Directly-observed therapy (DOT) for the radical 14-day primaquine treatment of Plasmodium vivax malaria on the Thai-Myanmar border

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium vivax </it>has a dormant hepatic stage, called the hypnozoite, which can cause relapse months after the initial attack. For 50 years, primaquine has been used as a hypnozoitocide to radically cure <it>P. vivax </it>infection, but major concerns remain regarding the side-effects of the drug and adherence to the 14-day regimen. This study examined the effectiveness of using the directly-observed therapy (DOT) method for the radical treatment of <it>P. vivax </it>malaria infection, to prevent reappearance of the parasite within the 90-day follow-up period. Other potential risk factors for the reappearance of <it>P. vivax </it>were also explored.</p> <p>Methods</p> <p>A randomized trial was conducted from May 2007 to January 2009 in a low malaria transmission area along the Thai-Myanmar border. Patients aged ≥ 3 years diagnosed with <it>P. vivax </it>by microscopy, were recruited. All patients were treated with the national standard regimen of chloroquine for three days followed by primaquine for 14 days. Patients were randomized to receive DOT or self-administered therapy (SAT). All patients were followed for three months to check for any reappearance of <it>P. vivax</it>.</p> <p>Results</p> <p>Of the 216 patients enrolled, 109 were randomized to DOT and 107 to SAT. All patients recovered without serious adverse effects. The vivax reappearance rate was significantly lower in the DOT group than the SAT group (3.4/10,000 person-days vs. 13.5/10,000 person-days, <it>p </it>= 0.021). Factors related to the reappearance of vivax malaria included inadequate total primaquine dosage received (< 2.75 mg/kg), duration of fever ≤ 2 days before initiation of treatment, parasite count on admission ≥ 10,000/µl, multiple <it>P. vivax</it>-genotype infection, and presence of <it>P. falciparum </it>infection during the follow-up period.</p> <p>Conclusions</p> <p>Adherence to the 14-day primaquine regimen is important for the radical cure of <it>P. vivax </it>malaria infection. Implementation of DOT reduces the reappearance rate of the parasite, and may subsequently decrease <it>P. vivax </it>transmission in the area.</p

Longitudinal study of Plasmodium falciparum and Plasmodium vivax in a Karen population in Thailand

<p>Abstract</p> <p>Background</p> <p>Clinical case treatment of malaria infections where <it>Plasmodium falciparum </it>and <it>Plasmodium vivax </it>are sympatric has achieved effective reductions in <it>P. falciparum </it>prevalence and incidence rates, but has been less successful for <it>P. vivax</it>. The high transmissibility of <it>P. vivax </it>and its capacity to relapse have been suggested to make it a harder parasite species to control.</p> <p>Methods</p> <p>A clinical malaria case treatment programme was carried out over a decade in a Karen community composed of seven hamlets on the Thai-Myanmar border.</p> <p>Results</p> <p>From 1994 to 2004, prevalence rates of both <it>P. falciparum </it>and <it>P. vivax </it>decreased by 70–90% in six of the seven study hamlets, but were unchanged in one hamlet. Overall, incidence rates decreased by 72% and 76% for <it>P. falciparum </it>and <it>P. vivax </it>respectively over the period 1999–2004. The age-incidence and prevalence curves suggested that <it>P. vivax </it>was more transmissible than <it>P. falciparum </it>despite a greater overall burden of infection with <it>P. falciparum</it>. Male gender was associated with increased risk of clinical presentation with either parasite species. Children (< 15 years old) had an increased risk of presenting with <it>P. vivax </it>but not <it>P. falciparum</it>.</p> <p>Conclusion</p> <p>There was a considerable reduction in incidence rates of both <it>P. vivax </it>and <it>P. falciparum </it>over a decade following implementation of a case treatment programme. The concern that intervention methods would inadvertently favour one species over another, or even lead to an increase in one parasite species, does not appear to be fulfilled in this case.</p

Optimally timing primaquine treatment to reduce Plasmodium falciparum transmission in low endemicity Thai-Myanmar border populations

<p>Abstract</p> <p>Background</p> <p>Effective malaria control has successfully reduced the malaria burden in many countries, but to eliminate malaria, these countries will need to further improve their control efforts. Here, a malaria control programme was critically evaluated in a very low-endemicity Thai-Myanmar border population, where early detection and prompt treatment have substantially reduced, though not ended, <it>Plasmodium falciparum </it>transmission, in part due to carriage of late-maturing gametocytes that remain post-treatment. To counter this effect, the WHO recommends the use of a single oral dose of primaquine along with an effective blood schizonticide. However, while the effectiveness of primaquine as a gametocidal agent is widely documented, the mismatch between primaquine's short half-life, the long-delay for gametocyte maturation and the proper timing of primaquine administration have not been studied.</p> <p>Methods</p> <p>Mathematical models were constructed to simulate 8-year surveillance data, between 1999 and 2006, of seven villages along the Thai-Myanmar border. A simple model was developed to consider primaquine pharmacokinetics and pharmacodynamics, gametocyte carriage, and infectivity.</p> <p>Results</p> <p>In these populations, transmission intensity is very low, so the <it>P. falciparum </it>parasite rate is strongly linked to imported malaria and to the fraction of cases not treated. Given a 3.6-day half-life of gametocyte, the estimated duration of infectiousness would be reduced by 10 days for every 10-fold reduction in initial gametocyte densities. Infectiousness from mature gametocytes would last two to four weeks and sustain some transmission, depending on the initial parasite densities, but the residual mature gametocytes could be eliminated by primaquine. Because of the short half-life of primaquine (approximately eight hours), it was immediately obvious that with early administration (within three days after an acute attack), primaquine would not be present when mature gametocytes emerged eight days after the appearance of asexual blood-stage parasites. A model of optimal timing suggests that primaquine follow-up approximately eight days after a clinical episode could further reduce the duration of infectiousness from two to four weeks down to a few days. The prospects of malaria elimination would be substantially improved by changing the timing of primaquine administration and combining this with effective detection and management of imported malaria cases. The value of using primaquine to reduce residual gametocyte densities and to reduce malaria transmission was considered in the context of a malaria transmission model; the added benefit of the primaquine follow-up treatment would be relatively large only if a high fraction of patients (>95%) are initially treated with schizonticidal agents.</p> <p>Conclusion</p> <p>Mathematical models have previously identified the long duration of <it>P. falciparum </it>asexual blood-stage infections as a critical point in maintaining malaria transmission, but infectiousness can persist for two to four weeks because of residual populations of mature gametocytes. Simulations from new models suggest that, in areas where a large fraction of malaria cases are treated, curing the asexual parasitaemia in a primary infection, and curing mature gametocyte infections with an eight-day follow-up treatment with primaquine have approximately the same proportional effects on reducing the infectious period. Changing the timing of primaquine administration would, in all likelihood, interrupt transmission in this area with very good health systems and with very low endemicity.</p

The impact of human reservoir of malaria at a community-level on individual malaria occurrence in a low malaria transmission setting along the Thai-Myanmar border

Abstract Background The probability of contracting malaria in a given individual is determined not only by the individual's characteristics, but also the ecological factors that characterize the level of human-vector contact in the population. Examination of the relationship between "individual" and "supra-individual" variables over time is important for understanding the local malaria epidemiology. This is essential for planning effective intervention strategies specifically for each location. Methods A retrospective cohort study was conducted, which followed a community-cohort of about 3,500 residents in seven hamlets along the Thai-Myanmar border between 1999 and 2006. Potential malaria determinants measured at different levels (temporal variables, individual variables, and hamlet variables) were incorporated into multilevel models to estimate their effects on an individual's risk of malaria attack. Results The monthly minimum temperature was significantly associated with the seasonal variation of malaria risk. An individual risk of malaria attack decreased by about 50% during the period that active surveillance was conducted; an additional 15% and 25% reduction of Plasmodium falciparum and Plasmodium vivax incidence, respectively, was observed after the use of artesunate-mefloquine combination therapy (ACT) for treatment of P. falciparum. Male children (age P. falciparum and P. vivax attack. An increase in the hamlet's incidence of P. falciparum and P. vivax by 1 per 100 persons in a previous month resulted in 1.14 and 1.34 times increase in the risk of P. falciparum and P. vivax, respectively, among individuals in a particular hamlet. Conclusion In a small area with low malaria transmission intensity, the variation in mosquito abundance is relatively similar across the residential areas; incidence of malaria between hamlets, which reflects the community level of human infectious reservoirs, is an important predictor for the malaria risk among individuals within these hamlets. Therefore, local malaria control strategies should focus on interventions that aim to reduce the gametocyte carriage in the population, such as early detection and treatment programmes and the use of ACT for P. falciparum.</p

Shown are the weighted mean (± 95% Confidence intervals) percentage of each age group infected during cross-sectional surveys in 1994 and 2004 across the seven study hamlets

<p><b>Copyright information:</b></p><p>Taken from "Longitudinal study of and in a Karen population in Thailand"</p><p>http://www.malariajournal.com/content/7/1/99</p><p>Malaria Journal 2008;7():99-99.</p><p>Published online 2 Jun 2008</p><p>PMCID:PMC2443811.</p><p></p

Additional file 1: Table S1. of Very high carriage of gametocytes in asymptomatic low-density Plasmodium falciparum and P. vivax infections in western Thailand

Performance of qPCR and qRT-PCR. The threshold cycles (CT) are shown for detection of plasmid standards at different copy numbers per reaction. The means and the standard errors of the mean (SEM) are shown for CT values used to determine the amplification efficiency (E) and r 2, with values in parenthesis excluded. Neg indicates no amplification. The limit of detection (red) is defined as the lowest copy number with > 50% success rate. (DOCX 24 kb