Lassa fever, a viral hemorrhagic disease endemic to West Africa, remains a major public health concern because of its high mortality and limited therapeutic options. For decades, ribavirin has been used as the standard treatment despite ongoing uncertainty regarding its efficacy and safety profile. Findings from the phase 2 SAFARI trial suggest that favipiravir, an antiviral initially developed for influenza, could emerge as a safer and well-tolerated alternative for patients with acute Lassa fever.
The SAFARI trial was a randomized, open-label phase 2 study conducted at two reference hospitals in Nigeria between 2021 and 2022. Investigators enrolled 41 adults with mild-to-moderate RT-PCR confirmed Lassa fever. Participants were randomized to receive either intravenous ribavirin (21 patients) or oral favipiravir (20 patients). Thirty-six participants completed the 10-day treatment and follow-up period, and all patients survived and were discharged from isolation wards.
A major focus of the study was evaluating favipiravir’s pharmacokinetic profile. Using a one-compartment model, researchers demonstrated reliable drug exposure with a median steady-state maximum plasma concentration of 50.9 mg/L, a half-life of 10.9 hours, and an area under the curve (AUC0–240h) of 9,275 mg·h/L. Body weight significantly influenced drug clearance, with heavier patients showing faster elimination of favipiravir.
By comparison, ribavirin exhibited more complex three-compartment pharmacokinetics, including notable sex-related differences in clearance. Female participants had approximately 36% lower ribavirin clearance than males. Pharmacokinetic simulations further suggested that optimized favipiravir dosing strategies may improve antiviral activity while limiting peak plasma concentrations associated with adverse effects. One proposed regimen, consisting of 2,400 mg twice daily on day 1 followed by 1,600 mg twice daily from days 2 to 10, maintained drug concentrations above inhibitory thresholds for most of the treatment period, indicating strong potential for sustained viral suppression.
Safety outcomes were among the co-primary endpoints of the trial. Across both treatment groups, investigators documented 86 treatment-emergent adverse events, of which 30 were considered drug-related. Vomiting was the most frequently reported adverse event with favipiravir, occurring in 30% of patients, whereas ribavirin was more commonly associated with anemia, reported in 24% of patients. One patient receiving ribavirin developed life-threatening anemia that required multiple blood transfusions and discontinuation of therapy. In contrast, no severe or serious drug-related adverse events were observed in the favipiravir arm. Additional adverse events included pyrexia, dizziness, rash, and transient electrocardiographic abnormalities. One favipiravir-treated patient developed first-degree atrioventricular block, prompting withdrawal from treatment as a precaution, although the condition resolved without complications. Hyperuricemia occurred more frequently among favipiravir recipients but remained asymptomatic and clinically insignificant.
Both treatment groups demonstrated comparable antiviral effects. Viral clearance, assessed by increases in RT-PCR cycle threshold values for Lassa virus genes, showed median increases of 9.4 in the ribavirin group and 8.9 in the favipiravir group. Average hospital stay was approximately 10 days in both treatment arms, and no deaths occurred during the study period.
Exploratory pharmacokinetic-pharmacodynamic analyses suggested that favipiravir may produce a slower but sustained increase in cycle threshold values compared with ribavirin, particularly in patients presenting with higher baseline viral loads. Investigators noted that this pattern may support prolonged viral suppression during therapy.
Researchers also drew parallels between the SAFARI trial and earlier phase 2 studies evaluating favipiravir in severe influenza infections. Both studies identified declining favipiravir exposure over time and emphasized the importance of optimized dosing strategies to maintain therapeutic drug levels in severe viral illnesses. By systematically assessing pharmacokinetics, safety, and antiviral activity in hospitalized patients, these studies collectively strengthen the evidence base for favipiravir as a potential treatment for serious RNA virus infections.
The SAFARI trial represents the first interventional clinical study in Lassa fever in nearly four decades. Its findings position favipiravir as a pharmacologically promising and well-tolerated candidate for further development. Although ribavirin remains the current standard of care, concerns regarding its risk-benefit balance continue to grow.
Investigators emphasized that larger, controlled studies are still required to confirm clinical efficacy and define favipiravir’s role in routine Lassa fever management. The SAFARI trial marks an important step toward expanding therapeutic options for a disease that continues to lack approved vaccines and effective targeted treatments.
References
- Erameh C, Okwaraeke K, Kleist C, Edeawe O, Adedosu N, Ekata E, et al. Favipiravir for Lassa fever: an open-label, randomized controlled phase 2 trial. Nature Medicine. 2026 May 15:1-1.
- Wang Y, Zhong W, Salam A, Tarning J, Zhan Q, Huang JA, et al. Phase 2a, open-label, dose-escalating, multi-center pharmacokinetic study of favipiravir (T-705) in combination with oseltamivir in patients with severe influenza. EBioMedicine. 2020 Dec 1;62.