Section 3 of 6
Product information and disease description 824 evidence topics · 203 sources
2.1.1 Phase of product development
Regulatory submission: NDA submitted February 2026 and approved October 2026 Launch: Anticipated before the end of 2026 FDA approval on 9 October 2026 Evidence supporting approval Expedited programs named at approval Priority review and PDUFA target date NDA submission: plans announced before the filing NDA submission: company assessment of the likelihood of approval, February 2026 Breakthrough therapy designation, June 2020 Fast track designation, 2017 Clinical hold imposed by the FDA in May 2013 “On May 9, 2013, the US Food and Drug Administration (FDA) imposed a clinical hold (an order to the sponsor to suspend ongoing investigation), based on hematologic and dermatologic findings such as dry skin, crusty skin lesions, and alopecia in a chronic toxicity study involving monkeys.” (opens the source at this quote in a new tab) Copy Flag
“Because the duration of the clinical hold was uncertain, the sponsor terminated the study on June 24, 2013.” (opens the source at this quote in a new tab) Copy Flag
“The trial was placed on clinical hold by the FDA and terminated by the sponsor based on findings in monkeys in a 39-week toxicity study.” (opens the source at this quote in a new tab) Copy Flag
“These findings included skin related findings such as dry skin, crusty skin lesions, and alopecia as well as anemia (decreases in hemoglobin and in most animals an increase in the percentage of reticulocytes).” (opens the source at this quote in a new tab) Copy Flag
“So far the mechanism of dermatologic and hematologic findings is not understood.” (opens the source at this quote in a new tab) Copy Flag
“However, in the present study participants did not experience any similar adverse events (eg, anemia), although one person developed a rash (hives).” (opens the source at this quote in a new tab) Copy Flag
Clinical hold: status described in December 2016 Clinical hold: date lifted No evidence found.
PRIOH-1 milestones: first site of the phase 2 part opened in May 2017 PRIOH-1 milestones: phase 3 part started in July 2021 “WUPPERTAL, GERMANY / ACCESSWIRE / July 8, 2021 / AiCuris Anti-infective Cures AG, a leading company in the discovery and development of drugs against infectious diseases, today announced the start of pivotal phase 3 development with its proprietary lead compound pritelivir, a novel helicase-primase inhibitor, following encouraging phase 2 interim results achieved in the phase 2 part of its clinical phase 2/3 trial, PRIOH-1.” (opens the source at this quote in a new tab) Copy Flag
“Following the strong results achieved in phase 2, AiCuris directly amended this trial with a pivotal phase 3 part as a basis for NDA submission.” (opens the source at this quote in a new tab) Copy Flag
“The phase 3 part of the trial with a study design based on the phase 2 part will compare lesion healing in a given time frame and is conducted worldwide at up to 70 sites in the US, South America, Europe, and China and plans to enroll 128 patients.” (opens the source at this quote in a new tab) Copy Flag
“First clinical sites are already initiated.” (opens the source at this quote in a new tab) Copy Flag
PRIOH-1 milestones: timelines projected in 2023 and 2024 PRIOH-1 milestones: enrollment completed in July 2025 PRIOH-1 milestones: topline results in October 2025 Acquisition of AiCuris by Asahi Kasei: agreement of February 2026 Acquisition of AiCuris by Asahi Kasei: completion in April 2026 Patent term and generic entry: company statement, February 2026 Patent coverage described in a 2026 review of helicase-primase inhibitor patents “Initial patents filed by Bayer between 1999 and 2003 established the foundational chemical space around thiazolyl amide derivatives (Table 7).” (opens the source at this quote in a new tab) Copy Flag
“However, most of these early patents have now expired.” (opens the source at this quote in a new tab) Copy Flag
“A key milestone was the introduction of tablet formulations containing pritelivir salts, with protection in some regions extending into the late 2020s.” (opens the source at this quote in a new tab) Copy Flag
“The most significant intellectual property emerged from patents filed in 2012, which describe both the synthesis and specific crystalline forms of pritelivir, particularly the mesylate monohydrate.” (opens the source at this quote in a new tab) Copy Flag
“This form, along with defined particle size distributions, represents a central element of the current protection strategy and is covered until approximately 2032.” (opens the source at this quote in a new tab) Copy Flag
“Further diversification of solid forms was disclosed in later patents, including the free base hemihydrate and the maleate salt, both of which are associated with pharmaceutical formulations and manufacturing processes and extend protection until around 2037.” (opens the source at this quote in a new tab) Copy Flag
“The definitive crystalline form used in a marketed formulation has not been publicly disclosed.” (opens the source at this quote in a new tab) Copy Flag
“Overall, while the original compound class is no longer protected, the current patent estate for pritelivir is strongly centered on specific crystalline forms, formulation technologies, and methods of manufacture, which together are expected to play a decisive role in the eventual commercial product strategy.” (opens the source at this quote in a new tab) Copy Flag
Priority review voucher: company statement, February 2026 Drugs@FDA record, NDA number, and approval letter No evidence found.
Orange Book patent and exclusivity listings No evidence found.
Regulatory status outside the United States: company statements on plans Regulatory status outside the United States: European Union paediatric investigation plan Regulatory status outside the United States: compassionate use in Germany and early access in other countries Regulatory status outside the United States: compassionate use programme in Belgium Regulatory status outside the United States: compassionate access authorisation in France
2.1.2.1 Generic, brand name and therapeutic class of product
Manufacturer: Asahi Kasei Therapeutics Corporate structure: Asahi Kasei Therapeutics brand Developer: AiCuris Anti-infective Cures AG Development codes and nonproprietary name status Therapeutic class: herpes simplex virus helicase-primase inhibitor Therapeutic class: company description at approval Chemical class: thiazolylamide 2.1.2.2 Dosage forms and strengths
Tablet strength and appearance Salt form and pritelivir content per tablet Inactive ingredients “The tablet core contains standard excipients: colloidal silica dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose, as well as the film-coat (hydroxy propyl methyl cellulose and polyethylene glycol) and the colorant/opacifier calcium diphosphate.” (opens the prescribing information at this quote) Copy Flag
“Inactive ingredients: colloidal silica dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The film-coat contains hydroxy propyl methyl cellulose and polyethylene glycol, and calcium diphosphate.” (opens the prescribing information at this quote) Copy Flag
Packages and national drug codes Selection of the mesylate monohydrate solid form during development Pharmaceutical form and planned oral suspension in the European Union paediatric investigation plan Other formulations studied: topical pritelivir Material safety data sheet No evidence found.
2.1.2.3 Average sales price and wholesale acquisition cost
Wholesale acquisition cost published at or after approval No evidence found.
Pre-approval market research assumption for the monthly wholesale acquisition cost: AiCuris corporate presentation, August 2025 Company sales expectations: Asahi Kasei, February and April 2026 Difference between the AiCuris and Asahi Kasei sales assumptions Company statement on prices outside the United States Royalties on United States sales Average sales price Not applicable.
2.1.2.4 American hospital formulary service (AHFS), or other drug classification
AHFS classification No evidence found.
ATC classification No evidence found.
Pharmacologic class stated in the prescribing information NCI Drug Dictionary description
U.S. indication: full prescribing information U.S. indication: Highlights of prescribing information U.S. indication: FDA plain-language description U.S. indication: patient information wording Definition of refractory infection in the trial supporting the indication Limits of the indication stated in the label Indication as stated on the manufacturer's healthcare professional website Indication targeted by the European Union paediatric investigation plan
2.1.2.6.1 Mechanism of action
Mechanism of action: prescribing information Antiviral activity in cell culture: prescribing information Resistance selected in cell culture: prescribing information Pritelivir resistance-associated amino acid substitutions in cell culture: prescribing information Resistance in clinical trials: prescribing information Cross-resistance: prescribing information Mechanism as described in the approval announcement Helicase-primase complex: subunits and position in viral DNA replication “The heterotrimeric helicase–primase complex is formed by UL5 (the helicase subunit, which unwinds and separates the duplex DNA to form the replication fork, exposing the two individual DNA strands), UL52 (the primase, which synthesizes short RNA primers as substrates for DNA polymerase), and UL8 (noncatalytic subunit, essential for coordination between UL5 and UL52).” (opens the source at this quote in a new tab) Copy Flag
“Dedicated studies revealed that pritelivir, while allowing cell infection and initiation of expression of viral immediate early genes, was associated with reduction, suppression, or loss of initiation of early and late gene expression.” (opens the source at this quote in a new tab) Copy Flag
“showing that operation of the helicase–primase complex precedes that of the DNA polymerase, the target of nucleoside analogue drugs like acyclovir.” (opens the source at this quote in a new tab) Copy Flag
“Resistance mutation studies (see section 2.2.4 for more detail) suggest that pritelivir interacts with the helicase–primase complex at its DNA-binding site, binding simultaneously to the helicase and primase components, thereby stabilizing the interaction between the HSV helicase–primase complex and nucleic acid” (opens the source at this quote in a new tab) Copy Flag
Activity without activation by viral thymidine kinase First report of the helicase-primase inhibitor class Enzyme inhibition and cell culture potency in the first nonclinical report Selectivity for the viral helicase over human helicases Antiviral spectrum limited to HSV-1 and HSV-2 Structural basis: binding site at the UL5 and UL52 interface “Here, we report cryo–electron microscopy structures of HSV-1 HP bound to a forked DNA template alone and in complex with pritelivir or amenamevir.” (opens the source at this quote in a new tab) Copy Flag
“The pritelivir fills a partially accessible groove at the UL5-UL52 interface (Fig. 5B) and is positioned nearly 12 Å apart from the ATP-binding site of UL5.” (opens the source at this quote in a new tab) Copy Flag
“Pritelivir forms hydrophobic interactions with the side chains of UL5 amino acid residues N98, N342, N343, C346, M355, K356, E359, and Y360 and the α-carbon of G352 and with the side chains of UL52 amino acid residues Y356, L357, F360, A899, N902, A903, H906, and F907 (Fig. 5D).” (opens the source at this quote in a new tab) Copy Flag
“In addition, five potential H-bonds were observed between pritelivir and the HP complex.” (opens the source at this quote in a new tab) Copy Flag
“However, in each inhibitor-bound HP complex, either amenamevir or pritelivir occupies this space (Fig. 6, C and D), preventing the relative movement of domains 1A and 2A and, thus, inhibiting UL5 helicase activity.” (opens the source at this quote in a new tab) Copy Flag
Structural basis: allosteric inhibition that does not compete with DNA or ATP Structural basis: helicase locked in an open, inactive conformation Concentration-dependent slowing and pausing of DNA unwinding by the purified enzyme “In the presence of the wild-type (WT) HSV-1 H/P complex alone, we observed robust and continuous DNA unwinding, with no detectable pausing, at an average rate of 33 nt s−1 (n = 41).” (opens the source at this quote in a new tab) Copy Flag
“At 100 nM pritelivir, the average unwinding rate decreased to 25 nt s−1 (n = 38), with a corresponding pause fraction of 17.9% (n = 11).” (opens the source at this quote in a new tab) Copy Flag
“At 200 nM, the rate further declined to 17 nt s−1 (n = 37), and the pause fraction increased to 25.6% (n = 15).” (opens the source at this quote in a new tab) Copy Flag
“At the highest concentration tested, 500 nM, unwinding activity was severely impaired, with an average rate of only 9.5 nt s−1 (n = 51) and a pause fraction of 51.5% (n = 16).” (opens the source at this quote in a new tab) Copy Flag
“These results indicate that pritelivir slows the helicase translocation rate and promotes pausing in a dose-dependent manner, consistent with stabilization of an inactive conformation of the H/P complex.” (opens the source at this quote in a new tab) Copy Flag
Inhibition of ATP hydrolysis, primer synthesis, and replication fork activity in vitro Baseline susceptibility of clinical isolates and activity against acyclovir-resistant strains Location of resistance mutations in the UL5 helicase and UL52 primase genes Resistance substitutions mapped onto the inhibitor binding pocket Interaction with both the helicase and the primase inferred from a UL52 mutation Reduction in susceptibility by substitution: recombinant virus and dose-escalation studies “Substitutions such as HSV-1 UL5 K356N, HSV-2 UL5 K355N and VZV K350N (equivalent positions) reduced sensitivity to PTV and/or AMNV by 200 to >2,000-fold” (opens the source at this quote in a new tab) Copy Flag
“Interestingly, an N342K substitution reduces the potency of PTV (≈40-fold)” (opens the source at this quote in a new tab) Copy Flag
“In the HSV-1 dose-escalation study, emergence of the UL5 K356N variant was observed (Extended Data Fig. 5a).” (opens the source at this quote in a new tab) Copy Flag
“This substitution conferred a substantial loss of sensitivity to PTV (210-fold) when introduced into a recombinant HSV-2 virus (UL5 K355N; Extended Data Fig. 5b and Extended Data Table 2).” (opens the source at this quote in a new tab) Copy Flag
“In the HSV-2 dose-escalation studies, a UL5 K355R variant was detected, either alone or paired with two additional substitutions, UL5 L805I and UL52 A906V (Extended Data Fig. 5a).” (opens the source at this quote in a new tab) Copy Flag
“By contrast, UL52 A906 (equivalent to HSV-1 A899) stabilizes the PTV sulfonamide head (Fig. 2b), and an A-to-V substitution was associated with a 17-fold decrease in sensitivity to PTV (Fig. 2f).” (opens the source at this quote in a new tab) Copy Flag
“Strikingly, a recombinant HSV-2 virus bearing all three substitutions (UL5 K355R, L805I and UL52 A906V) was virtually insensitive to PTV (EC50 change >1,300-fold) (Extended Data Fig. 5b and Extended Data Table 2).” (opens the source at this quote in a new tab) Copy Flag
“Our study emphasizes that the acetamide carboxyl oxygen present in all known HPIs is crucial for interacting with HSV-2 UL5 K355, rendering them susceptible to the emergence of resistant variants at this position.” (opens the source at this quote in a new tab) Copy Flag
Reduction in susceptibility by substitution: HSV-1 clones selected under drug pressure Selection of resistance in cell culture under pritelivir alone and combined with acyclovir or foscarnet “In this study, we assessed whether combining antivirals with different targets affects drug resistance emergence by passaging wild-type HSV-1 under increasing concentrations of acyclovir (ACV), foscarnet (phosphonoformic acid, PFA), or the helicase–primase inhibitor pritelivir (PTV), individually or in combination (ACV + PTV or PFA + PTV).” (opens the source at this quote in a new tab) Copy Flag
“Deep sequencing and subsequent phenotyping showed the rapid acquisition of resistance mutations under monotherapy pressure, whereas combination therapy resulted in either no mutations or mutations conferring ACV and/or PFA resistance.” (opens the source at this quote in a new tab) Copy Flag
“Notably, mutations associated with PTV resistance were not detected after five passages under combination pressure.” (opens the source at this quote in a new tab) Copy Flag
“Strains resistant to both ACV and PTV were eventually obtained upon further passaging under ACV + PTV pressure initiated from lower drug concentrations.” (opens the source at this quote in a new tab) Copy Flag
“PFA + PTV dual treatment induced PFA resistance mutations in the DP, but PTV resistance mutations were not acquired, even after 15 passages.” (opens the source at this quote in a new tab) Copy Flag
“Three mutations were detected at frequencies >10% in the helicase (K356N and K356Q) and primase (S364G) genes of the PTVL viral culture at Passage 5, while in the case of PTVH, the K356N (91.8%) mutation was the only mutation detected at a frequency >10%.” (opens the source at this quote in a new tab) Copy Flag
Replication capacity and pathogenicity of pritelivir-resistant virus Frequency of pre-existing resistant variants in laboratory and clinical isolates Natural polymorphism of UL5 and UL52 among clinical isolates Resistance sequencing during 28 days of daily therapy in immunocompetent adults “We sequenced resistance regions from 87 participants' samples, the UL5 gene in 73 samples from 44 participants, and the UL52 gene in 71 samples from 43 participants.” (opens the source at this quote in a new tab) Copy Flag
“We found no evidence that pritelivir induced known resistance-mediating mutations or for amino acid variation at other loci.” (opens the source at this quote in a new tab) Copy Flag
“Of these, 823 swab specimens (median time of collection after treatment initiation, 22 days; range, 1–44 days), collected from 87 subjects (20 in the placebo group and 67 in one of the 4 dosage groups; Supplementary Table 4), contained an HSV-2 quantity of ≥5000 copies/mL and were subjected to resistance-region sequencing.” (opens the source at this quote in a new tab) Copy Flag
“Of the 823 samples, 688 (84%), from 80 patients, underwent successful sequencing of the UL5 gene, and 775 (94%), from 83 patients, underwent successful sequencing of the UL52 gene (Figure 2).” (opens the source at this quote in a new tab) Copy Flag
“As this isolate was susceptible to pritelivir, the H334R mutation was not regarded to confer resistance (Figure 3).” (opens the source at this quote in a new tab) Copy Flag
“This study demonstrates evidence of retained susceptibility of HSV-2 to pritelivir in immunocompetent persons following daily therapy for up to 28 days.” (opens the source at this quote in a new tab) Copy Flag
Resistance sequencing in the crossover trial against valacyclovir Emergent resistance in the phase 2 parts of PRIOH-1 Emergent resistance in the phase 3 part of PRIOH-1: congress presentation Helicase-primase resistance mutations in a published resistance dataset 2.1.2.6.2 Pharmacodynamics
Exposure-response: prescribing information Cardiac electrophysiology: prescribing information Doses evaluated in the thorough QT trial Inhibition of hERG potassium channels in vitro Secondary pharmacology: inhibition of carbonic anhydrases Dose-dependent reduction of genital HSV-2 shedding in the phase 2 dose-finding trial “HSV shedding among placebo recipients was detected on 16.6% of days; shedding among pritelivir recipients was detected on 18.2% of days among those receiving 5 mg daily, 9.3% of days among those receiving 25 mg daily, 2.1% of days among those receiving 75 mg daily, and 5.3% of days among those receiving 400 mg weekly.” (opens the source at this quote in a new tab) Copy Flag
“The relative risk of viral shedding with pritelivir, as compared with placebo, was 1.11 (95% confidence interval [CI], 0.65 to 1.87) with the 5-mg daily dose, 0.57 (95% CI, 0.31 to 1.03) with the 25-mg daily dose, 0.13 (95% CI, 0.04 to 0.38) with the 75-mg daily dose, and 0.32 (95% CI, 0.17 to 0.59) with the 400-mg weekly dose.” (opens the source at this quote in a new tab) Copy Flag
“When HSV was detected, the median log10 number of HSV DNA copies was 5.1 with placebo, 4.5 with 5 mg of pritelivir daily, 3.6 with 25 mg daily, 2.4 with 75 mg daily, and 3.6 with 400 mg weekly (P<0.001 for the comparisons of placebo with doses of pritelivir of 25 mg or more) (Table 2 and Figure 1B).” (opens the source at this quote in a new tab) Copy Flag
“The effect was dose-related, with a daily dose of 75 mg having the greatest antiviral effect.” (opens the source at this quote in a new tab) Copy Flag
“Furthermore, at this dose, pritelivir reduced the quantity of HSV in breakthrough shedding by more than 98%.” (opens the source at this quote in a new tab) Copy Flag
“Although the HSV shedding rate was reduced by more than 85% at the highest doses of pritelivir, as compared with placebo, some breakthrough shedding remained.” (opens the source at this quote in a new tab) Copy Flag
Genital HSV-2 shedding at 100 mg daily compared with valacyclovir Mathematical model of HSV-2 shedding against dose: structure and inputs Mathematical model: in vivo EC50 estimate and time above it by dose Mathematical model: predicted and observed shedding at higher doses Mathematical model: effect on viral spread between sites HSV DNA in lesion swabs during treatment of refractory infection in PRIOH-1 Animal models: efficacy stated in the first report of the compound Murine lethal challenge model: dose protecting 50% of animals Murine lethal challenge model: ED50 by compound in mg/kg Murine and rat models: viral burden, rebound after treatment, and once-daily dosing Potency relative to nucleoside analogues on a molar basis Murine encephalitis model: survival when treatment started 72 hours after infection “Mice lethally infected with HSV type 1 or 2, including acyclovir-resistant strains, were treated 72 hours after infection for 7 days with pritelivir or acyclovir.” (opens the source at this quote in a new tab) Copy Flag
“When PTV was administered twice daily orally at doses of 30, 10, 3 or 1 mg/kg, survival was significantly increased to 80–100% as compared to the vehicle treatment (7%, P<0.0001) when therapy was initiated 72 h post viral inoculation.” (opens the source at this quote in a new tab) Copy Flag
“Even the lowest PTV dose of 0.3 mg/kg twice daily was effective in increasing survival to 53% (P=0.0015).” (opens the source at this quote in a new tab) Copy Flag
“With twice daily ACV treatment at 50 mg/kg, the positive control, survival was also significantly increased to 87% (P<0.0001).” (opens the source at this quote in a new tab) Copy Flag
“HSV-2 survival was significantly increased to 93–100% (P<0.0001) during PTV therapy when treatments of 30, 10 or 3 mg/kg twice daily were initiated 72 h post viral inoculation in comparison to the vehicle treated group with 13% survival.” (opens the source at this quote in a new tab) Copy Flag
“The 1 mg/kg twice daily dose of PTV also increased survival (73%) compared to the vehicle treated group (P=0.0005), but not the 0.3 mg/kg twice daily dose.” (opens the source at this quote in a new tab) Copy Flag
Murine encephalitis model: acyclovir-resistant HSV-1 and HSV-2 strains Murine encephalitis model: combination with acyclovir Murine encephalitis model: plasma and brain concentrations by dose Murine skin infection model: effective dose and exposure relative to the cell culture EC90 Murine skin infection model: treatment of a pritelivir-resistant mutant with a higher dose “Hence, the mutant strain cl-2-r1-Rec showed a 27-fold decrease in sensitivity with regard to EC90, confirming the previously described resistance phenotype” (opens the source at this quote in a new tab) Copy Flag
“Therapy using 5 mg/kg, exceeding the ED50 for the wild-type virus, had no significant impact on clinical signs or virus titers for the pritelivir-resistant mutant cl-2-r1-Rec (Fig. 3).” (opens the source at this quote in a new tab) Copy Flag
“Interestingly, by increasing the dose 6-fold and prolonging the treatment duration to 8 days, it was possible to treat mice infected with an approximately 30-fold pritelivir-resistant but fully pathogenic HSV-1 virus.” (opens the source at this quote in a new tab) Copy Flag
“As shown in Fig. 5, the plasma concentration in mice after a single dose of 60 mg/kg exceeded the cell culture EC50 for HSV-1 mutant cl-2-r1-Rec for approximately 20 h, but the EC90 was exceeded for only approximately 10 h.” (opens the source at this quote in a new tab) Copy Flag
“Corresponding plasma concentrations exceeded the EC90 of this mutant for <8 h, indicating that even suboptimal exposure to pritelivir is sufficient to achieve antiviral efficacy, possibly augmented by other factors such as the immune system.” (opens the source at this quote in a new tab) Copy Flag
Translation of the murine exposure target to the phase 2 dose range Murine skin infection model: mixtures of wild-type and resistant virus Immunocompetent and immunodeficient mice: virus titers after short treatment courses Guinea pig model of genital herpes: shedding, lesion score, and recurrence Ocular HSV-1 models: reactivation in mice and keratitis in rabbits “Oral BAY 57-1293 suppressed reactivation in HSV-1-infected mice and reduced the viral load in TG up to four orders of magnitude.” (opens the source at this quote in a new tab) Copy Flag
“In an additional heat-stressed mouse study, orally administered BAY 57-1293 reduced the presence of herpes virus in the tears statistically significantly (P = 0.0061; exact chi-square test) more effectively than vehicle alone (Table 1).” (opens the source at this quote in a new tab) Copy Flag
“In the first oral dosage study, once-daily oral treatment with 500 mg/kg BAY 57-1293 was as effective as twice-a-day topical treatment with trifluridine (Fig. 3A), with no statistically significant differences seen in the severity of keratitis on PI days 4, 5, or 6 (P = 1.000 all times).” (opens the source at this quote in a new tab) Copy Flag
“Keratitis in the animals treated with 40 mg/kg/day BAY-1293 was significantly less severe, compared with the animals treated with valacyclovir alone (P = 0.0116, < 0.0001, < 0.0001, and < 0.0001, on PI days 4, 5, 6, and 7, respectively).” (opens the source at this quote in a new tab) Copy Flag
Combined antiviral activity with acyclovir or foscarnet in cell culture 2.1.2.6.3 Pharmacokinetics
Pharmacokinetic properties of pritelivir: prescribing information Basis of the values in the pharmacokinetic properties table Dose proportionality, time to steady state, and accumulation Covariates: age, sex, race, body weight, and underlying immunocompromised condition “There were no clinically significant differences in the pharmacokinetics of pritelivir based on age (19 to 84 years), gender, race (including American Indian/Alaska Native, Asian, Black/African American, White, or other), body weight (48 to 176 kg), or underlying immunocompromised condition (including HIV/AIDS, oncology, transplant, or autoimmune/inflammatory disorder).” (opens the prescribing information at this quote) Copy Flag
First-in-human trials: design, linearity, half-life, and time to steady state First-in-human trials: sex, absolute bioavailability, and food effect Clearance, volume of distribution, and protein binding reported from the phase 1 trials Median time to maximum concentration under fasted conditions Sex and body weight: steady-state exposure in two interaction trials Mass balance trials: design Mass balance trials: recovery and routes of excretion Mass balance trials: metabolic pathways “The major metabolic pathway was amide hydrolysis leading to amino thiazole sulfonamide (ATS) and pyridinyl phenyl acetic acid (PPA).” (opens the source at this quote in a new tab) Copy Flag
“These results suggest that pritelivir was mainly cleared by amide hydrolysis, resulting in 2 cleavage products: PPA (the carboxylic acid derivative of pritelivir), which subsequently conjugated to form PPA-glucuronide and corresponding isomers or further hydroxylated, and ATS (the thiazole sulfonamide derivative of pritelivir), which was subsequently N-demethylated.” (opens the source at this quote in a new tab) Copy Flag
“Aliphatic hydroxylation (hydroxylated pritelivir) is a minor elimination pathway as well as glucuronidation and hydroxylation of pritelivir (hydroxylated and glucuronidized pritelivir and pritelivir-glucuronide).” (opens the source at this quote in a new tab) Copy Flag
“In human microsomes, the major metabolite was formed by aliphatic hydroxylation, which was mediated by CYP3A4, although this was identified to be a minor elimination pathway in the human mass balance studies.” (opens the source at this quote in a new tab) Copy Flag
“Furthermore, in human hepatocytes, roughly half of the loss of parent drug in suspended human hepatocytes was attributed to nonenzymatic amide hydrolysis, which was observed in the human mass balance studies.” (opens the source at this quote in a new tab) Copy Flag
Mass balance trials: components in plasma as stated in the abstract Mass balance trials: components in plasma as stated in the results Mass balance trials: components in urine and feces Steady-state pharmacokinetic parameters in the multiple-dose mass balance trial Distribution into red blood cells after a single dose Pharmacokinetics in animal species and comparison with humans Exposure relative to effective concentrations in a murine infection model 2.1.2.7 Contraindications/Warnings/Precautions/Adverse effects
2.1.2.7.1 Warnings and precautions
Warning: drug interactions with acid-reducing agents Interpretation of adverse reaction rates from clinical trials Size of the clinical safety database Adverse reactions in PRIOH-1 Part C: safety population and exposure “The safety of HOVILPRI was evaluated in a Phase 3, randomized, open-label, comparator-controlled trial, PRIOH-1 (Part C), in immunocompromised participants with mucocutaneous (mucosal and/or cutaneous lesions) HSV infection that was refractory (with or without documented resistance) to treatment with acyclovir, valacyclovir, or famciclovir” (opens the prescribing information at this quote) Copy Flag
“Participants received HOVILPRI (400 mg loading dose on Day 1 followed by 100 mg once daily) or Investigator’s Choice treatment (IV foscarnet, IV/topical cidofovir, or 5% topical imiquimod) for up to 28 days until all lesions healed, extended up to 42 days if lesions were improving.” (opens the prescribing information at this quote) Copy Flag
“A total of 101 participants were randomized 1:1 and treated with either HOVILPRI or the Investigator’s Choice.” (opens the prescribing information at this quote) Copy Flag
“Across the 51 participants treated with HOVILPRI, the mean duration of treatment was 27.1 days (range 6–43).” (opens the prescribing information at this quote) Copy Flag
Adverse reactions in PRIOH-1 Part C: headache, overall incidence, and discontinuations Adverse reactions and hepatic laboratory abnormalities in PRIOH-1 Part C by treatment arm Laboratory abnormalities: hepatic enzymes in PRIOH-1 Part C Safety in PRIOH-1 Parts D and F Side effects as stated in the patient information Nonclinical toxicology: carcinogenesis and mutagenesis Nonclinical toxicology: ocular findings in repeat-dose rodent studies Nonclinical safety pharmacology: hERG channel and carbonic anhydrase 2.1.2.8 Special populations
Pregnancy risk summary: no adverse developmental effects in animal reproduction studies Pregnancy: embryo-fetal development studies in rats and rabbits “Pritelivir was administered orally to pregnant rats at 30, 200 and 1,000 mg/kg/day from gestation days 6 to 17 and to pregnant rabbits at 5, 20, 40, 60 and 80 mg/kg/day from gestation days 6 to 20.” (opens the prescribing information at this quote) Copy Flag
“In both species, developmental toxicities were only observed at maternally toxic doses, ≥200 mg/kg/day in the rat, and ≥40 mg/kg/day in the rabbit, resulting in low birth weights in both species, skeletal variations in the rat and fetal loss in rabbits at doses ≥60 mg/kg/day.” (opens the prescribing information at this quote) Copy Flag
“No adverse maternal or embryofetal effects were observed in rats at the low dose (30 mg/kg/day) and rabbits at 20 mg/kg/day resulting in systemic pritelivir exposures (AUC) approximately 5-times for rat, and equal to the human exposure at the therapeutic dose of 100 mg, for rabbits.” (opens the prescribing information at this quote) Copy Flag
Pregnancy: prenatal and postnatal development study in rats Pregnancy: published preliminary embryo-fetal development study in mice Pregnancy: transfer across the perfused term human placenta ex vivo “Our data demonstrated the transfer of pritelivir across the placenta ex vivo from the maternal to the fetal circuit and vice versa.” (opens the source at this quote in a new tab) Copy Flag
“Clearance index of pritelivir (ie, the transfer of pritelivir normalized to the transfer of a freely diffusible reference compound antipyrine) in the fetal-to-maternal direction (0.98 ± 0.07, n = 9) exceeded its clearance index in the maternal-to-fetal direction (0.86 ± 0.08, n = 9, P = .006), suggesting involvement of mechanisms other than diffusion in the placental disposition of this drug (possibly, efflux membrane transporters P-glycoprotein and breast cancer resistance protein that accept pritelivir as a substrate in vitro).” (opens the source at this quote in a new tab) Copy Flag
“Although our data suggested plausible fetal exposure to the drug, pritelivir did not affect the production of lactate, the consumption of glucose and oxygen, and the release of human chorionic gonadotropin from the perfused placental tissue, indicating its favorable safety profile.” (opens the source at this quote in a new tab) Copy Flag
“Moreover, pritelivir did not alter the viability of the tested cells in vitro.” (opens the source at this quote in a new tab) Copy Flag
“Further preclinical developmental toxicity studies of PRV are required in support of development of PRV for pregnant patients.” (opens the source at this quote in a new tab) Copy Flag
Pregnancy and breastfeeding as stated in the patient information Females and males of reproductive potential: infertility Nonclinical toxicology: impairment of fertility “In fertility studies in rats, doses of pritelivir at 50, 150, or 500 mg/kg/day were administered to females for 2 weeks before mating, during mating and until day 7 of pregnancy.” (opens the prescribing information at this quote) Copy Flag
“Treatment related effects on male fertility including an increase in fetal loss, reduced sperm counts, and morphological and functional deficits in sperm were evident in rats at 500 mg/kg/day because of progressive disturbances to the primary and secondary sex organs.” (opens the prescribing information at this quote) Copy Flag
“These effects were no longer apparent after a 6-week recovery, indicating full reversibility.” (opens the prescribing information at this quote) Copy Flag
“There were no effects on fertility, mating or early embryonic development in females dosed with 150 mg/kg/day and males at 50 mg/kg/day resulting in systemic pritelivir exposures (AUC) approximately 6-times the human exposure at the therapeutic dose of 100 mg.” (opens the prescribing information at this quote) Copy Flag
“Of note, no effects on the reproductive organs or semen were seen in male sexually mature monkeys over a 39-week treatment period with 1,000 mg/kg/day.” (opens the prescribing information at this quote) Copy Flag
Minimum age in the PRIOH-1 registry record Pediatric development plan agreed with the European Medicines Agency Pediatric use outside the label: case series in allogeneic transplant recipients Renal impairment: dosing recommendation Renal impairment: pharmacokinetics in the prescribing information Hepatic impairment: dosing recommendation Hepatic impairment: pharmacokinetics in the prescribing information Renal and hepatic impairment trials: design and participants “The renal impairment trial included subjects with mild, moderate, and severe impairment, while the hepatic impairment trial included subjects with moderate impairment. Both trials recruited a matched control group of healthy subjects.” (opens the source at this quote in a new tab) Copy Flag
“In total, 32 healthy subjects (20 men, 12 women) were enrolled in the trial, with 8 subjects included in each of the following groups: control, mild, moderate, and severe renal impairment.” (opens the source at this quote in a new tab) Copy Flag
“In total, 16 healthy subjects (8 men, 8 women) were enrolled in the trial, with 8 subjects included in each of the following groups: control and moderate hepatic impairment.” (opens the source at this quote in a new tab) Copy Flag
“In both trials, the effect of impairment was evaluated after administration of a single oral dose of 100 mg of pritelivir.” (opens the source at this quote in a new tab) Copy Flag
“All subjects in the hepatic impairment group had Child-Pugh total scores within the prespecified range (7-9), and the full range of scores representing moderate hepatic impairment was included.” (opens the source at this quote in a new tab) Copy Flag
Renal and hepatic impairment trials: pritelivir exposure ratios against matched controls Renal impairment trial: pritelivir exposure, clearance, and half-life Renal impairment trial: metabolite exposure “For the metabolite PPA, the LS means ratios for AUCinf were 94.6%, 132.8%, and 296.9% for subjects with mild, moderate, and severe renal impairment compared with matched control subjects, respectively.” (opens the source at this quote in a new tab) Copy Flag
“For the metabolite ATS, the LS means ratios for AUCinf were 96.1%, 167.3%, and 259.7% and for the metabolite PPA-acyl glucuronide, the LS means ratios for AUC0-inf were 104.2%, 201.7%, and 559.4% for subjects with mild, moderate, and severe renal impairment compared with matched control subjects, respectively.” (opens the source at this quote in a new tab) Copy Flag
“These results were not unexpected, as the primary route of excretion for metabolites is renal and about 77% of pritelivir-related material was recovered in urine.” (opens the source at this quote in a new tab) Copy Flag
Hepatic impairment trial: unbound exposure, clearance, half-life, and metabolites “Free fraction was higher for subjects with moderate hepatic impairment compared with matched control subjects, resulting in a 23% higher systemic exposure of unbound pritelivir.” (opens the source at this quote in a new tab) Copy Flag
“Mean fu was slightly higher for subjects with moderate hepatic impairment (0.738%) compared with matched control subjects (0.551%).” (opens the source at this quote in a new tab) Copy Flag
“For pritelivir, mean t1/2z and CL/F were comparable for subjects with moderate hepatic impairment (45.9 hours and 1.3 L/h, respectively) and matched control subjects (52.0 hours and 1.3 L/h, respectively) with overlapping ranges.” (opens the source at this quote in a new tab) Copy Flag
“For the metabolites PPA, ATS, and PPA-acyl glucuronide, the LS means ratios for AUC0-inf were 122.2%, 168.8%, and 95.1%, respectively, for subjects with moderate hepatic impairment compared with matched control subjects.” (opens the source at this quote in a new tab) Copy Flag
“While the renal impairment trial included subjects with mild, moderate, and severe renal impairment, the hepatic impairment trial included subjects with moderate hepatic impairment only, which is generally considered appropriate,” (opens the source at this quote in a new tab) Copy Flag
“observations from the moderate hepatic impairment group could be applied to subjects with mild hepatic impairment as well.” (opens the source at this quote in a new tab) Copy Flag
Renal and hepatic impairment trials: adverse events 2.1.2.9 Drug/Drug, drug/disease interactions
2.1.2.9.1 Effects of other drugs on pritelivir
Gastric pH and pritelivir bioavailability Clinically significant drug interactions: proton pump inhibitors, H2-receptor antagonists, and antacids Acid-reducing agents as summarized in the label highlights Esomeprazole interaction study: prescribing information Changes in pritelivir pharmacokinetics with esomeprazole: geometric mean ratio (90% CI), with and without the co-administered drug Lower-dose proton pump inhibitors and H2-receptor antagonists in PRIOH-1 Parts C to F Esomeprazole interaction trial: design Esomeprazole interaction trial: pritelivir pharmacokinetic parameters as posted on the registry Esomeprazole interaction trial: participant flow as posted on the registry Esomeprazole interaction trial: adverse events as posted on the registry Solubility of pritelivir at acidic and higher pH Pritelivir as a substrate of cytochrome P450 enzymes Pritelivir as a substrate of drug transporters 2.1.2.9.2 Effects of pritelivir on other drugs
Breast cancer resistance protein substrates Rosuvastatin interaction study: prescribing information Changes in rosuvastatin pharmacokinetics with pritelivir: geometric mean ratio (90% CI), with and without pritelivir Substrates of CYP2B6, CYP2C8, CYP2C9, CYP3A4, and OATP2B1: prescribing information In vitro enzyme and transporter studies: prescribing information In vitro findings that led to the clinical interaction trials Clinical interaction trials with probe substrates: design “This was a sequential, single-center, open-label phase 1 trial in 16 healthy male or female subjects. The OATP2B1 substrate celiprolol (200 mg) was administered on days 1 and 8 and a cocktail of substrates, including 10 mg flurbiprofen (CYP2C9 substrate), 20 mg bupropion (CYP2B6 substrate), and 1 mg midazolam (CYP3A4 substrate), was administered on days 3 and 19.” (opens the source at this quote in a new tab) Copy Flag
“A loading dose of 400 mg of pritelivir was administered on day 6, followed by once-daily administrations of 100 mg of pritelivir from day 7 to day 21, inclusive.” (opens the source at this quote in a new tab) Copy Flag
“This was a sequential, single-center, open-label phase 1 trial in 16 healthy male or female subjects. The CYP2C8 substrate repaglinide (0.5 mg) was administered on days 1, 7, and 20 and the BCRP substrate rosuvastatin (20 mg) was administered on days 2 and 9.” (opens the source at this quote in a new tab) Copy Flag
“A loading dose of 400 mg of pritelivir was administered on day 7, followed by once-daily administrations of 100 mg of pritelivir from day 8 to day 20, inclusive.” (opens the source at this quote in a new tab) Copy Flag
“Although it was not powered to show the absence of an effect, the generally accepted no-effect boundaries of 80%-125% for the 90% CIs for systemic exposure ratios were used for the interpretation of the results.” (opens the source at this quote in a new tab) Copy Flag
Clinical interaction trials with probe substrates: exposure ratios with and without pritelivir Rosuvastatin: weak inhibition of intestinal BCRP Repaglinide: CYP2C8 after the loading dose and at steady state Midazolam, flurbiprofen, bupropion, and celiprolol: CYP3A4, CYP2C9, CYP2B6, and OATP2B1 Overall conclusion of the clinical interaction trials 2.1.2.10 Dosing and administration
Co-administration with acid-reducing agents Dosage in renal and hepatic impairment Treatment duration studied in PRIOH-1 Part C Treatment duration as registered for PRIOH-1 Parts C to F Treatment duration rule in the phase 2 parts of PRIOH-1 Rationale for the loading dose Selection of the 100 mg once daily dose Exposure-response at the recommended dose Dose range studied in healthy adults
Route of administration and food Food effect with a high-fat meal Patient instructions for taking the tablets Patient instructions for timing with H2-receptor blockers and antacids Patient instructions for a missed dose and for an overdose Counseling on adherence and missed doses Administration conditions in the phase 1 interaction trials Gastric route and oral suspension in the European paediatric investigation plan Administration through a gastrostomy tube in a published case 2.1.2.11 Access and distribution
U.S. commercial availability Distributor named on the label and company contact Specialty pharmacy or distribution network named after approval No evidence found.
Commercial infrastructure for the U.S. launch: Asahi Kasei statements, February 2026 Pre-approval commercial plan: AiCuris corporate presentation, August 2025 Information requests on the healthcare professional website Patient support or copay assistance program named by the manufacturer No evidence found.
Expanded access protocol in the United States: purpose and population Expanded access protocol in the United States: main inclusion criteria Expanded access protocol in the United States: registry record fields Early access program with myTomorrows: establishment in 2020 Early access program with myTomorrows: company description Early access program with myTomorrows: request process Compassionate use in Germany Compassionate use programme in Belgium: indication, eligibility, and supply Compassionate use programme in Belgium: request, delivery, and treatment duration Compassionate access authorisation in France 2.1.2.12 Co-prescribed/Concomitant therapies
Acid-reducing agents named in the patient information Proton pump inhibitors to avoid during treatment Proton pump inhibitor doses that may be continued, and timing of H2-receptor antagonists and antacids Acid-reducing agents taken with pritelivir in PRIOH-1 Parts C to F Proton pump inhibitors interrupted in the renal and hepatic impairment trials Substrates of the breast cancer resistance protein Disclosure of all other medicines Underlying conditions of participants treated in PRIOH-1 Part C “Participants represented a wide range of immunosuppressive clinical conditions, including one or more of the following underlying conditions: hematologic malignancy/disorder (47%), hematopoietic stem-cell transplantation (40%), HIV infection (38%), autoimmune/inflammatory diseases (29%), non-hematologic malignancies (26%) or solid-organ transplantation (4%).” (opens the prescribing information at this quote) Copy Flag
“There were no clinically significant differences in the pharmacokinetics of pritelivir based on age (19 to 84 years), gender, race (including American Indian/Alaska Native, Asian, Black/African American, White, or other), body weight (48 to 176 kg), or underlying immunocompromised condition (including HIV/AIDS, oncology, transplant, or autoimmune/inflammatory disorder).” (opens the prescribing information at this quote) Copy Flag
Antiretroviral therapy in PRIOH-1 Part A Other antivirals active against herpes simplex virus during PRIOH-1 Therapy after lesion healing: prescribing information Recurrence after the end of treatment in PRIOH-1 Part A Secondary prophylaxis after healing in a published case 2.1.2.13 Effect of pritelivir on quality measuresNo evidence found.
2.1.2.14 Product comparison
Pritelivir: labeled indication Pritelivir: pharmacologic class and target Pritelivir: route, dose, and duration of treatment Pritelivir: contraindications, warnings, and most common adverse reaction Pritelivir: dosing in renal and hepatic impairment Pritelivir: cross-resistance with nucleoside analogues and foscarnet Pritelivir against investigator's choice in PRIOH-1 Part C: comparator treatments Pritelivir against investigator's choice in PRIOH-1 Part C: lesion healing Pritelivir against investigator's choice in PRIOH-1 Part C: adverse reactions and discontinuations Pritelivir after foscarnet failure or intolerance: PRIOH-1 Parts D and F Intravenous foscarnet: labeled indication Intravenous foscarnet: boxed warning Intravenous foscarnet: route and administration Intravenous foscarnet: dose for acyclovir-resistant HSV Intravenous foscarnet: hydration with each infusion Intravenous foscarnet: renal impairment warning and use in renal dysfunction Intravenous foscarnet: incidence of renal impairment, electrolyte changes, and seizures in labeled trials Intravenous foscarnet: trials in acyclovir-resistant HSV described in the label Intravenous foscarnet: relapse and resistance after treatment Intravenous cidofovir: labeled indication Intravenous cidofovir: boxed warning Intravenous cidofovir: route and labeled dose Intravenous cidofovir: renal contraindications Topical imiquimod: labeled indications and route Intravenous acyclovir: labeled indication and dose for HSV in immunocompromised patients Intravenous acyclovir: resistance statement in the label Oral acyclovir: labeled HSV indication Valacyclovir: labeled HSV indication in HIV infection and limitation in other immunocompromised patients Famciclovir: labeled HSV indication in HIV infection and limitation in other immunocompromised patients Cross-resistance among acyclovir, valacyclovir, and famciclovir Regulatory status of each second-line agent in a review of transplant recipients Amenamevir: approvals in Japan Amenamevir: phase 3 trial in recurrent genital herpes in immunocompetent adults Amenamevir: phase 3 trial in recurrent herpes labialis in immunocompetent adults Amenamevir: case reports in acyclovir-resistant HSV after transplantation Amenamevir: central nervous system complications reported during herpes zoster treatment Brincidofovir: labeled indication and boxed warning Brincidofovir: reports of use in acyclovir-resistant HSV Brincidofovir: registered phase 3 trial of the intravenous formulation in adenovirus infection Helicase-primase inhibitors as a class: review statements Helicase-primase inhibitors: dosing regimens compared in a review Helicase-primase inhibitors: limitations of the class stated in a review Author interests declared in the two helicase-primase inhibitor reviews ABI-5366 (GS-5366): registered phase 1a/1b trial ABI-5366 (GS-5366): phase 1 findings summarized in a review ABI-1179 (GS-1179): registered phase 1a/1b trial ABI-1179 (GS-1179): phase 1 findings summarized in a review ABI-5366 and ABI-1179: license to Gilead and development status Adibelivir (IM-250): registered phase 1 trial Adibelivir (IM-250): phase 2a trial in recurrent genital herpes HDIT101 monoclonal antibody: registered phase 2 trial in recurrent anogenital HSV-2 infection HDIT101 monoclonal antibody: registered phase 2 trial of the topical formulation in orolabial HSV-1 infection UB-621 monoclonal antibody: registered phase 2 trial in recurrent genital HSV-2 infection 2.2 Place of product in therapy
2.2.1.1 Definition and etiology
Regulatory description of the condition Definition of refractory infection in the prescribing information Consensus definition of refractory mucocutaneous infection for clinical trials “Refractory HSV infection is defined by at least 1 of the following 2 criteria:” (opens the source at this quote in a new tab) Copy Flag
“The lack of clinical improvement in HSV-positive mucocutaneous lesion(s) after at least 7 days of appropriately dosed, directed anti-HSV therapy, in the absence of other plausible causes of mucositis, such as recent high-dose chemotherapy, irradiation, oral GVHD, fungal or other viral infections, or” (opens the source at this quote in a new tab) Copy Flag
“The occurrence of a new HSV-positive mucocutaneous lesion(s) after receiving appropriately dosed, directed anti-HSV therapy for at least 7 days (excluding prophylaxis and suppressive antiviral therapy).” (opens the source at this quote in a new tab) Copy Flag
“The diagnosis of clinical failure should be based on objective parameters, such as unchanged lesion size or the development of new lesions.” (opens the source at this quote in a new tab) Copy Flag
“In addition, this definition could be used for eligibility for enrollment in clinical trials without necessitating laboratory confirmation of antiviral resistance.” (opens the source at this quote in a new tab) Copy Flag
Consensus definition of antiviral-resistant infection Consensus definitions of recurrent and breakthrough infection Authorship and intended use of the consensus definitions Limits of the consensus definition Criteria used in studies before the consensus definitions Absence of a standard clinical definition Definitions applied in observational studies and in the phase 2 trial Guideline criteria for suspecting resistance Laboratory thresholds that define resistance Chronic mucocutaneous infection as a related definition Clinical significance of resistant infection in immunocompromised patients Causative viruses: HSV-1 and HSV-2 Causative virus type by underlying condition and lesion site Reactivation and persistence in immunocompromised hosts Risk factors tabulated in the consensus review Risk factors: type and severity of immunosuppression Risk factors in hematopoietic cell transplant recipients: reviews Risk factors in hematopoietic cell transplant recipients: cohort findings Risk factors in solid organ transplant recipients Risk factors in people with HIV Antiviral exposure as a risk factor
2.2.1.2.1 Incidence of Refractory mucocutaneous herpes simplex virus infection in immunocompromised adults
Hematopoietic cell transplant recipients: two-year probability of acyclovir-resistant disease by duration of prophylaxis, United States “The effect that long-term use of suppressive acyclovir (ACV) has on both overall herpes simplex virus (HSV) disease and ACV-resistant HSV disease was examined in 3 consecutive cohorts of hematopoietic stem-cell transplant (HCT) recipients (n=2049); cohort 1 received ACV for 30 days after HCT, cohort 2 received it for 1 year after HCT, and cohort 3 received it for an extended period (i.e., >1 year) if the patient's immunosuppression continued after 1 year.” (opens the source at this quote in a new tab) Copy Flag
“ACV-resistant HSV disease developed in 10 patients in cohort 1 (2-year probability, 1.3% [95% CI, 0.8%-2.7%]), in 2 patients in cohort 2 (2-year probability, 0.2% [95% CI, 0%-0.8%]; P=.006), and in 0 patients in cohort 3 (cohort 2 vs. cohort 3, P=.3).” (opens the source at this quote in a new tab) Copy Flag
Allogeneic transplant recipients at one United States cancer center: incidence of laboratory-confirmed acyclovir-resistant infection Adult allogeneic transplant recipients on prophylaxis: breakthrough and refractory or resistant infection within 100 days, United States preprint Hematopoietic stem cell transplant recipients: median incidence of acyclovir-resistant infection across studies in a systematic review Hematopoietic stem cell transplant recipients: emergence of acyclovir-resistant HSV-1 shedding within 100 days, prospective study in Japan Allogeneic stem cell transplant recipients: severe acyclovir-resistant HSV-1 infections over 29 months, France Allogeneic hematopoietic cell transplant recipients: severe acyclovir-resistant HSV-1 stomatitis among consecutive recipients, Germany Allogeneic stem cell transplant recipients: clinical and laboratory resistance among 75 recipients, United Kingdom Haploidentical transplant recipients with lymphocyte-depleted grafts: reactivation and resistance among 14 adults, United States Solid organ transplant recipients: time from transplantation to resistant infection in a French case series Ranges of incidence in hematopoietic cell transplant recipients stated in reviews and study introductions Incidence of any HSV reactivation or disease after hematopoietic cell transplantation 2.2.1.2.2 Prevalence of Refractory mucocutaneous herpes simplex virus infection in immunocompromised adults
Resistance rates by population in the consensus review Prevalence by population in a review of resistance to nucleoside analogues Systematic review of prevalence: immunocompetent and immunocompromised populations Hematopoietic cell transplant recipients: range of prevalence of refractory and resistant infection in a narrative review Stability of prevalence over two decades: resistance among isolates by immune status Reported cases of clinical resistance by underlying condition French surveillance network of 15 laboratories: patients excreting acyclovir-resistant strains by immune status “Between May 1999 and April 2002, 4,098 isolates, corresponding to 3521 patients, were collected.” (opens the source at this quote in a new tab) Copy Flag
“The population studied was 55% immunocompetent patients (n = 1,855) and 45% immunocompromised patients (n = 1,502) (Table 1).” (opens the source at this quote in a new tab) Copy Flag
“In conclusion, 0.3% of immunocompetent patients excreted ACV-resistant strains, in contrast to 3.6% of immunocompromised patients (P < 0.001). The percentage of ACV-resistant HSV-2 strains is not significantly higher than the percentage of HSV-1 strains.” (opens the source at this quote in a new tab) Copy Flag
“Only six immunocompetent patients excreted ACV-resistant HSV strains (0.32%), including one female patient not treated with ACV who was infected primary by an ACV-resistant strain. Among the 54 immunocompromised patients from whom ACV-resistant HSV strains were isolated (3.5%), the bone marrow transplantation patients showed the highest prevalence of resistance (10.9%), whereas among patients infected by human immunodeficiency virus, the prevalence was 4.2%.” (opens the source at this quote in a new tab) Copy Flag
“The main causes of immunosuppression were hemopathy (32% of the cases), HIV infections (21% of the cases), organ transplantations (13.5% of the cases), and bone marrow transplantations (13.5% of the cases) (Table 5).” (opens the source at this quote in a new tab) Copy Flag
French surveillance network: bone marrow transplant recipients excreting acyclovir-resistant strains French surveillance network: patients with hematologic disease excreting acyclovir-resistant strains French surveillance network: patients with HIV infection excreting acyclovir-resistant strains French surveillance network: solid organ transplant recipients excreting acyclovir-resistant strains French surveillance network: other immunocompromised groups French surveillance network: foscarnet resistance and clinical resistance among patients with acyclovir-resistant strains Survey in northwest England: resistance among isolates by immune status Survey in northwest England: patients treated for cancer shedding resistant virus Survey in northwest England: heart or lung transplant recipients shedding resistant virus Survey in northwest England: HIV-infected patients shedding resistant virus Survey in the Netherlands: patients with resistant isolates by immune status and transplant status Ten-year French survey: change in prevalence among immunocompromised patients and allogeneic transplant recipients Four-year French laboratory survey: resistance among samples referred for suspected resistance United States tertiary care center: patients with resistant isolates by immune status United States sexually transmitted disease and HIV clinics: acyclovir-resistant genital isolates by HIV status People with HIV in a French hospital cohort: patients with confirmed acyclovir-resistant infection over 10 years People with HIV: resistance among genital isolates as stated in guidelines Allogeneic transplant recipients with HSV-1 infection in a United Kingdom center: share with acyclovir resistance Hematopoietic cell transplant recipients with refractory infection at 7 United States centers: laboratory-confirmed resistance among those tested Immunocompromised adults treated with foscarnet at 5 United States sites: resistant and refractory episodes Pivotal trial population: share with laboratory-confirmed acyclovir resistance at enrollment Allogeneic transplant recipients with resistant infection at one United States center: dual resistance to foscarnet and acyclovir Solid organ transplant recipients: susceptibility of isolates after prophylaxis Solid organ transplant recipients: guideline statement on relative frequency Patients with a positive HSV polymerase chain reaction at a French center: confirmed genotypic resistance over 8 years German laboratory collection of HSV-1 strains over four decades: acyclovir-resistant strains and trend United States patient-count estimate stated by the company United States patient-count estimates by line of treatment in the company briefing United States claims and health record analysis: data source and cohort definitions “Retrospective cohort study using linked U.S. EHR and administrative claims data (HealthVerity, Inovalon closed claims, Arcadia EHR) from Jan 1, 2022–Dec 31, 2024. This study included patients with ≥1 ICD-10 HSV diagnosis and activity in both data sources.” (opens the source at this quote in a new tab) Copy Flag
“Treatment-modification patterns included: switching within first line (1L) therapy, dose escalation, route of administration transitions, and escalation to second line (2L) therapies. These patterns were proxies, not confirmation of R±R HSV.” (opens the source at this quote in a new tab) Copy Flag
“IC patients were identified via evidence of ICD-10 codes for HCT, SOT, PLWH, or IC Rx within a 12-month look-back; IC-specific analyses required ≥1 medical and ≥1 pharmacy claim within 12 months post-diagnosis.” (opens the source at this quote in a new tab) Copy Flag
“U.S. prevalence estimates were projected by applying age- and sex-specific HSV prevalence rates from claims to Census data.” (opens the source at this quote in a new tab) Copy Flag
“Funding: AiCuris Anti-infective Cures AG” (opens the source at this quote in a new tab) Copy Flag
United States claims and health record analysis: diagnosed HSV cases and immunocompromised subgroups “A total of 1,928,480 patients with HSV infection were identified, of whom 189,412 had overlapping claims and EHR activity during 2022–2024. Applying age- and sex-specific prevalence rates from the claims dataset to U.S. Census data projected approximately 3.9 million diagnosed HSV cases nationally in 2024.” (opens the source at this quote in a new tab) Copy Flag
“Of the 189,412 patients, 152,835 had ≥1 medical and ≥1 pharmacy claim within 12 months of HSV diagnosis and were included in the analyses.” (opens the source at this quote in a new tab) Copy Flag
“Among the study cohort (n=152,835), 6.8% (n=10,412) were IC. Subgroup prevalence within the IC cohort was: 0.19% (n=285) for HCT, 0.35% (n=537) for SOT, 2.12% (n=3,244) for PLWH, and 4.15% (n=6,346) for IC Rx.” (opens the source at this quote in a new tab) Copy Flag
United States claims and health record analysis: treatment-modification patterns used as proxies for refractory infection “Patterns of treatment used as proxies for refractory HSV infection were observed in this cohort. Upward dose titration occurred in 7.6% (n=9,138), switching between first-line agents in 11.8% (n=14,196), and route changes in 5.3% (n=6,367); escalation from first-line to second-line therapy agents occurred in 1% (n=1,247) (Figure 2).” (opens the source at this quote in a new tab) Copy Flag
“Overall, 2,110 (20.3%) IC patients exhibited at least one treatment-change pattern (HCT: n=138; SOT: n=130; PLWH: n=612; IC Rx: n=1,230). Among HCT patients, 72.5% switched between first-line agents and 42% required dose titration. Similar trends were observed across other IC groups: 54.6% and 43.8% in SOT patients, 51.3% and 36.8% in PLWH, and 58.9% and 43.5% in patients receiving IC Rx, respectively (Figure 3).” (opens the source at this quote in a new tab) Copy Flag
“Counts represent IC patients with ≥1 modification pattern and are not prevalence figures; counts are not mutually exclusive.” (opens the source at this quote in a new tab) Copy Flag
United States claims and health record analysis: modification patterns among immunocompromised patients with any pattern, by subgroup Size of the United States immunocompromised adult population: National Health Interview Survey 2021 Size of the United States immunocompromised adult population: National Health Interview Survey 2013 Seroprevalence of HSV-1 and HSV-2 in the United States Seroprevalence of HSV among people with HIV 2.2.1.3 Natural history, survival, and mortality
Clinical significance of resistant isolates by immune status Seven-center United States cohort of 125 hematopoietic cell transplant recipients with refractory infection: design and follow-up Seven-center United States cohort: complete healing, death on therapy, and time to healing Seven-center United States cohort: sensitivity analyses of time to healing “Among patients excluding those treated with pritelivir (N = 121), the median time to healing was 38 days (Q1, Q3: 26, 65), with cumulative incidence of healing of 16.6% at day 28, 31.8% at day 42 and 53.9% at day 90.” (opens the source at this quote in a new tab) Copy Flag
“In the contemporary cohort (2017–2024; N = 90), the median time to healing was 37.5 days (Q1, Q3: 23, 63), with cumulative incidence of healing of 19.1% at day 28, 30.6% at day 42 and 52.6% at day 90.” (opens the source at this quote in a new tab) Copy Flag
“Among patients excluding the 14 patients who only received NUC therapy (N = 111), the median time to healing was 38 days (Q1, Q3: 26, 65), with cumulative incidence of 16.2% at day 28, 31.2% at day 42, and 53.4% at day 90.” (opens the source at this quote in a new tab) Copy Flag
“The median follow-up time among censored patients was 76 days (Q1, Q3: 35.5, 97.5), exceeding the median time to healing in the overall cohort (38 days; Q1, Q3: 26, 65), indicating that censored observations contributed substantial follow-up time and were unlikely to bias the estimates of time to healing.” (opens the source at this quote in a new tab) Copy Flag
Seven-center United States cohort: recurrence and death within 1 year after healing “Sixty-nine patients achieved complete healing of the index HSV episodes. These patients were followed for HSV recurrence for up to 1 year after healing, death, or last follow up. At 1 year, 22 patients (31.9%) died and 27 patients (39.1%) had 1 or more recurrent HSV episode(s).” (opens the source at this quote in a new tab) Copy Flag
“The time to first recurrence was a median of 61 days (Q1, Q3: 29, 97; minimum, maximum: 10, 298). Of a total of 30 recurrent episodes, 7 had acyclovir resistance testing and acyclovir resistance was confirmed in 5 episodes.” (opens the source at this quote in a new tab) Copy Flag
“Recurrent HSV was defined as appearance of new, laboratory-confirmed HSV lesions >7 days after complete healing of the index episode until death or last follow up, up to 1 year from healing of the index refractory episode.” (opens the source at this quote in a new tab) Copy Flag
Seven-center United States cohort: authors' explanation of prolonged healing and recurrence Five-center United States foscarnet cohort of 29 immunocompromised adults with 31 episodes: design and population Five-center United States foscarnet cohort: healing and time to healing Five-center United States foscarnet cohort: recurrence after healing Five-center United States foscarnet cohort: deaths Single-center United States cohort of 18 allogeneic transplant recipients with plaque-reduction-confirmed resistance: timing after transplant Single-center United States transplant cohort: clinical response at 2 weeks and duration of therapy Single-center United States transplant cohort: recurrence Single-center United States transplant cohort: 1-year mortality and causes of death Israeli hematology cohort of 18 participants with plaque-reduction-confirmed resistance: time to resistance diagnosis Israeli hematology cohort: mortality and survivor follow-up Single-center United States series of 5 allogeneic transplant recipients classified by the consensus definitions: response and mortality Prospective Japanese transplant cohort of 268 recipients: 100-day death rates by shedding of acyclovir-resistant virus United Kingdom transplant series of 8 recipients with resistant HSV-1: recurrence, persistence, and death French transplant series of 14 recipients with severe resistant HSV-1: response to foscarnet and cidofovir United Kingdom cohort of 75 allogeneic transplant recipients: clinical failure of acyclovir and foscarnet Haploidentical transplant series: healing coincided with T-cell recovery German series of 6 transplant recipients with resistant HSV-1 stomatitis: mortality French series including 5 solid organ transplant recipients: time to resistance detection and response to foscarnet Risk of dissemination from chronic mucocutaneous infection
Latency in sensory ganglia and reactivation Cell-mediated immunity in control of reactivation and healing Emergence and persistence of resistant virus in immunocompromised hosts Activation of nucleoside analogues by viral thymidine kinase and action at the DNA polymerase Genes associated with resistance by antiviral agent Share of acyclovir resistance attributed to thymidine kinase and DNA polymerase mutations in reviews Thymidine kinase and DNA polymerase mutations observed in patient series Thymidine kinase phenotypes among acyclovir-resistant isolates Frameshift mutations in homopolymer runs and point mutations of the thymidine kinase gene Mechanism of action of foscarnet and cidofovir and resistance to them Cross-resistance within the nucleoside analogue class Cross-resistance between nucleoside analogues, foscarnet, and cidofovir “DRMs in HSV-1 or HSV-2 TK do not confer resistance to FOS or CDV. However, certain DRMs in HSV-1 POL confer cross-resistance to multiple drugs, including ACV and FOS, ACV and CDV, or all three (e.g. Q727R, L778M, L802F, Y818C, W821M, G841C, R959H)” (opens the source at this quote in a new tab) Copy Flag
“Our data indicate that cross-resistance may occur, and switching to another antiviral drug does not always ensure treatment success.” (opens the source at this quote in a new tab) Copy Flag
Foscarnet-resistant isolates: acyclovir susceptibility and prior foscarnet exposure in patients with AIDS Cidofovir susceptibility of acyclovir-resistant and foscarnet-resistant isolates from transplant recipients Mixed populations of susceptible and resistant virus Differences in susceptibility between anatomic sites and between successive episodes Fitness, latency, and reactivation of resistant mutants Transmission of resistant strains Refractory infection without laboratory-confirmed resistance Catalogued resistance mutations and natural polymorphisms of the thymidine kinase and DNA polymerase genes
Consensus definition of refractory mucocutaneous infection for clinical trials “Refractory HSV infection is defined by at least 1 of the following 2 criteria:” (opens the source at this quote in a new tab) Copy Flag
“The lack of clinical improvement in HSV-positive mucocutaneous lesion(s) after at least 7 days of appropriately dosed, directed anti-HSV therapy, in the absence of other plausible causes of mucositis, such as recent high-dose chemotherapy, irradiation, oral GVHD, fungal or other viral infections, or” (opens the source at this quote in a new tab) Copy Flag
“The occurrence of a new HSV-positive mucocutaneous lesion(s) after receiving appropriately dosed, directed anti-HSV therapy for at least 7 days (excluding prophylaxis and suppressive antiviral therapy).” (opens the source at this quote in a new tab) Copy Flag
“The diagnosis of clinical failure should be based on objective parameters, such as unchanged lesion size or the development of new lesions.” (opens the source at this quote in a new tab) Copy Flag
“In addition, this definition could be used for eligibility for enrollment in clinical trials without necessitating laboratory confirmation of antiviral resistance.” (opens the source at this quote in a new tab) Copy Flag
Consensus definition of antiviral-resistant infection Criteria for clinical failure used before the consensus definition Definitions of refractory infection applied in observational cohorts Differential diagnosis and confirmation of viral etiology in refractory lesions Laboratory confirmation of mucocutaneous infection: polymerase chain reaction and culture Diagnostic method used in the seven-center United States transplant cohort Biopsy and histopathology for hypertrophic and tumoral lesions When to suspect resistance and test: National Institutes of Health guideline for people with HIV When to suspect resistance and test: Centers for Disease Control and Prevention guideline When to test: European Conference on Infections in Leukaemia recommendation When to test: German hematology and oncology society guideline for patients with cancer Confirmation threshold and test availability: United Kingdom guideline for anogenital herpes When to test: recommendations from cohort investigators and reviews Phenotypic testing: plaque reduction assay, cutoffs, and limitations Phenotypic thresholds applied by individual laboratories Genotypic testing: sequencing of UL23 and UL30 Genotypic testing: limitations Two-step genotypic and phenotypic testing in a French reference laboratory: yield among samples with suspected resistance Commercial phenotypic test in the United States: Labcorp test 138370 Academic genotypic test in the United States: University of Washington reflex sequencing of UL23 Availability of resistance testing in the United States as described in cohort reports Observed intervals from diagnosis to resistance testing, result, and change of therapy Resistance assays performed and results in the seven-center United States transplant cohort Discordance between susceptibility results and clinical response 2.2.1.6 Clinical presentation - signs and symptoms
Overall pattern: mucocutaneous lesions that are more extensive and persistent in immunocompromised hosts Distribution of lesion sites in the seven-center United States transplant cohort Distribution of lesion sites and virus type in the five-center United States foscarnet cohort Orolabial and oropharyngeal lesions Genital and perianal lesions Chronic ulcerative lesions Hypertrophic, pseudotumoral, and tumoral lesions Necrotizing cutaneous lesions Visceral, ocular, and disseminated disease Onset during antiviral prophylaxis 2.2.1.7 Long-term morbidity
Outcomes associated with refractory or resistant infection after transplantation Chronic non-healing lesions Recurrent episodes over long-term follow-up in people with HIV Renal injury from second-line antiviral therapy Prolonged hospitalization and deconditioning Emergence of foscarnet resistance after foscarnet exposure Scarring No evidence found.
Delay of chemotherapy or transplantation attributable to refractory infection No evidence found.
2.2.1.8 Burden of Refractory mucocutaneous herpes simplex virus infection in immunocompromised adults
2.2.1.8.1 Humanistic burden and health-related quality of life
Health-related quality of life measured with a validated instrument in refractory or resistant infection No evidence found.
Duration of lesional pain in the five-center United States foscarnet cohort Oral intake, analgesia, and quality of life as described by cohort investigators Proxy evidence: systematic review of health-related quality of life in genital herpes, with 1 of 19 primary studies in people living with HIV 2.2.1.8.2 Economic burden and healthcare resource utilization
Cost-of-illness, claims-based cost, and length-of-stay studies of refractory or resistant infection No evidence found.
Resource use and cost left unquantified in the seven-center United States transplant cohort Hospitalization in the single-center United States transplant cohort of 18 recipients Setting and duration of second-line therapy in the seven-center United States transplant cohort “A total of 110 patients (88%) received second line therapy(ies), including foscarnet (94), intravenous cidofovir (6), and/or topical antivirals (21).” (opens the source at this quote in a new tab) Copy Flag
“Ninety-four patients received foscarnet, 6 received IV cidofovir, and 21 received topical antivirals for a total of 109 foscarnet courses, 6 IV cidofovir courses, and 28 topical antiviral courses.” (opens the source at this quote in a new tab) Copy Flag
“The treatment duration was a mean (SD) of 21.8 (13.8), 20.3 (10.1), and 41.0 (37.5) days for foscarnet, IV cidofovir, and topical antivirals, respectively.” (opens the source at this quote in a new tab) Copy Flag
“Foscarnet was the most common second-line therapy, administered in a health care setting (hospital and/or hospital-associated infusion clinic) for a mean duration of 21.8 days.” (opens the source at this quote in a new tab) Copy Flag
“The number of antiviral courses and duration of exposure highlight the burden of therapy for refractory HSV infections.” (opens the source at this quote in a new tab) Copy Flag
Intravenous administration and hospitalization required for foscarnet and cidofovir Compounded topical cidofovir: pharmacy logistics and cost as described in a single-center series Escalation to second-line and intravenous therapy in a United States claims-linked cohort of 152,835 people with diagnosed infection “Retrospective cohort study using linked U.S. EHR and administrative claims data (HealthVerity, Inovalon closed claims, Arcadia EHR) from Jan 1, 2022–Dec 31, 2024.” (opens the source at this quote in a new tab) Copy Flag
“Upward dose titration occurred in 7.6% (n=9,138), switching between first-line agents in 11.8% (n=14,196), and route changes in 5.3% (n=6,367); escalation from first-line to second-line therapy agents occurred in 1% (n=1,247) (Figure 2).” (opens the source at this quote in a new tab) Copy Flag
“These patterns were proxies, not confirmation of R±R HSV.” (opens the source at this quote in a new tab) Copy Flag
“Overall, 2,110 (20.3%) IC patients exhibited at least one treatment-change pattern (HCT: n=138; SOT: n=130; PLWH: n=612; IC Rx: n=1,230).” (opens the source at this quote in a new tab) Copy Flag
“Among patients treated with IV therapy (n=443), 40% (n=179) experienced at least one AE within 30 days.” (opens the source at this quote in a new tab) Copy Flag
Proxy evidence: outpatient foscarnet days in transplant recipients treated for cytomegalovirus or human herpesvirus 6 2.2.1.8.3 Economic impact of Refractory mucocutaneous herpes simplex virus infection in immunocompromised adults on familiesNot applicable.
2.2.1.8.4 Economic impact of diagnostic testing
Published cost or cost-effectiveness analysis of resistance testing No evidence found.
Billing codes listed by laboratories for phenotypic resistance testing Billing codes listed by laboratories for genotypic resistance testing Medicare Clinical Laboratory Fee Schedule records for the listed codes, fourth-quarter file Number of resistance assays ordered in the seven-center United States transplant cohort Access to genotypic testing named as an unmet need 2.2.2 Approaches to treatment
2.2.2.1 Current treatment options and standard of care
2.2.2.1.1 Intravenous foscarnet
NIH guideline for people with HIV: preferred therapy and its rating NIH guideline for people with HIV: specialist consultation and laboratory monitoring during foscarnet CDC sexually transmitted infections guideline: treatment of choice for acyclovir-resistant genital herpes Hematopoietic cell transplantation guideline: treatment of choice for resistant disease European Conference on Infections in Leukemia: regimen for resistance to acyclovir or famciclovir American Society of Transplantation guideline for solid organ transplant recipients British Association for Sexual Health and HIV guideline: systemic therapy for drug-resistant herpes European guideline for genital herpes: systemic therapy for drug-resistant herpes Position in guidelines as summarized in a review of transplant recipients Foscarnet regimen, monitoring, and regulatory status as tabulated in a review Labeled indication for acyclovir-resistant mucocutaneous HSV infection Labeled dose and duration for acyclovir-resistant HSV infection Labeled administration: controlled infusion through an infusion pump Labeled hydration with each infusion Labeled dose adjustment by creatinine clearance: rules Labeled dose adjustment by creatinine clearance: induction doses for HSV infection Randomized trial against vidarabine in AIDS: design as reported in the published abstract Randomized trial against vidarabine in AIDS: healing, pain, and viral shedding as reported in the published abstract Randomized trial against vidarabine in AIDS: toxicity and relapse after treatment Controlled trial against vidarabine as described in the prescribing information Dose-comparison trial of twice-daily and three-times-daily dosing as described in the prescribing information Dose-comparison trial in AIDS: preliminary published report Case series of 26 people with AIDS: response, viral shedding, and discontinuation Uncontrolled trial in 4 people with AIDS and acyclovir-resistant HSV-2 infection Multicenter cohort of 31 foscarnet-treated episodes: design and population Multicenter cohort of 31 foscarnet-treated episodes: treatment duration, healing, and recurrence Real-world cohort of 125 hematopoietic cell transplant recipients: design and use of foscarnet “This multicenter, retrospective, observational study describes real-world treatment patterns and clinical outcomes of refractory mucocutaneous HSV infections in a cohort of 125 HCT recipients from 7 major HCT centers in the United States.” (opens the source at this quote in a new tab) Copy Flag
“First anti-HSV treatment was a NUC (standard or high dose) in 100 patients (80.0%) and foscarnet in 25 patients (20.0%).” (opens the source at this quote in a new tab) Copy Flag
“The most common second line therapy was foscarnet in 94 patients (75.0%).” (opens the source at this quote in a new tab) Copy Flag
“The median time from the treatment index dated to the start of the first course of foscarnet was 12 days (Q1, Q3: 0, 23).” (opens the source at this quote in a new tab) Copy Flag
“Ninety-four patients received foscarnet, 6 received IV cidofovir, and 21 received topical antivirals for a total of 109 foscarnet courses, 6 IV cidofovir courses, and 28 topical antiviral courses.” (opens the source at this quote in a new tab) Copy Flag
“The treatment duration was a mean (SD) of 21.8 (13.8), 20.3 (10.1), and 41.0 (37.5) days for foscarnet, IV cidofovir, and topical antivirals, respectively.” (opens the source at this quote in a new tab) Copy Flag
Real-world cohort of 125 hematopoietic cell transplant recipients: healing and recurrence across all treatments Real-world cohort of 125 hematopoietic cell transplant recipients: care setting for foscarnet Single-center cohort of 18 allogeneic transplant recipients: regimens and response Allogeneic transplant recipients in the United Kingdom: foscarnet in 8 participants with aciclovir-resistant HSV-1 Single-center series of 5 allogeneic transplant recipients: response to foscarnet with or without cidofovir Allogeneic stem cell transplant recipients in France: response by foscarnet susceptibility Acyclovir-resistant HSV-1 stomatitis after transplantation in Germany: intravenous foscarnet in 3 participants Relapse after healing and resistance after repeated treatment: prescribing information Foscarnet resistance among treated patients in a French surveillance network Foscarnet resistance in transplant cohorts Foscarnet-resistant HSV-2 in 6 people with HIV after prior foscarnet exposure Boxed warning for foscarnet Renal impairment: label warning and incidence with and without hydration Mineral and electrolyte abnormalities: label warning and incidence Seizures: label warning and incidence QT prolongation, hypersensitivity, and other label warnings and precautions Adverse events in five controlled trials in AIDS and cytomegalovirus retinitis Severe adverse events in five controlled trials in AIDS and cytomegalovirus retinitis Laboratory monitoring recommended in the prescribing information Drug interactions that add to renal, calcium, and QT risk “Because of foscarnet’s tendency to cause renal impairment, the use of FOSCAVIR should be avoided in combination with potentially nephrotoxic drugs such as aminoglycosides, amphotericin B, cyclosporine, acyclovir, methotrexate, tacrolimus and intravenous pentamidine (see above) unless the potential benefits outweigh the risks to the patient.” (opens the source at this quote in a new tab) Copy Flag
“Because FOSCAVIR can reduce serum levels of ionized calcium, extreme caution is advised when used concurrently with other drugs known to influence serum calcium levels (e.g., intravenous pentamidine).” (opens the source at this quote in a new tab) Copy Flag
“Because of the risk of QT prolongation and the potential for torsades de pointes, the use of FOSCAVIR should be avoided in combination with agents known to prolong the QT interval including Class IA (e.g., quinidine or procainamide) or Class III (e.g., dofetilide, amiodarone, sotalol) antiarrhythmic agents, phenothiazines, tricyclic antidepressants, and certain macrolides and fluoroquinolones.” (opens the source at this quote in a new tab) Copy Flag
Multicenter cohort of 31 foscarnet-treated episodes: adverse events and discontinuation Multicenter cohort of 31 foscarnet-treated episodes: electrolyte and kidney adverse events Multicenter cohort of 31 foscarnet-treated episodes: inpatient management and monitoring Real-world cohort of 125 hematopoietic cell transplant recipients: toxicity during 109 foscarnet courses Single-center cohort of 18 allogeneic transplant recipients: hospitalization, kidney injury, and hemodialysis Single-center cohort of 18 allogeneic transplant recipients: renal toxicity among foscarnet recipients as tabulated in a review Nephrotoxicity, electrolyte imbalance, and genital ulceration as summarized in a review Single-center series of 5 allogeneic transplant recipients: acute renal failure and electrolyte disturbance Acute kidney injury and electrolyte abnormalities in transplant recipients given foscarnet for cytomegalovirus or human herpesvirus 6 2.2.2.1.2 Topical imiquimod
National Institutes of Health opportunistic infections guideline: imiquimod 5% cream as an alternative therapy rated BIII Centers for Disease Control and Prevention sexually transmitted infections guideline: imiquimod 5% as an alternative for acyclovir-resistant genital herpes European genital herpes guideline: immunomodulators for hypertrophic herpes simplex Labeled indications of imiquimod 5% cream “ALDARA is indicated for the topical treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses (AK) on the face or scalp in immunocompetent adults.” (opens the source at this quote in a new tab) Copy Flag
“ALDARA is indicated for the topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) in immunocompetent adults, with a maximum tumor diameter of 2.0 cm, located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet), only when surgical methods are medically less appropriate and patient follow-up can be reasonably assured.” (opens the source at this quote in a new tab) Copy Flag
“ALDARA is indicated for the topical treatment of external genital and perianal warts (EGW) in immunocompetent patients 12 years of age and older.” (opens the source at this quote in a new tab) Copy Flag
“ALDARA is for topical use only. ALDARA is not for oral, ophthalmic, or intravaginal use.” (opens the source at this quote in a new tab) Copy Flag
Off-label status, dose, and monitoring of imiquimod 5% as tabulated in a review Licensed use and proposed basis for use in refractory genital ulcers Clinical trials of imiquimod in herpes labialis and genital herpes as summarized in a review Systematic review and individual-patient meta-analysis of imiquimod for hypertrophic herpes simplex Case series in HIV infection with herpes simplex virus type 2 resistant to aciclovir and foscarnet Case series of pseudotumoral anogenital herpes in HIV infection treated with immunomodulators Case series of three immunocompromised participants with presumed aciclovir-resistant anogenital disease Case report in HIV infection after failure of oral antivirals Adjunctive imiquimod in people living with HIV in a French case series “Among PLHIV, infections included recurrent genital herpes and atypical pseudo-tumoral lesions, managed with foscarnet or adjunctive topical cidofovir or imiquimod.” (opens the source at this quote in a new tab) Copy Flag
“Several alternative therapies were introduced, including topical cidofovir and imiquimod, prolonged VACV therapy (6 weeks), and pritelivir.” (opens the source at this quote in a new tab) Copy Flag
“However, all treatment attempts resulted in only partial clinical responses, and the herpetic lesions persisted.” (opens the source at this quote in a new tab) Copy Flag
“At that time the patient was treated with VACV 1 gram twice daily, resulting in significant clinical improvement and regression of the lesion, after adjunction of topical imiquimod.” (opens the source at this quote in a new tab) Copy Flag
“Complete healing was achieved, and no recurrences were observed over a one-year follow-up period under VACV prophylaxis.” (opens the source at this quote in a new tab) Copy Flag
Combination use with intravenous foscarnet in allogeneic transplant recipients Reports of topical imiquimod in transplant recipients as tabulated in a review Absence of clinical trials supporting topical therapy added to systemic treatment Label warnings: local skin reactions and inflammatory skin conditions Label warnings: hypopigmentation and systemic reactions Local skin reactions in vehicle-controlled trials of imiquimod 5% cream for external genital warts Selected adverse reactions in vehicle-controlled trials of imiquimod 5% cream for external genital warts Discontinuation for local reactions in the genital wart trials Severe local reaction rate in the meta-analysis of hypertrophic herpes simplex Tolerability in a single-center series of allogeneic transplant recipients 2.2.2.1.3 Compounded topical antivirals (Cidofovir, trifluridine, and foscarnet)
National Institutes of Health opportunistic infections guideline: topical cidofovir, trifluridine, and foscarnet as alternative therapies rated BIII Centers for Disease Control and Prevention sexually transmitted infections guideline: compounded cidofovir gel 1% European Conference on Infections in Leukaemia recommendations: topical trifluridine and cidofovir gel rated CIII United Kingdom anogenital herpes guideline: foscarnet cream and cidofovir gel rated 1A and trifluorothymidine rated 2D Absence of commercial topical formulations and extemporaneous compounding Food and Drug Administration decision on topical cidofovir and compounding hazards Cidofovir gels evaluated in recurrent genital herpes and their commercial status Labeled indication and formulation of cidofovir injection Labeled formulation of foscarnet Labeled indication and formulation of trifluridine ophthalmic solution Off-label status, dose, and monitoring of topical antivirals as tabulated in a review Guideline-recommended topical regimens and their evidence base as described in a review Cidofovir gel: randomized, double-blind, placebo-controlled trial in AIDS, design Cidofovir gel: lesion healing, viral shedding, and pain in the randomized trial Cidofovir gel: application-site reactions in the randomized trial Topical cidofovir: first reports in infection resistant to acyclovir and foscarnet Topical cidofovir and foscarnet: stomatitis after allogeneic hematopoietic cell transplantation Topical cidofovir: oral rinse in a transplant recipient with multidrug-resistant infection Topical cidofovir: perianal ulcer in a transplant recipient Topical cidofovir: oral infection in a transplant recipient unable to tolerate systemic antivirals Topical cidofovir and foscarnet in transplant recipients as tabulated in a review Topical cidofovir: results and kidney injury in transplant recipients as summarized in a review Topical cidofovir: irreversible acute kidney injury in two immunocompromised participants Topical cidofovir: duration and renal monitoring in a transplant cohort Topical cidofovir: compounding logistics and cost in a single-center series Foscarnet 1% cream: phase 1/2 open-label trial in AIDS, design Foscarnet 1% cream: lesion response, viral culture, and pain Foscarnet 1% cream: adverse events and new lesions at untreated sites Trifluridine 1% ophthalmic solution: open-label pilot study in AIDS, design Trifluridine 1% ophthalmic solution: healing and discontinuation Trifluridine 1% ophthalmic solution: toxicity and new lesions outside the treated area Trifluorothymidine combined with interferon alfa in three participants with AIDS Trifluridine ophthalmic solution: labeled adverse reactions and mutagenic potential Use and duration of topical antivirals in a United States multicenter transplant cohort “Non-NUCs (second-line therapies) include mainly foscarnet, IV cidofovir, or topical cidofovir and topical imiquimod.” (opens the source at this quote in a new tab) Copy Flag
“Ninety-four patients received foscarnet, 6 received IV cidofovir, and 21 received topical antivirals for a total of 109 foscarnet courses, 6 IV cidofovir courses, and 28 topical antiviral courses.” (opens the source at this quote in a new tab) Copy Flag
“The treatment duration was a mean (SD) of 21.8 (13.8), 20.3 (10.1), and 41.0 (37.5) days for foscarnet, IV cidofovir, and topical antivirals, respectively.” (opens the source at this quote in a new tab) Copy Flag
“Topical antiviral preparations may be occasionally used as an adjunct to systemic antivirals or as step-down therapy, with scant supporting evidence” (opens the source at this quote in a new tab) Copy Flag
2.2.2.1.4 Intravenous cidofovir
NIH guideline for people with HIV: alternative therapy and its rating NIH guideline for people with HIV: specialist consultation and laboratory monitoring during cidofovir CDC sexually transmitted infections guideline: weekly intravenous cidofovir Hematopoietic cell transplantation guideline: alternative to foscarnet European Conference on Infections in Leukemia: regimen for resistance to foscarnet British Association for Sexual Health and HIV guideline: regimen and grade European guideline for genital herpes: systemic therapy and alternating courses Position after foscarnet as summarized in reviews Cidofovir regimen, monitoring, and regulatory status as tabulated in a review Labeled indication: cytomegalovirus retinitis in AIDS Use for HSV infection outside the labeled indication In vitro activity against herpes simplex virus in the prescribing information Labeled dose for the approved indication Required probenecid with each dose Required saline hydration with each dose Dose adjustment and discontinuation for changes in renal function Real-world cohort of 125 hematopoietic cell transplant recipients: intravenous cidofovir in 6 participants “Ninety-four patients received foscarnet, 6 received IV cidofovir, and 21 received topical antivirals for a total of 109 foscarnet courses, 6 IV cidofovir courses, and 28 topical antiviral courses.” (opens the source at this quote in a new tab) Copy Flag
“The treatment duration was a mean (SD) of 21.8 (13.8), 20.3 (10.1), and 41.0 (37.5) days for foscarnet, IV cidofovir, and topical antivirals, respectively.” (opens the source at this quote in a new tab) Copy Flag
“Among 6 IV cidofovir courses, renal function abnormalities were reported during 3 courses (50%).” (opens the source at this quote in a new tab) Copy Flag
“One of 6 courses of IV cidofovir was discontinued because of the renal function abnormalities.” (opens the source at this quote in a new tab) Copy Flag
“Systemic cidofovir requires weekly IV administration and, although it could theoretically be given in the outpatient setting, concerns for nephrotoxicity and limited efficacy data hinder its applicability for refractory HSV.” (opens the source at this quote in a new tab) Copy Flag
Allogeneic stem cell transplant recipients in France: cidofovir after foscarnet in 8 participants Single-center cohort of 18 allogeneic transplant recipients: intravenous cidofovir after foscarnet Single-center cohort of 18 allogeneic transplant recipients: renal toxicity with intravenous cidofovir as tabulated in a review Single-center series of 5 allogeneic transplant recipients: cidofovir as step-down therapy in 2 participants Case report after haploidentical transplantation: healing with cidofovir after foscarnet toxicity Case from a transplant series: response followed by acute renal failure and neutropenia In vitro susceptibility of isolates from allogeneic transplant recipients Boxed warning for cidofovir Nephrotoxicity: label warnings “Dose dependent nephrotoxicity is the major dose-limiting toxicity related to cidofovir injection administration.” (opens the source at this quote in a new tab) Copy Flag
“Proteinuria, as measured by urinalysis in a clinical laboratory, may be an early indicator of cidofovir injection-related nephrotoxicity.” (opens the source at this quote in a new tab) Copy Flag
“Continued administration of cidofovir injection may lead to additional proximal tubular cell injury, which may result in glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, elevations in serum creatinine, and/or acute renal failure, in some cases, resulting in the need for dialysis.” (opens the source at this quote in a new tab) Copy Flag
“Renal function that did not return to baseline after drug discontinuation has been observed in clinical studies of cidofovir injection.” (opens the source at this quote in a new tab) Copy Flag
“The safety of cidofovir injection has not been evaluated in patients receiving other known potentially nephrotoxic agents, such as intravenous aminoglycosides (e.g., tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and non-steroidal anti-inflammatory agents” (opens the source at this quote in a new tab) Copy Flag
Nephrotoxicity: incidence in clinical trials in cytomegalovirus retinitis Neutropenia, ocular hypotony, uveitis, and metabolic acidosis Serious adverse events or laboratory abnormalities in more than 5% of patients Adverse events, laboratory abnormalities, or intercurrent illnesses of any severity in more than 15% of patients Laboratory monitoring before each dose Nephrotoxicity and myelosuppression as summarized in reviews 2.2.2.1.5 High-dose and continuous-infusion acyclovir
British Association for Sexual Health and HIV guideline: partially resistant strains European guideline for genital herpes: partially resistant strains Cross-resistance of acyclovir-resistant strains in United States guidelines High-dose intermittent acyclovir as a first step in a review algorithm Labeled indication and dose of intravenous acyclovir for mucocutaneous HSV infection in immunocompromised patients Continuous-infusion regimen and regulatory status as tabulated in a review Continuous infusion in 6 allogeneic transplant recipients: population and prior treatment failure Continuous infusion in 6 allogeneic transplant recipients: dose and outcome by case Continuous infusion in 6 allogeneic transplant recipients: clinical response Continuous infusion in 6 allogeneic transplant recipients: tolerability Continuous infusion in 6 allogeneic transplant recipients: limits of the evidence and conclusion Earlier reports of continuous infusion as summarized in the transplant series Continuous infusion for HSV-2 proctitis in 2 people with AIDS Real-world cohort of 125 hematopoietic cell transplant recipients: high-dose intravenous acyclovir before second-line therapy Single-center cohort of 18 allogeneic transplant recipients: intravenous acyclovir before foscarnet or cidofovir Continuous infusion as assessed in a review of transplant recipients Published evidence for systemic options as characterized in a multicenter cohort report Renal warnings and precautions in the intravenous acyclovir prescribing information Neurologic and other adverse reactions in the intravenous acyclovir prescribing information “Approximately 1% of patients receiving intravenous acyclovir have manifested encephalopathic changes characterized by either lethargy, obtundation, tremors, confusion, hallucinations, agitation, seizures, or coma.” (opens the source at this quote in a new tab) Copy Flag
“Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), which has resulted in death, has occurred in immunocompromised patients receiving acyclovir therapy.” (opens the source at this quote in a new tab) Copy Flag
“The adverse reactions listed below have been observed in controlled and uncontrolled clinical trials in approximately 700 patients who received ZOVIRAX at ~5 mg/kg (250 mg/m2) 3 times daily, and approximately 300 patients who received ~10 mg/kg (500 mg/m2) 3 times daily.” (opens the source at this quote in a new tab) Copy Flag
“The most frequent adverse reactions reported during administration of ZOVIRAX were inflammation or phlebitis at the injection site in approximately 9% of the patients, and transient elevations of serum creatinine or BUN in 5% to 10%” (opens the source at this quote in a new tab) Copy Flag
“Nausea and/or vomiting occurred in approximately 7% of the patients” (opens the source at this quote in a new tab) Copy Flag
Dose adjustment of intravenous acyclovir for renal impairment 2.2.2.1.6 Limitations of current therapies
Summary Before pritelivir, intravenous foscarnet was the only medication approved by the FDA for refractory or resistant HSV infection. Among 125 hematopoietic cell transplant recipients at 7 United States centers, 69 (55.2%) healed completely at a median of 38 days, 40 (32.0%) died on therapy, and 27 of the 69 who healed (39.1%) had a recurrence within 1 year. Of 31 foscarnet-treated episodes in a second cohort, 15 (48%) healed, 20 (65%) had electrolyte disturbance, 13 (42%) had kidney injury, and 10 (32%) ended in discontinuation for an adverse event. Foscarnet is infused intravenously by pump with hydration. In a French surveillance network, 7 of 12 people given foscarnet for acyclovir-resistant strains excreted foscarnet-resistant strains. Guideline alternatives are rated BIII or CIII, and topical cidofovir, trifluridine, and foscarnet are not commercially available.
Healing, death on therapy, and time to healing in a United States multicenter transplant cohort Recurrence and death within one year of healing in the multicenter transplant cohort Treatment sequence before second-line therapy in the multicenter transplant cohort Healing, recurrence, and pain in foscarnet-treated episodes in a United States multicenter study Deaths in the foscarnet-treated cohort Response, treatment duration, and one-year mortality in a United States cancer center cohort Delay to susceptibility testing and to a change of therapy Mortality in a series of 18 participants with hematologic disease with acyclovir-resistant infection Healing and mortality in a series of five allogeneic transplant recipients Outcomes with foscarnet in eight allogeneic transplant recipients in the United Kingdom Complete response to foscarnet and cidofovir in allogeneic stem cell transplant recipients in France Clinical resistance and outcome in 75 allogeneic stem cell transplant recipients One-hundred-day death rates by acyclovir susceptibility after transplantation in Japan Recurrence during long-term follow-up in HIV infection Healing and relapse with foscarnet as stated in its label Foscarnet boxed warning: renal impairment and seizures Foscarnet label: rates of renal impairment, electrolyte changes, and seizures Foscarnet label: genital ulceration Foscarnet label: intravenous infusion, infusion pump, hydration, and laboratory monitoring Foscarnet adverse events and discontinuation in the United States multicenter study Most common adverse events during foscarnet therapy by organ system in 31 episodes Toxicity and discontinuation during foscarnet and cidofovir courses in the multicenter transplant cohort Hospitalization, acute kidney injury, and hemodialysis in the United States cancer center cohort Renal failure and electrolyte disturbance in the series of five transplant recipients Acute kidney injury with foscarnet given for any herpesvirus infection after transplantation Foscarnet for resistant or refractory cytomegalovirus infection in transplant recipients Intravenous administration and care setting for foscarnet Intravenous cidofovir: boxed warning, contraindications, and outpatient use Foscarnet resistance after foscarnet exposure: label statement Herpes simplex virus DNA polymerase substitutions conferring foscarnet resistance with cross-resistance to acyclovir or cidofovir Foscarnet resistance among foscarnet-treated patients in a French surveillance network Foscarnet resistance in transplant cohorts Foscarnet-resistant infection in patients with AIDS Shared DNA polymerase target and cross-resistance among approved antivirals Evidence base behind treatment recommendations Guideline ratings of the alternatives to foscarnet Topical alternatives: commercial availability and supporting evidence Federal guideline statements on nephrotoxicity and monitoring of systemic alternatives Consensus working group statement on alternative treatment Review statements on the toxicity of foscarnet and cidofovir Investigator conclusions on unmet need in cohort studies 2.2.2.2 Place in treatment, anticipated use, and care setting
Summary Pritelivir is indicated for immunocompromised adults with mucocutaneous HSV lesions refractory, with or without documented resistance, to acyclovir, valacyclovir, or famciclovir. The indication follows failure of a nucleoside analogue; PRIOH-1 Part C defined failure as no clinical improvement after at least 7 days. It is an oral tablet taken once daily until lesions heal. Part C compared it with investigator's choice of intravenous foscarnet (70% of 50 participants), topical imiquimod (14%), intravenous cidofovir (12%), or topical cidofovir (4%). Parts D and F enrolled 35 participants refractory to or intolerant of foscarnet. Trial investigators state that intravenous foscarnet “requires hospitalization for monitoring and administration”. NIH and hematopoietic cell transplant guidelines name foscarnet as the treatment of choice for acyclovir-resistant HSV, and the CDC guideline names it for acyclovir-resistant genital herpes. The NIH and transplant guidelines list cidofovir as an alternative. The NIH guideline lists pritelivir as an expanded access option. Asahi Kasei describes pritelivir as “the first oral agent” in second-line treatment.
Population described in the FDA approval announcement Line of therapy: definition of refractory infection in the pivotal trial Comparator therapies in PRIOH-1 Part C: prescribing information Comparator therapies in PRIOH-1 Part C: participants by treatment received Use after foscarnet failure or intolerance Activity against virus resistant to nucleoside analogues and foscarnet Disease sites not enrolled in the pivotal trial Federal HIV opportunistic infection guideline: preferred and alternative therapy for acyclovir-resistant infection Federal HIV opportunistic infection guideline: expanded access note and investigational status of pritelivir Sexually transmitted infections treatment guideline: antiviral-resistant genital herpes Hematopoietic cell transplant guideline: resistant disease European leukemia guideline: alternative regimens for resistant virus Solid organ transplant guideline: acyclovir-resistant infection United Kingdom anogenital herpes guideline: drug-resistant herpes and compassionate access to pritelivir European genital herpes guideline: recalcitrant herpes and the pritelivir access program Route of administration against the intravenous standard Care setting of intravenous foscarnet as described by trial investigators Care setting of standard therapy as described by the developer Company positioning as second-line therapy Treatment centers and prescribers targeted by the company Investigator statements on anticipated use Position of helicase-primase inhibitors: review of refractory and resistant infection after hematopoietic cell transplantation Position of helicase-primase inhibitors: review of drug resistance Position of helicase-primase inhibitors: review by authors affiliated with the developer Concomitant acid-reducing agents Expected commercial availability 2.2.2.3 Heterogeneity of treatment effect
Predefined subgroup analyses in PRIOH-1 Part C Overall population as shown beside the subgroup analyses Adjustment of the primary analysis for protocol version Underlying conditions represented in Part C: prescribing information Underlying disease by treatment arm in Part C Immunosuppressive condition categories used for the subgroup analyses Transplant recipients: lesion healing in Part C Oncology and other non-transplant conditions: lesion healing in Part C People living with HIV: lesion healing in the hierarchical HIV category People living with HIV: post hoc analysis of all 38 participants with HIV People living with HIV: antiretroviral therapy, CD4 count, and comparator received Documented acyclovir resistance against refractory infection without documented resistance: participants at baseline Documented acyclovir resistance against refractory infection without documented resistance: lesion healing in Part C HSV type: distribution at baseline in Part C Lesion healing by HSV type in Part C No evidence found.
Lesion healing by lesion site in Part C No evidence found.
Comparator received: lesion healing in Part C by investigator's choice treatment Region: lesion healing in Part C Sex: lesion healing in Part C Age: lesion healing in Part C Age 65 years or older: prescribing information Race: lesion healing in Part C Foscarnet-refractory or foscarnet-intolerant participants: Parts D and F Foscarnet-refractory or foscarnet-intolerant participants: phase 2 Part B Non-randomized cohorts, including acyclovir-sensitive participants Lesion healing in acyclovir-sensitive participants No evidence found.
Exposure, response, and pharmacokinetics across immunocompromising conditions “No exposure-response relationship was identified between steady-state plasma pritelivir exposures at 100 mg once daily and the occurrence of all lesions healed by Day 28.” (opens the prescribing information at this quote) Copy Flag
“There were no clinically significant differences in the pharmacokinetics of pritelivir based on age (19 to 84 years), gender, race (including American Indian/Alaska Native, Asian, Black/African American, White, or other), body weight (48 to 176 kg), or underlying immunocompromised condition (including HIV/AIDS, oncology, transplant, or autoimmune/inflammatory disorder).” (opens the prescribing information at this quote) Copy Flag
Company statements on consistency across subgroups Heterogeneity of underlying conditions in the phase 2 parts Populations not enrolled: ocular, central nervous system, and disseminated disease Populations not enrolled: participants with myelosuppression Hemodialysis and severe hepatic impairment 2.2.2.4 Care management intervention strategies
When to suspect resistance and obtain susceptibility testing: federal HIV guideline When to suspect resistance and obtain susceptibility testing: sexually transmitted infection guideline Resistance testing in hematologic malignancy and transplantation: guideline statements Timing of resistance testing and change of therapy in transplant cohorts Turnaround and availability of resistance tests Genes tested for resistance and the genes in which pritelivir resistance arises Infectious disease specialist involvement Monitoring during intravenous foscarnet: renal function Monitoring during intravenous foscarnet: electrolytes and electrocardiogram Monitoring during intravenous foscarnet: concomitant nephrotoxic drugs Monitoring during intravenous foscarnet, cidofovir, or acyclovir: guideline and cohort statements Monitoring listed for each systemic agent in a review of transplant recipients Monitoring and co-administered therapy during intravenous cidofovir Care setting for intravenous foscarnet and cidofovir Compounding of topical agents Pritelivir: review of acid-reducing agents before and during treatment Pritelivir: consequence of reduced exposure with acid-reducing agents Pritelivir: co-administered BCRP substrates Pritelivir: adherence and missed doses Pritelivir: treatment until lesions heal and counseling on cure Pritelivir: medication history at each visit Duration of second-line therapy in the federal HIV guideline Suppressive antiviral therapy after resolution of a resistant episode Prophylaxis practices in transplant recipients that bear on resistance Recurrence after healing in a multicenter transplant cohort Pritelivir as secondary prophylaxis in a case report from an expanded access program Antiretroviral therapy and immune reconstitution in people with HIV Immunosuppression at the time of resistant infection in a transplant cohort Management of recalcitrant herpes in immunocompromised individuals: European guideline Proposed management algorithm for transplant recipients: basis stated by its authors Infection control for severe mucocutaneous disease in transplant units 2.2.2.5 Other product development or post-marketing obligations required by the FDA
Postmarketing requirements and commitments in an FDA approval letter No evidence found.
Nonclinical studies ongoing at approval: carcinogenicity Populations not evaluated at approval European Union paediatric investigation plan: agreed measures European Union paediatric investigation plan: completion date, deferral, and waiver Further clinical trials: company statement, February 2026 Other product development: broader herpes simplex virus populations 2.2.2.6 Ongoing post-approval monitoring
Adverse reaction reporting Monitoring and follow-up actions stated in the prescribing information Hepatic laboratory abnormalities reported in the prescribing information Laboratory monitoring schedule required by the prescribing information No evidence found.
Risk evaluation and mitigation strategy No evidence found.
Monitoring within the expanded access protocol Post-approval registry or observational study No evidence found.
2.2.2.7 Expected outcomes of therapy
Lesion healing as the treatment goal Proportion healed by day 28: prescribing information Proportion healed by day 28: FDA approval announcement Proportion healed by day 42: prescribing information Proportion healed by day 28 and day 42: congress presentation Proportion healed after foscarnet failure or intolerance Time to lesion healing in Part C No evidence found.
Time to lesion healing: phase 2 Parts A and B “The primary end point, time to lesion healing up to a maximum of 28 days of treatment as assessed by IPR, demonstrated a median time to healing of 26.0 days (95% CI, 13.0–31.0) in the pritelivir arm vs NE (95% CI, 20.0–NE) in the foscarnet arm (NE as <50% were assessed as healed).” (opens the source at this quote in a new tab) Copy Flag
“Based on investigator assessment, the median time to lesion healing was 19.0 days (95% CI, 15.0–25.0) in the pritelivir arm and 21.0 days (95% CI, 11.0–NE) in the foscarnet arm.” (opens the source at this quote in a new tab) Copy Flag
“Overall, 93.3% of participants in the pritelivir arm and 57.1% in the foscarnet arm achieved lesion healing, corresponding to a treatment difference of 36.2% (95% CI, −10.1% to 74.1%; P = .077)” (opens the source at this quote in a new tab) Copy Flag
“Median time to lesion healing assessed by IPR within 28 days in Part B was 19.0 days” (opens the source at this quote in a new tab) Copy Flag
Time to undetectable HSV DNA in lesions HSV DNA detection rate and cessation of detection in Part C HSV DNA detection in the phase 2 parts Pain outcomes No evidence found.
Recurrence after treatment in Part C No evidence found.
Recurrence after treatment: phase 2 Parts A and B Emergence of resistance during treatment: prescribing information Emergence of resistance during treatment: congress presentation Emergence of resistance during treatment: phase 2 parts Treatment duration: prescribing information Treatment duration: days of exposure by treatment in Part C Completion and discontinuation of treatment in Part C Adverse reactions and discontinuation because of adverse reactions: prescribing information Renal and electrolyte safety relative to investigator's choice in Part C Renal and electrolyte safety relative to foscarnet in the phase 2 Part A Dosing in renal impairment