Costs of human papillomavirus vaccine delivery in low- and middle-income countries: A systematic review.

Vaccines to protect against human papillomavirus (HPV) infection are recommended for all adolescents by the World Health Organization (WHO) and are primarily delivered in school-based settings. This systematic review aims to summarize the available evidence on the cost of HPV vaccine delivery in low- and middle-income countries (LMICs). This updated evidence is eminent given recent global efforts to revitalize HPV vaccine delivery following the COVID-19 pandemic and can be used to inform planning for program sustainability. We carried out a systematic review of published literature reporting the costs of HPV vaccine delivery in LMICs published between 2005 and 2023. Eligibility criteria were developed using the Population, Intervention, Comparator, Outcome (PICO) framework, and studies that reported primary costing data and unit costs of HPV vaccine delivery were included. From the included studies, we extracted data such as phase of HPV vaccine implementation when costing was done, delivery strategy, and unit costs. Unit costs were converted into 2022 US$ for comparability. All included studies underwent critical appraisal using an adapted framework including Consolidated Health Economics Evaluation Reporting Standards criteria, the WHO-led consensus statement on vaccine delivery costing, and other frameworks. Our research identified 226 records, of which 15 met our inclusion criteria. Most studies (64 %) were carried out in African countries and during HPV vaccine pilots or demonstrations (60 %). Vaccine delivery cost ranged from $0.31 to $24.07 per dose for financial costs and $1.48 to $48.70 per dose for economic costs. The critical appraisal showed that most studies did not describe the uncertainty of reported delivery cost. Our systematic review evidence suggests that HPV vaccine delivery costs vary widely depending on country and stage of implementation when costing was done. Areas for further research include costing when programs are beyond the introduction phase and in LMICs outside of Africa.

The cost of human papillomavirus vaccination delivery at the administrative and health facility levels in the Philippines.

Background: The World Health Organization has recommended the inclusion of human papillomavirus (HPV) vaccines in national immunization programs to address the global problem of cervical cancer. In the Philippines, HPV vaccination was introduced in a phased approach in 2015. This study seeks to estimate the cost of delivery of the HPV vaccination program and its operational context in the Philippines. Methods: This was a retrospective, cross-sectional micro-costing study focused on ongoing HPV vaccination delivery and its operational context across all levels of the health system. Using structured questionnaires and data collection from secondary sources, the weighted mean financial and economic costs and costs per dose at the national, subnational, and health facility levels were estimated. Results: The weighted mean financial and economic costs per dose of the HPV vaccination program aggregated across all levels of the health system were $US3.72and $29.74, respectively. Activities contributing most significantly to costs were service delivery and vaccine collection or distribution and storage at the health facility and administrative levels, respectively. The opportunity costs for health worker and non-health worker time accounted for 77% of the economic cost per dose. Conclusion: The total weighted mean financial and economic costs of HPV delivery are within range of those reported in other countries. Costing studies can help identify cost drivers with local operational context to help inform policymakers and program managers in budgeting and planning interventions to improve program implementation.

Human papillomavirus (HPV) vaccination program in Sri Lanka: Ongoing costs and operational context of a routinized program.

Existing evidence on the cost of human papillomavirus (HPV) vaccination programs has focused on pilot and demonstration projects or initial introductions, which resulted in a perceived high cost. We aimed to study the ongoing cost and operational context of an established HPV vaccination program in Sri Lanka. We conducted a retrospective operational research and microcosting study focusing on 2019. We collected data from 30 divisional health units, 10 districts, and the central level. We then evaluated financial and economic costs, reported by level of the health system, program activity, cost types, and per dose delivered. In 2019, Sri Lanka delivered a total of 314,815 doses of HPV vaccine. In our study sample, 95 % of the HPV vaccination sessions took place at schools, with peaks of delivery in February-March and September-October. The weighted mean financial cost per dose delivered was $0.27 (95 % confidence interval [CI]: $0.15-$0.39) and the economic cost per dose was $3.88 (95 % CI: $2.67-$5.10), excluding the cost of vaccines and supplies. Most of the cost was borne by the divisional health unit level. Service delivery and social mobilization were major contributors to overall costs at the divisional health unit level, and vaccine collection or distribution and storage were the most costly activities at the district and central levels. Cost drivers included the opportunity cost of health worker and non-health worker time at the divisional health unit level and capital costs for vehicles and equipment, along with fuel, maintenance, and energy, at the district and central levels. This study provides new evidence on the cost and cost drivers of a routinized HPV vaccination program. Results can be used for financial planning purposes in Sri Lanka and may inform other countries as they consider use of HPV vaccines.

Cost and operational context for national human papillomavirus (HPV) vaccine delivery in six low- and middle-income countries.

INTRODUCTION: There are concerns from immunization program planners about high delivery costs for human papillomavirus (HPV) vaccine. Most prior research evaluated costs of HPV vaccine delivery during demonstration projects or at introduction, showing relatively high costs, which may not reflect the costs beyond the pilot or introduction years. This study sought to understand the operational context and estimate delivery costs for HPV vaccine in six national programs, beyond their introduction years. METHODS: Operational research and microcosting methods were used to retrospectively collect primary data on HPV vaccination program activities in Ethiopia, Guyana, Rwanda, Senegal, Sri Lanka, and Uganda. Data were collected from the national level and a sample of subnational administrative offices and health facilities. Operational data collected were tabulated as percentages and frequencies. Financial costs (monetary outlays) and economic costs (financial plus opportunity costs) were estimated, as was the cost per HPV vaccine dose delivered. Costing was done from the health system perspective and reported in 2019 United States dollars (US$). RESULTS: Across the study countries, between 53 % and 99 % of HPV vaccination sessions were conducted in schools. Differences were observed in intensity and frequency with which program activities were conducted and resources used. Mean annual economic costs at health facilities in each country ranged from $1,207 to $3,190, while at the national level these ranged from $7,657 to $304,278. Mean annual HPV vaccine doses delivered per health facility in each country ranged from 162 to 761. Mean financial costs per dose per study country ranged from $0.27 to $3.32, while the economic cost per dose ranged from $3.09 to $17.20. CONCLUSION: HPV vaccine delivery costs were lower than at introduction in some study countries. There were differences in the activities carried out for HPV vaccine delivery and the number of doses delivered, impacting the cost estimates.

Cost of Acute and Sequelae Care for Japanese Encephalitis Patients, Bangladesh, 2011-2021.

Japanese encephalitis (JE) is associated with an immense social and economic burden. Published cost-of-illness data come primarily from decades-old studies. To determine the cost of care for patients with acute JE and initial and long-term sequelae from the societal perspective, we recruited patients with laboratory-confirmed JE from the past 10 years of JE surveillance in Bangladesh and categorized them as acute care, initial sequalae, and long-term sequelae patients. Among 157 patients, we categorized 55 as acute, 65 as initial sequelae (53 as both categories), and 90 as long-term sequelae. The average (median) societal cost of an acute JE episode was US $929 ($909), of initial sequelae US $75 ($33), and of long-term sequelae US $47 ($14). Most families perceived the effect of JE on their well-being to be extreme and had sustained debt for JE expenses. Our data about the high cost of JE can be used by decision makers in Bangladesh.

Estimating the cost of illness of acute Japanese encephalitis and sequelae care in Vietnam and Laos: A cross-sectional study.

BACKGROUND: Japanese encephalitis (JE) is a leading cause of acute encephalitis syndrome and resulting neurological disability in Asia and the Western Pacific. This study aims to estimate the cost of acute care, initial rehabilitation and sequelae care, in Vietnam and Laos. METHODOLOGY: We conducted a cross-sectional retrospective study using a micro-costing approach from the health system and household perspectives. Out-of-pocket direct medical and non-medical costs, indirect costs, and family impact were reported by patients and/or caregivers. Hospitalization costs were extracted from hospital charts. Acute costs covered expenditures from pre-hospital to follow-up visits while sequelae care costs were estimated from expenditures in the last 90 days. All costs are in 2021 US dollars. PRINCIPAL FINDINGS: 242 patients in two major sentinel sites in the North and South of Vietnam and 65 patients in a central hospital in Vientiane, Laos, with laboratory-confirmed JE were recruited regardless of age, sex, and ethnicity. In Vietnam, the mean total cost was $3,371 per acute JE episode (median $2,071, standard error [SE] $464) while annual costs were $404 for initial sequelae care (median $0, SE $220) and $320 for long-term sequelae care (median $0, SE $108). In Laos, the mean hospitalization costs in acute stage were $2,005 (median $1,698, SE $279) and the mean annual costs were $2,317 (median $0, SE $2,233) for initial sequelae care and $89 (median $0, SE $57) for long-term sequelae care. In both countries, most patients did not seek care for their sequelae. Families perceived extreme impact from JE and 20% to 30% of households still had sustained debts years after acute JE. CONCLUSIONS: JE patients and families in Vietnam and Laos suffer extreme medical, economic, and social hardship. This has policy implications for improving JE prevention in these two JE-endemic countries.

The cost-effectiveness of human papillomavirus vaccination in the Philippines.

Cervical cancer is the second most common cancer among women in the Philippines. Human papillomavirus (HPV) vaccination provides protection from the most common cancer-causing HPV types. This analysis used a proportionate outcomes model to estimate the potential cost-effectiveness of four different HPV vaccine products-Cervarix™, Cecolin®, GARDASIL®, and GARDASIL®9-for routine HPV vaccination of 10 cohorts of 9-year-old girls from the government and societal perspectives. Model parameters included cervical cancer burden, healthcare and program costs, vaccine efficacy with and without potential cross-protection, and vaccination coverage. Univariate and probabilistic sensitivity analyses evaluated the impact of uncertainty on model results. Compared to no vaccination, HPV programs with Cecolin®, Cervarix™, and GARDASIL® are projected to be cost-effective at US$1,210, US$1,300, and US$2,043 per DALY averted, respectively, from the government perspective, and at US$173, US$263, and US$1,006 per DALY averted, respectively, from the societal perspective when cross-protection was considered. When direct comparisons were made across vaccines, GARDASIL® was dominated by Cervarix™ and Cecolin®. In a scenario where cross-protection was not considered, results were similar except that Cervarix™ and GARDASIL® were both dominated by Cecolin®. GARDASIL®9 was not cost-effective under any of the modeled scenarios.

Health Outcomes at 1 Year After Thermal Ablation for Cervical Precancer Among Human Papillomavirus- and Visual Inspection With Acetic Acid-Positive Women in Honduras.

PURPOSE: This study aims to assess the detection of cervical intraepithelial lesions grades 2 and 3 (CIN2-3) at 1 year after treatment with thermal ablation among human papillomavirus (HPV)-positive and visual inspection with acetic acid (VIA)-positive women. METHODS: All women screened and triaged for cervical cancer at four government health facilities in Honduras who were eligible for ablative treatment were enrolled and treated with thermal ablation. Women with confirmed CIN2-3 and a subset of women with CIN1/normal diagnoses at baseline were evaluated at 12 months. Follow-up procedures included HPV testing (careHPV), VIA, directed biopsy (if VIA-positive), and Papanicolaou test (if HPV positive, VIA negative). Outcomes at 1 year included histologic or cytologic assessment of CIN lesions among those with any abnormal test. RESULTS: Among the 319 women treated with thermal ablation, baseline histologic diagnoses were available for 317. Two (0.6%) had invasive cancer, 36 (11.4%) had CIN3, 40 (12.6%) had CIN2, and 239 (75.4%) had CIN1/normal histology. Among the 127 women eligible for follow-up, 118 (92.9%) completed all study procedures at 1 year. Overall, 98 (83.1%) had no evidence of CIN2-3 or persistent low-grade infection, 13 (11.2%) had CIN1/atypical squamous cells of undetermined significance, six (5.1%) had CIN2/high-grade squamous intraepithelial lesion, and 1 (0.8%) had a persistent CIN3. No adverse events associated with thermal ablation at 1 year were registered. CONCLUSION: A high proportion of women had no evidence of CIN2-3 at 1 year after thermal ablation treatment. Thermal ablation is an alternative to cryotherapy that may facilitate greater treatment coverage and prevent unnecessary deaths from cervical cancer.

Age patterns of human papillomavirus infection as primary screening test for cervical cancer and subsequent triage with visual inspection in Honduras / Patrones de edad de infección por el virus del papiloma humano como prueba primaria en el tamizaje de cáncer de cuello uterino y triaje posterior con inspección visual en Honduras

Abstract Objective: To evaluate age patterns in human papillomavirus (HPV) prevalence and visual inspection with acetic acid (VIA) positivity among women participating in cervical cancer screening in Honduras. Materials and methods: Data on the HPV status (careHPV) and subsequent VIA in HPV-positive women were retrieved from three provinces within the Public Health Sector. Results: Between 2015 and 2018, 60 883 women aged 15-85 years were screened. HPV was detected in 15%, with variation by age, peaking at 20-24 years (27.8%) decreasing to 16% at 30-49 years. Differences in point age-specific HPV prevalence were observed between provinces, but with similar age pattern. VIA was positive in 24.5% of the women aged 30-44 years. Conclusions: The age pattern of the HPV prevalence supports starting HPV testing at age 30+. The low positivity of VIA in ages close to menopause suggest underdetection of cervical lesions in this age group.

Resumen Objetivo: Evaluar la prevalencia del virus del papiloma humano (VPH) y la positividad a la inspección visual con ácido acético (IVA) de cáncer cervicouterico, según edad en mujeres tamizadas en Honduras. Material y métodos: Se extrajo información sobre la prueba de VPH (careHPV) y de IVA en tres provincias en el ámbito de la Atención Pública en Salud. Resultados: Durante 2015-2018, 60 883 mujeres de 15-85 años fueron tamizadas, 15% fueron VPH positivas con valores máximos en mujeres de 20-24 años (27.8%), con una disminución a 16% entre 30-49 años. Se observaron diferencias mínimas entre provincias, con un patrón de edad similar. La IVA fue positiva en 24.5% en mujeres de 30-44 años, con una posterior disminución. Conclusiones: La curva de prevalencia del VPH respalda el tamizar con VPH a los 30+ años. La baja positividad de la IVA en edades cercanas a la menopausia sugiere una subdetección de lesiones cervicales en este grupo.

Age patterns of human papillomavirus infection as primary screening test for cervical cancer and subsequent triage with visual inspection in Honduras.

OBJECTIVE: To evaluate age patterns in human papillomavi-rus (HPV) prevalence and visual inspection with acetic acid (VIA) positivity among women participating in cervical cancerscreening in Honduras. MATERIALS AND METHODS: Data on the HPV status (careHPV) and subsequent VIA in HPV-positivewomen were retrieved from three provinces within the PublicHealth Sector. RESULTS: Between 2015 and 2018, 60 883 women aged 15-85 years were screened. HPV was detected in 15%, with variation by age, peaking at 20-24 years (27.8%) decreasing to 16% at 30-49 years. Differences in point age-specific HPV prevalence were observed between provinces,but with similar age pattern. VIA was positive in 24.5% of the women aged 30-44 year. CONCLUSIONS: The age pattern of the HPV prevalence supports starting HPV testing at age 30+. The low positivity of VIA in ages close to menopause suggest underdetection of cervical lesions in this age group.

OBJETIVO: Evaluar la prevalencia del virus del papilomahumano (VPH) y la positividad a la inspección visual con ácido acético (IVA) de cáncer cervicouterico, según edad en mujeres tamizadas en Honduras. MATERIAL Y MÉTODOS: Se extrajo información sobre la prueba de VPH (careHPV) y de IVA en tres provincias en el ámbito de la Atención Pública en Salud. RESULTADOS: Durante 2015-2018, 60 883 mujeresde 15-85 años fueron tamizadas, 15% fueron VPH positivas con valores máximos en mujeres de 20-24 años (27.8%),con una disminución a 16% entre 30-49 años. Se observaron diferencias mínimas entre provincias, con un patrón de edad similar. La IVA fue positiva en 24.5% en mujeres de 30-44 años, con una posterior disminución. CONCLUSIONES: La curva de prevalencia del VPH respalda el tamizar con VPH a los 30+ años. La baja positividad de la IVA en edades cercanas a la menopausia sugiere una subdetección de lesiones cervicales en este grupo.

HPV-based cervical cancer screening in Nicaragua: from testing to treatment.

BACKGROUND: In Nicaragua, cervical cancer is the leading cause of cancer death among women. Human papillomavirus (HPV) testing, primarily using self-sampling, was introduced between 2014 and 2018 in three provinces. We analyzed data from the HPV screening program with the goal of describing key characteristics including reach, HPV prevalence, triage and treatment, and factors associated with follow-up completion. METHODS: We analyzed individual-level data from routinely collected forms for women attending HPV-based cervical cancer screening. HPV-positive women were triaged with Pap or visual inspection with acetic acid (VIA) prior to treatment. Logistic regression was used to identify factors associated with receiving triage and treatment; analyses were adjusted for province, age, and self- vs. provider-collected sampling. RESULTS: Forty-four thousand six hundred thirty-five women were screened with HPV testing; 96.6% of women used self-sampling. Six thousand seven hundred seventy-six women were HPV positive (15.2%), 54.0% of screen-positive women received triage, and 53.1% of triage-positive women were treated, primarily with cryotherapy. If women lost at triage are included, the overall treatment percentage was 27.8%. Province and provider sampling were significantly associated with completing triage. Province and triage type were significantly associated with receiving treatment. The odds of receiving treatment after Pap triage as compared to VIA was significantly lower (aOR: 0.05, 95% CI: 0.04-0.08, p < 0.001), and the relative proportion of women receiving treatment after Pap triage versus VIA was 0.29. CONCLUSIONS: Introduction of HPV testing resulted in a substantial number of women screened, and acceptance of self-sampling was high. Management of screen-positive women remained a challenge, particularly with Pap triage. Our results can inform other developing countries as they work to reach World Health Organization (WHO) elimination targets.

Introduction of HPV testing for cervical cancer screening in Central America: The Scale-Up project.

The Scale-Up project introduced vaginal self-sampling and low-cost human papillomavirus (HPV) testing as the primary approach for cervical cancer screening in selected public health centers in Guatemala, Honduras, and Nicaragua. We evaluate the country-specific accomplishments in screening: target-coverage, triage, and treatment. Between 2015 and 2018, cervical cancer screening was offered to women at least 30 years of age. Triage of HPV-positive women was based on visual inspection with acetic acid or Pap. Aggregated data included total women screened, use of self-sampling, age, time elapsed since last screening, HPV results, triage tests, triage results, and treatment. A total of 231,741 women were screened for HPV, representing 85.8% of the target populations within the project. HPV positivity was lower in Guatemala (12.4%) compared to Honduras and Nicaragua (14.5% and 14.2%, respectively, p < 0.05). A follow-up triage test was completed for 84.2%, 85.8%, and 50.1% of HPV-positive women in Guatemala, Nicaragua, and Honduras, respectively. Of those with a positive triage test, 84.7%, 67.1%, and 58.8% were treated in Guatemala, Nicaragua, and Honduras, respectively. First-time screening was highest in Nicaragua (55.8%) where self-sampling was also widely used (97.1%). The Scale-Up project demonstrated that large-scale cervical cancer screening and treatment intervention in a high-burden, low-resource setting can be achieved. Self-sampling and ablative treatment were key to the project's achievements. Data monitoring, loss to follow-up, and triage methods of screen- positive women remain critical to full success.

Acceptability and safety of thermal ablation for the treatment of precancerous cervical lesions in Honduras.

OBJECTIVE: To evaluate the acceptability and safety of thermal ablation (TA) for the treatment of precancerous cervical lesions in women in Honduras. METHODS: Human papillomavirus (HPV) and visual inspection with acetic acid (VIA) screen-positive eligible women received TA. After treatment, women rated the level of pain experienced during treatment using the Wong-Baker FACES® pain-rating scale from 0 to 10. Short-term safety outcomes that could require medical attention were assessed one month after treatment. RESULTS: A total of 319 women received TA treatment. The average pain rating was 2.5 (95% CI: 2.3-2.8), and 85% rated their pain levels as less than 6. No significant differences in low (below 6) or high (6 and above) pain were found by age or number of biopsies performed, but there was a significant difference by the number of TA applications (P < 0.01). When asked if they would recommend this treatment, all women said they would. At the one-month follow-up visit, the most common reported discomforts were bleeding (10%) and cramping (8.4%); 11 women reported severe lower abdominal pain, and none required medical attention. CONCLUSIONS: TA is safe and acceptable to patients as a treatment option for precancerous cervical lesions in low-resource settings.

OBJECTIF: Evaluer l'acceptabilité et la sécurité de l'ablation thermique (AT) pour le traitement des lésions cervicales précancéreuses chez les femmes au Honduras. MÉTHODES: Les femmes éligibles, portant le virus du papillome humain (VPH) et avec une inspection visuelle positive au test de dépistage à l'acide acétique (IVA) ont reçu une AT. Après le traitement, les femmes ont estimé le niveau de douleur ressenti au cours du traitement à l'aide de l'échelle d'évaluation de la douleur Wong-Baker FACES® de 0 à 10. Les résultats de sécurité à court terme pouvant nécessiter une attention médicale ont été évalués un mois après le traitement. RÉSULTATS: 319 femmes ont reçu un traitement d'AT. L'estimation moyenne de la douleur était de 2,5 (IC95%: 2,3-2,8) et 85% estimaient que leur niveau de douleur était inférieur à 6. Aucune différence significative dans la douleur faible (moins de 6) ou élevée (6 et plus) n'a été constatée en fonction de l'âge ou du nombre de biopsies réalisées, mais il y avait une différence significative selon le nombre d'applications d'AT (P < 0,01). Lorsqu'on leur a demandé si elles recommanderaient ce traitement, toutes les femmes ont répondu qu'elles le feraient. Lors de la visite de suivi à un mois, les malaises les plus fréquents signalés étaient les saignements (10%) et les crampes (8,4%). Onze femmes ont rapporté des douleurs sévères dans le bas de l'abdomen et aucune n'a nécessité de soins médicaux. CONCLUSIONS: L'AT est sûre et acceptable pour les patientes comme option de traitement pour les lésions cervicales précancéreuses dans les régions à faibles ressources.

Statistical Modeling for Quality Assurance of Human Papillomavirus DNA Batch Testing.

OBJECTIVES: Our objective was to simulate the distribution of human papillomavirus (HPV) DNA test results from a 96-well microplate assay to identify results that may be consistent with well-to-well contamination, enabling programs to apply specific quality assurance parameters. MATERIALS AND METHODS: For this modeling study, we designed an algorithm that generated the analysis population of 900,000 to simulate the results of 10,000 microplate assays, assuming discrete HPV prevalences of 12%, 13%, 14%, 15%, and 16%. Using binomial draws, the algorithm created a vector of results for each prevalence and reassembled them into 96-well matrices for results distribution analysis of the number of positive cells and number and size of cell clusters (≥2 positive cells horizontally or vertically adjacent) per matrix. RESULTS: For simulation conditions of 12% and 16% HPV prevalence, 95% of the matrices displayed the following characteristics: 5 to 17 and 8 to 22 total positive cells, 0 to 4 and 0 to 5 positive cell clusters, and largest cluster sizes of up to 5 and up to 6 positive cells, respectively. CONCLUSIONS: Our results suggest that screening programs in regions with an oncogenic HPV prevalence of 12% to 16% can expect 5 to 22 positive results per microplate in approximately 95% of assays and 0 to 5 positive results clusters with no cluster larger than 6 positive results. Results consistently outside of these ranges deviate from what is statistically expected and could be the result of well-to-well contamination. Our results provide guidance that laboratories can use to identify microplates suspicious for well-to-well contamination, enabling improved quality assurance.

Implementation of HPV testing in Latin America.

Cervical cancer is one of the leading killers among women in Latin America, a region where most countries have not been successful in implementing population-level cytology-based screening programs. This disease is caused by persistent infection with oncogenic HPV; in recent years, more HPV tests have become available and prices have dropped significantly, making it possible for countries to adopt these technologies. Pilot programs that took place in Nicaragua, Mexico, and Argentina showed a high level of efficacy in detecting precancerous cervical lesions and good feasibility and acceptance of self-sampling. El Salvador, Guatemala, Honduras, and Nicaragua are beginning to institutionalize HPV testing at the population level. The experience from the different countries has created rich information about the barriers and requirements for implementing HPV screening at large scale in these resource-constrained countries. There are several challenges for implementation, including a need to update screening guidelines, strengthen treatment capacity, and develop a comprehensive quality assurance plan for the HPV testing. At the same time, there are several opportunities in Latin America that make the process more feasible and faster than in other regions of the world: most Latin American countries already have screening programs funded by their national governments, several countries in the region are already implementing HPV testing, and there is a regional pooled procurement mechanism that could facilitate the purchase of HPV tests at an accessible price. We envision that most countries in the region will include HPV testing in their national program within the next three to five years.