Drug eruptions are more common in HIV-infected individuals, up to 100-fold by some estimates - Mild and transient to life threatening, skin deep or multisystem. The reason for the increased incidence of drug eruptions in HIV-infected individuals may be as a result of the use of multiple medications including treatment for opportunistic infections and antiretroviral therapy; genetic predisposition; and HIV-associated immune dysregulation, which lowers the threshold of T cell activation coupled with persistent stimulation of CD8 T cells.
Two types of reactions to medications and they are either predictable (type A) and unpredictable (type B). Type A includes lipodystrophy and pigmentation. Type B reactions include morbilliform eruptions, Steven Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, erythroderma, vasculitis and fixed drug eruptions, lichenoid reactions.
| Antiretroviral drug | Cutaneous reaction |
|---|---|
| Nucleoside reverse transcriptase inhibitor (NRTI) | |
| Zidovudine | Mucocutaneous and nail hyperpigmentation, rarely: Hypertrichosis, vasculitis, paronychia |
| Stavudine | Lipodystrophy |
| Didanosine | Vasculitis, SJS, alopecia |
| Abacavir | Hypersensitivity reaction -Maculopapular eruption, urticaria, erythema multiforme |
| Lamivudine | Paronychia, allergic contact dermatitis |
| Non-nucleoside reverse transcriptase inhibitor (NNRTI) | |
| Nevirapine | DRESS, SJS |
| Efavirenz | Skin eruption (usually mild) |
| Etravirine | Maculopapular eruption (mild to moderate) |
| Protease inhibitors (PI) | |
| General | Lipodystrophy, hypersensitivity reaction |
| Indinavir | Paronychia, porphyria, SJS, alopecia, gynaecomastia |
| Nelfinavir | Maculopapular eruption, urticaria |
| Atazanavir | Maculopapular eruption, asymptomatic jaundice and sclera icterus |
| Darunavir | Maculopapular eruption |
| Integrase inhibitor | |
| Raltigravir | Diaphoresis |
Lipodystrophy syndrome (includes lipoatrophy and lipohypertrophy) is one of the long-term toxicities of stavudine (d4T) which was one of the back bones of first line antiretroviral therapy. Protease inhibitors (PIs) are also implicated in causing this syndrome. Lipoatrophy is characterized by loss of subcutaneous tissue from facial pads, extremities, and buttocks. Apart from abnormal fat redistribution in stavudine toxicity, metabolic abnormalities including hyperlipidaemia may also be associated. Studies have reported a prevalence of between 18% and 33%. Stavudine is thought to cause lipoatrophy by inducing adipocyte apoptosis. As a result of lipodystrophy and other toxicity effects of stavudine, national treatment programmes have dropped d4T and moved to zidovudine or abacavir based regimens. Replacing stavudine with abacavir or zidovudine resulted in improvement in established stavudine-induced lipoatrophy in HIV-infected subjects.
Definition and clinical presentation: Morbilliform (measles-like) drug eruption or maculopapular exanthems usually manifest 7–14 days after drug exposure. The lesions can progress and become confluent resulting in erythroderma. There are no associated systemic features. The rash is transient and treatment should not be interrupted. However, morbilliform rash can be the initial presentation of more serious reactions such as DRESS.
Aetiology: There is a very wide spectrum of drugs that cause morbilliform eruptions.
Epidemiology: This accounts for 95% of all cutaneous drug reactions.
Treatment: Usually not necessary, but topical steroids may speed up resolution.
Definition and presentation: Also known as drug hypersensitivity syndrome is a drug reaction characterized by a long latency period (> 3 weeks), a rash, fever, oedema, lymphadenopathy, leukocyte abnormalities (leucocytosis, eosinophilia and/or atypical lymphocytosis) and hepatitis. The eruption is usually urticaria-like or maculopapular, but may present as vesicles, pustules or purpura.
Aetiology:A large number of drugs are associated with DRESS; however, in HIV-infected persons anti-tuberculosis drugs, co-trimoxazole and nevirapine are often implicated.
Epidemiology: The incidence in HIV-infected people is much higher.
Treatment: Immediate withdrawal of the offending drug improves outcomes but treatment is mainly supportive. Topical steroids are helpful but in severe cases systemic steroids are used.
Complications: DRESS has mortality of up to 10%. Complications include liver failure, renal failure, myocarditis, pneumonitis and pancreatitis.
Abacavir (ABC) is a nucleoside analogue reverse transcriptase inhibitor. Approximately 3-5% of individuals who receive abacavir develop an immune-mediated hypersensitivity reaction (HSR) which occurs within the first six weeks of therapy. The HSR is rare but life threatening and is associated with individuals who carry the *57:01 variant in the human leukocyte antigen B (HLA-B) gene.
Diagnosis: The most common symptoms are fever, skin rash, gastrointestinal disorders and respiratory symptoms. A reduction in the incidence of abacavir hypersensitivity and unwarranted interruptions of therapy have been demonstrated with prospective screening for HLA-B*57:01 allele.
Considering the lower risk for abacavir hypersensitivity reaction and cost implications, implementation of genetic testing in this regard, in African settings in routine clinical practice may not be feasible. The importance of clinical monitoring of patients on abacavir cannot be overemphasized.
Treatment: Clinical management of suspected hypersensitivity reaction is discontinuation of abacavir and supportive care with analgesics, antihistamines, adequate fluids and appropriate laboratory monitoring for systemic organ involvement. Rechallenge with abacavir is contraindicated due to the risk of precipitating a life-threatening reaction.
Nevirapine (NVP) induced rash or toxicity occur in estimated 7-15% of patients receiving the drug. NVP rash can vary from a mild morbilliform rash to Stevens-Johnson syndrome. The rash typically develops within six weeks of initiating therapy. The introduction of NVP at a low dose with escalation over a 2-week period is recommended.
Patients with higher CD4 cell counts, including patients using NVP as post-exposure prophylaxis, are reported to have a higher risk of systemic hypersensitivity reaction, and therefore NVP is not recommended as part of post-exposure prophylaxis regimens.
A patient on NVP who develops a rash should be assessed for hepatotoxicity. If a morbilliform exanthem occurs in the setting of a fever, hepatitis, or other systemic symptoms, NVP must be discontinued immediately.
SJS and TEN represent a spectrum of rare but potentially fatal mucocutaneous diseases characterized by widespread epidermal necrosis and mucosal involvement. SJS and TEN are considered to be part of a spectrum of severe cutaneous adverse reactions with increasing severity and extent of skin detachment, ranging from SJS (less than 10% body surface area skin detachment, 1-5% mortality) to TEN (greater than 30% skin detachment, 25-35% mortality).
In HIV-infected patients, the most common antiretroviral drug implicated to cause SJS/TEN is nevirapine and less commonly protease inhibitors. Co-trimoxazole and antituberculosis drugs are also implicated. Re-exposure to the drug results in recurrence.
Diagnosis: The reaction develops around 7-14 days after initiation of the drug. The rash is preceded by a prodrome with constitutional symptoms of high fever, malaise, myalgia and arthralgia. This is often misdiagnosed as an upper respiratory infection and treated with drugs that are later incorrectly blamed as offenders. Mucocutaneous lesions develop abruptly as macules that progress to papules, vesicles, bullae or confluent erythema.
Although minor presentations may occur, significant involvement of oral, nasal, eye (acute conjunctivitis, eyelid oedema, and crusting to conjunctival membrane or pseudomembrane, corneal erosions, conjunctival fornix foreshortening, and corneal ulcers), vaginal, urethral, gastrointestinal, and lower respiratory tract mucous membranes may develop in the course of the illness.
Treatment: Treatment should involve a multi-disciplinary team in a high-level health facility. Identification and withdrawal of the suspected offending agent is important. Supportive care involves analgesia and maintenance of adequate fluid and electrolyte balance. Frequent ophthalmological assessment and antiseptic/antibiotic eye drops 2-hourly are advocated. Barrier nursing and infection control prevention measures are important.
The use of prophylactic broad-spectrum systemic antibiotics, intravenous immunoglobulin (IVIG) and steroids is controversial. Topical cleansing/antibacterial agents could include 0.5% silver nitrate solution on gauze or 10% chlorhexidine gluconate washes or saline washes or polymixin/bacitracin or 2% mupirocin.
For wound care, silver sulfadiazine needs to be avoided. Removal of necrotic epidermis is discouraged, as intact epidermis prevents bacterial inoculation onto the underlying viable dermis. Paraffin gauze or hydrogel dressings may be beneficial. Biological dressings may be required (xenografts, allografts, skin substitutes).
Complications: Acute complications are similar to those of extensive burns. The high morbidity and mortality associated with the condition occurs mainly from infection. Long-term sequelae of SJS/TEN include; recurrence, dyspigmentation, oesophogeal and genital tract stenosis, eye problems, genital fibrosis. Multidisciplinary care during the acute stage is necessary to prevent these complications.
A fixed drug eruption characteristically recurs in the same site or sites each time the drug is administered. With each exposure, the number of involved sites may increase. Usually, just one drug is involved, although independent lesions from more than one drug have been described.
Cross-sensitivity to related drugs may occur, such as between tetracycline-type drugs, and between anticonvulsants. Fixed drug eruptions may occur with protease inhibitors. There may be a refractory period after the occurrence of a fixed eruption. Acute lesions usually develop 30 min to 8 hours after drug administration as sharply marginated, round or oval itchy plaques of erythema and oedema becoming dusky violaceous or brown, and sometimes vesicular or bullous.