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We assessed the efficacy of artemisinin-based combination therapies for treatment of uncomplicated falciparum malaria, with or without co-infecting Plasmodium spp. Mixed Plasmodium infections were included; P. We retrospectively restricted the analysis to cases with polymerase chain reaction PCR —confirmed parasitemia.
Recurrent parasitemia in follow-up was identified by species-specific nested PCR. Of the participants screened, were enrolled and randomized. In the dihydroartemisinin-piperaquine arm, P. In the artemether-lumefantrine arm, P. Both regimens were well tolerated, and symptoms improved rapidly in all treated participants. In the dihydroartemisinin-piperaquine arm, 1 P. In the artemether-lumefantrine arm, 1 P. In Sumatera, both regimens effectively cleared initial parasitemia, but P.
Molecular species detection should be deployed in antimalarial efficacy trials in Indonesia. Artemisinin-based combination therapy ACT , co-formulating a short-acting artemisinin with a long-acting partner drug, is currently recommended for uncomplicated falciparum malaria. The widespread deployment of ACT, together with other control strategies, has reduced malaria morbidity and mortality, particularly in Africa [ 1 ].
ACT efficacy is threatened by Plasmodium falciparum with reduced susceptibility to both artemisinin and its partner drugs in the Greater Mekong subregion GMS [ 2—5 ]. Declining ACT efficacy against P. Indonesia lies to the south and east of mainland Southeast Asia, and nearly 70 million of its population are at risk of malaria, including multispecies co-infections [ 8—10 ]. The ACT artesunate-amodiaquine, plus a single dose of primaquine to clear gametocytes, has been used for the treatment of uncomplicated falciparum malaria in Indonesia since [ 11 ].
For non- falciparum malaria, the standard 3-day course of DP is also recommended in combination with 1—14 days of primaquine for certain infecting species [ 14 ]. Published estimates of ACT efficacy against the non- falciparum parasite species in Indonesia exist only for P.
DP efficacy throughout Indonesia is reported to be excellent, and there are no reports of delayed clearance of P. However, a potential threat remains of artemisinin-resistant parasites being introduced from the GMS [ 6 ], adjacent to West Indonesia, or from Niugini PNG , with a land border to East Indonesia [ 7 ].
Thus, there is a need to evaluate P. We aimed to compare the efficacy of DP, the first-line treatment for falciparum malaria, with artemether-lumefantrine AL , also licensed in Indonesia, for treatment of uncomplicated falciparum malaria as single- and multispecies infections. The work was carried out in the North Sumatera province, which is a short sea crossing from Southern Thailand.
We conducted a prospective, open-label, randomized comparison of DP and AL for the treatment of uncomplicated falciparum malaria in the Batubara, Langkat, and South Nias regencies in the North Sumatera province, Western Indonesia Supplementary Figure 1. Patients with uncomplicated P. The study was registered at ClinicalTrials. Consent forms were prepared in English and translated into Bahasa Indonesia. AL Coartem, Novartis Pharma, China; 40 mg artemether, mg lumefantrine was given according to weight, with 1 half-tablet for every 5 kg of body weight, at enrollment and hours 8, 24, 36, 48, and DP was given on an empty stomach, and AL was given with biscuits or milk.
Administration of all doses was supervised by study staff. Re-administration of a full dose or half-dose occurred if the patient vomited within 30 minutes or 30—60 minutes after treatment, respectively. As set out in Indonesian Government Treatment Guidelines, an additional single dose of primaquine at 0. Signs, symptoms, and adverse events were assessed and recorded before and during treatment and at all follow-up visits.
Finger-prick blood samples provided blood films for microscopic assessment and dried filter paper blood spots for post hoc molecular analysis. Parasitological assessments were made from Giemsa-stained thick and thin blood smears and were single-read by a study team microscopist. Hemoglobin levels were assessed using HemoCue at enrollment and day Recurrent P. Patients who developed a non- falciparum Plasmodium infection were re-treated according to the national guidelines [ 11 ].
Recurrent infections identified by microscopy were confirmed post hoc by species-specific nested PCR amplification of 18S rRNA or merozoite antigen genes [ 8 , 21 ]. Subpatent P. Secondary and exploratory end points included qPCR parasite clearance over days 0 to 3; the proportion of patients with parasitemia at day 3 measured by microscopy and qPCR; efficacy of treatment against PCR-confirmed non- falciparum Plasmodium spp.
Those lost to follow-up or who withdrew from the study were censored as having treatment failure. Only those outcomes determined in the PCR-defined population are presented in this report.
A total of participants were screened from January to June in the Regencies of in Batubara, Langkat, and South Nias Supplementary Figure 1 , as previously described [ 8 ]. Three hundred two individuals, comprising P. Both regimens were well tolerated, and symptoms improved rapidly in all treated subjects. A single P. Trial profile. PCR-defined cohorts were identified in each treatment arm as shown. Lower cells show PCR outcomes for 22 follow-up blood samples identified as recurrent infections by microscopy.
We performed species-specific nested PCR retrospectively on DNA from enrollment samples of all randomized individuals. Surprisingly, Plasmodium spp. DNA was successfully detected in only individuals Figure 1 , indicating that lack of accuracy in microscopic diagnosis had resulted in the inappropriate recruitment of individuals without a detectable malaria infection.
Further, P. Table 1. Comparison of baseline characteristics for the evaluable P. Thus, all results are qualitative, so it cannot be assumed that, in a mixed infection, the species denoted by row is circulating at higher density than the species denoted by column in any particular individual. Within the PCR-defined cohort, microscopically identified recurrent P.
Of the remainder, the majority harbored P. Therefore, the specificity of microscopic identification of recurrent parasitemia was poor in our study, as judged by post hoc PCR. An exploratory analysis of drug efficacy was then performed on both treatment arms of our PCR-defined cohort. First, we investigated parasite clearance dynamics of PCR-confirmed P.
Of the confirmed P. These data are consistent with continuing susceptibility to artemisinin in this P. Parasite prevalence and relative parasite density as determined by qPCR at days 0, 1, 2, and 3.
Prevalence of detectable Plasmodium DNA at each time point is shown as a percentage of tested individuals in each treatment group vertical bars. Parasite density relative to day 0 in the same individual is presented as the geometric mean of all DNA-positive samples at each time point colored lines.
Data are shown for all evaluable patients confirmed PCR-positive for P. Second, with PCR-confirmed P. Survival rate of P. Post hoc exploratory efficacy assessment of patients with PCR-confirmed P. Abbreviations: AL, artemether-lumefantrine; DP, dihydroartemisinin-piperaquine. Third, we explored ACT efficacy in patients harboring only non- falciparum malaria parasites, as measured by parasite clearance in the first 72 hours of treatment. Of 76 evaluable patients not harboring P. Parasite clearance was measured in 30 of these individuals: All cleared qPCR-detectable parasitemia within 48 hours, except for 1 individual treated with DP who cleared parasitemia within 72 hours and 1 individual treated with AL who harbored persistent day 3 parasitemia, estimated as 0.
Three of 17 AL-treated patients with P. Of 19 P. Four individuals with P. Our qPCR detection target is specific only to the genus level, and further identification of the species present was unsuccessful in post-treatment isolates, which were of a low density.
However, later recurrence of P. In conclusion, this off-protocol analysis demonstrates the potential for qPCR to provide estimates of post-treatment parasite clearance dynamics and to detect recrudescence in non- falciparum malaria.
We sought information on the current efficacy of ACT in these settings. Poor diagnostic accuracy of clinic microscopy led to enrollment and randomization of many individuals who did not meet the enrollment criteria, thus hampering any meaningful analysis on an intention-to-treat basis. Similarly, post hoc species-specific PCR indicated that many microscopically identified recurrent infections in follow-up did not harbor Plasmodium spp.
DNA and had been misclassified. We therefore deviated from our original study protocol and restricted analysis to a PCR-defined per-protocol cohort comprising and 88 PCR-confirmed infections and assessed drug efficacy using both qualitative and quantitative DNA detection end points. Clearance of PCR-confirmed P. This suggests that P. The pfcrt genotype is known to be an important modulator of parasite response to a variety of current antimalarials, including artemisinin, lumefantrine, and piperaquine [ 23 , 24 ], but no studies have systematically examined the impact of the SVMNT haplotype on P.
We recently identified isolates from the China-Myanmar border region with the SVMNT haplotype of pfcrt also harboring pfk13 propeller-domain mutations [ 25 ]. Two elements of our study provide reasons to be cautious regarding any firm conclusions about P. First, our study was planned as a treatment trial for falciparum malaria patients, with and without other co-infecting species, expected to be P.
Randomization may also have potentially been compromised by the ad hoc screening procedure, in which participants were identified by different means across the 3 sites [ 8 ]. For this reason, we do not present any comparative statistical analysis between the drug arms, but present descriptive statistics only. Second, as demonstrated by our community-wide study, carried out simultaneously during recruitment, there is a complex mix of 4 Plasmodium species circulating in our study areas [ 8 ].
The use of DNA amplification methods to confirm the species present and to verify cases of putative treatment failure, was therefore important in determining the real per-protocol denominator of treatment failure in each treatment group, but is not a recognized approach to therapeutic efficacy studies. A minority of microscopically detected parasite recurrences were confirmed to be PCR-positive for Plasmodium spp.
Early malaria resurgence in pre-elimination areas in Kokap Subdistrict, Kulon Progo, Indonesia
Metrics details. Indonesia is among those countries committed to malaria eradication, with a continuously decreasing incidence of malaria. However, at district level the situation is different. This study presents a case of malaria resurgence Kokap Subdistrict of the Kulon Progo District in Yogyakarta Province, Java after five years of low endemicity.
Metrics details. Malaria has been targeted for elimination from Indonesia by , with varying timelines for specific geographical areas based on disease endemicity. The regional deadline for malaria elimination for Java island, given the steady decrease of malaria cases, was the end of This study documents factors that affect incidence and spatial distribution of malaria in Purworejo, such as geomorphology, topography, health system issues, and identifies potential constraints and challenges to achieve the elimination stage, such as inter-districts coordination, decentralization policy and allocation of financial resources for the programme. Historical malaria data from to were collected through secondary data, in-depth interviews and focus group discussions during study year —
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