HAART and Skin Problems

“Several antiretroviral agents , including amprenavir, efavirenz and enfuvirtide, have also been linked with HSRs; however, the best characterized reactions occur with nevirapine and abacavir…Nevirapine hypersensitivity can include any combination of fever, rash and internal organ involvement, but most commonly manifests as isolated rash within 6 weeks of initiating drug (mean delay 14 days [44,45]). Nevirapineattributable rash occurs at a rate of about 16% in clinical trials, and approximately 7% of patients discontinue treatment because of cutaneous events. Although rashes are mostly mild to moderate, a relatively high incidence of more severe cutaneous reactions, such as SJS (0.3%), has been reported with nevirapine…The abacavir hypersensitivity syndrome is a well characterized systemic inflammatory reaction that usually occurs within 6 weeks of initiating abacavir-containing therapy (mean delay 11 days), with an incidence of approximately 5% in clinical trials. It is associated with a more nonspecific range of clinical signs and symptoms than nevirapine HSR, including fever, malaise, gastrointestinal symptoms and respiratory symptoms, which can mimic other infectious and inflammatory causes. Rash is absent in about 30% of cases of abacavir HSR and is often a late feature. Rechallenge is associated with severe, rapid and potentially life-threatening reactions, and is therefore contraindicated”

“Porphirya cutanea tarda (PCT) has been reported in HIV-1-infected individuals. It has been related to HIV, other viral infections (hepatitis C virus; HCV) alcohol abuse and antiretroviral therapy (ART). We describe for the first time a case of PCT that developed during ART switch, after the introduction of tipranavir/ritonavir to a backbone with tenofovir and lamivudine…In August 1991 (CD4 cell count 274 cells/µl) she began ART with zidovudine monotherapy. Since then, she has been treated with all available antiretroviral drugs, and the ART regimens have frequently been stopped or modified for immunological or virological failure, side effects, rash and low tolerance…The diagnosis of PCT was based on cutaneous signs (blisters, hyperpigmentation and skin fragility) and high protoporphyrine and coproporphyrin levels in the urine [signs of a serious blood disorder, and a possible attempt by the body to flush toxins]”

“Some people infected with HIV who have started such treatment in countries where leprosy is endemic have developed florid leprosy lesions in the initial months of treatment…The manifestations described, however, are a well recognised complication of antiretroviral treatment known as immune reconstitution disease or immune reconstitution inflammatory syndrome (IRIS). This presents with the manifestation (or “unmasking”) of a previously subclinical coinfection or the deterioration of an opportunistic infection that had been responding to treatment…The first published case of leprosy associated immune reconstitution disease occurred in 2003 in a Ugandan living in London…Antiretroviral treatment has been available since 1996 in countries with high average incomes. Immune reconstitution disease has been well characterised in this setting and is associated with a predictable range of opportunistic infections…Immune reconstitution disease has, for example, recently been described in association with the parasitic infections leishmaniasis, strongyloidiasis, and schistosomiasis…From the patient’s perspective, HIV infection and leprosy are both highly stigmatising diseases, and having both is understandably distressing. This distress may be heightened by the patient’s perception that the leprosy was caused by the antiretroviral drugs. Frequent cases of this disease could make patients less enthusiastic about antiretroviral treatment programmes. Importantly, some lesions seen in leprosy associated with immune reconstitution disease are unusually florid, and severe neuropathy triggered during antiretroviral treatment might lead to permanent disability”

“We report two cases of SJS [Stevens-Johnson Syndrome: life-threatening erosion of the skin] among first-degree relatives [mother and son] receiving stavudine, lamivudine, and nevirapine…in rural Uganda…[the mother recovered] after a one month hospitalization…[the son] despite initial improvement with supportive therapy and steroids, on day 25 of hospitalization he developed fever, restlessness, and altered mental status, and died of probable sepsis.”

“Of 202 patients, 95 (47%) and 69 (34.2%) developed a rash from all reasons and from NNRTI [the non-nucleoside reverse transcriptase inhibitors Efavirenz (EFV) and Nevirapine (NVP)], respectively. For NNRTI-related rash the incidences were EFV (20%), NVP BD [twice daily] (21%), NVP OD [once daily] (38%) and NVP + EFV (67%). The proportions of patients with grade I, II and III within the four treatment arms are as follows: EFV, 4.3, 13 and 2.9%; NVP BD, 2.3, 15.9 and 2.3%; NVP OD, 12.8, 19.1 and 6.4%; and NVP + EFV, 11.9, 47.6 and 7.1%…There were six patients (2.9%) who developed NNRTI related serious adverse events, as defined by hospitalization or death. Four were women and five were treated NVP: namely three taking NVP OD and two taking NVP BD. All patients were hospitalized and one died. Two patients had Stevens Johnson syndrome (one each in the NVP OD and NVP BD arms) and three had a serum sickness-like reaction with fever and rash (One each in the NVP OD, NVP BD and EFV arms). One patient with underlying congenital heart disease (ventral septal defect) died of heart failure during hospitalization for rash and severe liver toxicity from NVP. All the other patients on NVP except one were switched to EFV and did not have recurrent rash. The single patient on EFV did well after having EFV temporarily stopped.”

“On 24 September 2002 at 08:00 hours, he received his first 300 mg dose of abacavir under observation at the psychiatric hospital, together with didanosine and tenofovir DF. Lopinavir/ritonavir was administered at 08:30 hours, at which time the patient was complaining of dizziness, muscle pain, distal dyseasthesias in the lower extremities, nausea, and abdominal discomfort. At 09:00 hours, his blood pressure was 85/55 mmHg, and at 09:30 hours he lost consciousness when sitting in a wheelchair…Supine blood pressure was 78/ 50 mmHg and a normal saline intravenous infusion was started. He was noted to have a confluent, maculopapular rash starting on the chest and spreading to his neck, face, and arms. Subcutaneous epinephrine was administered…Hypotension [dangerously low blood pressure] persisted despite aggressive intravenous saline infusion and the patient was transferred to intensive care at 13:30 hours. While there he had fever (40.18C), hypotension (75/28 via central line), and lost consciousness for approximately 3 min. An intravenous dopamine infusion was commenced. Oedema of the face and lips and urticaria on the face and chest were treated with corticosteroids and antihistamines.”

“12 non-HIV-infected individuals developed severe cutaneous [skin] toxicity, including 3 with Stevens-Johnson syndrome, after 7 to 12 days of nevirapine-containing PEP regimens…The use of PEP regimens containing nevirapine should be discouraged.”

“Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with VIRAMUNE [Nevirapine]. These have included severe cases of SJS [Stevens-Johnson syndrome], TEN [Toxic Epidermal Necrosis (skin death)], and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs and symptoms of severe skin reactions or hypersensitivity reactions must discontinue VIRAMUNE as soon as possible.”

“Between May 1997 and November 1999, a diagnosis of SJS [Stevens-Johnson syndrome] or TEN [toxic epidermal necrosis (skin death)] was established in 246 patients [both are severe skin disorders characterized by acute skin blisters and mucous membrane erosions. SJS is generally diagnosed if skin detachment is <10% and TEN if it is >30%]. Eighteen [of these patients] were known to be infected by HIV-1 (7.3%), 15 out of these 18 had been exposed to nevirapine. The reaction began 10-240 days after the introduction of nevirapine (median, 12 days) and all patients had received escalating doses. In 10 patients the reaction occurred with the initial dosage. All but one patients received simultaneously a variety of other antiretroviral agents but no specific drug combination emerged, and nevirapine was the only drug significantly associated with an increased risk of SJS or TEN in HIV-infected persons...In European countries the risk of SJS or TEN in the context of HIV infection appears to be associated with nevirapine. The respect of a lead-in period does not appear to prevent SJS or TEN. Because of the severity of these reactions and the long elimination half-life of nevirapine, we suggest discontinuation of the drug as soon as any skin eruption occurs.”

“Fatal hypersensitivity reactions have been associated with therapy with Ziagen [Abacavir]. Patients developing signs or symptoms of hypersensitivity (which include fever; skin rash; fatigue; gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms such as pharyngitis, dyspnea, or cough) should discontinue Ziagen as soon as a hypersensitivity reaction is suspected. Ziagen should not be restarted following a hypersensitivity reaction because more severe symptoms will recur within hours and may include life-threatening hypotension and death (see warnings precautions: information for patients, and adverse reactions).”