Female sex and the use of anti-allergic agents increase the risk of developing cutaneous rash associated with nevirapine therapy

To identify factors associated with cutaneous rash, we performed a retrospective multicentre analysis of HIV outpatients starting a highly active antiretroviral therapy regimen containing nevirapine. A total of 62 cutaneous adverse events were observed in 429 patients. Rash hazard was increased in women, by the prophylactic use of glucocorticoids or antihistaminics, and was reduced by escalating the initial dose of nevirapine. Women receiving glucocorticoids had a 3 month cumulative probability of rash of 0.41. Cutaneous hypersensitivity reactions are the most common adverse events associated with the clinical use of nevirapine. The mean incidence is 16%, most episodes occur during the initial weeks of therapy and require treatment discontinuation [1]. Prophylaxis with glucocorticoids or antihistamine drugs during the initial weeks has been advocated [2–4]. Furthermore, initiating treatment with half the daily dose for the first 2 weeks is associated with a reduced incidence of rash and has been recommended for general practice [1,5]. We retrospectively analysed a cohort of patients starting antiretroviral combination therapies that included nevirapine in an attempt to describe the incidence and the predictors of cutaneous hypersensitivity reactions. Observational databases from two large infectious diseases clinics in Rome, Italy, were analysed. Clinical and laboratory findings and treatments are recorded at each visit and hospitalizations are abstracted. We looked at all patients who were given nevirapine in a non-randomized fashion and were confirmed to have taken the drug for at least one week by a subsequent visit to the clinic, and selected those starting nevirapine as part of a potent regimen (three or more antiretroviral agents). Cutaneous adverse reactions were retrieved, and the severity of the event was deduced from the clinical description, the subsequent outcome and from laboratory results. Adverse events were graded using WHO criteria [6]. We analysed 429 patients of whom 34% were women, and the median age was 37 years. The transmission category was injecting drug use (33%) and sexual (60%). At baseline, 24% were treatment naive, 8% had a history of hypersensitivity to drugs, the median CD4 cell count was 326 cells/μl and HIV RNA was 4.0 log10 copies/ml. The most frequently used combinations were: zidovudine plus lamivudine plus nevirapine in 147 patients (34%); stavudine plus lamivudine plus nevirapine in 131 patients (31%); stavudine plus didanosine plus nevirapine in 51 patients (12%); stavudine plus nevirapine plus nelfinavir in 20 patients (5%); and zidovudine plus didanosine plus nevirapine in 14 patients (3%). The initial 2 week nevirapine lead-in 200 mg daily dose was given to 86% of patients. A total of 120 patients (28%) were given corticosteroid prophylaxis, as decided by their treating physician after some communications had suggested a potential benefit [2,3] : the majority (n = 103) received prednisone 25–75 mg a day, the duration was less than 2 weeks in 13% 2–3 weeks in 49% and 3–5 weeks in 34% of the cases. Antihistamines were given to 10 patients and concomitant treatments, i.e. drugs used for prophylaxis or the treatment of opportunistic illnesses or other conditions, were given to 27% of individuals: 53 patients were given sulpha agents. After a median follow-up of 339 days (398 patient-years), 62 cutaneous adverse events occurred (14.5%) (15.6 events per 100 patient-years) with 55 (88%) permanent drug discontinuations. Fourteen cutaneous events were grade 1, 45 grade 2, and three grade 3, with permanent discontinuations in 10, 42 and three cases, respectively; there was no adverse event-related death. The median time to the onset of rash was 14 days: 84% of rashes occurred within the first 4 weeks of nevirapine therapy. Cutaneous reactions occurred in 40 out of 147 women (27%) and in 22 out of 282 men (8%). They occurred in 27 out of 120 patients taking corticosteroid prophylaxis (22%), and in 35 out of 309 not taking glucocorticoids (11%). There was a 3 month cumulative risk of rash of 0.11 in patients without and 0.23 in patients with glucocorticoid prophylaxis; women receiving glucocorticoids had a 0.41 3 month cumulative probability of rash (women taking glucocorticoids versus all the rest, crude hazard ratio 3.87; 95% confidence interval 1.77–8.47;P = 0.0007). The mean time to the onset of rash did not differ between patients given glucocorticoids and those not taking them (18 and 24 days, respectively, P = 0.24). The severity of the allergic episodes did not differ between the sexes and was not influenced by the use of glucocorticoids. The factors associated with rash episodes are listed in Table 1. In the multivariate analysis, female sex, taking glucocorticoids, and antihistaminic prophylaxis were all independently related to an increased hazard of rash, whereas starting nevirapine with an initial 200 mg lead-in dose was independently associated with a reduced hazard of rash. Higher CD4 cell counts showed a trend towards an independent association with the hazard of rash. A protective effect of the concomitant exposure to other drugs was not confirmed by the multivariate analysis. There was no association with previous allergic reactions to drugs, other co-administered antiretroviral agents, co-infection with hepatitis viruses, naive status, the concomitant use of sulpha or other agents and HIV-RNA levels (not shown).Table 1: Crude and adjusted hazard ratios of developing a cutaneous rash in 429 HIV-1 positive individuals who started nevirapine-containing highly active antiretroviral therapy. Our findings show that short-course glucocorticoid prophylaxis fails to prevent nevirapine-associated rash; even more, those taking prophylaxis might have an increased hazard of rash compared with those without prophylaxis. This unexpected result was strongly confirmed after adjusting for all variables associated with a modified hazard of rash. These findings are in agreement with preliminary data from two randomized studies [7,8], showing a similarly increased incidence of rash in the corticosteroid-treated arm of nevirapine recipients. In contrast, another randomized open-label study [4], indicated that corticosteroid prophylaxis is associated with a reduced incidence of rash. There is no clear explanation for these profound discrepancies. The unblinded nature of some of the trials and the different criteria for the definition of the event (observed by the physician or referred by the patient) might have influenced the judgement on the relevance of the clinical events. Differences in the composition of the study populations might also have played a role. We also observed a strongly increased hazard of rash in patients taking antihistaminic prophylaxis, showing that the phenomenon might not be specifically related to glucocorticoids. We hypothesize that the mechanism for the increased incidence might come from the fact that antiallergic agents hinder the induction of tolerance [9]. This is consistent with the beneficial effect of the initial nevirapine dose escalation on the incidence of rash, an observation in agreement with others [4,10]. Higher CD4 cell counts when beginning nevirapine therapy showed a trend towards an increased probability of rash. Consistently, in HIV-infected patients with allergic reaction to other agents, tolerance can more easily be induced in those with lower CD4 cell counts [11]. An intriguing finding, in agreement with a smaller study [12], was the fourfold higher probability of rash in women. Whether hormonal or pharmacokinetic differences play a role requires specific investigation. It should be noted that it has already been shown that women have an increased risk of adverse reactions leading to the discontinuation of highly active antiretroviral regimens not containing nevirapine [13]. In conclusion, we show that antiallergic agents should not be employed in the initial period of nevirapine administration. The other predictors of cutaneous reactions to nevirapine identified by this study might be considered when carefully weighing the risks and benefits of different therapeutic strategies for individual patients in clinical practice. Andrea Antinoria Francesco Baldinib Enrico Girardia Antonella Cingolanib Mauro Zaccarellia Simona Di Giambenedettob Annalisa Barracchinia Patrizio De Longisa Rita Murrib Valerio Tozzia Adriana Ammassarib Maria Gabriella Rizzob Giuseppe Ippolitoa Andrea De Lucab