Electrocardiographic Safety of Repeated Monthly Dihydroartemisinin-Piperaquine as a Candidate for Mass Drug Administration

Malaria elimination is set to be a global health priority in coming years, and ambitious plans for scaling up from malaria control to elimination already exist in many areas of endemicity worldwide. New strategies being actively considered for interrupting malaria transmission include mass drug administration (MDA) (1). This strategy requires the treatment of entire populations with effective antimalarial drugs to reduce the human reservoir of high and low parasite density blood-stage infections, in addition to conferring posttreatment prophylaxis that prevents reinfection and relapse over a time period that significantly exceeds the life span of the anopheline vector (2). Because most individuals treated in an MDA program are asymptomatic parasite carriers or uninfected, the ideal antimalarial for MDA must (i) have a prolonged duration of effect that optimizes the period of prophylaxis against reinfection and relapse and (ii) be demonstrated to be safe when delivered in sequential repeated treatment courses in the manner proposed for MDA deployment (2).

Dihydroartemisinin-piperaquine (DHA-PQP) is a good candidate for MDA. The rapid-acting artemisinin-derivative reduces the parasite biomass of existing infections, and the long-acting PQP component exerts an especially long posttreatment prophylactic effect (3). Repeated monthly exposure to standard 3-day treatment courses of DHA-PQP over 3 consecutive months should theoretically prevent new infections for a period of at least 90 to 120 days. In a meta-analysis of 11 studies, monthly DHA-PQP for high-risk populations was associated with an 84% reduction in the incidence of malaria parasitemia (4–6).

Nevertheless, the feasibility of DHA-PQP for MDA has been questioned because PQP can cause dose-dependent prolongation of the electrocardiographic QT interval. As such, PQP is contraindicated in patients with congenital long-QT syndrome (about one in 2,500 children) or those taking other drugs that prolong the QT. Mild QT prolongation is clinically silent, but extreme prolongation can cause fatal arrhythmias, such as torsades de pointes (TdP). Prior studies have demonstrated that QTc prolongation associated with DHA-PQP is predominantly mild and not associated with clinical adverse cardiac outcomes (4, 7). However, PQP is eliminated slowly (elimination half-life, ∼23 days), and the risk of QT prolongation may be exacerbated when repeated doses are given, especially if given monthly (8). Therefore, the drug manufacturer and the European Medicines Agency (EMA) recommend that repeated treatment courses of DHA-PQP (brand name Eurartesim) in 160-mg/20-mg film-coated tablets should not be administered within 2 months of initial treatment (9). Unfortunately, this is unlikely to be optimally effective if DHA-PQP is given as part of MDA; mathematical models suggest a maximum interval of 1 month between treatment rounds in order to interrupt transmission (10).

The current study aims to assess the cardiac safety of three repeated monthly courses of DHA-PQP in Lihir Island, Papua New Guinea (PNG), a population of endemicity for malaria likely to be targeted in future MDA activities.

Of 110 individuals screened, 84 (76.3%) individuals met the inclusion criteria and consented to participate in the study. Eighteen individuals declined consent, and 8 individuals were ineligible (first trimester pregnancy, n = 2; uncontrolled hypertension, n = 2: asymptomatic arrhythmia, n = 2; clinical heart failure, n = 1; and congenital heart disease, n = 1). Of the 84 participants who were initially enrolled, 69 (82.2%) participants completed all treatment courses and follow-up appointments (per-protocol population) and were included in subsequent analysis.

The mean age of participants in the per-protocol population was 27.4 years (standard deviation [SD], 12.6 years); 7 (10%) participants were children (age 3 to 15 years), and 34 (49%) participants were female. One female participant was pregnant (confirmed second trimester by dates and clinical examination). At baseline, the mean QT interval with Fridericia’s correction (QTcF) was 397.3 ms (SD, 17.2 ms). Sixty-five (94%) participants had a normal baseline ECG, and 4 (6%) participants had minor abnormalities of no clinical relevance (i.e., 3 with nonpathological T-wave inversion and 1 with poor R-wave progression). A comparison of baseline demographic, clinical, and electrocardiographic characteristics of participants who completed follow-up and those who were lost to follow-up were not significantly different (Table 1).

The mean (SD) ΔQTcF (from 0 h to 52 h) was 19.6 ms (17.8 ms) in course 1, 23.6 ms (15.3 ms) in course 2 (difference, 4.0 ms [95% confidence interval {95% CI}, 0.1 to 8.0 ms]; P = 0.043), and 17.1 ms (17.1 ms) in course 3 (difference, −2.4 [95% CI, −6.9 to 2.1] P = 0.285; Table 2 and Fig. 1 and 2).

In subgroup analyses (Table S1), the mean (SD) ΔQTcF was higher in females (25.8 ms [20.5 ms]) than in males (13.5 ms [12.2 ms]) after course 1 (P = 0.003). However, there was no significant difference in ΔQTcF values between males and females after the second and third courses (22.7 ms [15.9 ms] in males and 24.5 ms [14.9 ms] in females, P = 0.623 for the second course; and 14.3 ms [15.5 ms] in males and 20.1 ms [18.4 ms] in females, P = 0.158 for the third course). The mean QTcF segment and ΔQTcF values did not differ significantly according to age group (data not shown).

Figure 1 shows the evolution of QTcF at all time points (days 0, 2, 7, 28, 30, 35, 56, 58, and 63). Table 3 shows the resolution in ECG parameters at 7 days after the start of each DHA-PQP treatment course and prior (at 0 h) to the following course. The QTcF at 0 h for course 3 (QTcF 0 h_course3) was shorter than QTcF 0 h_course1 (−4.0 ms, P < 0.001), which represents a full resolution of the QTcF prolongation 28 days after the start of treatment of course 2. The QTcF and ΔQTcF parameters on 7 days_course2 and 7 days_course3 showed no differences compared to those at 7 days_course1 (Table S2).

No participant had cardiac-related severe adverse effects (SAEs) during the study period. Table 4 shows the recording of cardiac adverse effects of special interest (AESIs) occurring any time during the 63-day study observation period. A ΔQTcF of >60 ms was observed in 3 (4.3%), 1 (1.4%, P = 0.50), and 2 (2.9%, P = 1.00) participants after the first, second, and third courses of treatment, respectively. None of the participants had QTcF readings of more than 500 ms. QTcF readings of ≥450 to <500 ms were noted in 6 (8.9%), 5 (7.2%, P = 1.00), and 5 (7.2%, P = 1.00) participants after the first, second, and third courses of treatment, respectively. Other reported cardiac AESIs included sinus bradycardia (<40 beats per minute [bpm]) in 1 (1.4%) participant in each treatment course, and 2 (2.9%) participants with changes in T-wave morphology after the second courses of treatment. No AESIs were accompanied by clinical symptoms. Other previously defined AESIs (new bundle branch block and arrhythmia of new appearance) were not reported by any participant at any time during the study.

Noncardiac AEs occurred in 29 (14.0%) of 207 patient visits. All reported AEs were mild and transient, with no participant requiring specialized treatment. The most commonly reported AE were abdominal pain (n = 12 [5.8%]), followed by headache (3.8%), cough (2.4%), and nausea (1.9%). All rapid diagnostic tests (RDTs) and microscopy smears collected at 0 h_course2 and 0 h_course3 were negative for malaria parasitemia.

Other ECG measurements (HR, ΔHR, PR, ΔPR, QRS, and ΔQRS) along the 63 days of evolution are described in Tables S3 and S4.

In this study, three monthly repeated courses of DHA-PQP resulted in our primary study endpoint, a change in the mean post-final-dose QTcF between the first and final courses, 17.7 ms; this is a magnitude generally similar to those described after a single course and lying below the U.S Food and Drug Administration’s 20-ms threshold of high level of concern (11). Our findings that QTcF prolongation did not increase in a cumulative manner with repeat courses was supported by the observation that the QTcF returned to normal prior to each subsequent course of treatment. Interestingly, the QTcF difference increased slightly (23.6 ms) after the second but not the third course. This result is intriguing and will require correlation with drug concentrations once the results related to the drug’s pharmacokinetics of the current study become available. In addition, it is reassuring that no individual had any QTcF of >500 ms and that the number of cases with an absolute increase of >60 ms were limited to 6 individuals evenly spread throughout each of the monthly courses. This therefore does not add to concerns raised by a recent large multicentric clinical trial about the possibility of increased incidence of this event after a repeated dose (7). Our results support previous findings that QT/QTc prolongation following DHA-PQP administration is consistently lower than that caused by other commonly used antimalarial drugs, such as quinine (12, 13) or chloroquine (14). Previous studies assessing the cardiotoxicity of DHA-PQP have shown minimal QTc prolongation following a single 3-day course. For example, in Cambodia, the mean (corrected by Bazett’s formula [QTcB]) prolongation in 62 individuals was 11 ms at 24 h after first dose (15), and the mean QTcF prolongation in 56 adults in Thailand was 29 ms at 52 h after the start of treatment (16). In a cohort of 1,002 malaria patients from a study conducted in four African countries, only 3 (0.3%) patients had a QTcF of >500ms after a standard 3-dose treatment (1-month course), and fewer than 10% of participants had an increase in QTcF more than 60 ms from baseline (17). A recent meta-analysis of 11 studies involving repeated exposures of DHA-PQP for seasonal malaria chemoprevention or treatment of clinical malaria found no increased incidence of AEs with repeated dosing; however, only one of these (a study of 13 pregnant women [G. Dorsey, unpublished data]) performed electrocardiographic assessments of QTc prolongation. The authors called for more studies incorporating electrocardiogram measurements (4). Recent MDA programs using DHA-PQP in large populations have shown that this drug combination is safe to use due to the minimal occurrence of serious adverse events; however, electrocardiographic assessments were not performed to monitor cardiac side effects (18–20).

Several secondary observations are worth noting, including sex-related differences in the measurements of QT-related parameters. The study showed an increase in QTcF among females at all time points that is consistent with previous studies (21, 22). Regarding AEs, less than one-fifth of patients reported mild abdominal pain, headache, cough, or nausea. All appeared to be self-limiting, and none required specific treatment or intervention. Although this trial was not designed to evaluate the efficacy of DHA-PQP, all participants remained parasite negative for the duration of the study. This lack of breakthrough infections, in an area where malaria transmission is high (5, 6, 23) and endogenous Plasmodium vivax relapses are common, reassuringly suggested that posttreatment prophylaxis was satisfactory.

This study, however, does present certain limitations. The first one includes the lack of a control group, which may hinder some of the interpretation of our results. Another limitation was the relatively high attrition rate that saw 18% of enrolled participants fail to complete the scheduled follow-up appointments, and these were therefore excluded from our per-protocol analysis. If those lost to follow-up had been prone to greater QTc prolongation, this could have been a source of bias. However, there were no statistically significant differences in baseline characteristics between participants who were lost to follow-up and those who completed follow-up. We also acknowledge an issue of generalizability of our findings regarding the way we managed food coadministation in this study. Administration of DHA-PQP with food, particularly fat, increases bioavailability, leading to increased drug concentrations and greater degree of QT prolongation (8). We carefully controlled this by advising all participants to avoid food intake for the 3 h before and after drug administration. However, while feasible in the context of a tightly controlled research study, this level of compliance may be difficult to achieve in a real MDA campaign delivered on a very large scale. Hence, it is possible that individuals not following this dietary advice could be prone to greater drug absorption, higher cumulative doses, and greater QTc prolongation than seen in our study.

Our primary endpoint was to examine changes in mean QTcF values consistent with guidelines by the U.S. FDA and other regulatory bodies. However, in terms of population risk, the way in which values are distributed across populations is perhaps more important than the measures of centrality reported here. It is those individuals who lie on the upper edge of the population distribution who are most important. For example, if an MDA intervention is deployed in 100,000 people, presuming that QTc distribution has a normal population distribution, 2,500 people will have QTc prolongations that are 2 SD above the population mean. These would be the individuals at greatest risk of a serious cardiac event. Our clinical study, like all others performed to date, did not have anywhere near the sample size required to define the population distribution accurately enough to define risk in this group. In practice, the only way this will ever be further clarified is by robust pharmacovigilance employed during large-scale MDA implementation programs.

In this study, all patient QTc measurements after three courses of DHA-PQP treatment were within approved safety margins outlined by U.S. drug regulatory institutions. The data do not suggest that the known risk of QT prolongation increases cumulatively with repeated monthly courses out to the 3rd course. However, the observation of slightly increased QT prolongation after two courses of treatment requires further investigation. At this stage, data from this study, together with the lack of reported adverse cardiac events in repeated-course MDA intervention programs elsewhere (5, 23), suggest that DHA-PQP can be used safely as MDA delivered using conventional dosing in up to 3 monthly rounds as a tool for malaria elimination. Cautions need to be articulated in relation to the antimalarial major drawbacks. First, multidrug resistance could reduce the impact; therefore, monitoring the drug’s efficacy will be required (24). Second, the three daily doses required for each round of MDA result in a major logistic burden and stretch the tolerance of the target population. Nevertheless, the absence of a single-dose antimalarial with safety data for repeated dosing support DHA-PQP as one of the best available options for MDA.

We acknowledge all the participants in the study and the Lihirian communities for the acceptance and collaboration in this research. We thank Anitua Mining Services and Newcrest Mining Limited for their support with the logistics in Lihir Island and Medicines for Malaria venture (MMV) for the research grant provided to ISGlobal as part of its collaborative agreement with Newcrest to support the Lihir Malaria Elimination Programme. We acknowledge International SOS and the staff at the Lihir Medical Centre for their work and support during the study, especially the Public Health Department and the Laboratory Department.

ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. CISM is supported by the Spanish Agency of International Cooperation (AECID). Q.B. is member of the WHO Malaria Treatment Guidelines Group. This group produces global guidance on the treatment of malaria, and this includes decisions about pyronaridine-artesunate. The views expressed by the authors are personal opinions and do not represent the recommendations of the WHO. The other authors declare no conflicts of interest.

O.M. and Q.B. conceived the study and developed the analysis plan. P.M.-M. and R.I. conducted the study, including patient enrollment and data collection. H.A. and K.P. conducted the laboratory tests. P.M.-M. and S.S. conducted the statistical analyses. O.M., P.M.-M. and Q.B. prepared the first draft of the article with important intellectual input and revisions from R.I., M.L., L.R., H.K., L.M., and B.M. All authors approved the final version of the article.