Amenamevir for acyclovir‐resistant genital HSV ‐2 infection in people living with HIV

This is the authors' abstract. We don't add key points for this paper.

Acyclovir-refractory or resistant (R/R) genital HSV-2 infections are relatively frequent in people living with HIV (PLWH), with a prevalence of 3–7%.1 The use of second-line treatments, foscarnet or cidofovir, is limited by toxicity and parenteral administration.2, 3 Amenamevir, an oral helicase–primase inhibitor, has recently emerged as an alternative for HSV and VZV infections.4 However, its use in PLWH with R/R genital HSV-2 infection has not yet been reported. We describe here four such cases successfully treated with amenamevir. We retrospectively included PLWH with R/R genital HSV-2 infection managed in the infectious diseases departments of Pitié-Salpêtrière and Avicenne hospitals between 2022 and 2025. The diagnosis of HSV-2 was established by swabbing lesions and using the HSV-1-HSV-2/VZV R-GENE® PCR assay (BIOMERIEUX, Marcy-l'Étoile, France). Antiviral resistance was assessed by sequencing UL23 and UL30 viral genes.5 All patients had a positive HSV-2 PCR and mutations in the UL23 gene associated with acyclovir phenotypic resistance. Four patients—three men and one woman, aged 51–67 years—were included. The three men presented with painful pseudotumoral ulcerated lesions involving the penis or scrotum, whereas the female patient exhibited multiple vulvar ulcerations persisting for several weeks despite oral valacyclovir (Figure 1). All had a long history of HSV-2 recurrent genital herpes (6–21 years). They had been treated with valacyclovir and foscarnet and required hospitalization; three patients had also received topical imiquimod. All patients were receiving antiretroviral therapy. Two had undetectable HIV loads (<20 copies/mL), and two had low-level viremia (31 and 46 copies/mL). Immune reconstitution was established in all, with stable CD4 counts; only one had a CD4 count <200 cells/mm3 at treatment initiation. Amenamevir was given orally at 400 mg once daily for 30–90 days. All patients achieved clinical remission within the first month (M1) without adverse effects or non-compliance. One patient received suppressive therapy for 2 months after remission. Three relapsed between M3 and M12, with complete responses after retreatment. No genotypic resistance to amenamevir was detected. Patient characteristics and outcomes are summarized in Table 1. Amenamevir and pritelivir act by targeting the viral helicase–primase complex, thereby bypassing reliance on the viral thymidine kinase pathway, which is impaired in acyclovir resistance.4 Previous reports in haematology patients have suggested efficacy in R/R HSV infections.6, 7 A Phase III clinical trial (NCT03073967) is currently underway to evaluate the safety and efficacy of pritelivir in immunocompromised patients. To date, no HSV resistance to amenamevir has been observed in patients; reported mutations have only been selected in vitro.4 While amenamevir is approved in Japan for the treatment of herpes zoster as well as genital and recurrent labial herpes (HSV-1/2) in immunocompetent patients, in France it is only available through early-access authorization.8 The European guidelines for the management of genital herpes recommend foscarnet as the second-line therapy for PLWH with R/R HSV infection, or cidofovir if foscarnet is unavailable.9 Both antivirals require hospitalization with intravenous administration and are associated with frequent adverse effects (electrolyte disturbances, cytopenias and acute kidney injuries).2, 3 The topical or intralesional treatment with cidofovir was not considered, as this approach is not routinely performed in our departments. Regarding treatment duration, the European guidelines recommend continuing therapy until complete re-epithelialization.9 A suppressive strategy was proposed for the patient with more than 10 recurrences. No data are currently available on the long-term tolerability of amenamevir. This case series highlights the potential of this novel oral antiviral amenamevir compared with other lines of therapy for R/R HSV-2 infections in PLWH. Future studies in immunocompromised patients will help to define better its role in both curative and preventive treatments. None to declare. None to declare. Not applicable. The patients in this manuscript have given written informed consent to publication of their case details. The data that support the findings of this study are available from the corresponding author upon reasonable request.