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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

Definition and etiology

25 evidence topics · 39 sources

Labeled indication

“HOVILPRI is indicated in immunocompromised adults for the treatment of mucocutaneous lesions caused by herpes simplex virus (HSV) infection that is refractory (with or without documented resistance) to treatment with acyclovir, valacyclovir, or famciclovir” (opens the prescribing information at this quote)

Regulatory description of the condition

“Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are common viral infections that typically cause painful mucocutaneous lesions, or fluid-filled blisters that break open and crust over the infectious site. Once a person has HSV, the infection cannot be cured. The virus can be dormant or can reactivate, leading people to have outbreaks or release contagious viral particles without being symptomatic.” (opens the source at this quote in a new tab)

“Patients with compromised immune systems can have more frequent and serious HSV outbreaks that might not respond well to available treatments because their virus is resistant to the medications or they cannot tolerate side effects.” (opens the source at this quote in a new tab)

“Mucocutaneous lesions occur on skin or mucosal surfaces, such as lips, nostrils, eyes and genitals.” (opens the source at this quote in a new tab)

Definition of refractory infection in the prescribing information

“Refractory HSV infection (clinical failure) was defined as no clinical improvement after at least 7 days of standard-of-care nucleoside analogue treatment [acyclovir (ACV), valacyclovir (VACV) or famciclovir (FCV)], with or without laboratory confirmed genotypic/phenotypic resistance for the current HSV outbreak.” (opens the prescribing information at this quote)

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 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)

Consensus definitions of recurrent and breakthrough infection

“A recurrent HSV infection is defined as a new HSV mucocutaneous lesion(s) occurring at least 1 week after the total resolution of the prior episode of HSV infection while not receiving an antiviral drug effective against HSV.” (opens the source at this quote in a new tab)

“A breakthrough recurrent HSV mucocutaneous infection is defined as the appearance of a new HSV mucocutaneous lesion(s) while receiving prophylactic or suppressive antiviral drug effective against HSV.” (opens the source at this quote in a new tab)

“To differentiate recurrence from ongoing infection, the patient should be free of clinical signs and symptoms of infection for at least 1 week in the absence of antiviral therapy.” (opens the source at this quote in a new tab)

Authorship and intended use of the consensus definitions

“The diagnosis of refractory HSV infection is based on the lack of clinical response to nucleoside analogs. Antiviral resistance is confirmed via genotypic and/or phenotypic testing.” (opens the source at this quote in a new tab)

“To provide consensus definitions of refractory and/or resistant (R/R) HSV mucocutaneous infections for clinical trial use, the HSV Resistance Working Group of the Transplant Associated Viral Infections Forum, which includes international clinicians, scientists, industry representatives, and regulatory officials, conducted a literature review of previously published data related to R/R HSV infections in immunocompromised patients.” (opens the source at this quote in a new tab)

“We propose definitions of R/R HSV mucocutaneous infections, which will be subject to re-evaluation and revision based on forthcoming data and future studies.” (opens the source at this quote in a new tab)

“Because a refractory HSV diagnosis is clinical, prospective validation and adjustment of these definitions would be of great significance for targeting the appropriate patients for enrollment in clinical trials.” (opens the source at this quote in a new tab)

Limits of the consensus definition

“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)

“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)

Criteria used in studies before the consensus definitions

“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)

“Virologic failure was defined as detectable viral shedding (a positive viral culture or polymerase chain reaction [PCR] detected in the infected lesion specimen) at the end of antiviral therapy” (opens the source at this quote in a new tab)

“Multiple recurrences were considered part of the definition of clinical failure” (opens the source at this quote in a new tab)

Absence of a standard clinical definition

“A clear clinical definition of refractory HSV infection is currently not available, which can lead to delays in diagnosis and treatment, negatively impacting patient care.” (opens the source at this quote in a new tab)

“Previously used criteria are varied and include the duration of the failing treatment with antiviral agents (ranging from 5 to 14 days), the extent of the lesions, microbiological failure with documented prolonged viral shedding, and recurrences. 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)

“The lack of an accepted definition of R/R HSV infections may impede enrollment in clinical trials or delay the initiation of appropriate therapy with subsequent increased risk of progression to severe and/or disseminated infections” (opens the source at this quote in a new tab)

Definitions applied in observational studies and in the phase 2 trial

“Acyclovir-resistant HSV infection was defined based on genotypic or phenotypic testing results; refractory infection was defined as infection not improving after 5 days of treatment-dosed antiviral therapy in those not tested for resistance.” (opens the source at this quote in a new tab)

“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)

“Multicenter, retrospective study of laboratory confirmed HSV infection and failure to improve after ≥7 days of appropriately dosed anti-HSV therapies.” (opens the source at this quote in a new tab)

“Resistant HSV is defined as refractory HSV infection plus laboratory-confirmed resistance by phenotypic or genotypic assays to acyclovir and/or foscarnet during the index HSV episode.” (opens the source at this quote in a new tab)

“HCT patients suffering from HSV-1 stomatitis without response after 1 week of high-dose acyclovir (ACV) were tested for ACV resistance.” (opens the source at this quote in a new tab)

“HSV infection may become refractory to standard antiviral treatment, defined as a lack of clinical response after at least 7 days of therapy, often due to a lack of immune response, suboptimal drug exposure, and/or antiviral resistance frequently caused by mutations in the TK (UL23) gene” (opens the source at this quote in a new tab)

Guideline criteria for suspecting resistance

“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)

“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)

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

“The persistence of lesions for more than 1 week after the beginning of therapy without appreciable decrease in size, an atypical appearance of the lesions, or the emergence of new satellite lesions despite antiviral administration is suggestive of treatment failure.” (opens the source at this quote in a new tab)

Laboratory thresholds that define resistance

“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)

“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)

Chronic mucocutaneous infection as a related definition

“Chronic herpes simplex virus (CHSV) and chronic varicella zoster virus (CVZV) are defined as atypical mucocutaneous wart-like and/or ulcerative HSV or VZV infections, persisting for at least 1 month.” (opens the source at this quote in a new tab)

“Both are commonly associated with HIV infection and may occasionally present with other types of immunosuppression.” (opens the source at this quote in a new tab)

“Treatment is frequently complicated by resistance to thymidine kinase (TK)-dependent antivirals, including acyclovir, valacyclovir and famciclovir.” (opens the source at this quote in a new tab)

Clinical significance of resistant infection in immunocompromised patients

“Acyclovir-resistant herpes simplex virus is uncommon but clinically significant, particularly in immunocompromised patients, in whom delayed recognition can lead to chronic nonhealing ulceration and disseminated disease.” (opens the source at this quote in a new tab)

“Although fairly rare, acyclovir resistant herpes infections can be challenging to diagnose. Clinicians should be aware of this entity when facing refractory herpes infections.” (opens the source at this quote in a new tab)

“Immunosuppressed patients are at risk for developing acyclovir-resistant herpes, which can be challenging to diagnose and treat, although emerging therapeutic options look promising.” (opens the source at this quote in a new tab)

“Acyclovir-resistant HSV infection is a rare clinical problem typically seen in the immunocompromised population, where it can cause painful protracted mucocutaneous disease associated with significant morbidity and mortality” (opens the source at this quote in a new tab)

Causative viruses: HSV-1 and HSV-2

“Herpes simplex viruses (HSVs) are α-herpesviruses consisting of 2 types: HSV-1 and HSV-2. HSV-1 primarily infects orofacial and ocular areas, whereas HSV-2 primarily infects anogenital areas. However, HSV-1 has been causing an increasing proportion of genital herpes infections in resource-rich countries.” (opens the source at this quote in a new tab)

“Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are highly prevalent, infecting approximately 64 % and 13 % of the world's population, respectively. Traditionally, HSV-1 has been associated with orofacial infections and HSV-2 with anogenital infections, but HSV-1 is increasingly the cause of genital infections.” (opens the source at this quote in a new tab)

“The clinical spectrum of HSV disease ranges from mild cold sores to severe conditions such as encephalitis or systemic infection, particularly in immunocompromised individuals and neonates.” (opens the source at this quote in a new tab)

Causative virus type by underlying condition and lesion site

“HSV-1 strains were excreted by patients who had had a bone marrow transplant (n = 22) or an organ transplant (n = 4), who had shown a hemopathy (n = 9), or who had had corticotherapy for pemphigus (n = 1)” (opens the source at this quote in a new tab)

“HSV-2 strains were excreted by patients with HIV infection (n = 13), hemopathy (n = 2), or common variable immune deficiency (n = 2) or who had had an organ transplant (n = 1)” (opens the source at this quote in a new tab)

“More than 75% of the patients presented with refractory orofacial lesions caused by HSV-1. All patients developed HSV infection during HSV prophylaxis.” (opens the source at this quote in a new tab)

“Twelve patients had oral/labial HSV infections identified as HSV1, and six patients had genital/perineal HSV infections identified as HSV2.” (opens the source at this quote in a new tab)

“Herpes simplex virus was isolated from 2088 of 3602 patients, and 90.2% of isolates were HSV-2. Fifteen isolates, all HSV-2, were acyclovir resistant.” (opens the source at this quote in a new tab)

“Seven patients were infected with resistant HSV-1 strains, including five solid organ transplant (SOT) recipients, one patient with pemphigus vulgaris receiving immunosuppressive therapy, and one immunocompetent individual. Three people living with HIV (PLHIV) had resistant anogenital HSV-2 infections.” (opens the source at this quote in a new tab)

Reactivation and persistence in immunocompromised hosts

“In general, host immunity is sufficient to clear viral shedding and recurrences, although it is insufficient to prevent subsequent virologic reactivations. In immunocompromised patients, prolonged and difficult-to-treat HSV infections may develop.” (opens the source at this quote in a new tab)

“Herpes simplex virus (HSV) infections in allogeneic haematopoietic stem cell transplantation (HSCT) recipients pose significant challenges, with higher incidence, severity, and risk of emergence of resistance to antivirals due to impaired T-cell mediated immunity.” (opens the source at this quote in a new tab)

“In immunocompromised patients, HSV tends to be more persistent with chance of dissemination.” (opens the source at this quote in a new tab)

“A majority of transplant recipients are seropositive for HSV-1 or 2. Compared with immunocompetent persons, SOT recipients shed HSV more frequently, have more severe clinical manifestations, and are slower to respond to therapy.” (opens the source at this quote in a new tab)

“cancer patients are at particularly higher risk of complications including disseminated and visceral infections due to impaired cell-mediated immunity” (opens the source at this quote in a new tab)

“In immunocompromised adults, including hematopoietic stem cell and solid organ transplant recipients, people living with HIV, and patients with malignancies or autoimmune and inflammatory conditions, HSV infection can occur more frequently and may be more severe. Refractory HSV infection can result in prolonged and difficult-to-treat mucocutaneous disease.” (opens the source at this quote in a new tab)

Risk factors tabulated in the consensus review
CategoryRisk factors listed
Host factors“HIV/AIDS”; “Haploidentical, allogeneic, or cord blood HCT”; “HCT for relapsed hematologic cancer or prior HCT”; “HSV-seronegative HCT donor”; “GVHD”; “Hematologic cancer”; “Myelofibrosis”; “SOT (especially heart and lung transplantation)”; “Congenital immunodeficiency syndrome”; “Anti-TNF therapy”; “Keratitis”
Viral factors“Recurrent HSV infection”; “Ongoing viral replication”; “HSV-2”
Antiviral therapy factors“Nucleoside analog exposure”; “Prolonged antiviral treatment”; “Inadequate/intermittent antiviral treatment”
Risk factors: type and severity of immunosuppression

“An immunocompromised status is a major risk factor for R/R HSV infection. The type and severity of immunosuppression, particularly when it entails defects of cell-mediated immunity, are important predisposing factors for ACV resistance” (opens the source at this quote in a new tab)

“Indeed, the probability of developing unresponsive lesions appears to be related to the severity of immunosuppression.” (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)

Risk factors in hematopoietic cell transplant recipients: reviews

“The strongest predictor of ACV-r HSV infections in HCT recipients is the presence and severity of graft-versus-host disease (GVHD; grade ≥2)” (opens the source at this quote in a new tab)

“Other risk factors reported in HCT recipients include the type of transplant, source of transplanted cells, HSV seropositivity mismatch, and relapsed hematologic malignancy” (opens the source at this quote in a new tab)

“HCT recipients are most prone to R/R HSV infections during the pre-engraftment period, GVHD flares concomitant with steroid therapy, and during periods of enhanced chemotherapy owing to relapse of the underlying malignancy” (opens the source at this quote in a new tab)

“Despite limitations in available studies, potential risk factors of emergence of HSV resistance to acyclovir include human leucocyte antigen (HLA) mismatches, myeloid neoplasms and acute leukaemias, and graft-versus-host disease (GVHD).” (opens the source at this quote in a new tab)

Risk factors in hematopoietic cell transplant recipients: cohort findings

“Relapsed malignancies were a significant risk factor for the emergence of ACVr HSV-1.” (opens the source at this quote in a new tab)

“The risk factors for clinical resistance to antiviral drugs were a GVHD grade >/=2 (P=.001) and the lack of ganciclovir prophylaxis (P=.01), with a higher nonrelapse mortality in the latter group (P<.0001).” (opens the source at this quote in a new tab)

“Recipients of unrelated stem cell transplants were at higher risk.” (opens the source at this quote in a new tab)

“The prolonged immunodeficiency associated with stringent lymphocyte depletion of the graft appears to strongly predispose to emergence of drug-resistant HSV.” (opens the source at this quote in a new tab)

“All 8 patients received T-cell depleted allogeneic HSCT for hematological malignancies.” (opens the source at this quote in a new tab)

“Chronic Graft versus Host disease (cGVHD) affected 7 patients before HSV-1 diagnosis.” (opens the source at this quote in a new tab)

“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)

“Antithymocyte globulin was part of the conditioning regimen in 14 cases (78%).” (opens the source at this quote in a new tab)

“All the patients were recipients of unrelated or mismatched donors. Three (60%) had relapsed hematological disease.” (opens the source at this quote in a new tab)

“All 6 patients suffered from relapse of acute myeloid leukemia (AML) after HCT.” (opens the source at this quote in a new tab)

Risk factors in solid organ transplant recipients

“Refractory and/or resistant HSV infections in SOT recipients are uncommon, mainly occurring in heart or lung transplant recipients” (opens the source at this quote in a new tab)

“These transplants consisted of two heart transplants, two heart-lung transplants, and one liver transplant.” (opens the source at this quote in a new tab)

Risk factors in people with HIV

“In patients with HIV, R/R HSV is associated with the duration of the current genital infection episode and with a history of recurrent HSV infections” (opens the source at this quote in a new tab)

“Low CD4 T-cell counts correlate with an increased risk of symptomatic HSV infections” (opens the source at this quote in a new tab)

“In patients with advanced HIV disease, the development of an R/R HSV infection has been reported as part of immune reconstitution” (opens the source at this quote in a new tab)

“Twelve (5.3%) of 226 HIV-positive patients yielded resistant HSV isolates (95% CI, 2.8%-9.1%); resistance was associated with oral acyclovir use (P<.001), duration of the current episode (P<.001), history of recurrent genital herpes (P<.01), and low CD4 cell count (P<.05).” (opens the source at this quote in a new tab)

“Perirectal HSV lesions are more likely to be resistant to acyclovir compared to lesions at other locations.” (opens the source at this quote in a new tab)

“All patients reported previous acyclovir exposure and median CD4 count was 183 cells/mm(3)” (opens the source at this quote in a new tab)

Antiviral exposure as a risk factor

“Most ACV-r HSV infections have been associated with prior nucleoside analog exposure, especially in prolonged intermittent or suppressive therapy” (opens the source at this quote in a new tab)

“Inadequate or intermittent antiviral treatment, along with improper renal function dose adjustments, enhanced the risk of resistant infections” (opens the source at this quote in a new tab)

“In contrast, in a large observational study, long-term daily prophylactic treatment with ACV was protective against the emergence of resistance in HCT recipients” (opens the source at this quote in a new tab)

“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)

“Experience with another group of immunocompromised persons (e.g., hematopoietic stem-cell recipients) demonstrated that persons receiving daily suppressive antiviral therapy were less likely to experience acyclovir-resistant HSV infection compared with those who received episodic therapy for outbreaks” (opens the source at this quote in a new tab)

“Long-term use of suppressive prophylactic ACV appears to prevent the emergence of drug-resistant HSV disease in HCT.” (opens the source at this quote in a new tab)

“Long-term treatment and prophylaxis with antiviral agents predisposes to drug resistance, especially in immunocompromised patients.” (opens the source at this quote in a new tab)

“Long-term administration of ACV for the treatment of severe infections in immunocompromised patients can lead to the development of drug resistance.” (opens the source at this quote in a new tab)

“The median cumulative exposure to (val)acyclovir prior to R/R HSV was 30 months (range: 18 to 51 months).” (opens the source at this quote in a new tab)

“All resistant isolates were from acyclovir-treated patients and had absent or altered thymidine kinase activity by plaque autoradiography.” (opens the source at this quote in a new tab)