Evaluation of chloroquine therapy for vivax and falciparum malaria in southern Sumatra, western Indonesia

BACKGROUND: Chloroquine was used as first-line treatment for Plasmodium falciparum or Plasmodium vivax in Indonesia before the initial launch of artemisinin combination therapy in 2004. A study to evaluate efficacies of chloroquine against P. falciparum and P. vivax was undertaken at Lampung in southern Sumatra, western Indonesia in 2002. METHODS: Patients infected by P. falciparum or P. vivax were treated with 25 mg/kg chloroquine base in three daily doses over 48 hr. Finger prick blood was collected on Days 0, 2, 3, 7, 14, 21 and 28 after starting drug administration. Whole blood chloroquine and its desethyl metabolite were measured on Days-0, -3 and -28, or on the day of recurrent parasitaemia. RESULTS: 42 patients infected by P. falciparum were enrolled, and 38 fullfilled criteria for per protocol analysis. Only six of 38 (16%) showed a response consistent with senstivity to chloroquine. 25 of 32 failures were confirmed resistant by demonstrating chloroquine levels on day of recurrence exceeding the minimally effective concentration (200 ng/mL whole blood). The 28-day cumulative incidence of resistance in P. falciparum was 68% (95% CI: 0.5260 - 0.8306). Thirty one patients infected by P. vivax were enrolled, and 23 were evaluable for per protocol analysis. 15 out of 23 (65%) subjects had persistent or recurrent parasitaemia. Measurement of chloroquine levels confirmed all treatment failures prior to Day-15 as resistant. Beyond Day-15, 4 of 7 recurrences also had drug levels above 100 ng/mL and were classified as resistant. The 28-day cumulative incidence of chloroquine resistance in P. vivax was 43% (95% CI: 0.2715 - 0.6384). CONCLUSION: These findings confirm persistantly high levels of resistance to chloroquine by P. falciparum in southern Sumatra, and suggest that high-grade and frequent resistance to chloroquine by P. vivax may be spreading westward in the Indonesia archipelago

Intestinal Amebiasis: Diagnosis and Management

Intestinal amebiasis is an infection due to Entamoeba Histolytica and has the highest prevalence in tropical countries, including Indonesia. Amebiasis is responsible for approximately 70,000 deaths annually every year. High prevalence is found especially in endemic area which had poor hygiene and sanitation or crowded population. Human is the main reservoir, while the disease can be transmited by mechanical vector such as cokckroach and flies. Making diagnosis of intestinal amebiasis sometimes can be a problem. Clinical presentation and disease severity may be varied. Complication due to late management of the disease can be fatal. Lifestyle education, early diagnosis and proper management of amebiasis are very important measures to promote by health workers

Recent Findings in Malaria Emergence of Piperaquine-Resistant Plasmodium falciparum Genes in Malaria Endemic Areas of Indonesia: a Literature Review

Background: In recent years, artemisinin and piperaquine (PPQ) resistance in the Greater Mekong Sub-region alarmed Southeast Asian countries, especially those relying on artemisinin- based combinations as antimalarial drugs. This study aims to review the current status of malaria research and examine the frequencies of piperaquine resistance in Plasmodium falciparum isolates originating from malaria-endemic areas in Indonesia.Methods: We undertook a review to identify empirical data on antimalarial piperaquine-inclusive artemisinin combination therapies (ACT) in Indonesia using studies conducted since 2015. Journal articles were searched using the keywords combination of malaria, piperaquine, Pfcrt, Pfmdr, Pfpm2, and Indonesia. The search was conducted in four databases. Trends in empirical data were summarised in a table and compared with emerging malaria prevalence and conditions in Indonesia.Results: Our study found that dihydroartemisinin-piperaquine (DHA-PPQ) is still effective in most area. Survey of PPQ resistance in regions using DHA-PPQ as the first-line treatment heavily depends on phenotypic tests of the given drug resistance. Molecular surveys exploring polymorphisms of Pfcrt, Pfmdr1, and Pfpm2 were not found.Conclusion: This study supports the use of dihydroartemisinin-piperaquine as the first-line antimalarial drug in malaria endemic areas of Indonesia. Further research examining efficacy is required to monitor piperaquine resistance in Indonesia

Polymorphism of Human FcγRIIa and Its Association with P. Falciparum Density and Efficacy of Dihydroartemisinin- Piperaquine

FcγRlla dimorphism has been related to the ability of the host to eliminate malaria parasite so it is necessary to investigate the allele polymorphism FcγRlla of population in malaria-endemic areas in Indonesia in order to know the role of immunity in eliminating malaria parasite. A total of 120 samples of Dried Blood Spot (DBS) falciparum malaria acquired from DHP drug efficacy studies in 5 regions in Indonesia were analyzed by Polymerase Chain Reaction (PCR) and sequencing, to look at variants of FcγRIIa-131 allele and its Association with Parasite DensityandEfficacy ofDihydroartemisinin- Piperaquine. The FcγRIIa gene analysis indicated that genotype RH has the highest frequency (50.8%) compared to RR (17.5%) and HH (31.7%). Allele R131 showed a protective effect against High Density Parasitemia (HDP) (>5000 parasites/μL; odds ratio [OR]= 0.133, 95% confidence interval [CI]= 0.053–0.334, P< 0.001) and associated with longer gametocytes carrier clearance time (> 72 hours; Relative Risk [RR]= 1,571, 95% confidence interval [CI]= 1,005–2,456, P= 0.090). &nbsp

Seasonal changes in the antibody responses against Plasmodium falciparum merozoite surface antigens in areas of differing malaria endemicity in Indonesia.

BACKGROUND: The transmission of malaria in Indonesia is highly heterogeneous spatially and seasonally. Anti-malaria antibody responses can help characterize this variation. In the present study antibody responses to Plasmodium falciparum MSP-1 and AMA-1 were measured to assess the transmission intensity in a hypo-endemic area of Purworejo and a meso-endemic area of Lampung during low and high transmission seasons. METHODS: Filter-paper blood spot samples collected from Purworejo and Lampung by cross-sectional survey during high and low transmission season were stored at -20°C. Indirect ELISA assays were carried out using PfMSP1-19 and PfAMA1 antigens. A positivity threshold was determined by samples from local unexposed individuals, and the differences in seroprevalence, antibody level and correlation between antibody level and age in each site were statistically analysed. RESULTS: Prevalence of antibodies to either PfMSP1-19 or PfAMA1 was higher in Lampung than in Purworejo in both the low (51.3 vs 25.0%) and high transmission season (53.9 vs 37.5%). The magnitude of antibody responses was associated with increasing age in both sites and was higher in Lampung. Age-adjusted seroconversion rates showed an approximately ten-fold difference between Lampung and Purowejo. Two different seroconversion rates were estimated for Lampung suggesting behaviour-related differences in exposure. In both settings antibody responses to PfMSP1-19 were significantly lower in the low season compared to the high season. CONCLUSION: Seasonal changes may be detectable by changes in antibody responses. This is particularly apparent in lower transmission settings and with less immunogenic antigens (in this case PfMSP1-19). Examination of antibody levels rather than seroprevalence is likely to be a more sensitive indicator of changes in transmission. These data suggest that sero-epidemiological analysis may have a role in assessing short-term changes in exposure especially in low or seasonal transmission settings

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/personyear). The efficacy of primaquine against relapse was 92% (95% confidence interval [CI]=81% to 96%) for quinine plus primaquine and 98% (95% Cl=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

Agreement between serological data on schoolchildren and the number of malaria cases in the remaining high-burden villages of Indonesia

Introduction: In areas where malaria transmission has been successfully reduced, surveillance based solely on clinical cases becomes increasingly challenging. Antibodies generated by the host in response to malaria infections may persist in the circulation for several months or longer. We assessed a serological surveillance tool to measure malaria transmission in eastern Indonesia where reported cases have been recently declining. Methods: In June 2021, we conducted a cross-sectional survey of elementary schoolchildren aged 5 to 14 years residing in six villages in an endemic area of West Timor, Indonesia. Annual Parasite Incidence (API, cases/1,000 residents/year) of these villages ranged from 0.0 to 4.1 in 2021. Finger-prick plasma samples were tested using a multiplexed Luminex MAGPIX® bead array system to measure IgG antibodies against a panel of 8 Plasmodium vivax antigens. Using a random forest classification algorithm, individuals with predicted exposure to P. vivax in the prior 9 months were identified. Results: 15 of 398 (4%) schoolchildren were seropositive for recent P. vivax exposure. Remarkably, 87% (13/15) of seropositive children were from one village, the one with the highest API (4.1). In contrast, one seropositive child was from a village with an API of 1.3, and another from a village with an API of 0.0. Conclusion: Our serological survey data confirms the reported malaria cases from PHC in the villages with likely ongoing transmission. Malaria programs may consider Lamea as the target for intervention

Does treatment of intestinal helminth infections influence malaria? Background and methodology of a longitudinal study of clinical, parasitological and immunological parameters in Nangapanda, Flores, Indonesia (ImmunoSPIN Study)

Contains fulltext : 88856.pdf (publisher's version ) (Open Access)BACKGROUND: Given that helminth infections are thought to have strong immunomodulatory activity, the question whether helminth infections might affect responses to malaria antigens needs to be addressed. Different cross-sectional studies using diverse methodologies have reported that helminth infections might either exacerbate or reduce the severity of malaria attacks. The same discrepancies have been reported for parasitemia. METHODS/DESIGN: To determine the effect of geohelminth infections and their treatment on malaria infection and disease outcome, as well as on immunological parameters, the area of Nangapanda on Flores Island, Indonesia, where malaria and helminth parasites are co-endemic was selected for a longitudinal study. Here a Double-blind randomized trial will be performed, incorporating repeated treatment with albendazole (400 mg) or placebo at three monthly intervals. Household characteristic data, anthropometry, the presence of intestinal helminth and Plasmodium spp infections, and the incidence of malaria episodes are recorded. In vitro cultures of whole blood, stimulated with a number of antigens, mitogens and toll like receptor ligands provide relevant immunological parameters at baseline and following 1 and 2 years of treatment rounds. The primary outcome of the study is the prevalence of Plasmodium falciparum and P. vivax infection. The secondary outcome will be incidence and severity of malaria episodes detected via both passive and active follow-up. The tertiary outcome is the inflammatory cytokine profile in response to parasite antigens. The project also facilitates the transfer of state of the art methodologies and technologies, molecular diagnosis of parasitic diseases, immunology and epidemiology from Europe to Indonesia. DISCUSSION: The study will provide data on the effect of helminth infections on malaria. It will also give information on anthelminthic treatment efficacy and effectiveness and could help develop evidence-based policymaking. TRIAL REGISTRATION: This study was approved by The Ethical Committee of Faculty of Medicine, University of Indonesia, ref:194/PT02.FK/Etik/2006 and has been filed by ethics committee of the Leiden University Medical Center. Clinical trial number:ISRCTN83830814. The study is reported in accordance with the CONSORT guidelines for cluster-randomized studies

Adapting international clinical trials during COVID-19 and beyond

Background: The COVID-19 pandemic and resulting restrictions, particularly travel restrictions, have had significant impact on the conduct of global clinical trials. Our clinical trials programme, which relied on in-person visits for training, monitoring and capacity building across nine low- and middle-income countries, had to adapt to those unprecedented operational challenges. We report the adaptation of our working model with a focus on the operational areas of training, monitoring and cross-site collaboration. The new working model: Adaptations include changing training strategies from in-person site visits with three or four team members to a multi-pronged virtual approach, with generic online training for good clinical practice, the development of a library of study-specific training videos, and interactive virtual training sessions, including practical laboratory-focused training sessions. We also report changes from in-person monitoring to remote monitoring as well as the development of a more localized network of clinical trial monitors to support hybrid models with in-person and remote monitoring depending on identified risks at each site. We established a virtual network across different trial and study sites with the objective to further build capacity for good clinical practice–compliant antimalarial trials and foster cross-country and cross-study site collaboration. Conclusion: The forced adaptation of these new strategies has come with advantages that we did not envisage initially. This includes improved, more frequent engagement through the established network with opportunities for increased south-to-south support and a substantially reduced carbon footprint and budget savings. Our new approach is challenging for study sites with limited prior experience but this can be overcome with hybrid models. Capacity building for laboratory-based work remains difficult using a virtual environment. The changes to our working model are likely to last, even after the end of the pandemic, providing a more sustainable and equitable approach to our research

Methaemoglobin as a surrogate marker of primaquine antihypnozoite activity in Plasmodium vivax malaria: A systematic review and individual patient data meta-analysis

Background: The 8-aminoquinolines, primaquine and tafenoquine, are the only available drugs for the radical cure of Plasmodium vivax hypnozoites. Previous evidence suggests that there is dose-dependent 8-aminoquinoline induced methaemoglobinaemia and that higher methaemoglobin concentrations are associated with a lower risk of P. vivax recurrence. We undertook a systematic review and individual patient data meta-analysis to examine the utility of methaemoglobin as a population-level surrogate endpoint for 8-aminoquinoline antihypnozoite activity to prevent P. vivax recurrence. Methods and findings: We conducted a systematic search of Medline, Embase, Web of Science, and the Cochrane Library, from 1 January 2000 to 29 September 2022, inclusive, of prospective clinical efficacy studies of acute, uncomplicated P. vivax malaria mono-infections treated with radical curative doses of primaquine. The day 7 methaemoglobin concentration was the primary surrogate outcome of interest. The primary clinical outcome was the time to first P. vivax recurrence between day 7 and day 120 after enrolment. We used multivariable Cox proportional-hazards regression with site random-effects to characterise the time to first recurrence as a function of the day 7 methaemoglobin percentage (log base 2 transformed), adjusted for the partner schizonticidal drug, the primaquine regimen duration as a proxy for the total primaquine dose (mg base/kg), the daily primaquine dose (mg/kg), and other factors. The systematic review protocol was registered with PROSPERO (CRD42023345956). We identified 219 P. vivax efficacy studies, of which 8 provided relevant individual-level data from patients treated with primaquine; all were randomised, parallel arm clinical trials assessed as having low or moderate risk of bias. In the primary analysis data set, there were 1,747 patients with normal glucose-6-phosphate dehydrogenase (G6PD) activity enrolled from 24 study sites across 8 different countries (Indonesia, Brazil, Vietnam, Thailand, Peru, Colombia, Ethiopia, and India). We observed an increasing dose-response relationship between the daily weight-adjusted primaquine dose and day 7 methaemoglobin level. For a given primaquine dose regimen, an observed doubling in day 7 methaemoglobin percentage was associated with an estimated 30% reduction in the risk of P. vivax recurrence (adjusted hazard ratio = 0.70; 95% confidence interval [CI] [0.57, 0.86]; p = 0.0005). These pooled estimates were largely consistent across the study sites. Using day 7 methaemoglobin as a surrogate endpoint for recurrence would reduce required sample sizes by approximately 40%. Study limitations include the inability to distinguish between recrudescence, reinfection, and relapse in P. vivax recurrences. Conclusions: For a given primaquine regimen, higher methaemoglobin on day 7 was associated with a reduced risk of P. vivax recurrence. Under our proposed causal model, this justifies the use of methaemoglobin as a population-level surrogate endpoint for primaquine antihypnozoite activity in patients with P. vivax malaria who have normal G6PD activity