1. INTRODUCTION A previous cohort study from our unit suggested a benefit for the use of efavirenz compared to nevirapine in a group of patients initiating antiretroviral therapy within a clinic setting. Other cohorts have demonstrated similar results, although a recent RCT of 48 weeks duration failed to show any significant differences between the use of efavirenz and nevirapine in antiretroviral naïve patients (2NN) (Fig. 1). AIMS AND METHODS We aimed to examine outcomes of therapy, including time to virological and treatment failure within a large cohort of NNRTI (efavirenz vs nevirapine) treated patients followed for up to 260 weeks. All antiretroviral naïve patients initiating EFV or NVP containing regimens since 01/96 were identified from an observational database. The durability analysis concentrated only on patients who achieved at least one undetectable HIV viral load since treatment start. Virological failure was defined as at least 2 consecutive HIV VL > 500 copies/ml. Treatment failure (toxicity/intolerance) was defined as a switch of NNRTI for any reason whilst HIV VL undetectable. Patients may have switched between EFV and NVP, to a PI or to a triple NA. Multivariate analysis was used to determine significant factors associated with regimen failure and Kaplan-Meier curves calculated of Time-To Failure (TTF) for the whole cohort. RESULTS 694 patients commenced therapy with either NVP or EFV since 01/96. 69 (10%) never achieved an undetectable HIV VL on first line therapy. 625 patients did achieve a VL < 500 copies/ml after starting therapy and were included in the durability analysis. 297 commenced NVP and 328 commenced EFV. Patients receiving both EFV and NVP ( n=10) were excluded. The outcomes of patients with regard to treatment failure are given in Fig 2. 35 (11.8%) of patients on NVP switched therapy to either EFV (n=17) or a PI (n=18). 22 (6.7%) of patients on EFV switched therapy, 14 to NVP and 8 to a PI. Overall 77% of the NVP patients and 89% of the EFV patients remained on their original NNRTI throughout follow-up. Reasons for switch from NVP were predominantly rash and hepatotoxicty, the reasons for switch of EFV were CNS toxicity or rash (except 2 patients who were switched because of pregnancy). At baseline there were no significant differences between EFV and NVP in terms of gender, baseline VL or CD4, or prior AIDS. EFV tended to be commenced in later years and with a backbone of AZT/3TC (Combivir). NVP was more likely to be commenced with a D4T/DDI backbone. In multivariate analysis the only factors significantly associated with an increased likelihood of virological/treatment failure were the use of NVP, a baseline CD4 of <100 cells/mm 3 and the use of a D4T/DDI NA backbone (Fig 4.) Stratifying by year of therapy start had no effect on outcome. Kaplan-Meier curves showed an advantage for EFV over NVP both in Time to Virological Failure (p=0.003) and Time to Treatment Failure (Virological and Toxicity failures combined) (p=0.0324) (Fig 3a/b.) CONCLUSIONS Both NVP and EFV continue to demonstrate good durability with the majority of patients remaining on first line NNRTI therapy with extended follow-up. Most switches of therapy were undertaken for the expected toxicities seen with NVP and EFV respectively. Although a switch in NA backbone alone was not counted as failure in this analysis, the greater tendency of NVP to be prescribed with D4T/DDI may have led to some total therapy switches in the NVP group, as patients were transferred from D4T/DDI regimens because of mitochondrial toxicity. Despite this, EFV remains significantly associated with lower likelihood of treatment cessation in multivariate analysis and continues to demonstrate a reduced risk of virological failure over NVP in this extended cohort. Durability of efavirenz compared to nevirapine with long term follow-up of an antiretroviral naïve cohort Matthews GV, Mandalia S, Orkin C, Gilleece Y, Fisher B, Bower M, Nelson M, Gazzard BG Chelsea & Westminster Hospital, London, UK Fig 1. Studies comparing Efavirenz to NevirapineFig 2. Therapy outcomes of patients on EFV and NVP Fig 3a. Time to either treatment or virological failure (days) Fig 4. Univariate and multivariate analysis of factors predicting virological and/or treatment failure NNRTI studies RCT Naïve Cohorts Experienced Cohorts 2NN Keiser Matthews EUROSIDA ICONA N=625 EFV n=328 NVP n=297 N=17 No switch in therapy N=230 N=8 N=32 LFU N=14 No switch in therapy N=292 N=14 (15 months)(28 months) EFV 1.00 0.75 0.50 0.25 0.00 200017501500125010007505002500 NVP Time to Fail Survival Distribution Function P=0.0324 1.00 0.75 0.50 0.25 0.00 200017501500125010007505002500 Strata: EFV NVP Time to Fail Survival Distribution Function EFV NVP P=0.003 EFV NVP Fig 3b. Time to virological failure (days) VariableAdjusted HR (95%CI) P-value AZT+3TC backbone D4T+DDI backbone 1 1.93 (1.19-3.12)0.008 Baseline CD4 Count <=100 cells mm 3 >100 cells mm 3 1 0.47 (0.31-0.71)<0.001 NVP EFV 1 0.60 (0.40-0.89)0.012 Risk FactorRisk of FailureP value EFV vs NVP0.58 (0.41-0.84)0.003 Prior ADI1.87 (1.29-2.71)0.002 Year Started Pre 1998 vs 20011.66 (0.76-3.66)0.228 Baseline CD4 count >100 vs <=1000.56 (0.38-0.83)0.003 D4T+DDI vs AZT+3TC2.34 (1.52-3.61)<0.001 Univariate model Multivariate model PI N=18