivudine (LAM), a low ge- netic barrier NA. They are eligible to use TDF or ETV if re- sistance occurs. One could argue that previous studies had shown a successful viral suppression in those who were treated with TDF as salvage therapy after not responding successfully to LAM.9 However, most of the patients treated with LAM in Asia remain on LAM without knowing their HBV viral load, because access to viral load monitoring is limited and not all countries reimburse the cost of the lab- oratory tests. Therefore, this approach could increase HBV resistance, leading to unsuccessful viral suppression and complications. Another example is that some countries (e.g., Taiwan and Indonesia) will reimburse a limited dura- tion of treatment,7 which is undoubtedly not adequate to suppress viral replication in the long term, and could lead to HBV reactivation and liver disease progression.
The earlier limitations are great examples to support the fact that the availability of high genetic barrier NAs for CHB treatment are not as great as when they are used for HIV therapy. Only 59% of countries that are Member States of WHO Southeast Asia and Western Pacific regions have access to TDF and ETV as the first-line CHB treat- ment10 (Fig. 1), and LAM is still commonly used in this region, given its low cost.
All in all, it would be ideal if high genetic barrier NAs, together with the rigid treatment monitoring protocol, are added to the reimbursement program. However, changing the existing policy requires a governmental approval sys- tem, which usually takes several years.
HePaTiTis C
DAAs have revolutionized HCV treatment, offering a short treatment course with a nearly 100% cure rate and minute adverse effects. Therefore, WHO has recom- mended treatment for all patients with CHC regardless of age, risk group, or disease stage.11 A major issue is that all DAAs are subject to patent, resulting in a hefty price tag. One mechanism that assists low- and middle-income countries to access generic DAAs at a more affordable
price is voluntary licensing, which is an agreement with the original company (e.g., Gilead and Bristol-Myers Squibb) that enables other manufacturers to produce and sell ge- neric versions of DAAs in countries listed in the agreement.
Countries that are excluded from the agreement have to use other strategies, such as price negotiations, patent op- position, and compulsory licenses. Malaysia used a com- pulsory license to grant local parties permission to produce generic sofosbuvir while paying a royalty fee to Gilead.
Soon after issuing this compulsory license, Malaysia was included in the voluntary license for sofosbuvir, ledipasvir, and velpatasvir.11
With the earlier mechanisms, the cost of one CHC treatment course in this region has dramatically decreased from nearly $100,000 when using original DAAs to less than $100 with generic DAAs.12 The previous study has also shown that providing HCV treatment with generic DAAs can be cost-effective in 2 years and cost-saving in 10 years.13 This relatively lower DAA price also attracts patients from the Western countries to travel to Asia for medications and creates a growth of the hepatitis C buyers’ clubs online. However, we do not think that this phenomenon would negatively affect the drug supply in Asia because most generic drugs are oversupplied in this region.
Even though the final cost of generic DAAs is attractive to patients from Western countries, it is still high in rela- tion to patients’ and the majority of Asia-Pacific countries’
affordability. Each country, therefore, has its own criteria to control the reimbursement, which further discourages DAA access. For example, in Thailand, patients need to have ≥F2 fibrosis to receive DAAs. As a result, more than one-third of countries that are Member States of WHO Southeast Asia and Western Pacific regions have no access to interferon (IFN)-free DAA regimens10 (Fig. 1).
Even in countries that have access to DAAs, those DAAs are usually the early generations that are not effec- tive against all genotypes, and access to the pan-genotypic regimen remains limited. Consequently, HCV treatment, especially for difficult-to-treat genotypes, for example, genotype 3, which is predominant in this region, partic- ularly South and Southeast Asia,14 still requires IFN, and its efficacy is not as good as the pan-genotypic regimen;
again, this could lead to ineffective viral suppression and complications.
a HUGe GaP in an iGnOreD GaP
Although viral hepatitis in general has been ignored as a health and development priority compared with other FIG 1 Proportion of countries that are Member States of WHO Southeast Asia and Western Pacific regions that use standard recommended therapy for HBV and HCV.10
TaBle 1. COMParisOns OF FaCTOrs THaT MiGHT COnTriBUTe TO DisCrePanCY in THe MaGniTUDe OF PUBliC HealTH COnCerns BeTween HBv anD HCv
Different condition between HBV and
HCV HBV HCV
Epidemiology Disproportionally affects populations in low- to middle-
income countries Affects populations from low- to high-income countries
Research and development funding Less More
Curability with current standard therapy No Yes
Duration of treatment Usually indefinite Usually 3 months but could be up to 6 months in some
circumstances
Complexity of follow-up plan More Less
Support from community and civil society Less More
communicable diseases, HBV is relatively more neglected than HCV.15 Several reasons might explain this (Table 1).
First, high-income countries are more affected by the bur- den of HCV than HBV; therefore, more funding has gone to research and drug development for HCV. Second, although HCV has become curable with the availability of DAAs, leading to increased awareness for HCV, it is mostly led by drug company treatment campaigns rather than the affected community. Third, even though HBV, HCV, and HIV share the same mode of transmission, HCV/HIV coinfection is more common than HBV/HIV coinfection.16 HCV was therefore brought to the spotlight with HIV more often and gained more social movements from the civil society (Global Fund to Fight AIDS, Tuberculosis, and Malaria; Clinton Health Access Initiative; and Médecins Sans Frontières). These organizations help advocate the need for HCV screening, and support funding and distribu- tion of DAA treatment in low- to middle-income countries, especially among the HIV-coinfected population.12
COnClUsiOn
The World Health Assembly has called for the elimina- tion of viral hepatitis as a public health threat by 2030.1 However, in most Asia-Pacific countries, budgetary con- straints remain a major barrier that compromise the ability to provide education, prevention, screening, scaling up the treatment, and adherence to standard recommendation for HBV and HCV care. Collaboration within the region to exchange experiences and develop a practical approach for viral hepatitis care with cost-conscious strategy could be another tool to help each country eliminate viral hep- atitis. Thailand and Malaysia could be the prototypes of care among low- to middle-income countries. At the same time, South Korea and Japan are excellent models of care for high-income countries.
Also, a joint effort between viral hepatitis and other health programs might help increase access to care for patients in need, for example, integrating viral hepatitis care with the current HIV program at the strategic, pol- icy, technical implementation, and data management lev- els. However, financing solutions remain a cornerstone to overcome this barrier and would require an urgent action, as well as concerted efforts by all stakeholders. Otherwise, millions of people living with viral hepatitis in Asia-Pacific regions will be left behind, and the elimination of HBV and HCV will become only an intangible dream.
COrresPOnDenCe
Tawesak Tanwandee, M.D., Division of Gastroenterology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkok Noi, Bangkok 10700, Thailand. E-mail:
tawesak.tan@mahidol.ac.th reFerenCes
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