Background and rationale
Despite a reduction in the incidence over the last decade, malaria remains a major problem of public health, with 214 million cases and 438,000 deaths occurring yearly. Sub-Saharan Africa is the most affected region, where 90% of deaths are accounted. Malaria control was hindered by the spread of resistance of Plasmodium falciparum to chloroquine and sulfadoxine-pyrimethamin, the most available and affordable antimalarial drugs at that time. An overtreatment resulted from prescribing those antimalarials without laboratory confirmation and contributed to the selection and spread of resistant strains. As a response to that situation, the World Health Organization (WHO) recommended the use of effective but expensive Artemisin-based Combination Therapies (ACTs) for first-line treatment of uncomplicated malaria cases. Further, are all National Malaria Control Programs (NMCP) recommended to change the treatment guidelines when the efficacy of the recommended antimalarial drugs is below 90%. Therefore, a regular monitoring of the efficacy is paramount. In addition, the confirmation of the diagnosis was meant to be mandatory prior prescription of ACTs. In case of treatment failure, a rescue treatment either an alternative ACT or a quinine+antibiotic with antiplasmodial properties is recommended since 2010. However, in the field reality, patients are, for several reasons, often retreated with the same first-line medication, without clear evidence on the efficacy and safety. Furthermore, the implementation of malaria policies may be challenging in the field, especially at community and primary health care level (PHC).
Our main objective was to contribute to the improvement of malaria diagnosis and treatment at the PHC. Our specific objectives were: a) to assess the accuracy of malaria diagnosis at PHC in Kinshasa, the Democratic Republic of Congo (DRC); b) to describe an innovative diagnostic tool with a potential to detect malaria infection and assess its accuracy under experimental laboratory conditions as well as in field conditions; c) to assess the discrepancy between malaria policies and practices at PHC in Kinshasa, the DRC; d) to describe the clinical malaria features, update the efficacy of artesunate-amodiaquine (ASAQ) and assess their relation with the multiplicity of infection in DRC; e) to assess the efficacy and safety of retreatment with the same ACT compared to recommended rescue treatments; f) to assess the impact of repeated malaria attacks on children’s health and persistence of recrudescent Plasmodium falciparum strains.
Design and methods
Between 2011 and 2014, we conducted studies in DRC and Uganda, both accounted among highly malarious countries in Africa. A cross-sectional design allowed to assess at PHC the accuracy of malaria diagnosis and to describe the discrepancies between malaria policies and the field reality. The development and assessment of the accuracy of the new malaria diagnostic device (multi-angle light scattering spectroscopy, MALS technique) implied in vitro and in vivo assessments. The randomized, open label, 3-arm clinical trial was embedded in a cascade-cohort study (with assessments before and after the randomized clinical trial), where children with uncomplicated malaria were treated, followed up and retreated until they remained malaria parasite-free for four weeks after the last treatment.
We found that RDTs are more reliable than microscopy in the diagnosis of malaria at PHC. More precisely, compared to the result of expert microscopists, half of patients with positive result of microscopy were false positive (50.9%), while for RDTs it was 3.0% and 8.3%. Furthermore, we described a proof of concept of the MALS technique, a potential future malaria diagnostic tool. The assessment of accuracy under experimental laboratory conditions showed a sensitivity of 62.2% and a specificity of 100%. In field circumstances, the accuracy was low with a sensitivity and specificity of 47.1% and 51.1% respectively. An optimization of this technique is required in order to overcome potential confounding factors and technical constraints.
Malaria cases management
In the first study, testing the accuracy of RDTs and microscopy, we additionally assessed the patients’ seeking behavior and health practitioners’ practices. We observed that most patients (66.2%) attend the health facility (HF) after 2 to 3 days of fever onset. Fifty five percent of patients start with self-medication before attending the HF. On the health practitioners’ side, only 45.7% of patients were managed in line with malaria policies, meaning to prescribe ACTs to malaria positive patients and no antimalarials to those who were tested negative.
Efficacy of artesunate-amodiaquine (ASAQ) and its impact on the multiplicity of infection
ASAQ has been recommended in DRC as first-line malaria treatment in 2005. Our assessment revealed a PCR-adjusted adequate clinical and parasitological response (ACPR) of 92.8% (95% CI: 91.0-94.6). Polyclonal Plasmodium falciparum infections were predominant at recruitment as well as on the day of failure. No recrudescence was reported in patients infected with a single haplotype of P. falciparum. However, the risk of recrudescence in those infected with polyclonal infection was 28%.
Uncomplicated malaria rescue treatment
571 children aged from 12 to 59 months were enrolled in a randomized, open label, three-arm clinical trial that aimed to assess efficacy and safety of retreatment of uncomplicated clinical failures with the first-line ACT, as compared to other rescue treatments. The PCR corrected ACPR was 91.4% (95% CI: 87.5-95.2), 91.3% (95% CI: 87.4-95.1) and 89.5% (95% CI: 83.0-96.0) respectively in the group retreated with the same ACT, the alternative ACT and QnC. The estimates for rates of malaria recrudescence in the three treatment arms were similar (Log rank test: χ2 = 0·22, p = 0·89). The group assigned to alternative ACT experienced less drug-related adverse events (p<0.001). ACTs (either retreatment with the first line ACT or an alternative ACT), are suitable for malaria rescue treatment.
Dynamics of Plasmodium falciparum haplotypes over treatment courses
The recruitment in the Quinact study was lower than expected but the proportion of recurrent malaria was relatively high. The prolonged analysis indicated persistent recrudescences, over several treatment courses, which may contribute to the selection of resistant strains. This was observed regardless of the chosen rescue treatment.
Conclusion and perspectives for future research
The health system needs to be strengthened, with a focus at PHC, for implementation of malaria control strategies. Since RDTs are more accurate than microscopy on the field, they should be preferred and/ or microscopist be permanently trained. ASAQ efficacy was found to be above the required threshold in Kinshasa. Furthermore, the efficacy of retreatment with the same ACT was similar to the recommended rescue treatments. However, ACTs constitute the better option for rescue treatment.
This analysis indicated a small group of children at high risk for subsequent malaria attacks. This group likely contributes on the community-level, heavily to the burden of the disease. The risk factors for this increased vulnerability should be assessed in all the aspects of the epidemiological triangle (host, environment and agent). In addition, the identification of malaria hotspots and focusing prevention strategies in that group may have optimal impact on reducing the burden of the disease in a community.