Resistant Herpes Simplex Virus Research Articles

Novel UL23 and UL30 substitutions in HSV1 and HSV2 viruses related to polymorphism or drug resistance

Data on herpes simplex virus (HSV) polymorphism as well as acyclovir (ACV) and foscarnet (FOS) resistance mutations are not exhaustive and may hinder accurate diagnosis by next-generation sequencing (NGS). Here, we report novel UL23 and UL30 substitutions for HSV1 and HSV2 identified in immunocompromised patients treated for hematological malignancies during the last 6 years of HSV resistance surveillance at the University Hospital of Lyon. For HSV1, 35 novel UL23 substitutions and 52 novel UL30 substitutions were identified. For HSV2, 2 novel UL23 substitutions and 12 novel UL30 substitutions were identified. These results allow to complete the database of HSV1 and HSV2 substitutions, related either to polymorphism or to ACV and FOS resistance.

Management of oral herpes simplex virus infections: The problem of resistance. A narrative review.

Herpes Simplex Virus (HSV) type 1 (HSV-1) and type 2 (HSV-2) are among the most common human viral pathogens, affecting several billion people worldwide. Although in healthy patients clinical signs and symptoms of HSV infection are usually mild and self-limiting, HSV-infections in immunocompromised patients are frequently more aggressive, persistent, and even life-threatening. Acyclovir and its derivatives are the gold standard antiviral drugs for the prevention and treatment of HSV infections. Although the development of acyclovir resistance is a rather uncommon condition, it may be associated with serious complications, especially in immunocompromised patients. In this review, we aim to address the problem of drug resistant HSV infection and discuss the available alternative therapeutic interventions. All relative studies concerning alternative treatment modalities of acyclovir resistant HSV infection published in PubMed between 1989 to 2022 were reviewed. Long-term treatment and prophylaxis with antiviral agents predisposes to drug resistance, especially in immunocompromised patients. Cidofovir and foscarnet could serve as alternative treatments in these cases. Although rare, acyclovir resistance may be associated with severe complications. Hopefully, in the future, novel antiviral drugs and vaccines will be available in order to avoid the existing drug resistance.

In silico investigation of acyclovir derivatives potency against herpes simplex virus

Herpes simplex virus (HSV) is a major human pathogen, sub-divided into two types: HSV-1 which causes oral and perioral infections and HSV-2 which causes genital herpes. The global disease burden is high with 67% and 11% of the World's population being infected with HSV-1 and HSV-2 respectively. Acyclovir, an FDA approved drug, is a synthetic purine nucleoside analogue used for the treatment of HSV infections. The drug acts via the viral encoded thymidine kinase and competitively inhibits viral DNA polymerase. Emerging HSV resistance to acyclovir and lack of approved vaccines necessitates need for effective strategies to circumvent the viral infection. Derivatives of acyclovir were modelled using computer aided drug design techniques through Chemsketch and drugability determined based on Lipinski's Ro5 where a Python filtering code was created and derivatives with zero non-violations were selected. Putative biological targets were determined through network pharmacology and validated through gene ontology. Molecular docking with known and putative targets was done to determine the binding affinities of the acyclovir derivatives. Based on enzyme inhibition scores, pharmacokinetics prediction was done on Molinspiration while pharmacodynamics predictions were done on AdmetSAR based on bioavailability scores. Thirty acyclovir derivatives were modelled of which 22 had zero non-violations. 2-[(3, 6-dihydro-9H-purin-9-yl)methoxy]ethan-1-ol) had the highest enzyme inhibition score at 1.0 compared to 0.84 for acyclovir. The molecule was further optimized generating (2‐[(6‐methyl‐6,9‐dihydro‐3H‐purin‐9‐yl)methoxy]ethan‐1‐ol which had a better bioavailability and a higher blood brain barrier value of 0.9880 indicating possible better patient tolerance. 2‐[(6‐methyl‐6,9‐dihydro‐3H‐purin‐9‐yl)methoxy]ethan‐1‐ol had an enzyme inhibition score of 0.90 and binding energies of -5.1 kcal/mol when docked against thymidine kinase. The intra-viral HSV PPI network was analysed and DNA replication helicase (UL5) and serine /threonine-protein kinase (US3) were selected due to functional similarity with thymidine kinase with kappa statistics value of 0.30 and 0.24 respectively. Gene enrichment analysis indicated that the biological targets UL5 and US3 had a significant P value of 0.62 based on Benjamin Correction at P<0.05. The study recommends in vitro and in vivo validation of this novel compound and molecular validation of the two new potential biological targets for possible development of new anti-herpes therapeutic compounds.

Herpes simplex virus resistance to antivirals

Herpes simplex virus (HSV) infections remain an important cause of morbidity among immunocompromised patients, such as transplant recipients and human immunodeficiency virus [HIV]-infected individuals. Only few antiviral drugs are available to treat HSV infections: (val)acyclovir, foscarnet, and cidofovir. Prophylactic and curative antiviral treatments administered during prolonged periods among patients with altered T-cell immunity may lead to the emergence of HSV resistance to antivirals, contributing to a challenging therapeutic management of viral infection. The persistence of herpetic lesions after 10 days of well-conducted antiviral therapy is suggestive of viral resistance. Resistance to antivirals can be detected using genotypic methods (identifications of antiviral resistance-associated mutations by sequencing genes encoding viral proteins involved in the mechanism of action of antivirals) or phenotypic methods (measure of antiviral drug concentration inhibiting 50% of viral replication in cell culture). The prevalence of HSV resistance to acyclovir is below 1% in immunocompetent individuals, except those with herpetic keratitis for whom prevalence can reach 7%, and varies from 3.5% to 11% in immunocompromised patients. Adverse effects and the absence of eradication of viral latent infection constitute other limits to the use of antiviral drugs. New antiviral compounds undergoing clinical trials and novel potential viral targets seem very promising to enlarge the panel of efficient compounds to treat HSV infections.

THYMIDINE KINASE AS A CAUSATIVE FACTOR FOR TYPE 1 HERPES SIMPLEX VIRUS RESISTANCE AGAINST ACYCLOVIR

ABSTRACTBackground: Herpes Simplex Virus (HSV) infection demonstrates a high prevalence in the world. Acyclovir, one of guanine synthetic analogues, is commonly used to treat infections caused by HSV. HSV resistance against acyclovir may occur, especially in immunocompromised and immunocompetent patients, as the consequence of viral mutations. Thymidine kinase (TK) is an HSV tegument protein which plays an important role in HSV-1 resistance against acyclovir. Purpose: The purpose of this article is to review the mechanisms of TK mutation that cause HSV-1 resistance against acyclovir. Review: Acyclovir involves three stages of viral thymidine kinase phosphorylation to form acyclovir triphosphate. It prevents HSV replication by acting as a competitive inhibitor of viral DNA polymerase and a chain terminator in viral DNA synthesis. Resistance is associated with viral TK mutation that is encoded by UL23 gene. Long-term use of acyclovir may promote thymidine kinase mutation in immunocompromised and immunocompetent patients via three mechanisms, namely absolute insufficiency in TK activity (TK-negative), depletion in TK synthesis, and inability in TK phosphorylation which consequently hinders the phosphorylation of acyclovir. Herpes TK gene contains a series of cytosine and guanosine, that are important for the function and the mutation of HSV by producing incomplete or fewer enzymes as the result of nucleotide addition or elimination in homopolymer process. Conclusion: HSV-1 resistance against acyclovir is evolved from TK mutations, in the form of TK-negative, TK low-producing, and TK altered mutants, that are unable to phosphorylate TK and accordingly disrupt acyclovir phosphorylation to convert acyclovir triphosphate. Keyword : Acyclovir, Herpes simplex virus, Resistance, Thymidine kinase

Challenges of aciclovir-resistant HSV infection in allogeneic bone marrow transplant recipients

The emergence of herpes simplex virus (HSV) resistance to aciclovir (ACV) has increasingly been reported among hematopoietic stem cell transplant (HSCT) recipients and often associated with extended ACV prophylaxis. Between June 2011 and June 2019, medical records of 532 HSCT recipients with suspected HSV infection were retrospectively analyzed. HSV-1 and HSV-2 positive samples were identified in 47 and 16 patients respectively. Analysis of HSV resistance to antivirals was performed at the Public Health England reference laboratory in London using phenotypic and/or genotypic resistance assays. The prevalence of ACV-resistant HSV accounted for 17% (8/48) of infected HSV-1 cases. All 8 patients received T-cell depleted allogeneic HSCT for hematological malignancies. Half of these patients were male with a median age was 57.5 years (range; 26-63). Chronic Graft versus Host disease (cGVHD) affected 7 patients before HSV-1 diagnosis. HSV-1 infection developed while receiving either intravenous ACV (n = 2) or oral ACV (n = 6 patients) prophylaxis at a median of 373 [range,18-2183] days post-HSCT. 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. All patients presented with hemorrhagic oral mucositis refractory to treatment dose ACV. Foscarnet (FOS) treatment was initiated in all 8 patients (pending laboratory confirmation of ACV resistance) with some effect but associated with significant toxicity burden. Four patients presented again with recurrent HSV infection or no resolution. Three with recurrent HSV died from other causes while suffering from persistent oral HSV lesions. A prolonged immunosuppressed state following T-deplete HSCTs alongside extended use of ACV, early onset systemic HSV infection, presence of cGVHD, and treatment toxicities pose a significant challenge to the management of ACV resistant HSV infections and alternative effective antiviral options remains an unmet need in this clinical setting.

Mangiferin: A promising natural xanthone from Mangifera indica for the control of acyclovir – resistant herpes simplex virus 1 infection

Mangiferin is found in many plant species as the mango tree (Mangifera indica) with ethnopharmacological applications and scientific evidence. The emergence of resistant herpes simplex virus (HSV) strains to Acyclovir (ACV) has encouraged the search for new drugs. We investigated the in vitro and in vivo activity of mangiferin obtained from M. indica against ACV-resistant HSV-1 (AR-29) and sensitive (KOS) strains. The in vitro activity was performed under varying treatment protocols. The substance showed a CC50 > 500 μg/mL and IC50 of 2.9 μg/mL and 3.5 μg/mL, respectively, for the AR-29 and KOS strains. The in vivo activity was performed in Balb/c mice treated with 0.7% topical mangiferin formulation. This formulation inhibited most effectively the AR-29 strain, attenuated the lesions, postponed their appearance or enhanced healing, in comparison to control group. We demonstrated the potentiality of mangiferin from M. indica to control HSV replication with emphasis to ACV-resistant infection.

Added value of ultra-deep sequencing (UDS) approach for detection of genotypic antiviral resistance of herpes simplex virus (HSV)

Classically, Sanger sequencing is considered the gold standard for detection of HSV drug resistance mutations (DRMs). As a complementary method, ultra-deep sequencing (UDS) has an improved ability to detect minor variants and mixed populations. The aim of this work was to apply UDS performed on MiSeq® Illumina platform to the detection of HSV DRMs and to the evaluation of the subpopulation diversity in clinical samples in comparison with Sanger sequencing. A total of 59 HSV-positive clinical samples (31 HSV-1 and 28 HSV-2) recovered from 50 patients mainly immunocompromised (70%) were retrospectively analyzed. Remarkably, UDS analysis revealed significant differences of relative abundance according to the type of DRMs within TK and Pol: natural polymorphisms and amino acid changes associated with resistance to antivirals were identified as high-abundant mutations (>96%), whereas TK frameshifts conferring resistance to ACV were systematically detected at lower abundance (≈80%). This work also revealed that UDS can detect low-frequency DRMs and provides extensive information on viral population composition.

Acyclovir Sensitivity and Neurovirulence of Herpes Simplex Virus Type 1 with Amino Acid Substitutions in the Viral Thymidine Kinase Gene, Which Were Detected in the Patients with Intractable Herpes Simplex Encephalitis Previously Reported.

Several cases of herpes simplex encephalitis (HSE) caused by acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) have been reported. Amino acid substitutions of R41H, Q125H, and A156V in the viral thymidine kinase (vTK) gene have been reported to confer ACV resistance. Recombinant HSV-1 clones, containing each amino acid substitution in the vTK gene, were generated using the bacterial artificial chromosome system. A recombinant HSV-1 with the Q125H substitution showed ACV resistance while the R41H or A156V substitutions were ACV-sensitive. Furthermore, the Q125H recombinant HSV-1 was less virulent than the repaired virus, but it maintained neurovirulence in mice at relatively high levels. Substitution of Q125H, which was detected in the neonatal HSE patient, conferred ACV resistance, but the substitutions of R41H and A156V, which were detected in immunocompetent adult HSE patients, did not. This suggests that HSE caused by ACV-resistant HSV-1 might be a very rare event to occur during the course of ACV treatment in immunocompetent patients. Showing resistance to ACV treatment does not always indicate emergence of ACV-resistant HSV-1 in HSE patients.

Herpes simplex virus virucidal activity of MST-312 and epigallocatechin gallate

Herpes Simplex Virus (HSV) is the cause of cold sores, blindness and encephalitis and often leads to recurrent infections. Use of current anti-viral therapies can be limited when drug resistant HSV mutants arise. Thus, novel drugs for the treatment of HSV are needed. Previous research in our laboratory has determined that the telomerase inhibitor, MST-312, interferes with multiple steps of the HSV life cycle. The structure of MST-312 contains moieties related to a natural compound found in green tea, epigallocatechin gallate (EGCG). EGCG has been reported to possess direct virucidal activities toward HSV-1. Here, we tested the virucidal activity of MST-312 and compared it to that of EGCG. Specifically, HSV-1 was exposed to various concentrations of MST-312 or EGCG for time periods between 1 and 60 min and then the ability of the treated virions to form plaques on Vero cells was assessed. When treated for 60 min, 40 μM MST-312 and 0.5–1.0 μM EGCG significantly reduced the number of HSV-1 plaque forming units. The temperature at which treatment occurred impacted the ability of the compounds to limit viral replication. Both compounds were effective when treatment occurred at 37 °C and room temperature (RT). However, no inhibition was seen when virions were treated with MST-312 at 4 °C. 1 min treatment with 2 μM EGCG at RT was sufficient to significantly reduce HSV titers. Higher concentrations of MST-312 were required to inactivate HSV-1 virions compared to EGCG. These data indicate that both EGCG and MST-312 possess direct virucidal properties on HSV-1.

A new promising candidate to overcome drug resistant herpes simplex virus infections

Infections with Herpes simplex viruses (HSV) belong to the most common human diseases worldwide, resulting in symptoms ranging from painful, but commonly self-limiting lesions of the orofacial or genital tract to severe infections of the eye or life-threatening generalized infections. Frequent HSV-reactivations at the eye may lead to the development of herpetic stromal keratitis, which is one of the major causes of infectious blindness in developed countries. The vast majority of life-threatening generalized infections occur in immunocompromised individuals, such as transplant recipients or patients suffering from advanced human immunodeficiency virus (HIV) infection with concurrent HSV-reactivation. Over the past decades, Acyclovir (ACV) became the golden standard for the treatment of HSV infections. However, long-term antiviral treatment, as it is required mainly in immunocompromised patients, led to the emergence of resistances towards ACV and other antivirals. Therefore, there is a clear need for the development of new potent antivirals which combine good oral bioavailability and tolerability with low side effects. In the current study we present SC93305 as a novel potent antiviral substance that proved to be highly effective not only against different HSV-1 and HSV-2 strains but also towards ACV- and multi-resistant HSV-1 and HSV-2 isolates. SC93305 shows comparable antiviral activity as reported for ACV and very importantly it does not interfere with the activation of specific immune cells. Here we report that SC93305 does not affect the biological function of dendritic cells (DC), the most potent antigen presenting cells of the immune system to induce antiviral immune responses, nor T cell stimulation or the release of inflammatory cytokines. Thus, SC93305 is a new and promising candidate for the treatment of HSV-1 and HSV-2 infections and in particular also for the inhibition of drug-resistant HSV-1/2 strains.

Application of next-generation sequencing to detect acyclovir-resistant herpes simplex virus type 1 variants at low frequency in thymidine kinase gene of the isolates recovered from patients with hematopoietic stem cell transplantation

Ion Torrent next-generation sequencing (NGS) technology was applied to study the mode of emergence of acyclovir (ACV)-resistant (ACVr) herpes simplex virus type 1 (HSV-1) in patients with hematopoietic stem cell transplantation (HSCT) by quantitatively detecting mutations in the viral thymidine kinase (vTK) gene in the HSV-1 isolates recovered from HSCT patients. All of the mutations detected with the Sanger sequencing method in the vTK genes of HSV-1 isolates were also detected with the NGS assay. Furthermore, different mutations, which conferred ACV resistance and were not detected with the Sanger sequencing method, were also detected in a quantitative manner by using the NGS assay. The approach described here is applicable to studying the emergence process of vTK gene mutation-associated ACVr HSV-1 more in detail than the Sanger method. The NGS assay makes it possible to make a diagnosis of vTK gene mutation-associated ACVr HSV-1 infections at the early stage, which the ratio of ACVr HSV-1 is much lower than that of ACV-sensitive (ACVs) HSV-1.

Association between sensitivity of viral thymidine kinase-associated acyclovir-resistant herpes simplex virus type 1 and virulence

BackgroundAcyclovir (ACV)-resistant (ACVr) herpes simplex virus type 1 (HSV-1) infections are concern in immunocompromised patients. Most clinical ACVr HSV-1 isolates have mutations in the viral thymidine kinase (vTK) genes. The vTK-associated ACVr HSV-1 shows reduced virulence, but the association between the level of resistance and the virulence of the vTK-associated ACVr HSV-1 is still unclear.MethodsThe virulence in mice of 5 vTK-associated ACVr HSV-1 clones with a variety of ACV sensitivities, when inoculated through intracerebral and corneal routes, was evaluated in comparison with ACV-sensitive (ACVs) parent HSV-1 TAS.ResultsAlthough all the 5 ACVr HSV-1 clones and ACVs HSV-1 TAS showed a similar single-step growth capacity in vitro, the virulence of ACVr HSV-1 clones significantly decreased. A 50% lethal dose (LD50) of each clone was closely correlated with 50% inhibitory concentrations (IC50), demonstrating that the higher the ACV-sensitvity, the the higher the virulence among the ACVr clones. One of the ACVr HSV-1 clones with a relatively low IC50 value maintained similar virulence to that of the parent TAS. The infection in mice with ACVr HSV-1 due to a single amino acid substitution in vTK induced local diseases, keratitis and dermatitis, while vTK-deficient clone did not.ConclusionsA statistically significant correlation between the virulence and susceptibility to ACV among ACVr HSV-1 clones was demonstrated.

Brincidofovir (CMX-001) for refractory and resistant CMV and HSV infections in immunocompromised cancer patients: A single-center experience

BackgroundThe emergence of resistance to available antiviral drugs may cause higher Cytomegalovirus (CMV)-associated morbidity and mortality in hematopoietic cell transplant (HCT) recipients. Few novel antiviral drugs are being developed with potential effect against refractory or resistant CMV infections. Brincidofovir, an oral nucleotide analog and prodrug of cidofovir, has shown in vitro activity against CMV. MethodsWe reviewed data of 4 cancer patients with resistant CMV or herpes simplex virus (HSV) infections and were treated with brincidofovir under emergency IND application. ResultsThree out of the 4 patients with resistant CMV or HSV infections responded to brincidofovir. Brincidofovir achieved virological response in 2 patients with confirmed UL97 mutation (ganciclovir-resistant CMV infection), but failed to control CMV when a specific UL54 mutation was present (conferring resistance to foscarnet and cidofovir), as seen with patient 3. Furthermore, brincidofovir was effective for treatment of acyclovir resistant HSV infection, as described in patient 4 which is in alignment with the high in vitro potency of brincidofovir (about 100-fold more than acyclovir) for inhibition of HSV replication. Only one patient had brincidofovir-related diarrhea without any evidence of concurrent gastrointestinal GVHD. ConclusionWithout the nephrotoxicity of cidofovir, brincidofovir could be an effective alternative for CMV-resistant and HSV-resistant infections. Combination therapy of brincidofovir with other antiviral agent, at a conventional or a lower dose, could be considered to potentiate efficacy and minimize side effects of the approved antiviral agents.

Complex management of resistant oral herpes simplex virus infection following hematopoietic stem cell transplantation: potential role of topical cidofovir

Herpes simplex virus (HSV) infection commonly occurs during the immunosuppression associated with hematopoietic stem cell transplantation (HSCT). Prophylaxis of recurrent infection and management of clinical infection have relied upon acyclovir and congeners. More recently, resistant HSV infection is seen in HSCT and presents new challenges in management. We present a case of HSV following HSCT that provided effective symptomatic management. Oral symptoms and lesions were repeatedly reduced when topical cidofovir was used, strongly supporting the effect of cidofovir used in a host who could not tolerate systemic antiviral medications. Topical cidofovir can provide effective management of symptomatic oropharyngeal HSV while reducing risk of systemic toxicity and drug interaction and represents an additional approach to management for management in medically compromised patients.

New strategies against drug resistance to herpes simplex virus.

Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV.

Acyclovir Resistant Herpes Simplex Virus in Stem Cell Transplant Recipients

Acyclovir Resistant Herpes Simplex Virus in Stem Cell Transplant Recipients Ella J. Ariza-Heredia , Roy F. Chemaly , Ying Jiang , Victor E. Mulanovich . 1 Department of Infectious Diseases, Infection Control & Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Infectious Diseases, Infection Control & Employee Health, UT MD Anderson Cancer Center, Houston, TX

Subclinical generation of acyclovir-resistant herpes simplex virus with mutation of homopolymeric guanosine strings during acyclovir therapy

BackgroundSuppressive therapy in patients with genital herpes has been used in Japan since 2006. Susceptibility and resistance of herpes simplex virus (HSV)-2 to acyclovir were examined in genital isolates from patients receiving suppressive therapy and compared with those from those naïve to acyclovir and receiving episodic treatment with acyclovir. ObjectiveThe aim of this study was to analyze the effect of acyclovir use on the susceptibility to acyclovir and analysis of the thymidine kinase gene by acyclovir treatment. MethodsGenital HSV isolates were obtained from three patients groups. Susceptibility to acyclovir, the frequency of acyclovir-resistant clones and mutations in the thymidine kinase gene of acyclovir-resistant clones were determined. ResultsSusceptibility to ACV was significantly higher in isolates from patients receiving suppressive therapy than those naïve to acyclovir and receiving episodic treatment, but the frequencies of resistant clones were similar among the three groups. Mutation in guanosine homopolymeric strings (G-string mutation) was significantly more frequent in clones during episodic treatment and suppressive therapy than clones from patients naïve to ACV. The frequency of G-string mutation was significantly less frequent in isolates from patients naïve to ACV than those experienced ACV therapy. ConclusionThe frequency of acyclovir-resistant mutants was not increased by episodic and suppressive therapy, but exposure to acyclovir significantly generated G-string mutations, possibly induced by acyclovir. Acyclovir therapy had no substantial effects on the susceptibility of HSV-2 or frequency of resistant virus but did generate subclinical G-string mutants in patients’ HSV-2.

High conservation of herpes simplex virus UL5/UL52 helicase-primase complex in the era of new antiviral therapies

The emergence of herpes simplex virus (HSV) resistance to current antiviral drugs, that all target the viral DNA polymerase, constitutes a major obstacle to antiviral treatment effectiveness of HSV infections, especially in immunocompromised patients. A novel and promising class of inhibitors of the HSV UL5/UL52 helicase-primase (HP) complex has been reported to hinder viral replication with a high potency. In this study, we describe the low natural polymorphism (interstrain identity >99.1% at both nucleotide and amino acid levels) of HSV HP complex subunits pUL5 and pUL52 among 64 HSV (32 HSV-1 and 32 HSV-2) clinical isolates, and we show that the HSV resistance profile to the first-line antiviral drug acyclovir (ACV) does not impact on the natural polymorphism of HSV HP complex. Genotypic tools and polymorphism data concerning HSV HP complex provided herein will be useful to detect drug resistance mutations in a relevant time frame when HP inhibitors (HPIs), i.e., amenamevir and pritelivir, will be available in medical practice.

Resistance of herpes simplex viruses to acyclovir: An update from a ten-year survey in France

The widespread use of acyclovir (ACV) and the increasing number of immunocompromised patients have raised concern about an increase in ACV-resistant herpes simplex virus (HSV). ACV resistance has traditionally been a major concern for immunocompromised patients with a frequency reported between 2.5% and 10%. The aim of this study was to reassess the status of HSV resistance to ACV in immunocompetent and immunocompromised patients over a ten year period, between 2002 and 2011. This was done by retrospectively following 1425 patients. In immunocompetent patients, prevalence of resistance did not exceed 0.5% during the study period; whereas in immunocompromised patients, a significant increase was observed, rising from 3.8% between 2002 and 2006 (7/182 patients) to 15.7% between 2007 and 2011 (28/178) (p=0.0001). This sharp rise in resistance may largely be represented by allogeneic hematopoietic stem cell transplant patients, in which the prevalence of ACV resistance rose similarly from 14.3% (4/28) between 2002 and 2006 to 46.5% (26/56) between 2007 and 2011 (p=0.005). No increase in ACV resistance was detected in association with other types of immune deficiencies. 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.