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by Helmut Schoefer, Dana Sachs, Falk Ochsendorf

Since 1981, when the first reports about AIDS were published in themedical literature, skin and mucocutaneous diseases have played an important role in the clinical diagnosis of acquired immunodeficiency. Kaposi's sarcoma in young homosexual men was the clinical manifestation of AIDS (Friedman-Kien 1981, 1990). Additionally, opportunistic infections of the skin and oral cavity such as herpes simplex and candidiasis were noted to be clinical markers of acquired immunodeficiency (Gottlieb 1981, Siegal 1981). In the early years of HIV infection, a broad spectrum of common cutaneous infections was noted in patients due to viruses, bacteria, fungi, protozoa, and parasites as well as many unusual manifestations of common dermatoses (Friedman-Kien 1989, Farthing 1989, Schöfer 1990, Schöfer 1991, Berger 1997).

The alterations of the cell-mediated immune system enable organisms considered to be non-pathogens to penetrate into the tissue and cause infections. Such opportunistic infections, as well as any other infections in the immunodeficient host, sometimes behave aggressively leading to a life-threatening clinical course.

The most frequent skin diseases documented in a prospective long-term study in HIV-infected patients at the Department of Dermatology and Venereology, University Hospital, Frankfurt/M, Germany, between 1983 and 2004, are summarized in Table 1.

Differences in the prevalence and incidence of mucocutaneous disease between countries may be attributable to climate, endemic diseases, hygienic standards and the availability of specialized medical facilities and drugs, as well as social, economic and cultural factors. The risk groups observed - homosexual men, IVDA, heterosexuals, and children - play an important role in the incidence and prevalence of HIV-associated mucocutaneous diseases.

Among sexually transmitted diseases, chancroid is an important indicator of the spread of the HIV epidemic in tropical and subtropical regions; whereas in Europe and North America, herpes simplex infections and a resurgence of syphilis in homosexual men are more important indicators. Since 2003, there has been increased reporting of lymphogranuloma venereum, an STD caused by Chlamydia trachomatis (L1-3), in homosexual men in the Netherlands, France and several big cities in Germany (Hamburg, Berlin) . It is suspected that the resurgence of STDs is due to the changing sexual behavior of homosexual men during the past 5 to 7 years. Fear of acquiring HIV infection by unsafe sexual practices has lessened as patients live longer, healthier lives on HAART therapy. There may be a sense among patients that HIV infection no longer confers a death sentence because HAART decreases viral loads resulting in fewer diseases. In addition, many men are not aware of the risk of co- infection through orogenital contact with other STDs such as syphilis. There is an increasing incidence of oral primary chancres.

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Table 1: Frequency of skin diseases No. patients % of all HIV patients Oral candidiasis 636 30% Seborrheic dermatitis 619 28% Xeroderma 600 28% Tinea 502 23% Folliculitis 492 23% Syphilis (active/seropositive) 485 23% Kaposi's sarcoma 460 21% Pruritus 436 20% Genital warts 368 17% Candida infections, others 355 16% Drug eruptions 349 16% Herpes simplex genitoanalis 349 16% Herpes zoster 345 16% Gonorrhea (active/history) 340 16% Bacterial infections 315 15% Mollusca contagiosa 301 14% Warts (HPV) 278 13% Herpes simplex labialis 214 10% Oral hairy leukoplakia 188 9% Hair loss 135 6% Psoriasis 117 5% Basal cell carcinoma (BCC) 25 1.2% Squamous cell carcinoma (SCC) 23 1.1% Malignant melanoma 9 0.4% Total number of patients 1982 - 2000 2149 100% Notice: The frequency of skin diseases listed here mirrors the clinical symptoms of 2149 HIV-infected patients, who visited the Frankfurt University Hospital between 1982 and 2000 because of skin problems. Most of these patients were referred with a known HIV infection. Others were detected to be HIV-positive by their dermatological symptoms, which were interpreted as clinical markers of severe acquired immunodeficiency and led to HIV antibody testing. The majority of these patients (75 %) was seen in the pre-HAART era (between 1982-1996). Since 1996, more than 80 % of the patients living with HIV/AIDS in Frankfurt/M. are on HAART. This led to a significant reduction in opportunistic skin diseases (by 90 %) and Kaposi's sarcoma (by 90 %). The high frequency of skin disease summarized in this table is still seen in patients who are not on HAART or not yet diagnosed to be HIV-infected. In urban areas, syphilis is now seen 4 to 10 times more frequently in homosexual men compared to 2000. Until today, there has been no observable increase in the incidence and prevalence of syphilis in European women, but it is very likely that the epidemic in homosexual men will be followed by a heterosexual epidemic within a few years. According to the epidemiological data, provided by the Robert Koch Institute in Berlin, the incidence of syphilis in Germany (3.8 per 100 000 inhabitants per year) exceeded the incidence of newly registered HIV infections (3.2) in 2006 (RKI 2006). It has become evident that a functional cell-mediated immune system plays an important role in the protection against epithelial tumors. The likelihood of developing squamous cell carcinomas, basal cell carcinomas, lymphomas, or even malignant melanoma is correlated with the length of time HIV-infected immunocompromised patients survive. Nowadays, HIV-infected patients survive longer than patients from the pre-HAART era. For this reason, these patients need to be monitored for primary cutaneous malignancies such as basal cell carcinoma, squamous cell carcinoma, melanoma, and cutaneous lymphomas. Analogous to the long-term immunosuppressed organ transplant recipient, the HIV-infected patient has to be examined periodically (6 month intervals suggested) for melanoma as well as non-melanoma skin cancers including actinic keratoses (Schöfer 1998, Honda 2006). Factors such as UV-light, smoking and oncogenic viruses (especially mucocutaneous infections with HPV 16 and HPV 18) must be considered as cofactors in carcinogenesis. Skin cancer precursors such as actinic keratoses, bowenoid papulosis, Bowen's disease, and intraepithelial neoplasias of the genital or anal region must be treated early and aggressively. The incidence of anal carcinoma, an epithelial tumor typically found in old men, is now increasing in young HIV-infected homosexual men. Contrary to the manifestation of Kaposi`s sarcoma effective HAART does not reduce the incidence of anal carcinoma. It seems that the total duration, rather than the severity of immunodeficiency is important for the manifestation of these tumors. As in non-immunocompromised patients, risk factors such as pigmentation characteristics, sun sensitivity, sun exposure behavior patterns, and geographic location must be considered in the evaluation. Dermatological examination and therapy in HIV-infected patients HIV-infected patients with advanced disease often suffer from common skin diseases (Table 1), but they also present with rare dermatoses, unique to HIV infection. Careful dermatologic evaluation may lead to the diagnosis of serious systemic infections in this population such as cryptococcosis, bacillary angiomatosis, oral hairy leukoplakia, and Penicillium marneffei infections of the skin. Common dermatoses often present with atypical findings and may pose diagnostic dilemmas. For example, herpes simplex labialis may present as large superficial erosions or deeply ulcerating lesions rather than the classical small vesicles on an erythematous base. Eruptions of secondary syphilis may ulcerate and form rupial lesions accompanied by high fever and constitutional symptoms (malignant syphilis). It is therefore important to pursue diagnosis of all cutaneous eruptions through appropriate tests such as tissue cultures, biopsy, and swabs of lesions prior to the initiation of therapy. Because HIV-infected patients are at high risk of contracting other STDs due to the common modes of transmission, they should be screened for them. During the past three years, 39 % of all syphilis patients who attended our Department, had HIV co-infection. Dermatologic evaluation should include complete cutaneous inspection, oral cavity examination, inspection of the anogenital region and palpation of the lymph nodes. Standard treatment regimens for skin and mucocutaneous diseases may be inadequate in HIV-infected patients due to unusual strains of organisms leading to drug resistance. In these cases, high dose regimens or second and third line therapies may have to be considered (Osborne 2003). Diagnostic and therapeutic regimens of the most frequent HIV-associated skin diseases are compiled in alphabetical order in Appendix 1 of this chapter. Table 2: Clinical Diagnostic Tools Indication Performance Interpretation Differential diagnosis of tumors, skin lesions without definite clinical diagnosis, or to confirm a clinical diagnosis Biopsy Under local anesthesia: 4-mm punch-biopsy; if necessary: excisional biopsy. Fixation of the material in 10 % formalin; for special investigations (immunohistology, electron-microscopy, HPV-typing) use only saline. Dermatopathologist Presumptive diagnosis of dermatophytosis Skin-scraping for KOH examination Clean the skin with 70 % alcohol, let it dry. Use a scalpel or glass slide to scrape scales at the active edge onto a glass slide. A drop 10 - 15 % KOH is put on top of the specimen and covered with a cover slip. After ~ 20 mi-nutes or immediately after gentle heating the specimen can be examined microscopically (10-40x magnification) for fungal elements. The specimen may be cultured as well. Fungal elements (spores and hyphae) are not digested by KOH and can be visualized with light microscopy. Presumptive diagnosis of herpes infections (grouped vesicles or ulcers) Herpes-virus detection A smear of cells from the base of the skin lesion is taken (for culture: special swabs: Culturette™; use pressure to obtain cells). Sample can be put onto a glass slide for immediate direct fluorescent antibody testing (DFA) which will distinguish between HSV and VZV infections. Tzanck-preparation: multinucleated giant cells (Giemsa- or Wright-stain; 400x magnification) Viral lab, positive culture proves diagnosis; demonstration of DNA or antigen does not differentiate between living and dead viruses Drug eruptions, presumptive allergic contact dermatitis Allergy testing Serology: (RAST, lymph. transformation test); skin tests Type I reactions: Prick- and intra-cutaneous-tests. Type IV reactions: "Scratch"- and patch testing. A specialist in allergy should perform tests and interpretation. Allergist Presumptive diagnosis of ulcers (mainly of syphilitic ulcers) Exudative lesions (condylomata lata, possibly secondary syphilis lesions). Dark-field microscopy Secretion (mechanical pressure, if necessary use ether in local anesthesia) of serous exudate is applied to a glass slide, covered with a coverslip. Examination by dark-field microscopy (1000x). Lesions in the mouth: examination not possible due to saprophytic bacteria Negative test does not exclude syphilis; false negative testing may be due to: prior treatment with antibiotics/ antiseptics A positive test confirms the diagnosis Presumptive diagnosis of dermatophytosis, erythrasma Malassezia folliculitis, Pseudomonas infections and phorphyria Wood`s lamp Skin inspection in a darkened room with a special lamp (Wood`s lamp, 365nm, invisible long-wave ultraviolet light). Shine UV-light closely to the skin area of interest. Characteristic fluorescence (green, red, orange etc.) of chemicals produced by several fungi and bacteria. False-positive tests by some soaps, deodorants, make-ups etc. HAART: Influence on (muco-) cutaneous diseases The introduction of HAART in 1996 revolutionized the dermatological management of HIV-infected patients. Opportunistic infections and Kaposi's sarcoma have decreased to a level of 10 % compared to the pre-HAART era (Reinmöller 1997, Schöfer 1998, Sepkowitz 1998, Calista 2002). An Italian hospital reported that HAART had reduced the total number of HIV patients with skin problems by 40 %. The percentage of patients with cutaneous infections dropped from 66 to 53 %; the percentage of non-infectious, inflammatory diseases from 25 to 21 %; however, the percentage of patients with drug reactions increased from 8 to 23 % (Calista 2002). Appendix 2 is a compilation of antiretroviral drugs, and their cutaneous side effects. Atypical clinical courses of skin diseases and resistance to therapy, which were very common in patients with severe immunodeficiency in the pre-HAART era, are rare conditions now. They still occur, however, in patients not taking antiretroviral therapy (Mirmirani 2001). Cutaneous infections and inflammatory skin diseases have been replaced by drug eruptions caused by 26 currently available antiretroviral drugs. In some patients, immune system reconstitution, following 1 to 3 months after the introduction of HAART, causes clinical disease summarized as immune reconstitution inflammatory syndrome (IRIS). Drug eruptions have many clinical patterns including macular or maculopapular exanthemas, follicular eruptions, urticaria, and toxic epidermal necrolysis (TEN), . Severe, sometimes life-threatening reactions such as Stevens-Johnson-syndrome or TEN were mainly reported in patients on combination therapy with zidovudine, didanosin, nevirapine, indinavir or amprenavir. In 86 % of these patients, the drug eruptions occurred within the first 4 weeks of treatment (Rotunda 2003). Instead of discontinuing therapy, less severe drug eruptions without mucosal involvement, blistering, or constitutional symptoms (apart from pruritis), may be treated with antihistamines and corticosteroids. This is especially important for patients, whose choice of antiretroviral combination drugs is already limited by drug resistance or severe side effects such as hematotoxicity or polyneuritis. Patients who are "treated through" drug eruptions must be monitored frequently. Corticosteroid treatment should not exceed the equivalent of 1 mg/kg/d bodyweight of prednisone. General considerations about how to recognize and manage drug reactions are updated by Knowles and Shear (2007). Miller and Warshaw (2007) focus on adverse cutaneous reactions to antimicrobials that are commonly used in the management of HIV infected patients. Blister formation, involvement of the mucous membranes and constitutional symptoms as well as drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) are absolute indications to stop antiretroviral therapy. TEN (e.g. induced by efavirenz, nevirapine) and hypersensitivity syndrome (e.g. induced by abacavir) may be fatal. Drug interactions between HAART and agents used to treat cutaneous diseases are frequent and need to be carefully evaluated before being prescribed (see Chapter "Drug interactions", McNicoll 2004 or http://www.hivguidelines.org/Content.aspx?pageID=262). Azole derivatives, retinoids and drugs metabolized via the p450 pathway frequently interact with antiretrovirals. Immunosuppressive therapies, such as ultraviolet light and cyclosporin, should be limited to a few conditions such as severe autoimmune diseases, and used only with careful clinical and laboratory monitoring. Photo(chemo)therapy is able to provoke viral infections such as herpes zoster and herpes simplex, epithelial tumors, and to increase the HIV viral load. Despite this, we have seen the benefit of narrowband UVB phototherapy in HIV-infected patients with extreme pruritus associated with papular dermatoses or eosinophilic folliculitis, resistant to all other therapies. As long as these patients were under the protection of HAART, UV therapy caused no observable worsening of the immune status. Eliciting the cause of a drug eruption can be challenging, especially if the patient is taking complementary medication not prescribed by a physician. It is necessary to ask explicitly whether any herbal medicines, vitamins, minerals, or food complements are being taken to improve the general health. Substances with a potential risk of sensitization or toxicity can be the cause of drug reactions (Witkowski 2003). Urticaria, angioedema, and exanthemas due to food complements are reported in the literature (GISED 1996). The treatment of KS varies with the clinical manifestation of the tumor, the immune status of the patient and his additional symptoms associated with the HIV infection (details see Chapter "Kaposi's sarcoma"). Conclusions The dermatologist's role in the care of HIV-infected patients is to be familiar with HIV-associated skin and mucocutaneous diseases, their diagnoses, and management. It is also a part of the extensive interdisciplinary knowledge necessary for any physician who takes care of HIV-infected patients. Considering the lifelong duration of antiretroviral therapy with complications such as drug intolerance, development of epithelial tumors induced by UV-light exposure or oncogenic viruses, it is recommended that patients have a dermatologic consultation before the start of antiretroviral therapy. Complete skin examination with attention to the presence of STDs should be performed. Education should include prevention of photodamage, safe sex practices, and skin care to avoid infections, especially when HIV-associated xerosis is already evident. Despite the fact that HIV-associated opportunistic infections are less frequent in the HAART era, knowledge about these diseases and adequate treatment is still of high clinical relevance. The full spectrum of these skin diseases is still found in untreated patients around the world. Dermatological markers of disease of severe acquired immunodeficiency (see Appendix 1) play an important role in this situation (Schöfer 1991), especially if several diseases are diagnosed in the same patient. In the absence of other immunodeficiency, HIV antibody testing must be offered to the patient as a diagnostic tool to elicit the cause of the clinical presentation. At present, syphilis and HIV co-morbidity is of special interest. The incidence of syphilis in Western Europe has increased 4 to 10 times over the past 4 years. As HIV and Treponema pallidum share the same route of transmission, any patient with syphilis must be evaluated for HIV infection. The delayed seroconversion for HIV antibodies should be taken into account and, if initially negative, HIV testing should be repeated after 3 months. Untreated syphilis might result in severe, irreversible damage of multiple organs, accelerate the clinical course of HIV disease and facilitate HIV transmission between sexual partners. Appendix 1: Most frequent HIV-associated skin diseases Acute HIV exanthema: In 40-90 % of all patients infected with HIV-1, an acute, febrile, mononucleosis-like disease with constitutional symptoms and an exanthem occurs (details see Chapter "Acute HIV-1 Infection"). This nonspecific eruption starts 1 to 3 weeks after HIV transmission, and several weeks before HIV seroconversion (Stekler 2007). The macular exanthem favors the upper trunk and is characterized as fairly non-pruritic with erythematous macules from 0.5 to 1 cm in diameter. Morbilliform or rubella-like eruptions and palmoplantar hyperkeratotic eczema occur less frequently. Histopathology reveals a nonspecific perivascular and interstitial infiltrate in the upper and mid dermis (Barnadas 1997). Oral aphthous ulcers, frequently in combination with shallow genital ulcers (bipolar aphthosis) are another important clinical sign (Hulsebosch 1990, Porras-Luque 1998). Differential diagnosis includes other viral infections (EBV, CMV), Mediterranean spotted fever, secondary syphilis, drug eruptions (Hecht 2002, Daar 2001) and Behcet's disease. Aphthous ulcers and other oral lesions: At least three different kinds of aphthous ulcers occur in the oral cavity of HIV-infected patients. The most frequent diagnosis is recurrent aphthous stomatitis (canker sores) (1) with single or few painful lesions usually localized in the vestibule of the mouth. The ulcers occur at sites of mechanical injuries, are 3 to 10 mm in diameter and heal spontaneously after a few days. Single or multiple large aphthae (2) which are >1cm in diameter and usually persist for several weeks are less common. Both variants are of unknown origin. In a few cases, especially when multiple small lesions occur, herpes simplex viruses can be involved. Large ulcers in combination with severe immunodeficiency can be caused by cytomegaloviruses, which are usually part of a generalized CMV infection. Bipolar aphthosis (3), involving the oral and genital mucosal membranes, is an important clinical symptom of acute HIV infection or Behcet's disease. In addition to these clinical variants of aphthous ulcers, several authors have discussed the direct role of HIV retroviruses in aphthous stomatitis (Kerr 2003). The treatment of recurrent aphthosis is based upon topical anesthetics, and corticosteroids. Large persistent aphthae can require intralesional corticosteroids or systemic prednisone. Immunomodulators, such as thalidomide, are suggested for use as prophylaxis in patients with frequent and painful recurrences(Shetty 2005). The incidence of oral disease has decreased since HAART was introduced (Hodgson 2006). But comparable to the situation in the anal mucosa, high-risk HPV infections, e.g. flat warts of the oral mucosa, oral squamous cell carcinoma and tonsil-related cancers (43% HPV associated) are increasing (Pintos 2007). Differential diagnoses and treatment of oral lesions in HIV infected patients were recently updated by Baccaglini et al (2007). Folliculitis: Pustular, papular or edematous-papular follicular lesions, involving the proximal limbs and the upper trunk. Possible causes include Staphylococus, Malassezia furfur, Demodex folliculorum, and drugs such as indinavir. Treatment depends on the etiologic agent detected by bacterial swabs and histopathology if needed. Antimicrobials against staphylococcus, and malassezia, or changing the antiretroviral drug regimen may be required. DADPS, a 10 % crotamiton or polidocanol ointment, or narrowband UVB are effective against severe pruritus in these patients (Ellis 2004). Today, it is well established that HAART naive patients with pruritic eosinophilic folliculitis (Nervi 2006) significantly improve after the initiation of antiretroviral therapy. Genital warts (condylomata acuminata): Genital warts are sexually transmitted hyperkeratotic and verrucous papules of the anogenital region, caused by a variety of human papilloma viruses (HPV 6, 11, 16, 18, etc.) . HIV-infected patients have a high prevalence of these lesions (17 %), and genital warts are directly related to the number of sexual partners. Genital warts, located in the perianal or intra-anal region are characteristic of receptive anal intercourse. Patients who have anogenital warts, should be offered HIV testing, especially if they have other HIV risk factors. In general, the clinical manifestations of common genital warts in immunodeficient patients do not differ from those in immunocompetent patients. They are diagnosed by their typical clinical features as condyloma acuminata, condyloma plana, bowenoid papulosis, Bowen's disease and giant condyloma (Buschke-Loewenstein tumor). In contrast to the findings in the immunocompetent population, HPV 16-associated lesions, such as bowenoid papulosis and Bowen's disease (squamous cell carcinoma in situ), which are now classified as anal intraepithelial neoplasias (AIN I-III including the erythroplasia of Queyrat), are more prevalent in immunodeficient patients. These premalignant conditions have a low rate of spontaneous remission and are very resistant to therapy (frequent relapses). It is now accepted, that genitoanal lesions due to oncogenic HPV types, especially HPV 16 and 18, are substantial risk factors for malignant cervical, penile, and anal carcinomas . HPV 16 and 18 are able to immortalize human keratinocytes by downregulating the tumor suppressor genes p53 and pRB. The transformation rate to malignant carcinomas is low in bowenoid papulosis, but almost 30 % in Bowen's disease. In contrast to the beneficial effects of HAART on the incidence and the clinical course of Kaposi's sarcoma and NHL, there is no clear impact on cervical and anal carcinoma. The incidence of these tumors is still increasing (Kreuter 2006). Analogous to cervical intraepithelial neoplasia (CIN) and cervical cancer in women, regular screening (every 2 to 3 years) for AIN and anal carcinoma is advised for all HIV-infected patients on HAART (Papathanasiou 2003). Screening should include clinical inspection, aceto-white-stain, colposcopy, proctoscopy, cytology (Pap smear) and, if necessary, histopathology (Horster 2003). Due to orogenital sexual contacts HPV 16 and other oncogenic HPV are also found in the oral cavity (Pintos 2007). Conventional therapy for anogenital warts is destruction by cryosurgery, electrocautery, carbon dioxide, Nd-YAG laser, trichloroacetic acid, or podophyllotoxin. CIN, PIN, and AIN are treated surgically with histological control of the margins to ensure complete removal of the lesion. All of the destructive treatments have disadvantages. Since virus-harboring keratinocytes can remain in the clinically normal surrounding tissue, relapses are as frequent as 50 % in immunocompetent patients and up to 70 % in immunodeficient patients within 4 months. Alternative therapies with immunomodulatory activity, such as systemic and topical interferons, have shown some efficacy, but the outcome of the studies was closely related to the different treatment regimens and the cost of therapy was extremely high. Topical interferon (IFN-gel with 0,15 Mio IU/g) was only effective in very small warts and as an adjuvant after surgery. The relapse rate could be reduced by almost 50 %. The immune response modifier imiquimod has been approved for the treatment of genital warts since 1998. As demonstrated in several controlled studies ( Yan 2006), imiquimod treatment is safe and effective and has the lowest relapse rate of all treatments (6-13 % in immunocompetent patients, Schöfer 2007). Imiquimod is not approved for the treatment of anogenital warts in immunodeficient patients and intraepithelial neoplasias, but results of several successful treatments of genital warts (Cusini 2004), bowenoid papulosis and Bowen's disease in HIV-infected patients have been published (Kreuter 2004, Klencke 2003, Cooley 2003, Wieland 2006). The only antiviral agent active against HPV is cidofovir, but there is little experience in HIV-infected patients (Snoeck 2001, De Clercq 2007). Tinea (dermatophytosis, ringworm infections): Infections of the skin, hair or nails with dermatophytes (in Western Europe predominantly Trichophyton, Microsporum and Epidermophyton species). Tinea has a high prevalence in the general population. There is no significant difference between HIV-negative and HIV-infected adults. The prevalence is dependent upon climate, profession, clothing, and participation in team sports. In homosexual men, the prevalence is 29 to 37 % (Torssander 1988, Schöfer see Table 1). Typical clinical findings are superficial, scaling, round or oval erythematous plaques, that expand centrifugally with an inflammatory edge and central clearance. Deep infections, with tissue destruction and abscess formation, are rare in Europe and North America, but common in tropical regions. According to Torssander (1988), onychomycosis due to dermatophytes is frequent in HAART-naive patients and difficult to treat. Nails are discolored (white, yellow, green, black), thickened, and show growth disturbances (onychodystrophy). Subungual hyperkeratosis and onycholysis are common. Psoriasis, yeast infections and trauma can imitate onychomycosis, so it is necessary to identify the causative organisms on KOH and fungal culture. Direct microscopic examination with addition of 10-15 % KOH solution shows translucent, septated hyphae (mycelium) and arthrospores. Culture on Sabouraud's or Kimmig's medium identifies different fungi by their growth characteristics. Treatment of superficial fungal infections of the skin is best achieved with topical broad spectrum antifungals such as ciclopirox or azoles, applied twice daily. In severe inflammatory disease, it is helpful to start with combination therapy including topical corticosteroids for 3 or 4 days, to achieve quick relief of discomfort. Deep infections and infections involving terminal hairs (tinea capitis, tinea barbae) require systemic treatment with griseofulvin (500-1000 mg/day), terbinafine (250 mg/day), fluconazole (50 mg/day), or itraconazole (100-400 mg/day). There are different regimens to treat onychomycosis. Itraconazole (pulse therapy) and terbinafine (250mg per day) are typically used for two months for fingernails and three months for toenails. Griseofulvin may be used for up to 9 months or longer, until the infection clears (Aly 1996, Myskowski 1997, Gupta 2000). If only the distal part of the nail plate is infected, topical treatment with nail varnish containing antifungals (e.g. amorolfin, ciclopiroxalamine), which are able to penetrate the nail plate, are advised to avoid drug interactions between systemic antifungals and antiretroviral medications (see Chapters "Drug Profiles" and "Drug interactions"). If systemic therapy is necessary, fluconazole has less drug interactions in HIV-infected patients than the other antifungals mentioned. Yeast infections (candidiasis etc.) see Chapter "Opportunistic Infections") Herpes simplex virus infections: Herpetic infections of the skin and mucous membranes are frequent opportunistic infections in HIV-infected patients. The clinical symptoms differ substantially according to the patient's immune status. As long as the cell-mediated immune functions are normal, typical localized infections with itching, erythema and grouped vesicles will appear and heal spontaneously within a few days. In contrast, very painful, deep and large ulcerations of the anogenital region, but also of the face and other parts of the body (e.g. herpetic whitlow) will appear in patients with advanced HIV infection and severe immunodeficiency (CD4+ T-cell count < 100/µl). Clinical diagnosis can be difficult in these patients because grouped vesicles might be absent and only erosions or ulcers might be visible. Along with other STDs, genital herpes plays an important role in the dynamic of the worldwide HIV pandemic. Herpes lesions ease HIV transmission between sexual partners by breaking the epithelial barriers, stimulating HIV reproduction via pro-inflammatory cytokines, and enhancing expression of cellular HIV receptors (CD4, etc.) on the surfaces of immunocompetent cells (Kapiga 2007, Linqappa 2007, Corey 2007) (see Chapter "Opportunistic Infections"). (Herpes) Zoster: Shingles is an early marker disease during the natural course of HIV infection. Frequently, this secondary endogenous Varicella zoster virus infection is diagnosed several years prior to any other opportunistic infection. HIV infection or any other kind of acquired immunodeficiency must be suspected in any zoster patient who is (1) younger than 50 years and has no other known cause of immunodeficiency, or (2) shows atypical clinical features such as multisegmental or generalized distribution of normal, hemorrhagic, or necrotic lesions. Latent VZV infections can be activated in the frame of immune reconstitution syndrome a few weeks after the initiation of effective HAART (See also Chapter "Opportunistic Infections"). Immune reconstitution inflammatory syndrome (IRIS) related skin reactions: HAART recovers the TH-1 immune response and the tuberculin test reactivity (Girardi 2002). In association with this immune reconstitution, clinical manifestations of herpes zoster, mucocutaneous herpes simplex infections, mycobacterial infections, eosinophilic folliculitis, foreign-body granulomas, cutaneous sarcoidosis and aggressive Kaposi`s sarcoma were reported (Handa 2001, Hirsch 2004, Leidner 2005). These infectious, as well as some non-infectious inflammatory skin diseases and tumors, occur within a few days to 3 months after the initiation of HAART. The therapy depends on the severity of clinical manifestations and consists of specific antibiotics, steroidal and non-steroidal anti-inflammatory drugs (For details, see Chapter "IRIS"). Kaposi's sarcoma: See Chapter "Kaposi's sarcoma"). Lipodystrophy and metabolic syndrome: See Chapter "Lipodystrophy syndrome". Cutaneous lymphomas: Malignant B and T-cell lymphomas are rare in HIV-infected patients (, Biggar 2007). Cutaneous B-cell lymphomas usually grow as red to violaceous nodules, that are easily mistaken for Kaposi's sarcoma. They can also look like persistent hematoma or nonspecific asymptomatic papules. A biopsy should be performed on any clinically unclear tumor of the skin. Cutaneous T-cell lymphomas are rare malignancies in HIV-infected patients. The prevalence among 2149 HIV patients in Frankfurt/M. was 0.06 %. The clinical course starts with nonspecific eczematous patches (stage I), which are usually not diagnosed as cutaneous lymphoma, even after several biopsies because of the paucity of findings such as cellular atypia. These lesions are usually diagnosed as eczematous dermatitis. A linear pattern of patchy or slightly infiltrated lesions in the relaxed skin tension lines can be an early clinical indication of cutaneous T-cell lymphoma known as parapsoriasis (Munoz-Peres 1999). Histopathology becomes more evident during the plaque stage (stage II), and is striking when in stage III multiple tumors of the mycosis fungoides present. Biggar et al (2007) calculated a relative risk for cutaneous T-cell lymphomas in HIV-infected patients of 15.0 in comparison to the general population. In both HIV-infected and HIV-negative patients, the leukemic phase (Sézary syndrome) is characterized by erythroderma involving the palms and soles. In patients with erythroderma who have darker skin types and lack the histopathological signs of cutaneous T-cell lymphoma, the so-called "pseudo-Sézary syndrome" has to be considered in the differential diagnosis (Picard-Dahan 1996). Therapy with potent topical steroids (e.g. clobetasol) is effective in the patch and plaque stages. Solitary tumors can be controlled by radiotherapy (20-24 Gy) or photodynamic therapy (Paech 2002). Widespread, multiple tumors, and Sézary syndrome are treated with a combination of retinoids and interferons or chemotherapy. Remission of a CD8+ pseudolymphoma treated solely with HAART was reported (Schartz 2003). Molluscum contagiosum: This is a benign viral infection of the skin, usually seen in children, and often in association with atopic dermatitis. The poxvirus (MCV1-4) causes multiple papular skin-colored lesions with a typical central umbilication. The diagnosis is usually made on clinical grounds. After several weeks or months, an inflammatory reaction indicates the onset of spontaneous healing. In adults, mollusca are detected in the anogenital area and regarded as a sexually transmitted disease . In HIV-infected patients, the clinical manifestations can differ significantly from those seen in the normal host. Spontaneous healing is rare; most patients have high numbers of lesions, typically occurring in the face and neck region, which is otherwise a rare location. The presence of multiple mollusca on the face, is a typical disease marker, indicating advanced cell-mediated immunodeficiency with CD4+ T-cell counts <100/µl (Schöfer 1991, Schwartz 1992). The growth of mollusca in the immunocompromised host is not always exophytic, sometimes endophytic lesions occur. Multiple mollusca have to be differentiated from hematogenous dissemination of cryptococcosis, histoplasmosis, and coccidioidomycosis, which are usually associated with fever, headache, and sometimes pulmonary infiltrates. In such cases, skin biopsies (and tissue culture) and chest x-rays are indicated. Single molluscum can exceed 1 cm in diameter and grow exophytically, which can cause confusion with keratoacanthoma, squamous cell carcinoma, basal cell carcinoma, or common warts. Mollusca are treated surgically with , electrocautery, curettage, or cryotherapy. Photodynamic therapy with 5-aminolevulinic acid (Moiin 2003, Gold 2004) and imiquimod 5 % cream were effective as well ( Jones 2007). Imiquimod is applied by the patient 3x/week (off label use). An inflammatory reaction (erythema), occurring after 3 to 4 weeks of topical treatment, indicates the beginning of the immune reaction, which leads to complete resolution of the mollusca after 6-8 weeks. In a Cochrane review van der Wouden et.al (2006) concluded: "No single intervention has been shown to be convincingly effective in treating molluscum contagiosum." Oral hairy leukoplakia (OHL): is a clinical manifestation of Epstein-Barr virus infection, which is almost exclusively found in patients with untreated advanced HIV disease. Non-cytolytic viral replication in the glossal epithelium, especially in the lateral parts of the tongue, leads to asymptomatic white verrucous plaques that do not rub off. OHL is diagnosed on clinical findings; initially parallel white or grayish hyperkeratotic rows arranged vertically on the lateral aspects of the tongue are characteristic. Unilateral lesions are seen , but bilateral occurrence of plaques is more typical. Important differential diagnoses include other leukoplakias, lichen planus mucosae and oral candidiasis (Patton 2002, Cherry-Peppers 2003). If the diagnosis is in doubt, a biopsy or cytology can confirm the diagnosis. As the lesions will respond to antiviral drugs such as aciclovir, ganciclovir, or foscarnet (Walling 2003), but not antifungals, treatment can be used as a diagnostic tool to distinguish OHL from candidiasis. Both diseases however, respond well to HAART, which has led to a significant decrease (80-90%) of these oral diseases (Triantos 1997, Ramirez-Amador 2003). Topical treatments with podophyllin resin (25%) with or without acyclovir cream are effective (Moura 2007). Pruritus: Chronic, often unremitting pruritus is one of the most frequent clinical symptoms of HIV infection. One in three patients is affected. Etiology remains unclear in most patients, and therefore only symptomatic treatment can be offered which may be unsatisfying (Moses 2003, Singh 2003). Pruritus in HIV-infected patients can be a complication of infectious diseases. Viral, bacterial, and fungal infections (e.g. Malassezia furfur folliculitis) and scabies can cause severe itching. Also, dry eczematous skin (xerosis), papulosquamous skin diseases, systemic lymphomas, renal insufficiency and hepatic disease are causative conditions. Finally, many antiretroviral and other drugs given to the HIV-infected patient can cause pruritus (with or without rash). It has been suggested that a viral load of more than 55 000 copies/ml are associated with pruritus (Zancanoro 2006). To diagnose idiopathic pruritus, it is necessary to exclude all skin and systemic diseases mentioned above. In patients on HAART, it can be useful to change the treatment regimen. Systemic antihistamines and topical corticosteroids are symptomatic treatment standards. If they are ineffective, or a prolonged systemic treatment is necessary, phototherapy (UVA-1, UVB-311nm) or photochemotherapy (PUVA) is an alternative or adjuvant therapy. (Smith 1997, Gelfand 2001, Zirwas 2001, Singh 2003) Concerning the immunosuppressive effects of ultraviolet light, it seems that patients on HAART are at less risk. Papular dermatoses: Patients can present either with monomorphic skin colored to red papules (size 2 - 5 mm) or with combined eruptions consisting of papules and pustules (sterile eosinophilic pustulosis Ofuji). There is no special predilection for any site. The etiology of papular eruptions is heterogeneous (Ramos 2006). According to the clinical presentation and to laboratory findings (elevation of IgE, eosinophilia in peripheral blood and affected skin) they resemble the prurigo of atopic dermatitis found in adults. Autoimmune reactions against follicular antigens have also been discussed (eosinophilic folliculitis; Nervi 2006)e). These papules can be due to a hypersensitivity reaction to drugs, microbiological agents (viruses, bacteria, fungi), parasites, or saprophytes (Sarcoptes scabiei, Demodex folliculorum, Malassezia and others). A drug history and microbiological and histological examinations (including special stains such as PAS) are required for a correct diagnosis. If infections are identified, they are treated with antimicrobials. , . In the case of sterile eosinophilic pustulosis (Ojufi), or papular dermatosis of unknown origin, therapy is symptomatic. Depending on the clinical situation, antihistamines, itraconazole (200 mg/d for 2 weeks), isotretinoin, dapsone, mild PUVA or narrowband UVB or 5 % permethrin-cream can be tried . Topical tacrolimus (0.1 %) also was shown to be effective (Kawaguchi 2004). Paronychia and ingrown nails: Ingrown toenails and inflammatory reactions of the proximal nailfold are a well known complication in diabetics, but also in patients on beta-blockers, or retinoid therapy. A few cases might be due to local pressure (poorly fitting footwear) or occur spontaneously. Patients on HAART are the most recent group of patients to regularly develop ingrown nails. These are ascribed to retinoid-like side effects of several antiretrovirals, especially indinavir, but also lamivudine and nelfinavir. Usually, the great toenails are involved, but all other toenails and fingernails can be affected. The therapy of choice , is to substitute indinavir or lamivudine with other antiretrovirals. This has led to complete remission in several of our patients. Surgical measures, such as Emmetplasty or its modification after Hanneke, should only be performed on patients in whom the exchange of HAART medications did not lead to a remission after 3 to 6 months (Tosti 1999, Alam 1999, Garcia-Silva 2002). Psoriasis vulgaris: Psoriasis is regarded as an autoimmune disease and affects approximately 1 % of the general population. It has multifactorial inheritance with variable penetrance. Physical stimuli such as friction and UV-light, or endogenous factors such as infections, drugs, and "stress" may trigger psoriatic flares. When HIV-infected persons are exposed to such factors, psoriasis may appear for the first time or can be aggravated. The incidence of psoriasis has been reported to be between 2.5 % (and 4.9 % (Schöfer 1990). Being a T-cell mediated disease, the pathomechanisms of severe and recalcitrant psoriasis in HIV infected patients with a substantial decrease in CD4 cell counts, are not well understood (Namazi 2004, Fife 2007). The use of antiretrovirals improves psoriasis. Typical psoriatic plaques can be eruptive, guttate, or chronic and stationary.) Atypical findings include inverse localization on the palms or soles and in the genital region and axillae, exudative, pustular, or erythrodermic manifestations. In general, the severity of psoriasis parallels the impairment of the immune system. Besides infection, drugs have to be considered as possible triggers. In the final stages of HIV infection, psoriasis can be generalized and extremely resistant to therapy. Alternatively, the disease may disappear completely. The typical psoriatic plaque is a sharply demarcated, erythematous plaque covered with silvery scales. Clinically and histologically, it may be difficult to differentiate from seborrheic dermatitis. Triggering factors should be eliminated, if possible. Treatment is more difficult if the immune system is impaired. An antiretroviral therapy should be initiated or optimized. Localized lesions can be treated topically with corticosteroids, anthralins, calcium-agonists (calcipotriol or tacalcitol) or the topical retinoid, tazarotene. The scalp and nails can be treated topically with corticosteroids. Generalized or exudative eruptions are usually treated systemically: acitretin (25 - 75 mg/d) is not immunosuppressive. Methotrexate or cyclosporin are immunosuppressive and should be avoided. In some cases, however, it is necessary to use them. Several years ago, , the successful use of hydroxyurea was reported (Kumar 2001), but no further studies have been published. AZT has a beneficial effect on psoriasis, probably by improving the immune status. To treat refractory psoriasis, experimental therapies such as cimetidine (400 mg, 4x/d) have been tried successfully. The clinical relevance of immunosuppression by UV-radiation is unknown. At present, it is believed that phototherapy or photochemotherapy have no real detrimental effect for HIV patients (Akarapathanth 1999, Schoppelrey 1999). These treatments are as effective as in patients without HIV-infectionNarrowband UVB) is well tolerated and effective. Broadband UVB can also be used.. In case of treatment failure, photochemotherapy can be instituted (local = bath or cream PUVA, or systemic PUVA). Interactions of the mentioned antipsoriatics with antiretroviral substances are unknown. Recently, several "biologics" were introduced for the therapy of psoriasis. These compounds specifically interact with certain elements of the inflammatory cascade in psoriasis, such as TNF-a and cause additional immunodeficiency. . Although, restricted to exceptional cases, several authors reported promising treatment results. Long-term experiences are lacking (Bartke 2004, Ting 2006, Sellam 2007). Reiter's syndrome: Reiter's syndrome is regarded as a variant of psoriasis in patients who carry HLA B27. This rare chronic-relapsing disease mainly affects young men, the incidence being higher in HIV-infected men than in the general population (0.6 to 6 %; Kaye 1989). Recently, it was reported to occur as a symptom of IRIS. The classical triad consists of: urethritis (sterile yellow urethral discharge), conjunctivitis (serous or purulent) and arthritis (mainly knee-, foot- or sacroiliac joints; causing pain and leading to immobility). The triad is found in about 30 % of patients. Furthermore, constitutional symptoms (attacks of fever, malaise, leukocytosis, elevated ESR) and skin lesions can be found. The skin lesions are characterized by erythema with sterile pustules on the palms and soles, and later, hyperkeratotic, scaling, exudative lesions known as keratoderma blenorrhagicum. Psoriatic plaques can be seen as well as the typical circinate balanitis presenting as crusting, desiccated plaques in circumcised men and shallow, moist, serpiginous, painless ulcers with slightly raised borders in uncircumcised men. The diagnosis depends on the typical pattern of arthritis plus one or more of the mentioned clinical symptoms. Gonorrhea or Chlamydia urethritis have to be excluded by microbiological methods. Psoriatic arthritis should have other clinical signs of psoriasis (nail changes) and lacks fever. Initially, symptomatic therapy with non-steroidal anti-inflammatory agents, or possibly corticosteroids (short-term, high-dose pulse-therapy) should be given. Acitretin (25 - 75mg/d) in combination with topical fluorinated corticosteroids has also proved to be effective as has been sulfasalazine.. Arthritis can be treated with oral gold. Doxycyline has been reported to induce remissions (Neumann 2003). There is one report on the successful use of infliximab in a patient with Reiter's syndrome without a negative impact on the HIV viral load (Gaylis 2003). Scabies: Scabies can be found worldwide; the prevalence varies from < 1 % to 30 % depending on the socio-economic circumstances. Scabies is characterized by extreme pruritus, especially at night.. In the interdigital areas, volar sides of the joints of the hands, breasts, axillae, periumbilical region, or penile shaft, fine red burrows (S-shaped or straight lines) may be found. There may be a small papule or vesicle at one end. Excoriations and/or secondary infections make the identification of burrows difficult. Generalized eczematous eruption may be seen. Typically, in the groin or on the genitals, red-brown pruritic nodules are found. These scabies granulomas can persist for months, even after successful therapy. In the case of severe cellular immunodeficiency, crusted scabies or Norwegian scabies can occur. Besides HIV-patients, persons with general physical or mental debilitation are affected. Over weeks to months, eczematous lesions covered with asbestos-like crusts extend over large areas and the plaques can be mistaken for psoriasis. Crusted scabies is extremely infectious and carries many more mites than regular scabies - up to 10,000 mites/g scales. The history of unremitting and intractable itching is suggestive of scabies. The diagnosis is made by the clinical picture and proven by the demonstration of the mites, their ova, or fecal droppings in the scales by light microscopy of KOH treated scales. On histology, the female mite can be visualized in the stratum corneum. A single application of permethrin 5 % cream is performed (whole body application from chin to toes, usually excluding the face; leave on skin for 8 hrs, then shower off). In cases of crusted scabies, the scales have to be removed over several days (salicylic ointments) and therapy has to be repeated over 3 - 4 days. Alternative therapies are: hexachlorcyclohexane (lindane), benzoylbenzoate, pyrethrum-extracts or allethrin/piperonylbutoxid, which all have to be applied for 3 days. It is important to treat all contactactants at the same time as well! Linen and bed-clothes have to be changed daily. Depending on the clinical presentation, another treatment one week later is sometimes recommended ("safety-day"). In cases of severe immunodeficiency, the scalp has to be treated too. If more than 50 % of the skin is affected, or several recurrences have occurred, a combination of keratolytic/topical therapy and systemic treatment with ivermectin is recommended. Oral therapy with 2 tablets (6 mg each; some 200µg/kg) repeated after one week is generally sufficient. But special attention should be payed to nail involvement, which is not treated sufficiently with ivermectin (Ohtaki 2003). Ivermectin is not licensed for this indication. There have been no reports of complications after this therapy in HIV-infected patients (Dourmishev 1998). Hygienic measures to prevent contact infections are extremely critical. Seborrheic dermatitis: The incidence in the general population is estimated to be 3-5 % of all young men. The liphophilic yeast Malassezia furfur (formerly known as pityrosporum ovale) is believed to be of pathogenetic relevance. Here the specific subtype appears to be more important than the density of colonization. In HIV-infection 20-60 % are affected depending on the immune status. Seborrheic dermatitis appearing de novo or exacerbation of mild seborrheic dermatitis in a known HIV-positive patient could indicate seroconversion from a latency state to a symptomatic state (Ippolito 2000). Areas rich in sebaceous glands, such as the scalp, forehead, eyebrows, nasolabial folds, over the sternum, between the shoulder blades, external ear canal, and retroauricular area, develop yellowish, oily scales and crusts on mildly erythematous to very red plaques. The lesions may be pruritic. The clinical picture is typical in most cases. Differentiation from psoriasis may be difficult both clinically and histologically. Initially, other forms of eczema such as allergic contact dermatitis and atopic dermatitis may have similar presentations. Due to the pathogenic role of pityrosporum ovale, topical antifungals such as ketoconazole cream, other topical imidazoles or triazoles, or alternatively selenium sulfide, metronidazole, and low-dose dithranol or lithiumsuccinate- and zinc-sulfate-creams are used. In addition, pimecrolimus 1% cream is an alternative in patients which do not respond to antifungals (de Moraes 2007). For the scalp, antimycotic shampoos, zinc pyrithione or tar-containing products are used. In severe cases, systemic antimycotics are given: ketoconazole (1 x 200 mg/d), itraconazole (1 x 100 mg/d) or terbinafine (250 mg/d) (Gupta 2004, Kose 2005). . Syphilis: In general, syphilis in HIV-infected patients is not clinically different from syphilis in the immunocompetent host. In some patients however, atypical findings complicate the clinical and serological diagnosis as well as the treatment. In primary syphilis, painful anal or oral chancres occur. Persistent chancres can still be found when the exanthems of secondary syphilis and symptoms such as generalized lymphadenopathy appear. In secondary syphilis, syphilids can ulcerate and develop thick crusts (rupia syphilitica or rupial syphilid), which are accompanied by high fever and severe illness. This unusual and otherwise rare course of syphilis, which is termed "malignant" syphilis, is found in 7 % of all syphilis associated with HIV infection. In addition, early neurosyphilis and a very short latent period before the onset of tertiary symptoms of syphilis are described. Neurosyphilis is partly due to a reduced blood-brain barrier, and a failure of benzathine penicillin G to prevent neurosyphilis in these patients is reported. The interpretation of syphilis serologies, especially in patients with repeated infections and severe immunodeficiency, can be complicated by false negative results and persistent antibodies. Therefore, it is advisable to verify T. pallidum infection in any clinical manifestation suspected to be syphilis by direct proof (dark-field microscopy, direct fluorescent antibody testing of exudates, or biopsy specimens). The recommended treatment of syphilis, which is penicillin for all stages of the disease, has not changed over the past 60 years. T. pallidum has developed some resistance against macrolides (erythromycin, azithromycin), but not against penicillin. Syphilis therapy, as recommended by the CDC, WHO, and the German STD Society (DSTDG) is identical for HIV-infected and non-HIV-infected patients. It is advised however, not to use benzathine penicillin G in patients, in whom early neurosyphilis cannot be excluded. If neurosyphilis is suspected by clinical symptoms, and the patient refuses CSF puncture, high-dose penicillin G (6x5 Mega or 3x10 Mega IV should be given for 2 (early syphilis) or 3 weeks (late syphilis). Ceftriaxone, 1-2g/day IM or IV for 10 days (early syphilis) or 2 weeks (late syphilis) is a widely used, but not approved alternative. Standard regimens for early syphilis (primary and early secondary syphilis until one year after infection) are procaine penicillin G, 1.2 million units IM/day for 14 days, or benzathine penicillin G, 2.4 million units IM in a single dose, injected into different sites. Late syphilis (any stage of disease at more than one year after infection and any syphilis of unknown duration, excluding neurosyphilis) is treated like early syphilis, but for three weeks instead of two weeks. (For more details about HIV and T. pallidum coinfection, see Chapter "HIV and Sexually Transmitted Diseases"). HIV-infected patients should be evaluated clinically and serologically for failure of treatment at 3, 6, 9, 12, and 24 months after therapy. Xerosis/Dry skin: Dry skin is a very frequent complication of any kind of immunodeficiency. In the pre-HAART-era, we diagnosed dry skin in one in three HIV-infected patients (see Table 1). The patients complain of dry, itchy skin, which is exacerbated by a multitude of stimuli. Overall, these skin problems are very much like atopic dermatitis (Rudikoff 2002) and can culminate in acquired ichthyosis. The prevalence of dry skin in HIV-infected patients decreased after the introduction of HAART, but is sometimes seen in patients on indinavir (Garcia-Silva 2000, Singh 2003). Some years ago, we showed that the lipid film of the skin surface has a different composition in HIV-infected patients, but is not diminished in quantity (C. Semrau: unpublished data, doctoral thesis). Dry itchy skin is treated with the application of emollients that contain 5 to 10 % urea, or 3 to 4 % lactic acid, and dexpanthenol. If the patients take too many showers, the frequency should be reduced to one shower every (other) day, and 1 to 2 oil baths per week should be recommended. In cases with severe inflammation and fissures (eczema craquele) topical class 3 or 4 corticosteroids are very helpful in reducing the patients symptoms. They should not be used for longer than 3 to 5 days. Appendix 2: Skin and mucocutaneous disease related to antiretroviral drugs 1. Nucleoside analog reverse transcriptase inhibitors (NRTIs) AZT, zidovudine, RetrovirTM: Drug eruptions (6 %) mostly macular, rarely severe reactions such as erythema multiforme and Stevens-Johnson syndrome, melanony-chia striata medicamentosa, pigmentation and lichenoid eruptions of mucosal membranes, vasculitis, urticaria, pruritus, hyperhidrosis (5-19 %), tongue ulcers. ddI, didanosine, VidexTM: Drug eruptions and itching (4 %), erythema multiforme, oral dryness (30 %), papuloerythrodermia Ofuji. d4T, stavudine, ZeritTM: Drug eruptions with fever. 3TC, lamivudine, EpivirTM: Exanthems, vasculitis, light sensitivity, linear nail hyperpigmentation, hair loss, paronychia, ingrown toenails. FTC, emtricitabine, EmtrivaTM: Exanthems, especially in combination with ddI and efavirenz (10 %), cause unidentified. ABC, abacavir, ZiagenTM: Maculopapular exanthems, hypersensitivity syndrome (5 %) after 9 (3-42) days, frequently associated with respiratory problems, nausea, and vomiting, increase in liver transaminases. Any suspicion of hypersensitivity syndrome forces immediate cessation of treatment (Clay 2002). Abacavir re-exposure is contraindicated (severe, sometimes lethal reactions). For details of the management of abacavir hypersensitivity syndrome, see alphabetical drug register. Tenofovir, VireadTM: rare exanthemas. 2. Non-nucleoside analog reverse transcriptase inhibitors (NNRTIs) Nevirapine, ViramuneTM: frequent drug eruptions (33 %), severe reactions 6 % (mostly within the first 6 weeks of treatment), Stevens-Johnson syndrome 0.5 %, and few cases of toxic epidermal necrolysis. Less frequent drug reactions (22 %), when therapy is initiated with low doses, and very low rate, when HLA-Cw 8 positive patients are excluded from nevirapine therapy (Gatanga 2007). Cetirizine, as a prophylactic, is not effective (Launay 2004). Treatment must be stopped in 3-5 %. Reasons are severe skin reactions, exanthemas with fever, conjunctivitis, pain of the limbs, meningitis, eosinophilia (DRESS syndrome = Drug rash with eosinophilia and systemic symptoms; Bourezane 1998, Lanzafame 2001), occasionally diffuse loss of hair. Exanthems are 7x more frequent, and therapy has to be stopped 3.5 x more often in women compared to men (Bersoff-Matcha 2001). According to the producer's report (Boehringer Ingelheim, February 2004), complications have to be expected mainly during the first 6 weeks of treatment (up to 18 months). During this period, hepatotoxic reactions with high transaminases and exanthemas are frequent. Patients, especially women older than forty, with residual cell mediated immune functions (CD4 cells > 250/µl), are particularly at risk. Delavirdine, RescriptorTM: Maculopapular or erythematous rashes, with or without pruritus in up to 50 %, starting 2-3 weeks after initiation of treatment and involving especially the trunk and upper arms. Mild exanthems without other complications can regress spontaneously without a need to discontinue treatment. Efavirenz, SustivaTM: Frequent macular or urticarial exanthems (11 %). Light exanthems can regress spontaneously without discontinuation of treatment. In case of complications, it is necessary to stop treatment. Fat wasting. 3. Protease inhibitors (PI) Saquinavir, InviraseTM: Aphthous oral lesions (6 %), cheilitis, exanthems- (4 %), rarely Stevens-Johnson syndrome, bullous eruptions, papular pruritic folliculitis. Ritonavir, NorvirTM: exanthems (0.9-2.6 %), papular pruritic folliculitis (8 %), perioral paresthesia (25 %). Indinavir, CrixivanTM: In many patients a sicca syndrome with very dry skin, dry mouth and eyes is observed. In addition, exanthems are frequently papular and intensely itching, involving the lateral parts of the upper arms, the upper trunk and the lateral neck in particular, can occur. Differential diagnosis: papular pruritic eruption (folliculitis). Paronychia (pyogenic granuloma-like) and ingrown toenails, light diffuse loss of hair (12 %), severe and generalized loss of terminal and vellus hair in 1-2 %. Hematoma and hemarthrosis in hemophiliacs. Lipodystrophy ("Crixi-belly", buffalo hump, facial lipotrophy, etc.), metabolic syndrome and asymptomatic hyperbilirubinemia. Nelfinavir, ViraceptTM: Exanthems (infrequent), paronychia (single cases, Dominguez 2007). Amprenavir, AgeneraseTM: Exanthems (3 %, mostly starting during the 2nd week of treatment, Pedneault 2000), perioral paresthesia. Atazanavir, ReyatazTM: Exanthems (Goldsmith 2003), hyperbilirubinemia, in some cases with jaundice and scleral icterus (Orrick 2004). Lopinavir/r, KaletraTM: Exanthems (infrequent). Lipodystrophy. 4. Entry-Inhibitors T-20, Enfuvirtide, FuzeonTM: Erythems and indurations at the injection sites (96%, almost obligatory), exanthems <1% (Ball 2003). References 1. Agromayor M, Ortiz P, Lopez-Estebaranz JL, et al. Molecular epidemiology of molluscum contagiosum virus and analysis of the host-serum antibody response in Spanish HIV-negative patients. J Med Virol 2002; 66:151-8. http://amedeo.com/lit.php?id=15282318 2. Akaraphanth R, Lim HW. HIV, UV and immunosuppression. Photodermatol Photoimmunol Photomed 1999; 15:28-31. http://amedeo.com/lit.php?id=9990666 3. Alberici F, Pagani L, Ratti G, Viale P. Ivermectin alone or in combination with benzyl benzoate in the treatment of human immunodeficiency virus-associated scabies. 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