Artemether-lumefantrine versus pyronaridine-artesunate for the treatment of malaria in patients with mild to moderate COVID-19 in Kenya and Burkina Faso: a randomised open-label trial (MALCOV)

Background: It is unknown whether the choice of malaria treatment for uncomplicated malaria affects coronavirus disease 2019 (COVID-19) severity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load, or duration of viral shedding. Several antimalarials exhibit antiviral activity against SARS-CoV-2 in-vitro and have been suggested as potential therapeutic candidates for COVID-19, particularly pyronaridine-artesunate (PA), despite disappointing clinical results with chloroquine and hydroxychloroquine.

Methods: We conducted an open-label randomised trial comparing standard 3-day treatment with PA and artemether-lumefantrine (AL) in newly diagnosed SARS-CoV-2 infected patients aged >=6 months with rapid diagnostic test or microscopy-confirmed non-severe malaria in Kenya and Burkina Faso. SARS-CoV-2 was assessed by RT-PCR on days 3, 7, 14, and 28, and symptom resolution was assessed daily for 14 days using FLU-PRO-Plus. The primary endpoint was the proportion of participants with SARS-CoV-2 clearance by day 7. Secondary endpoints included SARS-CoV-2 clearance by days 14, 21, and 28, time to SARS-CoV-2 clearance over 28 days, median viral load on day 7, and time to symptom resolution. Complete case analysis was conducted using log-binomial regression for binary outcomes, Cox-regression for time-to-event outcomes, and negative binomial regression for count outcomes, all adjusted for disease severity and viral load at enrolment. The trial is registered with ClinicalTrials.gov NCT04695197.

Findings: From January 2021 to January 2022, 143 participants were randomised (PA=69, AL=74, intention-to-treat [ITT] population), including 117 with reverse transcription polymerase chain reaction (RT-PCR) confirmed (PA=58, AL=59, modified intention-to-treat [mITT] population) and 26 with rapid-antigen test confirmed SARS-CoV-2 infection. The median age was 19 years (interquartile range [IQR] 13-38), 66% were aged >=15 years. Baseline characteristics were comparable.
SARS-CoV-2 clearance by day-7 (primary endpoint) was 41% (22/54) with PA versus 58% (33/57) with AL (adjusted risk ratio [aRR]=0.78, 95% confidence interval [CI] 0.45-1.35, p=0.37); by day-14: PA=80% (44/55) versus AL=96% (55/57) AL (aRR=0.86, 0.58-1.29, p=0.47). Median (IQR) viral load on day-7 was higher with PA (855 [30-2883] versus AL:81 [12-209] copies/mL, p=0.023). Time to SARS-CoV-2 clearance over 28 days was slower with PA (adjusted hazard ratio [aHR]: 0.55, 0.37-0.83, p=0.004). Time to symptom clearance between treatments was similar (aHR=1.01, 0.91-1.13, p=0.79). Parasitological cure rates by day 42 were PA=100% and AL=99%. Five serious adverse events occurred (PA=2, AL=3) in three participants (PA=1, AL=2), including three hospitalisations (PA=1, AL=2), resulting in two deaths, both from respiratory failure (PA=1, AL=1). No serious adverse events (SAEs) were considered treatment-related.

Interpretation: Pyronaridine-artesunate in COVID-19 patients co-infected with malaria was associated with slower viral clearance than standard treatment with artemether-lumefantrine but similar symptom resolution. Both treatments were highly effective as antimalarials and should continue to be considered first- or second-line treatments options for uncomplicated malaria in patients with mild to moderate COVID-19.