Original Article Efficacy and Safety of a Switch to Rilpivirine-Based Regimens in Treatment-Experienced HIV-1-Infected Patients: a Cohort Study

Antiviral Therapy 2016; 21:329–336 (doi: 10.3851/IMP3010)

Original article Efficacy and safety of a switch to rilpivirine-based regimens in treatment-experienced HIV-1-infected patients: a cohort study

Sandrine Gazaignes1, Matthieu Resche-Rigon2,3, Caroline Gatey1, Chloe Yang4, Blandine Denis1, Julien Fonsart5, Kristell Desseaux2,3, Michel Guionie6, Willy Rozenbaum1, Constance Delaugerre7,8, Jean‑Michel Molina1,7*

1Department of Infectious Diseases, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, University of Paris Diderot, Paris, France 2Biostatistics and Computer Medicine, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, University of Paris Diderot, Paris, France 3ECSTRA Team INSERM, UMR 1153, Paris, France 4Department of Medicine, University of Toronto, Toronto, ON, Canada 5Department of Biochemistry, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris, Paris, France 6COREVIH Ile de France Est, Paris, France 7INSERM UMR 941, Paris, France 8Department of Virology, Saint-Louis Hospital, Assistance Publique Hôpitaux de Paris and University of Paris Diderot, Paris, France

*Corresponding author e-mail: [email protected]

Background: Rilpivirine (RPV) is a second-generation fumarate/emtricitabine. At month 12, the rate of viro- once-daily non-nucleoside reverse transcriptase inhibitor logical success was 59% and increased to 72% using (NNRTI) which has shown non-inferior antiviral activity to available data beyond month 12. Sixteen (6%) patients efavirenz in treatment-naive patients. Data in treatment- experienced virological failure, which was associated experienced patients are more limited. We wished to assess with the presence of the M184V/I resistance mutation the efficacy and safety of a switch to RPV-based regimens in prior genotypes (P=0.02) and the use of a non-NNRTI in well-suppressed treatment-experienced patients. as third agent before the switch (P=0.03). RPV-based Methods: Between September 2012 and June 2013, all regimens were overall well tolerated and only 23 (8%) antiretroviral therapy (ART)-experienced HIV-1-infected patients discontinued ART because of adverse events, patients with a plasma HIV RNA level <50 copies/ml, and mostly neuropsychiatric adverse events. Switching to RPV switching to an RPV-based regimen, were analysed in this was associated with significant but modest improvement retrospective observational monocentric cohort study. The of the lipid profile. primary end point was the proportion of patients with Conclusions: In patients fully suppressed on ART, a switch virological success defined as a plasma HIV RNA level <50 to an RPV-based regimen should only be considered copies/ml at 12 months using the FDA snapshot algorithm. in the absence of prior virological failure or resistance Results: A total of 281 participants were studied and mutations to nucleoside reverse transcriptase inhibitors 97% received a combination of RPV/tenofovir disoproxil and NNRTIs to avoid virological failures.

Introduction

Rilpivirine (RPV) is second-generation non-nucleoside analysis of two large placebo-controlled Phase III clini- reverse transcriptase inhibitor (NNRTI) that has recently cal trials, ECHO and THRIVE, which demonstrated the been approved for the treatment of HIV-1 infection [1]. non-inferiority and better tolerability of RPV compared RPV is taken once daily with meals as a single tablet in with efavirenz (EFV) for first-line treatment in patients combination with other antiretroviral drugs or as a fixed- with a baseline viral load below 100,000 copies/ml [2–4]. dose combination with emtricitabine (FTC) and tenofovir These results were confirmed in a third open-label study disoproxil fumarate (TDF). RPV approval was granted with RPV/FTC/TDF fixed-dose combination, the STAR on the basis of pooled 96-week efficacy and safety trial [5].

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Given that RPV is well tolerated and convenient to at the time of the switch or at the closest visit before take, it is also an attractive option for virologically the switch. suppressed treatment-experienced patients willing to All participants provided written informed consent switch their current treatment regimen to improve tol- prior to inclusion in the Nadis Database which was erability or convenience. Data with RPV in treatment- approved by the Paris Saint-Louis ethics committee experienced patients have been thus far limited and a (CPP Paris Saint-Louis) and the CNIL (Commission single randomized trial has shown that the combination Nationale Informatique et Libertés). of RPV/FTC/TDF was able to maintain virological sup- Treatment-naive patients, those who had received pression in patients switching from a ritonavir-boosted RPV prior to the study period (in the setting of clini- protease inhibitor-based (PI/r) antiretroviral therapy cal trials), and patients with a plasma HIV-1 RNA level (ART) [6–13]. >50 copies/ml at BL were excluded from this study. The purpose of our study was to assess the safety and efficacy of switching to an RPV-based regimen in Efficacy assessments treatment-experienced patients who are virologically The primary end point was the proportion of patients suppressed in ‘real life’ conditions. with a plasma HIV-1 RNA level <50 copies/ml at M12 using the FDA snapshot analysis. VF was defined as Methods a confirmed HIV-1 RNA level >50 copies/ml or an HIV-1 RNA level >50 copies/ml followed by RPV Study design and population discontinuation. We performed a single-centre, observational, retrospec- Secondary efficacy end points included the proportion tive cohort study enrolling all ART-experienced adult of patients with a plasma HIV-1 RNA level <50 copies/ml HIV-1-infected patients with plasma HIV-1 RNA level over time, the change in CD4+ T-cell counts from BL, and <50 copies/ml switching to an RPV-based regimen dur- the emergence of RAMs in patients with VF. ing the time period from 1 September 2012 (date of In case of VF, a genotypic test was performed on RPV approval in France) to 18 June 2013, and followed the confirmatory sample to detect emerging resistance at the Saint-Louis Hospital in Paris, France. There were mutations and measure RPV plasma concentrations to no pre-defined criteria for switching to an RPV-based assess drug adherence. Historical genotypic resistance regimen and this decision was left to each physician’s tests were collected at screening and analysed using the discretion. We were however willing to prospectively 2013 ANRS resistance group algorithm. RPV concen- collect data for each patient switching to RPV in order tration was assessed on plasma samples after protein to assess the safety and efficacy of this switch in a real- precipitation by liquid chromatography – tandem mass life setting. Clinical and biological data were collected spectrometry on ThermoFisher Scientific® U3000RS prospectively at the time of switch (baseline [BL]), coupled with a TSQ Quantum Ultra (Thermo Scientific, and up to month 12 (M12) after the switch using the Villebon-sur-Yvette, France). Lower limit of quantifi- Nadis electronic database [14]. Data collected included cation was 4 ng/ml with a lower limit of detection of reasons for the switch, patient demographics, route of 1 ng/ml and linearity from 4 to 400 ng/ml. Mean trough HIV infection, duration of HIV infection, CD4+ T-cell RPV plasma concentrations in the ECHO and THRIVE counts, duration of undetectable plasma HIV-1 RNA study ranged from 50 to 80 ng/ml [15]. levels before the switch, results of prior genotypic resistance tests when available with detection of resistance Safety assessments associated mutations (RAMs) to NNRTIs and nucleo- The primary safety end point was the proportion of side reverse transcriptase inhibitors (NRTIs), treatment patients who discontinued RPV for safety reasons. history (prior virological failure [VF] on an NNRTI + Safety was investigated by examining adverse events NRTIs, exposure to prior regimens with NNRTIs or (AEs) and laboratory abnormalities up to M12. The NRTIs), time from ART initiation to switch, hepatitis severity of AEs was evaluated using the 2008 ANRS B or C coinfection, antiretroviral drugs used before the grading scale for AEs [16]. switch and ART used in combination with RPV after the switch. Laboratory parameters included full blood Statistical analysis cell counts, CD4+ T-cell count, plasma HIV-1 RNA, ala- The primary analysis was an intent-to-treat (ITT) analy- nine aminotransferase (ALAT), aspartate aminotrans- sis including all patients who met the inclusion criteria, ferase (ASAT), total cholesterol, high-density lipoprotein using the FDA snapshot algorithm, at M12. Patients (HDL) and low-density lipoprotein (LDL) cholesterol, were classified in three categories: ‘virological success’ triglycerides, and creatinine levels, and estimated glo- when plasma HIV-1 RNA level was <50 copies/ml at merular filtration rate (eGFR) using the Cockroft–Gault M12, ‘virological failure’ when patients experienced two formula. These BL parameters were either collected consecutive plasma HIV-1 RNA levels ≥50 copies/ml or

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one viral load above 50 copies/ml and discontinuation All patients but eight (3%) switched to a fixed-dose of RPV, and ‘no data’ when virological data were miss- combination of RPV/FTC/TDF. Main reason for switch ing because of loss to follow-up, discontinuation of RPV was treatment simplification (n=177, 63%) and poor tol- for reasons other than VF, or missing data in the window erability of their current regimen (n=93, 33%), mostly period. The window period around M12 ranged from because of neuropsychiatric symptoms (n=65, 23%, all month 10 to month 14. Data outside the window period receiving EFV) and also gastrointestinal symptoms (4%). were excluded. Sensitivity analyses were performed using available data obtained after M12 in patients who Efficacy remained on their RPV-based regimen to assess the rate At M12, using the FDA snapshot algorithm, 167 of virological success. (59%) patients maintained full virological suppression Data are presented as medians with IQR for continu- (plasma HIV-1 RNA level <50 copies/ml) and met viro- ous variables and frequencies with percentages for qual- logical success, and 16 (6%) experienced VF (Figure 2). itative variables. Changes in CD4+ T-cell counts, plasma Among the 98 (35%) patients who had no data in the creatinine, total HDL and LDL cholesterol from BL to window period, 23 (8%) discontinued RPV for AEs, 6 M12 were assessed using paired Wilcoxon tests. discontinued RPV for other reasons (4 due to patient Comparisons between patients with VF and viro- decision and 2 to avoid drug interaction), 2 patients logical success were performed to assess BL risk fac- died of suicide, 35 (12%) patients had no plasma viral tors associated with VF including demographics, nadir load data in the window period and 32 (11%) were lost CD4+ T-cell count, duration of HIV-1 suppression in to follow-up. plasma, peak of plasma HIV-1 RNA levels, prior use of A sensitivity analysis performed with plasma viral NNRTIs, type of third agents used prior to the switch load data available beyond M12 in 35 patients who (NNRTIs: EFV or nevirapine) versus non-NNRTI- based regimens (including PIs, raltegravir and NRTIs alone), prior VF with an NNRTI-based regimen, prior Figure 1. Study flowchart NNRTI-associated RAMs and history of the M184V/I mutation. Categorical variables were compared using Fisher exact tests while quantitative variables were 3,491 Patients followed at Saint-Louis Hospital compared using Wilcoxon signed rank tests. All tests were two-sided at the 0.05 significance level. Analyses were performed using R statistical package (version 3.1.0; the R Foundation, Vienna, Austria). 385 Patients treated with RPV

Results Exclusion of patients treated in trials: 9

Study participants Exclusion of treatment-naive patients: 46 Among the 3,491 HIV-1-infected patients followed at Saint-Louis Hospital during the study period, 385 Exclusion of patients with VL>50 copies/ml: 42 patients received RPV and 281 treatment-experienced patients with a plasma HIV-1 RNA level <50 copies/ml Exclusion of patients without RPV: 7 who switched to an RPV-based regimen were analysed in this study (Figure 1). 281 Patients included Subjects were mostly male, Caucasian and men who have sex with men (MSM), with a median age of 47 32 (11%) Patients lost to follow-up years (Table 1). Patients had been on ART for a median of 7 years and had a median BL CD4+ T-cell count of 38 (14%) Patients discontinued RPV 3 630 cells/mm . Median duration of plasma HIV-1 RNA – 7 due to VF level <50 copies/ml before the switch was 38 months. – 23 due to AEs The vast majority of patients, 273 (97%), received – 6 due to other reasons – 2 patients died before the switch a combination of two nucleoside/ nucleotide reverse transcriptase inhibitors with a third agent. Among them, 80% received FTC/TDF, 15% 211 (75%) Patients remained on RPV at M12 lamivudine (3TC)/abacavir and 5% other combina- tions. The third agent was an NNRTI in 39% (EFV

in 32%), PIs in 51%, integrase inhibitors in 7% (all AE, adverse event; M12, month 12; RPV, rilpivirine; VF, virological failure; VL, received raltegravir) and another NRTI in 3%. viral load.

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Table 1. Baseline characteristics of the 281 patients Figure 2. Primary efficacy end point at M12 using the FDA snapshot analysis Characteristic n or median % or IQR

Male gender 214 76 100 M12 Age, years 47 40–53 90 >M12 Ethnicity 80 Sub-Saharan Africa 57 20 70 Europe 156 56 North Africa 27 10 60 Mode of HIV infection 50 Homosexual 169 60 40 Percentage Heterosexual 90 32 30 Intravenous drug users, transfusion, others 13 5 20 Duration of HIV infection, years 10 5–19 10 CD4+ T-cell count at baseline, cells/mm3 630 510–855 0 Duration of undetectable HIV RNA before 38 16–77 Virological Virological No data switch, months success failure Time between first ART and switch, years 7 3–13 M12 167 16 98 CDC category C 61 22 Post-M12 202 16 63 Hepatitis coinfection HBV (HBsAg-positive) 17 6 HCV (Ab anti-HCV-positive) 34 12 A sensitivity analysis using available HIV-1 viral load data beyond month (M) 12 ART regimen before the switch is also presented. Values below x-axis are number of patients. Combination of 2 N(t)RTIs 273 97 FTC/TDF 217 80 3TC/ABC 40 15 <50 copies/ml at some time beyond M12 (Figure 2). In 3TC/AZT 14 5 addition, using a threshold of 200 copies/ml instead of Other combination of 2 NRTIs 2 <1 50 copies/ml to define virological success, the rate of Third agent virological suppression would increase further to 74% EFV 88 32 and the rate of VF decrease to 3.5% (data not shown). NVP 15 5 Median CD4+ T-cell count remained unchanged from ETR 5 2 BL to M12 (+5 cells/mm3, IQR -94–120; P=0.45). PI + RTV 118 43 ATV + RTV 61 22 Virological failure and resistance DRV + RTV 42 15 Sixteen (6%) patients experienced VF at M12 (Table 2). LPV + RTV 15 5 ATV unboosted 21 8 Among 10 patients with genotypic resistance tests avail- INSTI 18 7 able before the switch, 4 had previous NRTI RAMs and NRTIs 8 3 1 had previous NNRTI RAMs which were unknown at Reasons for switch the time of switch in 2 patients. 4 of these 16 patients had Simplification of treatment regimen 177 63 a history of previous ART failure (2 with NNRTI-based Neuropsychiatric AEs 65 23 regimen) and the pattern of resistance mutations sug- Gastrointestinal AEs 12 4 gested that at least 2 other patients (patients 3 and 6) also Dyslipidaemia 4 1 had experienced previous failure. Lipodystrophy 3 1 VF was detected as early as one month after the Other AEs 9 3 switch in four patients, and at month 3 in three other To avoid drug interaction 5 2 patients. RPV plasma levels were measured at the time Other reasons 6 2 of VF in 12/16 patients and were consistent with good Ab, antibodies; ABC, abacavir; AEs, adverse events; ART, antiretroviral therapy; treatment adherence in 10/12, with only 2 patients with ATV, atazanavir; AZT, zidovudine; DRV, darunavir; EFV, efavirenz; ETR, etravirine; FTC, emtricitabine; HBsAg, hepatitis B surface antigen; INSTI, integrase inhibitor; no drug detected. LPV, lopinavir; N(t)RTI, nucleoside/nucleotide reverse transcriptase inhibitor; Among the 16 patients with VF, resistance genotype NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; RTV, ritonavir; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine. at the time of VF was performed in all but 1 patient, but was not amplified in 6. Among the remaining 9 patients, new emerging NRTI or NNRTI RAMs were remained under the same RPV-based regimen yielded a identified in 2 and 5 patients, respectively (Table 2). similar rate of VF (6%, no additional VF) but the rate of When assessing BL risk factors associated with VF, virological suppression increased to 72% (202 patients) previous M184V/I mutation and use of non-NNRTIs since all 35 patients had a plasma HIV-1 RNA level as third agent were significantly associated with VF

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Table 2. Characteristics of patients with VF

RPV level VL at VF, Time at VF, Previous genotypic test Genotypic test at VF Pt Previous VF Previous ART Durationa copies/ml of VF ng/ml NRTI RAM NNRTI RAM NRTI RAM NNRTI RAM

1 With NRTI 3TC/ABC; ATV 5.8 years 428 M6 122 M41L; M184V; M184V E138K T215Y 2 With, NRTI, FTC/TDF; RAL 2.3 years 346,054 M1 85 M41L; D67N; M41L; D67N; K103N; V106I; NNRTI, PI T69D; K70R; T69D; K70R; H221Y; M230L L74I; M184V; L74I; M184V; T215F; K219Q T215F; K219Q 3 No DRV+RTV; RAL 3.4 years 37,105 M3 303 M41L; D67N; K103N; V108I M41L; D67N; K103N; V179I; K70R; T215F; K70R; T215F; Y181C K219Q; M184V K219Q; M184V 4 No 3TC/AZT; ATV 3.2 years 54 M1 No data M41L Not amplified Not amplified 5 No FTC/TDF; ATV+RTV 3 years 40,985 M3 34 No data No data M184V K103N; E138A/K; V179I; P225H 6 No FTC/TDF; ATV+RTV 3 months 33,908 M1 139 No data No data D67N; K70R; K101E; Y181I M184V; T215F; K219Q 7 With NNRTI NVP; ATV+RTV 8.5 years 1,328 M12 104 No data No data Not amplified Not amplified 8 With PI FTC/TDF; ATV+RTV 4.2 years 51 M12 No data No mutation No mutation Not amplified Not amplified 9 No FTC/TDF; ATV 8 months 52 M6 No data No data No data Not amplified Not amplified 10 No 3TC/ABC; RAL 1.7 years 97 M6 62 No mutation No mutation Not amplified Not amplified 11 No AZT/3TC/ABC 12.8 years 90 M12 No data No data No data Not amplified Not amplified 12 No FTC/TDF/EFV 1 month 411,786 M1 <1 No mutation No mutation No data No data 13 No FTC/TDF; LPV+RTV 4.3 years 455 M3 160 No mutation No mutation No mutation No mutation 14 No FTC/TDF/EFV 1 month 224 M12 126 No mutation No mutation No mutation No mutation 15 No FTC/TDF; LPV+RTV 6 years 16,036 M12 <1 No data No data No mutation No mutation 16 No FTC/TDF; RAL 2.3 years 88 M12 88 No mutation No mutation No mutation No mutation

aDuration of undetectable plasma HIV RNA before switch (years/months). ABC, abacavir; AEs, adverse events; ART, antiretroviral therapy; ATV, atazanavir; AZT, zidovudine; DRV, darunavir; EFV, efavirenz; ETR, etravirine; FTC, emtricitabine; INSTI, integrase inhibitor; LPV, lopinavir; M, month; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; Pt, patient; RAL, raltegravir; RAM, resistance-associated mutation; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir disoproxil fumarate; VF, virological failure; 3TC, lamivudine.

whereas nadir CD4+ T-cell count, and duration of unde- 2013 because of persistent depressive mood, nightmares tectable plasma VL before the switch or peak viral load and insomnia. His psychiatrist introduced paroxetine were not (Table 3). There was also a trend toward more at the same time. In May 2013, following a separation VF in patients who have experienced previous VF while from his boyfriend, his depression increased, the dose receiving NNRTI-based regimens. of paroxetine was also increased and alprazolam and zopiclone were added. He committed suicide 6 months Safety later. The second patient was diagnosed with HIV-infec- A total of 50 (18%) patients reported at least 1 clinical tion in 2007. He was started on EFV/TDF/FTC in 2010 AE, 32 (11%) were neuropsychiatric AEs, 16 (6%) were and was addicted to amphetamines. He presented mul- gastrointestinal AEs and 9 (3%) patients experienced tiple episodes of delirious puffs following amphetamine rash. Twenty-three (8%) participants discontinued RPV intake and started treatment with methotrimeprazine due to one or more AEs, including 16 (6%) patients and olanzapine in 2012 while hospitalized in psychia- with neuropsychiatric disorders (sleep disturbances, ver- try. He was switched to RPV/TDF/FTC in January 2013 tigo and dizziness), 7 (2%) with gastrointestinal AEs, 5 because of severe depression. In March 2013, following (<2%) with rash, 3 with hepatitis and 1 with renal fail- a problem with his partner, he presented a new episode ure. Two patients, both young MSM aged 28 and 34 of delirium with amphetamines and expressed suicidal years, died during the study because of suicide (Addi- ideas. He committed suicide one month later. From tional file 1). The first patient had presented with anxi- BL to M12, a small but significant increase in median ety and depression since the diagnosis of HIV-infection ASAT and ALAT level was observed in 161 evaluable in 2012. He was started on EFV/TDF/FTC in Septem- patients: +4 UI/l (IQR=-1–9) and +5 UI/l (IQR -3–5) ber 2012 and was switched to RPV/TDF/FTC in April respectively (P<0.001). A total of 39 and 58 patients

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Table 3. Baseline risk factors associated with VF Discussion VFs (n=16), Virological n/median success (n=202), This study aimed to assess the efficacy and safety of Parameters (%/IQR) n/median (%/IQR) P-value a switch to RPV-based regimens in a real-life setting among 281 virologically suppressed treatment-experi- Age, years 47 (42–48) 47 (40–53) 0.90 enced patients in a single centre in Paris, France. Male gender 10 (63) 156 (77) 0.22 The rate of virological success at 12 months in this Mode of HIV infection 0.15 retrospective observational cohort study, defined as the Heterosexual 9 (56) 65 (32) proportion of patients who maintained a suppressed MSM 6 (38) 119 (59) plasma RNA level <50 copies/ml, was only 59%, which Others 1 (6) 18 (9) is lower than previously reported in clinical trials and Highest HIV VL, log 4.9 (4.6–5.2) 5 (4.5–5.5) 0.59 small cohort studies, despite a moderate proportion of copies/ml CD4+ T-cell count nadir, 210 (140–310) 260 (160–350) 0.37 patients lost to follow-up (11%) [6–13]. However in cells/mm3 this study a few patients who were likely to fail because Undetectable plasma VL 38 (17–560) 37 (17–78) 0.67 of prior NNRTI or NRTIs RAMs, or because of prior before the switch, months VF to NNRTI or NRTI-based regimens were inappro- Previous VF with NNRTI 2 (12.5) 4 (2) 0.06 priately switched to RPV-based regimens. Also, this regimen study was conducted in real-life conditions and there- Previous RAMs to NNRTIsa 1/10 (10) 3/109 (3) 0.30 fore a substantial number of patients had missing data Previous M184V/Ia 3/10 (30) 5/109 (5) 0.02 within the M12 window period used for the FDA-snap- NNRTIs as third agent 2 (13) 82 (41) 0.03 shot analysis. Indeed 35 (12%) patients who were still before switch vs others under follow-up and remained under the same RPV- (PIs, RAL, NRTIs) based regimen had no viral load data available during aGenotypic data were available for only 10/16 patient with virological failure the M12 window period, but using a sensitivity analysis (VF) and 109/202 patient with virological success. MSM, men who have sex with including data beyond M12 for these 35 patients who men; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RAL, raltegravir; RAM, remained all virologically suppressed, the rate of viro- resistance-associated mutation; VL, viral load. logical success increased to 72% (Figure 2). This relatively lower rate of treatment success in this open-label cohort is explained by higher rates than experienced elevations in ASAT and ALAT levels of at expected of both VFs and treatment discontinuations least 1 grade, respectively, but only 3 patients developed because of AEs. grade 3 ALAT/ASAT elevation leading to treatment Sixteen (6%) patients experienced VF during the study discontinuation. period although VF led to treatment discontinuation in Median change from BL in serum creatinine was only 7 (2.5%) patients. Indeed, 6 patients had low viral +6 µmol/l (IQR=-0.09–13; P<0.001) in 164 evaluable loads (<100 copies/ml) and two others were probably patients. Twenty-three patients developed a grade 1 not compliant according to the lack of RPV detection elevation of plasma creatinine and 1 patient discontin- in plasma (Table 2). Longer follow-up will provide a ued RPV because of renal failure. This patient switched better assessment of the risk of VF with this regimen. from zidovudine/3TC and boosted fosamprenavir to Interestingly, among patients with VF, 4 had previous RPV/TDF/FTC and had to stop his regimen because NRTI RAMs, 1 of whom had additional NNRTI-based of an increase in plasma creatinine to 495 µmol/l at mutations, and 4 have reported previous VF with NRTI, month 2. Plasma creatinine level returned to BL 6 NNRTI or PI-based regimens. Among the 9 patients months later. with VF who had a resistance genotype available at The serum lipid profile slightly improved from BL the time of VF, new emerging NRTI or NNRTI RAMs to M12 following the switch to RPV-based regimens. were identified in 2 and 5 patients, respectively. Also, we Significant changes in median total cholesterol (TC; assessed BL risk factors associated with VF and identi- -0.5 mmol/l, IQR -1.1– -0.13; P<0.001), LDL choles- fied the presence of the M184V mutation in prior geno- terol (-0.26 mmol/l, IQR -0.8–0.16; P<0.001), HDL types and the use of a non-NNRTI third agent before cholesterol (-0.06 mmol/l, IQR -0.026–0.06; P<0.008), the switch with an increased risk of VF. There was also triglycerides (-0.12 mmol/l, IQR -0.51–0.17; P=0.011) a trend toward a higher risk of VF among patients with and TC/HDL cholesterol ratio (-0.28, IQR -0.68–0.32; a history of previous failure with NNRTI-based regi- P=0.017) were seen in 89 evaluable patients. No sig- mens. Our study lacked power, however, to assess the nificant change from BL to M12 was seen in median risk of VF in patients with NNRTI RAMs, since only fasting plasma glucose levels in 81 assessable patients four patients had known NNRTI RAMs at the time (0.03 mmol/l, IQR -0.33–0.51; P=0.29). of the switch. These data are consistent with previous

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reports suggesting the efficacy of a switch from either with EFV [18]. Longer follow-up of this cohort will also EFV or nevirapine to RPV [9,11,12]. They also reinforce be important to better address this issue. Other AEs, the need to restrict the switch to an RPV-based regimen although rare, were more likely to be related to the use to patients not only fully suppressed under their cur- of RPV or the combination of RPV plus TDF/FTC: gas- rent regimen, but also to those with a previous genotype trointestinal AEs, renal failure (one patient), hepatitis available, without any RPV/TDF/FTC-associated RAMs, (3 patients) and rashes (5 patients). or without any history of VF, especially when they are As previously reported there was a modest improve- switched from non NNRTI-based regimens, such as PIs ment in the lipid profile following the switch to RPV/ or raltegravir [6]. It was definitely unwise in our study to TDF/FTC in our study where half of patients switched have switched to RPV-based regimens patients with prior from a boosted PI regimen. The clinical relevance of this RAMs to NNRTI and NRTIs, as well as patients with slightly improved lipid profile is yet unclear. previous VFs to NNRTI and NRTIs containing regimens. Another limitation of this study was that it was mainly These data are unfortunately not always easy to collect conducted in male Caucasian MSM and its results cannot or retrieve in patient charts from patients followed for therefore be easily extrapolated to other populations. years and sometimes at other institutions. In these cases, In conclusion, our study reinforced the need to care- when treatment history is not reliable, and a resistance fully select virologically suppressed patients who are genotype not available, it is safe to avoid a switch to RPV considered for a switch to an RPV-based regimen, here except maybe if the patient is currently suppressed under mainly a switch to RPV/TDF/FTC. an NNRTI-based regimen as previously reported with Patients without a reliable treatment history, those EFV and nevirapine [9,11,12]. In some cases, performing without a resistance genotypic test available, with prior a resistance genotype of HIV proviral DNA in peripheral RAMs to NNRTIs and NRTIs, and those with previ- blood lymphocytes could be helpful, but this test is not ous VF should avoid such a switch due to a higher risk perfect as it may underestimate the risk of resistance as of VF. In addition, although the tolerability of RPV compared to plasma HIV RNA [17]. overall is good, some patients may still complain of Rilpivirine is an attractive NNRTI because of its neuropsychiatric AEs which might lead to treatment good safety profile, which has been proven consistently discontinuation. better than EFV in randomized trials and also because of its convenience when coformulated in a single pill Acknowledgements with TDF and FTC [2–5]. Indeed, simplification was the main reason for the switch for 63% of the patients This study has been presented in part at the 53rd and 97% in this study received this single pill combina- ICAAC Meeting, 10–13 September 2013, Denver, CO, tion. In this study, up to 8% of patients discontinued USA, and at HIV Drug Therapy, 23–27 October 2014, RPV during follow-up for AEs, a rate that is somewhat Glasgow, UK. higher than previously reported. Patients are probably This study was sponsored, in part, by a grant from less carefully switched to RPV in such a cohort study Gilead sciences who had no role in data collection or than in a randomized trial, but this rate of treatment data analysis. discontinuation probably better reflects the safety in We would like to thank David Simo and Hervé Akpe real-life settings where patients have multiple treatment (both from Hopital St Louis, Paris) who participated in options should they experience tolerability issues. On data collection for this study. the other hand, since the study is open-label it is difficult to ascertain that reported AEs were due to RPV. Indeed, Disclosure statement in this study, 16 patients (6%) discontinued RPV for neuropsychiatric AEs, mostly sleep disturbances. Such J-MM has received grants from Gilead Sciences and sleeping disorders, although less frequent than with Merck, and has participated in advisory boards for EFV, have been already reported in randomized trials Gilead Sciences, Merck, Janssen, Bristol–Myers Squibb, with RPV [2–5]. However, neuropsychiatric disorders ViiV and Tobira. CD has received grants from Merck were also one of the main reasons for the switch in 65 and has participated in advisory boards for Gilead Sci- patients (23%) all of whom were receiving EFV before ences, Merck, Bristol–Myers Squibb. All other authors the switch. It is therefore difficult to know whether these declare no competing interests. symptoms were drug-related or due to associated psychiatric comorbidities which are quite prevalent in HIV- Additional file infected patients. Similarly, the two patients who died both had a long history of psychiatric disorders, and it Additional file 1: A table of adverse events reported during would be difficult to know whether the switch to RPV the study period can be found at http://www.intmedpress. was responsible for this outcome, as recently suggested com/uploads/documents/3705_Gazaignes_Addfile1.pdf

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Accepted 4 November 2015; published online 13 November 2015

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