Acyclovir-resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics

BACKGROUND: Genital herpes is epidemic in the United States; long-term acyclovir therapy is common; and long-term use of antimicrobials in suppressive doses favors development of resistance. OBJECTIVE: To determine the prevalence of and risk factors for acyclovir-resistant genital herpes. METHODS: We identified and attempted to enroll all patients 18 years or older with suspected genital herpes who attended 22 sexually transmitted disease and human immunodeficiency virus (HIV) clinics in the United States between October 1996 and April 1998. We conducted standardized interviews of all consenting patients. Lesions were cultured, and isolates were typed as herpes simplex virus (HSV) 1 or HSV-2 and tested for acyclovir sensitivity (using a 50% inhibitory concentration of 2 microg/mL) by plaque reduction, which was independently confirmed. RESULTS: 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. Three (0.18%) of 1644 HIV-negative patients had acyclovir-resistant isolates (95% confidence interval [CI], 0.04%-0.5%); resistance was associated with oral (P<.006) and topical (P<.001) acyclovir use. 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). CONCLUSIONS: In the 15 years following licensure of acyclovir, resistance to the drug remains low among immunocompetent patients. However, 5% of HIV-positive patients had resistant HSV-2 isolates. Continued surveillance is essential to monitor changes in acyclovir resistance and to characterize the clinical and public health importance of acyclovir-resistant HSV.     

Recurrent antiviral-resistant genital herpes in an immunocompetent patient

Herpes simplex virus type 2 (HSV-2) resistance to antiviral drugs has been described primarily in immunocompromised patients. We report an apparently immunocompetent, human immunodeficiency virus-negative male patient who has experienced repeated HSV-2 genital outbreaks despite receiving antiviral prophylaxis with several different drugs. Several of the HSV-2 genital isolates from this patient have been confirmed as resistant to acyclovir and penciclovir. Antiviral resistance occurred in the setting of long-term prednisone treatment and intermittent acyclovir prophylaxis at suboptimal doses and persisted despite the cessation of oral steroid treatment. The patient's genital herpes outbreaks were not controlled by high-dose prophylaxis with acyclovir, valacyclovir, and famciclovir. Cessation of antiviral prophylaxis resulted in reversion of this patient's HSV-2 isolates to acyclovir and penciclovir sensitivity, although resistant virus reappeared when antiviral prophylaxis was resumed. Transmission of a sensitive HSV-2 strain from this patient to a female sex partner was observed. These observations confirm previous reports that resistance to acyclovir may develop during prophylactic therapy in an otherwise well, immunocompetent patient. These findings support the conclusion that both drug-sensitive and drug-resistant HSV-2 strains established latency in this patient and that both strains are capable of frequent reactivation.     

Susceptibility to acyclovir of herpes simplex virus: emergence of resistance in patients with lymphoid and myeloid neoplasia

We have examined the susceptibility to acyclovir (ACV) of herpes simplex virus isolated from immunocompetent and immunocompromised patients. Susceptibility to ACV was determined in a dye-uptake assay with vero cells grown in 96-well microtitre plates. Resistant strains were found in two out of 35 (5.7%) patients and partially resistant strains in four out of 35 (11.4%) patients immunodeficient as a result of treatment for lymphoid or myeloid malignancy. Strains resistant to ACV were not found in organ transplant recipients or in immunocompetent patients.     

Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years' experience with acyclovir

An extensive clinical trial program combined with 5 years' postmarketing experience with valacyclovir provides evidence of favorable safety and efficacy in herpes simplex virus (HSV) management. Valacyclovir enhances acyclovir bioavailability compared with orally administered acyclovir. Long-term use of acyclovir for up to 10 years for HSV suppression is effective and well tolerated. Acyclovir is also approved for use in children, is available in some countries over the counter in cream formulation for herpes labialis, and has been monitored in over 1000 pregnancies. Safety monitoring data from clinical trials of valacyclovir, involving over 3000 immunocompetent and immunocompromised persons receiving long-term therapy for HSV suppression, were analyzed. Safety profiles of valacyclovir (相似文献   

Recurrent genital herpes and suppressive oral acyclovir therapy. Relation between clinical outcome and in-vitro drug sensitivity

To evaluate the association between in-vitro resistance of herpes simplex virus type 2 to acyclovir and breakthrough recurrences of herpes despite chronic suppressive therapy, we determined the in-vitro sensitivity of herpes simplex virus isolated before, during, and after therapy. One hundred eighty-three virus isolates from 107 patients were tested. Before therapy, the median amount of drug required to inhibit 50% of the virus in tissue culture (ID50) was 0.91 microgram/mL. The median ID50 after therapy was 0.99. Six isolates from patients with culture-positive breakthrough recurrences were evaluated. The median ID50 was 0.90 microgram/mL (range, 0.39 to 1.55). The development of breakthrough recurrences could not be correlated with infection with strains of herpes simplex virus type 2 that were resistant to acyclovir in vitro. Acyclovir-resistant strains are not commonly recovered from patients during acyclovir therapy, nor does there seem to be a high frequency of resistance after 4 months of chronic suppressive therapy.     

Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity?

Clinically acquired acyclovir resistance in herpes simplex has usually been associated with a deficiency in viral thymidine kinase, which, in turn, has been linked with attenuated virulence in animal models. Diminished pathogenicity in thymidine kinase-deficient isolates has been partly responsible for controversies about the clinical significance of antiviral resistance. We report on a series of resistant virus isolates from a patient who had severe, progressive esophagitis. These isolates had various thymidine kinase activities, ranging from 2.8% to 130% when compared with the activity of the isolate obtained before treatment; the resistant isolate 615 retained enzyme activity as well as neurovirulence in an encephalitis model. Plaque purification showed a heterogeneous mixture containing at least one acyclovir-resistant, foscarnet-resistant plaque isolate (615.8) fully able to phosphorylate acyclovir. The 3.3-kbp BamHI fragment containing most of the DNA polymerase gene from isolate 615.8 was purified and used to successfully transfer both acyclovir and foscarnet resistance. Acquisition of in-vitro acyclovir resistance was associated with progression of clinical disease, as well as with maintenance of pathogenicity in an animal model and at least one mutation in viral DNA polymerase. Patients with herpes simplex infections that progress during acyclovir therapy should be observed for acquisition of resistance in the setting of antiviral chemotherapy; future studies should also consider the presence of heterogeneous virus populations in such patients.     

Acyclovir sensitivity of sequential herpes simplex virus type 2 isolates from the genital mucosa of immunocompetent women

BACKGROUND: Despite widespread use of acyclovir, infection with acyclovir-resistant herpes simplex virus type 2 (HSV-2) remains uncommon. To understand the frequency and clinical significance of acyclovir-resistant isolates, we evaluated the in vitro acyclovir sensitivities of sequential isolates from 34 immunocompetent women. METHODS: HSV-2-seropositive women collected daily samples of genital secretions while receiving acyclovir or placebo, each for 10 weeks. In vitro acyclovir sensitivity testing was performed using the dye uptake assay; isolates for which the concentration of acyclovir that inhibited cytopathic effect by 50% (EC50) was > or = 3 microg/mL were defined as resistant. RESULTS: A total of 351 isolates from 26 women were tested (median, 10 isolates/woman [range, 3-45 isolates/woman]). The median EC50 was 0.91 microg/mL. Overall, 7 isolates (1.7%) from 6 women had EC50 values > or = 3 microg/mL. None of the women was receiving acyclovir when the acyclovir-resistant isolates were detected. Acyclovir-sensitive and acyclovir-resistant isolates were detected in samples collected on the same day from separate anatomic sites in 3 women. The acyclovir-resistant isolates were transient, because acyclovir-sensitive isolates were obtained before and after the acyclovir-resistant isolates from 5 women were detected. CONCLUSIONS: Among immunocompetent women, the finding of acyclovir-resistant HSV-2 isolates likely represents transient mucosal variants and does not predict treatment failure.     

Herpes simplex esophagitis in the immunocompetent patient: report of four cases and review.

Esophagitis due to herpes simplex virus is a well-recognized entity in immunocompromised patients but has only rarely been described in apparently immunocompetent hosts. We report four cases and review 27 additional cases identified in the English-language literature. Odynophagia, retrosternal chest pain, and fever are the most common symptoms. Single-contrast esophagography is insensitive and nonspecific, but double-contrast esophagography may be of more diagnostic value. Esophagoscopy with biopsy or collection of aspirate for cytologic examination and culture are required to make a definitive diagnosis. Patients are predominantly male, and most cases are associated with primary infection. Viral isolates were typed in 13 cases and were always type 1. Herpes simplex esophagitis in the immunocompetent patient is a self-limited infection; however, therapy with acyclovir may attenuate infection and hasten resolution of symptoms.     

Herpetic tracheobronchitis

Nine adult patients from three community teaching hospitals had bronchospasm unresponsive to standard therapy. Bronchoscopic, cytologic, histopathologic, and virologic studies confirmed that necrotizing and exudative tracheobronchitis was due to herpes simplex virus. No patient had a history of previous chronic lung disease; most were not immunocompromised. Three patients never had intubation during hospitalization. All patients were successfully treated with intravenous acyclovir. Herpetic tracheobronchitis may be a commoner clinical syndrome than generally assumed. In an elderly patient with unresolving acute bronchospasm, herpesvirus infection of the lower respiratory tract should be considered in the differential diagnosis. In the immunocompetent host, antiviral therapy can successfully treat herpesvirus respiratory infection, with reversal of clinical, virologic, and pathologic findings. A prompt and accurate diagnosis is crucial.     

Characterization of the DNA polymerase and thymidine kinase genesof herpes simplex virus isolates from AIDS patients in whom acyclovirand foscarnet therapy sequentially failed.

Herpes simplex virus (HSV) isolates were characterized from 8 AIDS patients in whom acyclovir and foscarnet therapy sequentially failed. The 6 postacyclovir (prefoscarnet) HSV isolates were resistant to acyclovir and susceptible to foscarnet. Of the 9 postfoscarnet isolates, 8 were foscarnet-resistant and acyclovir-susceptible, 1 was resistant to both drugs. Acyclovir- or foscarnet-resistant isolates retained susceptibility to cidofovir. The acyclovir-resistant isolates contained single-base substitutions or frameshift mutations in G or C homopolymer nucleotide repeats of the thymidine kinase gene. In contrast, the foscarnet-resistant strains contained single-base substitutions in conserved (II, III, or VI) or, more rarely, nonconserved (between I and VII) regions of the DNA polymerase (pol) gene. The single isolate exhibiting resistance to acyclovir and foscarnet contained mutations in both genes. In this study of clinical HSV isolates, DNA pol mutations conferring foscarnet resistance were not associated with decreased acyclovir or cidofovir susceptibility.     

Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation.

Fourteen cases of severe acyclovir-resistant herpes simplex virus type 1 (HSV-1) infection, 7 of which showed resistance to foscarnet, were diagnosed among 196 allogeneic stem cell transplant recipients within a 29-month period. Recipients of unrelated stem cell transplants were at higher risk. All patients received foscarnet; 8 subsequently received cidofovir. Strains were initially foscarnet-resistant in 3 patients and secondarily so in 4 patients. In vitro resistance to acyclovir or foscarnet was associated with clinical failure of these drugs; however, in vitro susceptibility to foscarnet was associated with complete response in only 5 of 7 patients. No strain from any of the 7 patients was resistant in vitro to cidofovir; however, only 3 of 7 patients achieved complete response. Therefore, acyclovir- and/or foscarnet-resistant HSV-1 infections after allogeneic stem cell transplantation have become a concern; current strategies need to be reassessed and new strategies must be evaluated in this setting.     

Frequency and significance of acyclovir-resistant herpes simplex virus isolated from marrow transplant patients receiving multiple courses of treatment with acyclovir

The sensitivity to acyclovir of virus isolates from 52 consecutive marrow transplant patients who received acyclovir for herpes simplex virus infections was studied in vitro. The median sensitivity of viruses obtained during first, second, third, and fourth recurrences was similar, and the median duration of virus positivity (three days) was the same for first and second treatment courses. However, acyclovir-resistant virus was recovered from one of 52 patients (1.9%) during the initial treatment course and from two of 22 patients (9.1%) treated for second recurrences. All three strains had reduced thymidine kinase activity. None caused severe infection. Three other patients remained virus-positive during treatment despite the isolation of acyclovir-sensitive virus. Although continuing surveillance is necessary, these data may suggest that acyclovir-resistant virus will not be the cause of significant clinical illness among immunosuppressed patients. In addition, not all instances of "resistance," defined by the persistence of virus during treatment, will be caused by virus strains that are resistant to acyclovir in vitro.     

HERPES SIMPLEX ESOPHAGITIS IN THE ELDERLY

Herpes simplex esophagitis (HSE) occurs mostly in immunocompromised patients and rarely in immunocompetent patients. We encountered an elderly patient, a biologically immunocompromised patient with HSE who had characteristic endoscopic features and responded to acyclovir therapy. An 82‐year‐old woman presented with high‐grade fever and epigastric discomfort for several days. A diagnosis of bacterial pneumonia was made based on imaging studies and cultures. Despite antibiotic treatment, epigastric discomfort persisted. Endoscopy revealed multiple exudative and circumscribed shallow ulcers with slightly raised edges in the mid‐distal esophagus. Esophageal biopsy specimens showed multinucleated giant cells with Cowdry type A intranuclear inclusion bodies in epithelial cells, which were positive for herpes simplex virus‐type 1 DNA by polymerase chain reaction. Because a diagnosis of HSE was made, she was treated with acyclovir, resulting in esophageal mucosal healing. In elderly patients with esophageal symptoms, HSE should be considered.     

Herpes Simplex Ulcerative Esophagitis in Healthy Children

Herpes simplex virus is a common cause of ulcerative esophagitis in the immunocompromised or debilitated host. Despite a high prevalence of primary and recurrent Herpes simplex virus infection in the general population, Herpes simplex virus esophagitis (HSVE) appears to be rare in the immunocompetent host. We report three cases of endoscopically-diagnosed HSVE in apparently immunocompetent children; the presentation was characterized by acute onset of fever, odynophagia, and dysphagia. In two cases, the diagnosis was confirmed histologically by identification of herpes viral inclusions and culture of the virus in the presence of inflammation. The third case was considered to have probable HSVE based on the presence of typical cold sore on his lip, typical endoscopic finding, histopathological evidence of inflammation in esophageal biopsies and positive serologic evidence of acute Herpes simplex virus infection. Two cases received an intravenous course of acyclovir and one had self-limited recovery. All three cases had normal immunological workup and excellent health on long-term follow-up.     

New treatments for genital herpes

Genital herpes is a sexually transmitted disease that has been widely investigated from both an epidemiological and a diagnostic viewpoint. Better knowledge of the disease has pointed to the important role of asymptomatic herpes simplex virus type 2 shedding as a major culprit for the spread of the virus in the world, the latest statistics showing that the incidence of genital herpes is constantly increasing. The reference compound for the treatment and prophylaxis of genital herpes is acyclovir. Recently, two drugs with better oral bioavailability, valaciclovir, the oral prodrug of acyclovir, and famciclovir, the oral prodrug of penciclovir, have been made available. Nevertheless, there is a need to develop additional approaches, to extend the therapeutic possibilities and to face the problem of emerging resistant viruses, mostly in immunocompromised patients. Therefore, efforts have been made in different directions including the exploration of new targets for antiviral chemotherapy, the use of immunomodulators and the development of specific vaccines.     

Acyclovir-resistant corneal HSV-1 isolates from patients with herpetic keratitis

The prevalence and molecular characteristics of isolates from 173 immunocompetent patients with herpetic keratitis (HK) who were infected with acyclovir (ACV)-resistant (ACV(R)) corneal herpes simplex virus (HSV)-1 was determined. Isolates from 11 (6.4%) of the patients were ACV(R), and 9 of these 11 patients were refractory to therapy with ACV; the ACV(R) isolates from 5 and 1 of these 9 patients were cross-resistant to gancyclovir and to both gancyclovir and foscarnet, respectively. Of the 11 ACV(R) isolates, 10 had, in the thymidine kinase gene, mutations that presumably conferred the ACV(R) phenotype. These data demonstrate a relatively high prevalence of corneal HSV-1 ACV(R) isolates in patients with HK, which emphasizes the need to monitor for ACV susceptibility in patients with HK who are refractory to therapy with ACV.     

Herpes simplex virus type 2 meningoencephalitis resistant to acyclovir in a patient with AIDS

A case is reported of relapsing fatal meningoencephalitis caused by a neurovirulent thymidine kinase-positive (TK+) type 2 herpes simplex virus (HSV) that developed thymidine kinase deficiency (TK-) during intravenous acyclovir therapy. A patient with AIDS was admitted for acyclovir treatment of a persistent perirectal herpetic ulcer. He subsequently developed meningoencephalitis. A TK+ type 2 HSV was isolated from a brain biopsy specimen. A progressive and fatal relapse occurred, and a TK- type 2 HSV was isolated from his cerebrospinal fluid. Restriction endonuclease analysis of viral DNA from perianal, brain, and cerebrospinal fluid isolates were similar, suggesting that they were the same viral strain. Animal virulence studies indicated significant cutaneous virulence in immunocompromised mice models for the TK- isolates. This case is notable because TK- HSV have, in the past, lacked neurovirulence and because acyclovir resistance developed during therapy and caused the patient's death.     

Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation

Oral acyclovir was found to be safe and effective for the prevention of herpes simplex virus reactivation after marrow transplantation in a double-blind, placebo-controlled trial. Acyclovir or placebo was administered to 49 patients for 5 weeks beginning 1 week before transplantation: 5 of 24 patients receiving acyclovir developed herpes simplex virus infection during prophylaxis, compared to 17 of 25 patients receiving placebo (p less than 0.01). The median time to first virus reactivation was significantly longer among patients receiving acyclovir (78 days versus 9 days after transplant, p = 0.006). The effect was even more pronounced when the analysis was adjusted for drug compliance: Among patients taking a minimum of 40% of their prescribed drug, acyclovir was 96% virologically effective and 100% clinically effective during the period of administration. Acyclovir use was also associated with significantly more rapid marrow engraftment in patients receiving methotrexate. No virus resistant to acyclovir was isolated. Oral acyclovir provides effective prophylaxis against reactivation of herpes simplex virus among severely immunosuppressed patients able to take orally administered drugs.     

Genetic characterization of thymidine kinase from acyclovir-resistant and -susceptible herpes simplex virus type 1 isolated from bone marrow transplant recipients

Emergence of acyclovir (Acy)-resistant herpes simplex virus (HSV) is a major concern in bone marrow transplant recipients. Phenotypic and genetic characterization of thymidine kinase (TK) was done for 7 Acy-susceptible and 11 Acy-resistant HSV-1 isolated from 11 patients. In total, 19 amino acid substitutions were detected that were not related to Acy resistance but to TK gene polymorphism, including 5 mutations that have not been previously reported. The Acy-resistant strain from 1 patient presented no TK gene mutation related to resistance. Five patients (45%) had isolates that harbored point mutations leading to amino acid substitutions that could be associated with Acy resistance. Of the 5 substitutions detected, 3 have not been previously reported (codons 51, 83, and 175). A nucleotide insertion or deletion was detected in resistant isolates from 5 patients (45%); these mutations are located in homopolymer repeats at codon 92 (1 subject) and at codon 146 (4 subjects).     

Surgical excision for recurrent herpes simplex virus 2 (HSV-2) anogenital infection in a patient with human immunodeficiency virus (HIV)

Recurrent anogenital herpes simplex virus infections are common in patients with human immunodeficiency virus (HIV), of whom approximately 5% develop resistance to acyclovir. We present a case of a 49-year-old man with HIV who had an 8-year history of recurrent left inguinal herpes simplex virus type 2 ulcerations. He initially responded to oral acyclovir, but developed resistance to acyclovir and eventually foscarnet. The lesion progressed to a large hypertrophic mass that required surgical excision, which led to resolution without recurrences. Our case highlights the importance of surgical excision as a treatment option in refractory herpes simplex virus anogenital infections.