Abstract

Objectives

To assess the impact of switching to tenofovir disoproxil fumarate + emtricitabine on lipid parameters.

Methods

HIV-infected patients with plasma viral load <400 copies/mL, fasted triglycerides from 2.3 to 11.4 mmol/L and/or fasted low-density lipoprotein (LDL)-cholesterol >4.1 mmol/L were randomized to switch the nucleoside reverse transcriptase inhibitor (NRTI) backbone to fixed-dose combination tenofovir disoproxil fumarate + emtricitabine or to maintain the baseline antiretroviral regimen (the control group). The study has been registered with ClinicalTrials.gov under the identifier NCT00323492.

Results

Ninety-one patients were included in the intent-to-treat (ITT) analysis with triglycerides 2.4 mmol/L and LDL-cholesterol 4.0 mmol/L (median values). At week 12, the median changes from baseline of triglycerides were −0.5 mmol/L (−25%; n = 46) and −0.1 mmol/L (−6%; n = 45) in the tenofovir disoproxil fumarate + emtricitabine and control groups, respectively, indicating a difference of −0.4 mmol/L (P = 0.034) [95% confidence interval (CI): −0.9 to −0.0]. Similarly for LDL-cholesterol, changes of −0.4 mmol/L (−9%) and −0.1 mmol/L (−1%) were observed in the tenofovir disoproxil fumarate + emtricitabine and control groups, respectively, indicating a difference of −0.4 mmol/L (P = 0.031) [95% CI: −0.7 to −0.0]. The proportion of patients with LDL-cholesterol >4.1 mmol/L decreased from 48% at baseline to 26% at week 12 in the tenofovir disoproxil fumarate + emtricitabine group versus no change in the control group. No virological failure was observed during the study.

Conclusions

Switching to tenofovir disoproxil fumarate + emtricitabine in dyslipidaemic HIV-infected patients improves triglycerides and LDL-cholesterol.

Introduction

Today, the management of cardiovascular risk is an important clinical issue in HIV-1-infected patients who require life-long antiretroviral therapy. Indeed, several studies have demonstrated that HIV-1-infected patients are at higher risk of coronary heart disease throughout the course of HIV disease compared with the non-infected population of the same age and with the same risk factors.1 Different reasons may account for this difference. HIV itself seems to have a direct impact, as suggested by the SMART study, which showed that an interruption of antiretroviral therapy with a rebound in active viral replication is associated with co-morbidities, including cardiovascular events, twice as frequently as in patients in whom virological suppression is maintained.2

Antiviral drugs also play a role in the increased risk of coronary heart disease according to several studies, which have shown that exposure to antiretroviral drugs, particularly to protease inhibitors (PIs), was associated with an increased cardiovascular risk.3–5 In the D.A.D. cohort, an association between the risk of myocardial infarction and the use of abacavir was observed.6 The causal nature of this association remains controversial due to the various studies presented or published since then.7 Among the different factors defining a high-risk cardiovascular profile, hyperlipidaemia is one of the modifiable factors, as are smoking, hypertension or being overweight. Current guidelines for management of antiretroviral therapy in adults recommend maximally lowering lipid parameters in HIV-infected patients to minimize the cardiovascular risk; before using lipid-lowering treatment, these guidelines recommend modifying antiretroviral treatment.8–10

With its good long-term safety profile, in particular with regard to lipid parameters, and its efficacy, tenofovir disoproxil fumarate in combination with emtricitabine or lamivudine is a preferred nucleoside reverse transcriptase inhibitor (NRTI) backbone in combined antiretroviral therapy (cART) regimens.10–17

Therefore, the aim of the randomized TOTEM (‘Trial On Tenofovir disoproxil fumarate plus Emtricitabine on lipid Metabolism’) study was to evaluate whether a switch from any NRTI to tenofovir disoproxil fumarate + emtricitabine could modify the lipid profile in dyslipidaemic patients receiving a standard NRTI-containing regimen.

Patients and methods

Study design

The TOTEM trial was a 12 week, multicentre, open-label, randomized trial conducted in 22 AIDS clinical centres in France.

Virologically suppressed HIV-infected patients with high low-density lipoprotein (LDL)-cholesterol and/or high triglycerides receiving a cART including two NRTIs (except tenofovir disoproxil fumarate or emtricitabine) with a third agent [PI or non-NRTI (NNRTI)] were randomized (1:1) to receive a once-daily fixed-dose combination tablet of tenofovir disoproxil fumarate + emtricitabine (300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine; Truvada®) with the third antiretroviral agent unchanged, or to maintain their baseline cART (the control group).

Patient assessments were performed at screening, baseline and weeks 4 and 12 for clinical examination, adverse events assessment and biochemical and biological tests (including CD4 cell counts, HIV-1 RNA determination and lipid metabolic profile).

The study protocol was reviewed and approved by the appropriate institutional ethics committees (Pitié-Salpêtrière Hospital) and health authorities and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient. The study has been registered with ClinicalTrials.gov under the identifier NCT00323492.

Study participants

Patients were HIV-infected adults with viral load <400 copies/mL for at least the preceding 6 months, fasted triglycerides between 2.3 and 11.4 mmol/L and/or fasted LDL-cholesterol >4.1 mmol/L and stable cART for at least 3 months before inclusion, either without lipid-lowering treatment or with stable lipid-lowering treatment.

The main exclusion criteria were current treatment with tenofovir disoproxil fumarate or emtricitabine, history of virological failure on a tenofovir disoproxil fumarate- or emtricitabine-containing regimen, history of virological failure with lamivudine and not currently receiving a lamivudine-containing regimen, current treatment with a triple nucleoside association and creatinine clearance <50 mL/min.

Lipid analysis

Blood samples were taken under fasted conditions. All lipid measurements were performed in the lipid central laboratory at Pitié-Salpêtrière Hospital. Triglycerides were measured using Triglycerides enzymatic PAP 1000 (bioMérieux, Marcy-l'Étoile, France).18 Total cholesterol, direct LDL-cholesterol and direct high-density lipoprotein (HDL)-cholesterol were determined by automated enzymatic methods (Konelab Thermo Fisher Scientific, Cergy Pontoise, France).19–21 Free glycerol was measured independently when triglycerides were >2.28 mmol/L using the Randox® Glycerol colorimetric method (Randox Laboratories Ltd, UK). All lipid parameters were analysed using Konelab® 30i (Thermo Electron Corporation).

Statistical analysis

Data from a subgroup of patients of study 903 with high triglyceride levels at baseline were used to estimate the standard deviations.16,17 Assuming a standard deviation (in mg) of 40 for LDL-cholesterol and 150 for triglycerides, it was estimated that a sample size of 108 patients (54 per group) would provide 0.86 and >0.90 power, respectively, to detect a difference of 28 mg for LDL-cholesterol and 105 mg for triglycerides using a Mann–Whitney two-sided test with a 0.05 type I error. Finally, a total of 120 patients (60 per arm) was planned to account for a 10% discontinuation rate. Because the standard deviations of the primary endpoints were smaller than expected, the lower number of patients included in the analysis (n = 91) had no negative impact on the statistical power of the study.

The two primary endpoints were the between-group comparisons of the changes in serum LDL-cholesterol and triglycerides between baseline and week 12. The main analysis of the two primary endpoints was performed on the intent-to-treat (ITT) analysis set, which included all patients randomized who received at least one dose of study medication. The last observation carried forward (LOCF) method was used if the week 12 value was missing. All other analyses were performed on the ITT analysis set with available data. The per-protocol analysis set included patients with available week 12 results for lipid parameters.

The Mann–Whitney rank sum test was used for comparison between groups of treatment. The Hodges–Lehmann estimate of the difference between groups and its 95% confidence interval (CI) (Moses) were calculated for each endpoint.

No adjustment of P values for multiple comparisons was planned and all tests were bilateral at the 0.05 level. The analyses were performed using SAS version 9.1 (SAS Institute, Inc., Cary, NC, USA).

Results

Patient disposition

Between September 2005 and April 2007, 97 patients were randomized. The ITT analysis set included 91 patients: 46 in the tenofovir disoproxil fumarate + emtricitabine group; and 45 in the control group. Six randomized patients were not included in the ITT analysis set: two patients in the tenofovir disoproxil fumarate + emtricitabine group (one patient with proteinuria, an exclusion criterion, who did not receive the study regimen and one patient who received tenofovir disoproxil fumarate while maintaining, in error, his basal regimen); and four patients in the control group who did not receive the study regimen (pregnancy, decision of the patient, lost to follow-up and treatment with a triple NRTI combination).

The per-protocol analysis set included 88 patients (44 patients in each treatment group): 3 patients from the ITT analysis set were not included (2 patients in the tenofovir disoproxil fumarate + emtricitabine group discontinued the study due to adverse events and 1 patient in the control group had no available serum lipid results at week 12).

Baseline patient characteristics

Baseline demographic and biological characteristics were well balanced between the two treatment groups (Table 1). Median [interquartile range (IQR)] serum concentrations of lipids were: triglycerides, 2.4 mmol/L (1.9–3.8); LDL-cholesterol, 4.0 mmol/L (3.4–4.7); and HDL-cholesterol, 1.2 mmol/L (0.9–1.4). Fifty-five patients (60%) had triglycerides >2.3 mmol/L, 44 patients (48%) had LDL-cholesterol >4.1 mmol/L and 24 patients (26%) had both lipid disorders.

Table 1

Characteristics of patients at inclusion (ITT analysis set)

Characteristics TDF/FTC group (n = 46) Control group (n = 45) 
Sex, n (%) of women 8 (17) 4 (9) 
Median age, years (IQR) 50 (42–58) 43 (39–50) 
Sexual transmission, n (%) 41 (89) 35 (78) 
CDC stage C, n (%) 9 (20) 14 (31) 
HIV-1 RNA <200 copies/mLa, n (%) 45 (98) 44 (98) 
HIV-1 RNA <50 copies/mLb, n (%) 33 (72) 34 (76) 
Median CD4 cells/mm3 (IQR) 463 (314–674) 559 (337–714) 
Median weight, kg (IQR) 74 (65–78) 73 (66–81) 
Median body mass index, kg/m2 (IQR) 23.9 (21.6–26.8) 24.2 (22.0–27.4) 
 normal (18.5–25), n (%) 31 (67) 26 (58) 
 overweight (25–30), n (%) 10 (22) 15 (33) 
 obese (>30), n (%) 5 (11) 4 (9) 
Dyslipidaemia, n (%)   
 triglycerides > 2.3 mmol/L 26 (57) 29 (64) 
 LDL > 4.1 mmol/L 22 (48) 22 (49) 
 both 12 (26) 12 (27) 
Other cardiovascular risk factorsc, n (%)   
 smoking 24 (52) 24 (53) 
 cardiovascular family history 15 (33) 11 (24) 
 arterial hypertension 11 (24) 4 (9) 
 diabetes 3 (7) 4 (9) 
ARV therapy   
 median duration of cART, years (IQR) 9.1 (2.8–11.2) 8.2 (1.9–10.0) 
 NRTI associations at baseline, n (%) 46 (100) 45 (100) 
  zidovudine + lamivudine 25 (54) 27 (60) 
  abacavir + lamivudine 8 (17) 7 (16) 
  didanosine + lamivudine 6 (13) 5 (11) 
  stavudine + lamivudine 5 (11) 2 (4) 
  others 2 (4) 4 (9) 
 PI-containing regimen at baselined, n (%) 27 (59) 27 (60) 
  lopinavir/r 7 (15) 8 (18) 
  fosamprenavir/r 9 (20) 7 (16) 
  atazanavir/r 6 (13) 7 (16) 
  other PI 5 (11) 5 (11) 
 NNRTI-containing regimen at baseline, n (%) 19 (41) 18 (40) 
  nevirapine 8 (17) 11 (24) 
  efavirenz 11 (24) 7 (16) 
Stable lipid-lowering treatments at baselinee, n (%) 13 (28) 10 (22) 
 statins 9 (20) 6 (13) 
 fibrates 4 (9) 4 (9) 
Characteristics TDF/FTC group (n = 46) Control group (n = 45) 
Sex, n (%) of women 8 (17) 4 (9) 
Median age, years (IQR) 50 (42–58) 43 (39–50) 
Sexual transmission, n (%) 41 (89) 35 (78) 
CDC stage C, n (%) 9 (20) 14 (31) 
HIV-1 RNA <200 copies/mLa, n (%) 45 (98) 44 (98) 
HIV-1 RNA <50 copies/mLb, n (%) 33 (72) 34 (76) 
Median CD4 cells/mm3 (IQR) 463 (314–674) 559 (337–714) 
Median weight, kg (IQR) 74 (65–78) 73 (66–81) 
Median body mass index, kg/m2 (IQR) 23.9 (21.6–26.8) 24.2 (22.0–27.4) 
 normal (18.5–25), n (%) 31 (67) 26 (58) 
 overweight (25–30), n (%) 10 (22) 15 (33) 
 obese (>30), n (%) 5 (11) 4 (9) 
Dyslipidaemia, n (%)   
 triglycerides > 2.3 mmol/L 26 (57) 29 (64) 
 LDL > 4.1 mmol/L 22 (48) 22 (49) 
 both 12 (26) 12 (27) 
Other cardiovascular risk factorsc, n (%)   
 smoking 24 (52) 24 (53) 
 cardiovascular family history 15 (33) 11 (24) 
 arterial hypertension 11 (24) 4 (9) 
 diabetes 3 (7) 4 (9) 
ARV therapy   
 median duration of cART, years (IQR) 9.1 (2.8–11.2) 8.2 (1.9–10.0) 
 NRTI associations at baseline, n (%) 46 (100) 45 (100) 
  zidovudine + lamivudine 25 (54) 27 (60) 
  abacavir + lamivudine 8 (17) 7 (16) 
  didanosine + lamivudine 6 (13) 5 (11) 
  stavudine + lamivudine 5 (11) 2 (4) 
  others 2 (4) 4 (9) 
 PI-containing regimen at baselined, n (%) 27 (59) 27 (60) 
  lopinavir/r 7 (15) 8 (18) 
  fosamprenavir/r 9 (20) 7 (16) 
  atazanavir/r 6 (13) 7 (16) 
  other PI 5 (11) 5 (11) 
 NNRTI-containing regimen at baseline, n (%) 19 (41) 18 (40) 
  nevirapine 8 (17) 11 (24) 
  efavirenz 11 (24) 7 (16) 
Stable lipid-lowering treatments at baselinee, n (%) 13 (28) 10 (22) 
 statins 9 (20) 6 (13) 
 fibrates 4 (9) 4 (9) 

TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; /r, /ritonavir.

aHIV-1 RNA monitoring was performed using a local laboratory routine test with a 200 copies/mL cut-off as the upper limit of quantification.

bData for sites performing the HIV-1 RNA quantification with <20, <40 and <50 copies/mL cut-off tests.

cPatients could have more than one risk factor.

dUnboosted PI in four patients in the TDF/FTC group and two patients in the control group.

eTwo patients in the TDF/FTC group and one patient in the control group were receiving another lipid-lowering drug (benfluorex or ezetimide).

Twenty-three patients (25%) had a concomitant therapy with lipid-lowering treatment (15 patients with statins and 8 patients with fibrates). Other established cardiovascular risk factors are described in Table 1.

Metabolism of lipids

Between baseline and week 12, the median decrease in triglycerides was −0.5 mmol/L (−25%) in the tenofovir disoproxil fumarate + emtricitabine group versus −0.1 mmol/L (−6%) in the control group (P = 0.034) (Table 2). The LDL-cholesterol median change was −0.4 mmol/L (−9%) in the tenofovir disoproxil fumarate + emtricitabine group versus −0.1 mmol/L (−1%) in the control group (P = 0.031). The decrease in these lipid parameters was already evident at the week 4 visit. A slight but significant decrease in HDL-cholesterol was observed in the tenofovir disoproxil fumarate + emtricitabine group at weeks 4 and 12. The per-protocol analysis confirmed these results. The proportion of patients with LDL-cholesterol >4.1 mmol/L in the tenofovir disoproxil fumarate + emtricitabine group decreased from 48% (22/46) at baseline to 26% (12/46) at week 12, versus no change in the control group (49% at baseline and at week 12).

Table 2

Changes in lipid parameters from baseline

 Median (IQR)
 
 
Lipid parameters, mmol/L TDF/FTC group (n = 46) control group (n = 45) Difference in change between groups (95% CI) 
Triglycerides at baseline 2.3 (2.0–4.0) 2.7 (1.9–3.6) NA 
 change at week 4 −0.6 (−1.2 to 0.2) 0.0 (−0.6 to 0.6) −0.6 (−1.1 to −0.2)a 
   P = 0.01b 
 change at week 12 −0.5 (−1.2 to 0.0) −0.1 (−0.8 to 0.3) −0.4 (−0.9 to −0.0) 
   P = 0.034 
Total cholesterol at baseline 6.4 (5.7–6.9) 6.4 (5.7–7.0) NA 
 change at week 4 −0.6 (−1.2 to −0.1) 0.0 (−0.4 to 0.5) −0.7 (−1.0 to −0.3) 
   P < 0.001 
 change at week 12 −0.8 (−1.3 to −0.1) −0.1 (−0.7 to 0.5) −0.6 (−1.0 to −0.3) 
   P < 0.001 
LDL-cholesterol at baseline 4.0 (3.2–4.7) 4.0 (3.6–4.8) NA 
 change at week 4 −0.3 (−0.8 to 0.2) 0.2 (−0.3 to 0.4) −0.4 (−0.6 to −0.1) 
   P = 0.017 
 change at week 12 −0.4 (−1.0 to 0.1) −0.1 (−0.5 to 0.4) −0.4 (−0.7 to −0.0) 
   P = 0.031 
HDL-cholesterol at baseline 1.2 (1.0–1.5) 1.3 (1.1–1.5) NA 
 change at week 4 −0.1 (−0.2 to 0.0) 0.0 (−0.2 to 0.1) −0.1 (−0.2 to −0.0) 
   P = 0.021 
 change at week 12 −0.1 (−0.2 to 0.1) 0.0 (−0.0 to 0.1) −0.1 (−0.2 to −0.0) 
   P = 0.009 
 Median (IQR)
 
 
Lipid parameters, mmol/L TDF/FTC group (n = 46) control group (n = 45) Difference in change between groups (95% CI) 
Triglycerides at baseline 2.3 (2.0–4.0) 2.7 (1.9–3.6) NA 
 change at week 4 −0.6 (−1.2 to 0.2) 0.0 (−0.6 to 0.6) −0.6 (−1.1 to −0.2)a 
   P = 0.01b 
 change at week 12 −0.5 (−1.2 to 0.0) −0.1 (−0.8 to 0.3) −0.4 (−0.9 to −0.0) 
   P = 0.034 
Total cholesterol at baseline 6.4 (5.7–6.9) 6.4 (5.7–7.0) NA 
 change at week 4 −0.6 (−1.2 to −0.1) 0.0 (−0.4 to 0.5) −0.7 (−1.0 to −0.3) 
   P < 0.001 
 change at week 12 −0.8 (−1.3 to −0.1) −0.1 (−0.7 to 0.5) −0.6 (−1.0 to −0.3) 
   P < 0.001 
LDL-cholesterol at baseline 4.0 (3.2–4.7) 4.0 (3.6–4.8) NA 
 change at week 4 −0.3 (−0.8 to 0.2) 0.2 (−0.3 to 0.4) −0.4 (−0.6 to −0.1) 
   P = 0.017 
 change at week 12 −0.4 (−1.0 to 0.1) −0.1 (−0.5 to 0.4) −0.4 (−0.7 to −0.0) 
   P = 0.031 
HDL-cholesterol at baseline 1.2 (1.0–1.5) 1.3 (1.1–1.5) NA 
 change at week 4 −0.1 (−0.2 to 0.0) 0.0 (−0.2 to 0.1) −0.1 (−0.2 to −0.0) 
   P = 0.021 
 change at week 12 −0.1 (−0.2 to 0.1) 0.0 (−0.0 to 0.1) −0.1 (−0.2 to −0.0) 
   P = 0.009 

TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; NA, not applicable.

aHodges–Lehmann estimate of the difference between groups and its 95% CI (Moses).

bMann–Whitney rank sum test for comparison between groups of treatment.

Virological control

Throughout the 12 weeks of follow-up, there was no change in plasma HIV-1 RNA in any of the treatment groups.

Safety

Forty-eight patients reported at least one adverse event (27 in the tenofovir disoproxil fumarate + emtricitabine group and 21 in the control group). Two patients in the tenofovir disoproxil fumarate + emtricitabine group discontinued tenofovir disoproxil fumarate due to adverse events (myalgia for one patient and a combination of myalgia, nausea, diarrhoea and anxiety for the other patient).

Serious adverse events were reported in four patients: three in the control group, which were judged as not related to the study drugs (intestinal obstruction, sciatica and pneumonia); and one in the tenofovir disoproxil fumarate + emtricitabine group, possibly related to the study drugs. This last serious adverse event was a mild decrease in creatinine clearance, from 74 mL/min at screening to 63 mL/min at week 12. At week 24, a spontaneous and complete resolution occurred without any treatment modification (creatinine clearance returned to 76 mL/min).

Discussion

This randomized controlled study conducted in 91 patients with elevated lipid parameters shows a decrease in both LDL-cholesterol and triglyceride levels after switching from an NRTI-based regimen to a regimen containing a fixed-dose combination of tenofovir disoproxil fumarate + emtricitabine compared with patients who maintained their initial regimen. Decreases in lipid parameters were observed by week 4 in the tenofovir disoproxil fumarate + emtricitabine group and were maintained up to week 12. Moreover, according to the lipid goals of the NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III), the percentage of patients with LDL-cholesterol >4.1 mmol/L decreased from 48% at baseline to 26% 12 weeks after switching to tenofovir disoproxil fumarate + emtricitabine, compared with no change (49%) in the control group.22

Therefore, a simple modification of the NRTI backbone improved lipid parameters while maintaining viral suppression. These results are in line with current guidelines for HIV patients with lipid disorders, which recommend changes in lifestyle and change of antiretroviral treatment before prescription of lipid-lowering treatment.8–10

There are some limitations to this study. As usual in such a study, the TOTEM trial was not blinded. However, it should be noted that the primary endpoints of the study were objective measures, serum lipids, which were performed in a central laboratory. The difficulty in extrapolating the decrease in serum lipids to long-term cardiovascular risk is another limitation of the study. Also, the atherogenic lipoprotein profiles of patients, the lipoprotein subclass distribution and the size of the lipoprotein particles were not explored.23 A slight but statistically significant decrease in HDL-cholesterol in the tenofovir disoproxil fumarate + emtricitabine group was observed as in other studies.12–15 The reasons for the HDL-cholesterol decrease and the possible consequences of this on cardiovascular risk remain unclear.

Dyslipidaemia is a frequent side effect of cART. The lipid disorders usually consist of mixed hyperlipidaemia, but isolated hypercholesterolaemia and isolated hypertriglyceridaemia can also occur. In this context, the use of tenofovir disoproxil fumarate as the NRTI backbone in an antiretroviral regimen appears to combine viral suppression with a favourable lipid profile and safety. Long-term studies are now needed to evaluate its possible impact on cardiovascular events.

In conclusion, minimizing the long-term adverse effects of cART is a primary concern in HIV-infected patients. Antiviral drugs may have different impacts on lipid metabolism, and drugs associated with a favourable metabolic profile should be preferred. This study shows that switching the NRTI backbone to tenofovir disoproxil fumarate is a viable option for managing triglycerides and LDL-cholesterol in dyslipidaemic HIV-infected patients. Switching to tenofovir disoproxil fumarate leads to normalization of elevated LDL-cholesterol as defined by the NCEP.

Funding

This work was supported by Gilead Sciences, France.

Transparency declarations

M. A. V. has received lecture fees, travelling expenses and payment of registration fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Roche and Tibotec. D. C. has received travel grants, consultancy fees, honoraria or study grants from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Sharp & Dohme and Roche. L. S. has received lecture fees, travelling expenses and payment of registration fees from Bristol-Myers Squibb, MSD and Abbott. C. K. has served on the advisory board and has received lecture fees, travelling expenses and payment of registration fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme and Tibotec. C. A.-O. and P. P. are employees of Gilead Sciences. All other authors: none to declare.

Author contributions

M. A. V. was involved in the study design, patient recruitment, and writing and reviewing the manuscript. R. B. and D. B.-R. performed the lipid analysis. P. d. T., D. B. and L. S. were involved in patient recruitment. P. G. and P. P. were involved in the study design. C. A.-O. was involved in the study design and reviewing the manuscript. D. C. was involved in the study design, statistical analysis, and writing and reviewing the manuscript. C. K. was involved in the study design, and writing and reviewing the manuscript.

Acknowledgements

We would like to thank all of the patients who participated in this study and the investigators involved in this study: M. Bentata, F. Rouges and F. Touam (Hôpital Avicenne, Bobigny); J. F. Bergmann, A. Rami and M. Parrinello (Hôpital Lariboisière, Paris); Z. Ouazene and B. Lefèbvre (CHU Saint-Antoine, Paris); O. Bouchaud and T. Huynh (Hôpital Avicenne, Bobigny); O. Caubet and J. L. Pellegrin (Hôpital Haut-Lévêque, Pessac); L. De Saint Martin, V. Bellein and M. L. Guenegues (Hôpital de la Cavale Blanche, Brest); J. F. Delfraissy (CHU du Kremlin-Bicêtre); P. Dellamonica, J. Durant and M. A. Serini (CHU de Nice); C. Drobacheff-Thiébaut and A. Foltzer (Hôpital Saint Jacques, Besançon); J. A. Gastaut and E. Peyrouse (Hôpital Sainte-Marguerite, Marseille); B. Hoen and A. Foltzer (Hôpital Saint Jacques, Besançon); V. Jeantils and S. Tassi (Hôpital Jean Verdier, Bondy); L. Schneider and N. Bentaleb (CHU Pitié-Salpêtrière, Paris); C. Perronne and H. Berthé (Hôpital Raymond Poincaré, Garches); G. Pialoux and C. Fontaine (Hôpital Tenon, Paris); L. Piroth and S. Treuvelot (Hôpital de Dijon); T. Prazuck, L. Hocqueloux and B. De Dieuleveult (CHR d'Orléans); D. Sereni and C. Pintado (Hôpital Saint-Louis, Paris); J. M. Ragnaud, D. Neau and I. Raymond (Hôpital Pellegrin, Bordeaux); A. Simon (Hôpital Pitié-Salpêtrière, Paris); C. Trepo, B. Lebouché and C. Brochier (Hôtel Dieu, Lyon); and R. Verdon, J. J. Parienti and P. Feret (CHU de Caen). We also thank B. Bonnet, M. Doucet, R. Ebrahimi, A. Firek, J. Gonzalez, A. Trylesinski and F. Beauvais (Gilead Sciences, France) and V. Hérault and T. Caraes (Parexel, Paris) for their support and assistance.

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Author notes

Members are listed in the Acknowledgements section.