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Case 1: Discussion

Background and Epidemiology

Herpes simplex virus (HSV) infections frequently occur in persons with HIV infection[1,2]. As part of the initial description of AIDS in the United States, investigators reported four immunosuppressed male patients who developed gradually enlarging perianal ulcers caused by HSV[3]. In subsequent years, clinicians observed more cases of these atypical chronic ulcerative HSV lesions involving HIV-infected patients with advanced immune suppression (CD4 count less than 100 cells/mm3)[4,5]; the presence of a chronic ulcerative HSV lesion for at least 1 month's duration was established as a category C AIDS-defining condition[6]. In the United States, approximately 70% of HIV-infected adults have serologic evidence of established infection with HSV-2 infection and 95% are seropositive for either HSV-1 or HSV-2[1].

Clinical Manifestations

Although HIV-infected persons infected with HSV can develop an array of manifestations, most patients remain asymptomatic. Among HIV-infected persons with HSV-2 infection, nearly all shed HSV-2 in the genital tract[2]. Symptomatic HSV disease, when it occurs, most often manifests as orolabial or genital lesions, with HSV-1 typically isolated from orolabial lesions and HSV-2 from genital lesions[1]. Patients with orolabial or genital HSV infection often have a sensory prodrome that precedes the onset of visible lesions. Once a visible lesion appears, it can evolve through several stages that may include vesicles, ulcers, and crusts. Among HIV-infected persons who do not have severe immune suppression, the clinical presentation of orolabial and genital HSV is usually similar to that seen in persons not infected with HIV. Patients with advanced immunosuppression, however, can develop chronic, extensive, deep ulcerated lesions. These chronic ulcerative lesions can appear anywhere on the body (Figure 1 and Figure 2 and Figure 3). Several reports have described patients who developed atypical ulcerative genital HSV lesions after starting highly active antiretroviral therapy, presumably caused by immune reconstitution[2,7]; these lesions may be difficult to treat, despite the absence of acyclovir resistance.

Diagnosis

A definitive diagnosis of HSV can be made by scraping a lesion with a Dacron swab and obtaining an FA and culture on the sample. Both FA and culture can distinguish HSV-1 from HSV-2. Because HSV is an intracellular virus, the diagnostic yield increases if the base of the lesion is scraped and an adequate number of cells are obtained. The use of a Dacron swab is preferred. The overall yield on lesions decreases as the lesion heals. Approximately 90% of positive HSV cultures will show growth by day 5. Recent studies have shown that HSV PCR of genital lesions has a significantly greater sensitivity than viral culture[2]. The use of a Tzanck preparation to detect cytologic changes consistent with a herpes virus infection provides low sensitivity and specificity and thus is not recommended. Serologic testing for HSV, using a type-specific glycoprotein G (IgG)-based assay, can provide useful information in persons presenting with new lesions and no prior history of HSV infection; in addition, this assay distinguishes HSV-1 from HSV-2 antibody[2,8]. Some experts now recommend performing HSV serologic testing in HIV-infected persons as part of the initial evaluation to help identify unrecognized or asymptomatic HSV-2 infection[2].

Therapy for Initial or Recurrent Infection

The following recommendations are based on the 2009 guidelines for prevention and treatment of opportunistic infections[1]. The treatment of orolabial lesions and genital HSV infection (initial or recurrent) should consist of a 5 to 14 day course of valacyclovir (Valtrex), famciclovir (Famvir), or acyclovir (Zovirax) (Figure 4)[1,8,9]. For patients with severe mucocutaneous HSV lesions, intravenous acyclovir is recommend for initial therapy, followed by oral therapy when the lesions start to resolve. The presence of a chronic ulcerative HSV lesion does not necessarily indicate resistance to acyclovir. The 2009 opportunistic infections guidelines do not address the management of moderately severe cutaneous lesions[1]; in this author's opinion, most of the moderately severe cutaneous lesions will respond well, albeit slowly, to oral therapy. Although most HSV lesions require only 5 to 14 days of therapy, treatment of moderate-to-severe chronic ulcerative HSV lesions usually requires at least 14 days and patients should have close follow-up. In general, these patient should receive therapy for HSV until the lesions have completely healed[10]. If the patient has received multiple courses of therapy for recurrent HSV infection, or is taking chronic HSV suppressive therapy when new lesions develop, greater consideration should be given to possible acyclovir-resistant HSV. Evaluation and treatment of acyclovir-resistant HSV infection is discussed in Case 2 in this Dermatologic Manifestations module.

Suppressive Therapy

Patients who have frequent or severe recurrences of HSV infections should be considered for suppressive therapy with valacyclovir, famciclovir, or acyclovir(Figure 4)[1,8,9,10,11]. Additional support for use of suppressive therapy in HIV-infected patients arose from studies that have shown HSV outbreaks can result in increased HIV transcription and increased genital and plasma HIV RNA levels[12,13]. These findings correspond with data that show certain HSV regulatory proteins (ICPO, ICP27 and VP16) can induce HIV replication and herpes simplex virions can increase HIV expression in macrophages[14]. For persons co-infected with HIV and HSV, most available data suggest HSV suppressive therapy has a favorable impact on genital and plasma HIV levels[15,16,17,18]. In a placebo-controlled trial that involved men in Peru with HIV and HSV co-infection, subjects who received chronic suppressive therapy with valacyclovir 500 mg bid had reduced rectal and plasma HIV RNA levels[16]. Similarly, co-infected women in Africa who received chronic suppressive therapy with valacyclovir 500 mg bid had reduced genital and plasma HIV RNA levels[17]. In one study that involved HSV suppressive therapy for HIV and HSV co-infected women in Africa on highly active antiretroviral therapy, the women had reduced genital shedding of HSV, but no significant decrease in plasma HIV RNA levels. Two large clinical trials investigated the impact of suppressive herpes therapy on HIV acquisition in HIV-negative, HSV-2 co-infected individuals, but found no benefit of suppressive therapy[19,20]. The impact of HSV suppressive therapy in preventing transmission of HIV from persons co-infected with HIV and HSV remains unknown.

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    Figure 1. Chronic Ulcerated HSV Lesions on Face

    Multiple large ulcerated HSV lesions on face resembling impetigo.


    Figure 1
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    Figure 2. Chronic Ulcerated HSV Lesions on Scrotum

    Multiple persistent small ulcerated HSV lesions on scrotum.


    Figure 2
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    Figure 3. HSV Lesion on Ear
    Figure 3
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    Figure 4. Recommendations for Episodic and Suppressive Therapy for HSV

    Abbreviations: bid = twice daily; tid = three times daily

    This table is based on recommendations from: Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.


    Figure 4