DOI: /hiv British HIV Association HIV Medicine (2014), 15, SHORT COMMUNICATION

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1 DOI: /hiv SHORT COMMUNICATION Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load copies/ml in the pooled ECHO and THRIVE phase 3, randomized, double-blind trials* J-M Molina, 1 N Clumeck, 2 C Orkin, 3 LT Rimsky, 4 S Vanveggel 4 and M Stevens 4 on behalf of the ECHO and THRIVE Study Groups 1 Department of Infectious Diseases, Saint Louis Hospital-APHP, INSERM U941 and University of Paris Diderot, Paris, France, 2 Saint Pierre University Hospital, Brussels, Belgium, 3 Barts and The London NHS Trust, London, UK and 4 Janssen Infectious Diseases BVBA, Beerse, Belgium Objectives These 96-week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment-naïve, HIV-1-infected adults with viral load (VL) HIV-1 RNA copies/ml receiving rilpivirine or efavirenz. Methods ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed (ECHO) or investigator-chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/ml, using an intent-to-treat-population, time-to-loss-of-virological-response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated. Results Baseline characteristics were comparable between the rilpivirine (n = 368) and efavirenz (n = 329) groups. At week 96, response rates [84% for rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval (CI) 1.7% to 9.7%] and incidences of VF for the resistance analysis (VF res) (8% for rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VF res, a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). Among those with VF res, more patients in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 ( ) cells/μl in the rilpivirine group and by 206 ( ) cells/μl in the efavirenz group. Treatment-related grade 2 4 overall adverse events, any rash and dizziness were less frequent for rilpivirine than for efavirenz (P < ). Conclusions Rilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment-naïve adults with baseline VL copies/ml over 96 weeks. Frequencies of VF res and emergent NNRTI RAMs in each group were similar. More patients with VF res in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz. Correspondence: Dr Jean-Michel Molina, Department of Infectious Diseases, Saint Louis Hospital-APHP, INSERM U941 and University of Paris Diderot, Paris 7, France. Tel: ; fax: ; jean-michel.molina@sls.aphp.fr *Data contained in this article were presented at the 11th International Congress on Drug Therapy in HIV Infection, November 2012, Glasgow, UK (Abstract P270). 57

2 58 J-M Molina et al. Keywords: baseline viral load, efavirenz, nonnucleoside reverse transcriptase inhibitor, rilpivirine, TMC278, treatment-naïve Accepted 3 July 2013 Introduction The nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (TMC278), combined with other antiretroviral drugs, is approved for use in antiretroviral treatmentnaïve, HIV-1-infected adults in several countries including the USA, Canada and Europe [1,2]. In many countries, the indication for rilpivirine is restricted to patients with a viral load HIV-1 RNA copies/ml [1,2]. These approvals were based on the 48-week results of the phase 3 ECHO (Efficacy Comparison in treatment-naïve HIV-infected subjects Of TMC278 and efavirenz) and THRIVE (TMC278 against HIV, in a once-daily RegImen Versus Efavirenz) trials [3 5]. A single tablet, once-daily regimen containing rilpivirine, emtricitabine and tenofovir disoproxil fumarate has been approved in the USA, Canada, Europe and elsewhere [6,7]. Rilpivirine demonstrated noninferior antiviral efficacy vs. efavirenz in the primary preplanned week 48 pooled analyses of the ECHO/THRIVE trials [3,4]. Rilpivirine had an improved tolerability profile compared with efavirenz, with fewer discontinuations because of adverse events (AEs) [3 5]. Rilpivirine was associated with a higher virological failure rate than efavirenz [3 5]. Baseline viral load had a greater effect on the virological failure rate for rilpivirine than for efavirenz [5,8]. Therefore, efficacy, virology and safety were assessed in the predefined subset of ECHO/THRIVE patients with a baseline viral load copies/ml. Patients receiving rilpivirine who had a baseline viral load copies/ml demonstrated a higher response rate at week 48 than those receiving efavirenz [9]; 90% of rilpivirine patients vs. 84% of efavirenz patients achieved a viral load < 50 copies/ml [using an intent-to-treat, timeto-loss-of-virological-response (ITT-TLOVR) algorithm]. In this subpopulation, the rate of virological failure was the same for rilpivirine and efavirenz [9]. Here we report the efficacy, virology and safety results in patients with baseline viral load copies/ml, after 96 weeks of treatment. Methods ECHO (TMC278-C209; NCT ) and THRIVE (TMC278-C215; NCT ) were phase 3, randomized, double-blind, double-dummy, active-controlled, international trials. The design and methodology of these trials have been reported previously [3,4]. The primary objective of ECHO and THRIVE was to demonstrate the noninferiority, as assessed by response rates (viral load < 50 copies/ml), of rilpivirine vs. efavirenz at week 48 using an ITT population and a TLOVR imputation algorithm. The trials enrolled antiretroviral treatment-naïve, HIV- 1-infected adults with baseline viral load 5000 copies/ ml, confirmed viral sensitivity to the background nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) and no documented evidence of NNRTI resistance [10]. Patients were randomized 1:1 to receive rilpivirine 25 mg with efavirenz placebo once daily, or efavirenz 600 mg with rilpivirine placebo once daily. In ECHO, patients received a fixed N[t]RTI background regimen of tenofovir disoproxil fumarate and emtricitabine. In THRIVE, patients received an investigator-chosen N[t]RTI background regimen of tenofovir disoproxil fumarate/ emtricitabine, zidovudine/lamivudine or abacavir/ lamivudine. Randomization was stratified by background regimen (THRIVE) and screening viral load ( copies/ml, copies/ml and > copies/ml). Resistance analyses of the 96-week database were performed on the pooled ITT ECHO/THRIVE populations. Virological failure for the resistance analysis (VF res) was defined as either: (1) first achieving two consecutive viral load values < 50 copies/ml then having two consecutive (or only one if treatment was stopped) viral load values 50 copies/ml (rebounder); or (2) never achieving two consecutive viral load values < 50 copies/ml and having an increase in viral load 0.5 log 10 copies/ml above the nadir (never suppressed) [11]. Safety and tolerability were assessed throughout the trials. Laboratory parameters and changes in plasma lipids were also assessed. Only statistical comparisons between treatment groups that were preplanned for specific AEs and lipid measurements for the overall population [3 5] are presented for this 96-week analysis of data for the pooled ECHO/THRIVE population with baseline viral load copies/ml. For statistical comparison of AEs, Fisher s exact test (5% significance level) was used. For statistical comparison of lipids, the Wilcoxon rank-sum test was used.

3 RPV in patients with baseline VL copies/ml 59 Results Baseline demographic parameters and disease characteristics were similar between the 368 of 686 (54%) rilpivirine and 329 of 682 (48%) efavirenz patients who had baseline viral load copies/ml [9]. At the time of the week 96 analysis, 310 (84%) rilpivirine and 264 (80%) efavirenz patients remained in the study. The median treatment duration was 104 weeks in each group. At week 96, a high proportion of patients in both groups maintained a response of < 50 copies/ml (ITT-TLOVR) (Fig. 1). The difference in response rate was 4% between the rilpivirine (84%) and efavirenz (80%) treatment groups [95% confidence interval (CI) 1.7% to 9.7%] (Fig. 1). The mean (95% CI) increase in absolute CD4 cell count from baseline to week 96 was 224 ( ) cells/μl for rilpivirine and 206 ( ) cells/μl for efavirenz patients. Detailed week 96 analyses of the resistance data, including by baseline viral load, are published elsewhere [11]. The incidence of VF res was comparable between the groups. With rilpivirine, 28 of 368 (8%) patients experienced VF res (including one rilpivirine VF res occurring after the week 96 visit), while 20 of 329 (6%) efavirenz patients experienced VF res. In both groups, the majority of VF res occurred in the first year of treatment, with approximately half as many VF res occurring in the second year (Table 1). Of the patients with VF res with genotypic data, a comparable proportion in each group developed NNRTI resistance-associated mutations (RAMs) [10 of 27 (37%) and six of 17 (35%) for Responders* Rilpivirine Efavirenz Non-responders Discontinued due to other reasons Discontinued due to AE/death VFeff % patients Rilpivirine n = ( ) 80 Efavirenz n = 329 Fig. 1 Virological outcome [using an intent-to-treat, time-to-loss-ofvirological-response (ITT-TLOVR) algorithm] at week 96 in the rilpivirine and efavirenz treatment groups in patients with baseline viral load copies/ml in the pooled ECHO/THRIVE population. *Patients with viral load <50 copies/ml, using an ITT-TLOVR algorithm. Loss to follow-up, noncompliance, withdrawal of consent, ineligibility to continue or sponsor s decision. VF eff, virological failure in the efficacy analysis determined by TLOVR in the ITT population (threshold 50 copies/ml): either confirmed response before week 96 with confirmed rebound at or before week 96, or no response before week 96. Difference (95% confidence interval) in response rate (rilpivirine efavirenz). AE, adverse event. rilpivirine and efavirenz patients, respectively]. However, a greater proportion of rilpivirine patients with VF res (12 of 27; 44%) than efavirenz patients with VF res (two of 17; 12%) developed N[t]RTI RAMs, mostly M184I/V (Table 1). As reported elsewhere [8,11], E138K and M184I, usually in combination, were the most common RAMs in rilpivirine patients with VF res. The most common RAMs in efavirenz patients with VF res were K103N and M184V. No K65R RAM developed in patients with VF res in either group (Table 1). Patients receiving rilpivirine experienced fewer grade 2 4 AEs at least possibly related to treatment than efavirenz patients [66 of 368 (18%) vs. 104 of 329 (32%), respectively; P < ] (Table 1). AEs leading to permanent discontinuation occurred in 18 (5%) rilpivirine patients vs. 22 (7%) efavirenz patients. AEs most frequently leading to discontinuation were psychiatric disorders (2% in each group), infections and infestations (1% in each group), pregnancy (0.5% for the rilpivirine group and 1% for the efavirenz group) and nervous system disorders (0.3% vs. 1%, respectively). Of AEs of interest considered at least possibly related to treatment, any rash and neurological AEs, including dizziness, were less frequent among rilpivirine patients than among efavirenz patients (all P < ; Fisher s exact test). In both groups, the incidences of treatment-related grade 2 4 AEs, discontinuations because of AEs, serious AEs and AEs of interest were considerably lower in weeks than in the first 48 weeks (Table 1). In general, the incidence of treatment-emergent laboratory abnormalities, particularly abnormal levels of fasted total and low-density lipoprotein (LDL) cholesterol, was lower among rilpivirine patients than in the efavirenz treatment group. There were minimal mean (95% CI) changes from baseline to week 96 in the rilpivirine group in total cholesterol [0.74 ( 2.28 to 3.75) mg/dl], LDL cholesterol [ 0.81 ( 3.4 to 1.78) mg/dl] and triglyceride levels [ 10.1 ( to 0.82) mg/dl], which were smaller (P < ) than the changes in the efavirenz group [24.45 ( ), ( ) and ( ) mg/dl, respectively]. For efavirenz, the mean (95% CI) change in high-density lipoprotein (HDL) cholesterol [9.74 ( ) mg/dl] was greater (P < ) than for rilpivirine [3.05 ( ) mg/dl]. Therefore, at week 96, there was no difference between treatments in the mean change in the total cholesterol/hdl cholesterol ratio ( 0.22 for each group). There was a minimal mean (95% CI) increase from baseline to week 96 in serum creatinine in each group, but this increase was greater for rilpivirine [0.1 ( ) mg/dl] than for efavirenz [0.03 ( ) mg/dl]. There was only a 0.01 mg/dl increase in both groups from week 48 to 96. The smallest changes in serum creatinine were seen in patients receiving zidovudine/lamivudine. Grade 2 4

4 60 J-M Molina et al. Table 1 Week 96 analysis of resistance, safety and tolerability by trial period in patients with baseline viral load copies/ml in the pooled ECHO/THRIVE population Rilpivirine (n = 368) Efavirenz (n = 329) All* Weeks 0 48 Weeks All* Weeks 0 48 Weeks Resistance VF res [n (%)] 28 (8) 20 (5) 7 (2) 20 (6) 14 (4) 6 (2) Never suppressed 10 (3) 10 (3) 4 (1) 4 (1) Rebounders 18 (5) 10 (3) 7 (2) 16 (5) 10 (3) 6 (2) VF res with genotypes (n) VF res with treatment-emergent RAMs ( 2 patients) (n) NNRTI + N[t]RTI RAMs NNRTI RAMs E138K K101E 2 2 K103N 5 1 V90I N[t]RTI RAMs M184I M184V K219E 2 1 Safety AEs leading to discontinuation [n (%)] 18 (5) 13 (4) 3 (1) 22 (7) 18 (5) 2 (1) Grade 2 4 AEs at least possibly related to treatment [n (%)] 66 (18) 56 (15) 5 (1) 104 (32) 97 (29) 12 (4) Serious AEs [n (%)] 30 (8) 21 (6) 8 (2) 28 (9) 22 (7) 6 (2) AEs of interest at least possibly related to treatment [n (%)] Any neurological AE 70 (19) 67 (18) 1 (0.3) 135 (41) 132 (40) 2 (1) Dizziness 35 (10) 35 (10) 97 (29) 97 (29) 1 (0.3) Any psychiatric AE 61 (17) 54 (15) 2 (1) 75 (23) 68 (21) 5 (2) Abnormal dreams/nightmares 27 (7) 25 (7) 38 (12) 36 (11) 1 (0.3) Rash (grouped term) 9 (2) 8 (2) 1 (0.3) 43 (13) 43 (13) Rilpivirine (n = 367)** Efavirenz (n = 322)** Treatment-emergent laboratory abnormalities [n (%)] Any grade 2 4 laboratory abnormality 169 (46) 131 (36) 83 (23) 190 (59) 165 (51) 97 (30) Hypophosphataemia 42 (11) 28 (8) 19 (5) 46 (14) 34 (11) 16 (5) Pancreatic amylase 30 (8) 22 (6) 14 (4) 37 (11) 33 (10) 10 (3) Total cholesterol (fasted) 24 (7) 15 (4) 15 (4) 73 (23) 57 (18) 38 (12) LDL cholesterol (fasted) 25 (7) 19 (5) 14 (4) 57 (18) 43 (13) 34 (11) Aspartate aminotransferase 24 (7) 14 (4) 11 (3) 35 (11) 31 (10) 5 (2) Alanine aminotransferase 21 (6) 14 (4) 10 (3) 41 (13) 37 (11) 11 (3) Hyperglycaemia (fasted) 23 (6) 15 (4) 10 (3) 23 (7) 14 (4) 13 (4) Lipase 11 (3) 6 (2) 7 (2) 16 (5) 13 (4) 4 (1) Triglycerides (fasted) 6 (2) 3 (1) 3 (1) 16 (5) 12 (4) 4 (1) AE, adverse event; LDL, low-density lipoprotein; NNRTI, nonnucleoside reverse transcriptase inhibitor; N[t]RTI, nucleoside/tide reverse transcriptase inhibitor; RAM, resistance-associated mutation; VF res, virological failure in the resistance analysis (threshold 50 copies/ml). *Analysis performed using all available data, including beyond week 96. Resistance analyses were performed at time of failure, and weeks 0 48 included all patients with VF res up to and including the 48-week visit, and weeks included all patients with VF res after the 48-week visit and up to and including the 96-week visit. One patient with VF res after week 96 had treatment-emergent RAMs: E138K, M184I and K219E. For safety analyses, patients could be counted in both the week 0 48 and week periods, and data after week 96 are not included in the week period. Well-described AEs associated with current NNRTIs at least possibly related to treatment and observed in 10% of patients in either group (all grades). **Data not available for all patients. Occurring in 5% of patients in either group. creatinine increases occurred in two (1%) rilpivirine- and five (2%) efavirenz-treated patients. Discussion The pooled analysis of the ECHO/THRIVE trials demonstrated that rilpivirine had comparable efficacy to efavirenz over 96 weeks in antiretroviral treatment-naïve patients with baseline viral load copies/ml. At week 96, 84% of rilpivirine- vs. 80% of efavirenz-treated patients achieved < 50 copies/ml, and the mean changes from baseline in CD4 cell count were 224 and 206 cells/μl, respectively. At week 48, the response rates in this subset of patients were 90% for rilpivirine and 84% for efavirenz.

5 RPV in patients with baseline VL copies/ml 61 There was only a slight decline in response rates in both treatment groups compared with the week 48 responses, as also seen in previous studies of NNRTIs [12,13], because of the definition of the (ITT-based) primary efficacy endpoint. The mean changes from baseline in CD4 cell count were +185 and +161 cells/μl for rilpivirine and efavirenz patients, respectively [9]. The week 96 results, therefore, revealed a continued upward trend in CD4 cell count with both rilpivirine and efavirenz. In the week 48 primary analysis of the overall patient population from ECHO and THRIVE, there were more rilpivirine patients than efavirenz patients with VF res (9% vs. 5%, respectively) [5,8]. However, in patients with baseline viral load copies/ml, the incidence of VF res was comparable between treatment groups at both week 48 (5% with both rilpivirine and efavirenz [9]) and week 96 (8% and 6% for rilpivirine and efavirenz patients, respectively [11]). Thus, over the course of 96 weeks of treatment, the rate of VF res in patients who had a baseline viral load copies/ml was similar in the rilpivirine and efavirenz groups. Furthermore, in both treatment groups the rates of VF res were lower in the second year of the trials, being approximately half those in the first year. A comparable proportion of patients with VF res in each group developed NNRTI RAMs, while a higher proportion of rilpivirine patients with VF res than efavirenz patients with VF res developed N[t]RTI RAMs (mostly M184I/V associated with emtricitabine/lamivudine resistance) [3 5,8,9,11,14]. The incidences of discontinuations attributable to AEs and of serious AEs irrespective of relatedness were similar for rilpivirine and efavirenz in the current analysis. However, as for the overall population [3 5,14], rilpivirine was associated with lower incidences of grade 2 4 treatment-related AEs, grade 2 4 treatment-emergent laboratory abnormalities, treatment-related rash and neurological AEs than efavirenz. As previously reported for the overall population, relatively few AEs occurred after week 48 in either treatment group [14]. Also in line with the findings for the overall population [14], rilpivirine was associated with smaller mean changes from baseline in total cholesterol, LDL cholesterol and triglyceride levels than efavirenz. However, given that HDL cholesterol levels increased more in the efavirenz group than in the rilpivirine group, there was no difference between treatment groups in the change in the total cholesterol/hdl cholesterol ratio. The increase in serum creatinine seen in the rilpivirine group occurred after 2 weeks and remained stable thereafter. Cystatin C clearance did not decrease in the THRIVE trial [4], so this increase was probably related to changes in tubular creatinine secretion. In summary, these results suggest that rilpivirine, either as a single-tablet regimen or as a single agent combined with other antiretrovirals, is a valuable therapeutic option for the treatment of antiretroviral treatment-naïve, HIV-1- infected adults with a viral load copies/ml. Acknowledgements The authors are grateful to the patients and their families for their participation and support during the studies; the ECHO and THRIVE Janssen study teams; the study centre staff and principal investigators; and members of the Janssen rilpivirine team, in particular David Anderson, Bryan Baugh, Erik Leijskens, Peter Williams and Eric Wong for their input. Conflicts of interest: JMM has acted as a consultant, participated in advisory boards, received speaker fees and been an investigator for clinical trials for Janssen, ViiV Healthcare, Gilead Sciences, Bristol-Myers Squibb, Abbott Laboratories, Boehringer Ingelheim, and Merck, Sharp & Dohme. NC has participated as an expert or investigator for Abbott Laboratories, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck, Sharp & Dohme, Pfizer, Roche and Janssen. CO has served as a speaker for and received honoraria from Janssen, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, ViiV Healthcare and Abbott Laboratories. LR, SV and MS are Janssen employees. Funding: This work was supported by Janssen Pharmaceuticals. Medical writing support was provided by James Gregson and assistance in incorporating author comments was provided by Ian Woolveridge of Gardiner-Caldwell Communications, Macclesfield, UK. Medical writing support was funded by Janssen. 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