Forest-goers as a heterogeneous population at high-risk for malaria: a case-control study in Aceh Province, Indonesia.

BACKGROUND: A major challenge to malaria elimination is identifying and targeting populations that are harbouring residual infections and contributing to persistent transmission. In many near-elimination settings in Southeast Asia, it is known that forest-goers are at higher risk for malaria infection, but detailed information on their behaviours and exposures is not available. METHODS: In Aceh Province, Indonesia, a near-elimination setting where a growing proportion of malaria is due to Plasmodium knowlesi, a case-control study was conducted to identify risk factors for symptomatic malaria, characteristics of forest-goers, and key intervention points. From April 2017 to September 2018, cases and controls were recruited and enrolled in a 1:3 ratio. Cases had confirmed malaria infection by rapid diagnostic test or microscopy detected at a health facility (HF). Gender-matched controls were recruited from passive case detection among individuals with suspected malaria who tested negative at a health facility (HF controls), and community-matched controls were recruited among those testing negative during active case detection. Multivariable logistic regression (unconditional for HF controls and conditional for community controls) was used to identify risk factors for symptomatic malaria infection. RESULTS: There were 45 cases, of which 27 were P. knowlesi, 17 were Plasmodium vivax, and one was not determined. For controls, 509 and 599 participants were recruited from health facilities and the community, respectively. Forest exposures were associated with high odds of malaria; in particular, working and sleeping in the forest (HF controls: adjusted odds ratio (aOR) 21.66, 95% CI 5.09-92.26; community controls: aOR 16.78, 95% CI 2.19-128.7) and having a second residence in the forest (aOR 6.29, 95% CI 2.29-17.31 and 13.53, 95% CI 2.10-87.12). Male forest-goers were a diverse population employed in a variety of occupations including logging, farming, and mining, sleeping in settings, such as huts, tents, and barracks, and working in a wide range of group sizes. Reported use of protective measures, such as nets, hammock nets, mosquito coils, and repellents was low among forest-goers and interventions at forest residences were absent. CONCLUSIONS: Second residences in the forest and gaps in use of protective measures point to key malaria interventions to improve coverage in forest-going populations at risk for P. knowlesi and P. vivax in Aceh, Indonesia. Intensified strategies tailored to specific sub-populations will be essential to achieve elimination.

Geographical variations and district-level factors associated with COVID-19 mortality in Indonesia: a nationwide ecological study.

BACKGROUND: Ensuring health equity, especially for vulnerable populations in less developed settings with poor health system is essential for the current and future global health threats. This study examined geographical variations of COVID-19 mortality and its association with population health characteristics, health care capacity in responding pandemic, and socio-economic characteristics across 514 districts in Indonesia. METHODS: This nationwide ecological study included aggregated data of COVID-19 cases and deaths from all 514 districts in Indonesia, recorded in the National COVID-19 Task Force database, during the first two years of the epidemic, from 1 March 2020 to 27 February 2022. The dependent variable was district-level COVID-19 mortality rate per 100,000 populations. The independent variables include district-level COVID-19 incidence rate, population health, health care capacity, and socio-demographics data from government official sources. We used multivariable ordinal logistic regression to examine factors associated with higher mortality rate. RESULTS: Of total 5,539,333 reported COVID-19 cases, 148,034 (2.7%) died, and 5,391,299 (97.4%) were recovered. The district-level mortality rate ranged from 0 to 284 deaths per 100,000 populations. The top five districts with the highest mortality rate were Balikpapan (284 deaths per 100,000 populations), Semarang (263), Madiun (254), Magelang (250), and Yogyakarta (247). A higher COVID-19 incidence (coefficient 1.64, 95% CI 1.22 to 1.75), a higher proportion of ≥ 60 years old population (coefficient 0.26, 95% CI 0.06 to 0.46), a higher prevalence of diabetes mellitus (coefficient 0.60, 95% CI 0.37 to 0.84), a lower prevalence of obesity (coefficient -0.32, 95% CI -0.56 to -0.08), a lower number of nurses per population (coefficient -0.27, 95% CI -0.50 to -0.04), a higher number of midwives per population (coefficient 0.32, 95% CI 0.13 to 0.50), and a higher expenditure (coefficient 0.34, 95% CI 0.10 to 0.57) was associated with a higher COVID-19 mortality rate. CONCLUSION: COVID-19 mortality rate in Indonesia was highly heterogeneous and associated with higher COVID-19 incidence, different prevalence of pre-existing comorbidity, healthcare capacity in responding the pandemic, and socio-economic characteristics. This study revealed the need of controlling both COVID-19 and those known comorbidities, health capacity strengthening, and better resource allocation to ensure optimal health outcomes for vulnerable population.

The history and current epidemiology of malaria in Kalimantan, Indonesia.

Kalimantan is a part of Indonesia, which occupies the southern three-quarters of the island of Borneo, sharing a border with the Malaysian states of Sabah and Sarawak. Although most areas of Kalimantan have low and stable transmission of Plasmodium falciparum and Plasmodium vivax, there are relatively high case numbers in the province of East Kalimantan. Two aspects of malaria endemicity in Kalimantan differentiate it from the rest of Indonesia, namely recent deforestation and potential exposure to the zoonotic malaria caused by Plasmodium knowlesi that occurs in relatively large numbers in adjacent Malaysian Borneo. In the present review, the history of malaria and its current epidemiology in Kalimantan are examined, including control and eradication efforts over the past two centuries, mosquito vector prevalence, anti-malarial use and parasite resistance, and the available data from case reports of knowlesi malaria and the presence of conditions which would support transmission of this zoonotic infection.

Using syndromic measures of mortality to capture the dynamics of COVID-19 in Java, Indonesia, in the context of vaccination rollout.

BACKGROUND: As in many countries, quantifying COVID-19 spread in Indonesia remains challenging due to testing limitations. In Java, non-pharmaceutical interventions (NPIs) were implemented throughout 2020. However, as a vaccination campaign launches, cases and deaths are rising across the island. METHODS: We used modelling to explore the extent to which data on burials in Jakarta using strict COVID-19 protocols (C19P) provide additional insight into the transmissibility of the disease, epidemic trajectory, and the impact of NPIs. We assess how implementation of NPIs in early 2021 will shape the epidemic during the period of likely vaccine rollout. RESULTS: C19P burial data in Jakarta suggest a death toll approximately 3.3 times higher than reported. Transmission estimates using these data suggest earlier, larger, and more sustained impact of NPIs. Measures to reduce sub-national spread, particularly during Ramadan, substantially mitigated spread to more vulnerable rural areas. Given current trajectory, daily cases and deaths are likely to increase in most regions as the vaccine is rolled out. Transmission may peak in early 2021 in Jakarta if current levels of control are maintained. However, relaxation of control measures is likely to lead to a subsequent resurgence in the absence of an effective vaccination campaign. CONCLUSIONS: Syndromic measures of mortality provide a more complete picture of COVID-19 severity upon which to base decision-making. The high potential impact of the vaccine in Java is attributable to reductions in transmission to date and dependent on these being maintained. Increases in control in the relatively short-term will likely yield large, synergistic increases in vaccine impact.

Sub-national disparities in accessing anti-malarial drug treatment in eastern Indonesia.

BACKGROUND: Poor access to health care providers was among the contributing factors to less prompt and ineffective malaria treatment. This limitation could cause severe diseases in remote areas. This study examined the sub-national disparities and predictors in accessing anti-malarial drug treatment among adults in Eastern Indonesia. METHODS: The study analyzed a subset of the 2018 National Basic Health Survey conducted in all 34 provinces in Indonesia. We extracted socio-demographic data of 4655 adult respondents diagnosed with malaria in the past 12 months in five provinces in Eastern Indonesia. The association between socio-demographic factors and the access to anti-malarial drug treatment was assessed using logistic regression. RESULTS: Over 20% of respondents diagnosed with malaria within last 12 months admitted that they did not receive anti-malarial drug treatment (range 12-29.9%). The proportion of untreated cases was 12.0% in East Nusa Tenggara, 29.9% in Maluku, 23.1% in North Maluku, 12.7% in West Papua, and 15.6% in Papua. The likelihood of receiving anti-malarial drug treatment was statistically lower in Maluku (adjusted OR = 0.258; 95% CI 0.161-0.143) and North Maluku (adjusted OR = 0.473; 95% CI 0.266-0.840) than those in Eastern Nusa Tenggara (reference). Urban respondents were less likely to receive malaria treatment than rural (adjusted OR = 0.545; 95% CI 0.431-0.689). CONCLUSIONS: This study found that there were sub-national disparities in accessing anti-malarial drug treatment in Eastern Indonesia, with a high proportion of untreated malaria cases across the areas. Findings from this study could be used as baseline information to improve access to anti-malarial drug treatment and better target malaria intervention in Eastern Indonesia.

Defining malaria risks among forest workers in Aceh, Indonesia: a formative assessment.

BACKGROUND: Following a dramatic decline of malaria cases in Aceh province, geographically-based reactive case detection (RACD) was recently evaluated as a tool to improve surveillance with the goal of malaria elimination. While RACD detected few cases in households surrounding index cases, engaging in forest work was identified as a risk factor for malaria and infections from Plasmodium knowlesi-a non-human primate malaria parasite-were more common than expected. This qualitative formative assessment was conducted to improve understanding of malaria risk from forest work and identify strategies for targeted surveillance among forest workers, including adapting reactive case detection. METHODS: Between June and August, 2016, five focus groups and 18 in-depth interviews with forest workers and key informants were conducted in each of four subdistricts in Aceh Besar and Aceh Jaya districts. Themes included: types of forest activities, mobility of workers, interactions with non-human primates, malaria prevention and treatment-seeking behaviours, and willingness to participate in malaria surveys at forest work sites and using peer-referral. RESULTS: Reported forest activities included mining, logging, and agriculture in the deep forest and along the forest fringe. Forest workers, particularly miners and loggers, described often spending weeks to months at work sites in makeshift housing, rarely utilizing mosquito prevention and, upon fever, self-medicating and seeking care from traditional healers or pharmacies rather than health facilities. Non-human primates are frequently observed near work sites, and most forest work locations are within a day's journey of health clinics. Employers and workers expressed interest in undertaking malaria testing and in participating in survey recruitment by peer-referral and at work sites. CONCLUSIONS: Diverse groups of forest workers in Aceh are potentially exposed to malaria through forest work. Passive surveillance and household-based screening may under-estimate malaria burden due to extended stays in the forest and health-seeking behaviours. Adapting active surveillance to specifically target forest workers through work-site screening and/or peer-referral appears promising for addressing currently undetected infections.

On the road to universal health care in Indonesia, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.

BACKGROUND: As Indonesia moves to provide health coverage for all citizens, understanding patterns of morbidity and mortality is important to allocate resources and address inequality. The Global Burden of Disease 2016 study (GBD 2016) estimates sources of early death and disability, which can inform policies to improve health care. METHODS: We used GBD 2016 results for cause-specific deaths, years of life lost, years lived with disability, disability-adjusted life-years (DALYs), life expectancy at birth, healthy life expectancy, and risk factors for 333 causes in Indonesia and in seven comparator countries. Estimates were produced by location, year, age, and sex using methods outlined in GBD 2016. Using the Socio-demographic Index, we generated expected values for each metric and compared these against observed results. FINDINGS: In Indonesia between 1990 and 2016, life expectancy increased by 8·0 years (95% uncertainty interval [UI] 7·3-8·8) to 71·7 years (71·0-72·3): the increase was 7·4 years (6·4-8·6) for males and 8·7 years (7·8-9·5) for females. Total DALYs due to communicable, maternal, neonatal, and nutritional causes decreased by 58·6% (95% UI 55·6-61·6), from 43·8 million (95% UI 41·4-46·5) to 18·1 million (16·8-19·6), whereas total DALYs from non-communicable diseases rose. DALYs due to injuries decreased, both in crude rates and in age-standardised rates. The three leading causes of DALYs in 2016 were ischaemic heart disease, cerebrovascular disease, and diabetes. Dietary risks were a leading contributor to the DALY burden, accounting for 13·6% (11·8-15·4) of DALYs in 2016. INTERPRETATION: Over the past 27 years, health across many indicators has improved in Indonesia. Improvements are partly offset by rising deaths and a growing burden of non-communicable diseases. To maintain and increase health gains, further work is needed to identify successful interventions and improve health equity. FUNDING: The Bill & Melinda Gates Foundation.

Estimating the burden of dengue and the impact of release of wMel Wolbachia-infected mosquitoes in Indonesia: a modelling study.

BACKGROUND: Wolbachia-infected mosquitoes reduce dengue virus transmission, and city-wide releases in Yogyakarta city, Indonesia, are showing promising entomological results. Accurate estimates of the burden of dengue, its spatial distribution and the potential impact of Wolbachia are critical in guiding funder and government decisions on its future wider use. METHODS: Here, we combine multiple modelling methods for burden estimation to predict national case burden disaggregated by severity and map the distribution of burden across the country using three separate data sources. An ensemble of transmission models then predicts the estimated reduction in dengue transmission following a nationwide roll-out of wMel Wolbachia. RESULTS: We estimate that 7.8 million (95% uncertainty interval [UI] 1.8-17.7 million) symptomatic dengue cases occurred in Indonesia in 2015 and were associated with 332,865 (UI 94,175-754,203) lost disability-adjusted life years (DALYs). The majority of dengue's burden was due to non-severe cases that did not seek treatment or were challenging to diagnose in outpatient settings leading to substantial underreporting. Estimated burden was highly concentrated in a small number of large cities with 90% of dengue cases occurring in 15.3% of land area. Implementing a nationwide Wolbachia population replacement programme was estimated to avert 86.2% (UI 36.2-99.9%) of cases over a long-term average. CONCLUSIONS: These results suggest interventions targeted to the highest burden cities can have a disproportionate impact on dengue burden. Area-wide interventions, such as Wolbachia, that are deployed based on the area covered could protect people more efficiently than individual-based interventions, such as vaccines, in such dense environments.

Negligible Impact of Mass Screening and Treatment on Mesoendemic Malaria Transmission at West Timor in Eastern Indonesia: A Cluster-Randomized Trial.

Background: Mass screening and treatment (MST) aims to reduce malaria risk in communities by identifying and treating infected persons without regard to illness. Methods: A cluster-randomized trial evaluated malaria incidence with and without MST. Clusters were randomized to 3, 2, or no MST interventions: MST3, 6 clusters (156 households/670 individuals); MST2, 5 clusters (89 households/423 individuals); and MST0, 5 clusters (174 households/777 individuals). All clusters completed the study with 14 residents withdrawing. In a cohort of 324 schoolchildren (MST3, n = 124; MST2, n = 57; MST0, n = 143) negative by microscopy at enrollment, we evaluated the incidence density of malaria during 3 months of MST and 3 months following. The MST intervention involved community-wide expert malaria microscopic screening and standard therapy with dihydroartemisinin-piperaquine and primaquine for glucose-6 phosphate dehydrogenase-normal subjects. All blood examinations included polymerase chain reaction assays, which did not guide on-site treatment. Results: The risk ratios for incidence density of microscopically patent malaria in MST3 or MST2 relative to that in MST0 clusters were 1.00 (95% confidence interval [CI], .53-1.91) and 1.22 (95% CI, .42-3.55), respectively. Similar results were obtained with molecular analysis and species-specific (P. falciparum and P. vivax) infections. Microscopically subpatent, untreated infections accounted for 72% of those infected. Conclusions: Two or 3 rounds of MST within 3 months did not impact the force of anopheline mosquito-borne infection in these communities. The high rate of untreated microscopically subpatent infections likely explains the observed poor impact. Clinical Trials Registration: NCT01878357.

Randomized trial of primaquine hypnozoitocidal efficacy when administered with artemisinin-combined blood schizontocides for radical cure of Plasmodium vivax in Indonesia.

BACKGROUND: Safety and efficacy of primaquine against repeated attacks of Plasmodium vivax depends upon co-administered blood schizontocidal therapy in radical cure. We assessed primaquine (PQ) as hypnozoitocide when administered with dihydroartemisinin-piperaquine (Eurartesim®, DHA-PP) or artesunate-pyronaridine (Pyramax®, AS-PYR) to affirm its good tolerability and efficacy. A third arm, artesunate followed by primaquine, was not intended as therapy for practice, but addressed a hypothesis concerning primaquine efficacy without co-administration of blood schizontocide. METHODS: During March to July 2013, an open-label, randomized trial enrolled Indonesian soldiers with vivax malaria at Sragen, Central Java, after six months duty in malarious Papua, Indonesia. No malaria transmission occurred at the study site and P. vivax recurrences in the 12 months following therapy were classified as relapses. A historic relapse control derived from a cohort of soldiers who served in the same area of Papua was applied to estimate risk of relapse among randomized treatment groups. Those were: 1) AS followed 2d later by PQ (0.5 mg/kg daily for 14d); 2) co-formulated AS-PYR concurrent with the same regimen of PQ; or 3) co-formulated DHA-PP concurrent with the same regimen of PQ. RESULTS: Among 532 soldiers, 219 had vivax malaria during the four months following repatriation to Java; 180 of these were otherwise healthy and G6PD-normal and enrolled in the trial. Subjects in all treatment groups tolerated the therapies well without untoward events and cleared parasitemia within three days. First relapse appeared at day 39 post-enrollment, and the last at day 270. Therapeutic efficacy of PQ against relapse by incidence density analysis was 92 % (95 %CI = 83-97 %), 94 %(95 %CI = 86-97 %), and 95 %(95 %CI = 88-98 %) when combined with AS, AS-PYR, or DHA-PP, respectively. CONCLUSIONS: This trial offers evidence of good tolerability and efficacy of PQ against P. vivax relapse when administered concurrently with DHA-PP or AS-PYR. These offer alternative partner drugs for radical cure with primaquine. The AS arm demonstrated efficacy with a total dose of 7 mg/kg PQ without concurrently administered blood schizontocide, another option when primaquine therapy is removed in time from the treatment of the acute malaria or applied presumptively without an attack. TRIAL REGISTRATION: Current Controlled Trials ISRCTN82366390, assigned 20 March 2013.

Defining the relationship between Plasmodium vivax parasite rate and clinical disease.

BACKGROUND: Though essential to the development and evaluation of national malaria control programmes, precise enumeration of the clinical illness burden of malaria in endemic countries remains challenging where local surveillance systems are incomplete. Strategies to infer annual incidence rates from parasite prevalence survey compilations have proven effective in the specific case of Plasmodium falciparum, but have yet to be developed for Plasmodium vivax. Moreover, defining the relationship between P. vivax prevalence and clinical incidence may also allow levels of endemicity to be inferred for areas where the information balance is reversed, that is, incident case numbers are more widely gathered than parasite surveys; both applications ultimately facilitating cartographic estimates of P. vivax transmission intensity and its ensuring disease burden. METHODS: A search for active case detection surveys was conducted and the recorded incidence values were matched to local, contemporary parasite rate measures and classified to geographic zones of differing relapse phenotypes. A hierarchical Bayesian model was fitted to these data to quantify the relationship between prevalence and incidence while accounting for variation among relapse zones. RESULTS: The model, fitted with 176 concurrently measured P. vivax incidence and prevalence records, was a linear regression of the logarithm of incidence against the logarithm of age-standardized prevalence. Specific relationships for the six relapse zones where data were available were drawn, as well as a pooled overall relationship. The slope of the curves varied among relapse zones; zones with short predicted time to relapse had steeper slopes than those observed to contain long-latency relapse phenotypes. CONCLUSIONS: The fitted relationships, along with appropriate uncertainty metrics, allow for estimates of clinical incidence of known confidence to be made from wherever P. vivax prevalence data are available. This is a prerequisite for cartographic-based inferences about the global burden of morbidity due to P. vivax, which will be used to inform control efforts.

A comprehensive assessment of the malaria microscopy system of Aceh, Indonesia, in preparation for malaria elimination.

BACKGROUND: The Health Office of Aceh aims to eliminate malaria from Aceh Province, Indonesia by 2015. Malaria was formerly common in Aceh (population 4.5 million), but has declined dramatically in recent years consequent to post-tsunami control efforts. Successful elimination will depend upon rapid and accurate diagnosis and case follow-up at community level. A prerequisite to this is widespread coverage of high quality malaria diagnosis. This study describes the results of a comprehensive assessment of the malaria diagnostic capacity in Aceh as the province moves towards malaria elimination. METHODS: The study was conducted in 23 districts in Aceh from October 2010 to July 2011. Six types of questionnaires were used to collect data on competency of microscopists and laboratory capacity. Standardized slides were used to evaluate the proficiency of all microscopists. In addition, site visits to 17 primary health centres (PHC) assessed diagnostic practice and logistics capacity. RESULTS: Five hundred and seventy four malaria microscopists have been officially registered and assigned to duty in the 23 districts in Aceh Province. They work in 345 laboratories, predominantly in PHCs (69 %) and hospitals (25 %). Three laboratories were evaluated as adequate for all 30 elements, while 29 laboratories were adequate for less than five of 30 elements. Standardized proficiency tests showed that 413 microscopists were at basic (in training) level, with 10 advanced and 9 reference level. No microscopist achieved expert level. Neither the province nor any of Aceh's districts has a standardized inventory and logistics database for malaria diagnostics, nor did any of the surveyed laboratories operate a quality assurance programme for either microscopy or rapid diagnostic tests. CONCLUSIONS: The study highlights the importance of careful assessment of diagnostic capacity when embarking upon a large-scale malaria elimination programme. Aceh's laboratories have minimal infrastructure with nearly all microscopists still in training. On the positive side, a large workforce of microscopists has been assigned to laboratories with the needed equipment. Aceh will need to embark on a large-scale comprehensive quality assurance scheme if it is to achieve malaria elimination.

Implementation of a Randomized, Placebo-Controlled Trial of Live Attenuated Malaria Sporozoite Vaccines in an Indonesian Military Study Population.

Malaria eradication efforts prioritize safe and efficient vaccination strategies, although none with high-level efficacy against malaria infection are yet available. Among several vaccine candidates, Sanaria® PfSPZ Vaccine and Sanaria PfSPZ-CVac are, respectively, live radiation- and chemo-attenuated sporozoite vaccines designed to prevent infection with Plasmodium falciparum, the leading cause of malaria-related morbidity and mortality. We are conducting a randomized normal saline placebo-controlled trial called IDSPZV1 that will analyze the safety, tolerability, immunogenicity, and efficacy of PfSPZ Vaccine and PfSPZ-CVac administered pre-deployment to malaria-naive Indonesian soldiers assigned to temporary duties in a high malaria transmission area. We describe the manifold challenges of enrolling and immunizing 345 soldier participants at their home base in western Indonesia before their nearly 6,000-km voyage to eastern Indonesia, where they are being monitored for incident P. falciparum and Plasmodium vivax malaria cases during 9 months of exposure. The unique regulatory, ethical, and operational complexities of this trial demonstrate the importance of thorough planning, frequent communication, and close follow-up with stakeholders. Effective engagement with the military community and the ability to adapt to unanticipated events have proven key to the success of this trial.

Randomized, open-label trial of primaquine against vivax malaria relapse in Indonesia.

Radical cure of Plasmodium vivax infection applies blood schizontocidal therapy against the acute attack and hypnozoitocidal therapy against later relapse. Chloroquine and primaquine have been used for 60 years in this manner. Resistance to chloroquine by the parasite now requires partnering other blood schizontocides with primaquine. However, the safety and efficacy of primaquine against relapse when combined with other drugs have not been demonstrated. This randomized, open-label, and relapse-controlled trial estimated the efficacy of primaquine against relapse when administered with quinine or dihydroartemisinin-piperaquine for treatment of the acute infection. Among 650 soldiers who had returned to their malaria-free base in Java, Indonesia, after 12 months in malarious Papua, Indonesia, 143 with acute P. vivax malaria were eligible for study. One hundred sixteen enrolled subjects were randomized to these treatments: artesunate (200-mg dose followed by 100 mg/day for 6 days), quinine (1.8 g/day for 7 days) plus concurrent primaquine (30 mg/day for 14 days), or dihydroartemisinin (120 mg) plus piperaquine (960 mg) daily for 3 days followed 25 days later by primaquine (30 mg/day for 14 days). Follow-up was for 12 months. One hundred thirteen subjects were analyzable. Relapse occurred in 32 of 41 (78%) subjects administered artesunate alone (2.71 attacks/person-year), 7 of 36 (19%) administered quinine plus primaquine (0.23 attack/person-year), and 2 of 36 (6%) administered dihydroartemisinin-piperaquine plus primaquine (0.06 attack/person-year). The efficacy of primaquine against relapse was 92% (95% confidence interval [CI] = 81% to 96%) for quinine plus primaquine and 98% (95% CI = 91% to 99%) for dihydroartemisinin-piperaquine plus primaquine. Antirelapse therapy with primaquine begun a month after treatment of the acute attack with dihydroartemisinin-piperaquine proved safe and highly efficacious against relapse by P. vivax acquired in Papua, Indonesia.

Impact of the COVID-19 pandemic on tuberculosis control in Indonesia: a nationwide longitudinal analysis of programme data.

BACKGROUND: The impact of the COVID-19 pandemic on tuberculosis control in high-burden countries has not been adequately assessed. We aimed to estimate the impact of the COVID-19 pandemic on the national tuberculosis programme in Indonesia, in association with indicators of human development and health-system capacity across all 514 districts in 34 provinces. METHODS: We did a nationwide longitudinal analysis to compare tuberculosis case notification, treatment coverage, and mortality rates in Indonesia before (2016-19) and during (2020-21) the COVID-19 pandemic. The following outcomes were assessed: the district-level quarterly reported tuberculosis case notification rate (number of all reported tuberculosis cases per 100 000 population), treatment coverage (proportion of tuberculosis patients who started treatment), and all-cause mortality rate in patients with tuberculosis (number of reported deaths per 100 000 population). District-level data on COVID-19 incidence and deaths, health-system capacity, and human development and sociodemographics were also analysed. Multilevel linear spline regression was done to assess quarterly time trends for the three outcomes. FINDINGS: During the COVID-19 pandemic, the tuberculosis case notification rate declined by 26% (case notification rate ratio 0·74, 95% CI 0·72-0·77) and treatment coverage declined by 11% (treatment coverage ratio 0·89, 95% CI 0·88-0·90), but there was no significant increase in all-cause mortality (all-cause mortality rate ratio 0·97, 95% CI 0·91-1·04) compared with the pre-pandemic period. In the second year of the pandemic, we observed a partial recovery of the case notification rate from Q1 to Q4 of 2021, a persistent decrease in treatment coverage, and a decrease in the all-cause mortality rate from Q2 of 2020 to Q4 of 2021. The multivariable analysis showed that the reduction in the tuberculosis case notification rate was associated with a higher COVID-19 incidence rate (adjusted odds ratio 3·1, 95% CI 1·1-8·6, for the highest compared with the lowest group) and fewer GeneXpert machines for tuberculosis diagnosis (3·1, 1·0-9·4, for the lowest compared with the highest group) per 100 000 population. The reduction in tuberculosis treatment coverage was associated with higher COVID-19 incidence (adjusted odds ratio 11·7, 95% CI 1·5-93·4, for the highest compared with the lowest group), fewer primary health centres (10·6, 4·1-28·0, for the lowest compared with the middle-high group), and a very low number of doctors (0·3, 0·1-0·9, for the low-middle compared with the lowest group) per 100 000 population. No factors were shown to be significantly associated with all-cause mortality. INTERPRETATION: The COVID-19 pandemic adversely and unevenly affected the national tuberculosis programme across Indonesia, with the greatest impacts observed in districts with the lowest health-system capacity. These disruptions could lead to an escalation in tuberculosis transmission in the coming years, warranting the need for intensified efforts to control tuberculosis and strengthen local health systems. FUNDING: Wellcome Africa Asia Programme Vietnam. TRANSLATION: For the Bahasa translation of the abstract see Supplementary Materials section.

Clinical characteristics and factors associated with COVID-19-related mortality and hospital admission during the first two epidemic waves in 5 rural provinces in Indonesia: A retrospective cohort study.

BACKGROUND: Data on coronavirus disease 2019 (COVID-19) clinical characteristics and severity from resource-limited settings are limited. This study examined clinical characteristics and factors associated with COVID-19 mortality and hospitalisation in rural settings of Indonesia, from 1 January to 31 July, 2021. METHODS: This retrospective cohort included individuals diagnosed with COVID-19 based on polymerase chain reaction or rapid antigen diagnostic test, from five rural provinces in Indonesia. We extracted demographic and clinical data, including hospitalisation and mortality from a new piloted COVID-19 information system named Sistem Informasi Surveilans Epidemiologi (SISUGI). We used mixed-effect logistic regression to examine factors associated with COVID-19-related mortality and hospitalisation. RESULTS: Of 6,583 confirmed cases, 205 (3.1%) died and 1,727 (26.2%) were hospitalised. The median age was 37 years (Interquartile range 26-51), with 825 (12.6%) under 20 years, and 3,371 (51.2%) females. Most cases were symptomatic (4,533; 68.9%); 319 (4.9%) had a clinical diagnosis of pneumonia and 945 (14.3%) presented with at least one pre-existing comorbidity. Age-specific mortality rates were 0.9% (2/215) for 0-4 years; 0% (0/112) for 5-9 years; 0% (1/498) for 10-19 years; 0.8% (11/1,385) for 20-29 years; 0.9% (12/1,382) for 30-39 years; 2.1% (23/1,095) for 40-49 years; 5.4% (57/1,064) for 50-59 years; 10.8% (62/576) for 60-69 years; 15.9% (37/232) for ≥70 years. Older age, pre-existing diabetes, chronic kidney disease, liver diseases, malignancy, and pneumonia were associated with higher risk of mortality and hospitalisation. Pre-existing hypertension, cardiac diseases, COPD, and immunocompromised condition were associated with risk of hospitalisation but not with mortality. There was no association between province-level density of healthcare workers with mortality and hospitalisation. CONCLUSION: The risk of COVID-19-related mortality and hospitalisation was associated with higher age, pre-existing chronic comorbidities, and clinical pneumonia. The findings highlight the need for prioritising enhanced context-specific public health action to reduce mortality and hospitalisation risk among older and comorbid rural populations.

Tafenoquine co-administered with dihydroartemisinin-piperaquine for the radical cure of Plasmodium vivax malaria (INSPECTOR): a randomised, placebo-controlled, efficacy and safety study.

BACKGROUND: Tafenoquine, co-administered with chloroquine, is approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria. In areas of chloroquine resistance, artemisinin-based combination therapies are used to treat malaria. This study aimed to evaluate tafenoquine plus the artemisinin-based combination therapy dihydroartemisinin-piperaquine for the radical cure of P vivax malaria. METHODS: In this double-blind, double-dummy, parallel group study, glucose-6-phosphate dehydrogenase-normal Indonesian soldiers with microscopically confirmed P vivax malaria were randomly assigned by means of a computer-generated randomisation schedule (1:1:1) to dihydroartemisinin-piperaquine alone, dihydroartemisinin-piperaquine plus a masked single 300-mg dose of tafenoquine, or dihydroartemisinin-piperaquine plus 14 days of primaquine (15 mg). The primary endpoint was 6-month relapse-free efficacy following tafenoquine plus dihydroartemisinin-piperaquine versus dihydroartemisinin-piperaquine alone in all randomly assigned patients who received at least one dose of masked treatment and had microscopically confirmed P vivax at baseline (microbiological intention-to-treat population). Safety was a secondary outcome and the safety population comprised all patients who received at least one dose of masked medication. This study is registered with ClinicalTrials.gov, NCT02802501 and is completed. FINDINGS: Between April 8, 2018, and Feb 4, 2019, of 164 patients screened for eligibility, 150 were randomly assigned (50 per treatment group). 6-month Kaplan-Meier relapse-free efficacy (microbiological intention to treat) was 11% (95% CI 4-22) in patients treated with dihydroartemisinin-piperaquine alone versus 21% (11-34) in patients treated with tafenoquine plus dihydroartemisinin-piperaquine (hazard ratio 0·44; 95% CI [0·29-0·69]) and 52% (37-65) in the primaquine plus dihydroartemisinin-piperaquine group. Adverse events over the first 28 days were reported in 27 (54%) of 50 patients treated with dihydroartemisinin-piperaquine alone, 29 (58%) of 50 patients treated with tafenoquine plus dihydroartemisinin-piperaquine, and 22 (44%) of 50 patients treated with primaquine plus dihydroartemisinin-piperaquine. Serious adverse events were reported in one (2%) of 50, two (4%) of 50, and two (4%) of 50 of patients, respectively. INTERPRETATION: Although tafenoquine plus dihydroartemisinin-piperaquine was statistically superior to dihydroartemisinin-piperaquine alone for the radical cure of P vivax malaria, the benefit was not clinically meaningful. This contrasts with previous studies in which tafenoquine plus chloroquine was clinically superior to chloroquine alone for radical cure of P vivax malaria. FUNDING: ExxonMobil, Bill & Melinda Gates Foundation, Newcrest Mining, UK Government all through Medicines for Malaria Venture; and GSK. TRANSLATION: For the Indonesian translation of the abstract see Supplementary Materials section.

The effects of urbanization on global Plasmodium vivax malaria transmission.

BACKGROUND: Many recent studies have examined the impact of urbanization on Plasmodium falciparum malaria endemicity and found a general trend of reduced transmission in urban areas. However, none has examined the effect of urbanization on Plasmodium vivax malaria, which is the most widely distributed malaria species and can also cause severe clinical syndromes in humans. In this study, a set of 10,003 community-based P. vivax parasite rate (PvPR) surveys are used to explore the relationships between PvPR in urban and rural settings. METHODS: The PvPR surveys were overlaid onto a map of global urban extents to derive an urban/rural assignment. The differences in PvPR values between urban and rural areas were then examined. Groups of PvPR surveys inside individual city extents (urban) and surrounding areas (rural) were identified to examine the local variations in PvPR values. Finally, the relationships of PvPR between urban and rural areas within the ranges of 41 dominant Anopheles vectors were examined. RESULTS: Significantly higher PvPR values in rural areas were found globally. The relationship was consistent at continental scales when focusing on Africa and Asia only, but in the Americas, significantly lower values of PvPR in rural areas were found, though the numbers of surveys were small. Moreover, except for the countries in the Americas, the same trends were found at national scales in African and Asian countries, with significantly lower values of PvPR in urban areas. However, the patterns at city scales among 20 specific cities where sufficient data were available were less clear, with seven cities having significantly lower PvPR values in urban areas and two cities showing significantly lower PvPR in rural areas. The urban-rural PvPR differences within the ranges of the dominant Anopheles vectors were generally, in agreement with the regional patterns found. CONCLUSIONS: Except for the Americas, the patterns of significantly lower P. vivax transmission in urban areas have been found globally, regionally, nationally and by dominant vector species here, following trends observed previously for P. falciparum. To further understand these patterns, more epidemiological, entomological and parasitological analyses of the disease at smaller spatial scales are needed.

Identifying forms of interventions towards cross border malaria in the Asia-Pacific region: a scoping review protocol.

INTRODUCTION: An ambitious epidemiology strategy has been set by the WHO, targeting malaria elimination for at least 35 countries in 2030. Challenges in preventing malaria cross borders require greater attention to achieve the elimination target. This scoping review aims to identify successful forms of interventions to control malaria transmission across national borders in the Asia-Pacific region. METHODS AND ANALYSIS: This scoping review will search four electronic databases (PubMed, ScienceDirect, EBSCOhost and ProQuest) limiting the time of publication to the last 10 years. Two independent reviewers will screen all titles and abstracts during the second stage. Study characteristics will be recorded; qualitative data will be extracted and evaluated, while quantitative data will be extracted and summarised. Overall, we will follow the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. ETHICS AND DISSEMINATION: This scoping review has received ethical approval from the Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada. The results will be disseminated through peer-reviewed publications, conference presentations and policy briefs.

Evaluating Saliva Sampling with Reverse Transcription Loop-mediated Isothermal Amplification to Improve Access to SARS-CoV-2 Diagnosis in Low-Resource Settings.

Standard diagnosis of SARS-CoV-2 by nasopharyngeal swab (NPS) and real-time reverse transcriptase-polymerase chain reaction (PCR) requires a sophisticated laboratory, skilled staff, and expensive reagents that are difficult to establish and maintain in isolated, low-resource settings. In the remote setting of tropical Sumba Island, eastern Indonesia, we evaluated alternative sampling with fresh saliva (FS) and testing with colorimetric loop-medicated isothermal amplification (LAMP). Between August 2020 and May 2021, we enrolled 159 patients with suspected SARS-CoV-2 infection, of whom 75 (47%) had a positive PCR on NPS (median cycle threshold [Ct] value: 27.6, interquartile range: 12.5-37.6). PCR on FS had a sensitivity of 72.5% (50/69, 95% confidence interval [CI]: 60.4-82.5) and a specificity of 85.7% (66/77, 95% CI: 75.9-92.6), and positive (PPV) and negative (NPV) predictive values of 82.0% (95% CI: 0.0-90.6) and 77.6% (95% CI: 67.3-86.0), respectively. LAMP on NPS had a sensitivity of 68.0% (51/75, 95% CI: 56.2-78.3) and a specificity of 70.8% (63/84, 95% CI: 58.9-81.0), with PPV 70.8% (95% CI: 58.9-81.0) and NPV 72.4% (95% CI: 61.8-81.5%). LAMP on FS had a sensitivity of 62.3% (43/69, 95% CI: 49.8-73.7%) and a specificity of 72.7% (56/77, 95% CI: 61.4-82.3%), with PPV 67.2% (95% CI: 54.3-78.4) and NPV 68.3% (95% CI: 57.1-78.1%). LAMP sensitivity was higher for NPS and FS specimens with high viral loads (87.1% and 75.0% for Ct value < 26, respectively). Dried saliva on filter paper was stable for 4 days at room temperature. LAMP on either NPS or FS could offer an accessible alternative for SARS-CoV-2 diagnosis in low-resource settings, with potential for optimizing sample collection and processing, and selection of gene targets.