Adherence to 14-day radical cure for Plasmodium vivax malaria in Papua, Indonesia: a mixed-methods study.

BACKGROUND: Reducing the risk of recurrent Plasmodium vivax malaria is critical for malaria control and elimination. Primaquine (PQ) is the only widely available drug against P. vivax dormant liver stages, but is recommended as a 14-day regimen, which can undermine adherence to a complete course of treatment. METHODS: This is a mixed-methods study to assess socio-cultural factors influencing adherence to a 14-day PQ regimen in a 3-arm, treatment effectiveness trial in Papua, Indonesia. The qualitative strand, consisting of interviews and participant observation was triangulated with a quantitative strand in which trial participants were surveyed using a questionnaire. RESULTS: Trial participants differentiated between two types of malaria: tersiana and tropika, equivalent to P. vivax and Plasmodium falciparum infection, respectively. The perceived severity of both types was similar with 44.0% (267/607) perceiving tersiana vs. 45.1% (274/607) perceiving tropika as more severe. There was no perceived differentiation whether malaria episodes were due to a new infection or relapse; and 71.3% (433/607) acknowledged the possibility of recurrence. Participants were familiar with malaria symptoms and delaying health facility visit by 1-2 days was perceived to increase the likelihood of a positive test. Prior to health facility visits, symptoms were treated with leftover drugs kept at home (40.4%; 245/607) or bought over the counter (17.0%; 103/607). Malaria was considered to be cured with 'blue drugs' (referring to dihydroartemisinin-piperaquine). Conversely, 'brown drugs,' referring to PQ, were not considered malaria medication and instead were perceived as supplements. Adherence to malaria treatment was 71.2% (131/184), in the supervised arm, 56.9% (91/160) in the unsupervised arm and 62.4% (164/263) in the control arm; p = 0.019. Adherence was 47.5% (47/99) among highland Papuans, 51.7% (76/147) among lowland Papuans, and 72.9% (263/361) among non-Papuans; p < 0.001. CONCLUSION: Adherence to malaria treatment was a socio-culturally embedded process during which patients (re-)evaluated the characteristics of the medicines in relation to the course of the illness, their past experiences with illness, and the perceived benefits of the treatment. Structural barriers that hinder the process of patient adherence are crucial to consider in the development and rollout of effective malaria treatment policies.

Intermittent screening and treatment or intermittent preventive treatment compared to current policy of single screening and treatment for the prevention of malaria in pregnancy in Eastern Indonesia: acceptability among health providers and pregnant women.

BACKGROUND: The control of malaria in pregnancy in much of Asia relies on screening asymptomatic women for malaria infection, followed by passive case detection and prevention with insecticide-treated nets. In 2012, Indonesia introduced screening for malaria by microscopy or rapid diagnostic tests (RDTs) at pregnant women's first antenatal care (ANC) visit to detect and treat malaria infections regardless of the presence of symptoms. Acceptability among health providers and pregnant women of the current 'single screen and treat' (SSTp) strategy compared to two alternative strategies that were intermittent preventive treatment (IPTp) and intermittent screening and treatment (ISTp) was assessed in the context of a clinical trial in two malaria endemic provinces of Eastern Indonesia. METHODS: Qualitative data were collected through in-depth interviews with 121 health providers working in provision of antenatal care, heads of health facilities and District Health Office staff. Trial staff were also interviewed. Focus group discussions were conducted with 16 groups of pregnant women (N = 106) to discuss their experiences of each intervention in the trial. RESULTS: Health providers and pregnant women were receptive to screening for malaria at every ANC visit due to the increased opportunity to detect and treat asymptomatic infections. A primary concern for providers was the accuracy and availability of RDTs used for screening in the SSTp and ISTp arms, which they considered less accurate than microscopy. Providers had reservations about giving anti-malarials presumptively as IPTp, due to concerns of causing potential harm to mother and baby and as a possible driver of drug resistance. Pregnant women were accepting of all three interventions. Women in the IPTp arm were happy to take anti-malarials presumptively to protect themselves and their babies against malaria. CONCLUSIONS: The findings indicate that, within a trial context, malaria screening of pregnant women at every ANC visit ISTp was an acceptable strategy among both health providers and pregnant women owing to an existing culture of screening and treatment. The adoption of IPTp however would require a considerable shift in health provider attitudes and a clear communication strategy. By contrast, pregnant women welcomed the opportunity to prevent malaria infections during pregnancy.

Evaluation of the national policy of single screening and treatment for the prevention of malaria in pregnancy in two districts in Eastern Indonesia: health provider perceptions.

BACKGROUND: Malaria in pregnancy has devastating consequences for both the expectant mother and baby. Annually, 88.2 (70%) of the 125.2 million pregnancies in malaria endemic regions occur in the Asia-Pacific region. The control of malaria in pregnancy in most of Asia relies on passive case detection and prevention with long-lasting insecticide-treated nets. Indonesia was the first country in the region to introduce, in 2012, malaria screening at pregnant women's first antenatal care visit to reduce the burden of malaria in pregnancy. The study assessed health providers' acceptability and perceptions on the feasibility of implementing the single screening and treatment (SST) strategy in the context of the national programme in two endemic provinces of Indonesia. METHODS: Qualitative data were collected through in-depth interviews with 86 health providers working in provision of antenatal care (midwives, doctors, laboratory staff, pharmacists, and heads of drug stores), heads of health facilities and District Health Office staff in West Sumba and Mimika districts in East Nusa Tenggara and Papua provinces, respectively. RESULTS: Health providers of all cadres were accepting of SST as a preventive strategy, showing a strong preference for microscopy over rapid diagnostic tests (RDTs) as the method of screening. Implementation of the policy was inconsistent in both sites, with least extensive implementation reported in West Sumba compared to Mimika. SST was predominantly implemented at health centre level using microscopy, whereas implementation at community health posts was said to occur in less than half the selected health facilities. Lack of availability of RDTs was cited as the major factor that prevented provision of SST at health posts, however as village midwives cannot prescribe medicines women who test positive are referred to health centres for anti-malarials. Few midwives had received formal training on SST or related topics. CONCLUSIONS: The study findings indicate that SST was an acceptable strategy among health providers, however implementation was inconsistent with variation across different localities within the same district, across levels of facility, and across different cadres within the same health facility. Implementation should be re-invigorated through reorientation and training of health providers, stable supplies of more sensitive RDTs, and improved data capture and reporting.

Characterization of blood dendritic and regulatory T cells in asymptomatic adults with sub-microscopic Plasmodium falciparum or Plasmodium vivax infection.

BACKGROUND: Plasmodium falciparum and Plasmodium vivax infections compromise dendritic cell (DC) function and expand regulatory T (Treg) cells in both clinical disease (malaria) and experimental human sub-microscopic infection. Conversely, in asymptomatic microscopy-positive (patent) P. falciparum or P. vivax infection in endemic areas, blood DC increase or retain HLA-DR expression and Treg cells exhibit reduced activation, suggesting that DC and Treg cells contribute to the control of patent asymptomatic infection. The effect of sub-microscopic (sub-patent) asymptomatic Plasmodium infection on DC and Treg cells in malaria-endemic area residents remains unclear. METHODS: In a cross-sectional household survey conducted in Papua, Indonesia, 162 asymptomatic adults were prospectively evaluated for DC and Treg cells using field-based flow cytometry. Of these, 161 individuals (99 %) were assessed retrospectively by polymerase chain reaction (PCR), 19 of whom had sub-microscopic infection with P. falciparum and 15 with sub-microscopic P. vivax infection. Flow cytometric data were re-analysed after re-grouping asymptomatic individuals according to PCR results into negative controls, sub-microscopic and microscopic parasitaemia to examine DC and Treg cell phenotype in sub-microscopic infection. RESULTS: Asymptomatic adults with sub-microscopic P. falciparum or P. vivax infection had DC HLA-DR expression and Treg cell activation comparable to PCR-negative controls. Sub-microscopic P. falciparum infection was associated with lower peripheral CD4(+) T cells and lymphocytes, however sub-microscopic Plasmodium infection had no apparent effect on DC sub-set number or Treg cell frequency. CONCLUSIONS: In contrast to the impairment of DC maturation/function and the activation of Treg cells seen with sub-microscopic parasitaemia in primary experimental human Plasmodium infection, no phenotypic evidence of dysregulation of DC and Treg cells was observed in asymptomatic sub-microscopic Plasmodium infection in Indonesian adults. This is consistent with DC and Treg cells retaining their functional capacity in sub-microscopic asymptomatic infection with P. falciparum or P. vivax in malaria-endemic areas.

Preserved dendritic cell HLA-DR expression and reduced regulatory T cell activation in asymptomatic Plasmodium falciparum and P. vivax infection.

Clinical illness with Plasmodium falciparum or Plasmodium vivax compromises the function of dendritic cells (DC) and expands regulatory T (Treg) cells. Individuals with asymptomatic parasitemia have clinical immunity, restricting parasite expansion and preventing clinical disease. The role of DC and Treg cells during asymptomatic Plasmodium infection is unclear. During a cross-sectional household survey in Papua, Indonesia, we examined the number and activation of blood plasmacytoid DC (pDC), CD141(+), and CD1c(+) myeloid DC (mDC) subsets and Treg cells using flow cytometry in 168 afebrile children (of whom 15 had P. falciparum and 36 had P. vivax infections) and 162 afebrile adults (of whom 20 had P. falciparum and 20 had P. vivax infections), alongside samples from 16 patients hospitalized with uncomplicated malaria. Unlike DC from malaria patients, DC from children and adults with asymptomatic, microscopy-positive P. vivax or P. falciparum infection increased or retained HLA-DR expression. Treg cells in asymptomatic adults and children exhibited reduced activation, suggesting increased immune responsiveness. The pDC and mDC subsets varied according to clinical immunity (asymptomatic or symptomatic Plasmodium infection) and, in asymptomatic infection, according to host age and parasite species. In conclusion, active control of asymptomatic infection was associated with and likely contingent upon functional DC and reduced Treg cell activation.

Epidemiology and risk factors of Strongyloides stercoralis infection in Papua, Indonesia: a molecular diagnostic study.

Strongyloides stercoralis is a parasitic worm that is of considerable clinical relevance. Indeed, it may persist asymptomatically for many years, but can lead to potentially fatal dissemination when the host's immune status is impaired. As commonly employed stool microscopy techniques (e.g. Kato-Katz thick smear) fail to detect S. stercoralis, the epidemiology is poorly understood. In 2013, we conducted a cross-sectional household survey in the district of Mimika in Papua, Indonesia. A total of 331 individuals, aged 1 month to 44 years, had a single stool sample subjected to real-time polymerase chain reaction (PCR) for S. stercoralis diagnosis. The prevalence of S. stercoralis infection was 32.0% (106/331 individuals); higher than any of the three main soil-transmitted helminths (Ascaris lumbricoides, 23.9%; Trichuris trichiura, 18.4%; and hookworm, 17.2%). Amongst the S. stercoralis-infected individuals, 73.6% were concurrently infected with another helminth, with hookworm being the most frequent co-infection (27.4%). Fourteen percent of the S. stercoralis infections had low cycle threshold values on real-time PCR, which may indicate a higher infection intensity. Multivariate logistic regression analysis revealed that age ≥5 years (adjusted odds ratio (OR) 5.8, 95% confidence interval (CI): 3.1-10.8) was significantly associated with S. stercoralis infection. There is a need for in-depth clinical and diagnostic studies to elucidate the public health impact of S. stercoralis infection in Indonesia.

Genetic micro-epidemiology of malaria in Papua Indonesia: Extensive P. vivax diversity and a distinct subpopulation of asymptomatic P. falciparum infections.

BACKGROUND: Genetic analyses of Plasmodium have potential to inform on transmission dynamics, but few studies have evaluated this on a local spatial scale. We used microsatellite genotyping to characterise the micro-epidemiology of P. vivax and P. falciparum diversity to inform malaria control strategies in Timika, Papua Indonesia. METHODS: Genotyping was undertaken on 713 sympatric P. falciparum and P. vivax isolates from a cross-sectional household survey and clinical studies conducted in Timika. Standard population genetic measures were applied, and the data was compared to published data from Kalimantan, Bangka, Sumba and West Timor. RESULTS: Higher diversity (HE = 0.847 vs 0.625; p = 0.017) and polyclonality (46.2% vs 16.5%, p<0.001) were observed in P. vivax versus P. falciparum. Distinct P. falciparum substructure was observed, with two subpopulations, K1 and K2. K1 was comprised solely of asymptomatic infections and displayed greater relatedness to isolates from Sumba than to K2, possibly reflecting imported infections. CONCLUSIONS: The results demonstrate the greater refractoriness of P. vivax versus P. falciparum to control measures, and risk of distinct parasite subpopulations persisting in the community undetected by passive surveillance. These findings highlight the need for complimentary new surveillance strategies to identify transmission patterns that cannot be detected with traditional malariometric methods.

Submicroscopic and Asymptomatic Plasmodium Parasitaemia Associated with Significant Risk of Anaemia in Papua, Indonesia.

Submicroscopic Plasmodium infections are an important parasite reservoir, but their clinical relevance is poorly defined. A cross-sectional household survey was conducted in southern Papua, Indonesia, using cluster random sampling. Data were recorded using a standardized questionnaire. Blood samples were collected for haemoglobin measurement. Plasmodium parasitaemia was determined by blood film microscopy and PCR. Between April and July 2013, 800 households and 2,830 individuals were surveyed. Peripheral parasitaemia was detected in 37.7% (968/2,567) of individuals, 36.8% (357) of whom were identified by blood film examination. Overall the prevalence of P. falciparum parasitaemia was 15.4% (396/2567) and that of P. vivax 18.3% (471/2567). In parasitaemic individuals, submicroscopic infection was significantly more likely in adults (adjusted odds ratio (AOR): 3.82 [95%CI: 2.49-5.86], p<0.001) compared to children, females (AOR = 1.41 [1.07-1.86], p = 0.013), individuals not sleeping under a bednet (AOR = 1.4 [1.0-1.8], p = 0.035), and being afebrile (AOR = 3.2 [1.49-6.93], p = 0.003). The risk of anaemia (according to WHO guidelines) was 32.8% and significantly increased in those with asymptomatic parasitaemia (AOR 2.9 [95% 2.1-4.0], p = 0.007), and submicroscopic P. falciparum infections (AOR 2.5 [95% 1.7-3.6], p = 0.002). Asymptomatic and submicroscopic infections in this area co-endemic for P. falciparum and P. vivax constitute two thirds of detectable parasitaemia and are associated with a high risk of anaemia. Novel public health strategies are needed to detect and eliminate these parasite reservoirs, for the benefit both of the patient and the community.