An overview of sexually transmitted diseases. Part III ... - Dermatology

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410 Czelusta, Yen-Moore, and Tyring J AM ACAD DERMATOL SEPTEMBER 2000 chancroid, have been associated with an increased risk of acquiring and transmitting HIV. One estimation suggests that STDs increase the overall risk of acquiring HIV about 3 to 5 times. 3 Cross-sectional studies performed in Nairobi, Kenya have consistently found that HIV seropositivity was more common in persons with either a history or clinical evidence of genital ulcer disease, 4-7 and one prospective study from this same region showed an increased risk of seroconversion in patients with genital ulcer disease. 8 Similarly, Telzak et al 9 found that 2.9% of men with genital ulcer disease turned HIV-positive, whereas only 1% of men without genital ulcer disease seroconverted. Clearly, a relationship between genital ulcer disease and HIV transmission exists; subsequently, prevention of genital ulcer disease should decrease transmission of HIV. A Tanzanian study showed that communities that improved their recognition and treatment of STDs saw a decrease in the incidence of HIV infection in their population. 10 This is the first documented intervention involving treatment of STDs that was associated with a decrease in HIV incidence in a defined population. Thus, through the early recognition and treatment of all STDs, including genital ulcer disease, HIV transmission can be reduced. Numerous studies have isolated HIV from genital ulcer exudates. 11-14 Mechanisms by which genital ulcer disease appear to facilitate HIV transmission have been suggested. Disruption of the genital mucosa is associated with the recruitment of inflammatory cells such as CD4 + T lymphocytes and macrophages. The presence of these cells can facilitate transmission of HIV virions from HIV-infected persons to uninfected persons or provide additional targets for HIV entry in HIV-negative persons who are being exposed to the virus. 14-17 Studies implicating the specific agents of genital ulcer disease have focused mostly on genital herpes, syphilis, and chancroid. Several reports have shown an association between genital HSV lesions and the acquisition of HIV infection in the affected population. 4,9,18-23 Keet et al 23 showed in a prospective cohort that pre-existing herpes simplex virus type 2 (HSV-2) seropositivity was a predictor of HIV seroconversion. HIV virions have been shown in HSV ulcers, 24 and in one study HIV RNA was isolated from herpetic lesions on 67% of the days that lesions were present. 13 Similarly, arguments implicating syphilis and chancroid in the acquisition of HIV can be made. Two studies from Baltimore document strong associations between HIV seroconversion and either positive syphilis serology or a history of syphilis. 25,26 One cross-sectional study from Kenya found a similar association 5 ; however, the difficulty in making this association statistically significant may reflect the difficulty in identifying cases of syphilis with active genital ulcers during the study. 8 An outbreak of chancroid in Jackson, Mississippi showed a strong association between this infection and HIV seropositivity, 27 and most of the ulcers in an aforementioned Kenyan study were due to chancroid and were associated with increased HIV seropositivity. 6 Lymphogranuloma venereum and granuloma inguinale are rare diseases, and, as such, they have not been extensively studied in relation to HIV transmission. Granuloma inguinale has been associated with a significant number of HIV infections, 28 and its eradication (in an effort to prevent HIV transmission) has been suggested. 29 Clinical features and treatment Genital herpes. Genital herpes is the most common cause of genital ulceration worldwide, 30 and its association with HIV was noticed as early as 1981. 31 Although genital herpes is most commonly caused by HSV-2, an increasing number of cases are suspected to be caused by HSV-1. 1,32 In HIV-infected patients, genital herpes can result in severe and atypical clinical presentations, and treatment may require increased doses of antiviral medications. Suppressive therapy for HSV appears to significantly improve survival in HIV-positive patients. Clinically, HIV-infected patients may experience an increased number and size of lesions in both primary and reactivated HSV infections as compared with HIV-uninfected patients. 31,33,34 The vesicles and ulcers are more painful and heal slower than those experienced by an immunocompetent host. 35 As CD4 cell counts drop and immunosuppression worsens, recurrent outbreaks increase in frequency and severity. 36,37 Chronic HSV-2 ulcers of more than 1 month in duration are an AIDS-defining illness in HIV-infected patients. 38,39 Atypical HSV presentations occur relatively often in HIV-infected patients. Particularly severe lesions have been reported on patients’ lower backs, buttocks, or perianal regions, and these lesions may expand to 20 cm in diameter (Fig 1). 31,40 Such ulcers commonly become impetiginized and require intensive long-term therapy. 31 Several case reports describe HSV-2 presenting as hyperkeratotic verrucous lesions resembling condyloma in severely immunocompromised patients. 41-44 These masses can become large 41,43 and may represent concurrent HSV and cytomegalovirus infection. 44 A recent report describes a patient with a pseudotumor of the tongue that was discovered to be an atypical recurrence of HSV-2. 45 HSV may also cause esophagitis, hepatitis, pneumonitis, or life-threatening disseminated infections in AIDS patients. 46
J AM ACAD DERMATOL VOLUME 43, NUMBER 3 Acyclovir, valacyclovir, and famciclovir are recognized by the CDC as appropriate therapies for primary or recurrent genital herpes in the HIV-infected patient. 1 As in the immunocompetent patient, therapy should start as soon as possible, preferably during the prodromal period. Therapy is then continued until clinical resolution is obtained. 1 For acyclovir and famciclovir, increased dosages above those recommended for immunocompetent persons may be required. For example, whereas the recommended oral dose of acyclovir is either 400 mg 3 times per day or 200 mg 5 times per day, regimens of 400 mg given 5 times per day have been useful in immunocompromised patients. 1 Likewise, famciclovir 250 mg twice daily is recommended for suppression of genital herpes in the immunocompetent person, but 500 mg twice daily has been effective in decreasing both the rate of recurrences and the rate of subclinical shedding among HIV-seropositive persons. 47 When given at doses of 8 g per day to markedly immunocompromised persons for suppression of cytomegalovirus infections, valacyclovir was associated with either thrombotic thrombocytopenic purpura or the hemolytic uremic syndrome. 1,48,49 However, no cause-and-effect relationship was ascertained. When taken as a dose of 500 mg twice daily, valacyclovir appeared safe and effective for the suppression of genital HSV in HIV-seropositive persons and was superior to acyclovir 400 mg twice daily. 50 Therefore acyclovir, valacyclovir, and famciclovir all appear useful for treatment and suppression of HSV in immunocompromised persons. 47-55 Interestingly, acyclovir treatment of HSV infections in HIV-positive patients may offer a significant survival benefit. Eight randomized controlled trials, combined in a meta-analysis, showed that patients treated with acyclovir had a significant survival advantage compared with those who went untreated. 51 Two multicenter clinical trials noted that patients given acyclovir and zidovudine lived longer than those given only zidovudine. 56,57 These studies suggest that long-term suppressive acyclovir therapy prolongs survival in AIDS patients with extensive histories of HSV infections. The mechanism by which this occurs is unclear. Studies demonstrate that acute or reactivated HSV infection may stimulate HIV replication. 58-60 Furthermore, Mole et al 61 documented increased plasma HIV viral loads in HIV patients experiencing an outbreak of HSV. By reducing or attenuating the occurrences of HSV outbreaks, acyclovir therapy may help reduce these deleterious effects of the infections. Clearly, further investigation regarding this issue is required, as evidenced by the study of Gallant et al, 62 which found no asso- Czelusta, Yen-Moore, and Tyring 411 Fig 1. HIV-positive patient. Large suprapubic ulcer due to HSV type 2. ciation between survival and acyclovir use in HIVinfected patients. A preliminary report from the CDC noted that 6.4% of HSV isolates from 140 HIV-positive patients were resistant to acyclovir compared with less than 1% of isolates from immunocompetent persons. 63 Typically, resistance to acyclovir is also associated with resistance to the other thymidine kinase inhibitors. Resistance rates before the advent of these medicines appear similar to those currently seen in the population. Resistance does not appear to be increased or induced by long-term suppressive therapy with these medications. 64 In contrast, the increased HSV acyclovir-resistance rates seen in HIVpositive patients may reflect the increased replication of HSV in these patients; therefore resistance may actually be reduced by long-term suppressive thymidine kinase inhibitor therapy. 65 Resistance to acyclovir may be mediated by mutations in either the HSV thymidine kinase or HSV DNA polymerase genes with decreased substrate affinity or by decreased or absent production of the
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