Monthly sulfadoxine/pyrimethamine-amodiaquine or dihydroartemisinin-piperaquine as malaria chemoprevention in young Kenyan children with sickle cell anemia: A randomized controlled trial
Authors: Taylor Steve M , Korwa Sarah , Wu Angie , Green Cynthia L , Freedman Betsy , Clapp Sheila , Kirui Joseph Kipkoech , O’Meara Wendy P , Njuguna Festus M 
Published: August 2022

Background

Children with sickle cell anemia in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. The comparative efficacy of prevention regimens is largely unknown.

Methods and Findings

We enrolled Kenyan children aged 1-10 years with HbSS in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SP-AQ), or monthly dihydroartemisinin/piperaquine (DP). The primary outcome was the cumulative incidence of clinical malaria at 12 months and the main secondary outcome was the cumulative incidence of painful events. Negative-binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated Population. 246 children were randomized to daily Proguanil (n=81), monthly SP-AQ (n=83), or monthly DP (n=82). Overall, 53.3% (n=131) were boys and the mean age was 4.6 ± 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval [CI]: 0.36–26.14; p=0.39) and DP (IRR: 1.36, 95% CI: 0.21–8.85; p=0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP reduced the rate of dactylitis (IRR: 0.47; 95% CI: 0.23–0.96; p=0.038). The incidence of P. falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17—1.20; p=0.13) but reduced with monthly DP (IRR 0.21; 9 5% CI: 0.08—0.56; p=0.002). Serious adverse events were common and distributed between groups, though more children died receiving monthly SP-AQ (n=7) than Proguanil (2) or DP (1). Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle-cell care is more limited.

Conclusions

Despite limited malaria transmission, monthly malaria chemoprevention with dihydroartemisinin-piperaquine reduced dactylitis and P. falciparum parasitization in Kenyan children with sickle cell anemia. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted.

Trial registration

clinicaltrials.gov: NCT03178643; Pan-African Clinical Trials Registry: PACTR201707002371165

Author Summary

Why was this study done?

Sickle cell anemia (SCA) is a very common condition among children born in malaria-endemic areas of sub-Saharan Africa, but their supportive care regimens are poorly tailored to African settings

Among the complications that children with SCA suffer are more severe outcomes owing to malaria, and therefore many African countries recommend various malaria preventive regimens for children with SCA

It is important to compare the efficacy and safety of these regimens in order to enhance the supportive care of African children with SCA

What did the researchers do and find?

In this study, 3 malaria chemoprevention regimens were compared among children under 10 years old with SCA at a single site in Homa Bay, Kenya

Children were randomly assigned to take daily Proguanil (which is the standard of care in Kenya), a monthly combination of sulfadoxine-pyrimethamine with amodiaquine (SP-AQ), or a monthly combination of dihydroartemisinin-piperaquine (DP), and then followed monthly for 12 months

Cases of malaria were very low among all 3 groups, but the combination of DP reduced the risk of being infected by P. falciparum parasites and of dactylitis, which is a common complication of SCA

DP was not associated with a higher rate of serious adverse events, but SP-AQ was associated with an unexpectedly higher rate of deaths that nearly reached statistical significance

What do these findings mean?

Monthly DP may be an alternative to existing chemoprevention regimens for children with SCA owing to its safety, acceptability, and efficacy on hematologic events

SP-AQ-associated mortality among children with SCA was unexpected and requires further evaluation

Further studies are needed to compare chemoprevention regimens on parasitologic and hematologic outcomes in areas of high P. falciparum transmission and delivered through routine SCA providers