Rashes and Cutaneous Lesions

in HIV Patients

Chinese Version

Piyush Raman, D.O., Clay J. Cockerell, M.D.

INTRODUCTION

               Infection by Human Immunodeficiency Virus Type 1 (HIV) may result in a number of different clinical scenarios. When patients are first infected, skin diseases are usually similar to those seen in immunocompetent hosts. Later, they may be atypical, more severe, and less responsive to regimens usually used to treat them. It is important that clinicians be aware of cutaneous manifestations of HIV infection which are often the first signs of the disease in an otherwise clinically healthy individual. Familiarity with cutaneous disease patterns in the HIV infected population not only enables better diagnosis and treatment, but also facilitates the detection of unrecognized HIV infection so that treatment may be instituted that may delay or even prevent the progression to the fully developed Acquired Immunodeficiency Syndrome (AIDS). Early diagnosis of these disorders is essential for the timely institution of antiretroviral therapy, prophylaxis for opportunistic infections, prevention of further transmission and counseling.

               Like so much in the HIV epidemic, the incidence and types of dermatological conditions have changed dramatically since widespread use of highly active antiretroviral therapy (HAART). HAART can profoundly suppress viral replication with consequent restoration of CD4 lymphocyte counts. There is often a relation between dermatologic manifestations and the quantitative depletion of CD4 lymphocytes. For example, diseases such as seborrheic dermatitis and onychomycosis appear with modest drops in CD4 lymphocyte counts. Similarly, Kaposi's sarcoma and herpes zoster appear with further loss of CD4 cells and some disorders such as opportunistic infections and eosinophilic folliculitis are seen with profound depression of CD4 counts. Because of administration of HAART, many of the skin problems associated with HIV disease are seen less frequently now than they were just a few years ago. On the other hand, dermatological manifestations of toxicities associated with drug therapy have emerged as a new problem.

               This chapter will review the most common manifestations of HIV infections that may occur in the skin with an emphasis on the ways in which the new HAART regimens have affected them.

EPIDEMIOLOGY

               It was the occurrence of a skin disease, Kaposi's sarcoma, that developed with Pneumocystis carinii pneumonia  in young homosexual men that first alerted the Centers for Disease Control in mid-1981 that a new epidemic that eventually became know as AIDS had surfaced (39). Associations between other skin diseases and HIV infections have since been reported extensively. In a recent study of HIV-positive outpatients, among 55 men with a median age of 41 years and a median CD4 lymphocyte count of 125/µl, 93% had active oral conditions and 95% had skin conditions. Oral lesions included candidiasis, oral hairy leukoplakia, ulcers, Kaposi's sarcoma, and xerostomia while skin disorders included onychomycosis, dermatophytosis, seborrheic dermatitis, Kaposi's sarcoma, folliculitis, xerosis, and molluscum contagiosum (82).

               Infections comprise the largest category of dermatologic manifestations of HIV infection. In some cases, their mere presence alone is highly suggestive of HIV infection and the development of AIDS. Primary exposure to HIV leads to an acute infectious flu-like illness that is often associated with an eruption. The so-called acute HIV exanthem is seen with up to 90% of newly acquired HIV infections (1). This represents the earliest manifestation of HIV infection.

               Bacillary angiomatosis is a vascular proliferation caused by Bartonella henselae and Bartonella quintana (118) that usually involves the skin. It usually occurs as a late manifestation of HIV infection and in a study of 42 patients with bacillary angiomatosis, the median CD4 lymphocyte count was 21 cells/mm³ (83).

               Staphylococcus aureus is the most common cutaneous bacterial pathogen encountered in HIV-infected adults. Manifestations of staphylococcal disease include folliculitis, abscesses, cellulitis, furuncles, and impetigo. Most cases of folliculitis are caused by S. aureus, but other organisms such as S. epidermidis and Pseudomonas aeruginosa may also cause this complication (43). S. aureus may cause primary infections or secondarily infect underlying dermatoses or breaks in the epidermal integrity. Due to an increasing number of infections caused by methicillin-resistant S. aureus (MRSA) strains, therapy has become more important. High nasal carriage rates for S. aureus and altered immune function in conjunction with an impaired cutaneous barrier appear to play a role in the pathogenesis of infections in patients with HIV (67, 124).

               Syphilis is caused by the spirochete Treponema pallidum. Syphilis is a prevalent HIV manifestation and of all reported cases of syphilis between 1984 and 1990, 25% developed in HIV-infected individuals (102). Furthermore, sexually transmitted diseases that cause genital ulcerations may be cofactors for acquiring HIV infections (49).

               The most common viruses that cause skin lesions in HIV-infected patients are herpes simplex virus, varicella-zoster virus, molluscum contagiosum, cytomegalovirus, human papillomavirus, and Epstein-Barr virus. In the United States, herpes simplex virus infections develop in up to 20 to 50% of HIV infected patients at some point during their illness (113). In the immunocompetent host, recurrences are self-limited, but in those with severe immune suppression, recurrences may be progressive and may eventually lead to dissemination. Both herpes simplex virus types 1 and 2 are responsible for disease. HSV-1 most commonly causes the lesions in the mouth or lips while HSV-2 usually infects the perianal and genital areas. The virus is transmitted by mucous membrane contact and then travels along afferent nerves to the dorsal root ganglion. When it enters the cells of the dorsal root ganglion, the virus remains latent. Immunodeficiency during HIV infection allows the virus to become active which then travels along the efferent nerves to reinfect mucocutaneous surfaces.

               Molluscum contagiosum, a member of the pox family of viruses, predominantly affects children. Its occurrence in adults is rare except in immunosuppressed patients. In a study conducted by Husak, Garbe, and Orfanos, 456 patients with HIV-associated skin disorders were documented in the HIV follow-up clinics at the University Medical Center Department of Dermatology in Berlin during the years 1982-1992. Molluscum contagiosum was diagnosed in 39 patients (8.6%) and the median age was 34 years. Significant immunosuppression was present in the majority of patients with mollusca contagiosa at the time of their first diagnosis with median CD4 lymphocyte counts of 122/µl and the median CD4/CD8-ratio was 0.2. The median survival time was 12 months in those with mollusca contagiosa although there was no significant difference between the prognosis of patients with molluscum and other HIV-infected patients showing similar reduction of their immune status. Mainly localized to the face, molluscum lesions are easily diagnosed and may serve as an excellent clinical marker for recognizing advanced immunosuppression in HIV-infection (56).

               Up to 90% of patients with AIDS develop acute active cytomegalovirus (CMV) infection at some point during their illness (66). As with other viral infections, the frequency of this condition is diminishing because of the effects of HAART on the immune systems of these patients. CMV can result in several clinical illnesses, including colitis, esophagitis, chorioretinitis, and pneumonitis.

               Human papillomavirus is transmitted by skin to skin contact. HIV- infected individuals are at increased risk for developing intraepithelial neoplasm and invasive squamous cell carcinoma as a consequence of infection with oncogenic types of human papillomavirus such as 16 and 18.  These oncogenic human papillomavirus genotypes have been detected in 80% to 90% of cervical intraepithelial neoplasia grade 3 lesions and invasive cervical cancers (47, 98). In one study, 54% of homosexual men with AIDS were shown to have latent human papillomavirus infection of the anogenital area (93). Reports describe human papillomavirus in the anorectal carcinomas of homosexual men (42, 94). Cervical dysplasia and carcinoma is extremely common in HIV-infected women (95, 8a).

               Oral hairy leukoplakia is a benign oral lesion frequently seen in patients with HIV infections and has been noted in all the risk groups for AIDS. Evidence by histochemical analysis and electron microscopy has demonstrated Epstein-Barr virus in epithelial cells.

               Candidiasis, cryptococcosis, histoplasmosis, sporotrichosis, coccidioidomycosis, actinomycosis and aspergillosis are fungal infections seen in patients with symptomatic HIV disease and AIDS. The most common etiology of candidal infection is Candida albicans. Candida is a normal inhabitant of mucosal surfaces of the oropharynx. Mucosal candidiasis is a common finding in immunocompromised individuals. In fact, candidiasis may be the first clue to the presence of HIV infection (19). It has also been shown to be a reliable predictor for progression from HIV infection to AIDS.

               When highly pathogenic fungi infect AIDS patients, the outcome may be fatal. Cryptococcosis and histoplasmosis are systemic fungal infections most commonly found among patients with AIDS. Although these diseases occur in non-HIV-infected individuals, among HIV-infected patients, they tend to occur when the CD4 count is less than 200 cell/mm³. One case report described unusual cutaneous lesions resulting from co-infection with histoplasmosis and cryptococcus (85).

               Cryptococcus caused by Cryptococcus neoformans may develop in approximately 10% of those with AIDS (23, 59, 73, 75). Cutaneous lesions may precede or occur simultaneously with central nervous system (CNS) disease, specifically meningitis. Cryptococcal disease is the fourth most common cause of serious opportunistic infection after Pneumocystis carinii pneumonia, cytomegalovirus, and mycobacterial infection (13). The presence of cutaneous cryptococcosis in the absence of systemic disease is rare (26).

               Cutaneous lesions of histoplasmosis may develop in 10-17% of patients with systemic infection with Histoplasma capsulatum (20). The primary infection is subclinical. In immunocompromised individuals such as those with AIDS, the disorder becomes reactivated and hematogenous dissemination to the mucocutaneous surfaces can occur (20).

               Scabies is one of the most frequent skin conditions to develop in HIV-infected individuals. The causative agent is the mite Sarcoptes scabiei var. humanus. Although data regarding the overall incidence of scabies and HIV infection are not well documented, in one study, it was reported in 20% of patients (112). Scabies is spread by skin to skin contact or by contact with infested clothing or bedding (36).

              Eosinophilic folliculitis is the most common nonstaphylococcal form of folliculitis in HIV-infected individuals. This condition has been found to occur in approximately 5% of individuals who are HIV-seropositive (46). It is an important marker for advanced HIV infection due to this manifestation almost always develops in patients with CD4 lymphocyte counts below 200cells/mm³ (1).

               Papulosquamous eruptions are common is HIV-infected patients. These include seborrheic dermatitis, psoriasis and Reiter's syndrome. The incidence of seborrheic dermatitis has been estimated at 40% to 80% in patients with AIDS, 20% to 40% in HIV-seropositive patients without AIDS and in only 3 to 5% of immunocompetent individuals (77). Malassezia furfur is thought to play a role in the pathogenesis of seborrheic dermatitis by some.

               While psoriasis is not more common in HIV-infected patients, it may be more severe and more difficult to treat than in immunocompetent individuals. Overall, psoriasis develops in 5% of HIV-infected individuals (28, 63). The onset of severe psoriasis for the first time or a sudden exacerbation in a patient with previous stable psoriasis should alert the physician to the possibility of undiagnosed HIV infection (18). About one-third of cases represent exacerbation of known psoriasis. Psoriasis may develop at any point during the course of HIV infection but has been reported to be worse when CD4 cell numbers are between 50 cells/mm³ and 500cells/mm³ (19).

               Reiter's syndrome has been reported in 6 to 10% of HIV-infected patients (53, 64) although this is probably an overestimate. Patients with and without HIV infection have been associated with the presence of HLA-B27. It is unclear whether Reiter's syndrome is the result of an immune alteration secondary to HIV infection or the consequence of known risk factors such as enteric or sexually transmitted disease.

               Cutaneous drug induced eruptions are the most common manifestations of drug hypersensitivity in HIV-patients. The most common drug to cause eruptions is trimethoprim-sulfamethoxazole (TMP-SMX) which is used frequently in managing pneumocystis carinii pneumonia. Studies have demonstrated that 50-60% of HIV infected patients have been shown to develop a cutaneous eruption to this antibiotic. Other drugs that may cause cutaneous eruptions include zidovudine (ZDV/AZT, Retrovir®) and foscarnet.

               Kaposi's sarcoma is a vascular neoplasm first described by Moritz Kaposi in 1872. It is the most frequent neoplastic disorder seen in patients with AIDS (51). Shortly after the beginning of the AIDS epidemic, Kaposi's sarcoma was observed in approximately 50% of the male homosexual AIDS patients in San Francisco (110). This incidence has dropped significantly and is now reported in only 15% of HIV-seropositive patients, almost all of them homosexual men. The reason for this is not entirely known but may be related to the assumption of more safe sexual practices in the homosexual community. The disorder is far less common among intravenous drug users and is rare in women, hemophiliacs and their sexual partners. However, when Kaposi's sarcoma occurs in women, it is seen almost exclusively in women whose sexual partners are bisexual males (27). In addition to homosexual men, Kaposi's sarcoma has been reported in a group of homosexual men with no HIV infection yet with risk factors for such. In these patients Kaposi's sarcoma tends to have a more indolent course similar to that observed in elderly Italian and Jewish men (115).

               The cause of Kaposi's sarcoma is a sexually transmitted infectious agent. The virus, called Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus type 8 (HHV-8), has been detected in AIDS-related Kaposi's, as well as in the classical type (55).

DIFFERENTIAL DIAGNOSIS

               The acute HIV exanthem may mimic other viral exanthemata such as those caused by parvovirus, measles, and rubella.

               Confirmation of cutaneous bacillary angiomatosis either by culture, biopsy or serology is essential because lesions can mimic nodular Kaposi's sarcoma in appearance (54). Less frequently, pyogenic granuloma, cherry angioma, angiosarcoma, disseminated cryptococcus and dermatofibroma appear similar to bacillary angiomatosis.

               The differential diagnosis of folliculitis is extensive and includes the following: acneform disorders, eosinophilic folliculitis, chemical irritants, drug reaction, follicular atopic dermatitis, pityriasis rubra pilaris, chronic cutaneous lupus erythematosus and pseudofolliculitis barbae (36). Biopsy and culture may be required in order to establish a precise diagnosis.

               The list of diseases that may simulate syphilis includes many other bacterial and fungal infections as well as connective tissue diseases, Kaposi's sarcoma, and lymphoma. Lues maligna (ulceronodular syphilis) should be considered in individuals who present with ulcers and nodules lesions (117). Primary syphilis should be considered as a possible diagnosis of any genital lesion until it has been ruled out. In addition, it is important to consider cutaneous secondary syphilis in the differential diagnosis of virtually any inflammatory cutaneous disorder in HIV-seropositive individuals (45).

               The differential diagnosis of herpes simplex and varicella-zoster includes cellulitis, chancroid, contact dermatitis, and mycobacterial infection. A case of an AIDS patient with a chronic varicella zoster virus infection that simulated basal cell carcinoma has been reported (126).

               Clinically, solitary lesions of molluscum may mimic basal cell carcinoma, epidermal inclusion cyst, pyogenic granuloma, or keratoacanthoma. Multiple lesions may appear similar to condylomata acuminata, syringoma, or sebaceous hyperplasia. Disseminated cryptococcosis, herpetic folliculitis and penicilliosis may also appear similar to molluscum contagiosum (21). As a consequence, if the diagnosis is in question, a biopsy or smear should be done to exclude one of these more serious opportunistic infections.

               Cytomegalovirus cutaneous infection may present as prurigo nodularis-like lesions as well as purpuric lesions in the skin that may simulate vasculitis (15). The most common manifestation is an ulceration in which there is often concomitant infection with herpes simplex virus.

               Condyloma acuminatum must be differentiated from other papillomatous lesions including condylomata lata, granuloma inguinale as well as cutaneous malignancies such as Bowenoid papulosis and squamous cell carcinoma. These latter are usually caused by human papillomavirus infection and may develop from pre-existing condylomata acuminata.

               The differential diagnosis of oral hairy leukoplakia includes pseudomembranous candidiasis, condyloma acuminatum, geographic tongue, "leukoplakia", squamous cell carcinoma, white sponge nevus and the plaque form of lichen planus (116).

               Pseudomembranous candidiasis must be distinguished from oral hairy leukoplakia, condyloma acuminata, hairy tongue, and lichen planus. Cutaneous candidiasis may mimic psoriasis and erythrasma.

               The differential diagnosis of cryptococcus includes molluscum contagiosum (16,99), bacterial cellulitis, herpes simplex virus infection and Kaposi's sarcoma.

               Miliary tuberculosis, coccidiomycosis, cryptococcus, and lymphoma should also be considered in the differential diagnosis of disseminated histoplasmosis.

               Scabies in HIV infected patients must be distinguished clinically from a wide variety of disorders. Norwegian, or "crusted", scabies may appear similar to palmo-plantar hyperkeratotic disorders such as psoriasis. Diffuse scabies may mimic atopic dermatitis, or when the scalp is involved, it may simulate seborrheic dermatitis.

               Seborrheic dermatitis can be confused with psoriasis, scabies, dermatophytosis, pityriasis versicolor, and subacute lupus erythematosus.

               Psoriasis may have histologic features of other psoriasiform manifestations. Some of the other skin disorders that may progress to erythoderma include cutaneous T-cell lymphoma, drug eruptions, and atopic dermatitis (19). In addition, psoriasiform drug eruptions and glucagonoma syndrome must be ruled out.

               Reiter's syndrome must be distinguished from other forms of arthritis such as lupus erythematous and disseminated gonococcal infection.

               Eosinophilic folliculitis appears similar to a number of other pruritic dermatoses such as bacterial folliculitis, dermatophytic folliculitis, atopic dermatitis, scabies, insect bite reactions and dermatitis herpetiformis.

               Kaposi's Sarcoma must be distinguished from other vascular lesions such as bacillary angiomatosis, pyogenic granuloma, or glomus tumor. Malignant melanoma and lymphoma must also be ruled out in some cases.

RISK FACTORS

               Opportunistic and sexually transmitted infections have become more prevalent with the advent of AIDS and are also serious problems in other settings of immunosuppression. Behaviors associated with the development of HIV infection are, therefore, risk factors for the development of cutaneous manifestations. As the CD4 cell count decreases, the likelihood of an individual developing an unusual skin manifestation or a conditions that is more difficult to treat than usual increases.

               Bartonella henselae has been associated with cat exposure, namely, a cat scratch, bite, or potentially by the bite of cat fleas (69). Ownership of kittens or young cats pose a particularly high risk to HIV-infected persons for acquiring B. henselae-associated disease (123). As some patients with Bartonella infection do not have a history of cat exposure, other sources of infection probably exist. Infection with B. quintana is more frequently associated with homelessness and poor living conditions (44).

               Because syphilis is seen exclusively in humans and has no other known natural hosts, the most common route of spread is by direct sexual contact. There is a significant risk of transmission during primary, secondary and early latent stages that decreases in late stage disease (72). Factors that influence transmission of infection include the number of exposures, the type of sexual activity and the morphology and distribution of the lesions in the affected partner (11).

               Onorato and associates (92) found prior hospitalization, exposure to broad-spectrum antibiotics, presence of a central venous catheter, and dermatologic disease were risk factors for acquisition of methicillin-resistant S. aureus in their HIV-infected patient population.

               Herpes simplex virus usually establishes latency and as such, the infected person is a life-long source of contagion. It is transmitted in vesicle fluid, saliva, and vaginal secretions. Both types of HSV may cause either oral or genital lesions although HSV-1 is usually spread by oral contact or through the sharing of glasses, toothbrushes, or other saliva-contaminated items. In contrast, HSV-2 is spread mainly by sexual contact or autoinoculation or from an infected mother to her infant at birth.

               Potential sources of cytomegalovirus include saliva, urine, semen, breast milk, cervical and vaginal secretions, blood, and transplanted donor organs. The predominant mode of acquisition in adult life is sexual transmission. The type of sexual activity and the number of sexual partners are stronger predictors of the prevalence of CMV infection than race, age, or socioeconomic status.

               Close physical contact is usually necessary for molluscum contagiosum transmission although indirect transmission from shared towels and swimming pools may be responsible for infection in some cases. Shaving or scratching may cause the infection to spread.

               Human papillomavirus is common among sexually active people. Infections by this virus are transmitted by direct contact through breaks in the skin or mucosa. Inoculation can occur during sexual contact or and while an infant is passing through an infected birth canal. Human papillomavirus resists inactivation and can be transmitted on fomites such as the surfaces of counters or furniture, bathroom floors, and towels.

               Oral hairy leukoplakia has also been seen in other immunosuppressed states such as renal (62) and bone marrow transplant (31) patients. Epstein-Barr virus requires close person to person contact for transmission. Although Epstein-Barr virus is a ubiquitous virus, the risk of infection has statistically been shown to be lower in alcohol drinkers, those treated with fluconazole and those with increasing CD8 lymphocyte counts. Conversely, it has been found to be higher in higher in tobacco smokers (8).

               Cryptococcosis is distributed worldwide and its causative agent, Cryptococcus neoformans, is ubiquitous in soil and in bird droppings. Underlying conditions that most frequently predispose to opportunistic cryptococcosis include AIDS, leukemia, Hodgkin's disease, sarcoidosis and lymphoma. One case reported overwhelming cryptococcal disease that developed rapidly due, in part, to systemic corticosteroid therapy (6).

               Endemic areas for histoplasmosis include the Ohio and Mississippi River valleys, Haiti, Puerto Rico, and South and Central America (74). Infected individuals who have not visited endemic areas for many years likely represent reactivation of latent infection. It is transmitted by inhalation of fungal spores in soil contaminated with bird or bat droppings.

               Scabies is an obligate parasite of domestic animals and humans; however, it may survive for hours to days away from the host, thus facilitating its spread. Transmission is accomplished by direct contact or by contact with contaminated objects such as clothing. Sexual transmission has also been well documented. The infestation is thought to be spread to other areas of the body by scratching and manual transfer of mites. Scabies may occur in epidemic fashion when people are in crowded situations including nursing homes.

               Reiter's syndrome with and without HIV infection has been associated with the presence of HLA-B27. It is unclear whether Reiter's syndrome is the result of an immune alteration secondary to HIV infections or the consequence of a known risk factor such as enteric or sexually transmitted disease.

CLINICAL MANIFESTATIONS

               The correct clinical diagnosis of cutaneous manifestations in HIV-infected individuals may be difficult. Common cutaneous diseases may be florid and disseminated and may demonstrate unusual patterns. Many patients are likely to have more than one skin disease. Furthermore, clinical lesions may have more than one underlying etiology (91).

               The acute exanthem of HIV infection begins 2 to 4 weeks after exposure to the virus and may be associated with the prodromal symptoms such as fever, chills, lymphadenopathy, fatigue, pharyngitis and night sweats (60). Multiple erythematous macules and papules develop on the face, trunk and proximal upper extremities. Palms and soles may also be involved resembling secondary syphilis. The syndrome lasts for about 4 to 6 days and resolves with complete recovery.

               Bacillary angiomatosis is characterized by red to purple papules or nodules that resemble Kaposi's sarcoma or pyogenic granuloma in clinical appearance (101). Skin lesions range from solitary nodules to widespread papules and nodules. They range from one to several thousand and in size from 1 millimeter to several centimeters. Some lesions may be deeply seated, involving the subcutaneous tissue, underlying muscle, and bone (17). Oropharyngeal, gastric, esophageal, and endobronchial lesions have been reported (58). Virtually any organ system may be involved although the skin, liver, and spleen are the most common sites of involvement. Patients may develop systemic symptoms of weight loss, fever, and night sweats (68).

               Bacterial folliculitis is generally manifest as widely distributed acneiform papules and pustules. Lesions may be pruritic and excoriated and commonly involve the face, trunk or groin. If untreated, folliculitis may progress to abscesses, furuncles and/or carbuncles. Occasionally, cellulitis may supervene and the risk of systemic spread of infection is much greater in the HIV-infected individual. Although impetigo is seen most commonly on the face of immunocompetent individuals, in HIV seropositive patients, it is seen more often in the axillary, inguinal and other intertriginous locations. The infection begins with painful red macules that become vesicles and pustules and contain purulent fluid that rupture giving rise to the characteristic honey-colored crust.

               Primary and secondary syphilis usually present in characteristic fashion, namely a painless chancre in the former and a morbilliform eruption with a predilection for the palms, soles, and mucocutaneous areas in the latter. A number of unusual patterns may develop such as rapid progression from primary to the tertiary stage of mucocutaneous lesions and neurological involvement in a matter of a few months.

               Herpes simplex infection presents as painful grouped vesicles on an erythematous base at a mucocutaneous site. The vesicles rupture, crust, and heal in 7 to 10 days. Ulceration is commonly seen without a history of vesicles. In HIV infected patients, these ulcerations may be chronic and nonhealing. Any ulcerative or crusted lesion should be considered herpetic until proven otherwise. In the order of frequency, the most common sites of infection are the perianal, genital, orofacial, and digital (90). Furthermore, disseminated herpes virus infections may be seen that may cause significant morbidity and even mortality (19). Besides the skin, herpetic lesions in HIV-infected individuals can affect the brain, pericardium, liver, lung, esophagus, and eye (76, 132).

               Herpes zoster is usually manifest by painful vesicles on erythematous bases in a localized dermatomal distribution. However, in the HIV-infected patient, localized zoster infection may become multidermatomal and disseminated. In some cases of disseminated zoster, lung and central nervous system involvement may occur. When the nasal branch of the ophthalmic division of the trigeminal nerve is involved, the eye may become involved resulting in conjunctivitis, uveitis and keratitis (zoster opthalmicus) (107). Acyclovir-resistant herpesvirus infection is usually seen in patients with large, untreated, ulcerative lesions of herpes simplex virus and in those with chronic, verrucous lesions of varicella-zoster virus (124).

               Although not life threatening, molluscum contagiosum may lead to disfiguring cutaneous lesions. The lesions present as umbilicated, pearly 2- to 5-mm papules on the face, genital area, and scattered on the trunk. Mucosal surfaces are spared. Lesions may number from one to hundreds. In immunocompetent individuals, they may undergo spontaneous resolution but in immunocompromised hosts, lesions may persist for months to years. Viral structures recognizable as molluscum contagiosum are present within the clinically normal epidermis around molluscum lesions in many HIV-1-infected patients. This may explain the large number of lesions seen in these patients and the difficulty in controlling the spread and recurrence of the disease (121). A few cases of a localized dermatitis known as molluscum dermatitis have been reported which probably represents a localized cutaneous inflammatory process to rupture of lesions (4).

               Skin lesions due to cytomegalovirus infection are relatively uncommon. When the skin is involved, it may cause a number of different clinical manifestations including ulcers, verrucous lesions and palpable purpuric papules (32, 70). Vesicles, bullae, generalized morbilliform eruptions as well as hyperpigmented, indurated plaques have been reported (80, 84). The most commonly reported cutaneous CMV induced lesions are perianal ulcerations (2, 37, 89). A case of syringosquamous metaplasia of eccrine ducts caused by CMV infection has been reported (14a).

               Human papillomavirus induced lesions in HIV-infected patients usually appear similar to those in immunocompetent patients. Condylomata acuminata in men appear on the penis, urethra, scrotum, perianal, anal, and rectal areas. Perianal lesions appear as raised pink or brownish papules, usually in clusters, and occasionally, as large cauliflower-like lesions. When extensive, they may cause obstruction and constipation (19). Bowenoid papulosis presents as small, flat-topped, pink to brown papules usually on the shaft of the penis in males or vulva in females or on the perianal skin (19). Subclinical anal human papillomavirus infection is common in homosexual men and presents as diffuse foci of epithelial hyperplasia that are invisible on routine examination (108, 109). Therefore, in cases of anal lesions, anoscopy and biopsy are often required. Cervical and intravaginal condylomata acumina are commonly seen in women with external vulvar condylomata. All HIV-infected women should have a gynecologic examination with pelvic examination and Pap smears at initial evaluation and every 6 to 12 months as the risk for human papillomavirus infection is higher than in immunocompetent counterparts. Those with a known history of human papillomavirus infection or previously abnormal Pap smear results should have repeat testing every 6 months as the risk of human papillomavirus induced cervical carcinoma is much higher in this patient population.

               Oral hairy leukoplakia is manifest as white verrucous plaques usually found on the lateral margins of the tongue and buccal mucosa. Lesions range from a few millimeters to involvement of the entire dorsum of the tongue. It is usually asymptomatic; however, its presence may be associated with anxiety and complaints of dysphagia. Unlike thrush, oral hairy leukoplakia is not easily rubbed off with a tongue depressor. Infection with yeast such as C. albicans may be seen secondarily.

               Candidiasis may present as a mucocutaneous, perianal or vaginal infection. Pseudomembranous candidiasis (thrush) is the most common manifestation. Unlike oral hairy leukoplakia, these yellow-whitish loosely adherent plaques are easily removable from the oral mucosal surface. Lesions may appear at any location in the mouth or oropharynx and are often associated with symptoms of burning or changes in taste. Oral candidiasis is associated with an increased risk for HIV-associated peridontal disease (48). Angular cheilitis is characterized by erythema and fissures at the corners of the mouth that may be seen alone or in association with thrush. Vaginal candidiasis occurs in up to 50% of women early in the course of HIV infection (57). Esophageal candidiasis occurs at a later stage and is the AIDS-defining illness in 5% of patients (57). Cutaneous candidiasis occurs most commonly at moist cutaneous sites such as the inframammary, axillae, groin, and intergluteal cleft. These lesions usually appear as erythematous papules and pustules with satellite lesions in the periphery. Candida can produce paronychia, urethritis and balanitis.

               The diagnosis of cryptococcal infection should be considered in any patient with advanced HIV disease who presents with neurological or respiratory complaints. Cryptococcosis presents as widespread 2- to 5-mm dome-shaped translucent papules distributed on any body part but most commonly of the head and neck. These lesions bear a striking resemblance to the papules of molluscum contagiosum (106). Mucocutaneous lesions of cryptococcosis are polymorphous and may appear as erythematous papules, nodules, pustules, or ulcers of the skin and mucosa (73).

               Clinically, the lesions of histoplasmosis may appear as cutaneous and mucosal ulcers, erythematous macules and patches, fistulas, papules and nodules, pustules, and verrucous plaques (14, 52, 61, 71).

               Scabies may have many different clinical manifestations in those with HIV infection. The mite resides in the cornified layer, eventually inducing an immune response to mite products. The clinical presentation can vary from only scattered pruritic papules accompanied by slight scale to papulosquamous eruptions that may resemble atopic dermatitis. Hyperkeratotic plaques present on the palms, soles, trunk, or extremity may develop (19). Most patients complain of intense pruritus that is usually worse at night. Secondary infection is common in association with scabies and should be excluded in all cases. Furthermore, contacts are almost always infected so that they also require treatment.

               Seborrheic dermatitis is characterized by moderate to severe scaling and erythema of the scalp and face, especially the eyebrows, glabella and nasolabial folds. The scale is characteristically fine, yellowish and greasy. Involvement of the axillae and groin is common. When limited to the face, lesions are usually asymptomatic, but scalp and trunk lesions are often pruritic.

               Clinically, patients with eosinophilic folliculitis develop pruritic follicular papules measuring 1-4 mm in diameter. Most commonly, these lesions are found on the upper trunk, face, neck, and proximal upper extremity. Patients often have many lesions, often numbering in the hundreds. Individual lesions may coalesce into plaques and may undergo spontaneous exacerbations and remissions. Virtually all cases are associated with lichenification secondary to chronic rubbing and scratching. As with scabies, this may eventually lead to the development of prurigo nodularis.

               Psoriasis in the HIV-infected individual tends to be more severe, characterized by widely disseminated, thickened, red plaques with superimposed thick adherent and silvery scales located on the glabrous skin and scalp (41). Psoriatic arthritis may supervene. The nails on the feet and hands frequently demonstrated pitting and are often thickened. Pruritus and secondary infections may develop and are difficult to manage.

               Keratoderma blenorrhagicum and circinate balanitis are characteristic skin lesions of Reiter's syndrome seen in HIV-infected patients in association with the triad of arthritis, conjunctivitis, and urethritis. Lesions resemble those of psoriasis. The palms and soles are involved and develop superficial pustules and thickened plaques often with fissures. There is nail dystrophy with periungal erythema, inflammation, hyperkeratosis and prominent crusting. The glabrous skin, glans penis, and scalp areas are also affected.

               Most drug eruptions caused by TMP-SMX occur in the second week of therapy and demonstrate a morbilliform morphology that may involve the entire skin surface. Anaphylaxis and fatal bullous eruptions, such as erythema multiforme or Stevens-Johnson syndrome, can occur but are rare. Nevertheless, a severe drug reaction should always be considered in any HIV infected patient with fever and an evolving eruption. Zidovudine may induce several cutaneous complications such as nail and mucous membrane hyperpigmentation. In addition, severe exanthematous eruptions may develop within 1 to 2 weeks following initiation of zidovudine. Foscarnet may cause ulcers as a consequence of direct toxicity of the agent on mucous membranes.

               The skin is most commonly the first site of presentation for Kaposi's sarcoma. It generally presents with one or more purple to violaceous macules, papules, or nodules. The surface of lesions usually has a somewhat shiny appearance. Individual lesions may be asymptomatic although pain and burning may develop. In advanced disease, cutaneous lesions can become confluent and form large tumor masses. Unlike patients with classical Kaposi's sarcoma, lesions may be present on any part of the body especially the head, neck, oral cavity, trunk, and legs (86) and tend to follow the lines of cutaneous distribution (105). In addition, the lesions of AIDS-related Kaposi's sarcoma, in contrast to those of classic Kaposi's sarcoma, tend to be smaller initially and frequently involve the mucous membranes, lymph nodes, and gastrointestinal tracts (79). Visceral involvement is extremely common and can involve almost any visceral site. Kaposi’s sarcoma of the bowel and/or lung is the cause of death in 10% to 20% of patients.

DIAGNOSIS

               A variety of tests are needed to diagnose skin lesions correctly. It is important that clinicians be aware of the manner in which unusual opportunistic infections may present and that they maintain close communication with pathology and clinical microbiology laboratories to ensure that proper stains and cultures are performed to avoid potential misdiagnosis (129).

               Histologic examination of biopsy specimens is often helpful. For example, when assessing a potential lesion of oral hairy leukoplakia, a biopsy is required if the diagnosis is in doubt as the differential diagnosis includes mucosal malignancy. Histologically, oral hairy leukoplakia demonstrates marked digitation and papillomatosis, hyperkeratosis, acanthosis, vacuolation of the upper keratinocytes, and usually minimal subepithelial inflammation (19). Many inflammatory diseases, some of them potentially life threatening such as opportunistic infections, demonstrate nondescript features or may simulate a less serious condition. These processes, too, should undergo biopsy if the diagnosis is in question.

               The diagnosis of the acute HIV exanthem is based on the clinical suspicion of HIV infection through history and physical examination and diagnostic tests. Seborrheic dermatitis, psoriasis, condylomata acuminata, and Kaposi's Sarcoma, and Reiter's syndrome can usually be diagnosed on the basis of clinical and histologic features. Physicians must rule out other spondylo- and reactive arthropathies when the clinical picture is suggestive of Reiter's syndrome. No specific laboratory findings are associated with Reiter's syndrome other than the presence of HLA-B27.

               The diagnosis of bacterial infection such as staphylococcal disease is confirmed by Gram stain, culture and/or histopathology. Potassium hydroxide preparations should be performed to rule out the diagnosis of a fungal infection in the appropriate circumstances.

               The most common histological pattern of bacillary angiomatosis is a lobular vascular proliferation of round blood vessels with plump epithelioid cells in the interstitium (17). Numerous neutrophils are seen within the substance of lesions. Because Kaposi's sarcoma lesions can appear quite similar to bacillary angiomatosis clinically, it is reasonable for a biopsy to be considered when a new vascular lesion develops in an HIV infected patient. Gram-negative coccobacilli are usually detectable by a silver stain such as the Warthin-Starry stain. Bartonella antibodies in the serum of patients with bacillary angiomatosis can be detected by an indirect fluorescence antibody (104). Isolation of Bartonella directly from cutaneous bacillary angiomatosis lesions is also possible but difficult due to its fastidious characteristics.

               In syphilis, Standard Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests are used for screening while fluorescent treponemal antibody absorption tests (FTA-abs) and MHA-TP are used to confirm positive screening tests. VDRL and FTA-abs in HIV patients may be unreliable on occasion, however, yielding higher rates of false negatives. In questionable cases, a biopsy of a skin lesion for darkfield examination or direct fluorescent antibody (DFA) may be necessary. A positive darkfield examination or DFA stain is diagnostic even with negative serology.

               Viral infections are diagnosed by means of clinical findings, viral cultures, and smears. In herpes simplex and varicella-zoster, viral culture remains the gold standard for the diagnosis of active HSV infections. For rapid diagnosis of herpesvirus infection, a Tzanck smear can be performed. Multinucleated virally infected cells are visualized by microscopic examination of a Wright's or Giemsa stain of scrapings from the roof and base of a herpetic ulcer. Other methods include direct antigen detection by immunofluorescent, immunoperoxidase, or enzyme-linked immunoassay; serology demonstrating seroconversion; and biopsy of the skin from the edge of the ulcer. Type specific polymerase chain reaction-based assays performed directly of specimens taken from ulcerations have been shown to be quick and effective means from HSV detection (87).

               The diagnosis of molluscum contagiosum is usually made on clinical findings. Molluscum bodies may be detected by Giemsa-stained smear of the central keratotic plug. Histopathologically, pinkish oval shaped molluscum bodies are seen within the cytoplasm of suprabasilar keratinocytes.

               Stains for fungi and acid-fast bacilli should be performed routinely on histologic sections taken from patients with HIV infection, especially if the possibility of an infection exists. In addition, fungal infections such as candidiasis can be diagnosed with potassium hydroxide preparation from the affected area showing pseudohyphae and budding yeasts. Cryptococcosis and histoplasmosis require confirmation by skin biopsy and culture. Special stains such as the periodic acid-Schiff (PAS) and Gomori methamine silver are often needed to facilitate detection of organisms in tissue. When the number of microorganisms is small, the sensitivity of diagnosis can be increased by immunoperoxidase staining using antibodies directed to fungi that cross-react with them.

               Any patient with severe, intractable pruritus and a scaly dermatosis should be examined for scabies. The physician should check thoroughly for burrows in the digital webs, flexor aspects of the wrists, vulva, or penis. Microscopic examination of potassium hydroxide or oil preparation may show mites, eggs, and/or fecal pellets.

               The diagnosis of eosinophilic folliculitis is based on clinical features and biopsies and scrapings when appropriate. Cultures taken from skin lesions are usually negative although occasionally Corynebacterium may be isolated. The serum IgE and blood eosinophil count may be raised. Skin biopsy reveals numerous eosinophils surrounding and within the lumina of hair follicles. Features of lichen simplex chronicus and/or prurigo nodularis are often present in long-standing lesions.

Invasive Diagnostic Tests

               When dealing with skin diseases, the correlation of microscopic findings with clinical morphology as well as the results of laboratory tests is of utmost importance in arriving at the correct diagnosis. This is especially true when dealing with immunocompromised patients such as those with AIDS. In dermatology, the most invasive diagnostic test performed is the skin biopsy. When dealing with inflammatory processes, most are performed by punch technique although saucerization and incision techniques are used on occasion.

               Skin biopsies are performed for diagnostic purposes as well as to perform morphological studies of the histogenesis and/or pathogenesis of a dermatosis or neoplasm. Although most skin biopsies performed in HIV infected patients are taken from inflammatory conditions, neoplastic conditions such as Kaposi's sarcoma, squamous cell carcinoma and lymphoproliferative processes such as lymphoma also require biopsies routinely. Skin biopsies are often required in defining infectious processes such as fungal infections, mycobacterial infections, bacillary angiomatosis and unusual presentations of herpes virus infection such as verrucous herpes infection. Inflammatory conditions such as psoriasis, the exanthems of the acute retroviral replication, and drug eruptions which may be correlated with the decline and dysregulation of immune function should be considered for biopsy especially if the clinical diagnosis is in question. In addition to routine, direct morphologic examination, a skin biopsy may be submitted for culture and special studies such as immunofluorescence, immunohistochemistry, electron microscopy, and molecular biology studies. The performance of a skin biopsy is a simple procedure so that it should be done virtually any time a neoplasm or an infectious process is suspected and should probably be considered to be a part of the work-up of most cutaneous diseases in HIV infected patients.

MANAGEMENT

               In HIV-infected individuals, cutaneous manifestations may be more extensive and refractory to treatment. The use of combination drug regimens known as Highly Active Anti-retroviral Therapy (HAART), most commonly in the form of two nucleoside reverse transcriptase inhibitor drugs plus a protease inhibitor, has the capability of profoundly suppressing viral replication with the reconstitution of patients' CD4-positive lymphocyte counts (38). HAART has resulted in a significant drop in morbidity and mortality with patients living significantly longer than before advent of this regimen (96). It has also resulted in a significant decrease in the incidence of many of the cutaneous disorders that were observed in severely immunocompromised patients. In addition, however, a new condition known as the Immune Restoration Syndrome has been recognized of which skin disorders may be a component. Molluscum contagiosum and pneumocystis carinii pneumonia have decreased in incidence. Furthermore, patients with Kaposi's sarcoma may demonstrate an almost immediate arrest in the development of new lesions as well as diminution in the number of lesions while the HIV viral load remains below the level of detection. In some cases, lesions disappear altogether so that the initial treatment of choice of cutaneous Kaposi's sarcoma today is initiation of HAART with observation. Other conditions may improve dramatically as well. In one report, Spach and Colven describe an HIV-infected man with persistent, severe warts of the hand that did not respond to multiple treatments including liquid nitrogen cryotherapy, topical dinitrochlorobenzene, topical podophyllin and intralesional interferon-alpha injections (122). Approximately 1 year after starting a potent protease inhibitor-containing antiretroviral regimen, the patient's recalcitrant cutaneous warts markedly diminished in size even though the patient did not receive any additional specific therapy for the warts. The patient continued on a potent protease inhibitor-containing antiretroviral regimen and, approximately 2 years later, the warts completely resolved.

               In addition to improvement of skin diseases, there have been new complications associated with improved immune status. Eosinophilic folliculitis may initially flare with institution of HAART but it tends to clears as the CD4 count rises above 100 to 250cells/µl. While on continuous therapy, patients have also developed sulfamethoxazole/trimethoprim allergy associated with high fever, conjunctivitis and a morbilliform eruption. Development of herpes zoster has been observed when CD4 cell counts rise to a level of between 300 and 500 cells/µl. New complications of sarcoidosis (81) and mycobacterial infections (24) have also been reported. Protease inhibitors themselves have retinoid-like effects and lead to an increase in triglycerides, cholesterol, glucose, and lactic acid (50). Disorders of fat and fat metabolism have been reported and patients may develop multiple angiolipomas and lipomas. Furthermore, 60% of patients on HAART therapy of long duration develop a thickened neck and fat loss on the cheeks. Some of the other findings include peripheral fat loss, central fat gain and development of a "buffalo hump" (97, 114). In addition, protease inhibitors may induce a spongiotic dermatitis, xerosis, alopecia, and paronychia. Most of these side effects are seen with Crixivan (Indinavir).

               Unfortunately, strains of HIV have been isolated that are resistant to all current protease inhibitors and reservoirs of HIV have been found in patients receiving HAART who have detectable viral loads (22, 34). This suggests that although multi-drug therapy can profoundly suppress viral replication, it is not able to completely eliminate the virus from the body.

               In most patients, bacillary angiomatosis is a self-limiting disease although it may be serious. The disease responds well to antibiotics, specifically erythromycin and some of the quinolones. The optimal length of antibiotic treatment in HIV-positive patients with bacillary angiomatosis is not yet known. Disseminated disease and a fatal outcome may follow inadequate therapy (119). Monitoring by PCR on the success of the treatment may be needed to determine the appropriate duration of treatment in some cases.

               Carriers of S. aureus should undergo treatment directed at eradication of any acute infection as well as nasal carriage. Oral prophylaxis with antistaphylococcal antibiotics as well as by washing with antibacterial soap or application of benzoyl peroxide containing preparations are often initially successful although recolonization is common. Uncomplicated folliculitis is treated with topical antibiotic agents. For more advanced infections such as furuncles or carbuncles, incision and drainage should be performed and antibiotics should be administered. Impetigo usually responds readily to topical antibiotics although in HIV infected patients, systemic antibiotics may be required.

               A number of effective antiviral agents are available for the treatment of many of the cutaneous viral infections. Topical and intralesional cidofovir may offer significant promise in the treatment of human papillomavirus, herpesviruses (including acyclovir-resistant strains), Kaposi's sarcoma-associated herpesvirus, and molluscum contagiosum (131). Depending on location and severity, treatment for herpes simplex and varicella-zoster requires oral, intravenous, or topical thymidine kinase inhibitor. Maintenance may be necessary in patients with advanced illness. Acyclovir-resistant herpes infections have been reported (5, 10, 124) but usually respond well to foscarnet therapy.

               Condyloma acuminata are usually treated initially with topical preparations such as podophyllotoxin or imiquamod. Refractory genital warts are treated with destructive measures such as the application of salicylic acid or trichloroacetic acid, cryotherapy or electrocauterization. Relapse is almost to be expected. It is important to examine and treat sexual contacts if they are affected.

               Treatment of molluscum contagiosum is generally by cryotherapy. Other destructive modalities used are light electrocautery, curettage and application of cantharidin. As with a number of other minor viral infections in HIV-infected individuals, when therapy with protease inhibitors is initiated and the CD4 lymphocyte count rises, the lesions may undergo regression. The pulse dye laser has been used with some success as well (88). As with papillomavirus infection, treatment of these lesions is problematic as they tend to recur and spread to other skin sites. In those with lesions in the beard area, shaving should be minimized to lessen the likelihood of spread.

               Oral hairy leukoplakia often requires no treatment. Local destructive measures with podophyllin containing preparations may be beneficial (65). Oral hairy leukoplakia has also been noted to regress with HAART.

               The frequency with which fungal infections are being reported is on the decline both as a consequence of early administration of systemic prophylactic antifungal agents and protease inhibitors. Although antifungal treatment is highly effective, recurrences are common so that chronic suppressive treatment may be required in some patients. Cutaneous candidiasis may be prevented by keeping intertriginous areas dry by keeping them cool and by the application of powders containing miconazole.

               In patients with scabies infestation, lindane cream or lotion or 5% permethrin cream applied from head to toe and left in place for 8 to 12 hours and then washed off is effective in uncomplicated cases. Alternating treatment with lindane and permethrin may be needed if resistance is documented or suspected and multiple treatments may be required. In severely immunocompromised patients or those with crusted scabies, a single oral dose of ivermectin (Stromectin) is highly effective although in some cases, more than one dose may be required. Administration of antipruritic agents is important as pruritus is often severe. Household and other contacts should also be treated and careful laundering of linen and clothing is necessary.

               Treatment of seborrheic dermatitis is palliative, not curative. As with other skin disorders in AIDS patients, it may be resistant to the traditional treatment regimens that consist of application of topical corticosteroid preparations and use of tar or selenium containing shampoos. In some cases, antifungal agents are partially effective.

               Depending on location and severity of psoriasis, topical corticosteroids, emollients, salicylic acid, crude coal tar, ultraviolet light (UVB), systemic retinoids, psoralen plus ultraviolet light A (PUVA) and/or methotrexate therapy should be considered. PUVA and UVB have been associated with upregulation of HIV production and the exacerbation of Kaposi's sarcoma (28), but if used with caution, patients tolerate these regimens well and not increase in morbidity or mortality have been repeatedly documented. (78, 103). Furthermore, HAART prevents the upregulation of HIV that might theoretically occur, further ensuring the safety of UV exposure in these individuals. Zidovudine at high doses has been used for HIV-infected individuals with psoriasis although it is not highly effective in most patients (29, 111, 25, 30). Treatment for Reiter's Syndrome is similar to psoriasis, except methotrexate is a relative contraindication (130, 28). Patients who receive methotrexate should not take TMP-SMX concomitantly as this causes rapid immunosuppression.

               Relief of pruritus is an important first goal in the treatment of eosinophilic folliculitis. Topical agents such as corticosteroid and permethrin cream are occasionally effective although systemic agents such as prednisone, isotretinoin, itraconazole and metronidazole are often required. Treatment with UVB phototherapy is also often quite effective (12).

               The first and most important part of the treatment of a cutaneous drug eruption is its early recognition and removal of the offending agent. Drug eruptions in HIV infected patients may persist long after the agent has been withdrawn and recurrences are likely if the patient is rechallenged. Hypersensitivity to trimethoprim-sulfamethoxazole has been successfully treated with desensitization and desensitization to other antibiotics may be attempted when necessary (33).

               Cutaneous Kaposi's sarcoma is rarely life threatening and consequently, the primary goals for therapy are palliation of symptoms and improvement of cosmetic appearance. Treatment must be individualized according to the extent and location of lesions, the presence of other AIDS associated manifestations, and the patient's desire for treatment. Local treatment includes intralesional chemotherapy, cryotherapy, application of retinoids and local radiotherapy. In those with extensive or symptomatic disease, both alpha-interferon and cytotoxic chemotherapy such as vinblastine, bleomycin, vincristine, etoposide, and doxorubicin are effective. However, the risk of opportunistic infections may be increased (100) and there is no significant difference in survival between the group of patients treated with chemotherapy and those who received no treatment (127).

CONCLUSIONS

               The HIV pandemic transformed the practice of medicine in the late 20th century and continues to challenge us in the new millennium. New effective treatments have been developed that allow patients to live much longer although they are associated with side effects that cause problems with quality of life. Many challenges remain before we can declare victory over this infectious disease and we must remain vigilant as strains resistant to new antiretroviral treatment regimens have already been documented. The skin remains an important site where complications develop both as a consequence of the disease itself as well as from complications related to therapy. Clinicians, especially those who care for individuals with HIV infection must continue to remain educated about how to recognize and treat the myriad cutaneous manifestations that may arise in this setting.

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