Abstract:
Children with sickle cell anemia (SCA) in areas of Africa with endemic malaria transmission
are commonly prescribed malaria chemoprevention. Chemoprevention regimens vary
between countries, and the comparative efficacy of prevention regimens is largely unknown.
Methods and findings
We enrolled Kenyan children aged 1 to 10 years with homozygous hemoglobin S (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 dihydroarte-
misinin-piperaquine (DP) and followed monthly for 12 months. 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 by self-report. Secondary outcomes included
other parasitologic, hematologic, and general 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. A total of 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 inter-
val [CI]: 0.36 to 26.14; p = 0.39) and DP (IRR: 1.36, 95% CI: 0.21 to 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 was associated with a reduced rate of dactylitis (IRR: 0.47; 95% CI: 0.23 to 0.96; p =
0.038). The incidence of Plasmodium falciparum infection relative to daily Proguanil was
similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17 to 1.20; p = 0.13) but reduced
with monthly DP (IRR 0.21; 95% CI: 0.08 to 0.56; p = 0.002). Serious adverse events were
common and distributed between groups, although compared to daily Proguanil (n = 2),
more children died receiving monthly SP-AQ (n = 7; hazard ratio [HR] 5.44; 95% CI: 0.92 to
32.11; p = 0.064) but not DP (n = 1; HR 0.61; 95% CI 0.04 to 9.22; p = 0.89), although differ-
ences did not reach statistical significance for either SP-AQ or DP. 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 gener-
alizability to higher-transmission settings where routine sickle cell care is more limited.
Conclusions
In this study with limited malaria transmission, malaria chemoprevention in Kenyan children
with SCA with monthly SP-AQ or DP did not reduce clinical malaria, but DP was associated
with reduced dactylitis and P. falciparum parasitization. Pragmatic studies of chemopreven-
tion in higher malaria transmission settings are warranted.