Artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Liberia: in vivo efficacy and frequency of molecular markers.

BACKGROUND: Artesunate-amodiaquine (ASAQ) and Artemether-lumefantrine (AL) are the recommended treatment for uncomplicated Plasmodium falciparum malaria in Liberia. Intermittent preventive treatment with sulfadoxine/pyrimethamine is also recommended for pregnant women. The therapeutic efficacy of Artesunate-amodiaquine and Artemether-lumefantrine, and the frequency of molecular markers associated with anti-malarial drug resistance were investigated. METHODS: The therapeutic efficacy of ASAQ and AL was evaluated using the standard World Health Organization protocol (WHO. Methods for Surveillance of Antimalarial Drug Efficacy. Geneva: World Health Organization; 2009. https://www.who.int/malaria/publications/atoz/9789241597531/en/ ). Eligible children were recruited and monitored clinically and parasitologically for 28 days. Polymorphisms in the Pfkelch 13, chloroquine resistance transporter (Pfcrt), multidrug resistance 1 (Pfmdr-1), dihydrofolate reductase (Pfdhfr), and dihydropteroate synthase (Pfdhps) genes and copy number variations in the plasmepsin-2 (Pfpm2) gene were assessed in pretreatment samples. RESULTS: Of the 359 children enrolled, 180 were treated with ASAQ (89 in Saclepea and 91 in Bensonville) and 179 with AL (90 in Sinje and 89 in Kakata). Of the recruited children, 332 (92.5%) reached study endpoints. PCR-corrected per-protocol analysis showed ACPR of 90.2% (95% CI: 78.6-96.7%) in Bensonville and 92.7% (95% CI: 83.4.8-96.5%) in Saclepea for ASAQ, while ACPR of 100% was observed in Kakata and Sinje for AL. In both treatment groups, only two patients had parasites on day 3. No artemisinin resistance associated Pfkelch13 mutations or multiple copies of Pfpm2 were found. Most samples tested had the Pfcrt 76 T mutation (80/91, 87.9%), while the Pfmdr-1 86Y (40/91, 44%) and 184F (47/91, 51.6%) mutations were less frequent. The Pfdhfr triple mutant (51I/59R/108 N) was the predominant allele (49.2%). For the Pfdhps gene, it was the 540E mutant (16.0%), and the 436A mutant (14.3%). The quintuple allele (51I/59R/108 N-437G/540E) was detected in only one isolate (1/357). CONCLUSION: This study reports a decline in the efficacy of ASAQ treatment, while AL remained highly effective, supporting the recent decision by NMCP to replace ASAQ with AL as first-line treatment for uncomplicated falciparum malaria. No association between the presence of the mutations in Pfcrt and Pfmdr-1 and the risk of parasite recrudescence in patients treated with ASAQ was observed. Parasites with signatures known to be associated with artemisinin and piperaquine resistance were not detected. The very low frequency of the quintuple Pfdhfr/Pfdhps mutant haplotype supports the continued use of SP for IPTp. Monitoring of efficacy and resistance markers of routinely used anti-malarials is necessary to inform malaria treatment policy. Trial registration ACTRN12617001064392.

Measuring Knowledge of Community Health Workers at the Last Mile in Liberia: Feasibility and Results of Clinical Vignette Assessments.

INTRODUCTION: Community health workers (CHWs) can provide lifesaving treatment for children in remote areas, but high-quality care is essential for effective delivery. Measuring the quality of community-based care in remote areas is logistically challenging. Clinical vignettes have been validated in facility settings as a proxy for competency. We assessed feasibility and effectiveness of clinical vignettes to measure CHW knowledge of integrated community case management (iCCM) in Liberia's national CHW program. METHODS: We developed 3 vignettes to measure knowledge of iCCM illnesses (malaria, diarrhea, and pneumonia) in 4 main areas: assessment, diagnosis, treatment, and caregiver instructions. Trained nurse supervisors administered the vignettes to CHWs in 3 counties in rural Liberia as part of routine program supervision between January and May 2019, collected data on CHW knowledge using a standardized checklist tool, and provided feedback and coaching to CHWs in real time after vignette administration. Proportions of vignettes correctly managed, including illness classification, treatment, and referral where necessary, were calculated. We assessed feasibility, defined as the ability of clinical supervisors to administer the vignettes integrated into their routine activities once per year for each CHW, and effectiveness, defined as the ability of the vignettes to measure the primary outcomes of CHW knowledge of diagnosis and treatment including referrals. RESULTS: We were able to integrate this assessment into routine supervision, facilitate real-time coaching, and collect data on iCCM knowledge among 155 CHWs through delivery of 465 vignettes. Diagnosis including severity was correct in 65%-82% of vignettes. CHWs correctly identified danger signs in 44%-50% of vignettes, correctly proposed referral to the facility in 63% of vignettes including danger signs, and chose correct lifesaving treatment in 23%-65% of vignettes. Both diagnosis and lifesaving treatment rates were highest for malaria and lowest for severe pneumonia. CONCLUSION: Administration of vignettes to assess knowledge of correct iCCM case management was feasible and effective in producing results in this setting. Proportions of correct diagnosis and lifesaving treatment varied, with high proportions for uncomplicated disease, but lower for more severe cases, with accurate recognition of danger signs posing a challenge. Future work includes validation of vignettes for use with CHWs through direct observation, strengthening supportive supervision, and program interventions to address identified knowledge gaps.