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• W2070171622 abstract "In a study of 685 antiretroviral-naïve HIV-infected adults initiating treatment with a nevirapine-based regimen, Phillips et al.[1] report that the nevirapine-related hypersensitivity reaction (HSR) in hepatitis C virus (HCV) co-infected individuals is associated with a higher mortality rate than in individuals not co-infected, and that the results obtained support the current recommendation advising against nevirapine use in HIV/HCV co-infected patients [1]. Given the definition of HSR adopted for this analysis and the characteristics of the study population, we present an alternative interpretation of their results below. Phillips et al.[1] defined the nevirapine-related HSR as those patients permanently stopping nevirapine after first prescription: (i) within 30 days with no report of adverse effects; (ii) within 90 days with reported adverse effects; or (c) within 90 days with alanine or aspartate aminotransferase elevation during treatment, or an decrease in either value after stopping nevirapine [1]. This definition of nevirapine-related HSR differs from that of the European Summary of Product Characteristics (SPC) [2] and the US Prescribing Information [3], and is not consistent with previous trials of nevirapine. Although no formal definition has been established for use in nevirapine trials, patients experiencing a grade 3 or more rash [i.e. a rash with constitutional findings or with elevated liver function tests (LFTs) including Stevens–Johnson syndrome with < 10% exfoliation], as assessed by experts on drug-induced skin reactions, should be considered as having HSR [4]. Based on the investigators' broad definition, 66/685 (9.5%) of enrolled patients were classified as having HSR. Since the median duration of nevirapine-therapy was 30 days in these 66 patients, we can assume that 50% experienced HSR within 30 days of first nevirapine dose, with no report of adverse effects (category ‘a’ of the definition). Clinical descriptions were available for 23 of 66 (35%) HSR patients; a very low percentage for validation purposes. Among these 23 patients, 16 (70%) developed rash (severe in three of these 16); five (22%) had abnormal LFTs and one (4%) had fever [1]. All LFT abnormalities were considered related solely to nevirapine use, even in the absence of constitutional symptoms. Consideration of SPC/Prescribing Information-defined HSR key indicators would have resulted in a lower, more accurate HSR rate, consistent with previously published data. Indeed, the authors acknowledge that misclassification bias may have occurred during their study. We concur and consider that the results would be more accurately interpreted if events had been classed as ‘early discontinuation’ of initial antiretroviral regimen, rather than HSR. Of the 66 HSR patients, 49 had known HCV serostatus and follow-up is reported; 13 patients did not resume antiretroviral therapy (nine died; 69%), 14 patients resumed therapy after 6 months (three died; 21%) and 22 patients resumed therapy within 12 months (one died; 5%). The reasons for not resuming therapy (whether nevirapine-related or not) are not described. The cessation of highly-active antiretroviral therapy is a major predictor of new AIDS/death [5], as demonstrated by the percentage of patients who died following permanent treatment discontinuation (69%). In addition, most deaths among nevirapine recipients with HSR were HIV-related (11/13; 85%) [1], reflecting disease progression after failure to resume antiretroviral treatment, rather than hepatotoxicity. Therefore, besides any considerations of the study design, it is difficult to conclude whether HSR is an effect modifier in the relationship between HCV co-infection and mortality. A higher risk of death is more likely to be a consequence of early treatment interruptions (whether adverse effect-related or not) in co-infected patients and lower exposure to active ART (early treatment discontinuation resulted in fewer patients resuming therapy and more deaths). Evidence of a similar prevalence of HCV infection among the ‘a’, ‘b’ and ‘c’ HSR categories, a clear relationship between permanent treatment discontinuation and nevirapine use, and a multivariate survival analysis indicating the same level of interaction between HCV status and HSR, when HSR is better defined, would be a more convincing indication of nevirapine HSR influencing HCV co-infection in terms of the effect on mortality. Furthermore, the study population might not be representative of the current antiretroviral-naïve HIV-1 population initiating highly-active antiretroviral therapy. The mortality rate of 15% after a median follow-up of 64 months (5 years) is far higher than the predictions made available via the large ART Cohort Collaboration [6]. The excessively broad HSR definition, applied to a selected study population by Phillips et al.[1], might explain their findings. The statement that the results ‘support the current recommendation against the use of nevirapine in HIV/HCV-coinfected patients’ is misleading because it refers to a local recommendation. The widely accepted DHHS, IAS and European guidelines do not make any recommendation to this effect [7–9]. In summary, the study by Phillips et al.[1] confirms the relationship between early failure on an initial antiretroviral regimen and mortality. However, the relationship is only observed in patients initiating ART with a nevirapine-containing regimen. A comparison of mortality rates in recipients of both nevirapine- and non-nevirapine-containing regimens, whether HCV-co-infected or not, is highly warranted for establishing recommendations regarding initial antiretroviral regimens. Conflicts of interest: François Raffi has received research funding or honoraria from, or consulted for, Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Pfizer, Roche, and Schering-Plough. Geneviève Chêne has received honoraria from Boehringer Ingelheim and Gilead Sciences." @default.
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• W2070171622 date "2008-01-30" @default.
• W2070171622 modified "2023-10-09" @default.
• W2070171622 title "Is nevirapine-based therapy discontinuation in hepatitis C co-infected patients a more important mortality determinant than hypersensitivity" @default.
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• W2070171622 doi "https://doi.org/10.1097/qad.0b013e3282f4a0b8" @default.
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