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Risk factors for treatment-limiting toxicities in patients starting nevirapine-containing antiretroviral therapy

Kesselring, Anouk Ma; Wit, Ferdinand Wb; Sabin, Caroline Ac; Lundgren, Jens Dd; Gill, M Johne; Gatell, Jose Mf; Rauch, Andrig; Montaner, Julio Sh; de Wolf, Franka; Reiss, Peterb; Mocroft, Amandacon behalf of the Nevirapine Toxicity Multicohort Collaboration

doi: 10.1097/QAD.0b013e32832d3b54

Background: This collaboration of seven observational clinical cohorts investigated risk factors for treatment-limiting toxicities in both antiretroviral-naive and experienced patients starting nevirapine-based combination antiretroviral therapy (NVPc).

Methods: Patients starting NVPc after 1 January 1998 were included. CD4 cell count at starting NVPc was classified as high (>400/μl/>250/μl for men/women, respectively) or low. Cox models were used to investigate risk factors for discontinuations due to hypersensitivity reactions (HSR, n = 6547) and discontinuation of NVPc due to treatment-limiting toxicities and/or patient/physician choice (TOXPC, n = 10 186). Patients were classified according to prior antiretroviral treatment experience and CD4 cell count/viral load at start NVPc. Models were stratified by cohort and adjusted for age, sex, nadir CD4 cell count, calendar year of starting NVPc and mode of transmission.

Results: Median time from starting NVPc to TOXPC and HSR were 162 days [interquartile range (IQR) 31–737] and 30 days (IQR 17–60), respectively. In adjusted Cox analyses, compared to naive patients with a low CD4 cell count, treatment-experienced patients with high CD4 cell count and viral load more than 400 had a significantly increased risk for HSR [hazard ratio 1.45, confidence interval (CI) 1.03–2.03] and TOXPC within 18 weeks (hazard ratio 1.34, CI 1.08–1.67). In contrast, treatment-experienced patients with high CD4 cell count and viral load less than 400 had no increased risk for HSR 1.10 (0.82–1.46) or TOXPC within 18 weeks (hazard ratio 0.94, CI 0.78–1.13).

Conclusion: Our results suggest it may be relatively well tolerated to initiate NVPc in antiretroviral-experienced patients with high CD4 cell counts provided there is no detectable viremia.

aHIV Monitoring Foundation, the Netherlands

bCenter for Poverty-Related Communicable Diseases, and Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

cUniversity College London Medical School, Royal Free Campus, London, UK

dRigshospitalet and University of Copenhagen, Copenhagen HIV Programme, Copenhagen, Denmark

eUniversity of Calgary, Calgary, Canada

fInfectious Diseases & AIDS Units, Hospital Clinic, University of Barcelona, Spain

gDivision of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland

hBritish Columbia Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, BC, Canada.

Received 22 January, 2009

Revised 20 April, 2009

Accepted 21 April, 2009

Correspondence to Anouk M. Kesselring, MD, HIV Monitoring Foundation, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.

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Nevirapine is frequently used as part of combination antiretroviral therapy (cART) regimens, and is currently listed as one of the alternative options for cART in treatment-naive patients [1]. Nevirapine may also be used in patients with prior cART experience, for example, to minimize diarrhea or to reduce cardiovascular risks associated with protease inhibitors, to avoid the neuropsychiatric side effects of efavirenz or to simplify the treatment regimen. However, nevirapine is occasionally associated with severe adverse events, typically hypersensitivity reactions that usually occur within the first 18 weeks of treatment (Viramune package insert). Six to seven percent of patients discontinue the use of nevirapine because of clinically significant hypersensitivity reactions [2–5]. Severe, life-threatening and even fatal cases of hepatotoxicity [6,7] and/or skin rashes [8–10] have occurred in patients taking nevirapine. HIV-1-seronegative adults using nevirapine for postexposure prophylaxis appear at particularly high risk of life-threatening hepatotoxicity [11]. Among HIV-positive patients, the risk of hypersensitivity reactions is highest in patients with higher CD4 cell counts, with a lower CD4 threshold observed in women. Asians may also be at an increased risk [12]. This has led to the recommendation not to use nevirapine in HIV-1-infected patients starting nevirapine at higher CD4 cell counts (>400/μl in men, >250/μl in women) [13], unless the benefits clearly outweigh the risks. This recommendation is based on data from clinical trials in treatment-naive HIV-1-infected patients. It is, however, unclear whether the risk of potentially fatal toxicities is increased similarly in other patient groups starting nevirapine-based cART (NVPc), for instance treatment-experienced patients starting NVPc for the first time with high CD4 cell counts. A recent study suggested that the risk of treatment-limiting toxicities for treatment-experienced patients who initiate NVPc with high CD4 cell counts may be similar to the risk in treatment-naive patients with low CD4 cell counts [14], whereas another study suggested that antiretroviral-experienced patients with low nadir CD4 cell counts and an undetectable viral load had a similar risk for hypersensitivity reactions (HSR) compared to antiretroviral-naive patients who started nevirapine with low CD4 cell counts [15]. Although these were large studies, the number of women included was relatively small. The risk of potentially fatal toxicities in treatment-experienced patients compared to treatment-naive patients cannot easily be studied within the setting of a randomized clinical trial. This collaboration of seven established cohort studies therefore aimed to retrospectively evaluate the safety of nevirapine-based cART in treatment-experienced patients with high CD4 cell counts.

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Patients from the ATHENA (n = 3906), British Columbia (n = 367), EuroSIDA (n = 1035), Hospital Clinic Barcelona (n = 750), Southern Alberta (n = 61), Swiss HIV (n = 795) and UK CHIC (n = 3272) cohort studies were included [16–22]. Information on socio-demographic characteristics, reasons for discontinuation of antiretroviral drugs when available, cause of death, laboratory markers and treatment history were collected from each cohort. We included all patients over 16 years of age, who started nevirapine-based cART (defined as nevirapine and two nucleosides/nucleotides) after 1 January 1998 with CD4 cell count and viral load measurements in the 6 months before starting cART. Women who started nevirapine-based cART during pregnancy were excluded from the analyses. Duplicate patients, that is, those who were included as part of a national cohort and also as part of EuroSIDA were included only once.

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We identified all patients who discontinued nevirapine due to a hypersensitivity reaction (skin rash and/or hepatotoxicity) in cohorts with detailed information on reasons for discontinuation and discontinued nevirapine due to all-cause toxicity and/or patient or physician choice. If a patient stopped another antiretroviral drug at the same time as nevirapine, the reported reasons for discontinuation of these drugs were also considered to apply to nevirapine. Some cohorts could provide the date of discontinuation of antiretroviral drugs, but not specific reasons for these discontinuations. From a total of 10 186 patients, 5269 patients discontinued nevirapine and the reason for discontinuation was unavailable for 1645 patients (31.2%). Percentages varied per cohort: 111 out of 193 patients (57.5%) from British Columbia discontinued because of unknown reasons, for Barcelona this rate was 44/428 (10.3%), for EuroSIDA 102/702 (14.5%), Swiss HIV Cohort Study 28/482 (5.8%), Southern Alberta 0/41 (0%), UK CHIC 1287/1825 (70.5%) and Athena 73/1539 (4.7%). For five cohorts (Barcelona, EuroSIDA, Swiss, Southern Alberta and Athena, n = 6547), specific information regarding reasons for discontinuation of antiretroviral therapy, including hypersensitivity reactions (skin rash and/or hepatotoxicity), was collected. By using hypersensitivity reactions as an endpoint in these five cohorts we may underestimate the occurrence of HSR in this population due to missing reasons for discontinuation or misclassification. To ensure we did not miss any treatment-limiting toxicities associated with nevirapine we performed an additional sensitivity analysis considering discontinuations due to all treatment-limiting toxicities associated with nevirapine and/or patient or physician choice at any time and within 18 weeks of starting nevirapine. Toxicities occurring more than 18 weeks after starting cART are more likely to arise from other factors, for instance, from the nucleosides/nucleotides backbone that are used together with nevirapine

For missing reasons for discontinuation, a standardized definition of discontinuation due to toxicity was used which takes the viral load at the time of discontinuation into account (C. Sabin, personal communication). Discontinuation with viral loads below 1000 cp/ml is not likely because of virological failure. Using this definition, any discontinuation within the first 3 months of starting nevirapine was regarded as discontinuation due to all-cause toxicity or patient/physician choice, as well as discontinuations in months 4–6 with a prediscontinuation viral load less than 1000 cp/ml or no viral load available prior to the discontinuation of nevirapine.

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Chronic hepatitis C was defined as a detectable plasma HCV-RNA, or in case HCV-RNA was missing presence of HCV antibodies. Chronic hepatitis B was defined as positive hepatitis B surface antigen, positive core antigen or positive plasma HBV-DNA. Detectable HIV viremia was defined as viral load at least 400 cp/ml.

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Statistical analyses

The CD4 cell count at the start of nevirapine-based cART was classified as high (>400 cells/μl in men and >250 cells/μl in women) or low. Patients were further classified according to prior antiretroviral treatment experience and viral load (≤ 400 vs. >400 cp/ml) at starting NVPc. The proportions of patients discontinuing NVP therapy because of hypersensitivity reactions or all-cause toxicity and/or patient or physician's choice (TOXPC) were compared between patient groups using the Chi-square test. Cox proportional hazards regression models were used to compare time to and risk factors for discontinuation of nevirapine in these patient groups due to hypersensitivity reactions (in patients when specific reasons for discontinuation were available) and TOXPC with missing reasons for discontinuation imputed using the methods described above.

All models were stratified by cohort. Individuals were followed from date of start of NVPc to the date of discontinuation of nevirapine, loss to follow-up, death or 1 February 2008, whichever occurred first. Potential risk factors that were investigated included demographic factors (age, sex, HIV transmission category and ethnic group), nadir CD4 cell count, CD4 cell count and plasma HIV-1 RNA levels at the start of NVPc, calendar year of starting NVPc, AIDS diagnosis prior to starting nevirapine, chronic hepatitis virus coinfections, exposure to various combinations of nucleosides/nucleotides concurrently used with nevirapine, prior exposure to efavirenz, prior use of antiretroviral therapy and concomitant use of cotrimoxazole. Sensitivity analyses also further adjusted for body mass index (BMI) in the cohorts in which this information was available. Parameters identified by univariate analysis as significantly associated with HSR (P < 0.05) were entered into a multivariate model for HSR with use of a stepwise selection of variables. Multivariate models for TOXPC within 18 weeks and TOXPC at any time were adjusted for significant variables identified in the multivariate model for HSR.

Mortality rates during the first 24 weeks after starting NVPc were compared between patients who discontinued nevirapine due to toxicities and those who did not. All analyses were performed using SAS, version 9.1 (SAS Institute, USA).

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Patient characteristics

Overall, 6227 (61%) of the 10 186 patients who started NVPc were Caucasian, 274 (3%) were of Asian ethnicity and 2791 (27%) were women. Three hundred and ninety-one patients (4%) were chronically HBV coinfected, 732 (7%) had chronic hepatitis C, 1011 (10%) were intravenous drug users. The median age was 38 years [interquartile range (IQR) 33–45]. Six thousand two hundred and twenty-nine (62%) were treatment-experienced at the start of nevirapine. Median CD4 cell count in women was 259 cells/μl (IQR 157–420), and 297 cells/μl (IQR 180–481) in men. The NRTI backbone most often used in combination with nevirapine was zidovudine/lamivudine (4620, 45%).

Table 1 shows baseline characteristics stratified by prior treatment experience, CD4 cell count and viral load. The majority of patients without prior treatment experience started nevirapine with low CD4 cell counts (3051 patients, 79%). The majority of treatment-experienced patients started nevirapine with high CD4 cell counts and undetectable viral load (2272, 34%) or with low CD4 cell counts and detectable viral load (1865, 29%).

Table 1

Table 1

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Reasons for discontinuation

The cohorts that collect the specific reasons for discontinuation of antiretroviral therapy contributed 6547 patients to this study. A total of 1535 out of these 6547 (23%) patients discontinued nevirapine because of all-cause toxicity and/or patient/physician's choice at any time after the start of nevirapine. Of these 1535 patients, 458 (30%) discontinued due to hypersensitivity reactions: 334 (22%) due to skin rash and 124 (8%) due to hepatotoxicity without concomitant skin rash. Other reasons for discontinuation were gastrointestinal symptoms (n = 402), pancreas-related (n = 4), central nervous system disorders (n = 23), renal disorders (n = 2), endocrine disorders (n = 1), lactic acidosis (4), other toxicities (n = 38), or patient or physician's choice (603, 39%). Seven hundred and twenty-seven (11%) of the 6547 patients for which specific reasons for discontinuation of antiretroviral therapy were collected, discontinued nevirapine because of all-cause toxicity and/or patient or physician's choice within 18 weeks: 375 of these (52%) discontinued nevirapine due to hypersensitivity reactions, as manifested by skin rash (n = 299, 41%) or hepatotoxicity without concomitant skin rash (n = 76, 11%). Other reasons were gastrointestinal symptoms (n = 175), central nervous system disorders (n = 5) and renal disorders (n = 1). Twenty-nine patients discontinued due to other toxicities (n = 29) or patient/physician's choice (142, 20%).

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Of all patients who started nevirapine, 87 (1%) died within 24 weeks of starting. There were five deaths from complications related to hepatitis. Twenty-seven deaths were HIV-related, 22 non-HIV-related and the cause of death was unknown for 33 cases. Of the five patients who died from hepatitis, four had prior treatment experience, chronic hepatitis C and acquired HIV through intravenous drug use. Two of these five patients had switched to nevirapine with low CD4 cell counts and detectable viral load (these patients both died within 3 months after starting nevirapine) and two of these had switched to nevirapine with high CD4 cell counts and detectable viral load (one patient died after 1 month and one patient died 5 months after starting nevirapine). There was one treatment-naive patient who had started nevirapine with low CD4 cell count and who was not chronically infected with hepatitis. This patient died 49 days after starting nevirapine. Two patients who experienced a nevirapine-associated HSR died within 24 weeks of starting nevirapine. Both of these deaths were reported to be unrelated to the use of nevirapine. Although none of the deaths were explicitly reported to be nevirapine-related, complete information on cause of deaths, such as by using the CoDe system (www.cphif.df/CoDe/About/tabid/64/Default.aspx), were not routinely available and we cannot be certain that the deaths were unrelated to nevirapine use.

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Discontinuation due to toxicities in treatment-naive and experienced patients

The median time from starting NVPc to HSR and TOXPC was 30 days (IQR 17–60) and 162 days (IQR 31–737), respectively. Eighty (5.9%) treatment-naïve patients who started NVPc with low CD4 cell counts (the reference group) discontinued NVP due to HSR and 289 (9.5%) discontinued NVP due to TOXPC within 18 weeks. Table 2 shows the number of patients who discontinued nevirapine for the different endpoints. Of the treatment-experienced patients who initiated nevirapine with high CD4 cell counts and undetectable viral load, 142 (7.9%) discontinued due to HSR and 226 (10%) discontinued nevirapine due to TOXPC within 18 weeks, whereas of the treatment-experienced patients who initiated nevirapine with high CD4 cell counts and detectable viral load, 75 (10.7%) discontinued due to HSR and 135 (15.8%) due to TOXPC within 18 weeks.

Table 2

Table 2

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Risk factors for nevirapine-associated toxicity

In univariate analyses, current viral load and CD4 cell count, nadir CD4 cell count, ethnicity, calendar year of starting NVPc, nucleoside/nucleotide backbone used with nevirapine and HIV transmission category were associated with the risk of discontinuation due to HSR (P < 0.05). The final adjusted Cox models for the endpoints of discontinuation due to hypersensitivity reactions, TOXPC within 18 weeks and TOXPC at any time after starting nevirapine are presented in Fig. 1. All analyses were stratified by cohort and adjusted for current viral load and CD4 cell count, nadir CD4 cell count, region of origin, calendar year of starting nevirapine and HIV transmission category. The effect of having an undetectable viral load on all endpoints was considerable. Compared with treatment-naive patients with low CD4 cell count (and detectable viral load) as the reference group, treatment-experienced patients with low CD4 cell count were at increased risk of HSR and TOXPC within 18 weeks (although the estimate for HSR was not significant) if nevirapine was started with detectable viremia, whereas the hazard for HSR and TOXPC within 18 weeks was significantly lower if NVP was started in patients with low CD4 cell counts and undetectable viral loads. Compared to the reference group, the hazard for HSR and TOXPC within 18 weeks was significantly higher for treatment-experienced patients with high CD4 cell counts who started nevirapine with detectable viremia, whereas the hazards for all endpoints for treatment-experienced patients with high CD4 cell counts and undetectable viral loads were not significantly different from the reference group.

Fig. 1

Fig. 1

Age, sex, Asian ethnicity, nadir CD4, year of starting cART and IDU were associated with an increased risk for HSR (Table 3).

Table 3

Table 3

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We found that the risk for developing hypersensitivity reactions in treatment-experienced patients starting nevirapine-based cART with high CD4 cell counts strongly depends on whether patients have detectable viremia at the start of nevirapine. Treatment-experienced patients with high CD4 cell counts and undetectable viral loads had comparable risks of discontinuation of nevirapine due to hypersensitivity reactions compared to antiretroviral-naive patients with low CD4 cell counts. Undetectable viral load also had a protective effect in treatment-experienced patients starting nevirapine with low CD4 cell counts, with a risk of hypersensitivity reactions in this group of patients that was even lower then the risk in the reference group of treatment-naive patients with low CD4 cell counts.

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Rationale for different endpoints

One of the limitations of cohort studies and pooling cohort studies, are the different ways data are collected. In order to be sure we have not missed any nevirapine-associated toxicities, we also performed analyses considering all discontinuations due to toxicities within 18 weeks, or at any time point after starting nevirapine. Nevirapine-related hypersensitivity reactions are most likely to occur within 18 weeks after starting nevirapine (Viramune package insert). These additional analyses showed similar results compared to the HSR analysis. A limitation of using these broader endpoints is that we may have overestimated the proportion of patients that developed treatment limiting toxicities associated with nevirapine.

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Other studies

Recent data from EuroSIDA [14] showed that treatment-experienced patients starting NVPc with high CD4 cell counts had a significantly lower risk of discontinuation of nevirapine due to toxicities or patient/physician choice compared to antiretroviral-naive patients starting NVPc with high CD4 cell counts. A meta-analysis of randomized trials [23] found no evidence of an increased risk of hepatotoxicity, skin rash or death within the first 3 months after starting nevirapine in treatment-experienced patients who have an undetectable viral load at the start of nevirapine. In studies analyzing the safety and efficacy of switching to nevirapine in patients experiencing long-term control of virus replication on PI-based cART, few cases of hypersensitivity (skin rash) were observed [24,25]. Data from the Athena cohort study showed that treatment-experienced patients with low nadir CD4 cell counts and an undetectable viral load and high CD4 cell counts at the time of switching to nevirapine had a similar risk of developing HSR compared to treatment-naive patients who start nevirapine with low CD4 cell counts, whereas patients with low nadir CD4 cell counts, high current CD4 cell counts and detectable viral loads were at significantly higher risk of developing HSR [15]. However, these studies were limited by power. Our study, with its larger sample size, allowed more precise estimation of the effects of the various risk factors, and also allowed more detailed analyses for some of the smaller subgroups of patients.

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Immune-related mechanism

We found a strong association between nadir/current CD4 cell count and the risk of hypersensitivity reactions. Although the pathophysiology of nevirapine-associated hypersensitivity reactions remains unclear, the strong association with higher CD4 cell counts suggests the involvement of a CD4-dependent immune response directed to nevirapine-specific antigens. Several studies have described an association of HLA with a higher incidence of hypersensitivity reactions to nevirapine [26–28]. Nevirapine-associated skin rash appears to be immune-mediated by CD4 cells in an animal model of the female brown Norway rat [29].

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Viral load effect

We found a strong effect of viremia on the occurrence of hypersensitivity reactions. A possible explanation for this finding might be that in a setting in which HIV-1 replication is controlled, the lower antigenic HIV-1 load results in less hyperactivation [30], which in turn might lessen the tendency of the immune system to overreact to nevirapine. Patients with undetectable viremia were also less likely to discontinue nevirapine due to all-cause toxicity and/or patient or physician choice. These patients were more likely to substitute nevirapine for a single other drug, without simultaneously replacing the NRTI backbone (75%), and therefore we speculate that they experienced less toxicity related to the introduction of additional new antiretrovirals. Other studies have found a similar strong association between detectable viremia and the diagnosis of abacavir-associated hypersensitivity reactions [31].

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Risk factors

Our finding that females and patients with Asian ethnicity had an increased risk for developing treatment-limiting hypersensitivity reactions confirmed results from other studies [32–35]. The mechanisms for these differences are not known. It is possible that body weight and pharmacokinetic differences may play a role [36], although pharmacokinetic parameters of nevirapine did not show a relationship with adverse events in the 2NN study [37]. We performed an additional analysis in which we also adjusted for BMI (in a subset of patients for whom this information was available) and this did not explain the differences in the risk of discontinuation due to HSR observed for these patient groups (data not shown). Furthermore, we found no evidence that prior use of efavirenz, which induces the cytochrome p450 enzymes involved in the metabolization of nevirapine, lowers the risk of developing all-cause toxicity at any time, within 18 weeks or HSR (data not shown).

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The study has several limitations that are inherent to retrospective observational cohort studies in general. It was not fully possible to ascertain whether physicians who discontinued nevirapine because of skin rash and/or hepatotoxicity fully adhered to the toxicity management guidelines in the nevirapine package insert. One of the goals of this international collaboration was to examine the risk factors for nevirapine toxicity in more detail, especially in treatment-experienced patients, women and patients with an Asian ethnicity. Unfortunately, although the sample size of this collaboration is large, there were a relatively small number of Asian patients. Our finding that Asian patients have an increased risk for developing hypersensitivity reactions should be approached with caution. We encourage studies in Asia to further investigate the risk in Asian patients. As with all observational studies, we cannot rule out confounding by indication because it is impossible to retrospectively determine why doctors chose to start NVPc in any particular patient. For the participating cohorts with limited information on reasons for discontinuation, we used a standardized definition to estimate which of the discontinuations were due to toxicity. However, in sensitivity analyses excluding those cohorts, we found the same risk factors (data not shown). It is possible that experienced patients with detectable viremia were more likely to be nonadherent and therefore more likely to discontinue treatment. However, this possible source of bias is less likely a problem with HSR as an endpoint. Although 793 patients used nevirapine in combination with abacavir, only nine of these patients simultaneously started nevirapine and abacavir and discontinued these drugs due to HSR at the same time.

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We found that having a detectable viral load, higher current and nadir CD4 cell count, female sex and Asian origin were each independently associated with an increased risk for treatment-limiting toxicities and hypersensitivity reactions associated with nevirapine. Our results suggest that it may be relatively well tolerated to initiate nevirapine-based cART in antiretroviral-experienced patients with high CD4 cell counts provided there is no detectable viremia.

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We are grateful to all patients, doctors, nurses, and other persons who were involved with the participating cohort studies. We would like to thank participating cohort members who provided thoughtful review and feedback on the content of this manuscript.

Sources of funding of authors and individual cohorts: The ATHENA national observational cohort, maintained by the HIV Monitoring Foundation is supported by the Dutch Ministry of Health. J.S.M. has received an Avant-Garde Award from the National Institute of Drug Abuse, National Institutes of Health. Primary support for EuroSIDA is provided by the European Commission BIOMED 1 (CT94-1637), BIOMED 2 (CT97-2713), the 5th Framework (QLK2-2000-00773) and the 6th Framework (LSHP-CT-2006-018632) programs. Current support also includes unrestricted grants by Bristol-Myers Squibb, GlaxoSmithKline, Roche, Gilead, Pfizer, Merck and Co., Tibotec and Boehringer-Ingelheim. The participation of Hospital Clinic Barcelona was supported in part by RIS (grant no. 173). The participation of centres from Switzerland was supported by a grant from the Swiss Federal Office for Education and Science. The Swiss HIV Cohort Study is supported by the Swiss National Science Foundation (grant no. 3347-069366). Andri Rauch was supported by a Grant for Prospective Researchers from the Swiss National Science Foundation. Funding for the UK CHIC Study has been obtained from the Medical Research Council, UK (grant G0000199 and G0600337).

The members of the 7 cohorts include:

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ATHENA Cohort study (AIDS Therapy Evaluation Project Netherlands)

Participating physicians (with their cities): W. Bronsveld, M.E. Hillebrand-Haverkort (Alkmaar); J.M. Prins, J.C. Bos, J.K.M. Eeftinck Schattenkerk, S.E. Geerlings, M.H. Godfried, J.M.A. Lange, F.C. van Leth, S.H. Lowe, J.T.M. van der Meer, F.J.B. Nellen, K. Poga'ny, T. van der Poll, P. Reiss, T.A. Ruys, Sankatsing, R. Steingrover, G. vanTwillert, M. van der Valk, M.G.A. van Vonderen, S.M.E Vrouenraets, M. van Vugt, F.W.M.N.Wit, A. van Eeden, J.H. ten Veen, P.S. van Dam, J.C. Roos, K. Brinkman, P.H.J. Frissen, H.M. Weigel, J.W. Mulder, E.C.M. van Gorp, P.L. Meenhorst, A.T.A. Mairuhu, J. Veenstra, S.A.Danner, M.A. Van Agtmael, F.A.P. Claessen, R.M. Perenboom, A. Rijkeboer, M. van Vonderen (Amsterdam); C. Richter, J. van der Berg, R. van Leusen (Arnhem); R. Vriesendorp, F.J.F. Jeurissen, R.H. Kauffmann, E.L.W. Koger, HAGA (Den Haag); B. Bravenboer (Eindhoven);C.H.H. ten Napel,G.J. Kootstra (Enschede); H.G. Sprenger, W.M.A.J. Miesen, R. Doedens, E.H. Scholvinck (Groningen); R.W. ten Kate (Haarlem); D.P.F. van Houte, M. Polee (Leeuwarden); F.P. Kroon, van den Broek, J.T. van Dissel, E.F. Schippers (Leiden); G. Schreij, S. van de Geest, A. Verbon (Maastricht); P.P. Koopmans, M. Keuter, F. Post, A.J.A.M. van der Ven (Nijmegen); M.E. van der Ende, I.C. Gyssens,M. van der Feltz, J.G. den Hollander, S. de Marie, J.L. Nouwen, B.J.A. Rijnders, T.E.M.S. de Vries (Rotterdam); J.R. Juttmann, C. van de Heul, M.E.E. van Kasteren, St. Elisabeth (Tilburg); M.M.E. Schneider, M.J.M. Bonten, J.C.C. Borleffs, P.M. Ellerbroek, I.M. Hoepelman, C.A.J.J. Jaspers, I. Schouten, C.A.M. Schurink (Utrecht); W.L. Blok, A.A. Tanis (Vlissingen); P.H.P. Groeneveld (Zwolle).

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British Columbia Centre for Excellence in HIV (BCCfE-HIV), Canada

Chris Alexander, Rolando Barrios, Paula Braitstein, Zabrina Brumme, Keith Chan, Helen Cote, Nada Gataric, Josie Geller, Silvia Guillemi, P. Richard Harrigan, Marrianne Harris, Robert Hogg, Ruth Joy, Adrian Levy, Julio Montaner, Val Montessori, Anita Palepu, Elizabeth Phillips, Peter Phillips, Natasha Press, Mark Tyndall, Evan Wood, and Benita Yip.

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The EuroSIDA Study Group (national coordinators in parenthesis)

Argentina: (M Losso), C. Elias, Hospital J.M. Ramos Mejia, Buenos Aires. Austria: (N Vetter) Pulmologisches Zentrum der Stadt Wien, Vienna; (R Zangerle) Medical University Innsbruck, Innsbruck. Belarus: (I Karpov), A. Vassilenko, Belarus State Medical University, Minsk, V.M. Mitsura, Gomel State Medical University, Gomel; O. Suetnov, Regional AIDS Centre, Svetlogorsk. Belgium: (N Clumeck) S. De Wit, M. Delforge, Saint-Pierre Hospital, Brussels; R. Colebunders, Institute of Tropical Medicine, Antwerp; (L Vandekerckhove) University Ziekenhuis Gent, Gent. Bosnia: (V Hadziosmanovic) Klinicki Centar Univerziteta Sarajevo, Sarajevo. Bulgaria: K. Kostov, Infectious Diseases Hospital, Sofia. Croatia: J. Begovac, University Hospital of Infectious Diseases, Zagreb. Czech Republic: (L Machala) H. Rozsypal, Faculty Hospital Bulovka, Prague; D. Sedlacek, Charles University Hospital, Plzen. Denmark: (J Nielsen) G. Kronborg,T Benfield, M. Larsen, Hvidovre Hospital, Copenhagen; J. Gerstoft, T. Katzenstein, A-B. E. Hansen, P. Skinhøj, Rigshospitalet, Copenhagen; C. Pedersen, Odense University Hospital, Odense, L. Oestergaard, Skejby Hospital, Aarhus. Estonia: (K Zilmer) West-Tallinn Central Hospital, Tallinn, Jelena Smidt, Nakkusosakond Siseklinik, Kohtla-Järve. Finland: (M Ristola), Helsinki University Central Hospital, Helsinki. France: (C Katlama) Hôpital de la Pitié-Salpétière, Paris; J-P Viard, Hôpital Necker-Enfants Malades, Paris; P-M Girard, Hospital Saint-Antoine, Paris; J.M. Livrozet, Hôpital Edouard Herriot, Lyon; P. Vanhems, University Claude Bernard, Lyon; C. Pradier, Hôpital de l'Archet, Nice; F. Dabis, D. Neau, Unité INSERM, Bordeaux. Germany: (J Rockstroh) Universitäts Klinik Bonn; R. Schmidt, Medizinische Hochschule Hannover; J. van Lunzen, O. Degen, University Medical Center Hamburg-Eppendorf, Infectious Diseases Unit, Hamburg; H.J. Stellbrink, IPM Study Center, Hamburg; S. Staszewski, J.W. Goethe University Hospital, Frankfurt; J. Bogner, Medizinische Poliklinik, Munich; G. Fätkenheuer, Universität Köln, Cologne. Greece: (J Kosmidis) P. Gargalianos, G. Xylomenos, J. Perdios, Athens General Hospital; G. Panos, A. Filandras, E. Karabatsaki, 1st IKA Hospital; H. Sambatakou, Ippokration Genereal Hospital, Athens. Hungary: (D Banhegyi) Szent Lásló Hospital, Budapest. Ireland: (F Mulcahy) St. James's Hospital, Dublin. Israel: (I Yust) D. Turner, M. Burke, Ichilov Hospital, Tel Aviv; S. Pollack, G. Hassoun, Rambam Medical Center, Haifa;S Maayan, Hadassah University Hospital, Jerusalem. Italy: (A Chiesi) Istituto Superiore di Sanità, Rome; R. Esposito, I. Mazeu, C. Mussini, Università Modena, Modena; C. Arici, Ospedale Riuniti, Bergamo; R. Pristera, Ospedale Generale Regionale, Bolzano; F. Mazzotta, A. Gabbuti, Ospedale S. Maria Annunziata, Firenze; V. Vullo, M. Lichtner, University di Roma la Sapienza, Rome; A. Chirianni, E. Montesarchio, M. Gargiulo, Presidio Ospedaliero A.D. Cotugno, Monaldi Hospital, Napoli; G. Antonucci, F. Iacomi, P. Narciso, C. Vlassi, M. Zaccarelli, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A. Lazzarin, R. Finazzi, Ospedale San Raffaele, Milan; M. Galli, A. Ridolfo, Osp. L. Sacco, Milan; A. d'Arminio Monforte, Istituto Di Clinica Malattie Infettive e Tropicale, Milan. Latvia: (B Rozentale) P. Aldins, Infectology Centre of Latvia, Riga. Lithuania: (S Chaplinskas) Lithuanian AIDS Centre, Vilnius. Luxembourg: (R Hemmer), T. Staub, Centre Hospitalier, Luxembourg. Netherlands: (P Reiss) Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam. Norway: (J Bruun) A. Maeland, V. Ormaasen, Ullevål Hospital, Oslo. Poland: (B Knysz) J. Gasiorowski, Medical University, Wroclaw; A. Horban, E. Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; D. Prokopowicz, R. Flisiak, Medical University, Bialystok; A. Boron-Kaczmarska, M. Pynka, Medical Univesity, Szczecin; M. Beniowski, E. Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; H. Trocha, Medical University, Gdansk; (E Jablonowska) E. Malolepsza, K. Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz. Portugal: (F Antunes) E. Valadas, Hospital Santa Maria, Lisbon; K. Mansinho, Hospital de Egas Moniz, Lisbon; F. Maltez, Hospital Curry Cabral, Lisbon. Romania: (D Duiculescu) Spitalul de Boli Infectioase si Tropicale: Dr Victor Babes, Bucarest. Russia: (A Rakhmanova), Medical Academy Botkin Hospital, St Petersburg; A. Vinogradova, St Petersburg AIDS Centre, St Peterburg; S. Buzunova, Novgorod Centre for AIDS, Novgorod. Serbia: (D Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade. Slovakia: (M Mokráš) D. Staneková, Dérer Hospital, Bratislava. Slovenia: (J Tomazic) University Clinical Centre Ljubljana, Ljubljana. Spain: (J González-Lahoz) V. Soriano, L. Martin-Carbonero, P. Labarga, Hospital Carlos III, Madrid; (S Moreno) Hospital Ramon y Cajal, Madrid; B. Clotet, A. Jou, R. Paredes, C. Tural, J. Puig, I. Bravo, Hospital Germans Trias i Pujol, Badalona; J.M. Gatell, J.M. Miró, Hospital Clinic i Provincial, Barcelona; P. Domingo, M. Gutierrez, G. Mateo, M.A. Sambeat, Hospital Sant Pau, Barcelona. Sweden: (A Karlsson), Karolinska University Hospital, Stockholm; P.O. Persson, Karolinska University Hospital, Huddinge; L. Flamholc, Malmö University Hospital, Malmö. Switzerland: (B Ledergerber) R. Weber, University Hospital, Zürich; P. Francioli, M. Cavassini, Centre Hospitalier Universitaire Vaudois, Lausanne; B. Hirschel, E. Boffi, Hospital Cantonal Universitaire de Geneve, Geneve; H. Furrer, Inselspital Bern, Bern; M. Battegay, L. Elzi, University Hospital Basel. Ukraine: (E Kravchenko) N. Chentsova, Kiev Centre for AIDS, Kiev; (G Kutsyna) Luhansk AIDS Center, Luhansk; (S Servitskiy), Odessa Region AIDS Center, Odessa; (S Antoniak) Kiev; (M Krasnov) Kharkov State Medical University, Kharkov. United Kingdom: (S Barton) St. Stephen's Clinic, Chelsea and Westminster Hospital, London; A.M. Johnson, D. Mercey, Royal Free and University College London Medical School, London (University College Campus); A. Phillips, M.A. Johnson, A. Mocroft, Royal Free and University College Medical School, London (Royal Free Campus); M. Murphy, Medical College of Saint Bartholomew's Hospital, London; J. Weber, G. Scullard, Imperial College School of Medicine at St. Mary's, London; M. Fisher, Royal Sussex County Hospital, Brighton; C. Leen, Western General Hospital, Edinburgh.

Virology group: B. Clotet, R. Paredes(Central Coordinators) plus ad hoc virologists from participating sites in the EuroSIDA Study.

Steering Committee: F. Antunes, B. Clotet, D. Duiculescu, J. Gatell, B. Gazzard, A. Horban, A. Karlsson, C. Katlama, B. Ledergerber (Chair), A. D'Arminio Montforte, A. Phillips, A. Rakhmanova, P. Reiss (Vice-Chair), J. Rockstroh.

Coordinating Centre Staff: J. Lundgren (project leader), O. Kirk, A. Mocroft, N. Friis-Møller, A. Cozzi-Lepri, W. Bannister, M. Ellefson, A. Borch, D. Podlekareva, J. Kjær, L. Peters, J. Reekie, J. Kowalska.

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Hospital clinic of the University of Barcelona

Iñaki Perez, Jose Gatell.

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South Alberta Clinic, Canada

John Gill, Ron Read, Hartmut Krentz, Brenda Beckthold.

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Swiss HIV Cohort Study (SHCS)

The members of the Swiss HIV Cohort Study are M. Battegay, E. Bernasconi, J. Böni, H.C. Bucher, Ph. Bürgisser, A. Calmy, S. Cattacin, M. Cavassini, R. Dubs, M. Egger, L. Elzi, P. Erb, M. Fischer, M. Flepp, A. Fontana, P. Francioli (President of the SHCS, Centre Hospitalier Universitaire Vaudois, CH-1011- Lausanne), H. Furrer (Chairman of the Clinical and Laboratory Committee), C. Fux, M. Gorgievski, H. Günthard (Chairman of the Scientific Board), H. Hirsch, B. Hirschel, I. Hösli, Ch. Kahlert, L. Kaiser, U. Karrer, C. Kind, Th. Klimkait, B. Ledergerber, G. Martinetti, B. Martinez, N. Müller, D. Nadal, M. Opravil, F. Paccaud, G. Pantaleo, A. Rauch, S. Regenass, M. Rickenbach (Head of Data Center), C. Rudin (Chairman of the Mother & Child Substudy), P. Schmid, D. Schultze, J. Schüpbach, R. Speck, P. Taffé, P. Tarr, A. Telenti, A. Trkola, P. Vernazza, R. Weber, S. Yerly.

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The UK Collaborative HIV Cohort (CHIC) Study

UK CHIC Steering Committee: Andrew N. Phillips, Richard Gilson, Philippa Easterbrook, Martin Fisher, Brian Gazzard, Margaret Johnson, John Walsh, Clifford Leen, Chloe Orkin, Jane Anderson, Deenan Pillay, Valerie Delpech, Achim Schwenk, David Dunn, Mark Gompels, Teresa Hill, Kholoud Porter, Abdel Babiker, Caroline Sabin.

Central Co-ordination: Royal Free and University College, London (Loveleen Bansi, Teresa Hill, Andrew Phillips, Caroline Sabin); Medical Research Council Clinical Trials Unit (MRC CTU), London (Abdel Babiker, David Dunn, Kholoud Porter, Stephen Sheehan)

Participating Centres: King's College Hospital, London (Philippa Easterbrook, Anele Waters, Dorian Crates, Siti Mohamed-Saad); Brighton and Sussex University Hospitals NHS Trust (Martin Fisher, Nicky Perry, Anthony Pullin, Duncan Churchill, Wendy Harris); Chelsea and Westminster NHS Trust, London (Brian Gazzard, Steve Bulbeck, Sundhiya Mandalia, Jemima Clarke); Mortimer Market Centre, Royal Free and University College Medical School (RFUCMS), London (Richard Gilson, Julie Dodds, Andy Rider, Ian Williams); Health Protection Agency, Centre for Infections, London (Valerie Delpech); Royal Free NHS Trust and RFUCMS, London (Margaret Johnson, Mike Youle, Fiona Lampe, Colette Smith, Helen Gumley, Clinton Chaloner, Dewi Ismajani Puradiredja); St. Mary's Hospital, London (John Walsh, Jonathan Weber, Shane Cashin, Christian Kemble, Nicky Mackie, Alan Winston); Barts and The London NHS Trust, London (Chloe Orkin, Rachel Thomas, Kevin Jones); Homerton Hospital, London (Jane Anderson, Selina Gann, Kevin Jones); Edinburgh (Clifford Leen, Alan Wilson); North Middlesex (Achim Schwenk, Jonathan Ainsworth); North Bristol NHS Trust (Mark Gompels).

Anouk Kesselring helped develop the project, had access to the contributing data from each cohort, performed all statistical analyses and drafted the manuscript. Ferdinand Wit contributed to the development of the project, interpretation of analyses and writing the manuscript and co-supervised statistical analyses. Caroline Sabin, Jens Lundgren, John Gill, Jose Gatell, Andri Rauch, Julio Montaner, and Frank de Wolf provided data from their cohort study, and provided input into interpretation of analyses and contributed to writing the manuscript. Peter Reiss helped implement the study, contributed to study design, interpretation of analyses and writing the manuscript. Amanda Mocroft was responsible for overall supervision of this study, proposed the study and design, co-supervised the statistical analysis, provided data, and contributed to interpretation of statistical analysis and writing the manuscript.

There are no conflicts of interest for Anouk Kesselring and Ferdinand Wit. Over the past three years, Caroline Sabin has received fees for speaking, membership of advisory boards, organising education and consultancy from several companies, including Boehringer Ingelheim, Bristol Myers Squibb, Gilead Sciences and Tibotec. Jens Lundgren has received funding from a variety of pharmaceutical companies including Boehringer-Ingelheim for research, travel grants, speaking engagements and consultancy fees. John Gill has received grants and/or served on advisory boards for GSK,Merck,Pfizer, Boehringer Ingelheim,Bristol Myers Squibb, Tibotec, Gilead sciences and Abbott laboratories. Jose Gatell has received research grants and honoraria for participation in advisory boards or lectures from Boehringer Ingelheim. Andri Rauch none. Julio Montaner has received grants from, served as an ad hoc advisor to, or spoke at various events sponsored by; Abbott, Argos Therapeutics, Bioject Inc, Boehringer Ingelheim, BMS, Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche, Janssen-Ortho, Merck Frosst, Panacos, Pfizer, Schering, Serono Inc, TheraTechnologies, Tibotec (J&J), Trimeris. Frank de Wolf-none. Peter Reiss has received honoraria for speaking engagements, advisory board membership and consultancy, as well as research grants from companies including Boehringer Ingelheim, Hoffmann LaRoche, Merck, Tibotec, Gilead Sciences, GlaxoSmithKline, Pfizer, Bristol Myers Squibb and Theratechnologies. Amanda Mocroft has received funding from a variety of pharmaceutical companies including Boehringer-Ingelheim for research, travel grants, speaking engagements and consultancy fees.

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CD4 cell count; HIV; nevirapine; toxicity; viral load

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