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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

Pathophysiology

21 evidence topics · 29 sources

Latency in sensory ganglia and reactivation

“Herpes simplex viruses are neurotropic and establish lifelong latency in neuronal ganglia” (opens the source at this quote in a new tab)

“Viral reactivation is most often present through peripheral nerves to the skin and/or epithelium but can also cause central nervous system or systemic diseases such as encephalitis, meningitis/myelitis, pneumonitis, or hepatitis” (opens the source at this quote in a new tab)

“After primary infection, HSV establishes long-term latency in the ganglia of sensory nerves, from which it can reactivate episodically. These reactivations may be accompanied by symptoms or may be clinically silent.” (opens the source at this quote in a new tab)

“After primary infection, the virus remains latent in sensory ganglia but can sporadically reactivate typically causing lesions at or near the primary infection site” (opens the source at this quote in a new tab)

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

Cell-mediated immunity in control of reactivation and healing

“In conclusion, acyclovir-resistant HSV infection is more likely during the period of profound deficit in T-cell–mediated immunity and is associated with significant morbidities.” (opens the source at this quote in a new tab)

“Several lines of evidence highlight the importance of cell-mediated immunity (CD4+ and CD8+ T cells) in providing protection from HSV reactivation as well as healing of established lesions” (opens the source at this quote in a new tab)

“Healing of lesions coincided with T-cell recovery.” (opens the source at this quote in a new tab)

“Furthermore, immune reconstitution is necessary for eradication of infection.” (opens the source at this quote in a new tab)

“acyclovir-resistant HSV infection is more likely to occur during the period of profound deficiency in T-cell-mediated immunity (e.g., during pre-engraftment period or graft-versus-host disease (GVHD) treatment among HCT patients) and is associated with significant morbidities” (opens the source at this quote in a new tab)

Emergence and persistence of resistant virus in immunocompromised hosts

“The prevalence of ACV- or PCV-resistant HSV isolates differs greatly for immunocompetent and immunocompromised patients. This difference is most likely due to two reasons” (opens the source at this quote in a new tab)

“First, virus replication may be prolonged in immunocompromised patients, having a tendency toward true persistence. Second, and most important, the host responses are impaired and less pathogenic viruses that would not survive in the face of normal host responses may continue to replicate. Thus, even if some resistant viruses are less pathogenic, they are capable of producing overt diseases in these patients.” (opens the source at this quote in a new tab)

“The immunocompromised status allowing persistent viral replication enhances the chance of mutations to occur, especially with concurrent selective pressure by prolonged nucleoside analogs” (opens the source at this quote in a new tab)

“Resistant HSV can develop spontaneously, reflecting the natural variability of the HSV population, as evidenced by the detection of acyclovir-resistant HSV in patients who had not been treated with acyclovir” (opens the source at this quote in a new tab)

“Nonetheless, acquired resistance to acyclovir is extremely unusual in the immunocompetent population and almost all cases have occurred in severely immunocompromised patients.” (opens the source at this quote in a new tab)

“In summary, clinical resistance to acyclovir is exceptionally rare in immunocompetent patients even though resistant HSV is detectable, albeit at a low frequency, in this population. This is because the normal immune response leads to the rapid resolution of the infection. Clinical resistance in an apparently immunocompetent individual should raise suspicion of some unappreciated immune deficit.” (opens the source at this quote in a new tab)

“Resistance is more common in immunocompromised patients and typically arises after prolonged exposure to acyclovir” (opens the source at this quote in a new tab)

“The most common phenotype is absent or deficient TK in the HSV strain” (opens the source at this quote in a new tab)

“probably selected by the prolonged use of low dose acyclovir, as seen in our patients who received prophylaxis with acyclovir or valacyclovir for a median of 12 months before the diagnosis of acyclovir-resistant infection.” (opens the source at this quote in a new tab)

“these populations were more prone to develop resistant viral strains probably due to prolonged viral replication and selective pressure from ongoing antiviral treatment” (opens the source at this quote in a new tab)

Activation of nucleoside analogues by viral thymidine kinase and action at the DNA polymerase

“The nucleoside analog antiviral activity depends on initial phosphorylation by a virus-encoded thymidine kinase (TK; encoded by the UL23 gene). Cellular kinases further phosphorylated the monophosphate into the active triphosphate form. The active nucleotide analog is incorporated into the growing DNA strand by the viral DNA polymerase (encoded by the UL30 gene) and prompts chain termination” (opens the source at this quote in a new tab)

“These compounds are phosphorylated by the viral thymidine kinase (TK) and then by cellular kinases. The triphosphate forms selectively inhibit the viral DNA polymerase (DNA pol) activity.” (opens the source at this quote in a new tab)

Genes associated with resistance by antiviral agent
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”
Share of acyclovir resistance attributed to thymidine kinase and DNA polymerase mutations in reviews

“The primary mechanism of HSV-1/2 resistance to nucleoside analogs is the acquisition of mutations in the viral TK (95% of cases), resulting in the absence or defective viral TK or a change in the TK substrate specificity.” (opens the source at this quote in a new tab)

“An uncommon mechanism for nucleoside analog resistance is mutations in the viral DNA polymerase found in 5% of cases” (opens the source at this quote in a new tab)

“Herpes simplex viruses require a functional DNA pol to replicate, whereas the viral TK is dispensable in cultured cells and certain mammalian tissues. Consequently, there is a higher probability of inducing a viable ACV-resistant virus by a mutation in the UL23 gene than by a mutation in the UL30 gene. In this respect, UL23 gene mutations have been reported in 95% of clinical isolates exhibiting ACV resistance” (opens the source at this quote in a new tab)

“Mutations in the UL23 gene encoding for the thymidine kinase (TK) account for 95% of known resistance mutations to acyclovir; the UL30 gene (DNA polymerase, which is the common target for all nucleoside analogues, as well as foscarnet and cidofovir) mutations account for only 5% of known resistance mutations to acyclovir but can confer resistance to other classes of antivirals” (opens the source at this quote in a new tab)

Thymidine kinase and DNA polymerase mutations observed in patient series

“Acyclovir resistance was attributable to viral thymidine kinase and DNA polymerase mutations in 6 and 5 patients, respectively.” (opens the source at this quote in a new tab)

“A small study of patients after HCT reported a similar distribution in UL23 and UL30 DRMs” (opens the source at this quote in a new tab)

“Overall, mutations in UL23 occur more frequently than in UL30.” (opens the source at this quote in a new tab)

“Nine patients harbored UL23 mutations associated with acyclovir resistance, including one previously undescribed mutation (I54K) confirmed by phenotypic assays.” (opens the source at this quote in a new tab)

“One patient presented a UL30 mutation (R628C) conferring resistance to both acyclovir and foscarnet.” (opens the source at this quote in a new tab)

“Five cases of R/R HSV following HCT were identified. Four patients had documented UL23 gene resistance mutations.” (opens the source at this quote in a new tab)

Thymidine kinase phenotypes among acyclovir-resistant isolates

“Three different phenotypes of ACV-resistant TK mutants have been identified: TK-negative mutants which lack TK activity, TK-low-producer mutants which express reduced levels of enzymatic activity, and TK-altered isolates which are substrate-specific mutants, i.e., they phosphorylate thymidine but not ACV and/or PCV. Approximately 95% of ACV-resistant HSV clinical isolates are TK-negative and TK-low-producer mutants, whereas a minority consists of TK-altered mutants” (opens the source at this quote in a new tab)

“Approximately 95 to 96% of acyclovir-resistant HSV isolates are TK deficient (TKN or TKP), and the remaining isolates are usually TKA” (opens the source at this quote in a new tab)

“Mutants with altered DNA polymerase have also been identified” (opens the source at this quote in a new tab)

“Phenotypic and genotypic analyses were done on 30 acyclovir-resistant and 5 acyclovir-susceptible herpes simplex virus (HSV) isolates (22 HSV type 1 and 13 HSV type 2) recovered from 24 subjects. All isolates were susceptible to foscarnet. The phenotypes of the acyclovir-resistant HSV isolates were as follows: 17 were thymidine kinase (TK) deficient, 12 had decreased TK activity (produced low amounts of viral TK) or TK with altered substrate specificity, and 1 was undetermined.” (opens the source at this quote in a new tab)

“The majority of isolates (five of six) from treated, immunocompromised patients were TKD, although a single TKA variant was also identified.” (opens the source at this quote in a new tab)

“Aciclovir resistance is most commonly related to a mutation in the gene encoding HSV thymidine kinase (TK), which is responsible for initial phosphorylation of aciclovir to its active form, resulting in TK that either has reduced affinity for aciclovir or is not synthesised.” (opens the source at this quote in a new tab)

Frameshift mutations in homopolymer runs and point mutations of the thymidine kinase gene

“Half of the cases of ACV resistance are due to additions or deletions of nucleotides in the UL23 gene, particularly in homopolymer repeats of guanines (G) or cytosines (C), which are considered resistance hot spots” (opens the source at this quote in a new tab)

“These additions or deletions can lead to a frameshift reading, resulting in the synthesis of a nonfunctional truncated enzyme” (opens the source at this quote in a new tab)

“The remaining ACV resistance cases are due to nucleotide substitutions that are usually in the conserved sites of the UL23 gene” (opens the source at this quote in a new tab)

“Sequencing analysis of the HSV TK gene revealed that 14 (46.7%) of 30 acyclovir-resistant isolates had an insertion or deletion of 1 or 2 nucleotides, especially in homopolymer runs of Gs, Cs, and rarely in As. On the other hand, 16 (53.3%) of 30 acyclovir-resistant isolates had point mutations in conserved or nonconserved regions of the TK gene.” (opens the source at this quote in a new tab)

“The majority (i.e., 79.7%) of cases of ACV resistance conferred by TK mutations resulted from UL23 gene frameshift reading.” (opens the source at this quote in a new tab)

DNA polymerase mutations

“Although less frequently encountered in clinical isolates, mutants with altered DNA pol have also been identified” (opens the source at this quote in a new tab)

“The greatest clusters of mutations in the DNA pol enzyme have been found in conserved regions II and III.” (opens the source at this quote in a new tab)

“Mutants with alterations in both HSV TK and DNA pol can also occur, resulting in double resistance to both ACV and FOS.” (opens the source at this quote in a new tab)

“Mutations in the viral DNA polymerase gene confer resistance to foscarnet and are typically encountered after foscarnet exposure” (opens the source at this quote in a new tab)

Mechanism of action of foscarnet and cidofovir and resistance to them

“Foscarnet, a pyrophosphate nonnucleoside analog, and cidofovir, a nucleotide analog of cytosine monophosphate, inhibit the viral DNA polymerase directly by blocking the active site of the enzyme and do not require phosphorylation by the viral TK” (opens the source at this quote in a new tab)

“Resistance to both agents occurs through mutations at several loci along the DNA polymerase gene (Supplementary Tables 3 and 4), which can confer cross-resistance to nucleoside analogs” (opens the source at this quote in a new tab)

“FOS, which does not require phosphorylation by viral and cellular kinases, binds to the pyrophosphate binding site on the viral DNA pol and blocks the release of pyrophosphate from the terminal nucleoside triphosphate added onto the growing DNA chain.” (opens the source at this quote in a new tab)

“Thus, they circumvent the need for activation by the virus-encoded TK and so retain their activity against TK-negative or TK-altered strains of HSV” (opens the source at this quote in a new tab)

“TK-deficient strains are susceptible to foscarnet and cidofovir which do not depend upon TK but which inhibit viral DNA polymerase.” (opens the source at this quote in a new tab)

Cross-resistance within the nucleoside analogue class

“All acyclovir-resistant strains are also resistant to valacyclovir, and most are resistant to famciclovir.” (opens the source at this quote in a new tab)

“HSV resistance to PCV generally maps to mutations in the UL23 gene, with almost inevitable cross-resistance between the two nucleoside analogues” (opens the source at this quote in a new tab)

“It is very unlikely that a patient failing to respond to ACV or VACV therapy will respond to FCV because there will most probably be cross-resistance between ACV and PCV.” (opens the source at this quote in a new tab)

“Mutations in UL23 are linked to cross-resistance to other nucleoside analogues, including penciclovir and brivudine as these drugs also require activation by the viral TK” (opens the source at this quote in a new tab)

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)

“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)

“All antivirals approved for the treatment of HSV infections have the same target, i.e. the viral DNA polymerase, and cross-resistance to different antivirals has been described, complicating therapy of acyclovir resistant strains.” (opens the source at this quote in a new tab)

“Specific DNA polymerase mutations may confer cross-resistance to nucleoside analogues, FOS, and CDV” (opens the source at this quote in a new tab)

Foscarnet-resistant isolates: acyclovir susceptibility and prior foscarnet exposure in patients with AIDS

“Six human immunodeficiency virus-infected patients had clinical lesions of herpes simplex virus (HSV) type 2 that showed in vitro resistance to foscarnet. In each patient, lesions were unresponsive to foscarnet therapy or developed during daily suppressive foscarnet.” (opens the source at this quote in a new tab)

“Seven of 10 foscarnet-resistant isolates from 6 patients were susceptible to acyclovir in vitro, and 1 was of borderline susceptibility.” (opens the source at this quote in a new tab)

“Clinically significant resistance to foscarnet may occur in immunosuppressed patients with prior foscarnet exposure.” (opens the source at this quote in a new tab)

Cidofovir susceptibility of acyclovir-resistant and foscarnet-resistant isolates from transplant recipients

“All the isolates were sensitive to cidofovir, for which the IC(50) values correlated inversely with those for acyclovir (P=.01).” (opens the source at this quote in a new tab)

“No strain from any of the 7 patients was resistant in vitro to cidofovir; however, only 3 of 7 patients achieved complete response.” (opens the source at this quote in a new tab)

Mixed populations of susceptible and resistant virus

“Laboratory strains and clinical isolates of HSV that are resistant to ACV naturally constitute a heterogeneous population which contains mixtures of wild-type and resistant virus” (opens the source at this quote in a new tab)

“It has been estimated that the proportion of ACV-resistant HSV must exceed 20% of the viral population in order to shift the IC50 to more than 2 μg/ml” (opens the source at this quote in a new tab)

“In addition, heterogeneous populations (TK competent/TK negative) may coexist in HSV isolates from immunocompromised patients” (opens the source at this quote in a new tab)

“It has long been recognized that laboratory strains and clinical isolates of HSV contain mixtures of wild-type and acyclovir-resistant virus” (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)

“Fast and sensitive methods based on next-generation sequencing will improve the detection of heterogeneous viral populations of drug-resistant viruses and their temporal changes during antiviral therapy, which could allow better patient management.” (opens the source at this quote in a new tab)

Differences in susceptibility between anatomic sites and between successive episodes

“It should be noted that the first patient excreted an ACV-resistant strain (sacrum) and a ACV-sensitive strain (vulva) on the same day at two different sites and that the second patient excreted four ACV-resistant strains, two of which were resistant to PFA under treatment with PFA, and then a strain sensitive to ACV and to PFA.” (opens the source at this quote in a new tab)

“With regard to the five recurrent excretions, in one case there were successive excretions of ACV-resistant and ACV-sensitive strains, and in four cases there were excretions of only ACV-resistant strains.” (opens the source at this quote in a new tab)

“Recurrences following episodes of acyclovir-resistant HSV can be caused by either acyclovir-resistant or acyclovir-sensitive strains” (opens the source at this quote in a new tab)

“All patients recurred, 10 presenting at least one acyclovir-resistant HSV recurrence. The median number of acyclovir-resistant HSV recurrences per patient was 2 (0 - 5). Regarding the first and second recurrences, 7/13 (54%) and 5/11 (45%) HSV clinical isolates exhibited resistance to acyclovir, respectively.” (opens the source at this quote in a new tab)

“After healing of an infection caused by a TK-negative drug-resistant HSV strain and stopping antiviral therapy, recurrences are most often associated with a drug-sensitive strain, although some cases of spontaneous recurrences of ACV-resistant viruses have been reported” (opens the source at this quote in a new tab)

Fitness, latency, and reactivation of resistant mutants

“Most ACV-resistant mutants exhibit some reduction in their capacity to establish latency and to reactivate, as well as in their degree of neurovirulence in animal models of HSV infection. For instance, TK-negative HSV mutants establish latency with a lower efficiency than wild-type strains and reactivate poorly. DNA pol HSV mutants exhibit different degrees of attenuation of neurovirulence.” (opens the source at this quote in a new tab)

“Some of these isolates have been shown to express TK activity at ultra-low levels, demonstrating that the amounts of TK activity required for reactivation are far lower than previously appreciated” (opens the source at this quote in a new tab)

“Herpes simplex virus can grow in cell culture in the absence of a TK; however, its pathogenesis is affected. In animal models, TK-negative mutants were less efficient in establishing sensory ganglia latency and reactivated poorly. Also, neurovirulence was attenuated” (opens the source at this quote in a new tab)

“In humans, 1 report described a mixed population of TK-mutant and wild-type strains in immunocompromised host ganglia, suggesting that these strains can establish latency” (opens the source at this quote in a new tab)

“A TKN mutant was repeatedly isolated from the same patient following acyclovir treatment during two bone marrow transplantations separated by 2 years. Since the two mutants were genetically indistinguishable, it was concluded that the virus had established latency and subsequently reactivated.” (opens the source at this quote in a new tab)

“TK-deficient strains are of reduced pathogenicity in immunocompetent individuals but may cause serious local and systemic disease in severely immunocompromised individuals.” (opens the source at this quote in a new tab)

“They appear less likely to be associated with the development of latency; hence, subsequent clinical reactivations of genital herpes are often caused by aciclovir sensitive isolates.” (opens the source at this quote in a new tab)

Transmission of resistant strains

“The possibility of person-to-person transmission of R/R HSV strains was suggested in some case reports” (opens the source at this quote in a new tab)

“It should be noted that there has been no unequivocal evidence of transmission of resistant HSV from these patients to other individuals.” (opens the source at this quote in a new tab)

Refractory infection without laboratory-confirmed resistance

“However, 10% of cases not responding to antiviral therapy showed phenotypically susceptible virus isolates.” (opens the source at this quote in a new tab)

“Out of 513 DRM-drug combinations with both phenotypic and clinical data, we observed agreement between clinical assessment and phenotypic DST results in 461 cases (89.9%), with 52 cases (10.1%) showing disagreement. All disagreements involved cases phenotypically susceptible in vitro but diagnosed as resistant clinically.” (opens the source at this quote in a new tab)

“Furthermore, it is important to emphasize that treatment failure does not necessarily mean presence of DRM” (opens the source at this quote in a new tab)

“third spacing in critically ill patients (i.e. fluid shifts from the intravascular space to the interstitial space) may negatively affect pharmacokinetics leading to sub-therapeutic drug levels” (opens the source at this quote in a new tab)

“Conversely, the absence of known DRMs does not exclude the possibility of drug resistance, especially in a patient who is not responding to treatment” (opens the source at this quote in a new tab)

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

Catalogued resistance mutations and natural polymorphisms of the thymidine kinase and DNA polymerase genes

“We identified 221 novel DRMs (excluding novel polymorphisms), comprising 99 mutations in the HSV-1 TK gene, 66 in the HSV-1 POL gene, 12 in the HSV-1 HP gene, 19 in the HSV-2 TK gene, 10 in the HSV-2 POL, and 15 in the HSV-2 HP (Table S3).” (opens the source at this quote in a new tab)

“Of note, we found that location within or outside of conserved regions does not reliably predict whether a mutation confers resistance.” (opens the source at this quote in a new tab)

“Our results showed that TK and DNA polymerase are highly conserved among HSV strains, with a weaker variability for HSV-2 strains. This study provided a precise map of the natural polymorphism of both viral enzymes among HSV-1 and HSV-2 isolates, with the identification of 15 and 51 polymorphisms never previously described for TK and DNA polymerase, respectively, which will facilitate the interpretation of genotypic antiviral-resistant testing.” (opens the source at this quote in a new tab)

“Twenty-six novel natural polymorphisms could be detected in the TK gene and 69 in the DNA Pol gene. Furthermore, three novel resistance-associated mutations (two in the TK gene and one in the DNA Pol gene) were analyzed, and eight known but hitherto unclear amino acid substitutions (two encoded in TK and six in the DNA Pol gene) could be clarified.” (opens the source at this quote in a new tab)

“Genotypic characterization of HSV UL23 thymidine kinase and UL30 DNA polymerase genes revealed 11 and 7 previously unreported substitutions, respectively. These substitutions may be related to potential polymorphisms, drug resistance, or other mutations of unclear significance.” (opens the source at this quote in a new tab)

“Thus, this review presents a database of all non-synonymous mutations of TK and DNA pol genes of HSV-1 and HSV-2 whose association with resistance or natural gene polymorphism has been clarified by phenotypic and/or functional assays.” (opens the source at this quote in a new tab)