The HIV epidemic has drastically altered the medical

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1 CONTINUING MEDICAL EDUCATION An overview of sexually transmitted diseases. Part III. Sexually transmitted diseases in HIV-infected patients Adam Czelusta, MD, a Angela Yen-Moore, MD, b Melody Van der Straten, MD, c Daniel Carrasco, MD, c and Stephen K. Tyring MD, PhD c Houston, Dallas, and Galveston, Texas The HIV epidemic has dramatically altered the field of sexually transmitted diseases (STDs). HIV infection is unique among sexually transmitted diseases because it can modify the clinical presentation and features of other STDs. Conversely, other STDs can affect the transmission of HIV. This review is the third part of a series that has provided a general overview of STDs. In this article, genital ulcer diseases (genital herpes, syphilis, chancroid, lymphogranuloma venereum, and granuloma inguinale), human papillomavirus infection (anogenital warts and subclinical infections), molluscum contagiosum, human herpesvirus 8 infection, viral hepatitis, and ectoparasitic infestations (scabies and pediculosis pubis) are discussed as they occur in HIV-infected hosts. Additional features as they relate to HIV-infected patients, such as epidemiology and transmission, are discussed when applicable. Learning objective: At the conclusion of this learning activity, participants should improve their understanding of sexually transmitted diseases in the HIV-infected host. (J Am Acad Dermatol 2000;43: ) The HIV epidemic has drastically altered the medical community s approach to sexually transmitted diseases (STDs). For generations, multiple STDs occurred in individual patients. However, not until HIV did these infections interact so significantly with each other. Clinically, HIV can alter the presentation or treatments of other STDs as in, for example, a case of coexistent HIV and scabies. Conversely, an increasing recognition of the ways in which STDs influence HIV transmission has underscored the importance of early detection and treatment of all STDs. In 1998, the Centers for Disease Control and Prevention (CDC) published Guidelines for the Treatment of Sexually Transmitted Diseases, 1 and in addition the CDC published recommendations for the prevention of HIV through early detection and treatment of other STDs. 2 From the Department of Dermatology at the University of Texas Houston Health Science Center and St Joseph Hospital, Houston a ; the Department of Dermatology at the University of Texas Southwestern Medical School and Veterans Affairs Hospital, Dallas b ; and the Departments of Dermatology, Microbiology & Immunology and Internal Medicine at the University of Texas Medical Branch, Galveston. c Reprint requests: Stephen K. Tyring, MD, PhD, Department of Dermatology, Route 1070, University of Texas Medical Branch, Galveston, TX styring@utmb.edu. 16/2/ doi: /mjd Abbreviations used: ASIL: CDC: CSF: CSIL: HAART: HBV: HCV: HHV: HPV: HSV: KS: MCV: STD: anal squamous intraepithelial lesion Centers for Disease Control and Prevention cerebrospinal fluid cervical squamous intraepithelial lesion highly active antiretroviral therapy hepatitis B virus hepatitis C virus human herpesvirus human papillomavirus herpes simplex virus Kaposi s sarcoma molluscum contagiosum virus sexually transmitted disease Given the predominantly cutaneous manifestations of many STDs, dermatologists are uniquely situated to diagnose and treat these diseases in HIV-infected patients. This article reviews the STDs that affect HIV patients, with particular emphasis on those issues most pertinent to dermatologists. GENITAL ULCER DISEASE Effect on HIV acquisition and transmission Each of the major genital ulcer diseases, genital herpes simplex virus (HSV) infections, syphilis, and 409

2 410 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 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 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 associ- ation 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 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 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 HSV may also cause esophagitis, hepatitis, pneumonitis, or life-threatening disseminated infections in AIDS patients. 46

3 J AM ACAD DERMATOL VOLUME 43, NUMBER 3 Czelusta, Yen-Moore, and Tyring 411 Fig 1. HIV-positive patient. Large suprapubic ulcer due to HSV type 2. 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 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 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 association 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

4 412 Czelusta, Yen-Moore, and Tyring J AM ACAD DERMATOL SEPTEMBER 2000 Fig 2. HIV-positive patient. Primary syphilis: perianal chancres. HSV thymidine kinase. 66 If resistance is suspected, HSV cultures and susceptibility testing are indicated. As such, the virus remains susceptible to foscarnet (which competitively blocks the pyrophosphate binding site of viral DNA polymerase) and cidofovir (which is a nucleotide analogue not dependent on viral thymidine kinase). 67 In cases of acyclovir resistance, intravenous foscarnet, 40 mg/kg of body weight every 8 hours, or topical cidofovir 1% applied to the lesions daily is suggested therapy from the CDC. 1 Foscarnet resistance has been reported, and this may make cidofovir the most viable option. 68,69 Regardless, these two medicines have important potential side effects. Foscarnet is nephrotoxic and can produce severe hypocalcemia, and in a phase I/II trial, topical cidofovir gel in concentrations of 3% and 5% was associated with local toxicity and delayed healing. 70 Syphilis. The interactions between syphilis and HIV gained widespread attention after a 1987 case series described HIV-infected patients whose syphilis infection was either refractory to appropriate thera- pies or displayed a rapid progression from primary syphilis to neurosyphilis. 71 Since this report, many investigators have studied the atypical features of syphilis in the setting of HIV disease, but the significance of these features remains unclear. Syphilis in the HIV patient appears to progress more rapidly through the clinical stages of syphilis, often will have an atypical clinical presentation, may have a refractory course after appropriate intramuscular penicillin, and may lead to unusual serologic test results (Fig 2). Numerous reports describe an accelerated progression through the syphilitic stages in HIV patients This progression may be related to level of immunosuppression; one study described HIV-infected patients initially presenting to physicians with undiagnosed secondary syphilis when their CD4 cell counts were less than 500 cells/mm Others reported an association between accelerated ulcerating syphilis (malignant syphilis) and advancing HIV disease. 76,77 An association between advancing HIV disease and progression to neurosyphilis has also been noted. 76 In contradiction to these findings, Dowell et al 78 found no association between HIV stage and syphilitic progression or relapse after treatment. Although the clinical presentation is commonly the same in the HIV-infected host as it is in the otherwise healthy host, unusual features may be seen. The primary stage of syphilis may consist of multiple or more extensive chancres in the HIV patient. 79 Secondary syphilis affecting the immunocompetent host can present in a multitude of fashions, and likewise, the HIV patient can exhibit a wide range of cutaneous manifestations in this stage. Several reports document that patients with HIV are more likely to progress to neurosyphilis in the first 2 years after diagnosis, often despite appropriate therapy ,80-85 Unusual manifestations of neurosyphilis 86 have been documented in HIV-infected patients, as have unusual gummatous lesions. 87 Furthermore, rapidly developing cases of ocular syphilis 82,88,89 and syphilitic aortitis 90 have been reported in the HIV-infected population. Encephalitis and arteritis are other potential atypical presentations of syphilis in the HIV-infected host. For most people with coinfections of HIV and syphilis, laboratory tests can be interpreted as they would in an immunocompetent person. 1 However, atypical serologic responses in HIV-infected patients with syphilis do occur. Most reports involve falsepositive responses to the two nontreponemal screening tests: the rapid plasma reagin card test and the Venereal Disease Research Laboratory (VDRL) test. This sort of false-positive test is termed a biologic false positive. Several studies document an increased rate of biologic false positives in HIVinfected patients when compared with controls

5 J AM ACAD DERMATOL VOLUME 43, NUMBER 3 Czelusta, Yen-Moore, and Tyring 413 Fig 3. HIV-positive patient. Biopsy-confirmed, seronegative secondary syphilis. Fig 4. Photomicrograph of biopsy specimen of secondary syphilis shows dense lichenoid infiltrate with abundant plasma cells and histiocytes. In addition, one study noted an increased rate of biologic false-positive findings among those HIV patients who acquired their disease through intravenous drug abuse and in those who were coinfected with the hepatitis B virus (HBV), as compared with homosexual HIV-positive controls. 94 Other abnormalities reported in serologic tests involve delayed titer responses after treatment of syphilis in HIV-infected patients. Typically, a patient s biologic titers are expected to drop 4-fold after treatment. In HIV-infected patients, studies have documented both a normal serologic titer response after syphilis

6 414 Czelusta, Yen-Moore, and Tyring J AM ACAD DERMATOL SEPTEMBER 2000 Table I. Recommended management for syphilis in HIV-infected patients 1 Stage Treatment Follow-up Primary, secondary, or early latent U intramuscular benzathine Clinical and serologic exams at 3, 6, 9, 12, syphilis penicillin G once and 24 mo Late latent syphilis or syphilis of U of intramuscular Clinical and serologic exams at 6, 12, 18, unknown duration benzathine penicillin G weekly for and 24 mo 3 wk Neurosyphilis or ocular syphilis* U of intravenous aqueous If CSF pleocytosis was initially present, crystalline penicillin G every 4 h for CSF exams every 6 mo (for up to 2 yr) days (or) intramuscular until this parameter returns to normal procaine penicillin U daily and oral probenicid 500 mg 4 times per day for days *Some experts recommend the addition of a single intramuscular dose of U of benzathine penicillin G to the conclusion of therapy in cases of neurosyphilis. treatment 75,95,96 and a delayed serologic titer response after syphilis treatment. 79,97-99 Finally, other reports describe cases of seronegative syphilis, accelerated loss of antibody reactivity after treatment, antibody production to decreased numbers of treponemal antigens, and the return of titers to nonreactive as immunosuppression advances (Fig 3) When serologic tests are inconsistent with clinical suspicion, other tests are indicated, such as lesional biopsy (Fig 4), dark-field microscopy, or direct fluorescent antibody staining of lesion material. 1 Still, the histologic features of a biopsied lesion may be altered in HIV-infected patients. 106 Progression to neurosyphilis despite appropriate therapy 71-73,80-85 has prompted some experts to recommend regular cerebrospinal fluid (CSF) examinations in HIV-infected patients when they are first diagnosed with either primary or secondary syphilis 1 in addition to current recommendations for CSF examinations in HIV-infected patients with late latent syphilis. * These experts recommend modification of treatment based on the CSF laboratory results. However, the CSF results in this population may be difficult to interpret, given the fact that HIV-positive patients have high rates of CSF abnormalities without syphilis infection. 1 General treatment guidelines as recommended by the CDC are outlined in Table I. In the management of patients with primary, secondary, or early latent syphilis, some specialists recommend supple- *Early latent syphilis is defined as those asymptomatic patients with titers suggestive of a current syphilis infection who, within the past year, acquired syphilis as reflected either by a documented seroconversion, indisputable symptoms of primary or secondary syphilis, or a sex partner who had primary, secondary, or early latent syphilis in the past year. Almost all other patients have either late latent syphilis or syphilis of unknown duration. mental antibiotic therapy in addition to that listed, and some experts recommend a CSF examination at 6 months after therapy in this group. 1 Those patients in this group who do not respond to treatment but whose CSF findings remain normal are treated with intramuscular benzathine penicillin G U weekly for 3 weeks. 1 If during the follow-up of any patient with late latent syphilis or syphilis of unknown duration, he or she develops symptoms or a rise in antibody titers, then CSF should be examined and retreatment administered appropriately. 1 In any HIV-infected patient with syphilis of any stage, penicillin desensitization is recommended if the patient is allergic to penicillin. 1 The management of syphilis in the HIVinfected host is a complex issue in which further study is clearly necessary. Chancroid. Chancroid is the most common cause of genital ulceration in Africa, 107 and outbreaks have been reported in Europe, Canada, and the United States. 108,109 Men are most commonly affected, and the typical clinical presentation is single or multiple soft-edged ulcers that are accompanied by inguinal adenopathy in 40% to 70% of cases. 110 Although relatively few studies have evaluated chancroid in HIVpositive patients, the clinical presentation appears to have only minor differences from HIV-negative patients, and the rate of treatment failures may be slightly increased in HIV-positive patients Ulcer size was consistently unaffected by HIV serostatus in all studies surveyed The only differences reported include a longer ulcer duration 113,114 and a greater number of ulcers at initial presentation 113 in HIV-positive patients. Nonetheless, atypical presentations can occur as evidenced by an HIV-positive patient from New York who had chancroid that presented as a chronic penile ulcer

7 J AM ACAD DERMATOL VOLUME 43, NUMBER 3 Czelusta, Yen-Moore, and Tyring 415 Fig 5. HIV-positive patient. Chancroid with typical kissing ulcers. accompanied by the development of ulcers on his legs and digits 115 (Fig 5). Two studies that evaluated histologic features of punch biopsy specimens from chancroid ulcers found that specimens from HIV-negative and -positive patients had no notable differences. 114,116 As in the immunocompetent host, diagnosis of chancroid in the HIV-positive patient is ideally made by culture of the causative organism, Haemophilus ducreyi, or, if this is not possible, by the presence of a clinical presentation typical of chancroid (ie, genital ulcers, usually painful, often multiple, with ragged edges and a base covered by a necrotic, yellow-gray exudate), and negative laboratory evaluations for both Treponema pallidum and HSV. 1 Several clinical trials report the efficacy of antibiotic therapy for chancroid on the basis of their subjects HIV serostatus , Studies of a single quinolone (fleroxacin) dose demonstrated that HIVpositive patients are cured of chancroid less frequently with these treatments than are HIV-negative patients. 117,118 However, despite the apparent consistent difference in response rates, none of these studies achieved statistical significance in this comparison. One study actually extended the quinolone therapy of HIV-negative patients to 5 days and compared it with single-dose therapy in HIV-positive patients. 112 Again, while the HIV-positive patients were cured at a lower rate than the HIV-negative patients, the difference was not statistically significant. Single-dose ceftriaxone and single-dose azithromycin demonstrate statistically significant failure rates in treating HIV-positive patients with chancroid when compared with HIV-negative patients. 119,120 Similarly, 7-day erythromycin therapy has shown significantly lower rates of curing chancroid infections in HIV-infected patients at 1 and 2 weeks after starting therapy, 113,114,120 but when these patients are observed to 3 weeks, the cure rates are not significantly different between HIV-positive and -negative patients. 114 Current CDC recommendations for treatment of chancroid in immunocompetent and HIV-infected patients are the same: oral azithromycin 1 g in a single dose, intramuscular ceftriaxone 250 mg in a single dose, oral ciprofloxacin 500 mg twice daily for 3 days, or oral erythromycin base 500 mg 4 times daily for 7 days. 1 In addition, the CDC notes that HIVpositive patients may require longer courses of therapy than those listed and that any of the regimens may fail. For this reason, close follow-up of HIV-positive chancroid patients with chancroid is essential. Granuloma inguinale. Granuloma inguinale, caused by Calymmatobacterium granulomatis, is endemic to the Caribbean, South America, South Africa, Southeast India, Papua New Guinea, and among the Aborigines in central Australia, 121 but it is extremely rare in North America. 122 It typically involves the genitalia with a chronic, destructive, beefy red, nontender granulomatous ulcer, and diagnosis is made in both HIV-positive and HIV-negative patients by visualizing characteristic intracytoplasmic Donovan bodies on microscopic evaluation of either tissue smears or biopsy specimens. 123 Few data are

8 416 Czelusta, Yen-Moore, and Tyring J AM ACAD DERMATOL SEPTEMBER 2000 Table II. Recommended therapy for granuloma inguinale and lymphogranuloma venereum 1 Infection Recommended therapy Alternative therapy Granuloma inguinale* Oral trimethoprim-sulfamethoxazole Oral ciprofloxacin 750 mg twice daily (or) double-strength tablet twice daily oral erythromycin base 500 mg 4 times (or) oral doxycycline 100 mg twice daily until lesions heal or for at least 3 wk daily until lesions heal or for at least 3 wk Lymphogranuloma venereum Aspiration or incision and drainage of Aspiration or incision and drainage of buboes if necessary and oral buboes if necessary and oral erythromycin doxycycline 100 mg twice daily for 3 wk base 500 mg 4 times daily for 3 wk *Gentamicin (1 mg/kg intravenously every 8 h) should be strongly considered in HIV-positive patients. available about the effects of HIV infection on this disease, but it appears that HIV-positive patients have ulcers that persist for a longer duration and may require more intensive antibiotic therapy as compared with HIV-negative patients. 124 A prospective case-control study of 50 patients (21 HIV-positive and 29 HIV-negative) in India demonstrated that, while the ulcer size and clinical presentations of HIV-positive and HIV-negative patients with granuloma inguinale were not significantly different, the mean duration to complete ulcer healing was significantly longer in HIV-positive patients (25.7 vs 16.8 days) and associated with greater tissue destruction. 124 A retrospective study of pregnant women with granuloma inguinale demonstrated no difference in pregnancy outcome between HIV-negative and HIV-positive patients. 125 Although extragenital dissemination of granuloma inguinale has been reported in association with HIV infection, 126 most case reports note the failure of traditional antibiotic treatments In one case, a patient who did not respond to therapy or relapsed after treatment with doxycycline, tetracycline, erythromycin, cephalexin, ceftriaxone, and trimethoprim-sulfamethoxazole finally responded to a combination of trimethoprimsulfamethoxazole and ofloxacin. 129 Currently the CDC recommends the same treatments for granuloma inguinale in HIV-negative and HIV-positive patients (Table II) with the note that gentamicin (1 mg/kg administered intravenously every 8 hours) should be strongly considered in HIVpositive patients. 1 Although granuloma inguinale is a relatively rare infection, O Farell, Windsor, and Becker 28 have recommended a unified public health effort for its eradication based on its ease of treatment and strong association with HIV transmission. LYMPHOGRANULOMA VENEREUM Lymphogranuloma venereum, caused by the L 1, L 2, and L 3 immunotypes of Chlamydia trachomatis, may present clinically as primary (papule), secondary (inguinal), and tertiary (rectal) lesions. 130,131 Lymphogranuloma venereum occurs most frequently in tropical countries and is rare in the United States. 132 In both HIV-positive and HIV-negative patients, diagnosis is made by a combination of clinical presentation and high chlamydial complement fixation antibody titers ( 1:64). No studies have been performed on patients with concomitant HIV infection and lymphogranuloma venereum, and remarkably little anecdotal evidence regarding clinical features and treatment has been published. Retrospective analysis of 27 cases of lymphogranuloma venereum seen in a Paris hospital found 6 cases of concomitant HIV and lymphogranuloma venereum infection. HIV appeared to have no effect on the clinical presentation in each of these 6 cases. 133 Similarly, Heaton et al 134 reported a case in which an HIV-positive pregnant woman had uncomplicated lymphogranuloma venereum. Nonetheless, an atypical presentation of Parinaud s oculoglandular syndrome (unilateral follicular conjunctivitis followed by enlargement of preauricular lymph nodes) with associated inguinal lymphadenopathy due to Chlamydia trachomatis immunotype L 2 has been reported. This patient responded well to surgical management, topical (ocular) cefazolin and gentamicin, and oral tetracycline. 135 The CDC recommends the same treatments for lymphogranuloma venereum in HIV-negative and HIV-positive patients (see Table II), with the note that disease duration may be prolonged in HIV-positive patients. 1 HUMAN PAPILLOMAVIRUS Subclinical genital human papillomavirus infections Subclinical genital human papillomavirus (HPV) can affect the cervix, vagina, vulva, penis, anus, or any other genital skin. 136 The same types can also

9 J AM ACAD DERMATOL VOLUME 43, NUMBER 3 Czelusta, Yen-Moore, and Tyring 417 Fig 6. HIV-positive patient. Oral condyloma acuminatum (ie, HPV type 6). infect the oral epithelium (Fig 6). The association between certain HPV types (eg, HPV types 16, 18, 31, and 45) and the development of dysplastic lesions in the cervix is well known. 137 The dysplastic lesion, termed a cervical squamous intraepithelial lesion (CSIL), occurs in the transformation zone along the squamocolumnar junction near the cervical os. CSIL is a precursor to cervical cancer. Similarly, the anal canal has a squamocolumnar junction and transformation zone that is affected by HPV infections. Specifically, the anal squamous intraepithelial lesion (ASIL) and invasive anal cancer appear to be associated with HPV infections, most notably HPV type 16 infections Genital HPV infections occur more commonly in HIV-infected men and women when compared with age-matched healthy control populations. 140, The lesions are more frequently diffuse, dysplastic, and subclinical in HIV patients, whereas control populations more commonly have condylomatous lesions and less commonly have subclinical and dysplastic lesions. 146 In addition, HIV-positive patients tend to be infected with more HPV types than control populations. 144, As CD4 cell count decreases, shedding of HPV and extent of disease appear to increase. 150,151 Given these clinical features, HPV replication and disease progression appear to be potentiated by HIV infections. 150,151 The mechanism behind this phenomena is unclear. HIV appears to influence gene transcription in HPV. 152,153 This may lead to a defect in the host s local immune defenses and, when accompanied by the systemic immunosuppression of HIV infection, may explain the increased severity of HPV infections observed in this setting. Regardless of the exact mechanism, it is clear that HIV-infected persons have higher rates of cervical, anal, and other genital cancers (Figs 7 and 8). Those persons most at risk are women with a history of abnormal Papanicolaou (pap) smears and men or women who participate in receptive anal intercourse or have a history of anal condyloma. Not surprisingly, anal cancer is currently the fourth most common reportable cancer among HIV-positive men 154 and is about 7 times more common in homosexual men with HIV than those who are HIV seronegative. Likewise, cervical cancer in an HIV patient is an AIDS-defining illness. 38 Clinically, full genital examinations in HIV-positive patients are extremely important. In women, the CDC recommends two pap smears and pelvic examinations during the first year after a diagnosis of HIV. 1 If the results are normal, yearly pap smears and pelvic examinations are indicated thereafter. 1 Abnormal results should be managed in consultation with a gynecologist, and current CDC recommendations regarding this issue are listed in the Interim Guidelines for Management of Abnormal Cervical Cytology. 155 Some research suggests that pap smears are an insensitive method to screen for cervical cancer in AIDS patients. 156 Subsequently, some experts support colposcopy as a regular screening tool in patients when they are initially diagnosed with HIV. 156 Nonetheless, a more recent study con-

10 418 Czelusta, Yen-Moore, and Tyring J AM ACAD DERMATOL SEPTEMBER 2000 Fig 7. HIV-positive patient. Adenocarcinoma of the anus. (Courtesy of Axel Hoke, MD, Novato, Calif.) Fig 8. HIV-positive patient. Verrucous carcinoma of the penis. Anogenital warts In the immunocompetent host anogenital warts are most commonly caused by HPV types 6 and 11. Studies have demonstrated that when compared with normal hosts, HIV-infected patients anogenital warts more frequently represent infections with multradicts these arguments by finding that pap smears are adequately sensitive in HIV-infected patients. 157 The CDC specifically states that colposcopy is not indicated as a regular screening tool for women with HIV. 1 There is no established method of screening for anal disease in HIV patients. Certainly inspection of the anal region is an important part of the evaluation. Often, dysplastic lesions are highlighted in white after the application of acetic acid. Moreover, ASIL may present as Bowen s disease of the perianal region. 151 This usually presents as pigmented papules or plaques. Condylomata acuminata may harbor dysplastic lesions, and anal cancer frequently originates from epithelium external to the anal verge. Anal cancer may present with perirectal bleeding, constipation, or tenesmus, and occasionally perirectal induration or erythema. For these reasons, external inspection is an important tool in the screening for anal disease in HIV-infected patients. Palefsky 151 supports an ASIL screening process that would test only the persons at highest risk for ASIL in whom treatment would be most appropriate. Specifically, the group would include HIV-positive men with a history of receptive anal intercourse who might benefit from aggressive treatment of premalignant lesions. Excluded from this group would be HIV-infected patients with a poor prognosis, as determined by either CD4 cell counts or HIV plasma RNA levels. In addition, HIV-negative men who participate in receptive anal intercourse or have a history of perianal or intra-anal condylomas may represent an appropriate group for screening. Palefsky recognizes that similar risk groups in women might be appropriate for screening but admits that too few studies have evaluated ASIL in women for sound scientific recommendations regarding this population.

11 J AM ACAD DERMATOL VOLUME 43, NUMBER 3 Czelusta, Yen-Moore, and Tyring 419 tiple HPV types, including oncogenic types. 146, Clinically, although HIV patients may have the same condylomas as normal persons, they may also have more extensive or even disseminated condylomas that may be relatively refractory to treatment. Furthermore, HIV-infected patients condylomas are associated with a significant risk of transformation into squamous cell carcinoma. Proper diagnosis is essential in these cases. Usually, anogenital warts are diagnosed by clinical acumen, but in HIV-infected patients biopsy should be considered before therapy so that appropriate diagnosis of dysplastic changes or squamous cell cancer can be ascertained early in the disease management process. 1,158 Treatment options available to the HIV-infected host do not differ from those available to the immunocompetent host and are discussed by Brown, Tyring, and Yen-Moore 161 in part II of this series on sexually transmitted diseases. Some clinicians advocate treatment by excision and electrodesiccation because of the poor response and frequent recurrences after topical treatments 162 and the association between HPV and cancer in this population. 158,163 Notwithstanding, some studies have evaluated nonsurgical treatment modalities for genital warts in the immunocompromised host. Podophyllotoxin has been studied for genital warts in HIV-positive Tanzanian patients, 164 but given the association of HPV in HIV-infected patients with squamous cell cancer, this therapy may be inappropriate for this population. 165 Interferon has been studied in this population, 166,167 as has imiquimod. 168 Although both have some efficacy in treating HPV infection in HIV patients, neither appears to be effective as monotherapy in completely clearing clinical lesions from the most severely immunocompromised patients. Use of imiquimod as adjunctive therapy after surgical or cytodestructive treatment of condyloma acuminatum does appear effective in HIV-seropositive and in other immunocompromised patients in terms of significant delays or prevention of recurrences. Cidofovir gel has been studied in a phase I/II trial of HIV-positive patients with condylomata acuminata and appears safe and potentially effective in this population. 169 Finally, Orlando et al 170 recently reported that relapse rates of condyloma in HIV-infected patients decreased with improved treatment of their underlying HIV infection with antiretroviral medication. Successful treatment of condylomas thus appears easier when a person s underlying HIV infection is better controlled. Clearly, treatment of HPV infections in HIV-infected patients is an issue that deserves further study. MOLLUSCUM CONTAGIOSUM The association between HIV infection and molluscum contagiosum was first noticed in 1983 through an autopsy study of 10 patients with AIDS. 171 Many reports of severe and atypical infections have surfaced, and in AIDS patients, the prevalence of molluscum contagiosum lesions ranges from 5% to 18% Dann and Tabibian 177 document molluscum contagiosum as one of the 3 most common reasons nondermatologists referred HIVinfected patients to a university-based immunosuppression skin clinic. In HIV-infected patients, molluscum contagiosum manifests itself most commonly when immune function has been dramatically reduced. Several studies document that molluscum contagiosum infection is a clinical sign of marked HIV progression and very low CD4 cell counts. 176, Specifically, when the CD4 cell count drops below 200/mm 3, the incidence of molluscum contagiosum appears to increase dramatically. 182 The unfortunate clinical correlate with this finding is that AIDS patients in whom molluscum contagiosum occurs have a poor prognosis, with a median survival time of 12 months in one study. 176 The presence of mollusca, however, does not appear to be an independent prognostic indicator after accounting for immunosuppression. Considerable debate remains as to whether the disease is caused by the reactivation of latent virus or whether it represents a recently acquired infection complicating patients progressive immunosuppression. The molluscum contagiosum virus commonly infects the general population. In an Australian study incorporating both HIV-positive and HIV-negative patients, 23% of the studied population had antibodies consistent with either a current or previous infection. 183 As the age of the studied population increased, so did the frequency of molluscum contagiosum antibodies. 183 These findings were believed to support the theory that mollusca in AIDS patients reflect the reactivation of a latent infection. 184 However, other studies contradict this supposition. Molecular research demonstrates that molluscum contagiosum viruses can be divided into two major types (designated MCV-1 and MCV-2) based upon restriction fragment cleavage patterns of the viruses genome. 185 Although it is not yet clear what clinical implications these types may have, the ratio of MCV-1 to MCV-2 in one Japanese population was found to be 13: MCV-1 occurred in highest frequency in children and adult women, whereas MCV- 2 occurred more frequently in adult men and patients with HIV. 186 This study was consistent with an earlier Australian study that showed HIV-positive patients were significantly more likely to be infected

12 420 Czelusta, Yen-Moore, and Tyring J AM ACAD DERMATOL SEPTEMBER 2000 Fig 9. HIV-positive patient. Molluscum contagiosum. by the MCV-2 virus than control patients. 187 The presence of MCV-2 in these patients may suggest that HIV-positive patients are manifesting an adult acquired infection because young and healthy patients are more commonly infected with MCV Clinically, molluscum contagiosum in HIV-positive persons appears to be transmitted in both sexual and nonsexual patterns. Lesions in healthy, sexually active adults commonly occur on the lower abdomen, inner thighs, and genitalia. HIV-infected patients may have lesions with this distribution, but lesions on the face and neck are more common (Fig 9). In one study of mostly homosexual HIV-positive men, 14 of 27 patients had lesions on the face and neck, whereas only 7 patients had lesions in locations associated with sexual transmission. 188 Ophthalmologists have described many cases of complicated eyelid mollusca in HIV-infected patients. 189,190 The lesions can become quite large (up to 2 cm) 191 and numerous (numbering up to the hundreds). 192 They are prone to autoinoculation, and in male patients, shaving the beard area has been reported to cause particularly severe infec- tions, with lesions encompassing their entire face. 184,193,194 Certainly, numerous lesions on a patient who is not yet diagnosed with HIV disease should prompt discussion of an HIV test. 195 Atypical molluscum contagiosum is common in HIV patients. Lesions may resemble comedones, abscesses, furuncles, condylomas, syringomas, keratoacanthomas, basal cell carcinomas, ecthyma, a sebaceous nevus of Jadassohn, and a cutaneous horn Importantly, disseminated fungal infections, specifically cryptococcosis, 202,203 Penicillium marneffei infection, and histoplasmosis, 204 are reported to clinically mimic molluscum contagiosum and should be included in the differential diagnosis for these patients. Because of the atypical nature of mollusca in the HIV-positive patient, diagnosis is in large part dependent on biopsy. Studies evaluating the microscopic and ultrastructural (electron microscopic) features of mollusca identified no major differences between samples taken from healthy patients as compared with patients with AIDS. 184,205 One possible exception to this might be that AIDS patients are less likely to have the inflammation and lymphocytic infiltrates associated with mollusca regression in their tissue. Interestingly, Smith et al 206 noted ultrastructural evidence for the presence of viral particles in immunocompetent skin adjacent to mollusca in HIV-infected patients. This was thought to help explain the high recurrence rates of lesions after treatment. 206,207 Molluscum contagiosum in HIV-positive patients is notoriously difficult to treat, 208 and unlike otherwise healthy hosts, there is no evidence that lesions spontaneously resolve. Most available evidence regarding the management of molluscum contagiosum in HIV-infected patients is anecdotal. Some potential treatment modalities are listed in Table III. Perhaps the most widely used methods are curettage 209 and cryosurgery. Tretinoin may serve as a helpful adjunct to any locally destructive therapy through daily applications. 192 Although this medicine does appear to diminish the appearance of new lesions and help eliminate old lesions, its use is limited by local irritation. Nonetheless, some researchers have reported success in AIDS patients by using nightly tretinoin as an adjunct to cantharidin (applied for up to 24 hours) on body and facial lesions followed by curettage for recalcitrant lesions. 192 One study using trichloroacetic acid peels yielded an average reduction in molluscum contagiosum lesion counts of 40.5% in 7 HIV-seropositive patients. 210 Intralesional 211 and systemic interferon 212 have been used with minimal to moderate success in treating AIDS patients with mollusca.

13 J AM ACAD DERMATOL VOLUME 43, NUMBER 3 Czelusta, Yen-Moore, and Tyring 421 Imiquimod has been studied in AIDS patients and certainly deserves consideration as a potential therapy. 213 Crude podophyllin extract might be a poor choice in an HIV-infected patient, given the predisposition for the development of cancer in these patients and podophyllin s link to the mutagens quercetin and kaempherol. 165 Cidofovir is a nucleotide analog that is used most commonly for the treatment of cytomegalovirus retinitis in AIDS patients. 214 Because of its activity against DNA viruses, it may be effective as either an intravenous or topical therapy for recalcitrant mollusca. A recent case report describes resolution of extensive facial lesions in 3 AIDS patients after beginning either intravenous or topical cidofovir therapy. 215 The authors of this report point out that the patients improvement most closely correlates with the use of cidofovir, but that it is impossible to exclude the possible immune system enhancing effects of antiretroviral therapy. At least 3 case reports describe the reduction in number of patients extensive mollusca after beginning potent combination antiretroviral treatment. 190,216,217 In one early case, a patient improved after initiation of zidovudine, 190 and in a more recent case, a patient improved after starting ritonavir. 216 This highlights an important point: every attempt should be made to optimize treatment of the HIV infection in patients afflicted with molluscum contagiosum because this will make treatment of the molluscum contagiosum infection more feasible. 218 HUMAN HERPESVIRUS 8 Human herpesvirus 8 (HHV-8), formerly known as Kaposi s sarcoma associated herpesvirus, was originally identified in Kaposi s sarcoma (KS) from AIDS patients. 221 It has been linked with all other forms of KS as well HHV-8 is also associated with a rare type of non-hodgkin s lymphoma, termed primary effusion lymphoma, 227,228 and with the plasma cell variant of Castleman s disease. 229,230 Furthermore, patients with HIV-associated KS are at a significantly greater risk for the development of non-hodgkin s lymphoma than their unaffected counterparts Schwartz 235 discussed the major issues relating to KS in a comprehensive review, and a similar discussion would be inappropriate here. Although the biology of HHV-8 is not entirely understood, it appears to be a sexually transmitted infection in the United States and Western Europe. Most cases of AIDS-associated KS have appeared in men who participated in promiscuous homosexual activities or had a history of STDs Furthermore, homosexual men whose partners live in areas of high HHV-8 prevalence, such as San Francisco or New York City, appear to be at an Table III. Treatment modalities for molluscum contagiosum Surgical Curettage 192,209 Electrodesiccation 192,218 Cryotherapy 219 Laser surgery 220 Cytodestructive Cantharadin 192 Iodine 192,218 Lactic acid 207 Phenol 192,207 Salicylic acid 207 Silver nitrate 192 Tretinoin 192 Trichloroacetic acid 210 Chemotherapeutic/antiviral Cidofovir 215 Interferon 211,212 Imiquimod 213 increased risk of acquiring the virus. Those persons who acquired HIV nonsexually (eg, hemophiliacs or intravenous drug abusers) have much lower rates of KS than those people who contracted HIV from homosexual or bisexual contacts. Many studies have focused on shedding of HHV-8 into semen with variable results. Most studies were unable to detect HHV-8 in either the semen of healthy patients or HIV patients, and detection of HHV-8 in the semen of patients with KS proved similarly difficult. However, two controversial studies reported high rates of HHV-8 in the semen of healthy patients. 250,251 Oral secretions in patients with KS appear to consistently shed HHV-8 virions. 252,253 Other suggested, but less investigated methods of transmission, include oral-anal contacts or exposure to feces Further investigation regarding this virus, its transmission, and its relationship to HIV is indicated. KS was originally described in HIV-seronegative persons (ie, classic KS). This form usually presents as purple plaques or papules on the lower extremities of elderly men of Mediterranean and/or Jewish decent. Patients with classic KS may die with this sarcoma but rarely die from it. In HIV-positive persons, however, a much wider variety of lesions (eg, patches, plaques, papules, nodules, ulcers) may appear anywhere on the skin or mucous membranes (Fig 10). Visceral involvement of KS is common in HIVseropositive persons and is associated with significant morbidity and mortality. KS has been much less common in the past 3 years since the availability of highly active antiretroviral therapy (HAART), which

14 422 Czelusta, Yen-Moore, and Tyring J AM ACAD DERMATOL SEPTEMBER 2000 Fig 10. HIV-positive patient. Kaposi s sarcoma. suggests that the development or resolution of KS is tightly linked to immune system control of HHV-8. HEPATITIS B VIRUS AND HEPATITIS C VIRUS Both hepatitis B virus and hepatitis C virus (HBV and HCV, respectively) commonly coinfect HIVseropositive persons. Sexual transmission of HBV, however, appears to be more frequent than with HCV. Discussion of the cutaneous manifestations of those viruses as well as their treatment and prophylaxis can be found in part II of this 3-part STD review. 161 The relationship between hepatitis C infection and sporadic porphyria cutanea tarda in the immunocompetent host is well documented. 257,258 Similarly, sporadic porphyria cutanea tarda can occur in the HIV-positive patient in association with HCV infection Some reports evaluate the potential of HIV infection as an independent cofactor in the development of porphyria cutanea tarda One recent report describes a case in which an HCV- and HIV-infected man whose porphyria cutanea tarda subsided 18 months after starting HAART for HIV infection. 259 Regardless, any patients presenting with porphria cutanea tarda should be evaluated for both HCV and HIV infection. ECTOPARASITIC INFESTATIONS Scabies Scabies occurs commonly in young adults who acquire it through sexual contact. In 1848, Danielssen and Boeck first described a particularly contagious and fulminant form of scabies in Norwegian patients immunosuppressed as a consequence of Hansen s disease. These patients infestations were characterized by thick, friable plaques. This form of scabies, Norwegian or crusted scabies, has emerged as yet another harbinger of HIV infection. Published reports of atypical and crusted scabies infestations in association with HIV infection have become increasingly frequent since the first such report in The defining clinical features of scabies in the HIV-positive patient are often determined by the degree of immunocompromise. 299 The typical presentation of a person infested with scabies (papules and burrows in the axillae, groin, or digital web spaces associated with complaints of nocturnal pruritus) occurs in HIV-infected patients with relatively normal immune function. However, as patients become progressively more immunosuppressed, the more contagious and fulminant forms of scabies become apparent ,271,272,282 This conversion from ordinary scabies to more severe and unusual infestations has been documented in individual patients who experience declines in their CD4 cell counts to below 200/mm ,272,274,285 Still, as noted by Portu et al, 295 although low CD4 cell counts may be more commonly associated with the severe and unusual forms of scabies, these fulminant infections can occur in early stages of HIV disease. These severe and unusual forms of scabies can be divided into two overlapping and broad categories:

15 J AM ACAD DERMATOL VOLUME 43, NUMBER 3 Czelusta, Yen-Moore, and Tyring 423 papular (also known as atypical or exaggerated) scabies and crusted (also known as Norwegian or hyperkeratotic) scabies. 285,299,300 The papular forms are characterized by generalized papules, each of which is topped by a scabietic burrow, which may be scaly. Patients complain of severe pruritus with this form. 266,273,277,285 The crusted forms are characterized by thick, friable, white-gray plaques, which may also be diffuse, but are commonly localized to individual body regions including the scalp, face, back, buttocks, nails, and feet (Fig 11). The plaques are often associated with fissuring that may be mild to severe Furthermore, as a patient s lesions become crusted, they tend to become less pruritic. The distinction between papular and crusted scabies is not mutually exclusive, and some reports document patients with lesions characteristic of both forms. 270,284 Infestations may be mistaken for eczema, psoriasis, contact dermatitis, drug reactions, seborrheic dermatitis, Darier s disease, or dermatophytosis. Scabies must be suspected in any HIV-infected person with an atypical or pruritic rash. Similarly, young patients with HIV risk factors in whom papular or crusted scabies develops without an apparent underlying cause should be suspected of having HIV infection. Skin scrapings are often diagnostic in crusted or papular scabies and may be taken from any nonexcoriated region or from underneath the nails; however, if scrapings are negative and clinical suspicion remains, a skin biopsy can be very helpful. 285,299,300 It must be noted that a key feature of crusted scabies infestations in the HIV-infected patient is an exceptionally high mite burden. Whereas an immunocompetent host is estimated to have 10 to 15 live female mites during an infestation, 301 individual crusts in crusted scabies may harbor thousands of mites. Furthermore, although the scabies mite has a limited life span (<30 minutes) off an ordinary human host, a shed crust that is filled with mites can serve as a food supply and protection, sustaining organisms for up to 1 week. 302 For this reason, scabies in HIV-infected patients can be particularly contagious. Numerous reports have documented nosocomial transmission from infected patients to other patients and hospital staff. 272,274,275,279,292,295 One case reported 72 infested contacts (health care workers and inpatients) after admission of an HIV-infected man with undiagnosed crusted scabies. 295 A question that often arises in these situations concerns the possibility of spreading HIV through transmitted mites. No cases have documented such a phenomena. Corbett et al 291 reported a case from London in which 14 of 16 exposed hospital staff members became symptomatic for scabies after working with a crusted Fig 11. HIV-positive patient. Norwegian (crusted) scabies. scabies patient while wearing gloves and plastic aprons to minimize skin-to-skin contact. 291 This event prompted the hospital to distinguish between crusted and ordinary scabies in their infection control guidelines. Additional precautions were taken with patients who had crusted scabies to include full gowns rather than aprons, prophylactic medical treatment of staff members inadvertently exposed to skinto-skin contact, and regular damp dustings of the patient s room to decrease environmental mites. With these changes, the hospital has since admitted and treated patients with crusted scabies without nosocomial transmission. 291 The CDC treatment recommendations for ordinary scabies in the HIV-infected patient is the same as for HIV-negative patients: 5% permethrin cream applied from the neck down (many clinicians also treat the head) and washed off after 8 to 14 hours accompanied by treatment of close personal and household contacts and appropriate decontamination of bedding and clothing. 1 Treatments may be repeated if the patient remains symptomatic. If repeated treatments fail, the patient may be getting

16 424 Czelusta, Yen-Moore, and Tyring J AM ACAD DERMATOL SEPTEMBER 2000 reinfected from other untreated personal contacts or from improper cleaning of bedding and clothing. The CDC recommendation for HIV-infected patients with crusted or papular scabies is for consultation with an expert. 1 Five percent permethrin cream is the best topical agent currently available for treatment of crusted or papular scabies. 300 Although topical lindane preparations have been used frequently in published reports, this medicine has the potential for serious neurotoxicity. In crusted scabies, deep fissures often enhance the systemic absorption of lindane resulting in potentially high serum concentrations of the neurotoxin. Furthermore, many HIVpositive patients have AIDS-related neurologic changes, which may predispose them to any neurotoxic effects. At least one death in an HIV-infected patient with scabies has been attributed to lindane. 290 For these reasons, permethrin is the preferred treatment in HIV-positive patients. 300 Taplin and Meinking, 300 among others, have recommended ivermectin as an oral alternative to topical therapies for the treatment of scabies. Several studies document the safety and efficacy of ivermectin in the treatment of scabies, including one such study that evaluated the medicine s effects on HIV-positive patients who were taking multiple medications including antiretrovirals and antifungals. 305 However, no reports have directly compared the efficacy of ivermectin with the currently recommended regimens (permethrin or lindane), and it is not yet approved by the FDA for this purpose. In the treatment of crusted scabies, it is also clear that patients benefit from keratolytic agents (eg, 6% salicylic acid) or, if possible, manual debridement. This serves to decrease the patient s mite load and to facilitate the penetration of topical medications. Some researchers support combined topical permethrin, keratolytics, and oral ivermectin as a potential regimen in the management of these patients. 298,300 It is believed that the combination of topical therapy and oral therapy maximizes the penetration of antiscabietic medications into the crusts. Therapy for the infestation in crusted or papular scabies needs to be persistent because the high mite burdens in these patients are difficult to eradicate. Special attention should be paid to the head and neck as well as underneath the fingernail. Skin scrapings should be collected often, and treatment continued until repeated scrapings yield no mites. Permethrin treatments may be needed 2 to 3 times per week for up to 6 weeks to eradicate the menace. A unique complication that accompanies crusted scabies is bacteremia. This is seen when the patients have severe fissuring associated with their crusts and has led to the patients death on several occasions. Streptococcal, 268 staphylococcal, 271 and Pseudomonas spp 274,284 have caused bacteremia in patients with crusted scabies, and antibiotic prophylaxis appropriate to the bacterial flora profile of the hospital is highly recommended in these cases to avoid this complication. 283,288,299,300 Pediculosis pubis Very little has been written about the effect that HIV infection has on infestation with Phthirus pubis. It appears that the ectoparasite behaves the same clinically regardless of HIV serostatus. The CDC recommends the same treatment for HIV-positive patients with pediculosis pubis as it does HIV-negative patients. 1 Permethrin 1% cream rinse applied for 10 minutes, lindane 1% shampoo applied for 4 minutes, or pyrethrins with piperonyl butoxide applied for 10 minutes are all appropriate therapies when accompanied by appropriate decontamination of bedding and clothing. Pediculosis of the eyes should be treated with an occlusive ophthalmic ointment twice daily for 10 days. In summary, STDs may enhance both the acquisition and the transmission of HIV. This relationship is especially true of STDs causing genital ulcers. STDs in HIV-seropositive persons may differ qualitatively or quantitatively, or both, in both clinical and laboratory parameters from STDs in immuncompetent persons. Such measures as education, which may lead to early recognition of the signs and symptoms of STDs, have the potential to positively affect the HIV epidemic. 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