Tecovirimat Fails to Improve Mpox Resolution, May Fuel HIV Resistance
Recent research is casting doubt on the effectiveness of tecovirimat as a treatment for mpox, formerly known as monkeypox. Studies presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in February 2026, and published in the New England Journal of Medicine, indicate the antiviral drug doesn’t significantly improve clinical resolution of the infection and may even contribute to antiviral resistance, particularly in individuals with advanced HIV. These findings challenge the widespread use of tecovirimat during the 2022 global outbreak, when it was deployed despite limited efficacy data.
Limited Clinical Benefit Observed in STOMP Trial
The core of the new evidence comes from the STOMP/A5418 trial, a randomized, placebo-controlled study involving 412 patients with confirmed mpox and active skin or mucosal lesions. Participants received either tecovirimat or a placebo for 14 days. Researchers assessed clinical resolution, pain reduction, lesion healing, viral DNA clearance, and safety. The primary outcome – cumulative incidence of clinical resolution – showed no statistically significant difference between the two groups: 83% with tecovirimat versus 84% with placebo (competing risks HR = 0.98. 95% CI, 0.74-1.31). There were also no significant differences in pain reduction, lesion healing, or viral DNA clearance. Previous data from the STOMP trial, presented at CROI in 2025, had already suggested a lack of benefit in reducing lesions, pain, or viral clearance.
Antiviral Resistance Concerns in People with HIV
Adding to the concerns, researchers led by Alex Greninger, MD, PhD, MS, MPhil, at the University of Washington, investigated the emergence of antiviral resistance. They tested for viral isolation by culturing swabs from skin lesions at baseline and on day 8, and performed deep sequencing of swabs taken through day 57. The analysis focused on participants living with HIV. The study revealed that tecovirimat had no effect on viral isolation compared to placebo. However, treatment-emergent variants, including those associated with antiviral resistance, were observed in 6.5% of participants in the open-label tecovirimat arm. Notably, these resistance mutations were associated with significantly higher viral loads and were more common in individuals with lower CD4 counts (less than 80 cells/mm3). Dr. Greninger emphasized the require for vigilance regarding treatment-emergent resistance and suggested considering combinatorial therapy for individuals with advanced HIV.
Understanding Tecovirimat and its Approval
Tecovirimat, originally approved by the FDA for the treatment of smallpox under the Animal Rule (based on preclinical data), was rapidly adopted for mpox treatment during the 2022 outbreak due to a lack of alternative options. The FDA approval relied on efficacy data from animal models, and its effectiveness against mpox in humans remained uncertain. The recent study findings underscore the importance of robust clinical trials to evaluate the efficacy of therapeutics, even when faced with public health emergencies.
Implications for Current and Future Mpox Management
These findings have significant implications for how mpox is managed. The lack of demonstrated benefit from tecovirimat suggests that current treatment protocols may need to be re-evaluated. The emergence of antiviral resistance, particularly in immunocompromised individuals, highlights the need for careful monitoring and potentially alternative treatment strategies. The data also reinforce the importance of preventative measures, such as vaccination, to control the spread of the virus. The Centers for Disease Control and Prevention (CDC) continues to monitor mpox cases and provide updated guidance on prevention and treatment. The Social Security Administration also provides guidance on avoiding scams related to health information.
What’s Next: Research and Guidance Updates
Researchers are now focused on identifying safe and effective therapeutics for mpox and other orthopoxviruses. Further studies are needed to understand the mechanisms of antiviral resistance and to develop strategies to overcome them. Public health agencies are likely to review current treatment guidelines in light of these new findings. Ongoing surveillance of mpox cases and genomic sequencing of the virus will be crucial for detecting and tracking the emergence of resistance mutations. The development of new antiviral drugs and vaccines remains a priority.
The findings from the STOMP trial and related research emphasize the dynamic nature of infectious disease management and the importance of continuous evaluation of treatment strategies based on emerging evidence. While tecovirimat may still have a role in specific clinical scenarios, its widespread use as a first-line treatment for mpox is now questionable.