We assessed the role of single-dose combination therapy compared to praziquantel alone in treating African children with intestinal (S. mansoni) or urinary (S. haematobium) schistosomiasis. In general, cure and egg reduction rates, assessed at six weeks, were higher after treatment of S. haematobium-infected compared to S. mansoni-infected children. However, cure rates after combination therapy were not improved compared to praziquantel after treatment of children with either intestinal or urinary schistosomiasis. A single oral dose of artesunate plus sulfalene-pyrimethamine had a similar cure rate to praziquantel against urinary schistosomiasis but was inferior against intestinal schistosomiasis. Treatment of children with S. haematobium resulted in egg reduction rates above 90% in all three treatment groups, but these were below 90% in treating intestinal schistosomiasis. There was no difference in cure and egg reduction rates after treatment of children with mixed infections (data not shown). A similar number of children developed adverse events in the three treatment groups. However, the proportion of adverse events was significantly higher in the combination therapy group compared to the other two treatment groups. No serious adverse events were reported.
In our study site, the prevalence of schistosomiasis in school-aged children was 55%, with most children presenting with light-intensity infections, including 10% with mixed schistosome infections. A single oral dose of praziquantel cured 75.6% and 81.4% of children with S. mansoni and S. haematobium, respectively. Egg reduction rates for children with S. mansoni and S. haematobium were 80.1% and 95.6%, respectively. These cure and egg reduction rates are consistent with a meta-analysis of previous studies [36]. The WHO recommends a 90% egg reduction rate for satisfactory efficacy in treating schistosomiasis [37]. The egg reduction rates after treatment of S. mansoni were below 90%, indicating a reduced treatment efficacy by the WHO criteria. However, these were above 90% for S. haematobium, suggesting satisfactory treatment efficacy. We noted a higher cure rate in children with light-intensity S. mansoni infections than those with S. haematobium. This is consistent with the observation that cure rates after a single dose of praziquantel are usually inversely proportional to the infection intensities at baseline [8, 38, 39].
Artesunate plus sulfalene-pyrimethamine is an excellent antimalarial drug effective as a 24-hour or 3-day regime in treating uncomplicated falciparum malaria [40, 41]. In previous studies, artesunate plus sulfalene-pyrimethamine was less effective than praziquantel in curing children with S. mansoni (14% vs 65%, 3-day regime) or S. haematobium (44% vs 53%, 24-hour regime)[21, 22]. This study confirms that single-dose praziquantel is more effective than single-dose artesunate plus sulfalene-pyrimethamine for S. mansoni. These findings are consistent with a recent exploratory study that observed cure rates of 69% vs 80% when single doses of artesunate plus sulfalene-pyrimethamine and praziquantel were compared in the treatment of children with S. mansoni infection in Kenya [42]. These findings suggest a dose-response function indicating that a 3-day treatment regime using the same dose of artesunate plus sulfalene-pyrimethamine to treat malaria may be ineffective for curing S. mansoni. We found comparable cure rates between artesunate plus sulfalene-pyrimethamine and praziquantel against S. haematobium infection (71.1% vs. 81.4%). This may be attributed to the high percentage of light-intensity S. haematobium infection in our participants but may also suggest that the parasite is more responsive to ACT treatment than S.mansoni infection. For unclear reasons, our results contrast the study in Mali, where a similar treatment regime cured only 43.9% of children with S. haematobium [21].
In this study, combination therapy was as effective as praziquantel against urinary or intestinal schistosomiasis. However, for S. haematobium, combination therapy was associated with higher cure and egg reduction rates than S. mansoni infection. These differences in response rates can be explained by the high proportion of light S. haematobium infection intensity at enrollment and the differential sensitivity of the schistosome species to treatment. Overall, single-dose combination therapy did not improve treatment efficacy than praziquantel for either S. mansoni or S. haematobium infection. This contrasts the finding with praziquantel plus dihydroartemisinin-piperaquine vs praziquantel for S.mansoni [26], but is consistent with praziquantel plus artesunate-mefloquine for S.haematobium [27] and praziquantel plus artemether for S. japonicum infection [43]. It is unclear whether we would have found different cure rates if we had administered the study drugs sequentially rather than simultaneously.
The study drugs were well tolerated, and most adverse events were mild and transient. This study is consistent with previous studies that reported only mild adverse events with either praziquantel or artesunate plus sulfalene-pyrimethamine. The most frequent adverse events across the treatment groups were abdominal pain, nausea, vomiting, and dizziness, which is consistent with previous studies [39, 44–47]. However, participants in the combination therapy reported a significantly higher number of adverse events than the other two treatment arms. Drug-drug interactions from the simultaneous drug administration and the higher pill burden could explain the high risk of adverse events in the combined therapy group. The use of self-reports, limited sample size, and short duration of the study limited our ability to compare drug safety confidently. The relative safety of the drugs administered alone suggests that sequential, rather than simultaneous, administration may improve the efficacy and safety outcomes.
Our study had some limitations. Most of our participants had light-intensity infections at baseline, meaning these findings should be applied cautiously to high transmission areas since light-intensity infections are associated with high cure rates [8, 39, 40]. A double-blind design would have improved our study. However, incorporating matching placebo tablets for the drugs assessed in this study would have been impractical. We used single stool and urine samples during enrollment and follow-up for logistical reasons. Kato-Katz and urine filtration tests for schistosomiasis have low sensitivity to low-intensity infections and may have misclassified some participants. Six weeks following therapy may not have been the best time to determine Efficacy [48]. However, due to a lack of standardized treatment efficacy testing protocols, schistosomiasis treatment studies assessed efficacy three to 12 weeks post-treatment, making comparisons difficult. For this study, compliance was improved by the use of single-dose treatment. However, assessment of kidney and liver functions would have improved our drug safety evaluation.
If efficacious, safe, acceptable, and feasible, the introduction of combination therapy may shift schistosomiasis control from morbidity to transmission control and hasten the global elimination agenda. Combined therapy may be effective in malaria-free settings, in individuals with both malaria and schistosomiasis, as chemoprophylaxis for travellers to endemic areas, as a second-line treatment after praziquantel failure, and as seasonal chemoprophylaxis in malaria-endemic areas. Combination therapy is expensive and challenging to implement for mass drug administration. Additional studies are needed to validate these findings in different epidemiological settings, to assess other ACT-praziquantel combinations and drug-drug interactions, to evaluate appropriate dosing intervals, and the impact of sequential or simultaneous delivery. Other studies are needed to monitor the markers of antimalarial drug resistance and the beneficial impact of ACT implementation for malaria control on schistosomiasis control.
In conclusion, the role of combination therapy in treating and controlling schistosomiasis remains unclear. In this study, combination therapy was associated with a high risk of adverse events. It cured a high proportion of children with S. haematobium, but overall, it did not improve treatment efficacy for urinary or intestinal schistosomiasis. Sequential administration of praziquantel and artesunate plus sulfalene-pyrimethamine may improve the efficacy and safety outcomes.