Effectiveness, Safety, and Acceptability of Primaquine Mass Drug Administration in Low-Endemicity Areas in Southern Thailand: Proof-of-Concept Study.

BACKGROUND: A challenge in achieving the malaria-elimination target in the Greater Mekong Subregion, including Thailand, is the predominance of Plasmodium vivax malaria, which has shown extreme resilience to control measures. OBJECTIVE: This proof-of-concept study aimed to provide evidence for implementing primaquine mass drug administration (pMDA) as a strategy for P. vivax elimination in low-endemicity settings. METHODS: The study employed a mixed-methods trial to thoroughly evaluate the effectiveness, safety, acceptability, and community engagement of pMDA. The quantitative part was designed as a 2-period cluster-crossover randomized controlled trial. The intervention was pMDA augmented to the national prevention and control standards with directly observed treatment (DOT) by village health volunteers. The qualitative part employed in-depth interviews and brainstorming discussions. The study involved 7 clusters in 2 districts of 2 southern provinces in Thailand with persistently low P. vivax transmission. In the quantitative part, 5 cross-sectional blood surveys were conducted in both the pMDA and control groups before and 3 months after pMDA. The effectiveness of pMDA was determined by comparing the proportions of P. vivax infections per 1000 population between the 2 groups, with a multilevel zero-inflated negative binomial model adjusted for cluster and time as covariates and the interaction. The safety data comprised adverse events after drug administration. Thematic content analysis was used to assess the acceptability and engagement of stakeholders. RESULTS: In the pre-pMDA period, the proportions of P. vivax infections in the pMDA (n=1536) and control (n=1577) groups were 13.0 (95% CI 8.2-20.4) and 12.0 (95% CI 7.5-19.1), respectively. At month 3 post-pMDA, these proportions in the pMDA (n=1430) and control (n=1420) groups were 8.4 (95% CI 4.6-15.1) and 5.6 (95% CI 2.6-11.5), respectively. No statistically significant differences were found between the groups. The number of malaria cases reduced in all clusters in both groups, and thus, the impact of pMDA was inconclusive. There were no major safety concerns. Acceptance among the study participants and public health care providers at local and national levels was high, and they believed that pMDA had boosted awareness in the community. CONCLUSIONS: pMDA was associated with high adherence, safety, and tolerability, but it may not significantly impact P. vivax transmission. As this was a proof-of-concept study, we decided not to scale up the intervention with larger clusters and samples. An alternative approach involving a targeted primaquine treatment strategy with primaquine and DOT is currently being implemented. We experienced success regarding effective health care workforces at point-of-care centers, effective collaborations in the community, and commitment from authorities at local and national levels. Our efforts boosted the acceptability of the malaria-elimination initiative. Community engagement is recommended to achieve elimination targets. TRIAL REGISTRATION: Thai Clinical Trials Registry TCTR20190806004; https://www.thaiclinicaltrials.org/show/TCTR20190806004.

Transmission efficiency of Plasmodium vivax at low parasitaemia.

BACKGROUND: Plasmodium vivax is responsible for much of malaria outside Africa. Although most P. vivax infections in endemic areas are asymptomatic and have low parasite densities, they are considered a potentially important source of transmission. Several studies have demonstrated that asymptomatic P. vivax carriers can transmit the parasite to mosquitoes, but the efficiency has not been well quantified. The aim of this study is to determine the relationship between parasite density and mosquito infectivity, particularly at low parasitaemia. METHODS: Membrane feeding assays were performed using serial dilutions of P. vivax-infected blood to define the relationship between parasitaemia and mosquito infectivity. RESULTS: The infection rate (oocyst prevalence) and intensity (oocyst load) were positively correlated with the parasite density in the blood. There was a broad case-to-case variation in parasite infectivity. The geometric mean parasite density yielding a 10% mosquito infection rate was 33 (CI 95 9-120) parasites/µl or 4 (CI 95 1-17) gametocytes/µl. The geometric mean parasite density yielding a 50% mosquito infection rate was 146 (CI 95 36-586) parasites/µl or 13 (CI 95 3-49) gametocytes/µl. CONCLUSION: This study quantified the ability of P. vivax to infect Anopheles dirus at over a broad range of parasite densities. It provides important information about parasite infectivity at low parasitaemia common among asymptomatic P. vivax carriers.

Sensitive detection of Plasmodium vivax malaria by the rotating-crystal magneto-optical method in Thailand.

The rotating-crystal magneto-optical detection (RMOD) method has been developed for the rapid and quantitative diagnosis of malaria and tested systematically on various malaria infection models. Very recently, an extended field trial in a high-transmission region of Papua New Guinea demonstrated its great potential for detecting malaria infections, in particular Plasmodium vivax. In the present small-scale field test, carried out in a low-transmission area of Thailand, RMOD confirmed malaria in all samples found to be infected with Plasmodium vivax by microscopy, our reference method. Moreover, the magneto-optical signal for this sample set was typically 1-3 orders of magnitude higher than the cut-off value of RMOD determined on uninfected samples. Based on the serial dilution of the original patient samples, we expect that the method can detect Plasmodium vivax malaria in blood samples with parasite densities as low as [Formula: see text]5-10 parasites per microliter, a limit around the pyrogenic threshold of the infection. In addition, by investigating the correlation between the magnitude of the magneto-optical signal, the parasite density and the erythrocytic stage distribution, we estimate the relative hemozoin production rates of the ring and the trophozoite stages of in vivo Plasmodium vivax infections.

Malaria cross-sectional surveys identified asymptomatic infections of Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi in Surat Thani, a southern province of Thailand.

OBJECTIVES: Malaria cross-sectional surveys are rarely conducted in very low transmission settings. This study aimed to determine the prevalence and risk factors of Plasmodium infection in a near-elimination setting in southern Thailand. METHODS: Two cross-sectional surveys were conducted in areas of active transmission in the Surat Thani province of Thailand in January and May 2019. PCR was used to detect Plasmodium infection. RESULTS: The prevalence of Plasmodium blood infection was 0.45% and 0.61% in January and May 2019, respectively. The major parasite species was Plasmodium falciparum in January and Plasmodium vivax in May. Unexpectedly, Plasmodium knowlesi infections were also detected. Most infections, including those of Plasmodium knowlesi, were asymptomatic. Being male and staying outdoors at night-time were the only significant identified risk factors. Of people infected in January 28.0% were positive in May for the same parasite species, suggesting persistent asymptomatic infections. CONCLUSIONS: Despite the very low incidence rate in Surat Thani, most malaria infections were asymptomatic. Outdoor mosquito biting at night-time is likely an important mode of malaria transmission. Unexpectedly, asymptomatic Plasmodium knowlesi infection was found, confirming previous reports of such infection in mainland Southeast Asia.

Naturally acquired antibody responses to more than 300 Plasmodium vivax proteins in three geographic regions.

Plasmodium vivax remains an important cause of malaria in South America and the Asia-Pacific. Naturally acquired antibody responses against multiple P. vivax proteins have been described in numerous countries, however, direct comparison of these responses has been difficult with different methodologies employed. We measured antibody responses against 307 P. vivax proteins at the time of P. vivax infection, and at 2-3 later time-points in three countries. We observed that seropositivity rates at the time of infection were highest in Thailand, followed by Brazil then PNG, reflecting the level of antigenic input. The majority of sero-reactive antigens in all sites induced short-lived antibody responses with estimated half-lives of less than 6 months, although there was a trend towards longer-lived responses in PNG children. Despite these differences, IgG seropositivity rates, magnitude and longevity were highly and significantly rank-correlated between the different regions, suggesting such features are reflective of the individual protein.

High Efficacy of Primaquine Treatment for Plasmodium vivax in Western Thailand.

Primaquine is the only licensed antimalarial drug that is capable of clearing dormant Plasmodium vivax liver stage parasites. To date, there is no clear evidence of resistance of the liver stage parasite against this drug, because of the difficulty in ascertaining the cause of recurrent infection. We followed 52 Thai P. vivax patients for 9 months after directly observed treatment of 15 mg primaquine daily for 14 days. Blood samples taken at 2-4 weekly intervals were assessed by microscopy and polymerase chain reaction (PCR) for the presence of parasites. Only four of 52 (7.7%) volunteers had recurrent P. vivax infections, all at least 8 weeks after treatment. This demonstrates that primaquine retains a high efficacy in this population. Although a risk of new infections could not be ruled out, parasite genotyping at two polymorphic markers suggested a high probability of late relapsing infections in these volunteers. Continued monitoring of primaquine efficacy in this region is advisable.