Introduction

The human immunodeficiency virus (HIV) is the cause of the acquired immune deficiency syndrome (AIDS). Worldwide, 36.7 million children and adults are currently living with HIV according to current WHO (World Health Organization) statistics (2016). 54% of adults and 43% of children living with HIV are currently taking antiretroviral therapy (ART). Globally it is estimated that 70% of HIV-positive individuals know their status. As yet, there is no effective vaccine against HIV. Methods for reduced transmission of HIV include condoms, voluntary male circumcision, prevention of mother-to-child transmission, sterile injection equipment, screening blood products, and pre-exposure prophylaxis for sero-discordant couples are starting to reduce the number of new people becoming infected. Trials of pre-exposure prophylaxis with tenofovir disoproxil fumarate (TDF) 300 mg alone or with emtricitabine 200 mg have been shown to reduce the risk of acquiring HIV by 60-90% depending on adherence. It is estimated that between 2000 and 2016 there has been a 40% reduction in new HIV infections.

HIV is an RNA retrovirus that replicates itself by reverse transcriptase to produce a DNA copy; this then becomes incorporated into the host DNA where further replication occurs. HIV persists in the body within the host's immune cells - the CD4 lymphocytes and monocytes - thereby directly weakening the host's immune system. Initially, the virus remains latent for an average of 10 years before causing profound immunosuppression. The extent to which an individual's immune system is affected by HIV is measured through the CD4 cell count and the HIV viral load. AIDS is defined as a CD4 count of less than 200 cells/μl, or HIV associated with any one of 26 (mainly opportunistic infections) conditions.

Patients with low CD4 counts who are profoundly immunosuppressed tend to have more frequent and more severe skin disorders. Common cutaneous diseases such as psoriasis, eczema, seborrhoeic dermatitis (SD), and acne tend to be more severe, have atypical features and are often resistant to conventional treatments. The spectrum of cutaneous manifestations in HIV has changed over the past decade because of the use of ART. Once a patient's immune system has reconstituted on ART and their viral load remains undetectable they are thought to no longer be able to transmit the virus.

When ART is initiated occasionally the so-called immune reconstitution inflammatory syndrome (IRIS) can occur, where there is a brisk inflammatory response related to the presence of previously 'unrecognised antigen' e.g. from tuberculosis, cryptococcus, varicella zoster virus, etc. This paradoxical worsening, for example in pre-existing herpes simplex viral (HSV) in the genital region, on starting ART can give atypical clinical appearances such as nodular hyperkeratotic lesions. Treatment with valaciclovir and imiquimod is usually effective without the need to stop or reduce the ART. For other opportunistic infections these should be treated before the initiation of ART to try to prevent IRIS developing.

In general, HIV/AIDS should be considered in any patient with a florid or atypical inflammatory skin disease that is resistant to treatment or who has severe and extensive infection of the skin. Because of the atypical nature of cutaneous manifestations in HIV medical practitioners should have a low threshold for performing a skin biopsy for histology and culture (Box 15-1). Many modern heath care systems are introducing HIV screening for all patients newly registering at primary care facilities in the community or any patient who attends their local hospital. Diagnosing and treating those with HIV early on in the disease will result in less morbidity, less premature mortality, and reduced onwards transmission and ultimately be cost-effective.

Stages of HIV

Primary HIV infection

Eighty percent of individuals have acute signs and symptoms associated with their primary HIV infection - the so-called 'seroconversion illness'. The incubation period is two to six weeks. Symptoms include fever, malaise, headache, nausea, vomiting, and diarrhoea. Clinical signs include cervical lymphadenopathy, pharyngitis, weight loss, and rash. The skin eruption associated with primary HIV infection is present in 50% of patients and consists of a maculopapular rash mainly on the face, neck, and trunk lasting two to three weeks (Figure 15-1). Some patients develop a papulovesicular eruption or erosions in the mouth rather than a classic viral exanthem. During seroconversion abnormalities in the full blood count (FBC) may be seen (leukopenia, lymphopenia, thrombocytopenia, low haemoglobin) and diagnostically HIV RNA may be detected in the plasma.

Early stages

Within one to two months of the primary infection, 50% of patients will have detectable antibodies to HIV. The proportion of CD4 lymphocytes variably decreases and this is associated with an increased frequency and severity of skin disorders. Patients may experience worsening of premorbid skin complaints such as psoriasis or present de novo with sudden florid skin disease such as SD. Adverse drug reactions are more frequent and often severe.

Late-stage HIV infection

As the patient's immune system becomes increasingly suppressed and the CD4 count falls below 200 cells/μl, he or she is classified as having AIDS. Patients with AIDS may present with severe widespread dermatoses including SD, crusted scabies, multidermatomal varicella zoster virus, Kaposi's sarcoma (KS), widespread fungal/yeast infections, bacillary angiomatosis (BA), and eosinophilic folliculitis (EF). These conditions are described in more detail below.

Skin disorders in HIV

Seborrhoeic dermatitis

Fifty percent of HIV patients develop SD compared to 1-3% of the general population. SD may be one of the first indicators of HIV infection. It is interesting to note that as the immune system becomes increasingly suppressed by HIV, there is a higher incidence of allergic-type reactions. SD is thought to be an allergic contact dermatitis to the lipophilic yeast Malassezia globosa, which is a normal skin commensal. SD classically affects the scalp, eyebrows, nasal creases, moustache, and anterior chest. Adherent greasy scales cover underlying inflammatory eczema which may be very itchy (Figure 15-2). Management is aimed at reducing the numbers of yeast on the skin and suppressing the eczema. Ketoconazole shampoo can be used to wash the body and scalp once/twice weekly to reduce yeast carriage. Twice-daily topical steroids (±miconazole) can be used to control the dermatitis. In refractory cases systemic imidazoles such as itraconazole 200 mg daily for one to two weeks can be effective. However, if the patient's immune system reconstitutes with ART, SD usually abates (Box 15-2).

Psoriasis

It is estimated that 5% of HIV patients develop psoriasis and of those 50% suffer from psoriatic arthropathy. The pathophysiology of psoriasis is complex; however, there is a general consensus that it is a T-cell mediated autoimmune disease. The paradox in HIV is that immune dysregulation of T-cells goes hand in hand with severe, extensive, and refractory psoriasis, indicating that there are likely to be other cells involved in the development of psoriasis such as Th17. A dermatology specialist is usually needed to manage patients with HIV and severe psoriasis. Conventional immunosuppressive treatments such as ciclosporin and methotrexate can be used with care. Drug interactions need to be considered with ciclosporin. PUVA (psoralen plus ultraviolet A) can be very useful at controlling extensive thick plaques, particularly in patients with pigmented skin.

Eosinophilic folliculitis (EF)

EF is an intensely pruritic condition of unknown aetiology that tends to occur when the CD4 count falls below 250 cells/μl. Speculation that the causative agent is Demodex, a commensal skin mite that lives in the perifollicular region has not been proven in studies. An autoimmune process with responses against the sebocytes/sebum has also been suggested. Clinically, patients present with multiple discrete, erythematous, perifollicular papules and pustules affecting the face, neck, and trunk (Figure 15-3) that can look like acne (but no comedones are seen). Differential diagnoses include Staphylococcus or Pityrosporum folliculitis and acne. Microbiological swabs are negative in EF. Peripheral eosinophilia and raised IgE may be noted. ART therapy can help if the CD4 count rises above 250 cells/μl. Ultraviolet B (UVB) phototherapy can be very effective. Topical corticosteroids may reduce pruritus. Systemic indomethacin, minocycline, and itraconazole have also been used. Low-dose oral isotretinoin can be beneficial.

Nodular prurigo

Non-specific pruritus is common in HIV patients, with 30% developing itchy nodular lesions on the skin, called nodular prurigo. The cause is unknown. Classically, small red papules develop on the trunk and limbs, which itch intensely, and through scratching chronic nodules form (Figure 15-4). Nodular prurigo can be very aggravating and persistent. Relief from pruritus may be gained by regular applications of emollients. Potent topical steroids applied daily under occlusion of wraps or body suits may flatten lesions and relieve itching. UVB phototherapy and amitriptyline can also be used.

Infections

Fungal infections

Superficial dermatophyte and yeast infections are frequently more extensive in HIV patients with a higher incidence of dissemination systemically. Deep fungal infections that are not normally seen in healthy individuals occur in AIDS patients as opportunistic infections. Cryptococcus neoformans and Histoplasma capsulatum may cause inflammatory papular and necrotic lesions, particularly in the later stages of the disease.

Candidiasis is common and often associated with secondary bacterial infections. The oral mucosa can be extensively infected with Candida albicans that spreads to the pharynx and oesophagus. Clinically, there are extensive white plaques on a background of erythema. Candidiasis of the skin has a predilection for the flexures where classically there is confluent erythema with peripheral satellite lesions (Figure 15-5). Patients may complain of cutaneous discomfort and itching and oral ulceration and dysphagia (Figure 15-6). Women with HIV can develop severe vulvovaginitis caused by chronic candidiasis.

Bacterial infections

Impetigo caused by Staphylococcus aureus may be severe with large bullous lesions associated with strains producing exfoliative toxins A/B. Erythrasma (Corynebacterium) may be persistent and recurrent in the flexural areas and are often mistaken for a superficial fungal infection.

Bartonella henselae and Bartonella quintana infections can cause bacillary angiomatosis (BA) in AIDS patients, who present with multiple small haemangioma-like papules on the skin and mucous membranes. Skin lesions develop slowly over several weeks (Figure 15-7), and visceral organs may also be affected - most commonly, the liver. Differential diagnosis usually includes Kaposi's sarcoma. Blood cultures are usually diagnostic, but the laboratory must be alerted to the possibility of Bartonella as blood cultures must be incubated for three weeks under specific conditions. Skin biopsy for histology is usually diagnostic. Bartonella are highly sensitive to macrolide antibiotics which are bacteriostatic and therefore an anti-angiogenic effect through down-regulation of endothelial cells has been postulated as the mechanism of action in BA. The treatment of choice is erythromycin 500 mg qds for up to 12 weeks. Azithromycin 500 mg on the first day and then 250 mg daily for five days is also highly effective.

Syphilis

Approximately 12 million new cases of syphilis infection are reported each year according to the WHO, with a notable resurgence in many parts of the world where the incidence was previously low. Between 20% and 70% of patients in the United States and Europe are co-infected with HIV and syphilis simultaneously. Syphilis is caused by the spiral bacterium (spirochaete) Treponema pallidum. Syphilis is the great mimicker of other diseases and in the context of HIV infection presentations may be atypical.

Classically, a painless genital ulcer develops three to four weeks after transmission via sexual intercourse. Secondary syphilis presents with a rash, fever, arthralgia, and lymphadenopathy four to eight weeks after the initial infection. The rash is usually asymptomatic and characteristically affects the trunk, palms, and soles. Early lesions are usually annular erythematous brown macules (Figure 15-8). Serological testing for syphilis should be performed to confirm the diagnosis. Primary/secondary syphilis should be treated with a single dose of intramuscular benzathine penicillin 2.4 megaunits, or intramuscular procaine penicillin 600 000 units daily for 10 days. Latent syphilis requires prolonged treatment.

Mycobacteria may produce widespread cutaneous and systemic lesions. Varieties of mycobacteria that do not normally infect the skin may cause persistent necrotic papules or ulcers.

Viral infections

Herpesviruses

Herpesvirus types 1, 2, and 3 including herpes simplex (oral/genital) and herpes zoster infections may be unusually extensive, with large individual lesions in patients with HIV. Herpes zoster (shingles) classically spreads to involve adjacent dermatomes. Occasionally, persistent ulcerated lesions are seen with resultant squamous cell carcinoma, which can arise in any chronic ulcer. HSV infections may be particularly severe and recurrent such that patients require secondary long-term prophylaxis. In the context of highly active antiretroviral therapy (HAART), an IRIS can occur in association with genital HSV with florid debilitating inflammatory reactions, leading to extensive and persistent painful ulceration (Figure 15-9a) and occasionally proliferative change that can mimic squamous cell carcinoma (Figure 15-9b).

Epstein-Barr virus (EBV) is human herpesvirus type 4. Ninety percent of adults have evidence of past infection with EBV which remains latent in the body in B-cells. In 30-50% of AIDS patients, EBV enters a replicative phase, leading to oral hairy leukoplakia (OHL). OHL is characterised by overgrowth of epithelial plaques on the sides of the tongue (Figure 15-10) with a verrucous grey/white surface. Biopsies from OHL show a lack of host Langerhans cells, which may account for the lack of immune response to the virus. Looking for OHL in the mouth can be a very quick and simple way of assessing potential immunosuppression in a previously undiagnosed individual in the clinic or field setting. OHL has also been reported in the context of haematological malignancy and after organ transplantation.

Kaposi's sarcoma (KS) is an angioproliferative disorder caused by infection with human herpesvirus type 8. There is an endemic form of the disease (usually affecting the skin of the lower leg) seen mainly in elderly men living in sub-Saharan Africa who are HIV negative and more recently seen in MSM (men who have sex with men) who are also HIV negative. In HIV patients (epidemic form) lesions usually affect the face, oral cavity (Figure 15-11), and perineum. Early lesions may be erythematous-violaceous patches or papules which progress to firm nodules (Figure 15-12) or plaques with a purplish brown discolouration. Lesions may eventually ulcerate. KS koebnerises (occurs at sites of skin trauma) and secondary lymphoedema may occur, particularly in affected limbs. Histology from skin/mucosal lesions can be diagnostic. Patients traditionally had CD4 counts below 200 in order to present with KS; however, there are increasingly numbers of cases where patients present with CD4 counts between 300 and 400. Cutaneous therapy is directed at haemostasis, restoring function, improving the cosmetic appearance and debulking advanced disease. A variety of measures can be considered such as excision, radiotherapy, pulsed dye laser, and intralesional chemotherapy (vinblastine, vincristine, and bleomycin).

Other viruses

Molluscum contagiosum infections are frequent in HIV patients. Individual lesions may be larger than usual (giant molluscum) and they may be extensive. Mollusca are readily identified as firm papules with an umbilicated centre (Figure 15-13). The differential diagnosis of large mollusca-like lesions in the context of HIV includes fungal infections due to Cryptococcus and histoplasmosis. If the diagnosis is in question, then a skin biopsy for histology analysis can be very helpful.

Human papillomavirus (HPV) warts may be numerous and large in HIV patients (Figure 15-14). Perianal and genital warts can be particularly troublesome and may be associated with intra-epithelial neoplasia of the cervix and sometimes invasive perianal squamous cell carcinoma. With immune reconstitution HPV warts tend to resolve, but in the meantime, they may respond to wart therapies including salicylic acid, cryotherapy, imiquimod, and diphencyprone therapy.

Infestations

Scabies in HIV patients may present with classic burrows on the fingers and genitals or as widespread crusted scabies which is highly contagious (Figure 15-15). Patients present with hyperkeratotic papules and plaques with relatively little inflammation (helping to distinguish it from psoriasis). Itching may be mild or intractable. Microscopic examination of the crusts is a simple rapid diagnostic test. Topical treatment with 5% permethrin (two applications seven days apart) may be effective, but ivermectin 200 μg/kg as a single dose (or repeated after seven days) may be needed in refractory/crusted and recurrent infestations.

Drug rashes

HIV patients frequently take multiple medications, many of which have a reputation for causing drug rashes (sulfonamides and antibiotics). Nonetheless, the frequency of drug rashes in HIV patients is extremely high (10 times higher than in the general population), especially at CD4 counts below 200 cells/μl. This is partially explained by the fact that HIV itself affects the metabolism of many drugs. The majority of drug rashes occur within 7-20 days after starting the offending drug and take the form of toxic erythema (maculopapular eruption), which is usually mild and resolves when the medication is stopped.

However, severe life-threatening drug reactions such as toxic epidermal necrolysis (TEN) are 1000 times more common in HIV-positive individuals. In HIV patients, TEN has been reported in association with nevirapine, abacavir, and co-trimoxazole. Clinically, patients present with rapid, widespread (>30% of skin surface area), painful, full-thickness skin necrosis, which is associated with a 25-30% risk of mortality (Figure 15-16).

Other drug rashes in HIV patients include pigmentation of nails/tongue/skin (zidovudine and clofazimine), hyperpigmentation of the palms and soles (emtricitabine) mucosal ulceration (zalcitabine, foscarnet and saquinavir), rash and pruritus (abacavir and raltegravir), alopecia and in growing nails (indinavir), diffuse erythema (abacavir), phototoxic rashes (St John's wort), injection site reactions (enfuvirtide) Stevens-Johnson syndrome (co-trimoxazole and dapsone), and TEN.