FDA Approves Pritelivir for Refractory HSV in Immunocompromised Adults

The US Food and Drug Administration has approved pritelivir (Hovilpri, Asahi Kasei Therapeutics) tablets for immunocompromised adults with mucocutaneous herpes simplex virus (HSV) lesions that have not responded to acyclovir, valacyclovir or famciclovir. The agency announced the decision on 9 October 2026 after a priority review. Pritelivir is an oral helicase-primase inhibitor, which means it blocks viral DNA replication at a different step from every antiviral currently used against HSV in the United States.

The indication is narrow. It covers people whose immune systems are weakened by conditions such as blood cancers, stem-cell or solid-organ transplantation, HIV infection, other malignancies or autoimmune and inflammatory disease, and whose lesions have persisted despite standard nucleoside therapy. These patients have had few good options until now, and the main alternatives are intravenous drugs with significant kidney toxicity.

Why refractory HSV is a clinical problem

HSV-1 and HSV-2 establish lifelong latent infection in sensory nerve ganglia and reactivate periodically. In people with intact immunity, outbreaks are usually self-limiting and respond well to acyclovir or its prodrugs. In people with impaired T-cell immunity, reactivations can be more frequent, larger, deeper and much slower to heal. Persistent oral, genital or perianal ulcers cause pain, make eating difficult, provide an entry point for bacterial infection and can delay chemotherapy or transplant procedures.

Long or repeated courses of acyclovir in these patients also create conditions for drug resistance. When lesions keep growing despite adequate nucleoside dosing, clinicians usually switch to intravenous foscarnet or cidofovir. Both can work, but both are nephrotoxic. Foscarnet also causes electrolyte disturbances, and cidofovir is given with probenecid and hydration to protect the kidneys. Many patients with refractory disease are already taking other nephrotoxic drugs such as calcineurin inhibitors, so the second-line regimen can be hard to tolerate. Topical options such as imiquimod or compounded cidofovir are sometimes used, with inconsistent results.

How pritelivir works

Acyclovir, valacyclovir and famciclovir are nucleoside analogues. To act, they must first be phosphorylated by the virus's own thymidine kinase (TK), then by host kinases, before the active triphosphate competes with natural nucleotides at the viral DNA polymerase and terminates the growing chain. Dependence on viral TK makes the drugs selective for infected cells, but it is also their weak point. Most clinical acyclovir resistance comes from mutations that reduce or eliminate TK activity, and a smaller share from mutations in the polymerase itself. Foscarnet and cidofovir avoid the TK step, but they still act on the viral polymerase.

Pritelivir targets an earlier step in replication. HSV relies on a three-protein helicase-primase complex, made up of the UL5 helicase, the UL52 primase and the UL8 accessory protein, to unwind double-stranded viral DNA at the replication fork and to lay down the short RNA primers that the polymerase extends. By binding this complex, pritelivir stops the fork from progressing before the polymerase has a template to work on.

This has two practical consequences. The drug does not need activation by viral TK, so TK-deficient strains remain susceptible. And because its target differs from that of any polymerase-directed drug, cross-resistance with nucleoside analogues or foscarnet is not expected. The manufacturer reports activity against HSV-1 and HSV-2 strains resistant to both. Laboratory work on helicase-primase inhibitors has shown that resistance to this class can arise through mutations in the helicase or primase genes, so the new mechanism does not remove the possibility of resistance.

The class is new to HSV treatment in the US but not entirely new. Amenamevir, another helicase-primase inhibitor, has been approved in Japan since 2017 for herpes zoster. Asahi Kasei describes Hovilpri as the first FDA-approved HSV therapy with a new mechanism of action in nearly 30 years.

The evidence: PRIOH-1 Part C

The approval rests on Part C of the phase 3 PRIOH-1 trial (NCT03073967), a randomised, open-label, comparator-controlled superiority study. It enrolled 101 immunocompromised adults with mucocutaneous HSV lesions refractory to standard nucleoside therapy, with or without documented genetic resistance.

• Pritelivir arm: a 400 mg loading dose on day 1, then 100 mg orally once daily.
• Comparator arm: investigator's choice of intravenous foscarnet, intravenous or topical cidofovir, or 5% topical imiquimod.
• Duration: up to 28 days, or until all lesions healed, extendable to 42 days if lesions were improving but not fully healed.
• Primary endpoint: complete healing of all lesions within the 28-day treatment period.

All lesions healed by day 28 in 63% of participants given pritelivir and 34% of those given investigator's choice therapy. According to the company and the prescribing information summary, the adjusted difference was 28.4 percentage points (95% CI 9.6 to 47.3; p=0.0047). Some earlier reports cited 62.7% versus 34% with a difference of 28.7 points (95% CI 8 to 47.1). The headline rates are the same, and the small difference in the effect estimate most likely reflects adjusted versus unadjusted analyses presented at different times. Both intervals exclude zero.

In a secondary analysis through day 42, observed response rates were 82% with pritelivir and 42% with comparator therapy (adjusted difference 40.0 percentage points; 95% CI 22.7 to 57.7). Results have not been published separately for participants with documented resistance versus clinical refractoriness alone, or for individual immunosuppressive conditions.

Safety and practical use

In PRIOH-1, adverse reactions were reported in 22% of pritelivir recipients and 54% of comparator recipients. Discontinuation because of adverse reactions occurred in 2% and 20% respectively. Headache was the only adverse reaction reported in more than 5% of pritelivir recipients (6% versus 4%). No boxed warning has been reported.

The main practical issue is drug interactions, which matters in a population that typically takes many medicines:

• Acid suppression: pritelivir absorption falls when gastric pH rises. The labelling advises avoiding esomeprazole and rabeprazole, and limiting omeprazole or lansoprazole to 20 mg/day or less and pantoprazole to 40 mg/day or less. Doses should be taken at least 2 hours before or 12 hours after an H2-receptor antagonist, and at least 2 hours apart from antacids.
• BCRP inhibition: pritelivir inhibits breast cancer resistance protein (BCRP), a drug-efflux transporter, and may raise concentrations of drugs that are BCRP substrates.

For transplant and oncology patients, who often take proton pump inhibitors for gastrointestinal prophylaxis, these restrictions will need active medication review rather than a simple add-on prescription.

Limitations of the data

The trial supports the approval, but several features limit what it can show.

• Open-label design. Lesion healing was assessed with treatment assignment known, which can bias a partly subjective endpoint. Blinding would have been difficult given the comparators included intravenous and topical drugs.
• Heterogeneous comparator. Investigator's choice combined systemic and topical options of different potency. The trial shows pritelivir beat current practice as a whole, not that it beats each alternative individually.
• Small sample. With 101 participants, the confidence intervals are wide, and subgroup conclusions for specific transplant types, HIV or resistance genotypes are not yet possible.
• Short follow-up. The endpoints address healing of the current episode. Durability, recurrence rates after stopping and the emergence of resistance during longer or repeated courses have not been characterised in the public data.
• Narrow population. The approval does not extend to immunocompetent people, first-line treatment, suppressive therapy or children.

Why the approval matters

For decades, HSV drug development has been dominated by refinements of the nucleoside approach: prodrugs with better oral bioavailability and more convenient dosing, but the same activation pathway and the same resistance mechanism. A new mechanism gives clinicians a route around TK-mediated resistance that does not require hospital admission for intravenous therapy, and on the trial data it appears better tolerated than the current second-line options.

The approval also matters for antiviral development beyond HSV. Helicase-primase complexes are conserved across herpesviruses, so the PRIOH-1 programme helps establish a regulatory precedent for this class. It also adds to the case for a first-line antiviral and a mechanistically distinct second-line agent, a model already familiar from HIV and hepatitis C therapy.

What to watch

• Launch and access. Asahi Kasei expects US availability before the end of 2026. Pricing and hospital formulary decisions will determine how quickly the drug displaces foscarnet in practice.
• Full publication. A peer-reviewed report of PRIOH-1 Part C, with subgroup data by resistance status and immunosuppressive condition, will be important for refining patient selection.
• Resistance surveillance. Post-marketing genotypic monitoring for helicase and primase mutations will show how durable the new mechanism is under clinical pressure.
• Other regulators and indications. No decision outside the US has been announced. Whether the drug is studied for earlier use, prophylaxis or broader populations remains to be seen.

This article is for information only and is not medical advice. Treatment decisions should be made with a qualified clinician.

Sources: US FDA; Asahi Kasei; Contagion Live; Healio; ClinicalTrials.gov