2.5.11 Skin manifestations of HIV infection

Primary infection of the HIV virus can cause acute flu-like symptoms with a generalized transient maculopapular exanthematous skin eruption affecting face, throat, trunk and proximal limbs. The other symptoms include fever, fatigue, sore throat with occasional aphthous stomatitis and sometimes diarrhea but typically no respiratory symptoms. The primary infection can also be asymptomatic (although unfrequently); usually the acute infection ends with clinical recovery in 2-4 weeks.

Chronic HIV-infection or clinical latency follows the primary HIV infection and lasts for years or even decades. During this time, lymphadenopathy and a multitude of skin problems (e.g. infections, dermatoses) usually develop. There is not any specific skin symptom, but the severity of the skin problems progresses proportionately to the immunosuppression. Skin manifestations have a tendency to recur and may show an atypical or more severe course. Most important is to consider a possible HIV-infection in patients with skin problems that follow uncommon or severe disease courses or are recurrent and refractory to standard therapy. HIV-associated psoriasis and Kaposi’s sarcoma usually respond rapidly to antiretroviral therapy.

Common examples of HIV-associated skin symptoms during the chronic (latency) stage are as follows:

• Viral infections

Herpes simplex infection may have chronic and persistent ulcerations and may be widespread. A special type of chronic genital herpes is the hypertrophic/hyperplastic nodular type. Ulcers increase the risk of HIV-transmission.

Herpes zoster occurs even in young individuals and may show severe haemorrhagic and ulcerative lesions.

Eruption of viral warts in adult individuals, may grow to form confluent hyperkeratotic plaques or giant warts.

Molluscum contagiosum, not commonly seen in adults, may occur in uncommon body sites (e.g. face) or may present as large tumorous lesions.

• Bacterial infections

Recurrent folliculitis, impetigo, furunculosis and abscesses caused by Staphylococcus aureus or Streptococcus pyogenes are common. There may be a poor response to antibiotics. Bacillary angiomatosis; caused by bacteria of Bartonella species. Main symptoms are the appearance of numerous purplish papules and nodules on the trunk and limbs with flu-like symptoms and fever. Syphilis; concomitant HIV-infection can alter the course of syphilis. Clinical features may be atypical with haemorrhagic and necrotic skin lesions. Ulcers (primary chancre) increase the risk of HIV-transmission.

• Fungal infections

Oral Candida-infections may present as atrophic or hypertrophic, chronic or recurrent infections.

Candida albicans can become resistant to standard antifungal therapy.

Tinea; may be more severe and prolonged than sporadic forms and spread to wider areas of the skin, hair and nails.

Pityriasis versicolor may be widespread and respond poorly to therapy.

• Arthropod infestations

Scabies may be widespread and refractory to treatment. In some patients may progress to crusted scabies (Norwegian scabies).

• 5. Dermatoses

Seborrheic dermatitis may have an abrupt onset and may spread to uncommon body sites and be refractory to standard treatment.

Pruritic papular eruption; a chronic form of prurigo with scratched nodules on the extremities and trunk. General skin dryness (xerosis) and pruritus are common in HIV-patients.

Eosinophilic folliculitis; itchy follicular papules and pustules on the upper back, chest and shoulders. Refractory to standard acne and folliculitis treatments.

Chronic skin diseases (e.g. psoriasis, atopic dermatitis) may occur or become resistant to standard therapy during the course of HIV-infection.

• Malignancies

B-cell lymphomas; especially in oral cavity, nodules and plaques, may have an acute and aggressive course.

Papillomavirus-associated malignancies, e.g. penile or vulvar carcinoma may be more aggressive than sporadic forms.

• Drug eruptions

Drug eruptions, such as maculopapular rash, are common in HIV-infected patients. Frequent causative medicaments are antibiotics (e.g. sulfonamides) and ART drugs. Skin rashes occur as side effects of e.g. abacavir, nevirapine, darunavir, fosamprenavir and dolutegravir, while injection nodules may occur after enfuvirtide. Dry skin is common after indinavir. Severe systemic hypersensitivity- associated rash may occur with nevirapine (CD4 count and gender dependent) or with abacavir (HLA B*5701-dependent). Before starting abacavir, determination of the HLA B*5701 must be performed.

Late-stage (AIDS) skin conditions include the following:

1. Kaposi sarcoma, caused by HHV-8, appears first as asymptomatic violaceous or brownish patches or plaques anywhere on the skin or mucous membranes. Initially, the lesions are small and painless, but they can ulcerate and become painful, can also occur in internal organs such as the gastrointestinal system or lymph nodes. Disease extension and severity is often proportional to the grade of immunosuppression. In most cases, Kaposi’s sarcoma responds to the initiation of ART.

2. Oral hairy leukoplakia: whitish, stripe-like changes on the sides of the tongue. Caused by chronic mucosal reactivation of the Ebstein-Barr virus (EBV).

3. Cytomegalovirus (CMV); chronic reactivation can cause persistent and chronic ulcers in skin folds, especially in the genital area, which are often refractory to therapy.

4. Disseminated mycobacterial infections of the skin (MAC or Mycobacterium tuberculosis); opportunistic non-tuberculous mycobacteria (e.g. M. avium/M. intracellulare complex, MAC) can cause disseminated skin and soft tissue infections. In AIDS the skin lesions are frequently caused by hematogenous dissemination of a pulmonary infection; erythematous nodules, which can ulcerate and lead to draining abscesses.

5. Cryptococcosis of the skin; opportunistic fungi (e.g. Cryptococcus neoformans); spread by hematogenous dissemination usually from a pulmonary focus; skin lesions consist of eruptive skin coloured, sometimes umbilicated, papules that extent to large areas of the skin. They can imitate widespread dell warts (molluscum contagiosum-like papules) or cellulitis.

Diagnosis of the HIV-infection with HIV antigen/antibody test and confirmation with Western blot. The HIV AgAb test becomes positive earliest at 2 weeks and latest at 3 months after infection. A positive screening test always requires a second confirmatory test. In newborns with circulating maternal antibodies and during antiretroviral therapy, the detection of HIV RNA with nucleic acid quantitation (viral copies/ml) is used.

Pregnant women should be routinely offered HIV testing and counseling, since infection of the fetus can be prevented with ART during pregnancy.

Depends on the stage of the disease and the type of associated disease. Malignant tumors have specific histology depending on the tumor type.

HIV stage classification was revised to five stages (0, 1, 2, 3, or unknown) in 2014 by the CDC. Stage 0 indicates early HIV infection and stages 1 -3 are based on the CD4+ T-lymphocyte count. WHO uses stages 1-4, also based on the CD4 cell counts.

Acute retroviral syndrome (Primary HIV infection)/ WHO stage 1.

The acute retroviral syndrome (for symptoms see above) develops 2-4 weeks after exposure in 60-90% of infected individuals. At this time the HIV viral load (viremia) is very high in the body and the infected person is highly infectious. The acute infection ends with clinical recovery in 1-3 weeks.

HIV-antibody test usually turns positive 2-4 weeks after the onset of symptoms while a combined antibody- antigen test (HIVAgAb) becomes positive already 2-4 weeks after the transmission of HIV infection; in rare cases it may take up to 3 months for the antibodies to turn positive. In new-borns (with circulating maternal antibodies), HIV-infection can be confirmed with PCR-based quantitation of HIV RNA.

Chronic HIV-infection (Clinical latency)/ WHO stages 2-3

After the primary HIV infection, a period of clinical latency follows and this stage can last for years or even decades. The patient is infectious if not on antiretroviral therapy (ART). During this time, lymphadenopathy and a multitude of skin problems (e.g. infections, dermatoses) usually develop (see Symptoms above). The severity of the skin problems often progresses corresponding to the level of immunosuppression. The total amount CD4-positive T-lymphocytes in the blood is used as a marker of the severity of the immunosuppression (normally over 0,4 E9/l).

Examples of frequent skin manifestation of a symptomatic HIV-infection in Europe are oropharyngeal Candida-infections (atrophic or hypertrophic), recurrent or ulcerative herpes simplex or herpes zoster of the skin or mucosal surfaces, widespread seborrheic dermatitis, eruptions of warts or recalcitrant psoriasis.

Even with good viral control with ART, skin rashes remain common and may be caused by HIV infection itself, other infections, ART medication or other medicines.

AIDS (WHO stage 4)

In this advanced stage, the CD4 cell count is below 0,200 x 109/l, HIV viral load is high and the person is highly infectious. For skin symptoms at this stage, see Symptoms above.

Complications of an early infectious stage: none. In the latency stage depends on the type of infectious agents or dermatoses. HIV-associated dermatoses are typically recalcitrant to standard therapy unless antiretroviral therapy is initiated. Severe drug reactions due to HIV drugs may occur.

Recognition of HIV primary syndrome with maculopapular eruption on face and upper body, fever, tiredness, sore throat/apthae, diarrhoea. Latency stage with lymphadenopathy and different associated skin diseases (see above).

HIV-specific skin manifestations are usually suspected based on clinical features. HIV testing, microbiological (skin infections) and histopathological tests (dermatoses, malignancies) are necessary for confirmation. The viral load (virus copies/ml) and degree of immunosuppression (CD4-cell count) should be determined; screening tests for other STIs should be carried out.

In particular the primary HIV syndrome and associated exanthema is difficult to differentiate, may resemble syphilitic roseola. The differential diagnoses in the latency stage of HIV infection depends on the type of skin symptom.