Discussion
malaria, HPV-related disease, parasitemia, vulvar HPV-related disease, HSIL, anal disease, malarial deaths
RECURRENCE, MALARIA, PARASITEMIA, MAY, HSIL, SECONDARY
In May 2020, the FDA approved intravenous artesunate as first-line treatment for severe malaria, in infants, children, and adults. Between 2000–2020, 10.6 million malarial deaths were averted due to the utilization of artesunate combination therapy [Over the past years, office-based ablation via electrocautery has been used effectively in many HRA clinics and was the main treatment modality in the ANCHOR study [Topical treatments of anal HSIL are preferable for some patients due to ease of use and less invasiveness. Off-label topical treatments of anal HSIL include 5-FU and more commonly the TLR-7 agonists imiquimod, which stimulates anti-viral cytokines and natural killer cell responses against HPV-infected cells [In the current study, 59% of participants treated with artesunate suppositories had a partial or complete response over the study window, and 50% of the complete responders also had viral clearance. While the primary objective of this Phase 1 study was to evaluate safety and tolerability, data suggest that artesunate could be effective in the treatment of intra-anal HSIL. These findings are similar to the phase I study of artesunate vaginal inserts for the treatment of CIN2/3, where 67.9% had complete response, and 47.4% of those with complete response also underwent viral clearance [With the limitation of the small cohort size, subgroup analyses suggest that artesunate may be more effective in the treatment of anal HSIL of HIV negative patients versus PLWH, who are known to have a higher risk of HSIL recurrence and HSIL to ASCC progression [Once a MTD was determined to be 400mg, the study sponsor decided to further evaluate key secondary outcomes in a controlled Phase IIB study. A randomized, placebo-controlled phase IIB study of artesunate suppositories for HIV-negative individuals with intra-anal HSIL is currently open to enrollment. A second controlled Phase IIB study in HIV+ individuals will open soon. Evaluation of the treatment effect of intra-anal artesunate will be the primary focus of the ongoing Phase 2 trial in anal HSIL. Furthermore, clinical trials are ongoing to evaluate the efficacy of topical artesunate in cervical and vulvar HPV-related disease (clinicaltrials.gov: NCT03792516, NCT04098744, NCT05555862)A potential concern with topical artesunate therapy for treatment of HPV-related disease is that it might contribute to malarial resistance if used for patients in malaria endemic regions of the world. Resistance of The use of intra-anal artesunate to treat anal HSIL is not anticipated to contribute to global malarial resistance development, as patients acutely sick with acute malaria would be unlikely to receive simultaneous treatment for anal disease. Systemic absorption of the topical artesunate formulation used in this study will be evaluated during Phase 2; this information will provide further information to assess this risk, including in the setting of asymptomatic parasitemia in malaria endemic regions.