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Hovilpri (pritelivir)

Refractory mucocutaneous herpes simplex virus infection in immunocompromised adults

Also known as AIC316
Last updated
239 sources

Product information and disease descriptionPlace of product in therapyApproaches to treatment

Care management intervention strategies

31 evidence topics · 21 sources

When to suspect resistance and obtain susceptibility testing: federal HIV guideline

“Treatment failure due to acyclovir resistance should be suspected if herpes-related lesions do not begin to resolve within 7 to 10 days after initiation of anti-HSV therapy.” (opens the source at this quote in a new tab)

“Risk factors for acyclovir-resistant HSV include prolonged use of acyclovir, suboptimal acyclovir dosing, immunosuppression, and ongoing HSV replication.” (opens the source at this quote in a new tab)

“In people with suspected acyclovir-resistant HSV, viral culture of the lesion should be performed, and if virus is isolated, susceptibility testing should then be conducted to confirm drug resistance (AII).” (opens the source at this quote in a new tab)

“If a person with prior acyclovir resistance develops a recurrence while taking acyclovir suppressive therapy, susceptibility testing should be done.” (opens the source at this quote in a new tab)

When to suspect resistance and obtain susceptibility testing: sexually transmitted infection guideline

“If lesions persist or recur in a patient receiving antiviral treatment, acyclovir resistance should be suspected and a viral culture obtained for phenotypic sensitivity testing” (opens the source at this quote in a new tab)

“Molecular testing for acyclovir resistance is not available. Such persons should be managed in consultation with an infectious disease specialist, and alternative therapy should be administered.” (opens the source at this quote in a new tab)

Resistance testing in hematologic malignancy and transplantation: guideline statements

“Virus culture is required for testing of antiviral drug resistance (III).” (opens the source at this quote in a new tab)

“If HSV disease is unresponsive to antiviral therapy given at maximum dose, resistance testing should be performed (CIII).” (opens the source at this quote in a new tab)

“Clinical reactivation of HSV or VZV in patients on antiviral prophylaxis does not imply routine resistance testing.” (opens the source at this quote in a new tab)

“In contrast, testing for resistance has to be considered in patients on treatment with acyclovir, if no clinical improvement is seen after 5 days” (opens the source at this quote in a new tab)

“Genotypic resistance testing is recommended and established in specialized laboratories.” (opens the source at this quote in a new tab)

“Polymerase chain reaction is the preferred diagnostic test unless culture is needed for resistance testing.” (opens the source at this quote in a new tab)

“Acyclovir-resistant HSV is less common in SOT patients than in HSCT and can be treated with foscarnet, though other novel therapies are currently under investigation.” (opens the source at this quote in a new tab)

Timing of resistance testing and change of therapy in transplant cohorts

“The median time between diagnosis and susceptibility testing was 15 days, and antiviral therapy was changed at a median of 27 days.” (opens the source at this quote in a new tab)

“In HCT recipients, persistent HSV lesions that do not respond to or that progress after 1 week of acyclovir therapy, especially during the pre-engraftment period and during treatment with systemic corticosteroids, should be managed aggressively with a low threshold of early resistance testing. A switch to an alternative antiviral therapy must be considered if there is a lack of improvement or if new lesions occur after a week of therapy.” (opens the source at this quote in a new tab)

“ACV resistance was clinically suspected at a median of 25 [range,16-109] days after initial HSV diagnosis and subsequently laboratory confirmed at a median of 25 (range,10-59) days.” (opens the source at this quote in a new tab)

“Foscarnet (FOS) treatment was initiated in all 8 patients (pending laboratory confirmation of ACV resistance) with some effect but associated with significant toxicity burden.” (opens the source at this quote in a new tab)

“Antiviral resistance by phenotypic assays take weeks to perform; thus, results are not available in real time for treatment decisions” (opens the source at this quote in a new tab)

“Resistance testing was performed at clinicians' discretion.” (opens the source at this quote in a new tab)

Turnaround and availability of resistance tests

“Diagnosing R/R HSV infections in HCT recipients poses unique challenges, primarily owing to the varied clinical criteria for suspecting a refractory infection, the turnaround time of resistance testing, and the availability of drug-resistance assays.” (opens the source at this quote in a new tab)

“however, the turnaround time for this method, typically 21–24 days, the difficulty in defining resistance breakpoints and reproducibility are of concern” (opens the source at this quote in a new tab)

“Phenotypic testing of viral isolates has been the gold-standard method for assessing HSV resistance; genotypic testing is not widely available but may available at the University of Washington Department of Laboratory Medicine and Pathology.” (opens the source at this quote in a new tab)

FieldTest directory
Turnaround time“21 - 24 days”
Method“This test method uses a plaque reduction assay.”
Regulatory status“This test was developed and its performance characteristics determined by Labcorp. It has not been cleared or approved by the Food and Drug Administration.”
FieldTest directory
Scope“The HSV Acyclovir Drug Resistance assay detects and characterizes resistance-associated mutations in the Thymidine Kinase (UL23) gene of HSV-1 and HSV-2.”
Reflex rule“For positive specimens with a PCR Cycle Threshold (Ct) value <35.0, HSV Acyclovir Drug Resistance testing is reflexively performed.”
Frequency“Sequencing is performed Wednesday, results within a week.”
Genes tested for resistance and the genes in which pritelivir resistance arises

“Pritelivir-resistant HSV-1 and HSV-2 strains were isolated in cell culture with mutations in the viral helicase (UL5) and primase (UL52) genes.” (opens the prescribing information at this quote)

“Paired baseline and on-treatment/end-of-treatment sequences were obtained for 8.3% (4/48) of pritelivir-treated participants who experienced treatment failure (lesions not healed by Day 28).” (opens the prescribing information at this quote)

“The genotypic assay has been increasingly used and allows for the rapid detection of specific mutations in particular genes, UL23 and UL30, that confer resistance to nucleoside analogues, but no software for interpreting UL23 and UL30 sequences exists to our knowledge.” (opens the source at this quote in a new tab)

Infectious disease specialist involvement

“Treatment of acyclovir-resistant HSV should be given in consultation with an infectious disease expert (AIII).” (opens the source at this quote in a new tab)

“Systemic foscarnet and cidofovir are nephrotoxic medications; treatment should be given in consultation with an infectious diseases specialist (AIII) and with frequent laboratory monitoring” (opens the source at this quote in a new tab)

“Foscarnet and cidofovir are nephrotoxic medications that require intensive laboratory monitoring and infectious disease specialist consultation.” (opens the source at this quote in a new tab)

“Antiviral susceptibility testing for HSV is difficult to obtain in the UK but is currently still available through the UKHSA laboratory at Colindale. More often clinical response to antiviral therapy is used to guide decisions, Advice from a clinical virologist about appropriate drug dosages and duration may be sought when clinical resistance is suspected.” (opens the source at this quote in a new tab)

Monitoring during intravenous foscarnet: renal function

“The majority of patients will experience some decrease in renal function due to FOSCAVIR administration. Therefore it is recommended that creatinine clearance, either measured or estimated using the modified Cockcroft and Gault equation based on serum creatinine, be determined at baseline, 2–3 times per week during induction therapy and once weekly during maintenance therapy, with FOSCAVIR dose adjusted accordingly” (opens the source at this quote in a new tab)

“FOSCAVIR should be discontinued if creatinine clearance drops below 0.4 mL/min/kg.” (opens the source at this quote in a new tab)

“To reduce the risk of nephrotoxicity, creatinine clearance (mL/min/kg) should be calculated even if serum creatinine is within the normal range, and doses should be adjusted accordingly.” (opens the source at this quote in a new tab)

Monitoring during intravenous foscarnet: electrolytes and electrocardiogram

“Due to FOSCAVIR’s propensity to chelate divalent metal ions and alter levels of serum electrolytes, patients must be monitored closely for such changes. It is recommended that a schedule similar to that recommended for serum creatinine (see above) be used to monitor serum calcium, magnesium, potassium and phosphorus.” (opens the source at this quote in a new tab)

“Electrocardiograms (ECGs) and measurement of electrolytes should be obtained prior to treatment initiation and periodically during treatment with FOSCAVIR.” (opens the source at this quote in a new tab)

“Patients should be advised to report symptoms of low ionized calcium such as perioral tingling, numbness in the extremities and paresthesias.” (opens the source at this quote in a new tab)

Monitoring during intravenous foscarnet: concomitant nephrotoxic drugs

“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)

Monitoring during intravenous foscarnet, cidofovir, or acyclovir: guideline and cohort statements

“However, for people receiving IV acyclovir, cidofovir, or foscarnet, monitoring of renal function and dose adjustment as necessary is recommended at initiation of treatment and at least once or twice weekly for the duration of treatment, if stable” (opens the source at this quote in a new tab)

“Monitoring of renal function and electrolytes at least 2–3 times a week, vigorous hydration, and electrolyte repletion are necessary and require clinicians to be vigilant, especially when foscarnet is administered in the outpatient setting.” (opens the source at this quote in a new tab)

Monitoring listed for each systemic agent in a review of transplant recipients
AgentMonitoring
Intravenous foscarnet“Serum creatinine Electrolytes Electrocardiogram Signs of volume overload”
Intravenous cidofovir“Serum creatinine Electrolytes Urine protein Complete blood count”
Monitoring and co-administered therapy during intravenous cidofovir

“Serum creatinine and urine protein must be monitored within 48 hours prior to each dose. White blood cell counts with differential should be monitored prior to each dose.” (opens the source at this quote in a new tab)

“Probenecid must be administered orally with each cidofovir injection dose.” (opens the source at this quote in a new tab)

“Patients must receive at least one liter of 0.9% (normal) saline solution intravenously with each infusion of cidofovir injection.” (opens the source at this quote in a new tab)

“Note: Cidofovir should be avoided in patients with sulfonamide allergy because of cross-hypersensitivity with probenecid.” (opens the source at this quote in a new tab)

Care setting for intravenous foscarnet and cidofovir

“The need for frequent intravenous delivery and hydration, coupled with the electrolyte monitoring and repletion requirements of foscarnet, typically require hospitalization for initiation, which can be prolonged for some individuals.” (opens the source at this quote in a new tab)

“Furthermore, foscarnet therapy given over adequate durations to treat resistant HSV typically requires careful management in the inpatient setting that can lead to prolonged hospitalization.” (opens the source at this quote in a new tab)

“Foscarnet requires daily IV administration; consequently, initiation of foscarnet may be deferred until the lesions worsen and/or hospitalization is deemed necessary based on physician judgment and patient preferences. 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)

“Foscarnet administered as a continuous infusion could facilitate outpatient treatment without increasing the risk of adverse events” (opens the source at this quote in a new tab)

Compounding of topical agents

“Topical formulations of trifluridine, cidofovir, and foscarnet are not commercially available. Extemporaneous compounding of topical products can be prepared using trifluridine ophthalmic solution and the IV formulation of cidofovir and foscarnet.” (opens the source at this quote in a new tab)

Pritelivir: review of acid-reducing agents before and during treatment

“While taking HOVILPRI, avoid concomitant use of the following proton pump inhibitors” (opens the prescribing information at this quote)

“Esomeprazole or rabeprazole • Omeprazole or lansoprazole at daily doses above 20 mg • Pantoprazole at daily doses above 40 mg” (opens the prescribing information at this quote)

“Take HOVILPRI 2 hours before or 12 hours after taking a H2-receptor antagonist” (opens the prescribing information at this quote)

“Separate any dosing of antacids from HOVILPRI dosing by 2 hours” (opens the prescribing information at this quote)

“Concomitant use of omeprazole, lansoprazole, or pantoprazole below the doses listed above is acceptable, as these lower doses do not reduce pritelivir exposure to a clinically relevant extent.” (opens the prescribing information at this quote)

Pritelivir: consequence of reduced exposure with acid-reducing agents

“Elevation of gastric pH may decrease the systemic bioavailability of HOVILPRI” (opens the prescribing information at this quote)

“which may reduce its effectiveness or cause drug resistance to HOVILPRI” (opens the prescribing information at this quote)

“Co-administration of a single oral dose of 100 mg pritelivir (on Day 1) with esomeprazole 40 mg once daily (from Day -3 to Day 1; 4 days total) decreased Cmax by approximately 76% and AUC by approximately 59% compared to pritelivir administered alone” (opens the prescribing information at this quote)

Pritelivir: co-administered BCRP substrates

“Pritelivir is a breast cancer resistance protein (BCRP) inhibitor. Co-administration of HOVILPRI with a BCRP substrate may increase the plasma concentrations of the BCRP substrate” (opens the prescribing information at this quote)

“Refer to the prescribing information for co-administered drugs for additional information.” (opens the prescribing information at this quote)

Pritelivir: adherence and missed doses

“Inform patients that it is important not to miss or skip doses and to take HOVILPRI for the duration that is recommended by the healthcare provider.” (opens the prescribing information at this quote)

“If a dose of HOVILPRI is missed, take it as soon as it is remembered. If it is not taken until the scheduled dosing time on the next day, take two tablets at that time.” (opens the prescribing information at this quote)

Pritelivir: treatment until lesions heal and counseling on cure

“Take HOVILPRI as prescribed by your healthcare provider until your HSV lesions have healed.” (opens the prescribing information at this quote)

“Inform patients that HOVILPRI is indicated to heal lesions caused by HSV but is not a cure for HSV infection.” (opens the prescribing information at this quote)

“Because HSV establishes lifelong latent infection, treatment is not curative.” (opens the prescribing information at this quote)

“33 % of participant in the HOVILPRI arm extended treatment up to 42 days, whose lesions were improving by Day 28.” (opens the prescribing information at this quote)

Pritelivir: medication history at each visit

“Inform patients that HOVILPRI may interact with some drugs; therefore, advise patients to report the use of any other medications to their healthcare provider” (opens the prescribing information at this quote)

“Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.” (opens the prescribing information at this quote)

Duration of second-line therapy in the federal HIV guideline

“Duration Based on clinical response; typically 21–28 days or longer” (opens the source at this quote in a new tab)

“Topical imiquimod, cidofovir, trifluridine, and foscarnet also have been used successfully to treat external lesions (BIII), although prolonged application for 21 to 28 days or longer may be required.” (opens the source at this quote in a new tab)

Suppressive antiviral therapy after resolution of a resistant episode

“Recurrences following episodes of acyclovir-resistant HSV can be caused by either acyclovir-resistant or acyclovir-sensitive strains; after resolution of the acyclovir-resistant episode, suppressive therapy with acyclovir can be considered to prevent additional recurrences (CIII).” (opens the source at this quote in a new tab)

“Therefore, even in people with prior acyclovir resistance, suppressive acyclovir therapy should be offered after resolution of the episode (CIII).” (opens the source at this quote in a new tab)

“With the latter population, the risk of developing acyclovir-resistant HSV was lower with daily suppressive acyclovir therapy than with episodic therapy.” (opens the source at this quote in a new tab)

“Because relapse may be due to acyclovir-sensitive HSV, sensitivity testing of the viral isolate is advised.” (opens the source at this quote in a new tab)

Prophylaxis practices in transplant recipients that bear on resistance

“Acyclovir-resistant HSV infection occurs mainly in the setting of low-dose prophylaxis, intermittent treatment, or with HSV-seronegative donors” (opens the source at this quote in a new tab)

“If postengraftment acyclovir prophylaxis is given, experts recommend a sufficiently high dose to prevent the emergence of resistance” (opens the source at this quote in a new tab)

“Allogeneic HSCT recipients who develop graft-versus- host disease or receive immunosuppressive treatment, including steroids, usually require a prolonged HSV prophylaxis (BII).” (opens the source at this quote in a new tab)

“Thus, the longer the duration of acyclovir prophylaxis the lower the probability of HSV resistant disease (II).” (opens the source at this quote in a new tab)

“Higher doses of acyclovir prophylaxis might be needed for patients with history of HSV during pre-engraftment or GVHD treatment.” (opens the source at this quote in a new tab)

Recurrence after healing in a multicenter transplant cohort

“Among 69 patients with completed healing, 27 (39.1%) experienced HSV recurrence during follow up.” (opens the source at this quote in a new tab)

“The time to first recurrence was a median of 61 days (Q1, Q3: 29, 97; minimum, maximum: 10, 298).” (opens the source at this quote in a new tab)

Pritelivir as secondary prophylaxis in a case report from an expanded access program

“This is the first case report of pritelivir used for both treatment and secondary prophylaxis in an allogeneic stem cell transplant recipient with severe, relapsing multidrug-resistant HSV-1, administered through an expanded access programme.” (opens the source at this quote in a new tab)

“The patient started secondary prophylaxis with pritelivir (100 mg/d following loading dose of 400 mg) for 3 months through expanded access approval, and no recurrences were reported.” (opens the source at this quote in a new tab)

Antiretroviral therapy and immune reconstitution in people with HIV

“Orolabial and genital HSV should not influence the decision to start ART in people with HIV.” (opens the source at this quote in a new tab)

“The frequency and severity of clinical episodes of genital herpes are often reduced in individuals after immune reconstitution on ART. However, immune reconstitution does not reduce the frequency of genital HSV shedding.” (opens the source at this quote in a new tab)

“Mucocutaneous lesions that are atypical and occasionally recalcitrant to therapy have been reported in individuals initiating ART and have been attributed to immune reconstitution inflammatory syndrome (IRIS).” (opens the source at this quote in a new tab)

“HSV associated IRIS may be unresponsive to previously effective anti-herpes viral therapy in the absence of increased antiviral resistance. Management is difficult but topical cidofovir may be effective.” (opens the source at this quote in a new tab)

Immunosuppression at the time of resistant infection in a transplant cohort

“Most patients were in the pre-engraftment period or on systemic corticosteroid therapy for graft-versus-host disease (GVHD).” (opens the source at this quote in a new tab)

“One-third of the patients had their steroid doses tapered after the diagnosis of HSV infections.” (opens the source at this quote in a new tab)

Management of recalcitrant herpes in immunocompromised individuals: European guideline

“Although rare in immunocompetent individuals, clinically refractory lesions due to genital HSV are a major problem in patients with severe immunodeficiency, including late-stage HIV.” (opens the source at this quote in a new tab)

“There is evidence for alternating courses of treatment with aciclovir and cidofovir for subsequent recurrences as a strategy that may reduce the development of cidofovir-resistant strains. The efficacy, safety and durability of the therapeutic response of these agents have yet to be determined in prospective controlled trials.” (opens the source at this quote in a new tab)

Proposed management algorithm for transplant recipients: basis stated by its authors

“Navigating the complexities of R/R HSV infections requires an individualized approach.” (opens the source at this quote in a new tab)

“The recommendations outlined in this algorithm are not based on findings from randomized controlled clinical trials but rather on retrospective or observational studies, expert opinion, and clinical experience.” (opens the source at this quote in a new tab)

Infection control for severe mucocutaneous disease in transplant units

“Any person with disseminated, primary, or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of the illness (AII)” (opens the source at this quote in a new tab)