Skip to main content
PMC home page
PLOS Neglected Tropical Diseases logoLink to PLOS Neglected Tropical Diseases
. 2022 Nov 16;16(11):e0010915. doi: 10.1371/journal.pntd.0010915

Potential economic and clinical implications of improving access to snake antivenom in five ASEAN countries: A cost-effectiveness analysis

Chanthawat Patikorn 1,2, Ahmad Khaldun Ismail 3, Syafiq Asnawi Zainal Abidin 4, Iekhsan Othman 4, Nathorn Chaiyakunapruk 2,5,6,*, Suthira Taychakhoonavudh 1,*
Editor: Kalana Prasad Maduwage7
PMCID: PMC9668136  PMID: 36383562

Abstract

Background

Despite domestic production of antivenoms in the Association of Southeast Asian Nations (ASEAN) countries, not all victims with snakebite envenomings indicated for antivenom received the appropriate or adequate effective dose of antivenom due to insufficient supply and inadequate access to antivenoms. We aimed to conduct a cost-effectiveness analysis to project the potential economic and clinical impact of improving access to antivenoms when all snakebite envenomings in ASEAN countries were hypothetically treated with geographically appropriate antivenoms.

Methodology

Using a decision analytic model with input parameters from published literature, local data, and expert opinion, we projected the impact of “full access” (100%) to antivenom, compared to “current access” in five most impacted ASEAN countries, including Indonesia (10%), Philippines (26%), Vietnam (37%), Lao PDR (4%), and Myanmar (64%), from a societal perspective with a lifetime time horizon. Sensitivity analyses were performed.

Principal findings

In base-case analyses, full access compared to current access to snake antivenom in the five countries resulted in a total of 9,362 deaths averted (-59%), 230,075 disability-adjusted life years (DALYs) averted (-59%), and cost savings of 1.3 billion USD (-53%). Incremental cost-effectiveness ratios (ICERs) of improving access to antivenom found higher outcomes but lower costs in all countries. Probabilistic sensitivity analyses of 1,000 iterations found that 98.1–100% of ICERs were cost-saving.

Conclusion/Significance

Improving access to snake antivenom will result in cost-saving for ASEAN countries. Our findings emphasized the importance of further strengthening regional cooperation, investment, and funding to improve the situation of snakebite victims in ASEAN countries.

Author summary

In the Association of Southeast Asian Nations (ASEAN) countries, it was estimated that annually there were 242,648 snakebite victims in ASEAN of which 15,909 victims were dead. Despite domestic production of antivenoms in ASEAN countries, not all victims with snakebite envenomings indicated for antivenom received the appropriate or adequate effective dose of antivenom due to insufficient supply and inadequate access to antivenoms. Especially in Indonesia, Philippines, Vietnam, Lao PDR, and Myanmar, where 4–64% of victims who needed antivenoms were treated with antivenoms. We conducted a cost-effectiveness analysis to project the potential economic and clinical impact of improving access to antivenoms when all victims with snakebite envenomings in the five most impacted ASEAN countries were hypothetically treated with geographically appropriate antivenoms. Improving access to snake antivenom to the full level of access compared to the current level in the five ASEAN countries resulted in a total of 9,362 deaths averted (-59%), 230,075 disability-adjusted life years (DALYs) averted (-59%), and cost savings of 1.3 billion USD (-53%). Our study demonstrated improving access to snake antivenom from the current to the full level of access in ASEAN countries is a cost-saving strategy. Our findings emphasized the importance of further strengthening regional cooperation, investment, and funding to improve the situation of snakebite victims in ASEAN countries to reach the ultimate goal where all victims with snakebite envenoming needing antivenom adequately received the geographically appropriate antivenoms.

Introduction

Snakebite is a highly prioritized neglected tropical disease recognized by the World Health Organization (WHO). Due to the high global burden of snakebite, WHO has set its goal to reduce morbidity and mortality of snakebite by 50% by 2030 [1–3]. WHO has developed four strategic objectives to tackle the problems, including empowering and engaging communities, ensuring safe and effective treatment, strengthening health systems, and increasing partnerships, coordination, and resources [3].

The Association of Southeast Asian Nations (ASEAN) is an economic union comprising of ten member countries including Brunei Darussalam, Cambodia, Indonesia, Lao PDR, Malaysia, Myanmar, Philippines, Singapore, Thailand, and Vietnam with over 600 million population [4]. ASEAN is among the tropical regions with a disproportionately high incidence of snakebite. Our previous study estimated that there were approximately 243,000 snakebite victims with 16,000 deaths and 950 amputations from snakebite envenoming in seven ASEAN countries, namely, Malaysia, Thailand, Indonesia, Philippines, Vietnam, Lao PDR, and Myanmar. The annual economic and disease burden of snakebite in these countries was estimated at approximately 2.5 billion US Dollars (USD) and 392,000 disability-adjusted life years (DALYs) lost due to snakebite [5].

Previous economic evaluations have demonstrated the cost-effectiveness of antivenoms over no treatment for victims who suffered from snakebite envenoming indicating that antivenoms should be included as part of the pharmaceutical benefits schemes [6–8]. Antivenoms are already included in the essential medicine lists in many countries in the ASEAN [9]. However, not all victims with snakebite envenoming in ASEAN countries could access to geographically appropriate antivenoms for many reasons including inadequate supplies of antivenom, inefficient supply chain system, and inappropriate treatment seeking behavior [9]. Especially in Indonesia, Philippines, Vietnam, Lao PDR, and Myanmar, where 4–64% of victims with snakebite envenoming were treated with antivenoms [5].

Lack of access to antivenom in ASEAN countries could actually be avoided with evidence-informed strategies to improve access to snake antivenom with the goal that every victim with snakebite envenoming should receive antivenoms. However, strategies used to achieve this are likely to be complex and different across countries depending on each country’s context and situation. Moreover, improving access to antivenoms could not be solely done by increasing the production of antivenoms. It requires a multifaceted approach involving strengthening the whole system surrounding the management of snakebite victims, such as accurate informatics, rigorous regulations of antivenoms, efficient supply chain, rational use of antivenoms, appropriate treatment seeking behaviors, and good governance to support a strong healthcare system. To accelerate the development of strategies to improve access to snake antivenoms, it is needed to demonstrate the potential impact of treating all victims with snakebite envenoming with snake antivenoms.

Therefore, we aimed to conduct a cost-effectiveness analysis to project the potential economic and clinical impact of improving access to snake antivenoms when all victims with snakebite envenomings in ASEAN countries were hypothetically treated with geographically appropriate antivenoms. Our findings would emphasize the unmet medical needs of snakebite victims in ASEAN countries and the importance of developing strategies to provide access to geographically appropriate antivenoms for all victims with snakebite envenoming to reduce the burden of snakebite in the region.

Methods

An economic evaluation was conducted using a decision analytic model to assess the cost-effectiveness of improving access to snake antivenom from the current level to full access in ASEAN countries. We projected the economic and clinical implications of “full access” to antivenom relative to “current access” in a hypothetical cohort of snakebite victims in each country from a societal perspective with a lifetime time horizon to capture lifetime costs and consequences of snakebite victims. We developed our study following the methodological considerations for economic evaluations of snakebites described in the previous systematic review [6]. We reported our study following the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 statement [10].

Setting

We selected the five most impacted ASEAN countries for this study, including Indonesia, Philippines, Vietnam, Lao PDR, and Myanmar because the previous estimates in these countries found that only 4–64% of victims who were indicated for antivenoms were treated with antivenoms [5].

Malaysia and Thailand were not selected because more than 90% of victims in these countries who were indicated for antivenoms were treated with antivenoms [5]. Brunei Darussalam and Singapore were not selected because snakebite rarely occurs and/or exact data were lacking [1]. Cambodia was not selected due to a lack of information and key informants, although it is one of the countries with a high incidence of snakebites [1].

Decision analytic model

A decision analytic model (Fig 1) was adapted from the previously developed model to estimate the number of snakebite victims occurring in one year in ASEAN countries and the economic and disease burden of snakebite victims [5]. Briefly, victims who were bitten by snakes sought either conventional treatment or traditional treatment. The victims who were indicated for antivenom treatment might be treated with antivenom depending on the level of access. Snakebite victims might be alive, alive with disabilities, or dead. Disabilities included in this model were digit and limb amputation.

Fig 1. Decision analytic model to estimate economic and disease burden of snakebite in ASEAN countries.

Fig 1

Open in a new tab

Abbreviation: ADR–adverse drug reaction.

There were four key assumptions of the model [5]. First, one person can be bitten by a snake only once in a lifetime. Second, snakebite victims were accompanied by relatives or family members who took care of them during the snakebite episode. Third, due to lack of data, antivenom effectiveness was based on a study in Nigeria which found 2.33 folds (95% confidence interval; 1.26–4.06) increased risk of death in antivenom indicated victims who were not treated with antivenom compared to those treated with antivenom [11]. Fourth, current access to antivenom was determined as the proportion of the number of antivenoms treatment available by a total number of victims indicated for antivenom treatment with the values of 0.04 (Lao PDR), 0.10 (Indonesia), 0.26 (Philippines), 0.37 (Vietnam), and 0.64 (Myanmar) that were previously estimated [5]. Full access was modeled as all snakebite victims who were indicated for antivenom could be treated with geographically appropriate antivenoms. In the full access scenario, all snakebite victims who firstly sought traditional healers when access is now full are assumed to switch to conventional treatment.

Input parameters

Input parameters for each country (S1 Table) were based on the previous study that estimated the economic and disease burden of snakebite in ASEAN countries [5]. These parameters were sought from published literature, data from the Ministry of Health in each country, local data, and expert opinion [11–32]. The input parameters were validated by triangulation of data from the literature, local data, and interview with key informants who were experts in snakebite in ASEAN.

Main sources of information were national statistics and published research for the burden estimation of Malaysia, Thailand, and Myanmar. Published research and anecdotal evidence (local data, and expert opinion) were the main sources of information for the burden estimation of Vietnam and Lao PDR. Anecdotal evidence was the main source of information for the burden estimation of Indonesia, and Philippines.

Costs

Costs of snakebite in this model included direct costs and indirect costs (S1 Table) [5]. Direct costs included costs of hospitalization, antivenom treatment, antivenom logistics, adverse drug reaction management, amputation, transportation, and additional food for victims and their relatives. Costs of antivenom treatment were estimated based on the average dose of antivenom vials used in the treatment of snakebite envenoming with the consideration of different types of snakes and antivenoms in each country. Indirect costs included productivity losses during snakebite episodes of victims and their relatives and productivity losses due to premature death. Productivity losses due to premature death were discounted at the rate of 3% and adjusted for the annual growth of GDP per capita in each country [29–32].

Health outcomes

Health outcomes of the model included the number of deaths from snakebite envenoming and disability-adjusted life years (DALYs) lost due to snakebite. DALYs were estimated using the template developed by WHO [33]. DALYs were the sum of years of life lost (YLL) and years lived with disability (YLD). YLLs due to snakebite envenoming were calculated from the number of deaths multiplied by a global standard life expectancy at the age of death. YLDs of snakebite victims included YLDs for snakebite episodes and YLDs for amputations. YLDs were calculated from the duration of disability multiplied by a disability weight for each condition according to the Global Burden of Disease 2013 study (S1 Table) [19].

Discounting

Costs and health outcomes that occurred after one year were discounted at the rate of 3% [29,30].

Base-case analyses

In the base-case analyses, the expected costs and outcomes for each level of access were calculated. Primary outcomes of the model were deaths averted, DALYs averted, and incremental costs of full access compared to current access. Costs were expressed in 2019 US Dollars (USD) which equaled to 14,147.67 Indonesian Rupees, 51.80 = Philippine Pesos, 23,050.24, Vietnamese Dong, 8,679.41 Lao Kip, and 1,518.26 Myanmar Kyat [34].

The results were presented as incremental cost-effectiveness ratio (ICER) per death averted and ICER per DALY averted in each country. The willingness-to-pay (WTP) thresholds were based on the local pharmacoeconomic guidelines in Indonesia (4,136 USD) [30], set by the Formulary Executive Council in the Philippines (2,317 USD) [35], and based on the country’s GDP per capita in countries without explicit WTP thresholds including Vietnam (2,715 USD), Lao PDR (2,625 USD), and Myanmar (1,421 USD) [31]. ICERs per death averted and ICER per DALY averted with values below these WTP thresholds were considered cost-effective.

Sensitivity analyses

A series of sensitivity analyses were performed to evaluate the robustness of the base-case conclusions. One-way sensitivity analyses were performed to assess the impact of varying input parameters from minimum to maximum values on the ICERs.

We performed a series of scenario analyses. In the base-case analyses, antivenom had no effect on amputation. Thus, we performed scenario analyses by assuming that antivenom treatment could reduce the amputation rate of snakebite victims with the same relative risk of 2.33 in antivenom indicated victims who were not treated with antivenom compared to those treated with antivenom [11]. Scenario analyses were performed by incorporating post-traumatic stress disorder (PTSD) in the model as a mental disability occurring in 8% of victims who survived snakebite envenoming [5,36–38]. We performed scenario analyses by excluding indirect costs from the model. Lastly, scenario analyses were performed by increasing the logistic costs from 5% to 10% of antivenom price because these could be higher, especially in archipelagic countries like Indonesia and Philippines.

Threshold sensitivity analyses were performed to estimate the lowest level of antivenom effectiveness and the highest level of costs of antivenom treatment that would result in the “not cost-saving” situation where ICER is equal to zero but still considered cost-effective.

Probabilistic sensitivity analyses were performed to assess the model robustness and uncertainty of the base case input parameters over their plausible ranges on the model output. Monte Carlo simulations for 1,000 iterations of ICERs were performed by randomly sampling all input parameters based on the probability distributions. Results of probabilistic sensitivity analyses were presented using the cost-effectiveness plane and the cost-effectiveness acceptability curves (CEACs).

Results

Base-case analyses

We projected the economic and clinical impact of improving access to snake antivenom in ASEAN countries from the societal perspective (Table 1). When compared to current access, full access to antivenom in each country could save 433 lives in Philippines to 5,981 lives in Indonesia and reduce 10,473 DALYs in Philippines to 148,684 DALYs in Indonesia. However, full access to antivenom resulted in a higher number of patients with amputations (4 amputees in Philippines to 122 amputees in Indonesia) since more patients are being treated and as a result, more survivors from snakebite envenoming. Full access to antivenom had higher direct costs (2 million USD in Philippines to 50 million USD in Indonesia) but less indirect costs (-1,091 million USD in Indonesia to -28 million USD in Philippines) when compared to current access which resulted in total cost savings of 27 million USD in Philippines to 1,040 million USD in Indonesia. In total, when compared to current access, full access to snake antivenom in ASEAN countries resulted in 9,362 deaths averted (-59%), 230,075 DALYs averted (-59%), and cost savings of 1.3 billion USD (-53%).

Table 1. Estimated economic and clinical impact of snakebite victims between current access and full access to snake antivenom in ASEAN countries.

Indonesia Philippines Vietnam Lao PDR Myanmar
Current Full Difference Current Full Difference Current Full Difference Current Full Difference Current Full Difference
Health outcomes
Deaths, n 10,547 4,566 -5,981 550 117 -433 1,655 619 -1,037 1,007 141 -866 2,145 1,099 -1,046
Amputations, n 799 921 +122 12 16 +4 0 0 0 141 202 +60 0 0 0
DALYs for snakebite 262,888 114,203 -148,684 13,317 2,844 -10,473 40,250 15,111 -25,139 24,532 3,513 -21,019 50,830 26,070 -24,759
Economic burden, million USD
Direct costs 59 109 +50 1 2 +2 7 16 +9 0.1 1 +1 4 11 +7
Indirect costs 1,931 840 -1,091 83 54 -28 261 100 -161 80 12 -69 75 39 -36
Total costs 1,990 950 -1,040 83 57 -27 268 116 -152 81 13 -68 79 50 -29
Open in a new tab

Costs are presented as USD where 1 USD = 14,147.67 Indonesian Rupees = 51.80 Philippine Pesos = 23,050.24 Vietnamese Dong = 8,679.41 Lao Kip = 1,518.26 Myanmar Kyat. DALY—disability-adjusted life year; USD–US Dollar.

Base-case analyses of ICERs per death averted and ICERs per DALY averted of full access compared to current access found higher outcomes (0.02 deaths averted in Vietnam to 0.06 death averted in Lao PDR and 0.5 DALYs averted in Vietnam to 1.2 DALYs averted in Myanmar) but lower costs (-7,698 USD in Indonesia to -1,370 USD in Myanmar) in all five ASEAN countries. Thus, improving access to snake antivenom will result in cost-saving (Table 2).

Table 2. Cost-effectiveness of improving access to snake antivenom in ASEAN countries.

Costs, USD Deaths, n DALYs Incremental costs, USD Deaths averted, n DALYs averted Incremental costs per Death averted, USD Probability of being cost-saving* Incremental costs per DALY averted, USD Probability of being cost-saving* WTP Threshold, USD per DALY averted
Indonesia
Current access (reference) 14,733 0.08 1.9
Full access 7,035 0.03 0.8 -7,698 0.04 1.1 Cost-saving 99.8% Cost-saving 100% 4,136
Philippines
Current access (reference) 6,223 0.04 1.0
Full access 1,536 0.01 0.2 -4,687 0.03 0.8 Cost-saving 99.9% Cost-saving 99.9% 2,317
Vietnam
Current access (reference) 5,733 0.04 0.9
Full access 2,473 0.01 0.3 -3,260 0.02 0.5 Cost-saving 99.9% Cost-saving 100% 2,715
Lao PDR
Current access (reference) 5,620 0.07 1.7
Full access 910 0.01 0.2 -4,710 0.06 1.5 Cost-saving 100% Cost-saving 100% 2,625
Myanmar
Current access (reference) 3,760 0.10 2.4
Full access 2,390 0.05 1.2 -1,370 0.05 1.2 Cost-saving 98.1% Cost-saving 98.1% 1,421
Open in a new tab

*Percentage of 1,000 iterations that were cost-saving based on a probabilistic sensitivity analysis. Costs are presented as 2019 USD where 1 USD = 14,147.67 = Indonesian Rupees = 51.80 = Philippine Pesos = 23,050.24 Vietnamese Dong = 8,679.41 Lao Kip = 1,518.26 Myanmar Kyat. DALY–Disability-adjusted life year; USD–US Dollars; WTP–Willingness-to-pay.

Sensitivity analyses

One-way sensitivity analyses were presented with tornado diagrams to show the percentage change of base-case ICERs corresponding to varying values of the input parameters (S1 and S2 Figs). The most influential parameters for ICERs per death averted were discount rate and relative risk of death when antivenoms are not available. The most sensitive parameters for ICERs per DALY averted were relative risk of death when antivenoms are not available, discount rate, and probability of death in snakebite victims treated with antivenom. One-way sensitivity analyses found that the base-case conclusions were robust.

Scenario analyses were presented in S2 and S3 Tables. Incorporating PTSD in the model, assuming that antivenom could reduce the risk of amputation, and increasing the logistic costs of antivenom resulted in similar ICERs per death averted and ICERs per DALY averted in all countries indicating that improving access will result in cost-saving. Excluding indirect costs from the model resulted in ICERs per death averted ranging from 1,488 in Lao PDR to 8,632 USD per death averted in Vietnam. These ICERs per death averted were above the WTP thresholds in all countries except Lao PDR. While ICERs per DALY averted excluding indirect costs from the model ranged from 61 in Lao PDR to 356 in Vietnam. These ICERs per DALY averted were below the WTP thresholds in all countries.

Threshold analyses of antivenom effectiveness and costs of antivenom treatment resulted in an ICER of 0 are shown in S4 Table. The lowest level of antivenom effectiveness, presented as a risk ratio of death in indicated victims who were not treated with antivenom compared to those treated with antivenom, was ranging from 0.35 in Lao PDR to 1.19 in Myanmar. The highest level of costs of antivenom treatment was ranging from 9 to 149 times the base-case value in Myanmar and Lao PDR, respectively.

Probabilistic sensitivity analyses were performed for 1,000 iterations with the results presented in Figs 2 and S2 and S3. We found that 98.1–100% of 1,000 ICERs per death averted and 98.3–100% of 1,000 ICERs per DALYs averted were cost-saving.

Fig 2. Cost-effectiveness acceptability curves of improving access to snake antivenom in ASEAN countries.

Fig 2

Open in a new tab

Probabilities of full access to snake antivenom being cost-effective compared to current access in each ASEAN country at varying willingness-to-pay thresholds based on 1,000 iterations of a probabilistic sensitivity analysis are presented.

Discussion

This is the first study to our understanding that projected the cost-effectiveness of improving access to snake antivenom. This cost-effective analysis was not done to evaluate whether antivenom was cost-effective or not because antivenoms were already available in ASEAN but not all victims with snakebite envenoming were treated antivenoms [5,9]. Thus, we tried to evaluate the potential economic and clinical impacts of increasing the access to antivenom in ASEAN countries when all snakebite victims in the full access scenario are treated with geographically appropriate antivenom. We used a decision analytic model with input parameters from various sources including published literature, local sources, and expert opinion. We did not propose specific strategies to improve access to snake antivenoms as each country has different problems which require different strategies and policies to address them [9]. Rather, we demonstrated the potential economic and clinical impact when all victims with snakebite envenoming in ASEAN countries were treated with geographically appropriate antivenoms.

We found that improving access to snake antivenoms would result in cost-saving with higher outcomes (deaths and DALYs averted) but lower costs. In total, when compared to current access, full access to snake antivenom in five ASEAN countries resulted in 9,362 deaths averted (-59%), 230,075 DALYs averted (-59%), and cost savings of 1.3 billion USD (-53%). Although full access to antivenom compared to current access had higher direct costs because all victims with snakebite envenoming received antivenom treatment, the direct costs were entirely offset by indirect costs because antivenoms could save the victims’ lives which would avoid tremendously productivity losses due to premature death.

Mortality and disabilities of snakebite envenoming in each country differ in regards to differences in the toxicity and lethality of the snakes [5,9]. Nevertheless, improving access to antivenom was found to be cost-saving in all five ASEAN countries regardless of differences in snakes causing the snakebite envenoming and baseline level of access to antivenom. We performed a series of sensitivity analyses and found that the conclusion of our study remained robust. Threshold analyses found that the antivenom effectiveness could be as low as 0.35 to 1.19, and the costs of antivenom treatment could increase as high as 9 to 149 times of the base-case value to render improving access to antivenom no longer a cost-saving strategy. This emphasizes the cost-effectiveness of improving access to antivenom.

ASEAN has made significant progress in the management of snakebite and antivenom, but there remain challenges in this region to be addressed especially the lack of snakebite-related informatics system and inadequate access to antivenoms [9]. Our previous estimates highlighted the high burden of snakebite in ASEAN despite the availability of domestically produced antivenoms. It was estimated that there were approximately 243,000 snakebite victims with 16,000 deaths and 950 amputations from snakebite envenoming in these countries with the estimated annual economic and disease burden of snakebite of approximately 2.5 billion USD and 392,000 DALYs lost due to snakebite [5]. Findings of this study indicated that improving access to antivenoms in ASEAN countries would result in tremendous cost savings for the whole society. Thus, further investment and funding is warranted so that we could achieve the WHO’s goal to halve the snakebite burden in ASEAN [3].

This study supports and informs that improving access to snake antivenom where all victims with snakebite envenoming received geographically appropriate antivenoms will result in cost-saving. As a result, policy makers and relevant stakeholders in ASEAN to develop effective strategies to improve access to antivenom and reduce the burden of snakebite victims in the region given that antivenom is a lifesaving drug that should be universally accessible. However, improving access to antivenom is not only about increasing the production of antivenoms or purchasing more antivenoms, but also strengthening the whole health system to effectively deal with snakebite problems. More importantly, encouraging and engaging communities is needed to change the behavior of snakebite victims to seek care at appropriate healthcare facilities instead of traditional healers or seek no care at all. We previously discussed the potential opportunities to improve access to antivenom in ASEAN that included accurate estimation of antivenom demand, rigorous regulations of antivenom, strengthening the supply chain system, raising public awareness about the importance of treating snakebite envenoming by healthcare professionals, strengthening the health system to ensure appropriate snakebite management and rational use of antivenoms, and expanding collaboration of local and international stakeholders to better improve access to snake antivenom for victims in the region [9]. Nevertheless, there is no single strategy that could improve access to snake antivenom in every country. Strategies should be developed with consideration of the actual challenges and barriers to policy implementation in individual countries such as the infrastructure and capacity of the health system to appropriately tackle the snakebite problem.

Limitations

There were limitations in our approach that needed to be discussed. Firstly, although Cambodia is one of the countries with snakebite victims, Cambodia was not included in this study because of a lack of published literature and key informants. However, given our findings in five ASEAN countries, improving access to antivenom would be highly cost-saving as well. Secondly, all input parameters used in the model were derived from the available published literature, local data, and expert opinion when data were not available. These input parameters carried inherent uncertainty. We assumed antivenom effectiveness based on a study in Nigeria [11]. Most snakebites In Nigeria are inflicted by snakes of the genus Echis, for which antivenoms, in general, have high effectiveness [7]. This assumption may have a limitation as snakes in Nigeria are different from ASEAN. Nevertheless, our sensitivity analyses showed robust conclusions of the model. We strongly emphasized the need to conduct comprehensive research to estimate the true burden of snakebite in ASEAN. Thirdly, other disabilities of snakebite envenoming such as blindness, malignant ulcers, and pregnancy loss were not included due to lack of empirical evidence [7]. Chronic kidney disease due to Russell’s viper (Daboia russelii) bite was not included in our study. It was found that Russell’s viper bite caused acute kidney injury. However, information on chronic kidney disease following Russell’s viper bite in ASEAN was not documented because patients were lost to follow-up after they were discharged [39–41]. This emphasizes the importance of funding future studies in ASEAN to evaluate all relevant consequences and disabilities and associated costs of snakebite to allow better estimation of the cost-effectiveness of improving access to antivenom. Fourthly, we assumed that all snakebite victims in full access would eventually seek conventional treatment. However, this might not be possible because not all victims could have timely access to healthcare facilities, especially those who lived in the farthest rural areas. This is especially important as timely access to healthcare facilities is related to the prognosis of the victims, both in terms of mortality and long-term disability [42,43]. Lastly, costs of strategy to improve access of antivenoms from the current level to full e.g., costs of increasing antivenom manufacturing capacity, or costs of improving the supply chain, were not included in the analysis. However, these costs were assumed to be covered by the costs of antivenom treatment.

Conclusion

Our study demonstrated improving access to snake antivenom from the current to the full level of access in five ASEAN countries was cost-saving. Our findings indicated that the WHO’s goal to halve the snakebite burden could be achieved by providing full access to snake antivenoms for all victims in ASEAN which emphasized further strengthening regional cooperation, investment, and funding to improve the situation of snakebite victims in ASEAN countries to reach the ultimate goal where all victims with snakebite envenoming needing antivenom adequately received the geographically appropriate antivenoms.

Supporting information

S1 Appendix. CHEERS 2022 Checklist.

(DOCX)

Click here for additional data file. (34.3KB, docx)
S1 Table. Input parameters for economic evaluation of improving access to snake antivenom in ASEAN countries.

(DOCX)

Click here for additional data file. (63.4KB, docx)
S2 Table. Sensitivity analysis of cost-effectiveness analysis of improving access to snake antivenom in ASEAN countries in different scenarios.

(DOCX)

Click here for additional data file. (30.3KB, docx)
S3 Table. Sensitivity analysis of cost-utility analysis of improving access to snake antivenom in ASEAN countries in different scenarios.

(DOCX)

Click here for additional data file. (30.8KB, docx)
S4 Table. Threshold analyses of antivenom effectiveness and costs of antivenom treatment resulted in an incremental cost-effectiveness ratio of 0.

(DOCX)

Click here for additional data file. (30KB, docx)
S1 Fig. One-way sensitivity analysis of incremental costs per death averted of improving access to snake antivenom in ASEAN countries.

(DOCX)

Click here for additional data file. (1,003.6KB, docx)
S2 Fig. One-way sensitivity analysis of incremental costs per disability-adjusted life year (DALY) averted of improving access to snake antivenom in ASEAN countries.

(DOCX)

Click here for additional data file. (1.2MB, docx)
S3 Fig. Cost-effectiveness plane of incremental costs per death averted of improving access to snake antivenom in ASEAN countries.

Incremental costs and deaths averted of full access to snake antivenom in each ASEAN country based on a probabilistic sensitivity analysis of 1,000 iterations are presented in dots. Willingness-to-pay thresholds of each country are presented as dash lines with corresponding color.

(DOCX)

Click here for additional data file. (838.4KB, docx)
S4 Fig. Cost-effectiveness plane of incremental costs per disability-adjusted life year (DALY) averted of improving access to snake antivenom in ASEAN countries.

Incremental costs and disability-adjusted life years (DALYs) averted of full access to snake antivenom in each ASEAN country based on a probabilistic sensitivity analysis of 1,000 iterations are presented in dots. Willingness-to-pay thresholds of each country are presented as dash lines with corresponding color.

(DOCX)

Click here for additional data file. (913.2KB, docx)

Acknowledgments

The authors would like to thank members of the Pan ASEAN Antivenom (PAAV) consortium for their information and insightful recommendations on this work.

Data Availability

The data that support the findings of this study are available from the corresponding authors, ST and NC, upon reasonable request.

Funding Statement

This work is supported by the Wellcome Trust [218539/Z/19/Z] to CP, AKI, IO, SAZA, ST, and NC (https://wellcome.org). This research project is supported by the Second Century Fund (C2F), Chulalongkorn University to CP and ST (https://c2f.chula.ac.th). The funders had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication.

References

  • 1.Kasturiratne A, Wickremasinghe AR, de Silva N, Gunawardena NK, Pathmeswaran A, Premaratna R, et al. The global burden of snakebite: a literature analysis and modelling based on regional estimates of envenoming and deaths. PLoS Med. 2008;5(11):e218. doi: 10.1371/journal.pmed.0050218 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.World Health Organization. Snakebite envenoming: Geneva: World Health Organization; 2018. [February 26, 2019]. Available from: https://www.who.int/news-room/fact-sheets/detail/snakebite-envenoming. [Google Scholar]
  • 3.World Health Organization. Snakebite envenoming: a strategy for prevention and control [Internet]. 2019. Available from: https://apps.who.int/iris/bitstream/handle/10665/324838/9789241515641-eng.pdf. [DOI] [PubMed] [Google Scholar]
  • 4.Association of Southeast Asian Nations. ASEAN Member States [Internet]. Available from: https://asean.org/asean/asean-member-states/.
  • 5.Patikorn C, Blessmann J, Nwe MT, Tiglao PJG, Vasaruchapong T, Maharani T, et al. Estimating economic and disease burden of snakebite in ASEAN countries using a decision analytic model. PLoS Negl Trop Dis. 2022;16(9):e0010775. Epub 20220928. doi: 10.1371/journal.pntd.0010775 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Patikorn C, Leelavanich D, Ismail AK, Othman I, Taychakhoonavudh S, Chaiyakunapruk N. Global systematic review of cost of illness and economic evaluation studies associated with snakebite. J Glob Health. 2020;10(2). doi: 10.7189/jogh.10.020415 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Habib AG, Lamorde M, Dalhat MM, Habib ZG, Kuznik A. Cost-effectiveness of antivenoms for snakebite envenoming in Nigeria. PLoS Negl Trop Dis. 2015;9(1):e3381. Epub 2015/01/09. doi: 10.1371/journal.pntd.0003381 ; PubMed Central PMCID: PMC4287484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Hamza M, Idris MA, Maiyaki MB, Lamorde M, Chippaux JP, Warrell DA, et al. Cost-Effectiveness of Antivenoms for Snakebite Envenoming in 16 Countries in West Africa. PLoS Negl Trop Dis. 2016;10(3):e0004568. Epub 2016/03/31. doi: 10.1371/journal.pntd.0004568 ; PubMed Central PMCID: PMC4814077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Patikorn C, Ismail AK, Abidin SAZ, Blanco FB, Blessmann J, Choumlivong K, et al. Situation of snakebite, antivenom market, and access to antivenom in ASEAN countries. BMJ Global Health. 2022;0:e007639. doi: 10.1136/bmjgh-2021-007639 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Husereau D, Drummond M, Augustovski F, de Bekker-Grob E, Briggs AH, Carswell C, et al. Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) Explanation and Elaboration: A Report of the ISPOR CHEERS II Good Practices Task Force. Value in health: the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2022;25(1). doi: 10.1016/j.jval.2021.10.008 [DOI] [PubMed] [Google Scholar]
  • 11.Habib AG, Warrell DA. Antivenom therapy of carpet viper (Echis ocellatus) envenoming: effectiveness and strategies for delivery in West Africa. Toxicon. 2013;69:82–9. doi: 10.1016/j.toxicon.2013.01.002 [DOI] [PubMed] [Google Scholar]
  • 12.World Bank. Population, total [Internet]. 2019. Available from: https://data.worldbank.org/indicator/SP.POP.TOTL.
  • 13.Watt G, Padre L, Tuazon ML, Hayes CG. Bites by the Philippine cobra (Naja naja philippinensis): an important cause of death among rice farmers. Am J Trop Med Hyg. 1987;37(3):636–9. doi: 10.4269/ajtmh.1987.37.636 [DOI] [PubMed] [Google Scholar]
  • 14.Mahmood MA, Halliday D, Cumming R, Thwin K-T, Zu Kyaw MM, White J, et al. Snakebite incidence in two townships in Mandalay Division, Myanmar. PLoS Negl Trop Dis. 2018;12(7):e0006643. doi: 10.1371/journal.pntd.0006643 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Thang VV, Bao TQQ, Tuyen HD, Krumkamp R, Hai LH, Dang NH, et al. Incidence of snakebites in Can Tho Municipality, Mekong Delta, South Vietnam—Evaluation of the responsible snake species and treatment of snakebite envenoming. PLoS Negl Trop Dis. 2020;14(6):e0008430. doi: 10.1371/journal.pntd.0008430 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Adiwinata R, Nelwan EJ. Snakebite in Indonesia. Acta Med Indones. 2015;47(4):358–65. Epub 2016/03/05. . [PubMed] [Google Scholar]
  • 17.Vongphoumy I, Chanthilat P, Vilayvong P, Blessmann J. Prospective, consecutive case series of 158 snakebite patients treated at Savannakhet provincial hospital, Lao People’s Democratic Republic with high incidence of anaphylactic shock to horse derived F (ab’) 2 antivenom. Toxicon. 2016;117:13–21. doi: 10.1016/j.toxicon.2016.03.011 [DOI] [PubMed] [Google Scholar]
  • 18.Le Khac Q. Clinical evaluation of snakebites in Vietnam: A study from Cho Ray hospital. 2004. [Google Scholar]
  • 19.Salomon JA, Haagsma JA, Davis A, de Noordhout CM, Polinder S, Havelaar AH, et al. Disability weights for the Global Burden of Disease 2013 study. The Lancet Global Health. 2015;3(11):e712–e23. doi: 10.1016/S2214-109X(15)00069-8 [DOI] [PubMed] [Google Scholar]
  • 20.Shafie NA, Fauzi H, Wahab M, Senek M, Ismail A. The prevalence of hypersensitivity reactions to snake antivenoms administered in sultanah nur zahirah hospital from 2013 to 2016. Med J Malaysia. 2020;75(3):217. [PubMed] [Google Scholar]
  • 21.Menteri Kesehatan Republik Indonesia. Peraturan Menteri Kesehatan Republik Indonesia Nomor 63 Tahun 2014 tentang Pengadaan Obat Berdasarkan Katalog Elektronik (E-catalogue). 2014. [Google Scholar]
  • 22.Edillo FE, Halasa YA, Largo FM, Erasmo JNV, Amoin NB, Alera MTP, et al. Economic cost and burden of dengue in the Philippines. Am J Trop Med Hyg. 2015;92(2):360–6. doi: 10.4269/ajtmh.14-0139 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Department of Health, Republic of the Philippines. Drug Price Reference Index [Internet]. [cited 2021 May 10]. Available from: https://dpri.doh.gov.ph/index.php?page=search.
  • 24.Maternal and Reproductive Health Division, Department of Public Health Myanmar. Costed implementation plan to meet family planning 2020 commitments of Myanmar. Strategic prioritization of implementation 2018–2020 [Internet]. 2018. Available from: https://www.familyplanning2020.org/sites/default/files/myanmar_cip_2018.10.pdf.
  • 25.Flessa S, Dung NT. Costing of services of Vietnamese hospitals: identifying costs in one central, two provincial and two district hospitals using a standard methodology. The international journal of health planning and management. 2004;19(1):63–77. doi: 10.1002/hpm.747 [DOI] [PubMed] [Google Scholar]
  • 26.Riewpaiboon A. Standard cost lists for health economic evaluation in Thailand. Journal of the Medical Association of Thailand = Chotmaihet Thangphaet. 2014;97:S127–34. [PubMed] [Google Scholar]
  • 27.Riewpaiboon A. Economic burden of hand, foot, and mouth disease in Vietnam; An evidence for priority setting and efficiency management. [Google Scholar]
  • 28.Vodicka E, Zimmermann M, Lopez AL, Silva MW, Gorgolon L, Kohei T, et al. Japanese encephalitis vaccination in the Philippines: A cost-effectiveness analysis comparing alternative delivery strategies. Vaccine. 2020;38(13):2833–40. doi: 10.1016/j.vaccine.2020.02.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Teerawattananon Y. Guidelines for health technology assessment in Thailand (second edition). J Med Assoc Thai. 2014;97(5):S4–9. [PubMed] [Google Scholar]
  • 30.Indonesian Health Technology Assessment Committee MoHotRoI. Health Technology Assessment (HTA) guideline.
  • 31.World Bank. GDP per capita (current LCU) [Internet]. 2019. Available from: https://data.worldbank.org/indicator/NY.GDP.PCAP.CN.
  • 32.World Bank. GDP per capita growth (annual %) [Internet]. 2019. Available from: https://data.worldbank.org/indicator/NY.GDP.PCAP.KD.ZG.
  • 33.Mathers CD, Vos T, Lopez AD, Salomon J, Ezzati M. National burden of disease studies: a practical guide. Geneva: World Health Organization. 2001. [Google Scholar]
  • 34.World Bank. Official exchange rate (LCU per US$, period average) [Internet]. 2019. Available from: https://data.worldbank.org/indicator/PA.NUS.FCRF. [Google Scholar]
  • 35.Genuino AJ, Guerrero AM, Reungwetwattana T, Thakkinstian A. Cost-utility analysis of adjuvant trastuzumab therapy for HER2-positive early-stage breast cancer in the Philippines. BMC Health Serv Res. 2019;19(1):1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Waiddyanatha S, Silva A, Siribaddana S, Isbister GK. Long-term effects of snake envenoming. Toxins. 2019;11(4):193. doi: 10.3390/toxins11040193 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Kessler RC, Aguilar-Gaxiola S, Alonso J, Benjet C, Bromet EJ, Cardoso G, et al. Trauma and PTSD in the WHO world mental health surveys. European journal of psychotraumatology. 2017;8(sup5):1353383. doi: 10.1080/20008198.2017.1353383 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Ferry FR, Brady SE, Bunting BP, Murphy SD, Bolton D, O’Neill SM. The economic burden of PTSD in Northern Ireland. Journal of traumatic stress. 2015;28(3):191–7. doi: 10.1002/jts.22008 [DOI] [PubMed] [Google Scholar]
  • 39.Alfred S, Bates D, White J, Mahmood MA, Warrell DA, Thwin KT, et al. Acute Kidney Injury Following Eastern Russell’s Viper (Daboia siamensis) Snakebite in Myanmar. Kidney Intl Rep. 2019;4(9):1337–41. doi: 10.1016/j.ekir.2019.05.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Aye KP, Thanachartwet V, Soe C, Desakorn V, Thwin KT, Chamnanchanunt S, et al. Clinical and laboratory parameters associated with acute kidney injury in patients with snakebite envenomation: a prospective observational study from Myanmar. BMC Nephrol. 2017;18(1):92. Epub 2017/03/18. doi: 10.1186/s12882-017-0510-0 ; PubMed Central PMCID: PMC5353953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Waikhom R, Makkar V, Sarkar D, Patil K, Singh A, Bennikal M. Acute kidney injury following Russell’s viper bite in the pediatric population: a 6-year experience. Pediatr Nephrol. 2013;28(12):2393–6. Epub 2013/08/29. doi: 10.1007/s00467-013-2601-x . [DOI] [PubMed] [Google Scholar]
  • 42.Sharma SK, Bovier P, Jha N, Alirol E, Loutan L, Chappuis F. Effectiveness of rapid transport of victims and community health education on snake bite fatalities in rural Nepal. The American journal of tropical medicine and hygiene. 2013;89(1):145. doi: 10.4269/ajtmh.12-0750 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Sharma SK, Chappuis F, Jha N, Bovier PA, Loutan L, Koirala S. Impact of snake bites and determinants of fatal outcomes in Southeastern Nepal. Am J Trop Med Hyg. 2004;71(2):234–8. [PubMed] [Google Scholar]
PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0010915.r001

Decision Letter 0

Indika Gawarammana, Kalana Prasad Maduwage

21 Sep 2022

Dear Miss Taychakhoonavudh,

Thank you very much for submitting your manuscript "Potential economic and clinical implications of improving access to snake antivenom in ASEAN countries: a cost-effectiveness analysis" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

Since there are major methodological issues have been identified in the study, results and conclusions also affect by those issues. Hence it is mandatory to consider each of the stated issues in the methodology and revise the results and conclusions sections. The specific issues which could not be revised the adapted, those issues should be carefully described as limitations under the discussion. The details of how those limitations affects the conclusions should be described.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Kalana Prasad Maduwage, MBBS, MPhil, PhD, FRSPH (UK)

Academic Editor

PLOS Neglected Tropical Diseases

Indika Gawarammana

Section Editor

PLOS Neglected Tropical Diseases

***********************

Since there are major methodological issues have been identified in the study, results and conclusions also affect by those issues. Hence it is mandatory to consider each of the stated issues in the methodology and revise the results and conclusions sections. The specific issues which could not be revised the adapted, those issues should be carefully described as limitations under the discussion. The details of how those limitations affects the conclusions should be described.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The estimated logistic cost of only 5% is rather low.

Reviewer #2: The objectives of the study are clear and well founded. In this work the authors selected five most impacted ASEAN countries for this study, including Indonesia, Philippines, Vietnam, Lao PDR, and Myanmar. However the title refers to the whole group of ASEAN countries. The title should be modified as to mention that it includes only a group of ASEAN countries, the ones having the highest load of SBE. The methodology is clearly described, and the statistical analyses are presented. There are no ethical issues concerning this study.

I have several comments concerning specific issues in the Methodology:

The disabilities included in the model were digit and lib amputations. Although these disabilities are probably the most significant ones, studies in this topic have identified other types of physical and psychological disabilities which may have a great impact in the quality of life of affected people. In particular, victims of Daboia sp often develop chronic kidney failure, which involves high costs of treatment. This would be a relevant parameter to consider, and there is information in the literature on the incidence of this problem and the incidence of Daboia sp cases, at least in some of these countries or in neighbouring countries. Thus, the disability analysis could be expanded. In the section of limitations of the study, the authors indicated that “other disabilities of snakebite envenoming such as blindness, malignant ulcers, and pregnancy loss were not included due to lack of empirical evidence”. However, in the case of chronic renal failure, which involves high costs from the medical system, I believe there is published information which can provide valuable inputs to enrich the analysis.

The authors state that “antivenom effectiveness was based on a study in Nigeria which found 2.33 folds (95% confidence interval; 1.26-4.06) increased risk of death in indicated victims who were not treated with antivenom compared to those treated with antivenom”. Extrapolation of this assumption from Nigeria to South East Asia may have limitations. In Nigeria most snakebites are inflicted by snakes of the genus Echis, for which antivenoms in general have higher efficacy. In the case of Asia, many snakebites are inflicted by species of Naja and Bungarus, which may induce severe neurotoxicity of rapid onset, or by Daboia sp, which inflict highly complicated cases involving severe renal injury and other consequences. Hence, this extrapolation has limitations. It would be more pertinent to find such numbers in studies carried out in India, for example, where the types of snakes are similar to the ones in ASEAN countries.

It is stated that “In the full access scenario, all snakebite victims who firstly sought traditional healers when access is now full are assumed to switch to conventional treatment”. This assumption is valid for the purpose of the study. However, an additional factor is the time needed to reach health facilities, which may largely differ depending on the country and the region, the development of the public health system and circumstances such as the quality of the roads and climate variables, as has been studied for the case of SBE in Nepal. I realize these factors are difficult to introduce in the model used, but at least should be acknowledged in the Discussionm because the time to reach medical attention is directly related to the prognosis of the cases, both in terms of mortality and long term disability..

In estimating the cost of antivenom treatment, the authors have probably based their analyses in the current cost of antivenom in these countries (which I believe vary a lot) and on the usual number of antivenom vials used in a single treatment. However, if the study is based on the idea that the antivenoms to be used are geographically appropriate and effective, both the cost per vial and the number of vials needed for a treatment may vary as compared to the current situation. How are these parameters considered in the analysis?

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: It is interesting to know the Budget Impact that each country government (or another payer) needs to pay per year for this antivenom access.

Reviewer #2: Results are presented in a clear manner and the analysis matches the analysis plan described in the methodology. The figures and tables are good and of enough quality and clarity.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Yes

Reviewer #2: The main cionclusions are supported by the data presented. However, as indicated above in the comments to the methodology, there are extrapolations in this study which may affect the conclusions. The authors acknowledge some limitations of the study, but should expand this by including other aspects mentioned above.

Since only five countries of ASEAN countries were included in the analysis, it is recommended that the authors acknowledge this limitation and include some considerations on whether this could apply to the whole region or not.

It would be relevant to discuss possible differences between the countries analyzed regarding the snake species that inflict the majority of accidents in each country, the type of clinical picture that they induce and the possible types of sequelae. For example, the incidence of amputation may be higher in countries where bites are predominantly inflicted by snakes having necrotizing effects, such as viperid species and cytotoxic cobras. In contrast, in a country where most cases are inflicted by kraits (Bungarus sp), the likelihood of necrosis and amputation is low, but the likelihood of severe neurotoxic envenoming leading to death is high. On the other hand, in a country where many bites are inflicted by Daboia sp, the possibilities of chronic kidney failure is high. The analysis of these issues, or at least their Discussion, would be enriched with the description of these possible national differences.

As indicated above in the comments on the methodology, using the data on the reduction of the risk of death from a study in Nigeria, and extrapolating it to ASEAN countries has important limitations that need to be acknowledged. It would be relevant to check whether there is information on mortality due to SBE in India between people treated with antivenom and those who were not treated. At least some information on this regard may indicate whether the extrapolation from data of Nigeria is a valid approximation.

When acknowledging the limitation of including only amputations as disabilities, the authors did not mention the problem of chronic renal failure that often occurs in victims of Daboia sp. This needs to be discussed as well.

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: The manuscript is well written and presented, I do not have editorial suggestions.

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The authors performed a cost-effectiveness analysis of snake antivenom in ASEAN countries. By saving lives and preventing disabilities, the full antivenom access is cost-saving. The result is important for the health care policy changes in these countries.

1. It is interesting to know the Budget Impact that each country government (or another payer) needs to pay per year for this antivenom access.

2. It is interesting to know the reasons why the antivenom access is limited in each country. Are there major problems in antivenom production and/or logistics? The solution may not be simple by just increasing payment for the antivenom costs.

3. The problem in each country may be different. Can they produce antivenom by themselves? The antivenom distribution in countries comprising numerous islands, i.e., Philippines and Indonesia, may be difficult. The estimated logistic cost of only 5% is rather low.

Reviewer #2: This study aims to assess the cost-effectiveness of improving access to snake antivenom from current level to full access in ASEAN countries, built on a previous study in which the authors evaluated the burden of SBE in terms of number of cases, mortality and cost. As such, it is a relevant contribution to the field of SBE since this type of analysis is scarce and badly needed. These studies are difficult in part because of the lack of accurate information to feed the models used. Regardless of these limitations, the study clearly demonstrates the high impact that adequate access and use of effective and safe antivenoms would have in ASEAN countries. The authors should consider several issues mentioned in my comments to the methodology since they may contribute to further expanding and improving their analysis. I think tha inclusion of more analyses, along the lines indicated in my comments to the methods, would enrich this work.

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0010915.r003

Decision Letter 1

Indika Gawarammana, Kalana Prasad Maduwage

28 Oct 2022

Dear Suthira

We are pleased to inform you that your manuscript 'Potential economic and clinical implications of improving access to snake antivenom in five ASEAN countries: a cost-effectiveness analysis' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Kalana Prasad Maduwage, MBBS, MPhil, PhD, FRSPH (UK)

Academic Editor

PLOS Neglected Tropical Diseases

Indika Gawarammana

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

Both reviewers are agreed to accept the revised version of the manuscript and I am also agreed with the corrections done. Therefore, as the academic editor, I would like to accept the revised version of the manuscript to be published in PLoS NTD.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: See summary and general comments

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: See summary and general comments

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #2: See summary and general comments

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: See summary and general comments

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: I am satisfied with the revision.

Reviewer #2: Thge authors have carefully and satisfactorily addressed my comments and criticisms to the first version of this manuscript. Some of the limitations I mentioned are due to lack of available information (for example the issue of extrapolating data on mortality from Nigeria and not including the problem of chronic renal failure in the sequelae). The authors have expanded the text on limitations of the study, explaining in more detail why some of my suggestions cannot be answered with the available information.

**********

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0010915.r004

Acceptance letter

Indika Gawarammana, Kalana Prasad Maduwage

2 Nov 2022

Dear Miss Taychakhoonavudh,

We are delighted to inform you that your manuscript, "Potential economic and clinical implications of improving access to snake antivenom in five ASEAN countries: a cost-effectiveness analysis," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.

Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Appendix. CHEERS 2022 Checklist.

    (DOCX)

    Click here for additional data file. (34.3KB, docx)
    S1 Table. Input parameters for economic evaluation of improving access to snake antivenom in ASEAN countries.

    (DOCX)

    Click here for additional data file. (63.4KB, docx)
    S2 Table. Sensitivity analysis of cost-effectiveness analysis of improving access to snake antivenom in ASEAN countries in different scenarios.

    (DOCX)

    Click here for additional data file. (30.3KB, docx)
    S3 Table. Sensitivity analysis of cost-utility analysis of improving access to snake antivenom in ASEAN countries in different scenarios.

    (DOCX)

    Click here for additional data file. (30.8KB, docx)
    S4 Table. Threshold analyses of antivenom effectiveness and costs of antivenom treatment resulted in an incremental cost-effectiveness ratio of 0.

    (DOCX)

    Click here for additional data file. (30KB, docx)
    S1 Fig. One-way sensitivity analysis of incremental costs per death averted of improving access to snake antivenom in ASEAN countries.

    (DOCX)

    Click here for additional data file. (1,003.6KB, docx)
    S2 Fig. One-way sensitivity analysis of incremental costs per disability-adjusted life year (DALY) averted of improving access to snake antivenom in ASEAN countries.

    (DOCX)

    Click here for additional data file. (1.2MB, docx)
    S3 Fig. Cost-effectiveness plane of incremental costs per death averted of improving access to snake antivenom in ASEAN countries.

    Incremental costs and deaths averted of full access to snake antivenom in each ASEAN country based on a probabilistic sensitivity analysis of 1,000 iterations are presented in dots. Willingness-to-pay thresholds of each country are presented as dash lines with corresponding color.

    (DOCX)

    Click here for additional data file. (838.4KB, docx)
    S4 Fig. Cost-effectiveness plane of incremental costs per disability-adjusted life year (DALY) averted of improving access to snake antivenom in ASEAN countries.

    Incremental costs and disability-adjusted life years (DALYs) averted of full access to snake antivenom in each ASEAN country based on a probabilistic sensitivity analysis of 1,000 iterations are presented in dots. Willingness-to-pay thresholds of each country are presented as dash lines with corresponding color.

    (DOCX)

    Click here for additional data file. (913.2KB, docx)
    Attachment

    Submitted filename: 1. Author response EE improving access to antivenom.docx

    Click here for additional data file. (94.5KB, docx)

    Data Availability Statement

    The data that support the findings of this study are available from the corresponding authors, ST and NC, upon reasonable request.

    Articles from PLOS Neglected Tropical Diseases are provided here courtesy of PLOS

    RESOURCES