BACKGROUND: Cervical cancer is the fourth most common cancer among women globally, disproportionately affecting those in low- and middle-income countries (LMICs). In 2020, World Health Organization (WHO) Member States endorsed the 2030 Global Strategy toward Elimination of Cervical Cancer, recommending expanded access to human papillomavirus (HPV) vaccination. However, gaps remain in understanding how LMICs can sustain high HPV vaccine coverage. Tanzania, an early adopter among LMICs, introduced HPV vaccination into the national immunization schedule for 14-year-old girls in 2018 and achieved >90 % two-dose coverage by 2023. This study evaluated HPV vaccine program implementation in Tanzania, capturing stakeholder perspectives on barriers, facilitators, and recommendations. METHODS: Stakeholders were interviewed in April 2024 in a concurrent mixed-methods evaluation. Participants included national and subnational immunization staff (n = 18), and health workers, teachers, and community influencers (n = 80). Four of 31 regions were purposively selected based on criteria including first-dose HPV coverage (2020-2022) and urban/rural distribution. Two health facilities were randomly selected from a list of facilities in each region, along with two schools administering the vaccine from each facility's catchment area. Quantitative data were analyzed descriptively in STATA v.18, and qualitative data analyzed in ATLAS.ti Web (v19.3.1). RESULTS: Political support, quality improvement cycles, and integration with existing systems were identified as contributing to program success. Funding gaps and staff shortages-particularly in regions with low HPV vaccination coverage-were among the reported barriers, along with poor coordination between health and education sectors and low community awareness. Recommendations included increasing government funding, strengthening cross-sector collaboration, training stakeholders, and expanding dissemination channels to improve demand and address vaccine hesitancy. CONCLUSIONS: Tanzania's experience offers lessons for HPV vaccination in similar contexts. Addressing key barriers through increased funding, improved coordination, and enhanced community engagement could improve HPV vaccination implementation in Tanzania and elsewhere, contributing to global cervical cancer elimination.

BACKGROUND: Expanding malaria community case management (mCCM) to all ages could shift the point-of-care to the community leading to improved healthcare access in underserved populations. This study assesses the economic viability of such an expansion in Farafangana district, Madagascar. METHODS: A cluster-randomized trial was conducted across 30 health centres and the 502 community health workers (CHW) in their catchment areas, with the intervention arm implementing the age-expanded mCCM intervention. CHWs across both arms received training, supplies, and supervision to manage malaria. An economic evaluation assessed cost-effectiveness from health sector and societal perspectives, measuring outcomes in disability-adjusted life years (DALYs) averted. The impact of CHW compensation and economic risks were evaluated using sensitivity analyses. RESULTS: Without CHW compensation, annual costs were $794,000, primarily for antimalarials and diagnostic tests. Incremental cost-effectiveness ratios (ICERs) per DALY averted ranged from -$21.86 to $212.42. From a societal perspective, the ICER was -$135.64, and -$243.29 including mortality benefits, meaning the intervention was cost-saving. The programme could avert 99.6 deaths and 3,721.7 DALYs annually, yielding $1,172,283 in net economic benefits. Sensitivity analyses supported these findings. CONCLUSIONS: Age-expanded mCCM is highly cost-effective and can enhance malaria treatment access in resource-limited settings.

INTRODUCTION: An estimated 800 000 children (<15 years) globally living with HIV remain undiagnosed. To reach these children with timely HIV testing services during infancy, we implemented a community-based differentiated care model using mobile point-of-care (POC) technology for early infant diagnosis (EID) of HIV, and assessed its effects on EID positivity, antiretroviral therapy (ART) initiation and 3-month retention in care. METHODS: Between 1 June 2019 and 31 May 2020 at six health facilities in Lusaka, Zambia, we enrolled mother-infant pairs (MIPs) at high risk for vertical transmission of HIV based on missing or late infant EID testing or other maternal risk factors. We offered these MIPs community POC EID testing (post-intervention), and compared their outcomes to historical high-risk controls at the same sites (1 June 2017-31 May 2018; pre-intervention). We used propensity score matched weighting and mixed effects regression modelling to estimate outcome differences pre-intervention and post-intervention, and to identify MIP characteristics predictive of vertical transmission of HIV. RESULTS: 2577 MIPs were included in the analysis: 1763 and 814 high-risk MIPs from the pre-intervention and post-intervention periods, respectively. Infant HIV positivity was significantly higher in the post-intervention (2.2%) vs pre-intervention (1.1%) period (p=0.038), however this difference was attenuated (0.83%, 95% CI: -0.50%, 2.15%) after adjusting for differences in maternal age, maternal antenatal care visits, infant birth month and facility. During the post-intervention period, MIPs where the mother disengaged from care were 12.97 (95% CI: 2.41, 69.98) times as likely to have an infant diagnosed with HIV vs those in which the infant received late EID testing without maternal care disengagement. Among 18 infants diagnosed with HIV by the intervention, 16 (88.9%) initiated same-day ART and all continued ART at 3-month follow-up. CONCLUSION: Community-based differentiated care employing POC EID technology increased testing positivity in unadjusted analyses, and resulted in high ART initiation and early care retention, suggesting it may be a promising approach for reaching infants and young children living with HIV being missed by current facility-based approaches. TRIAL REGISTRATION NUMBER: This trial is registered under the following Clinicaltrials.gov Identifier: NCT03133728.

BACKGROUND: Global progress on malaria control has stalled recently, partly due to challenges in universal access to malaria diagnosis and treatment. Community health workers (CHWs) can play a key role in improving access to malaria care for children under 5 years (CU5), but national policies rarely permit them to treat older individuals. We conducted a two-arm cluster randomized trial in rural Madagascar to assess the impact of expanding malaria community case management (mCCM) to all ages on health care access and use. METHODS: Thirty health centers and their associated CHWs in Farafangana District were randomized 1:1 to mCCM for all ages (intervention) or mCCM for CU5 only (control). Both arms were supported with CHW trainings on malaria case management, community sensitization on free malaria care, monthly supervision of CHWs, and reinforcement of the malaria supply chain. Cross-sectional household surveys in approximately 1600 households were conducted at baseline (Nov-Dec 2019) and endline (Nov-Dec 2021). Monthly data were collected from health center and CHW registers for 36 months (2019-2021). Intervention impact was assessed via difference-in-differences analyses for survey data and interrupted time-series analyses for health system data. RESULTS: Rates of care-seeking for fever and malaria diagnosis nearly tripled in both arms (from less than 25% to over 60%), driven mostly by increases in CHW care. Age-expanded mCCM yielded additional improvements for individuals over 5 years in the intervention arm (rate ratio for RDTs done in 6-13-year-olds, RR(RDT6-13 years) = 1.65; 95% CIs 1.45-1.87), but increases were significant only in health system data analyses. Age-expanded mCCM was associated with larger increases for populations living further from health centers (RR(RDT6-13 years) = 1.21 per km; 95% CIs 1.19-1.23). CONCLUSIONS: Expanding mCCM to all ages can improve universal access to malaria diagnosis and treatment. In addition, strengthening supply chain systems can achieve significant improvements even in the absence of age-expanded mCCM. TRIAL REGISTRATION: The trial was registered at the Pan-African Clinical Trials Registry (#PACTR202001907367187).

INTRODUCTION: Indoor residual spraying (IRS) and insecticide-treated bed nets (ITNs) are cornerstone malaria prevention methods in Madagascar. This retrospective observational study uses routine data to evaluate the impacts of IRS overall, sustained IRS exposure over multiple years and level of spray coverage (structures sprayed/found) in nine districts where non-pyrethroid IRS was deployed to complement standard pyrethroid ITNs from 2017 to 2020. METHODS: Multilevel negative-binomial generalised linear models were fit to estimate the effects of IRS exposure overall, consecutive years of IRS exposure and spray coverage level on monthly all-ages population-adjusted malaria cases confirmed by rapid diagnostic test at the health facility level. The study period extended from July 2016 to June 2021. Facilities with missing data and non-geolocated communes were excluded. Facilities in IRS districts were matched with control facilities by propensity score analysis. Models were controlled for ITN survivorship, mass drug administration coverage, precipitation, enhanced vegetation index, seasonal effects and district. Predicted cases under a counterfactual no IRS scenario and number of cases averted by IRS were estimated using the fitted models. RESULTS: Exposure to IRS overall reduced case incidence by an estimated 30.3% from 165.8 cases per 1000 population (95% CI=139.7 to 196.7) under a counterfactual no IRS scenario, to 114.3 (95% CI=96.5 to 135.3) over 12 months post-IRS campaign in nine districts. A third year of IRS reduced malaria cases 30.9% more than a first year (incidence rate ratio (IRR)=0.578, 95% CI=0.578 to 0.825, p<0.001) and 26.7% more than a second year (IRR=0.733, 95% CI=0.611 to 0.878, p=0.001). There was no significant difference between the first and second year (p>0.05). Coverage of 86%-90% was associated with a 19.7% reduction in incidence (IRR=0.803, 95% CI=0.690 to 0.934, p=0.005) compared with coverage ≤85%, although these results were not robust to sensitivity analysis. CONCLUSION: This study demonstrates that non-pyrethroid IRS appears to substantially reduce malaria incidence in Madagascar and that sustained implementation of IRS over three years confers additional benefits.

Introduction Indoor residual spraying (IRS) and insecticide-treated bed-nets (ITNs) are cornerstone malaria prevention methods in Madagascar. This retrospective observational study uses routine data to evaluate the impacts of IRS overall, sustained IRS exposure over multiple years, and level of spray coverage (structures sprayed/found) in nine districts where non-pyrethroid IRS was deployed to complement standard pyrethroid ITNs from 2017 to 2020. Methods Multilevel negative-binomial generalized linear models were fit to estimate the effects of IRS exposure overall; consecutive years of IRS exposure; and spray coverage level on monthly all-ages population-adjusted malaria cases confirmed by rapid diagnostic test at the health facility level. The study period extended from July 2016 to June 2017. Facilities missing data and non-geolocated communes were excluded. Facilities in IRS districts were matched with control facilities by propensity score analysis. Models controlled for ITN survivorship, mass drug administration coverage, precipitation, enhanced vegetation index, seasonal effects, and district. Predicted cases under a counterfactual no IRS scenario and number of cases averted by IRS were estimated using the fitted models. Results Exposure to IRS overall reduced case incidence by an estimated 30.3% from 165.8 cases per 1,000 population (95%CI=139.7-196.7) under a counterfactual no IRS scenario, to 114.3 (95%CI=96.5-135.3), over 12 months post-IRS campaign in 9 districts. A third year of IRS reduced malaria cases 30.9% more than a first year (IRR=0.578, 95%CI=0.578-0.825, P<0.001) and 26.7% more than a second year (IRR=0.733, 95%CI=0.611-0.878, P=0.001). There was no significant difference between a first and second year (P>0.05). Coverage of 86%-90% was associated with a 19.7% reduction in incidence (IRR= 0.803, 95%CI=0.690-0.934, P=0.005) compared to coverage <=85%, although these results were not robust to sensitivity analysis. Conclusion This study demonstrates that non-pyrethroid IRS appears to substantially reduce malaria incidence in Madagascar and that sustained implementation of IRS over 3 years confers additional benefits. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.

BACKGROUND: Malaria remains a leading cause of morbidity and mortality worldwide, with progress in malaria control stalling in recent years. Proactive community case management (pro-CCM) has been shown to increase access to diagnosis and treatment and reduce malaria burden. However, lack of experimental evidence may hinder the wider adoption of this intervention. We conducted a cluster randomized community intervention trial to assess the efficacy of pro-CCM at decreasing malaria prevalence in rural endemic areas of Madagascar. METHODS: Twenty-two fokontany (smallest administrative unit) of the Mananjary district in southeast Madagascar were selected and randomized 1:1 to pro-CCM (intervention) or conventional integrated community case management (iCCM). Residents of all ages in the intervention arm were visited by a community health worker every 2 weeks from March to October 2017 and screened for fever; those with fever were tested by a rapid diagnostic test (RDT) and treated if positive. Malaria prevalence was assessed using RDTs on all consenting study area residents prior to and following the intervention. Hemoglobin was measured among women of reproductive age. Intervention impact was assessed via difference-in-differences analyses using logistic regressions in generalized estimating equations. RESULTS: A total of 27,087 and 20,475 individuals participated at baseline and endline, respectively. Malaria prevalence decreased from 8.0 to 5.4% in the intervention arm for individuals of all ages and from 6.8 to 5.7% in the control arm. Pro-CCM was associated with a significant reduction in the odds of malaria positivity in children less than 15 years (OR = 0.59; 95% CI [0.38-0.91]), but not in older age groups. There was no impact on anemia among women of reproductive age. CONCLUSION: This trial suggests that pro-CCM approaches could help reduce malaria burden in rural endemic areas of low- and middle-income countries, but their impact may be limited to younger age groups with the highest malaria burden. TRIAL REGISTRATION: NCT05223933. Registered on February 4, 2022.

BACKGROUND: Prompt diagnosis and treatment of malaria contributes to reduced morbidity, particularly among children and pregnant women; however, in Madagascar, care-seeking for febrile illness is often delayed. To describe factors influencing decisions for prompt care-seeking among caregivers of children aged < 15 years and pregnant women, a mixed-methods assessment was conducted with providers (HP), community health volunteers (CHV) and community members. METHODS: One health district from each of eight malaria-endemic zones of Madagascar were purposefully selected based on reported higher malaria transmission. Within districts, one urban and one rural community were randomly selected for participation. In-depth interviews (IDI) and focus group discussions (FGD) were conducted with caregivers, pregnant women, CHVs and HPs in these 16 communities to describe practices and, for HPs, system characteristics that support or inhibit care-seeking. Knowledge tests on malaria case management guidelines were administered to HPs, and logistics management systems were reviewed. RESULTS: Participants from eight rural and eight urban communities included 31 HPs from 10 public and 8 private Health Facilities (HF), five CHVs, 102 caregivers and 90 pregnant women. All participants in FGDs and IDIs reported that care-seeking for fever is frequently delayed until the ill person does not respond to home treatment or symptoms become more severe. Key care-seeking determinants for caregivers and pregnant women included cost, travel time and distance, and perception that the quality of care in HFs was poor. HPs felt that lack of commodities and heavy workloads hindered their ability to provide quality malaria care services. Malaria commodities were generally more available in public versus private HFs. CHVs were generally not consulted for malaria care and had limited commodities. CONCLUSIONS: Reducing cost and travel time to care and improving the quality of care may increase prompt care-seeking among vulnerable populations experiencing febrile illness. For patients, perceptions and quality of care could be improved with more reliable supplies, extended HF operating hours and staffing, supportive demeanors of HPs and seeking care with CHVs. For providers, malaria services could be improved by increasing the reliability of supply chains and providing additional staffing. CHVs may be an under-utilized resource for sick children.

BACKGROUND: Since 2005, artemisinin-based combination therapy (ACT) has been recommended to treat uncomplicated falciparum malaria in Madagascar. Artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are the first- and second-line treatments, respectively. A therapeutic efficacy study was conducted to assess ACT efficacy and molecular markers of anti-malarial resistance. METHODS: Children aged six months to 14 years with uncomplicated falciparum malaria and a parasitaemia of 1000-100,000 parasites/µl determined by microscopy were enrolled from May-September 2018 in a 28-day in vivo trial using the 2009 World Health Organization protocol for monitoring anti-malarial efficacy. Participants from two communes, Ankazomborona (tropical, northwest) and Matanga (equatorial, southeast), were randomly assigned to ASAQ or AL arms at their respective sites. PCR correction was achieved by genotyping seven neutral microsatellites in paired pre- and post-treatment samples. Genotyping assays for molecular markers of resistance in the pfk13, pfcrt and pfmdr1 genes were conducted. RESULTS: Of 344 patients enrolled, 167/172 (97%) receiving ASAQ and 168/172 (98%) receiving AL completed the study. For ASAQ, the day-28 cumulative PCR-uncorrected efficacy was 100% (95% CI 100-100) and 95% (95% CI 91-100) for Ankazomborona and Matanga, respectively; for AL, it was 99% (95% CI 97-100) in Ankazomborona and 83% (95% CI 76-92) in Matanga. The day-28 cumulative PCR-corrected efficacy for ASAQ was 100% (95% CI 100-100) and 98% (95% CI 95-100) for Ankazomborona and Matanga, respectively; for AL, it was 100% (95% CI 99-100) in Ankazomborona and 95% (95% CI 91-100) in Matanga. Of 83 successfully sequenced samples for pfk13, no mutation associated with artemisinin resistance was observed. A majority of successfully sequenced samples for pfmdr1 carried either the NFD or NYD haplotypes corresponding to codons 86, 184 and 1246. Of 82 successfully sequenced samples for pfcrt, all were wild type at codons 72-76. CONCLUSION: PCR-corrected analysis indicated that ASAQ and AL have therapeutic efficacies above the 90% WHO acceptable cut-off. No genetic evidence of resistance to artemisinin was observed, which is consistent with the clinical outcome data. However, the most common pfmdr1 haplotypes were NYD and NFD, previously associated with tolerance to lumefantrine.

BACKGROUND: Integrated community case management of malaria, pneumonia, and diarrhoea can reduce mortality in children under five years (CU5) in resource-poor countries. There is growing interest in expanding malaria community case management (mCCM) to older individuals, but limited empirical evidence exists to guide this expansion. As part of a two-year cluster-randomized trial of mCCM expansion to all ages in southeastern Madagascar, a cross-sectional survey was conducted to assess baseline malaria prevalence and healthcare-seeking behaviours. METHODS: Two enumeration areas (EAs) were randomly chosen from each catchment area of the 30 health facilities (HFs) in Farafangana district designated for the mCCM age expansion trial; 28 households were randomly selected from each EA for the survey. All household members were asked about recent illness and care-seeking, and malaria prevalence was assessed by rapid diagnostic test (RDT) among children < 15 years of age. Weighted population estimates and Rao-Scott chi-squared tests were used to examine illness, care-seeking, malaria case management, and malaria prevalence patterns. RESULTS: Illness in the two weeks prior to the survey was reported by 459 (6.7%) of 8050 respondents in 334 of 1458 households surveyed. Most individuals noting illness (375/459; 82.3%) reported fever. Of those reporting fever, 28.7% (112/375) sought care; this did not vary by participant age (p = 0.66). Most participants seeking care for fever visited public HFs (48/112, 46.8%), or community healthcare volunteers (CHVs) (40/112, 31.0%). Of those presenting with fever at HFs or to CHVs, 87.0% and 71.0%, respectively, reported being tested for malaria. RDT positivity among 3,316 tested children < 15 years was 25.4% (CI: 21.5-29.4%) and increased with age: 16.9% in CU5 versus 31.8% in 5-14-year-olds (p < 0.0001). Among RDT-positive individuals, 28.4% of CU5 and 18.5% of 5-14-year-olds reported fever in the two weeks prior to survey (p = 0.044). CONCLUSIONS: The higher prevalence of malaria among older individuals coupled with high rates of malaria testing for those who sought care at CHVs suggest that expanding mCCM to older individuals may substantially increase the number of infected individuals with improved access to care, which could have additional favorable effects on malaria transmission.