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AIDS
AIDS Timothy G. Berger, MD Since the appearance of acquired immunodeficiency syndrome (AIDS) in the late 1970s and early 1980s, more progress has been made in a relatively short time on the understanding of this disease and its cause, the human immunodeficiency virus (HIV), than for any other human infectious disease. As the new millennium begins, much of this knowledge has been transferred to the clinical setting. HIV infection has become a chronic disease (like diabetes) which, although fatal, can be treated. In addition, the HIV epidemic has led to our understanding the cause of other conditions previously recognized but of unknown pathogenesis. Kaposi's sarcoma (KS) and cat-scratch disease (Bartonella henselae infection) are examples. HIV infects and kills human helper T cells, leading to a progressive immunodeficiency disease. In its end stages, the condition is called AIDS. Cutaneous manifestations are prominent and appear in up to 90% of HIV-infected persons. Patients have many different skin lesions. The presence of skin lesions or combinations of skin conditions is sufficiently unique to arouse suspicion of HIV infection. The skin findings can be classified into 3 broad categories: (1) infections, (2) inflammatory dermatoses, and (3) neoplasms. The skin conditions also appear at specific times in the progression of HIV disease, making them useful markers for the various stages. In most patients, the natural history of HIV infection involves a gradual loss of helper T cells. The rate of decline varies; it is rapid in some patients and slow in others. Patients in which the decline does not occur are called long-term nonprogressors. Soon after infection, a seroconversion syndrome called primary HIV infection, or acute infection, occurs; patients in this stage are in group I. Patients recover from this syndrome and enter group II (asymptomatic), a relatively long latent stage that lasts approximately 10 years. During this period, patients (group III) may have persistent generalized lymphadenopathy. When symptoms begin to appear they are often nonspecific and include fever, weight loss, chronic diarrhea, and mucocutaneous disease; group IVA comprises these patients. (These nonspecific signs and symptoms are termed AIDS-related complex.) Helper T-cell counts in group II, III, and 30
IVA patients usually range from 200 to 500/mL. The skin findings at the AIDS-related complex stage include seborrheic dermatitis, pruritus ani, psoriasis, Reiter's syndrome, atopic dermatitis, herpes zoster, acne rosacea, oral hairy leukoplakia, onychomycosis, warts, recurrent Staphylococcus aureus folliculitis, and mucocutaneous candidiasis. When the helper T-cell count is 200/mL or less, the patient is considered to have AIDS. In this stage, the skin lesions are more specific of immunodeficiency and include characteristic opportunistic infections such as chronic herpes simplex, molluscum contagiosum, bartonellosis (bacillary angiomatosis), systemic fungal infections (cryptococcosis, histoplasmosis, coccidioidomycosis, and penicilliosis), and mycobacterial infection. Paradoxically, patients at this stage also have hyper-reactive skin and frequently have inflammatory (often pruritic) skin conditions such as eosinophilic folliculitis, granuloma annulare, drug reactions, and photodermatitis. When the T-cell count falls below 50, the patient is often said to have "advanced AIDS." These patients may present with unusual opportunistic infections such as multicentric, refractory molluscum contagiosum; chronic herpes simplex; chronic cutaneous varicella zoster infection; cutaneous acanthamebiasis, cutaneous atypical mycobacterial infections (caused by Mycobacterium avium complex and Mycobacterium hemophilum), and crusted scabies. Treatment of these infections is often difficult as a result of the patient's marked chronic immunosuppression. It is now clear that HIV itself causes the loss of helper T cells, and that effective treatment of HIV infection may halt or reverse the progress of HIV disease. There are numerous antiretroviral agents and they are usually used in combinations called "cocktails." This combination treatment is called "highly active antiretroviral therapy" (HAART). About half of HIV-infected patients respond to this treatment, and their condition might dramatically improve. The HIV virus disappears from the blood and helper T-cell counts rise. As expected, in patients who respond to HAART, opportunistic infections no longer occur, and the mortality rate decreases. This is also true of cutaCurr Probl Dermatol, January/February 2000
neous infectious conditions, but is not true of all the inflammatory disorders seen in patients with AIDS. The HIV-associated psoriasis improves, especially if zidovudine is part of the therapeutic cocktail. With HAART, however, eosinophilic folliculitis and drug eruptions might become more frequent or more severe.
Primary HIV Infection (Acute Seroconversion Syndrome) In a large proportion of persons infected with HIV, an acute illness develops several weeks after the infection occurs. The clinical syndrome is much like that of an Epstein-Barr virus infection, in that fever, sore throat, cervical adenopathy, a rash, and ulcerations of the oral, genital, and rectal regions are present. The skin eruptions may be polymorphous. Most characteristic is the eruption of discrete, slightly scaly, oval papular lesions of the upper trunk. These lesions superficially resemble those of pityriasis rosea, but the peripheral scale is not prominent and there is focal hemorrhage in the lesions. An eruption resembling the papules of Gianotti-Crosti syndrome might also occur. The mucosal erosions resemble aphthae, but are larger and can affect the mucosa of all parts of the mouth, pharynx, esophagus, and anus. Dysphagia might be prominent. The helper T-cell count falls abruptly during seroconversion. The level of immune impairment might be adequate to allow oral candidiasis or even Pneumocystis carinii pneumonia to occur. The disease should be suspected in any at-risk person having the correct constellation of symptoms. Direct measurement of the HIV viral load will confirm the diagnosis. Combination antiviral therapy is instituted immediately in these patients with the hope of halting or reducing the progression of the disease.
HIV-Associated Pruritus Since the early days of the HIV epidemic, it was clear that pruritus was a marker for HIV infection as it occurred throughout the world. Pruritus is not a result of HIV disease itself; it is related to the inflammatory dermatoses associated with the disease. "Papular pruritic eruption" is not a specific disease, but a "wastebasket" term used to describe the lesions seen in patients with many forms of HIV-associated pruritus. These eruptions are best subdivided as follicular and nonfollicular eruptions. The follicular eruptions are more common. Eosinophilic folliculitis is the most common pruritic follicular eruption. It is seen in patients with a helper Curr Probl Dermatol, January/February 2000
T-cell count of approximately 200/mL. Patients with this condition present with urticarial follicular papules on the upper trunk, face, scalp, and neck. Pustular lesions are uncommon; the pustules are usually smaller than those seen in cases of bacterial folliculitis, and represent end-stage lesions. These lesions are infrequently seen because the pruritus is so severe that the lesions are excoriated before they evolve to this degree. Ninety percent of the lesions appear above the nipple line on the anterior trunk, head, and neckl They typically extend down the midline of the back to the lumbar spine. The disease increases and decreases in severity, and might spontaneously clear up, only to unpredictably occur again. A peripheral eosinophilia may be present and the serum IgE level may be elevated, suggesting that the disorder is mediated by T H 2 helper T cells. Histologically, an infiltrate of mononuclear cells and eosinophils is seen around the upper portion of the hair follicle at the level of the sebaceous gland. As lesions evolve, eosinophils and lymphocytes enter the follicular structure and the sebaceous glands. Pustules form late and represent aggregates of eosinophils in the uppermost part of the follicle. Initial treatment consists of giving topical steroids and antihistamines. If the patient fails to respond, phototherapy (ultraviolet B or psoralen plus ultraviolet A) or the twice-daily administration of 200 mg itraconazole may be effective. In some patients, repeated applications of permethrin (every other night for up to 6 weeks) may be beneficial; this is directed at demodex mites, which might be the antigenic trigger of this condition. Isotretinoin is also effective, often after a few months, at a dosage of about 0.5 to 1 mg/kg/day. Staphylococcal folliculitis (which might be severely pruritic in the setting of HIV disease) and pityrosporum folliculitis should be included in the differential diagnosis. These are ruled in or ruled out with the results of bacterial culture and skin biopsy, respectively. The nonfollicular pruritic dermatoses can be divided into 2 types of eruptions: (1) primarily papular and (2) eczematous. The papular eruptions include scabies, insect bites, transient acantholytic dermatosis, granuloma annulare, and prurigo nodularis. The eczematous dermatoses include atopic-like dermatitis, seborrheic dermatitis, nummular eczema, xerotic eczema, photodermatitis, and drug-related eruptions. Patients may have multiple eruptions, making differential diagnosis difficult. The results of skin biopsies from every mophologic type of lesion might elucidate the true diagnosis(es). Determined by the diagnosis, treatment is 31
similar to that of persons with these same dermatoses, but without HIV infection. Special considerations in treating AIDS patients include the use of ivermectin for crusted scabies, and thalidomide for prurigo nodularis and photodermatitis. Both agents are effective if used appropriately.
HlV-Associated Neoplasia Neoplasia is prominent in HIV infection; in some cases, it is highly suggestive of the condition; KS is an example. Others include superficial basal cell carcinomas of the trunk, squamous cell carcinomas in sun-exposed areas, genital human papillomavirus (HPV)-induced squamous cell carcinoma, and extranodal B- and T-cell lymphoma. Nonmelanoma skin cancers are common in HIVinfected persons and usually occur as superficial multicentric basal cell carcinomas on the trunk in fairskinned men aged 20 to 59 years. The ratio of basal cell carcinomas to squamous cell carcinomas is not reversed in HIV disease, as in organ transplant recipients. Basal cell carcinomas behave as they do in immunocompetent hosts, and standard management is usually adequate. Actinically induced squamous cell carcinomas are also quite common, and patients present with nodules, keratotic papules, or ulcerations. In most cases the behavior of these carcinomas is relatively benign and standard management is adequate. Removal of sqnamous cell carcinomas in sun-exposed areas by curettage and desiccation in the setting of HIV infection is associated with an unacceptably high recurrence rate of approximately 15%. Complete excision is therefore recommended. In a small subset of AIDS patients, the actinic squamous cell carcinomas can be quite aggressive. They might double in size over weeks and metastasize to regional lymph nodes or to viscera, leading to the death of the patient. Nonmelanoma skin cancers in the HIV-infected patient behave in a manner intermediate between that of a normal host and that of an organ transplant recipient. In the setting of HIV infection, genital squamous cell carcinomas associated with HPV infections occur on the cervix, vagina, anus, penis, and nailbed. These neoplasms occur with increasing frequency and the progression from HPV infection to neoplasia appears to be accelerated. This is analogous to the situation in organ transplant patients and other immunosuppressed patients. It appears that these cancers are associated with primarily "high-risk" types of HPV infections. 32
For the dermatologist, there are 3 important manifestations of high-risk genital HPV infection. The most common is perianal dysplasia, seen frequently in homosexual men with a history of receptive anal intercourse. Dysplasia occurs as velvet-like white or hyperpigmented plaques, and involves the whole anal area, including the anal canal. These lesions might erode or ulcerate. Histologic examination shows squamous cell carcinoma in situ. The risk that these lesions will progress to anal squamous cell carcinoma is unknown, but is estimated at no less than 10 times the frequency of cervical cancer in women of the general population. The management of patients with such conditions is unclear, but regular follow-up is clearly indicated, and any mass appearing in the anal canal should be immediately referred for biopsy. Flat, white, or hyperpigmented macules a few millimeters to several centimeters in diameter might develop in the vulvar and penile skin. These show squamous cell carcinoma in situ, and are analogous to bowenoid papulosis in the immunocompetent host. Rare cases of progression to squamous cell carcinoma have occurred. Such lesions are best watched closely and cases should be managed conservatively, as with cases of warts. Lesions of the penis and vulva but not at a transition zone or on a mucosal surface have a low risk of progressing to invasive squamous cell carcinoma. Lesions of the glans penis that are red and fixed should be referred for biopsy. If biopsy results show changes of squamous cell carcinoma in situ, patients with the condition should be aggressively managed, as with erythroplasia of Queyrat. Topical 5-fiuorouracil and superficial radiation therapy are effective and close clinical follow-up is indicated. Periungual squamous cell carcinoma has also been seen in patients with HIV infection and is felt to be associated with high-risk HPV types. Any persistent keratotic or hyperpigmented lesion in the periungual area must be carefully evaluated. Management of such cases involves surgical excision of the lesion. Extranodal B-cell and, less frequently, T-cell lymphomas are associated with the advanced immunosuppression of AIDS. In cases of B-cell lymphomas, and some T-cell lymphomas, patients present with violaceous or plum-colored papules, nodules, or tumors. When the diagnosis is established from biopsy results, systemic chemotherapy is required for treatment. Epstein-Barr virus is found in some cases. Mycosis fungoides might also be seen in the setting of HIV infection, often in patients in which AIDS has not yet Curr Probl Dermatol, January/February 2000
developed. Patients present with pruritic patches or plaques that might progress to the tumor stage. Epstein-Barr virus in not found in these cases. Malignant melanoma is occasionally seen in persons with HIV infection. Patients show the same risk factors as other melanoma patients--multiple nevi, fair skin, and earlier intermittent but intense sun exposure. The prognosis of these patients is unknown, but the risk of metastasis has been suggested to be increased. Many fair-skinned, HIV-infected patients complain of the new atypical moles (analogous to organ transplant patients). Whether these confer an increased risk of melanoma is unknown.
AIDS Kaposi's Sarcoma Along with Pneumocystis carinii pneumonia, KS was the harbinger of the AIDS epidemic. Many homosexual and bisexual men presented with this tumor in the early 1980s, with a prevalence of up to 25% in some cohorts. A gamma herpes virus (HHV-8) has been identified in these lesions and appears to be pathogenically related. The clinical features of KS in AIDS are different from those seen in elderly men. The AIDS patients present with symmetrical widespread lesions; often many of them. Lesions begin as macules, and might progress to tumors or nodules. Any mucocutaneous surface could be involved, but areas of predilection include the hard palate, trunk, penis, lower legs, and soles. Visceral disease could be both present and progressive. Edema may accompany lower leg lesions, and if significant, is often associated with lymph node involvement in the inguinal area. The diagnosis of KS is established by skin biopsy; tissue should be taken from the center of the most infiltrated plaque. Excessive bleeding does not usually occur. Macular lesions in early stages show atypical, angulated, ectatic vessels in the upper dermis and are associated with an inflammatory infiltrate containing plasma cells. Plaque lesions show aggregates of small vessels and endothelial cells in the upper dermis and surrounding adnexal structures (especially the sweat glands). Nodules and tumors show the classic pattern of a spindle cell neoplasm, with prominent extravasation of erythrocytes. The treatment of AIDS-associated KS depends on the extent and aggressiveness of the disease. Effective HAART after approximately 6 months is associated with involution of KS lesions. This should be the initial management of most patients with mild to moderate disease (<50 lesions, <10 new lesions/month) and Curr Probl Dermatol, January/February 2000
who are not receiving anti-HIV treatment. When intralesional vinblastine (0.2 to 0.4 mg/mL) is infiltrated into lesions, the lesions will involute during severn weeks. Hyperpigmentation usually remains. Cryotherapy is also effective, but will leave postinflammatory hypopigmentation in pigmented persons. Persistent localized lesions and lesions of the soles and penis respond well to local radiation therapy (one dose of 800 rad or fractionated doses to 1,500 rad). Systemic chemotherapy is indicated for patients with symptomatic visceral disease, aggressive skin disease, marked edema, and pulmonary disease. Treatment options include c~-interferon, vinca alkaloids, Neomycin, and liposomal doxorubicin as first line choices, and taxol for cases in which these treatments fail.
HIV Fat-Redistribution Syndrome During the last 18 months, in many patients treated with HAART, a novel syndrome characterized by a loss of subcutaneous fat of the cheek, temples, and extremities has developed. In some patients, these changes are accompanied by the appearance of excess fat in the posterior neck (resembles a buffalo hump), around the neck (looks like the neck deformity of Madelung's disease), in the breasts (resulting in gynecomastia in men), and in the abdominal cavity. Patients might have some or all of these features. The body weight does not change. Although no endocrinologic abnormalities have been detected, hyperlipidemia and glucose intolerance can occur. The term "lipodystrophy" has been used to describe this condition. Most patients are receiving effective antiretroviral therapy, but the syndrome can occur without exposure to these medications. The treatment is most difficult, and largely surgical. The areas of excess fat can be removed by liposuction.
The Future With the help of HAART, we will manage patients with HIV infection as we manage those with other chronic diseases such as diabetes mellitus. With effective treatment, patients will have an improved quality of life and suffer fewer complications associated with the disease. Nonetheless, excess morbidity and mortality will occur. The immediate concern is that the currently effective antiviral medications will lose their efficacy, and patients will relapse. We hope that newer, more specific, and less toxic anti-HIV medications will continue to be developed, providing additional management options to both the patient and physician. 33
Elimination of the disease awaits the development of an effective vaccine and antiviral medications that eradicate the virus in currently inaccessible "reservoirs" within the body.
Additional Reading • Badger J, Berger TG, Gambla C, et al. HIV and psoriasis. Clin Rev Allergy Immunol 1997; 14:417-31. • Burdick AE, Carmichael C, Rady PL, et al. Resolution of Kaposi's sarcoma associated with undetectable levels of human herpesvirus 8 DNA in a patient with AIDS after protease inhibitor therapy. J Am Acad Dermatol 1997;37:648-9. • Kerschmann RL, Berger TG, Weiss LM, et al. Cutaneous presentations of lymphoma in HIV disease. Arch Dermatol 1995;131:1281-8. • Krown SE. Acquired immunodeficiency syndrome-associated Kaposi's sarcoma. Biology and management. Med Clin North Am 1997;81:471-94.
34
• Majors MJ, Berger TG, Blauvelt A, et al. HIV-related eosinophilic folliculitis: a panel discussion. Semin Cutan Med Surg 1997;16:219-23. Maurer TA, Christian KV, Kerschmann RL, et al. Cutaneous squamous cell carcinoma in human immunodeficiency virus infected patients. A study of epidemiologic risk factors, human papillomavirus, and p53 expression. Arch Dermatol 1997;133:577-83. • Pappert A, Grossman M, DeLeo V. Photosensitivity as the presenting illness in four patients with human immunodeficiency viral infection. Arch Dermatol 1994:130;618-23. • Schacker TW, Collier AC, Hughes J, et al. Clinical and epidemiologic features of primary HIV infection. Ann Int Med 1997;126:174. • Stern RS. Epidemiology of skin disease in HIV infection: a cohort study of health maintenance organization members. J Invest Dermatol 1994;102:34S-7S. • Williamson K, Reboli AC, Manders SM. Protease inhibitorinduced lipodystrophy. J Am Acad Dermatol 1999;40:635-6.
Curr Probl Dermatol, January/February 2000
IVA patients usually range from 200 to 500/mL. The skin findings at the AIDS-related complex stage include seborrheic dermatitis, pruritus ani, psoriasis, Reiter's syndrome, atopic dermatitis, herpes zoster, acne rosacea, oral hairy leukoplakia, onychomycosis, warts, recurrent Staphylococcus aureus folliculitis, and mucocutaneous candidiasis. When the helper T-cell count is 200/mL or less, the patient is considered to have AIDS. In this stage, the skin lesions are more specific of immunodeficiency and include characteristic opportunistic infections such as chronic herpes simplex, molluscum contagiosum, bartonellosis (bacillary angiomatosis), systemic fungal infections (cryptococcosis, histoplasmosis, coccidioidomycosis, and penicilliosis), and mycobacterial infection. Paradoxically, patients at this stage also have hyper-reactive skin and frequently have inflammatory (often pruritic) skin conditions such as eosinophilic folliculitis, granuloma annulare, drug reactions, and photodermatitis. When the T-cell count falls below 50, the patient is often said to have "advanced AIDS." These patients may present with unusual opportunistic infections such as multicentric, refractory molluscum contagiosum; chronic herpes simplex; chronic cutaneous varicella zoster infection; cutaneous acanthamebiasis, cutaneous atypical mycobacterial infections (caused by Mycobacterium avium complex and Mycobacterium hemophilum), and crusted scabies. Treatment of these infections is often difficult as a result of the patient's marked chronic immunosuppression. It is now clear that HIV itself causes the loss of helper T cells, and that effective treatment of HIV infection may halt or reverse the progress of HIV disease. There are numerous antiretroviral agents and they are usually used in combinations called "cocktails." This combination treatment is called "highly active antiretroviral therapy" (HAART). About half of HIV-infected patients respond to this treatment, and their condition might dramatically improve. The HIV virus disappears from the blood and helper T-cell counts rise. As expected, in patients who respond to HAART, opportunistic infections no longer occur, and the mortality rate decreases. This is also true of cutaCurr Probl Dermatol, January/February 2000
neous infectious conditions, but is not true of all the inflammatory disorders seen in patients with AIDS. The HIV-associated psoriasis improves, especially if zidovudine is part of the therapeutic cocktail. With HAART, however, eosinophilic folliculitis and drug eruptions might become more frequent or more severe.
Primary HIV Infection (Acute Seroconversion Syndrome) In a large proportion of persons infected with HIV, an acute illness develops several weeks after the infection occurs. The clinical syndrome is much like that of an Epstein-Barr virus infection, in that fever, sore throat, cervical adenopathy, a rash, and ulcerations of the oral, genital, and rectal regions are present. The skin eruptions may be polymorphous. Most characteristic is the eruption of discrete, slightly scaly, oval papular lesions of the upper trunk. These lesions superficially resemble those of pityriasis rosea, but the peripheral scale is not prominent and there is focal hemorrhage in the lesions. An eruption resembling the papules of Gianotti-Crosti syndrome might also occur. The mucosal erosions resemble aphthae, but are larger and can affect the mucosa of all parts of the mouth, pharynx, esophagus, and anus. Dysphagia might be prominent. The helper T-cell count falls abruptly during seroconversion. The level of immune impairment might be adequate to allow oral candidiasis or even Pneumocystis carinii pneumonia to occur. The disease should be suspected in any at-risk person having the correct constellation of symptoms. Direct measurement of the HIV viral load will confirm the diagnosis. Combination antiviral therapy is instituted immediately in these patients with the hope of halting or reducing the progression of the disease.
HIV-Associated Pruritus Since the early days of the HIV epidemic, it was clear that pruritus was a marker for HIV infection as it occurred throughout the world. Pruritus is not a result of HIV disease itself; it is related to the inflammatory dermatoses associated with the disease. "Papular pruritic eruption" is not a specific disease, but a "wastebasket" term used to describe the lesions seen in patients with many forms of HIV-associated pruritus. These eruptions are best subdivided as follicular and nonfollicular eruptions. The follicular eruptions are more common. Eosinophilic folliculitis is the most common pruritic follicular eruption. It is seen in patients with a helper Curr Probl Dermatol, January/February 2000
T-cell count of approximately 200/mL. Patients with this condition present with urticarial follicular papules on the upper trunk, face, scalp, and neck. Pustular lesions are uncommon; the pustules are usually smaller than those seen in cases of bacterial folliculitis, and represent end-stage lesions. These lesions are infrequently seen because the pruritus is so severe that the lesions are excoriated before they evolve to this degree. Ninety percent of the lesions appear above the nipple line on the anterior trunk, head, and neckl They typically extend down the midline of the back to the lumbar spine. The disease increases and decreases in severity, and might spontaneously clear up, only to unpredictably occur again. A peripheral eosinophilia may be present and the serum IgE level may be elevated, suggesting that the disorder is mediated by T H 2 helper T cells. Histologically, an infiltrate of mononuclear cells and eosinophils is seen around the upper portion of the hair follicle at the level of the sebaceous gland. As lesions evolve, eosinophils and lymphocytes enter the follicular structure and the sebaceous glands. Pustules form late and represent aggregates of eosinophils in the uppermost part of the follicle. Initial treatment consists of giving topical steroids and antihistamines. If the patient fails to respond, phototherapy (ultraviolet B or psoralen plus ultraviolet A) or the twice-daily administration of 200 mg itraconazole may be effective. In some patients, repeated applications of permethrin (every other night for up to 6 weeks) may be beneficial; this is directed at demodex mites, which might be the antigenic trigger of this condition. Isotretinoin is also effective, often after a few months, at a dosage of about 0.5 to 1 mg/kg/day. Staphylococcal folliculitis (which might be severely pruritic in the setting of HIV disease) and pityrosporum folliculitis should be included in the differential diagnosis. These are ruled in or ruled out with the results of bacterial culture and skin biopsy, respectively. The nonfollicular pruritic dermatoses can be divided into 2 types of eruptions: (1) primarily papular and (2) eczematous. The papular eruptions include scabies, insect bites, transient acantholytic dermatosis, granuloma annulare, and prurigo nodularis. The eczematous dermatoses include atopic-like dermatitis, seborrheic dermatitis, nummular eczema, xerotic eczema, photodermatitis, and drug-related eruptions. Patients may have multiple eruptions, making differential diagnosis difficult. The results of skin biopsies from every mophologic type of lesion might elucidate the true diagnosis(es). Determined by the diagnosis, treatment is 31
similar to that of persons with these same dermatoses, but without HIV infection. Special considerations in treating AIDS patients include the use of ivermectin for crusted scabies, and thalidomide for prurigo nodularis and photodermatitis. Both agents are effective if used appropriately.
HlV-Associated Neoplasia Neoplasia is prominent in HIV infection; in some cases, it is highly suggestive of the condition; KS is an example. Others include superficial basal cell carcinomas of the trunk, squamous cell carcinomas in sun-exposed areas, genital human papillomavirus (HPV)-induced squamous cell carcinoma, and extranodal B- and T-cell lymphoma. Nonmelanoma skin cancers are common in HIVinfected persons and usually occur as superficial multicentric basal cell carcinomas on the trunk in fairskinned men aged 20 to 59 years. The ratio of basal cell carcinomas to squamous cell carcinomas is not reversed in HIV disease, as in organ transplant recipients. Basal cell carcinomas behave as they do in immunocompetent hosts, and standard management is usually adequate. Actinically induced squamous cell carcinomas are also quite common, and patients present with nodules, keratotic papules, or ulcerations. In most cases the behavior of these carcinomas is relatively benign and standard management is adequate. Removal of sqnamous cell carcinomas in sun-exposed areas by curettage and desiccation in the setting of HIV infection is associated with an unacceptably high recurrence rate of approximately 15%. Complete excision is therefore recommended. In a small subset of AIDS patients, the actinic squamous cell carcinomas can be quite aggressive. They might double in size over weeks and metastasize to regional lymph nodes or to viscera, leading to the death of the patient. Nonmelanoma skin cancers in the HIV-infected patient behave in a manner intermediate between that of a normal host and that of an organ transplant recipient. In the setting of HIV infection, genital squamous cell carcinomas associated with HPV infections occur on the cervix, vagina, anus, penis, and nailbed. These neoplasms occur with increasing frequency and the progression from HPV infection to neoplasia appears to be accelerated. This is analogous to the situation in organ transplant patients and other immunosuppressed patients. It appears that these cancers are associated with primarily "high-risk" types of HPV infections. 32
For the dermatologist, there are 3 important manifestations of high-risk genital HPV infection. The most common is perianal dysplasia, seen frequently in homosexual men with a history of receptive anal intercourse. Dysplasia occurs as velvet-like white or hyperpigmented plaques, and involves the whole anal area, including the anal canal. These lesions might erode or ulcerate. Histologic examination shows squamous cell carcinoma in situ. The risk that these lesions will progress to anal squamous cell carcinoma is unknown, but is estimated at no less than 10 times the frequency of cervical cancer in women of the general population. The management of patients with such conditions is unclear, but regular follow-up is clearly indicated, and any mass appearing in the anal canal should be immediately referred for biopsy. Flat, white, or hyperpigmented macules a few millimeters to several centimeters in diameter might develop in the vulvar and penile skin. These show squamous cell carcinoma in situ, and are analogous to bowenoid papulosis in the immunocompetent host. Rare cases of progression to squamous cell carcinoma have occurred. Such lesions are best watched closely and cases should be managed conservatively, as with cases of warts. Lesions of the penis and vulva but not at a transition zone or on a mucosal surface have a low risk of progressing to invasive squamous cell carcinoma. Lesions of the glans penis that are red and fixed should be referred for biopsy. If biopsy results show changes of squamous cell carcinoma in situ, patients with the condition should be aggressively managed, as with erythroplasia of Queyrat. Topical 5-fiuorouracil and superficial radiation therapy are effective and close clinical follow-up is indicated. Periungual squamous cell carcinoma has also been seen in patients with HIV infection and is felt to be associated with high-risk HPV types. Any persistent keratotic or hyperpigmented lesion in the periungual area must be carefully evaluated. Management of such cases involves surgical excision of the lesion. Extranodal B-cell and, less frequently, T-cell lymphomas are associated with the advanced immunosuppression of AIDS. In cases of B-cell lymphomas, and some T-cell lymphomas, patients present with violaceous or plum-colored papules, nodules, or tumors. When the diagnosis is established from biopsy results, systemic chemotherapy is required for treatment. Epstein-Barr virus is found in some cases. Mycosis fungoides might also be seen in the setting of HIV infection, often in patients in which AIDS has not yet Curr Probl Dermatol, January/February 2000
developed. Patients present with pruritic patches or plaques that might progress to the tumor stage. Epstein-Barr virus in not found in these cases. Malignant melanoma is occasionally seen in persons with HIV infection. Patients show the same risk factors as other melanoma patients--multiple nevi, fair skin, and earlier intermittent but intense sun exposure. The prognosis of these patients is unknown, but the risk of metastasis has been suggested to be increased. Many fair-skinned, HIV-infected patients complain of the new atypical moles (analogous to organ transplant patients). Whether these confer an increased risk of melanoma is unknown.
AIDS Kaposi's Sarcoma Along with Pneumocystis carinii pneumonia, KS was the harbinger of the AIDS epidemic. Many homosexual and bisexual men presented with this tumor in the early 1980s, with a prevalence of up to 25% in some cohorts. A gamma herpes virus (HHV-8) has been identified in these lesions and appears to be pathogenically related. The clinical features of KS in AIDS are different from those seen in elderly men. The AIDS patients present with symmetrical widespread lesions; often many of them. Lesions begin as macules, and might progress to tumors or nodules. Any mucocutaneous surface could be involved, but areas of predilection include the hard palate, trunk, penis, lower legs, and soles. Visceral disease could be both present and progressive. Edema may accompany lower leg lesions, and if significant, is often associated with lymph node involvement in the inguinal area. The diagnosis of KS is established by skin biopsy; tissue should be taken from the center of the most infiltrated plaque. Excessive bleeding does not usually occur. Macular lesions in early stages show atypical, angulated, ectatic vessels in the upper dermis and are associated with an inflammatory infiltrate containing plasma cells. Plaque lesions show aggregates of small vessels and endothelial cells in the upper dermis and surrounding adnexal structures (especially the sweat glands). Nodules and tumors show the classic pattern of a spindle cell neoplasm, with prominent extravasation of erythrocytes. The treatment of AIDS-associated KS depends on the extent and aggressiveness of the disease. Effective HAART after approximately 6 months is associated with involution of KS lesions. This should be the initial management of most patients with mild to moderate disease (<50 lesions, <10 new lesions/month) and Curr Probl Dermatol, January/February 2000
who are not receiving anti-HIV treatment. When intralesional vinblastine (0.2 to 0.4 mg/mL) is infiltrated into lesions, the lesions will involute during severn weeks. Hyperpigmentation usually remains. Cryotherapy is also effective, but will leave postinflammatory hypopigmentation in pigmented persons. Persistent localized lesions and lesions of the soles and penis respond well to local radiation therapy (one dose of 800 rad or fractionated doses to 1,500 rad). Systemic chemotherapy is indicated for patients with symptomatic visceral disease, aggressive skin disease, marked edema, and pulmonary disease. Treatment options include c~-interferon, vinca alkaloids, Neomycin, and liposomal doxorubicin as first line choices, and taxol for cases in which these treatments fail.
HIV Fat-Redistribution Syndrome During the last 18 months, in many patients treated with HAART, a novel syndrome characterized by a loss of subcutaneous fat of the cheek, temples, and extremities has developed. In some patients, these changes are accompanied by the appearance of excess fat in the posterior neck (resembles a buffalo hump), around the neck (looks like the neck deformity of Madelung's disease), in the breasts (resulting in gynecomastia in men), and in the abdominal cavity. Patients might have some or all of these features. The body weight does not change. Although no endocrinologic abnormalities have been detected, hyperlipidemia and glucose intolerance can occur. The term "lipodystrophy" has been used to describe this condition. Most patients are receiving effective antiretroviral therapy, but the syndrome can occur without exposure to these medications. The treatment is most difficult, and largely surgical. The areas of excess fat can be removed by liposuction.
The Future With the help of HAART, we will manage patients with HIV infection as we manage those with other chronic diseases such as diabetes mellitus. With effective treatment, patients will have an improved quality of life and suffer fewer complications associated with the disease. Nonetheless, excess morbidity and mortality will occur. The immediate concern is that the currently effective antiviral medications will lose their efficacy, and patients will relapse. We hope that newer, more specific, and less toxic anti-HIV medications will continue to be developed, providing additional management options to both the patient and physician. 33
Elimination of the disease awaits the development of an effective vaccine and antiviral medications that eradicate the virus in currently inaccessible "reservoirs" within the body.
Additional Reading • Badger J, Berger TG, Gambla C, et al. HIV and psoriasis. Clin Rev Allergy Immunol 1997; 14:417-31. • Burdick AE, Carmichael C, Rady PL, et al. Resolution of Kaposi's sarcoma associated with undetectable levels of human herpesvirus 8 DNA in a patient with AIDS after protease inhibitor therapy. J Am Acad Dermatol 1997;37:648-9. • Kerschmann RL, Berger TG, Weiss LM, et al. Cutaneous presentations of lymphoma in HIV disease. Arch Dermatol 1995;131:1281-8. • Krown SE. Acquired immunodeficiency syndrome-associated Kaposi's sarcoma. Biology and management. Med Clin North Am 1997;81:471-94.
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• Majors MJ, Berger TG, Blauvelt A, et al. HIV-related eosinophilic folliculitis: a panel discussion. Semin Cutan Med Surg 1997;16:219-23. Maurer TA, Christian KV, Kerschmann RL, et al. Cutaneous squamous cell carcinoma in human immunodeficiency virus infected patients. A study of epidemiologic risk factors, human papillomavirus, and p53 expression. Arch Dermatol 1997;133:577-83. • Pappert A, Grossman M, DeLeo V. Photosensitivity as the presenting illness in four patients with human immunodeficiency viral infection. Arch Dermatol 1994:130;618-23. • Schacker TW, Collier AC, Hughes J, et al. Clinical and epidemiologic features of primary HIV infection. Ann Int Med 1997;126:174. • Stern RS. Epidemiology of skin disease in HIV infection: a cohort study of health maintenance organization members. J Invest Dermatol 1994;102:34S-7S. • Williamson K, Reboli AC, Manders SM. Protease inhibitorinduced lipodystrophy. J Am Acad Dermatol 1999;40:635-6.
Curr Probl Dermatol, January/February 2000