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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 therapyDisease description

Diagnosis

25 evidence topics · 29 sources

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)

“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)

“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)

“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)

“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)

Consensus definition of antiviral-resistant infection

“A resistant HSV infection is defined as a refractory HSV infection as described above, in addition to a viral genetic alteration(s) that decrease(s) susceptibility and/or phenotypic assay demonstrating increased EC50 above the assay cutoffs to 1 or more antiviral drugs.” (opens the source at this quote in a new tab)

“The availability of phenotyping and genotyping testing varies among countries and centers.” (opens the source at this quote in a new tab)

“The interpretation of a previously unrecognized mutation as conferring resistance to an antiviral drug or if only a polymorphism is detected is difficult and warrants confirmation with a recombinant phenotypic assay.” (opens the source at this quote in a new tab)

Criteria for clinical failure used before the consensus definition

“Previously used definitions for refractory HSV infections from different studies relied on clinical criteria for treatment failure, which are not standardized.” (opens the source at this quote in a new tab)

“Failure of the antiviral treatment was defined based on a duration of therapy as short as 5 days and as long as 14 days and also was affected by the treatment route” (opens the source at this quote in a new tab)

“Suboptimal healing of mucocutaneous HSV lesions was considered when the total surface lesion area decreased by only 25%–50% during treatment” (opens the source at this quote in a new tab)

“These criteria lack standardization across centres and providers” (opens the source at this quote in a new tab)

“Although this definition was originally designed for clinical trials, we advocate for its relevance in clinical practice as well.” (opens the source at this quote in a new tab)

Definitions of refractory infection applied in observational cohorts

“Resistant HSV infection was defined by genotypic or phenotypic testing indicating acyclovir resistance. Refractory HSV infection was defined clinically as HSV infection with no improvement after at least 5 days of treatment doses of acyclovir, valacyclovir, ganciclovir, valganciclovir, or famciclovir antiviral therapy.” (opens the source at this quote in a new tab)

“Our definitions for refractory HSV are in alignment with the recently published definitions for clinical trials with respect to requirement of 7 days of therapy for definition of clinical failure” (opens the source at this quote in a new tab)

“but are broader and include any appropriately dosed anti-HSV therapy, rather than strictly nucleoside analog therapy.” (opens the source at this quote in a new tab)

Differential diagnosis and confirmation of viral etiology in refractory lesions

“Oral HSV infection in an immunocompromised host is often hard to differentiate from mucositis due to chemotherapy, aphthae, and/or radiotherapy or GVHD in the mouth. Similarly, genital lesions can be caused by other infectious and noninfectious etiologies. Hence, confirming the viral etiology with HSV PCR, viral culture, or an immunohistochemical stain of a skin biopsy specimen is necessary.” (opens the source at this quote in a new tab)

“Repeated assessment of the lesion for viral shedding can verify an ongoing infectious etiology for refractory lesions, even though viral shedding can also occur for an extended period in asymptomatic patients.” (opens the source at this quote in a new tab)

“Notably, this definition does not apply to pseudotumor lesions, which improve more slowly and may require surgical intervention” (opens the source at this quote in a new tab)

Laboratory confirmation of mucocutaneous infection: polymerase chain reaction and culture

“Because mucocutaneous HSV infections cannot be diagnosed accurately by clinical examination alone, a laboratory diagnosis of all suspected HSV mucocutaneous infections should be pursued” (opens the source at this quote in a new tab)

“HSV DNA polymerase chain reaction (PCR) is the preferred method for mucocutaneous lesions potentially caused by HSV. PCR is the most sensitive method of diagnosis; viral culture sensitivity decreases as lesions heal” (opens the source at this quote in a new tab)

“HSV PCR of the blood should not be used to diagnose mucosal HSV unless there is concern for disseminated disease.” (opens the source at this quote in a new tab)

“Virus culture is one of the standard methods for detection of HSV in clinical specimens, and usually yields results within 48 hours of inoculation (III).” (opens the source at this quote in a new tab)

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

“In the presence of severe mucositis following chemotherapy or irradiation, the diagnosis of oropharyngeal HSV disease is difficult and identification of virus by appropriate diagnostic techniques is required (BIII).” (opens the source at this quote in a new tab)

“Most HSV infection is diagnosed on clinical grounds, but patients may present with atypical lesions and/or other clinical manifestations.” (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)

“While diagnosis of more common HSV and/or VZV infections is frequently clinically based, immunocompromised hosts may have atypical skin presentation or visceral involvement. Thus, diagnostic confirmation using virus-specific tests such as polymerase chain reaction or immunohistochemical staining is crucial in some cases.” (opens the source at this quote in a new tab)

Diagnostic method used in the seven-center United States transplant cohort
Diagnostic methodRecipients, N (%) of 125
Polymerase chain reaction“105 (84.0)”
Culture“12 (9.6)”
Immunohistochemistry“8 (6.4)”
Biopsy and histopathology for hypertrophic and tumoral lesions

“In addition, atypical presentations, such as hypertrophic genital HSV,” (opens the source at this quote in a new tab)

“which mimics neoplasia and requires biopsy for diagnosis, may be seen in people with HIV.” (opens the source at this quote in a new tab)

“On clinical basis, the initial hypothesis was neoplasia in 36/53 patients. Histopathological diagnosis was achieved in 90 % (90/100, missing 10) cases and was sample size-dependent.” (opens the source at this quote in a new tab)

“The clinical polymorphism of CHSV and CVZV makes recognition difficult. Histology, immunohistology, PCR and viral culture all help to confirm the diagnosis.” (opens the source at this quote in a new tab)

“Viral culture remains an essential tool for antiviral drug susceptibility testing.” (opens the source at this quote in a new tab)

When to suspect resistance and test: National Institutes of Health guideline for people with HIV

“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)

“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)

“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)

When to suspect resistance and test: Centers for Disease Control and Prevention 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)

When to test: European Conference on Infections in Leukaemia recommendation

“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)

When to test: German hematology and oncology society guideline for patients with cancer

“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)

“Whereas acyclovir resistance in VZV is a rarity, resistance in HSV is occasionally observed, necessitating a switch in antiviral treatment. Genotypic resistance testing is recommended and established in specialized laboratories.” (opens the source at this quote in a new tab)

Confirmation threshold and test availability: United Kingdom guideline for anogenital herpes

“Aciclovir resistance is confirmed if isolates require aciclovir concentrations >1–3 mg/l for inhibition.” (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.” (opens the source at this quote in a new tab)

When to test: recommendations from cohort investigators and reviews

“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.” (opens the source at this quote in a new tab)

“an alternative antiviral should be considered in patients who do not show signs of improvement after three to five days of anti-HSV therapy.” (opens the source at this quote in a new tab)

“Given the current turnaround times for genotypic HSV resistance testing, and considering the severity and high morbidity/mortality associated with R/R HSV, antiviral therapy should not be delayed while confirmatory genotypic testing is obtained.” (opens the source at this quote in a new tab)

“The indication for drug susceptibility testing (DST) in the clinical setting is usually based upon clinical or virological treatment failure after 7 days of high-dose antiviral therapy” (opens the source at this quote in a new tab)

“The NIH recommends HSV ADR testing in immunocompromised patients with persistent or progressive disease despite appropriate antiviral therapy, particularly after ≥7–10 days of ACV or VACV treatment” (opens the source at this quote in a new tab)

“When resistance is suspected, lesion sampling for resistance testing should be performed, and empiric transition to FOS is recommended while awaiting results” (opens the source at this quote in a new tab)

Phenotypic testing: plaque reduction assay, cutoffs, and limitations

“The plaque reduction assay (PRA) is the gold standard for assessing HSV susceptibility to antiviral drugs. However, as with all other HSV resistance testing assays, it is not approved or qualified by the US FDA or, to our knowledge, by any other regulatory authority. The accepted cutoff for ACV sensitivity is 2.0 μg/mL and for FOS is 100 μg/mL” (opens the source at this quote in a new tab)

“The PRA has several disadvantages, such as the difficulty in obtaining good clinical specimens, the long turnover time, possible selection bias in cases of heterogeneous viral populations, and its reliance on a subjective method for counting the number of plaques” (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)

“Among these, phenotypic DST (using plaque reduction or dye uptake assays) is considered the reference standard, as it entails the direct measurement of viral replication in the presence of antiviral agents, thereby offering a functional evaluation of the virus' ability to resist therapeutic intervention” (opens the source at this quote in a new tab)

“Despite its reliability, phenotypic testing presents significant challenges: it is time-intensive, suffers from a lack of standardization, and is not widely available, which can lead to delays in critical treatment decisions and discordant results when the same samples are tested by different laboratories” (opens the source at this quote in a new tab)

“There is no standardized consensus for HSV ADR grading. Phenotypic resistance thresholds vary across laboratories because of differences in assay methodology, cell lines, and reference strains, limiting reproducibility and clinical interpretability” (opens the source at this quote in a new tab)

Phenotypic thresholds applied by individual laboratories

“The inhibitory concentration (IC50) cutoffs for acyclovir and foscarnet were determined according to each institution's laboratory interpretive criteria.” (opens the source at this quote in a new tab)

“The fourth patient had remote history of foscarnet exposure and foscarnet IC50 was 130.9 µg/mL (IC50 cutoff ≥100 µg/mL).” (opens the source at this quote in a new tab)

“An ID‐50 between 1 and 3 μg/mL ACV defined an AVC‐sensitive strain while an ID‐50 equal to or above 5 μg/mL defined an ACV‐resistant strain.” (opens the source at this quote in a new tab)

Genotypic testing: sequencing of UL23 and UL30

“Genotypic assays allow for the detection of mutations in the genes of interest, mainly UL23 and UL30.” (opens the source at this quote in a new tab)

“These tests are not routinely available in clinical laboratories due to their complexity and the need for dedicated technology and expertise. In the United States, these genotypic assays are available in reference laboratories such as the virology laboratory of the University of Washington” (opens the source at this quote in a new tab)

“The interpretation of detected gene mutations is based on the comparison to the previously described mutations panel, phenotypic results, pretreatment HSV isolates sequencing, and/or generating a recombinant virus to substantiate that new mutations confer resistance.” (opens the source at this quote in a new tab)

“The most prevalent genotyping method is Sanger (dideoxy) sequencing” (opens the source at this quote in a new tab)

“which lacks sensitivity in detecting resistant variants with a frequency below 20%” (opens the source at this quote in a new tab)

GeneRoleAssociated drug resistance
UL23“Viral thymidine kinase”“Acyclovir, valacyclovir, penciclovir, and famciclovir”
UL30“Viral DNA polymerase”“Acyclovir, valacyclovir, penciclovir, famciclovir, cidofovir, foscarnet, and brincidofovir”
UL5“Viral helicase”“Pritelivir, amenamevir”
UL52“Viral primase”“Pritelivir, amenamevir”
Genotypic testing: limitations

“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)

“In addition, the most commonly used sequencing method (Sanger) lacks sensitivity to detect low-frequency resistant variants, interpreting unknown mutations is challenging, and, most importantly, commercially available genotypic assays are not readily available, requiring specialized labs with sequencing capabilities” (opens the source at this quote in a new tab)

“Currently, it can only identify resistance-associated mutations if the detected mutations have been previously described” (opens the source at this quote in a new tab)

“This means that the full set of potentially resistance-conferring genes needs to be sequenced (e.g. both TK and POL for ACV) to rule out DRMs” (opens the source at this quote in a new tab)

“Finally, classical Sanger sequencing cannot detect minority variants <20% of the viral quasispecies, which can be overcome by next-generation sequencing (NGS) approaches.” (opens the source at this quote in a new tab)

“Genotypic testing offers faster turnaround time (TAT) and improved scalability but is limited to known resistance mutations. Phenotypic testing enables functional assessment of antiviral susceptibility but is labor-intensive and less widely available.” (opens the source at this quote in a new tab)

“Although both phenotypic and genotypic HSV ADR testing are available as CLIA-validated LDTs, no FDA-approved assays currently exist” (opens the source at this quote in a new tab)

“Combining genotypic and phenotypic approaches can improve diagnostic accuracy” (opens the source at this quote in a new tab)

“The use of genotypic resistance testing of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) is increasing because the rapid availability of results significantly improves the treatment of severe infections, especially in immunocompromised patients.” (opens the source at this quote in a new tab)

“Genotypic testing is more frequently performed for the diagnosis of infections caused by drug-resistant HSV or VZV isolates.” (opens the source at this quote in a new tab)

“With updated diagnostics, the diagnosis is usually made through viral culture and sequencing.” (opens the source at this quote in a new tab)

Two-step genotypic and phenotypic testing in a French reference laboratory: yield among samples with suspected resistance

“Antiviral resistance testing consisted in a two-step procedure including a first-step genotypic assay, based on UL23 (thymidine kinase, TK) and UL30 (Pol) gene sequencing, and a second-step phenotypic assay (i.e., plaque reduction assay) performed when unpreviously described mutations were detected.” (opens the source at this quote in a new tab)

“As a whole, susceptibility and resistance to antivirals were evidenced for 58 (30.7%) and 86 (45.5%) HSV, respectively, whereas antiviral profile remained undetermined for 45 (23.8%) HSV.” (opens the source at this quote in a new tab)

Commercial phenotypic test in the United States: Labcorp test 138370
FieldQuoted record
Test name“Herpes Simplex Virus (HSV) Types 1/2 Phenotyping for Acyclovir Drug Resistance”
Turnaround time“21 - 24 days”
Method“This test method uses a plaque reduction assay. It measures the extent to which various concentrations of acyclovir inhibit the growth of virus in cell culture.”
Reported value“The concentration of drug which results in a 50% reduction in plaque formation induced by viral cytopathic effect (CPE) versus the no-drug control establishes an inhibitory dose (ID-50) drug concentration reportable value.”
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.”
Specimen“Actively-growing isolate (preferred) or eye, genital, oral, urethral, vesicle, or throat swab (from which HSV isolation will be attempted)”
Submission window“Submit as soon as possible, but within five days of collection.”

“Turnaround time is defined as the usual number of days from the date of pickup of a specimen for testing to when the result is released to the ordering provider.” (opens the source at this quote in a new tab)

Academic genotypic test in the United States: University of Washington reflex sequencing of UL23
FieldQuoted record
Test name“HSV Acyclovir Resistance with Rapid PCR, Swab/CSF”
Reflex rule“For positive specimens with a PCR Cycle Threshold (Ct) value <35.0, HSV Acyclovir Drug Resistance testing is reflexively performed.”
Gene sequenced“The HSV Acyclovir Drug Resistance assay detects and characterizes resistance-associated mutations in the Thymidine Kinase (UL23) gene of HSV-1 and HSV-2.”
Standalone ordering“assay is no longer orderable as a standalone test.”
Regulatory status“It is important to note that while this test has been validated for clinical use, it has not been cleared or approved by the US Food and Drug Administration (FDA).”
Specimen“Swabs, CSF”
Frequency“Rapid PCR is performed daily except Sunday. Sequencing is performed Wednesday, results within a week.”

“Genotypic acyclovir resistance testing was conducted in clinical specimens (i.e., mucocutaneous lesion swabs) at the University of Washington Department of Laboratory Medicine and Pathology using Sanger sequencing to detect specific mutations found in the UL23 gene encoding for the TK of both HSV type 1 and HSV type 2. Sequence analysis was performed on the full-length UL23 gene, amino acids 1 to 376, for HSV. The assay sensitivity is 1,000 copies/mL.” (opens the source at this quote in a new tab)

Availability of resistance testing in the United States as described in cohort reports

“Definitive diagnosis of acyclovir-resistant HSV is made by phenotypic testing that can take several weeks to result” (opens the source at this quote in a new tab)

“Genotypic testing for acyclovir-resistant in clinical HSV isolates is not commercially available in the United States (US).” (opens the source at this quote in a new tab)

“During the study period, all but 1 participating center used phenotypic assays for acyclovir resistance, which take weeks to be performed and may not be readily accessible.” (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)

“which, although not widely available in the U.S., can be performed at the University of Washington molecular laboratory with a turnaround time, in our experience, of about two weeks. Rapid diagnostic tests are therefore needed in this area. As a comparison, the current turnaround time for genotypic cytomegalovirus (CMV) resistance testing at our reference commercial laboratory is around four to five business days.” (opens the source at this quote in a new tab)

Observed intervals from diagnosis to resistance testing, result, and change of therapy

“Acyclovir resistance was suspected and susceptibility analyses ordered at a median of 15 days after HSV infection was clinically diagnosed (IQR: 0–96 days).” (opens the source at this quote in a new tab)

“The mean time to transition of antiviral therapy was 27 days (IQR: 10–70 days) in both groups but 9 days (IQR: 2–46) in the rapid responders, in contrast to 28 days (IQR: 7–96) in the slow and non-responders (p=0.15).” (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)

“The median turnaround time from sample collection to resistance genotypic results was 15 days (range: 11-19 days).” (opens the source at this quote in a new tab)

“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)

Resistance assays performed and results in the seven-center United States transplant cohort
MeasureRecipients, N (%) of 125
Acyclovir resistance assay performed“104 (83.2)”
Acyclovir phenotypic assay“98 (78.4)”
Acyclovir genotypic assay“6 (4.8)”
Foscarnet resistance assay performed“77 (61.6)”
Laboratory-confirmed acyclovir resistance“85 (68.0)”
Laboratory-confirmed foscarnet resistance“4 (3.2)”

“Of 104 patients tested for acyclovir resistance, 85 (81.7%) had laboratory-confirmed acyclovir resistance, by phenotypic assay (79 patients) or genotypic assays (6 patients)” (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)

“All 14 patients met criteria for refractory HSV, and 8 of 14 (57.1%) had confirmed acyclovir resistance.” (opens the source at this quote in a new tab)

Discordance between susceptibility results and clinical response

“The remaining 3 patients failed to respond to acyclovir, despite having sensitive isolates.” (opens the source at this quote in a new tab)

“Moreover, in our cohort, few patients responded to either intravenous foscarnet or high-dose intravenous acyclovir despite having isolates that were phenotypically resistant to either antiviral therapy.” (opens the source at this quote in a new tab)

“Importantly, four patients had acyclovir-susceptible HSV infections within 3 months before acyclovir-resistant isolates were identified.” (opens the source at this quote in a new tab)

“Phenotypic testing results for HSV resistance on D+55 demonstrated no apparent resistance to ACV or FOS” (opens the source at this quote in a new tab)