INTRODUCTION — Genital herpes simplex is a common sexually transmitted viral infection that is found worldwide . Most often genital herpes is secondary to herpes simplex virus type 2 (HSV-2), although HSV type 1 (HSV-1) has become more common than HSV-2 in high-income countries . Drug resistance to acyclovir and related drugs (eg, famciclovir or valacyclovir) is rare in immunocompetent hosts but is seen more commonly among immunocompromised hosts, including patients with HIV and transplant recipients.
This topic will review therapeutic options and strategies for prevention of drug-resistant infection in the patient with HIV. The epidemiology, natural history, clinical manifestations, and treatment of drug-sensitive HSV infection in the patient with HIV are discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus in patients with HIV" and "Treatment of genital herpes simplex virus type 2 in people living with HIV".)
MECHANISMS OF DRUG RESISTANCE — Acyclovir, famciclovir, and valacyclovir are antiviral agents within the nucleoside analog class. After intracellular uptake, acyclovir is converted to acyclovir monophosphate by virally-encoded thymidine kinase . The monophosphate derivative is subsequently converted by cellular enzymes to acyclovir triphosphate, which is a specific inhibitor of HSV DNA polymerase. HSV drug resistance to acyclovir confers broad cross-resistance to this entire class of antiviral agents. (See "Acyclovir: An overview", section on 'Mechanism of action'.)
●Reduced or absent thymidine kinase
●Altered thymidine kinase activity resulting in decreased acyclovir phosphorylation
●Altered viral DNA polymerase with decreased affinity for acyclovir triphosphate
Analysis of isolates from a series of 12 AIDS patients with resistant HSV-2 indicated marked thymidine kinase deficiency in each case; these strains were cross-resistant to ganciclovir, which also requires phosphorylation for antiviral activity, but were sensitive to foscarnet, which acts by directly inhibiting DNA polymerase . (See 'Management of drug-resistant ulcerative disease' below.)
PREVALENCE OF DRUG RESISTANCE
Epidemiologic studies of drug resistance — The prevalence of acyclovir drug resistance is rare among immunocompetent persons; epidemiologic surveys have documented acyclovir-resistant virus in less than 1 percent of immunocompetent individuals [6,7]. Acyclovir drug resistance is more prevalent among immunocompromised patients, including those with HIV [8-11]. In a study of 3602 patients seen in sexually transmitted disease (STD) clinics with genital ulcerative disease, 2088 had evidence of HSV-2 infection . Laboratory testing demonstrated that 3 of 1644 (0.18 percent) HIV-seronegative patients had evidence of HSV-2 drug resistance compared with 12 of 226 (5.3 percent) HIV-seropositive patients.
Clinical importance of drug resistance — The clinical importance of these laboratory findings is unclear since documentation of HSV-resistant strains from herpetic lesions does not necessarily predict failure of acyclovir therapy [4,12]. Most acyclovir-resistant viruses are TK-deficient strains, which appear less virulent in vitro than acyclovir-sensitive HSV. In addition, no person-to-person transmission of TK-deficient HSV stains has been documented . Rare reports of clinically important drug-resistant HSV disease have been documented in the immunocompetent host ; however, among normal hosts, TK-deficient strains usually spontaneously clear without treatment .
Clinically significant drug resistance to acyclovir has been infrequently reported in immunocompromised individuals. As an example, in one retrospective study from a single clinic in France, only 13 of 5295 (0.2 percent) patients with HIV were diagnosed with acyclovir-resistant HSV infection . Some experts suggest that the risk of drug resistance is higher in these patients because antiviral drug exposure is often prolonged due to slower healing and higher amounts of virus, increasing the risk of resistant mutants . Thus, the laboratory confirmation of acyclovir drug resistance is an important finding in a patient who has persistent or expanding HSV-related lesions, despite adequate antiviral therapy. Such a finding would support the need for alternative treatment, which is discussed below. (See 'Management of drug-resistant ulcerative disease' below.)
Risk factors — Among patients with HIV, risk factors for HSV drug resistance include a history of recurrent HSV infection, prior acyclovir exposure (particularly if the patient was treated with a suboptimal dose), history of a non-healing lesion, and low CD4 cell counts [16,17].
WHEN TO SUSPECT HSV-RELATED DRUG RESISTANCE — Drug-resistant infection should be suspected among patients with documented HSV who have minimal improvement, or an increase in lesion size, within 7 to 10 days of appropriately dosed antiviral therapy [18,19]. The dose and duration of antiviral therapy used to treat genital HSV infection in patients with HIV differs compared to those without HIV and is discussed in detail elsewhere. (See "Treatment of genital herpes simplex virus type 2 in people living with HIV", section on 'Dosing guidelines for antiviral therapy'.)
Unusual presentations of mucocutaneous HSV infection are more common in severely immunocompromised patients, such as patients with AIDS or bone marrow transplant recipients. However, atypical manifestations of HSV infection do not necessarily imply acyclovir drug resistance. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus in patients with HIV", section on 'Clinical manifestations'.)
DIAGNOSIS OF DRUG RESISTANCE — Drug resistance testing should only be performed in patients with clinical treatment failure in response to nucleoside analog therapy [20,21]. Routine baseline testing of all patients for acyclovir drug resistance is not recommended.
Phenotypic testing of viral isolates is used for assessing HSV resistance . The most widely recommended test is the plaque reduction assay: an IC50 ≥2 mcg/mL indicates that phenotypic resistance is present. A correlation has been established between in vitro acyclovir susceptibility and clinical response [4,22].
To perform phenotypic testing, an isolate from culture is needed; thus, a sample for viral culture must be obtained. Our institution sends samples to LabCorp (1-800-598-3345) for the "HSV 1/2 phenotyping for acyclovir drug resistance" test using a plaque reduction assay. Downsides of this assay include a long turn-around time (ie, 15 to 17 days). If there is any question regarding the underlying diagnosis, an additional sample can be obtained for polymerase chain reaction (PCR) testing, which is more sensitive than culture for documenting HSV infection. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Diagnosis'.)
Ninety-five percent of acyclovir-resistant strains have mutations in the viral thymidine kinase gene; the remaining 5 percent of acyclovir resistance is due to mutations in the viral DNA polymerase gene . Sequencing of these genes for genotypic diagnosis of acyclovir resistance is available for clinical use from at least one laboratory in the United States . With increasing identification of thymidine kinase polymorphisms and mutants associated with acyclovir drug resistance [23,25], there is hope that more widely available molecular assays for resistance testing will be developed in the future, as has been done for HIV and cytomegalovirus.
AVAILABLE AGENTS FOR ACYCLOVIR-RESISTANT HSV INFECTION — As noted above, acyclovir drug resistance infers cross-resistance to valacyclovir and famciclovir; there are no other oral therapeutic options to treat HSV. (See 'Mechanisms of drug resistance' above.)
Alternative intravenous and topical options include formulations of foscarnet and cidofovir, which target the viral DNA polymerase enzyme instead of thymidine kinase; continuous high-dose intravenous acyclovir; and imiquimod as discussed below . Although vidarabine has activity against herpes viruses , it is not effective in patients with acyclovir resistance, as discussed below.
Due to the toxicity of alternative therapies, it is recommended that an infectious disease physician co-manage patients with acyclovir-resistant herpes.
Foscarnet — Limited clinical data on the use of foscarnet for acyclovir-resistant HSV infection in persons with HIV infection are available from the early 1990s prior to the availability of potent antiretroviral therapy [17,28-30]; however, foscarnet remains the drug of choice for treatment of acyclovir-resistant herpes due to limited therapeutic options [19,31].
In a 1991 clinical trial involving 25 AIDS patients (CD4 <20 cells/mm3) with acyclovir-resistant mucocutaneous HSV infection, 14 patients were randomly assigned to antiviral therapy with foscarnet (40 mg/kg of body weight intravenously every eight hours) or vidarabine (15 mg/kg intravenous daily) . Severe neurologic toxicity was observed in three of six patients who received vidarabine, and as a result the Data Safety Monitoring Board recommended that the trial be stopped. Eleven additional patients were treated with open label foscarnet. All isolates were susceptible to foscarnet and vidarabine in vitro. Therapy was given for 10 days if all lesions had healed, or up to 42 days for patients with a partial response. The median number of lesions per patient was similar in both treatment arms at baseline (n = 2).
Lesions in the first eight patients assigned to foscarnet healed completely after 10 to 24 days of treatment. HSV lesions recurred in 17 of 25 patients within a median of 42 days of resolution . Patients who were retreated with foscarnet had clinical resolution of their recurrent ulcers. Of note, many of these viral isolates had improved in vitro sensitivity to acyclovir.
In contrast to acyclovir and its related compounds, foscarnet is associated with significant toxicity. Adverse effects related to foscarnet include renal toxicity and electrolyte abnormalities, such as hypomagnesemia, hypocalcemia and hypokalemia. Patient monitoring is discussed below and elsewhere. (See "Foscarnet: An overview", section on 'Toxicity'.)
Topical therapies — Topical therapies have been used with some reported success for acyclovir‐resistant HSV genital lesions that are refractory to foscarnet or in patients that cannot tolerate foscarnet [16,32].
Cidofovir — Cidofovir is a nucleotide analogue with in vitro activity against a broad range of herpesviruses, including thymidine-kinase deficient HSV-1 and HSV-2 isolates . In a double-blind clinical trial, 30 AIDS patients with acyclovir-resistant HSV infection (median of two lesions at baseline) were randomly assigned to topical cidofovir gel or placebo gel for five days . Ten of 20 patients receiving cidofovir attained complete lesion resolution or 50 percent improvement in clinical symptoms compared with none of the patients receiving placebo. The median time for a clinical response to therapy was 21 days. Application site reactions occurred in 25 percent of cidofovir-treated patients and 20 percent of placebo-treated patients.
The application of these data to clinical practice is mainly limited by the drug itself; topical cidofovir is not commercially available and must be compounded by the pharmacy. Thus, it is difficult to standardize dosing . Information on the use of intravenous cidofovir is found below. (See 'Intravenous cidofovir' below.)
Other therapies — Case reports describe the successful use of intralesional cidofovir  and topical 5% imiquimod [34-36]. Thalidomide has also been used as a salvage therapy in severe cases of acyclovir-resistant herpes [37,38].
MANAGEMENT OF DRUG-RESISTANT ULCERATIVE DISEASE
Intravenous acyclovir — Upon clinical suspicion of acyclovir-resistant HSV infection in patients receiving oral antiviral therapy, we suggest sending a culture for drug resistance testing and switching to intravenous acyclovir (10 mg/kg IV every 8 hours), which achieves higher serum concentrations than oral acyclovir . (See "Acyclovir: An overview", section on 'Basic pharmacokinetics'.)
Intravenous foscarnet — After the initiation of intravenous acyclovir, if there is no improvement in lesion size over approximately 5 to 10 days, or if the lesion progresses, the patient should be empirically treated with foscarnet (40 mg/kg intravenously every eight hours) while awaiting results of drug resistance testing. Foscarnet should be continued for a minimum of three weeks or until healing of all mucocutaneous ulcers.
During foscarnet therapy, patients should receive aggressive pre- and post-hydration to prevent nephrotoxicity and be carefully monitored twice weekly for electrolyte abnormalities, renal dysfunction, and bone marrow suppression. Elevations in creatinine can be seen within one to two weeks of foscarnet initiation. Concomitant nephrotoxic agents should be avoided, whenever possible.
Intravenous cidofovir — Rarely, resistance to foscarnet may occur; intravenous cidofovir (5 mg/kg/week) has been used with variable success in these cases, although there are limited data on the efficacy of intravenous cidofovir for the treatment of acyclovir-resistant HSV in the patient with HIV  and only scant data are available in other immunocompromised hosts [41-43].
Among patients with HIV, intravenous cidofovir has been used in patients with HIV and cytomegalovirus retinitis. However, intravenous administration of this drug is associated with severe toxicity, including neutropenia, nausea and vomiting, and nephrotoxicity; coadministration with oral probenecid and aggressive intravenous hydration (both pre- and post-dosing of cidofovir) are important adjunctive modalities to decrease the risk of adverse events.
Patients with intolerance to foscarnet — Therapeutic options for the patient who is intolerant to foscarnet, or who has severe toxicity on therapy, are limited:
●Continuous high-dose acyclovir (30 to 45 mg/kg/day) has been successfully utilized for acyclovir-resistant herpes in other immunocompromised patient populations (ie, hematopoietic stem cell transplant recipients) . There are no data on this approach in patients with HIV.
PATIENT MANAGEMENT AFTER RESOLUTION OF LESIONS
Antiviral suppression of genital HSV infection — Patients with recurrent drug-sensitive genital herpes can be usually managed with either chronic maintenance, or “suppressive therapy”, or with treatment of the episodes as they occur, known as “episodic therapy”. Acyclovir, famciclovir, or valacyclovir are all effective for reducing recurrences of HSV genital lesions among patients with drug-sensitive infection, both those with and without HIV. Of note, several of the recommended dosing regimens in the patient with HIV are higher for acyclovir, famciclovir, and valacyclovir compared with the HIV-seronegative patient. (See "Treatment of genital herpes simplex virus type 2 in people living with HIV", section on 'Treatment strategies for recurrent disease'.)
Unlike in many other infections, daily suppressive therapy with nucleoside analogues reduces, rather than increases, the risk of acyclovir resistance in immunocompromised patients. This concept was well illustrated in a retrospective study of three consecutive cohorts of hematopoietic stem-cell transplant recipients (n = 2049), which received acyclovir prophylaxis for varying durations of time after transplantation . Cohort 1 received acyclovir for 30 days; cohort 2 received acyclovir for one year and cohort 3 received acyclovir for an extended period (greater than one year). The two-year probability of HSV disease was highest in the one-month prophylaxis group compared with the one-year and extended acyclovir prophylaxis groups (32 percent versus 4 percent and none, respectively). In addition, acyclovir-resistant disease developed in more patients in the one-month prophylaxis group compared with the other acyclovir groups (10 patients versus 2 patients and none, respectively).
These data in an immunocompromised patient population suggest that long-term use of suppressive prophylactic acyclovir may prevent the emergence of drug-resistant HSV disease. This point is critical, because withholding anti-HSV therapy to preserve future therapeutic options is more likely to lead to emergence of resistant virus compared with antiviral suppression of HSV reactivation.
In patients who have a history of acyclovir-resistant herpes, future HSV recurrences can be caused by either acyclovir-sensitive or acyclovir-resistant strains . Because the risk of HSV reactivation persists, we suggest that patients with a history of acyclovir-resistant herpes be maintained on daily suppressive antiviral therapy with acyclovir or a related agent. If herpetic ulcers recur, repeat resistance testing is recommended to determine whether acyclovir-resistant HSV persists. Dosing recommendations for suppressive therapy are found elsewhere. (See "Treatment of genital herpes simplex virus type 2 in people living with HIV", section on 'Suppressive therapy'.)
Optimization of HIV therapy — It is important to note that the clinical trials of HSV treatment in the patient with acyclovir-resistant herpes infection were performed prior to the era of potent antiretroviral therapy (ART). Review of the patient's ART regimen, drug adherence, and drug-drug interactions is suggested to optimize HIV virologic suppression and CD4+ T-cell counts since the risk of drug-resistant herpes is related to immunosuppression. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "When to initiate antiretroviral therapy in persons with HIV".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sexually transmitted infections" and "Society guideline links: Opportunistic infections in adults and adolescents with HIV".)
SUMMARY AND RECOMMENDATIONS
●Genital herpes simplex is a common sexually transmitted viral infection that is found worldwide. Manifestations of HSV infection among immunosuppressed patients may be characterized by genital ulcers that are more frequent, severe, and of longer duration than in immunocompetent patient populations. (See 'Introduction' above.)
●The risk of drug resistance to acyclovir, or related members of the nucleoside analog class, is increased among immunocompromised compared with immunocompetent patients. (See 'Prevalence of drug resistance' above.)
●Other risk factors for HSV drug resistance include a history of recurrent HSV infection, prior acyclovir exposure, a history of a non-healing lesion, advanced immunosuppression, and intermittent exposure to or suboptimal dosing of acyclovir. (See 'Risk factors' above.)
●Drug resistance should be suspected in patients who do not have any improvement in lesion size after 7 to 14 days of antiviral therapy with oral acyclovir, or a related agent within this same class of drugs. A viral culture and a phenotypic assay for HSV drug resistance testing should be obtained and the patient should be switched to intravenous acyclovir (10 mg/kg IV every 8 hours). Lesion progression, despite intravenous therapy, would be suggestive of drug resistance. Clinicians should also be certain that the appropriate dosing regimens are being used. (See 'When to suspect HSV-related drug resistance' above.)
●We recommend foscarnet (40 mg/kg intravenously every eight hours) for treatment of suspected or documented drug-resistant HSV-associated ulcerative disease (Grade 1B). Foscarnet should be continued until full lesion resolution. Patients should be carefully monitored for renal toxicity, bone marrow suppression and electrolyte abnormalities twice weekly. (See 'Management of drug-resistant ulcerative disease' above.)
●In patients who have a history of acyclovir-resistant herpes, future HSV recurrences can be related to either acyclovir-sensitive or acyclovir-resistant strains. Daily suppressive therapy with nucleoside analogues reduces, rather than increases, the risk of acyclovir resistance in immunocompromised patients. (See 'Management of drug-resistant ulcerative disease' above.)
●Because the risk of HSV reactivation persists, we suggest that patients with a history of acyclovir-resistant herpes be maintained on chronic suppressive antiviral therapy with acyclovir or a related agent (Grade 2C).
●Scrutiny of the patient’s antiretroviral therapy regimen, drug adherence, and drug-drug interactions is suggested to optimize CD4+ T-cell counts since the risk of drug-resistant herpes is related to immunosuppression. (See 'Patient management after resolution of lesions' above.)
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