First Therapeutic Efficacy Study (TES) in Djibouti: A Critical Milestone Amid Rising Regional Threats

Background Malaria control in the Horn of Africa faces growing challenges from emerging antimalarial resistance, diagnostic failures due to gene deletions, and the invasive Anopheles stephensi. In Djibouti, where artemether-lumefantrine (AL) has been the first-line treatment since 2014, no prior therapeutic efficacy studies (TES) had assessed in-country drug performance. Methods A 28-day, single-arm TES was conducted at Arhiba Health Centre in Djibouti City from April 16 to May 5, 2024, enrolling patients aged ≥6 months with uncomplicated P. falciparum malaria. AL was administered under direct observation, with follow-up on days 1–3, 7, 14, 21, and 28 for clinical assessment, microscopy, rapid diagnostic tests (RDT), and qPCR. Molecular analyses included detection of resistance markers, gene deletions, parasite diversity, and identity-by-descent. Results Of 88 enrolled patients, 70 completed follow-ups. The PCR-adjusted adequate clinical and parasitological response (ACPR) was 98.6% (95% CI, 96.1–100.0), with one recrudescence. Gametocytes were observed in 11.4% at baseline and persisted through day 21. HRP2-based RDT detected only 37.5% of infections compared to 100% using pLDH-based RDT, consistent with pfhrp2/3 deletions (95.6%, 44/46). Resistance markers included Pfk13 R622I (one case), PfCRT CVIET 90.9% (70/77) and SVMNT 2.6% (2/77), PfDHFR AIRNI 40.2% (31/77) and PfDHPS ISGEAA 72.2% (52/72), and PfMDR1 NFSND 96.1% (74/77). Most infections were monoclonal (mean complexity of infection = 1.62) and exhibited high genetic relatedness. Conclusions AL remains effective in Djibouti; however, widespread pfhrp2/3 deletions, persistent gametocytaemia, and resistance markers underscore the need for integrated molecular surveillance and the adoption of transmission-blocking interventions such as single-dose primaquine.