Ethical approval

This study did not require ethical approval because it is a modeling study based on secondary data from previously published literature and publicly available sources. No primary data were collected, and no human participants were involved directly. As such, ethical review and approval were not applicable to the scope of this analysis.

Overall approach

We conducted an ECEA to evaluate the distributional impact of improving access to antivenom in urban and rural areas of Lao PDR. Building on a previous conventional CEA [20], this study additionally examined the distribution of health and financial consequences across equity-relevant subgroups. This ECEA adhered to the methodological framework established by Verguet and colleagues [22] and was reported following the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 guidelines (S1 Table) [23]. In line with the ECEA framework, we evaluated: (1) health outcomes, including mortality and disability-adjusted life years (DALYs); (2) financial consequences through household out-of-pocket expenditures; and (3) distributional impacts across urban and rural populations in Lao PDR. As household-level income distribution data were unavailable, we did not directly estimate catastrophic health expenditure (CHE), poverty cases averted, or money-metric insurance value. Instead, the percentage of household out-of-pocket (OOP) expenditure relative to monthly household income was used as a proxy indicator of financial hardship and affordability. Annual household income was not used because snakebite envenoming is generally an acute episodic event with high upfront costs during the envenoming episode [19].

Urban and rural areas were defined according to administrative classifications used in national statistics, with urban areas corresponding to provincial capitals and urban districts, and rural areas encompassing populations outside these administrative boundaries [18,24,25]. Approximately 20–30% of snakebite victims have systemic envenoming meeting clinical indications for antivenom treatment [10]. This evaluation compared the “current access” scenario (limited access), where only a small proportion of victims with systemic envenoming meeting clinical indications for antivenom treatment received antivenom treatment in conventional healthcare facilities due to limited supplies, with an alternative hypothetical “full access” scenario, where all victims were assumed to ideally seek conventional treatment, and all snakebite victims with systemic envenoming meeting clinical indications for antivenom treatment were assumed to receive antivenom at the conventional healthcare facilities, rather than universal administration to all snakebite victims.

Model

A decision model was developed based on the structure and assumptions of a previous CEA [20]. The model was modified to separately estimate the annual number of snakebite victims in urban and rural Lao PDR, accounting for differences in treatment-seeking behavior and healthcare access. Snakebite victims were modeled as seeking care from conventional healthcare facilities (public or private), traditional healers, or receiving no treatment. Antivenom treatment was provided based on the level of access at the conventional healthcare facilities, determined by the number of available antivenoms and the average number of antivenoms used per case (20 and 90 available antivenom treatments in rural and urban Lao PDR, respectively). Patient outcomes included survival, survival with disabilities, or death. This ECEA was conducted from three perspectives: household, healthcare system, and societal.

Input parameters

Input parameters specific to urban and rural settings were sourced from the prior CEA model [20] and publicly available data, including published literature and government websites [9,10,17,18,24–31]. Specifically, we searched PubMed for published articles on snakebite in the Lao PDR, complemented by Google and Google Scholar searches. Websites of the Ministry of Health of the Lao PDR and the Lao Statistics Bureau were also searched. The search period ended on 30 April 2023. All documents and websites with information on snakebites in the Lao PDR were included, and relevant details were extracted to serve as input parameters for the model. Candidate input parameters were initially identified from published literature, government databases, and official websites by three researchers (C.P., J.C., and N.C.). This process was followed by a virtual group discussion with three researchers (M.M., K.S., and J.B.) who have extensive experience in the clinical management and epidemiology of snakebite envenoming in Lao PDR, to evaluate their relevance and suitability in the Lao PDR context. When data were unavailable, expert opinion was used to estimate plausible parameter values. We validated assumptions through multiple sources and adopted conservative estimates whenever possible. Input parameters are listed in S2 Table.

Burden of snakebite

We estimated the impact of improving access to antivenom on the disease and economic burdens. Disease burdens included the case fatality rate (CFR), mortality rate, amputations due to snakebite envenoming, and DALYs, comprising years of life lost (YLLs) due to premature death and years lived with disability (YLDs) from snakebite envenoming and amputations. Economic burden was quantified as the costs of snakebites from various perspectives. Financial risk was assessed as the percentage of household OOP expenditure relative to monthly household income, serving as a proxy for financial hardship and affordability.

Costs

A micro-costing approach was employed to estimate the costs associated with snakebite. Through group discussion, three local clinicians (M.M., K.S., and J.B.) estimated the average resource utilization for managing snakebite patients in the context of Lao PDR (S3-S7 Tables). Direct medical costs included hospitalization, inpatient services, laboratory tests, tetanus toxoid administration, wound care, antivenom treatment, management of adverse reactions, amputations, and traditional treatment. Direct non-medical costs included transportation and additional food expenses for patients and their caregivers. Transportation costs were assumed to include only cars and motorcycles. Inter-facility transportation, medical evacuation, and ambulance cars were not captured in the costing framework. Indirect costs were calculated as productivity losses due to premature death and the productivity losses by patients and caregivers during treatment episodes. Local stakeholders indicated that, on average, five family members assisted in caregiving. All costs were reported in 2023 USD, with a conversion rate of 14,035.23 Laotian Kip (LAK) [32].

Household perspective included OOP expenditures on snakebite medical treatment, transportation, and food for victims and family members. The healthcare system perspective included direct medical costs for snakebites. The societal perspective included household and health system costs and indirect costs.

Base-case analysis

A base-case analysis was performed to estimate the health equity impact of improving access to antivenom, defined as differences in the burden of snakebite between urban and rural populations. Equity improvements were achieved if these differences decreased with improved access. Primary analysis was performed using the household perspective. Secondary analyses were performed using the healthcare system and societal perspectives. Additionally, we analyzed the cost distribution associated with snakebite in urban and rural areas to identify key drivers of societal and household OOP expenditures.

Sensitivity analyses

Several sensitivity analyses were conducted to assess uncertainties and explore the robustness of the results. Probabilistic sensitivity analysis (PSA) was performed using a Monte Carlo simulation with 1,000 iterations randomly sampled from a distribution of input parameters from distributions such as gamma (e.g., length of hospital stay) and beta (e.g., probabilities of adverse reactions, survival outcomes, and disability weights) (S2 Table). The 95% credible interval (95% CrI) for health equity impacts was estimated from the PSA to reflect the range of uncertainty in the model findings.

As Laotians cover 41.8% of their total health expenditure through OOP expenses [17], scenario analyses were conducted to examine the effects of changes in coverage of antivenom treatment and direct medical costs on OOP expenditures as a percentage of monthly household income. These analyses assumed coverage of medical care costs ranging from 0 to 100%, serving as a proxy for improving healthcare affordability under a fully implemented UHC system in Lao PDR.

Further scenario analyses were performed to evaluate the impact of no transportation expenditures, and only one caregiver assisted the victim. As some patients in rural areas might need to travel up to 20 km to access care [33], these analyses simulated the effect of improved geographic accessibility with increased availability of healthcare facilities closer to patient residences, resulting in lower costs for transportation and caregiving.

Two-way sensitivity analyses were performed to explore the combined effects of improved access to antivenom and changes in treatment-seeking behaviors. Additionally, two-way analyses evaluated the interaction between increased coverage of medical expenditures (from 58.2% to 100%) and reductions in transportation expenditures (from 0% to 100%) on household OOP expenditures in urban and rural areas. These analyses aimed to elucidate the interplay between geographical accessibility and healthcare affordability.

Estimated burden of snakebite in urban and rural Lao PDR

The estimated epidemiological, economic, and disease burdens of snakebites in urban and rural Lao PDR under current and full access scenarios are shown in Table 1. Annually, there were an estimated 1,506 snakebite victims in urban areas and 13,553 in rural areas.

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Table 1. Estimated burden of snakebite in urban and rural Lao PDR.

https://doi.org/10.1371/journal.pntd.0014420.t001

In urban areas, 301 snakebite envenoming cases were estimated, with 20 patients (6.6%) receiving antivenom treatment. This resulted in 10 deaths, corresponding to a CFR of 3.3%. The total societal cost of snakebites in urban areas was estimated at 744,077 USD, equivalent to 494 USD per victim. The disease burden was 8.86 DALYs lost per 100,000 population. Household OOP expenditures for snakebite treatment were estimated at 38% of the monthly household income for all victims. Victims with systemic envenoming treated in hospitals faced the highest financial risk, with OOP expenditures reaching 102% of monthly household income.

Rural areas were estimated to have 2,963 snakebite envenoming cases, with only 90 patients (3.0%) receiving antivenom treatment. These cases resulted in 147 deaths, corresponding to a CFR of 5.0%. The total societal cost of snakebites in rural areas was significantly higher, at 7,974,430 USD, or 589 USD per victim. The disease burden was 78.97 DALYs lost per 100,000 population. Household OOP expenditures for snakebite treatment were estimated at 39% of monthly household income for all victims. Victims with systemic envenoming treated in hospitals also faced the highest financial risk, with OOP expenditures reaching 169% of monthly household income.

Health equity impact of improving access to antivenom in urban and rural Lao PDR

Under the current access scenario, snakebite victims in rural areas experienced worse epidemiological outcomes and higher economic burdens compared to urban areas. Rural areas had higher mortality rates (+2.79 deaths per 100,000 population; 95% CrI + 0.40 to +4.29), DALYs lost (+70.11 DALYs per 100,000 population; 95% CrI + 12.04 to +105.47) and household economic burden (+1% OOP expenditures per monthly household income, 95% CrI -4% to +6%), than urban areas. These differences were associated with considerable uncertainty, as reflected in the wide credible intervals.

Improving access to antivenom reduced health inequities in deaths and DALYs lost between urban and rural areas. However, it exacerbated health inequities in the household economic burden. In the full access scenario, while rural areas still showed worse epidemiological outcomes than urban areas, the health inequities in mortality and DALYs lost were reduced. Rural areas exhibited higher mortality rates (+1.22 deaths per 100,000 population; 95% CrI -0.95 to +7.09) and greater DALYs lost (+32.14 DALYs per 100,000 population; 95% CrI -24.23 to +193.16) compared to urban areas. The household economic burden in rural areas increased significantly compared to urban areas (95% vs. 56% of OOP expenditures per monthly household income), with 39% higher OOP expenditures per monthly household income (95% CrI + 23% to +52%). Wide credible intervals indicated considerable uncertainty about these differences. These findings are presented in Table 2 and Fig 1.

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Table 2. Health equity impact of improving access to antivenom in urban and rural Lao PDR.

https://doi.org/10.1371/journal.pntd.0014420.t002

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Fig 1. Health equity impact of improving access to antivenom in financial risk and mortality of snakebite in urban and rural Lao PDR.

Full access was assumed that all snakebite victims sought conventional treatment and all victims with snakebite envenoming received antivenom treatment. Red lines indicate differences (health equality impact) between urban and rural areas. Black lines indicate a 95% credible interval from 1,000 probabilistic sensitivity analysis simulations. Differences were calculated using unrounded model outputs. Values presented are rounded for readability; therefore, arithmetic differences based on displayed values may not exactly match the reported differences. Abbreviation: OOP – Out-of-pocket.

https://doi.org/10.1371/journal.pntd.0014420.g001

The distribution of snakebite costs in urban and rural Lao PDR is shown in Fig 2. Indirect costs constituted most of the societal costs of snakebites, accounting for more than half of the total of each scenario across urban and rural areas (52–88%). Full access to antivenom led to a marked increase in the proportion of direct medical costs in both areas. Direct non-medical costs showed a substantial rise only in rural areas under improved access conditions. An analysis of the distribution of household OOP expenditures for snakebites demonstrated that food (38%) and hospitalization costs (18%) were the cost drivers in urban areas. Cost drivers in rural areas were mostly traditional healer costs (78%). Improving access to antivenom increased the relative share of direct medical costs in urban and rural areas.

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Fig 2. Distribution of costs of snakebite in urban and rural Lao PDR.

Full access was assumed that all snakebite victims sought conventional treatment and all victims with snakebite envenoming received antivenom treatment. Values presented are rounded for readability.

https://doi.org/10.1371/journal.pntd.0014420.g002

Sensitivity analyses

Scenario analyses examining the impact of coverage of direct medical costs and antivenom treatment on household OOP expenditures under the full access scenario in urban and rural Lao PDR are presented in Fig 3. Full coverage of direct medical costs provided an even greater reduction in health inequities, with urban costs decreasing from 56% to 27% and rural costs from 95% to 35%. Increasing the coverage of antivenom treatment to 100% significantly reduced health inequities in %OOP expenditures per monthly household income, lowering costs from 56% to 42% in urban areas and 95% to 64% in rural areas.

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Fig 3. Scenario analyses of the impact of coverage of direct medical costs, transportation cost, and antivenom on the household out-of-pocket expenditure in full access to antivenom in urban and rural Lao PDR.

Full access was assumed that all snakebite victims sought conventional treatment and all victims with snakebite envenoming received antivenom treatment. Scenario analyses were performed to see the impact of varying the coverage of direct medical costs and antivenom on the percentage of OOP expenditures per household monthly income. Red dashed lines indicate the current coverage of medical services at 58.2%. The residual household OOP expenditures resulted from non-reimbursable direct medical costs and OOP direct non-medical costs. Further analyses were performed by reducing the transportation costs to none (Solid lines vs Dashed lines), indicating the residual household OOP expenditures on food. Lastly, additional scenario analyses were performed by assuming only one family member assisting the patient in caregiving during hospitalization, as shown in the dotted lines. Differences were calculated using unrounded model outputs. Values presented are rounded for readability; therefore, arithmetic differences based on displayed values may not exactly match the reported differences. Abbreviation: OOP – Out-of-pocket.

https://doi.org/10.1371/journal.pntd.0014420.g003

Zero transportation costs on top of full coverage of direct medical costs reduced health inequities in %OOP expenditures per monthly household income, lowering costs from 27% to 18% in urban areas and 35% to 17% in rural areas. Additional scenario analyses assuming only one family member assisting the patient in caregiving during hospitalization further reduced health inequities in %OOP expenditures per monthly household income, lowering costs from 18% to 6% in urban areas and 17% to 5% in rural areas.

Two-way sensitivity analyses, presented in S8 Table, evaluated the combined impact of access to antivenom and treatment-seeking behavior on %OOP expenditures per monthly household income in urban and rural Lao PDR. The results demonstrated that improving access to antivenom and shifting treatment-seeking behavior toward conventional healthcare facilities substantially influenced the household economic burden. Additional two-way sensitivity analyses, presented in S9 Table, evaluated the impact of transportation costs and coverage of direct medical costs on %OOP expenditures per monthly household income. Improving the coverage of direct medical costs and reducing transportation costs reduced the financial impacts on households in both areas.

Limitations

This ECEA should be interpreted with the following limitations. Firstly, input parameters were derived from a handful of published observational studies of snakebites in the Lao PDR [9–12]. In addition, when data were unavailable, we relied on expert opinion obtained through group discussions with researchers and clinicians experienced in the clinical management and epidemiology of snakebite envenoming in Lao PDR. However, we did not use formal expert elicitation methods, such as structured interviews or Delphi techniques, which may limit the reproducibility and methodological rigor of the parameter estimation process. To address the inherent uncertainty in these input parameters, we validated our assumptions using multiple sources and adopted conservative estimates where possible. Secondly, while snakebite envenoming can result in multiple physical and mental complications and disabilities, such as secondary infections, surgical complications, acute kidney injuries, post-traumatic stress disorder, or anxiety [35,36], our model included only amputations, as they are the only disability of snakebite, for which we had sufficient evidence to incorporate into the model [10]. Severe anaphylactic shock due to antivenom was also not modeled separately. This simplification may underestimate some harms and costs associated with antivenom treatment. However, severe fatal reactions to antivenom are expected to be uncommon based on currently available evidence [30]. Thus, we adopted a conservative modeling approach and acknowledge that excluding additional complications and long-term sequelae may underestimate the overall burden of snakebite and the potential benefits of improving access to antivenom in Lao PDR. Incorporating these complications would likely increase the estimated burden of snakebite and OOP expenditures, particularly in rural populations, and may further widen the observed urban–rural inequities. This constraint underscores the need for further research to capture the broader spectrum of snakebite-related complications, sequelae, and disabilities in Lao PDR. Thirdly, we assumed that antivenom administration improves outcomes across all snakebite cases. While clinical outcomes vary by snake type and time to treatment, our model applies an average effectiveness across cases due to the lack of species-specific real-world data in Lao PDR. We acknowledge this may overestimate the impact in delayed cases or for envenomings where antivenom is less effective. Fourthly, mortality estimates in this study were primarily derived from hospital-based data and may not fully capture deaths occurring outside the formal healthcare system. In rural areas of Lao PDR, some snakebite victims may never reach healthcare facilities because of geographical barriers, delayed care-seeking, or reliance on traditional healers. In addition, some severely ill patients may be discharged home due to cultural preferences for dying at home, resulting in deaths that are not captured in hospital mortality statistics. Therefore, the mortality burden of snakebite envenoming in the Lao PDR may be underestimated in this analysis [9–12]. Lastly, the analysis did not incorporate household-level income distributions and therefore could not estimate the incidence of CHE. The %OOP per monthly household income should be interpreted as a proxy of financial risk protection.

Despite these limitations, modeling studies remain important for quantifying disease burden and informing mitigation strategies. Although models have been developed to estimate the burden of snakebites in various global settings [37], comprehensive studies are still needed to refine input parameters and enhance accuracy. While data availability is often considered a prerequisite for modeling, in some cases, modeling may serve as a starting point to guide data collection and research efforts. This approach could be particularly relevant for NTDs, where data gaps persist and may hinder effective policy development. Combining modeling with empirical research may help improve the evidence base for addressing the snakebite burden, particularly in low- and middle-income countries such as Lao PDR.

Policy implications

The findings from our ECEA highlight the urgent need for equity-focused strategies to address the health inequities in snakebite envenoming outcomes between urban and rural communities in Lao PDR. Our model incorporates expert-informed differential mortality by geography, reflecting real-world barriers to effective treatment in rural settings, and highlights the importance of integrated health system responses. However, antivenom access alone is unlikely to achieve optimal outcomes without concurrent investments in timely access to care, supportive treatment (e.g., ventilation, transfusions), health worker training, and community education. Policymakers should view antivenom access as a foundational but not a standalone intervention. Antivenom is crucial for treating systemic envenoming, and timely use prevents severe complications and death. Due to resource limits in low-income settings such as Lao PDR, antivenom should be targeted, not universal. Improving clinical triage, following guidelines, and early detection are key to using limited supplies efficiently and equitably. Training healthcare workers to recognize indications for antivenom, alongside improvements in referral pathways and supportive care capacity, can maximize the health gains achievable from existing antivenom resources while minimizing unnecessary use.

Furthermore, improving the accessibility, availability, and affordability of snakebite treatment is needed. While the NHI scheme has successfully expanded coverage in Lao PDR [16], increasing coverage of antivenom and associated medical costs is essential to alleviate the financial burden on households, particularly in rural areas. Transportation subsidies within the NHI framework can further reduce economic barriers to access to care. These measures would address the high OOP expenditures pushing many rural households into catastrophic health spending. However, increasing coverage and introducing subsidies require additional financial resources, which can be challenging for a low-resource country like Lao PDR. The government could explore international funding opportunities and regional collaborations to overcome this. Partnering with global health organizations, such as WHO and international donors, could provide financial and technical support. Additionally, regional pooled procurement systems, mainly through ASEAN partnerships [2], could help reduce antivenom costs, making increased coverage and subsidies more feasible. Advocacy efforts emphasizing the economic and health equity benefits of these strategies can help secure commitments from government policymakers and donors.

Efforts should focus on shifting treatment-seeking behaviors from traditional to conventional care. Targeted awareness campaigns and community engagement are critical to encouraging timely medical treatment. Training healthcare workers in rural facilities to manage snakebite envenoming effectively is essential for building trust in healthcare systems and ensuring prompt and effective care. Ensuring access to antivenom also requires strengthening procurement and supply chain mechanisms. Policymakers could explore regional pooled procurement and international collaborations to secure affordable, high-quality antivenom supplies. Improving inventory management systems at local health facilities would further ensure that antivenom is available where it is needed most. Establishing a national snakebite registry would improve data collection, enabling policymakers to monitor snakebite incidence, treatment outcomes, and associated economic impacts. In parallel, prevention strategies remain critical for reducing the incidence of snakebite, particularly in rural and agricultural settings. Environmental and occupational risk-reduction measures, such as community education on snake avoidance, the use of protective equipment during agricultural work, improved housing conditions, and targeted interventions in high-risk areas, should be integrated with healthcare system strengthening efforts. These policy implications, aligned with existing health system efforts and international best practices [2,8,16], can significantly reduce the health and economic burden of snakebite envenoming.