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Infections with human herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are common, with a seroprevalence of HSV-1 among adults of approximately 60% and a seroprevalence of HSV-2 among persons aged ≥12 years in the United States of 17% (731Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006;296:964-73.). Approximately 70% of HIV-infected persons are HSV-2 seropositive and 95% are seropositive for either HSV-1 or HSV-2 (732Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004;35:435-45.). In most HSV-infected persons, HSV infections are unrecognized clinically. However, regardless of the clinical severity of infection, reactivation on mucosal surfaces occurs intermittently and can result in transmission. HSV-2 is a risk factor for HIV acquisition, and HSV-2 reactivation results in increases in HIV RNA levels in coinfected patients.

Orolabial herpes is the most common manifestation of HSV-1 infection. Classic manifestations include a sensory prodrome in the affected area, rapidly followed by the evolution of lesions from papule to vesicle, ulcer, and crust stages on the lips. The course of illness in untreated subjects is 7-10 days. Lesions recur 1-12 times per year and can be triggered by sunlight or physiologic stress.

Genital herpes is the most common manifestation of HSV-2 infection. Genital mucosal or skin lesions are similar to external orolabial lesions in appearance and evolution. Local symptoms might include a sensory prodrome consisting of pain and pruritis. Ulcerative lesions are usually the only stage observed on mucosal surfaces. Mucosal disease is occasionally accompanied by dysuria or vaginal or urethral discharge; inguinal lymphadenopathy, particularly in primary infection, is common with genital herpes (733Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med 1983;98:958-72.). These classic manifestations occur in certain patients, but most persons with genital herpes have mild and atypical lesions that are not brought to medical attention and that cannot be diagnosed by physical examination. In profoundly immunocompromised patients, extensive, deep, nonhealing ulcerations might occur. These lesions have been reported most often in those with CD4⁺ counts of <100 cells/µL and also might be more commonly associated with acyclovir-resistant virus (734Safrin S, Elbeik T, Phan L, et al. Correlation between response to acyclovir and foscarnet therapy and in vitro susceptibility result for isolates of herpes simplex virus from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1994;38:1246-50.).

The episodes of genital HSV-1 infection are indistinguishable from genital HSV-2 infection but genital HSV-1 infection recurs less frequently than genital HSV-2 infection.

Nonmucosal HSV infections, such as HSV keratitis, HSV encephalitis, HSV hepatitis, and herpetic whitlow, are similar in presentation to those manifestations observed in HIV-seronegative persons; disseminated HSV infection is rare. HSV retinitis manifests as acute retinal necrosis (ARN) and can lead rapidly to loss of vision.

Because mucosal HSV infections cannot be diagnosed accurately without laboratory confirmation, especially in HIV-seropositive patients, a laboratory diagnosis should be pursued in all cases (529CDC. Workowski KA, Berman SM: Sexually transmitted diseases treatment guidelines. MMWR 2006;55(No. RR-11).). Viral culture, HSV DNA PCR, and HSV antigen detection are available methods for diagnosis of mucocutaneous HSV lesions caused by HSV. PCR is the most sensitive method, but is not widely available. The virus detected in genital lesions should be typed, because HSV-1 recurs less frequently than HSV-2 in the genital area. Type-specific serologic assays are commercially available and can be used in asymptomatic persons or those with atypical lesions. Because of the poor sensitivity and specificity of clinical diagnosis, extensive interactions between HIV and HSV-2, and the availability of effective therapy for HSV-2, routine type-specific serologic testing for HSV-2 should be considered in persons who seek HIV care. Diagnosis of HSV-2 should be accompanied by counseling that discusses the risk for transmission of infection to sex partners. Guidelines for counseling are provided in the 2006 CDC STD treatment guidelines (http://www.cdc.gov/std/treatment).

The majority of HIV-infected persons have HSV-1 and -2 infections. However, prevention of acquisition of HSV is important for those who are uninfected. HSV-2-seronegative HIV-infected persons should ask their partners to be tested using type-specific serology before initiating sexual activity, because disclosure of HSV-2 in heterosexual HSV-2-discordant couples was associated with reduced risk for transmission of HSV-2 (BII) (735Wald A, Krantz E, Selke S, Lairson E, Morrow RA. Zeh J: Knowledge of partners' genital herpes protects against herpes simplex virus type 2 acquisition. J Infect Dis 2006;194:42-52.). Consistent use of latex condoms reduced HSV-2 acquisition from women to men and from men to women, and their use should be encouraged for prevention of transmission of HSV-2 and other sexually transmitted pathogens (AII) (736Wald A, Langenberg AG, Krantz E, et al. The relationship between condom use and herpes simplex virus acquisition. Ann Intern Med 2005;143:707-13.). HIV-infected persons should specifically avoid sexual contact when their partners have overt (genital or orolabial) herpetic lesions (AII). However, sexual transmission of HSV can occur during asymptomatic shedding. The use of suppressive antiviral therapy (valacyclovir 500 mg once daily) in persons with genital herpes reduced HSV-2 transmission to susceptible heterosexual partners by 50% (737Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350:11-20.); the effectiveness of this approach in reducing HSV-2 transmission from HIV-seropositive persons or to HIV-seropositive persons has not been evaluated.

The dose, duration, and efficacy of antiviral prophylaxis after exposure to HSV have not been evaluated.

Patients with HSV infections can be treated with episodic therapy when lesions occur or with daily therapy to prevent recurrences. The management of genital HSV-2 in HIV-infected persons should include several factors, including frequency and severity of HSV recurrences, the risk for HSV-2 transmission to susceptible partners, and the potential for interactions between HIV and HSV-2 that might result in increased HIV in plasma and genital secretions. Treatment for individual recurrences does not influence the natural history of genital HSV-2 infection and does not reduce the risk for HSV-2 transmission to sex partners, a major concern of persons with genital herpes.

Patients with orolabial lesions can be treated with oral valacyclovir, famciclovir, or acyclovir for 5-10 days (AII). Severe mucocutaneous HSV lesions respond best to initial treatment with IV acyclovir (AII) (734Safrin S, Elbeik T, Phan L, et al. Correlation between response to acyclovir and foscarnet therapy and in vitro susceptibility result for isolates of herpes simplex virus from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1994;38:1246-50., 738Meyers JD, Wade JC, Mitchell CD, et al. Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host. Am J Med 1982;73:229-35.). Patients may be switched to oral therapy after the lesions have begun to regress. Therapy should be continued until the lesions have completely healed. Genital HSV infection should be treated with oral valacyclovir, famciclovir, or acyclovir for 5-14 days (AI). Short-course therapy (1, 2, or 3 days) should not be used in patients with HIV infection.

Acyclovir, valacyclovir, and famciclovir are occasionally associated with nausea or headache. No laboratory monitoring is needed in patients receiving episodic or suppressive therapy unless the patient has substantial renal impairment. For patients receiving high-dose IV acyclovir, monitoring of renal function and dose adjustment as necessary are recommended at initiation of treatment and once or twice weekly for the duration of treatment. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome has been reported among HIV-infected patients treated with high-dose (8 grams/day) valacyclovir but has not been reported at doses used for therapy of HSV infection (742Bell WR, Chulay JD, J.E. F. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine (Baltimore) 1997;76:369-80.).

Cutaneous lesions that are atypical and occasionally recalcitrant to therapy have been reported in persons initiating ART and have been attributed to IRIS

Treatment failure related to resistance to anti-HSV drugs should be suspected if lesions do not begin to resolve within 7-10 days after initiation of therapy. Among immunocompromised patients with suspected acyclovir-resistant HSV, viral culture of the lesion should be obtained and, if virus is isolated, susceptibility testing performed to confirm drug resistance (AII) (743Balfour HH, Jr. Antiviral drugs. N Engl J Med 1999;340:1255-68.).

The treatment of choice for acyclovir-resistant HSV is IV foscarnet (AI) (744Safrin S, Crumpacker C, Chatis P, et al. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. N Engl J Med 1991;325:551-5., 745Levin MJ, Bacon TH, Leary JJ. Resistance of herpes simplex virus infections to nucleoside analogues in HIV-infected patients. Clin Infect Dis 2004;39(Suppl 5):S248-57.). Topical trifluridine, cidofovir, and imiquimod also have been used successfully for lesions on external surfaces, although prolonged application for 21-28 days or longer might be required (CIII).

Most recurrences of genital herpes can be prevented using daily anti-HSV therapy, and this is recommended for persons who have frequent or severe recurrences (AI) (739DeJesus E, Wald A, Schacker TW, et al. Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis 2003;188:1009-16.). The option for suppressive therapy should be discussed with every HSV-2-infected patient. Suppressive therapy with oral acyclovir, valacyclovir, or famciclovir is effective in preventing recurrences (AI) (739DeJesus E, Wald A, Schacker TW, et al. Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis 2003;188:1009-16., 740Schacker T, Hu HL, Koelle DM, et al. Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons: a double-blind, placebo-controlled trial. Ann Intern Med 1998;128:21-8., 741Conant MA, Schacker TW, Murphy RL, Gold J, Crutchfield LT. Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Int J STD AIDS 2002;13:12-21.). Suppressive therapy with valacyclovir should be 500 mg twice daily in HIV-infected persons (AI), or twice-daily regimens with acyclovir or famciclovir should be used. Daily anti-HSV suppressive therapy in HIV-infected persons also results in a decrease in HIV concentration in plasma and anal and genital secretions. Whether this regimen results in clinical benefit or decreased infectiousness is not known.

HIV-infected patients receiving ART who have immune reconstitution often experience improvement in the frequency and severity of their clinical episodes of genital herpes. However, immune reconstitution does not reduce the frequency of genital HSV shedding.

Diagnosis of mucocutaneous HSV infections is the same for pregnant women as for nonpregnant women. Episodic therapy for first-episode HSV disease and for recurrences can be offered during pregnancy, but suppressive therapy is not used routinely. Visceral disease is more likely to occur during pregnancy and can be fatal. Acyclovir is the antiviral drug with the most reported experience in pregnancy and appears to be safe (746Stone KM, Reiff-Eldridge R, White AD, et al. Pregnancy outcomes following systemic prenatal acyclovir exposure: conclusions from the international acyclovir pregnancy registry, 1984-1999. Birth Defects Res A Clin Mol Teratol 2004;70:201-7.); therefore, acyclovir is the first choice for therapy of HSV infections in pregnancy (AIII).

An additional concern with HSV during pregnancy is the potential for HSV transmission to the fetus and neonate. The rate of HSV transmission to the newborn in HSV-2-seropositive pregnant women is low, unless the pregnant woman has acquired genital HSV in late pregnancy. The predominant risk for HSV transmission is maternal genital shedding of HSV at delivery. Cesarean delivery is recommended for women with a genital herpes prodrome or visible HSV genital lesions at the onset of labor (BII) (724). Maternal genital herpes is a risk factor for perinatal mother-to-child HIV transmission (747Chen KT, Seg M, Lumey LH, et al. Genital herpes simplex virus infection and perinatal transmission of human immunodeficiency virus. Obstet Gynecol 2005;106:1341-8.). Whether HSV suppression reduces the risk for HIV transmission during pregnancy, birth, or breastfeeding is unknown.

Use of acyclovir in late pregnancy suppresses genital herpes outbreaks and reduces the need for Cesarean delivery for recurrent HSV in HIV-seronegative women (748Sheffield JS, Hollier LM, Hill JB, Stuart GS, Wendel GD. Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review. Obstet Gynecol 2003;102:1396-403.) and is likely to have similar efficacy in HIV-seropositive women (BII). However, the use of acyclovir in HIV-infected pregnant women to reduce the risk for intrapartum HIV and HSV transmission to the neonate has not been evaluated.