Community access to rectal artesunate for malaria (CARAMAL): a large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda

The key to reducing malaria deaths in highly endemic areas is prompt access to quality case management. Given that many severe cases occur at peripheral level, rectal artesunate (RAS) in the form of suppositories was developed in the 1990s. RAS allows the rapid initiation of life-saving antimalarial treatment, before referral to a health facility with full case management capabilities. One randomized controlled trial published in 2009 showed a protective effect of RAS pre-referral treatment against overall mortality of 26%, but with significant differences according to study sites and length of referral. Two important issues remained unaddressed to-date: (1) whether the mortality impact of RAS observed under controlled trial conditions could be replicated under real-world circumstances; and (2) clear operational guidance for the wide-scale implementation of RAS, including essential health system determinants for optimal impact.From 2018 to 2020, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project was conducted as a large-scale observational implementation study in Nigeria, Uganda and the Democratic Republic of the Congo (DRC). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. In order to achieve this, a number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed to track cases of severe febrile illness from first contact at the periphery to a referral health facility, and then on to a Day 28 visit at the home of the patient. Community and provider cross-sectional surveys complemented the PSS.Here we describe in some detail RAS implementation, as well as the key CARAMAL study components and basic implementation experience. This manuscript provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and cost-effectiveness of the RAS intervention.

Treatment-seeking for children with suspected severe malaria attending community health workers and primary health centres in Adamawa State, Nigeria

BackgroundThe Community Access to Rectal Artesunate for Malaria project investigated the feasibility of introducing pre-referral rectal artesunate into existing community-based health services. In that study, the case fatality rate of children visiting primary health centres (PHCs) was 19% compared to 6% in children first visiting community health workers, locally called Community Oriented Resource Persons (CORPs). As case management practices did not fully explain this finding, this publication investigates other reasons underlying the observed difference in case fatality.MethodsThe observational study enrolled 589 children under the age of five years with fever and danger signs indicative of severe malaria attending CORPs and PHCs in Adamawa State, Nigeria, between June 2018 and July 2020. After 28 days, follow-up visits were conducted with caregivers to understand background characteristics, severity of symptoms, home treatment administration, and treatment seeking practices during the child’s illness. These factors were compared between children visiting CORPs versus those visiting PHCs as their first health provider.ResultsChildren visiting PHCs were more likely to display danger signs indicative of central nervous system involvement (90% vs. 74%, p < 0.01) and have four or more danger signs (50% vs. 39%, p = 0.02). The delay between illness onset and visiting the community-based provider did not differ between children attending a CORP and children attending a PHC. PHC attendances more often lived in urban areas (16% vs 4%, p=0.01) and travelled farther to their first health provider, which was usually a community-based provider. Although practicing home treatment was common, especially among children attending PHCs (42% vs 33%, p=0.04), almost none of the children were given an antimalarial. PHCs were visited for their professionalism and experience while CORPs were visited for their low cost and because caregivers personally knew and trusted the provider.ConclusionsOur comparison of children with suspected severe malaria seeking care from two kinds of community-based health care providers in Nigeria suggest that illness severity may be the primary driver behind the observed difference in case fatality rate.

Acceptability of Rectal Artesunate as pre-referral treatment for severe malaria in children under 5 years by health workers and caregivers in the Democratic Republic of the Congo, Nigeria and Uganda

Background In children below 6 years with suspected severe malaria who are several hours from facilities providing parenteral treatment, pre-referral rectal artesunate (RAS) is recommended by the World Health Organization to prevent death and disability. A number of African countries are in the process of rolling out quality-assured RAS for pre-referral treatment of severe malaria at community-level. The success of RAS depends, among other factors, on the acceptability of RAS in the communities where it is being rolled-out. Yet to date, there is limited literature on RAS acceptability. This study aimed to determine the acceptability of RAS by health care providers and child caregivers in communities where quality assured RAS was rolled out. Methods This study was nested within the comprehensive multi-country observational research project Community Access to Rectal Artesunate for Malaria (CARAMAL). The CARAMAL project was implemented in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda between 2018 and 2020. Data from three different sources were analysed to understand RAS acceptability: Interviews with health workers during three healthcare provider surveys, with caregivers of children under 5 years of age during three household surveys, and with caregivers of children who were recently treated with RAS and enrolled in the CARAMAL Patient Surveillance System. Results RAS acceptability was high among all interviewed stakeholders in the three countries. After the roll-out of RAS, 97-100% heath care providers in DRC considered RAS medication as very good or good, as well as 98-100% in Nigeria and 93-100% in Uganda. Majority of caregivers whose children had received rectal artesunate for pre-referral management of severe malaria indicated that they would want to get the medication again, if their child had the same illness (99.8% of caregivers in DRC, 100% in Nigeria and 99.9% in Uganda). Further, using data from three household surveys, 67-80% of caregivers whose children had not received RAS considered the medication as useful. Conclusion RAS was well accepted by health workers and child caregivers in DRC, Nigeria and Uganda. Acceptability is unlikely to be an obstacle to the large-scale roll-out of RAS in the studied settings.

Health worker compliance with severe malaria treatment guidelines in the context of implementing pre-referral rectal artesunate: an operational study in three high burden countries

Background: Appropriate clinical management of severe malaria is critical to avert morbidity and death. Recommended treatment consists of an injectable antimalarial followed by a full course of oral artemisinin-based combination therapy (ACT). Children who cannot access prompt parenteral treatment should be administered a single dose of rectal artesunate (RAS) and promptly referred to an appropriate facility for further care. This study aimed to assess compliance with the treatment recommendation in children under 5 years diagnosed with severe malaria and admitted to referral facilities in 3 high-burden sub-Saharan African countries. Methods and Findings: This study accompanied the implementation of RAS as a pre-referral treatment in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Children under 5 who were admitted at a referral health facility (RHF) with a diagnosis of severe malaria were included. Type and dosage of antimalarial treatment at RHFs was assessed for children referred from a community-based provider and those directly attending the RHF. We used multivariable regression models to assess factors associated with administration of compliant treatment. RHF data of 7,983 children was analysed for compliance with regards to antimalarials, a subsample of 3,449 children was assessed in more detail for schedule and dosage compliance and method of ACT provision. Overall, 42.0% (3,356/7,983) of admitted children were administered full treatment consisting of a parenteral antimalarial and an ACT, with large variation among study countries (2.7% in Nigeria, 44.5% in Uganda and 50.3% in DRC). Children receiving RAS from a community-based provider were more likely to be administered compliant post-referral medication at RHFs in DRC (adjusted odds ratio (aOR) =2.19, 95% CI 1.60-2.99), but less likely in Uganda (aOR = 0.43, 95% CI 0.19-0.96). Use of injectable antimalarials was very high in all three countries (99.2% (1,344/1,355) in Uganda, 98.1% (413/421) in Nigeria and 94.4% (1,580/1,673) in DRC), with most children receiving the recommended minimum of three doses (99.0% (1,331/1,344) in Uganda, 95.5% (1,509/1,580) in DRC and 92.0% (380/413) in Nigeria). Rather than being administered in the RHF, ACTs were often prescribed at discharge in Nigeria (54.4%, 229/421) and Uganda (53.0%, 715/1,349), while this was rarely done in DRC (0.8%, 14/1,669) where inpatient administration was more common. Conclusions: Directly observed treatment with both a parenteral antimalarial and an ACT was rare and variable between countries, bearing a high risk for incomplete parasite clearance and disease recrudescence. Parenteral artesunate not followed up with a full course of oral ACT constitutes an artemisinin monotherapy and may favour the selection or development of resistant parasites. Stricter health worker compliance with the WHO severe malaria treatment guidelines is therefore needed to effectively manage this disease and further reduce child mortality.

Pre-referral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda

Background: Children who receive pre-referral rectal artesunate (RAS) require urgent referral to a health facility where appropriate treatment for severe malaria can be provided. However, the rapid improvement of a child's condition after RAS administration may influence a caregiver's decision to follow this recommendation. Currently, the evidence on the effect of RAS on referral completion is limited. In this study, we investigated the relationship between RAS implementation and administration and referral completion. Methods and Findings: An observational study accompanied the roll-out of RAS in three malaria endemic settings in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Community health workers and primary health centres enrolled children under five years with suspected severe malaria before and after the roll-out of RAS. All children were followed up 28 days after enrolment to assess their treatment seeking pathways, treatments received, and their health outcome. In total, 8,365 children were enrolled, 77% of whom fulfilled all inclusion criteria and had a known referral completion status. Referral completion was 67% (1,408/2,104) in DRC, 48% (287/600) in Nigeria and 58% (2,170/3,745) in Uganda. In DRC and Uganda, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase (adjusted odds ratio [aOR] = 0.48, 95% CI 0.30-0.77 and aOR = 0.72, 95% CI 0.58-0.88, respectively). Among children seeking care from a primary health centre in Nigeria, RAS users were less likely to complete referral compared to RAS non-users in the post-roll-out phase (aOR = 0.18, 95% CI 0.05-0.71). In Uganda, among children who completed referral, RAS users were significantly more likely to complete referral on time than RAS non-users enrolled in the pre-roll-out phase (aOR = 1.81, 95% CI 1.17-2.79). Conclusions: The findings of this study raise legitimate concerns that the roll-out of RAS may lead to lower referral completion in children who were administered pre-referral RAS. To ensure that community-based programmes are effectively implemented, barriers to referral completion need to be addressed at all levels. Alternative effective treatment options should be provided to children unable to complete referral.

Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children <5 years of age

Background To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, higher-level facilities offering parenteral antimalarials are often difficult to access. A randomised controlled trial found pre-referral rectal artesunate (RAS) to reduce death and disability in children who delay arriving at a referral facility. This study examined the effectiveness of pre-referral RAS treatment in established community-based health care systems. Methods An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo, Nigeria and Uganda. Children < 5 years presenting to a community-based health provider with a positive malaria test and signs of severe malaria were followed-up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment. Findings Post-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 865/6286 patients were sick at follow-up. In all countries, the CFR was higher after RAS-roll-out (6.7 vs. 6.6% in DRC, 16.1 vs. 4.2% in Nigeria, 0.7 vs. 0.3% in Uganda). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR = 3.31, 95% CI 1.43-7.65 and aOR = 2.42, 95% CI 1.25-4.70, respectively). In Uganda, RAS users were less likely to be dead or sick at follow-up (aOR = 0.61, 95% CI 0.46-0.80). Post-referral parenteral antimalarials were protective in all countries; however, the effect of ACT administration was inconsistent. Interpretation RAS pre-referral treatment had no beneficial effect on child survival in three highly malaria endemic settings. RAS is unlikely to reduce malaria deaths unless health system shortfalls such as referral and post-referral treatment are addressed.

Pharmacokinetic study of rectal artesunate in children with severe malaria in Africa

When severe malaria is suspected in children, WHO recommends pre-treatment with a single rectal dose of artesunate before referral to an appropriate facility. This was an individually randomized, open-label, 2-arm, cross-over clinical trial in 83 Congolese children with severe falciparum malaria, to characterize the pharmacokinetics of rectal artesunate. At admission, children received a single dose of rectal artesunate (10 mg/kg) followed 12 hours later by intravenous artesunate (2.4 mg/kg) or the reverse order. All children also received standard doses of intravenous quinine. Artesunate and dihydroartemisinin were measured at eleven fixed intervals, following 0- and 12-hour drug administrations. Clinical, laboratory and parasitological parameters were measured. After rectal artesunate, artesunate and dihydroartemisinin showed large inter-individual variability (peak concentrations of dihydroartemisinin ranged from 5.63 to 8,090 nM). The majority of patients however, reached previously suggested in vivo IC50 (98.7%) and IC90 (92.5%) values of combined concentrations of artesunate and dihydroartemisinin between 15 to 30 minutes after drug administration. The median (IQR) time above IC50 and IC90 was 5.68 hours (2.90-6.08) and 2.74 hours (1.52-3.75), respectively. The absolute rectal bioavailability (IQR) was 25.6% (11.7-54.5) for artesunate and 19.8% (10.3-35.3) for dihydroartemisinin. The initial 12-hour parasite reduction ratio was comparable between rectal and intravenous artesunate: median (IQR) 84.3% (50.0-95.4) vs. 69.2% (45.7-93.6), respectively (p=0.49). Despite large inter-individual variability, rectal artesunate can initiate and sustain rapid parasiticidal activity in most children with severe falciparum malaria, while they are transferred to a facility where parenteral artesunate is available. (www.clinicalTrials.gov : NCT02492178)

Preparations of Rectal Suppositories Containing Artesunate

Rectal artesunate suppositories are a useful option for pre-referral treatment of severe malaria, specifically in children under 6 years of age in remote malaria-endemic areas. The main challenges are to improve the solubility of drugs in the rectal fluids and prevent the product from turning rancid or melting in a tropical climate. In this short proof-of-concept study, three types of rectal suppositories of artesunate were prepared: (i) polyethylene glycol (PEG)-based suppositories carrying free artesunate (non-modified artesunate), (ii) PEG-based suppositories carrying artesunate-loaded micelles and (iii) 3D-printed suppositories carrying a PEG/artesunate mixture. Physical parameters of suppositories, release profiles of artesunate (the fastest to the slowest: ii≥i>iii) and thermostability (the most stable to the least stable: iii>ii>i) of suppositories at increased temperature were assessed to determine the advantages and disadvantages of each formulation.