Week 96 efficacy of lopinavir/ritonavir monotherapy in virologically suppressed patients with HIV: a randomized non-inferiority trial (ANRS 140 DREAM)

Abstract

Background

Sparing of antiretroviral drug classes could reduce the toxicity and cost of maintenance treatment for HIV infection.

Objectives

To evaluate the non-inferiority of efficacy and the safety of lopinavir/ritonavir (r) monotherapy versus a single-tablet regimen of efavirenz, emtricitabine and tenofovir (EFV/FTC/TDF) over 2 years.

Methods

Adults on stable ART with plasma HIV-1 RNA viral load <50 copies/mL for the past 12 months and no documented treatment failure were randomized to receive either lopinavir/r or EFV/FTC/TDF for 2 years. The primary endpoint was the proportion of patients without treatment failure at week 96 (viral load <50 copies/mL at week 96, confirmed at week 98), without study treatment discontinuation, a new AIDS-defining illness, or death.

Results

In the ITT analysis, the primary endpoint was reached by, respectively, 64% and 71% of patients in the lopinavir/r (n = 98) and EFV/FTC/TDF arms (n = 97), yielding a difference of –6.8% (lower limit of the 95% two-sided CI: –19.9%). Sanger and UltraDeep sequencing showed the occurrence of PI mutations in the lopinavir/r arm (n = 4) and of NNRTI and/or NRTI mutations in the EFV/FTC/TDF arm (n = 2). No unexpected serious clinical events occurred.

Conclusions

Lopinavir/r monotherapy cannot be considered non-inferior to EFV/FTC/TDF. PI resistance rarely emerged in the lopinavir/r arm and did not undermine future PI options. Two years of lopinavir/r monotherapy had no deleterious clinical impact when compared with EFV/FTC/TDF.

Introduction

HIV infection is now a manageable chronic condition, but long-term exposure to antiretroviral drugs raises concerns regarding toxicity.^1,2 Several options have been evaluated to limit exposure to ART, including PI/ritonavir (PI/r) monotherapy.^3,4 We report the results of the ANRS 140 DREAM trial comparing lopinavir/r with efavirenz, emtricitabine and tenofovir (EFV/FTC/TDF) in virologically controlled patients.

Patients and methods

Study design

This was a non-inferiority, open-label, randomized (1:1), Phase II/III trial comparing lopinavir/r versus EFV/FTC/TDF in 36 French university hospitals.

Screening and eligibility criteria

Adult patients were eligible if they had (i) viral load (VL) <50 copies/mL over the past 12 months and no prior documented virological failure or resistance to ART, and (ii) CD4 cell count >200 cells/mm³ at screening and CD4 nadir >100 cells/mm³.

Ethics

The protocol was approved by an ethics committee and the competent French health authority. All participants gave their written informed consent. Trial registration name and number: ANRS 140 DREAM trial (ANRS: French Public Agency for HIV and viral hepatitis research). Clinicaltrials.gov identifier: NCT00946595.

Randomization

Randomization (1:1) was carried out centrally using the e-CRF system (CS software, Ennov-Clinical).

Intervention

Over a 98 week period, participants received either monotherapy with lopinavir 200 mg boosted by ritonavir 50 mg, two pills twice a day (lopinavir/r arm), or efavirenz 600 mg plus emtricitabine 200 mg and tenofovir 245 mg, one pill a day (EFV/FTC/TDF arm).

The protocol recommended treatment intensification with emtricitabine and tenofovir in the lopinavir/r arm in the case of two consecutive VL values ≥400 copies/mL within a 2 week period.

Study procedures

Clinical examinations and laboratory tests were performed at screening (week −5), baseline (week 0), week 4 and every 12 weeks until week 98. Antiretroviral resistance was defined according to the 2014 ANRS HIV-1 genotypic resistance interpretation algorithm.⁵ Ultrasensitive VL assay was done at week 0, 48 and 96 (detection limit <1 copy/mL).

Neurocognitive functions were assessed at week 0 and 96 by standardized neuropsychological tests and questionnaires. Bone mineral density and whole-body composition were measured at week 0, 48 and 96 among men taking part in the core trial at selected sites (DXA substudy). Clinical and biological adverse events were graded with the ANRS Scale for Grading Adult Adverse Events.⁶

Outcome measures

The primary endpoint was the proportion of patients without treatment failure at week 96 (defined as VL ≥50 copies/mL at week 96 and confirmed at week 98), treatment discontinuation, a new AIDS-defining illness or death.

In a robustness analysis, treatment was not considered to have failed in patients who experienced VL <50 copies/mL at week 96 after re-intensification.

Secondary virological outcomes were: the proportions of patients with VL <50 copies/mL at all timepoints and <1 copy/mL at week 0, 48 and 96; emergence of resistance-associated mutations; adverse events; changes in the CD4 cell count; and predictors of treatment failure and ancillary studies.

Statistical analysis

We assumed that the proportion of patients without treatment failure at week 96 would be similar (85%) in the two arms. The non-inferiority margin was set at –10%. The required number of participants was 420 (210 per arm), with a one-sided type I error of 2.5% and a power of 80%.⁷

The primary outcome and robustness analyses were based on the ITT approach. Differences in proportions and their 95% two-sided CIs were estimated by using the binomial distribution. Predictors of treatment failure based on the primary endpoint were estimated by using a logistic regression model.

Secondary outcome analyses were applied to available data.

Results

Enrolment and follow-up

From October 2009 to June 2011, 197 patients were randomized, 98 to lopinavir/r and 99 to EFV/FTC/TDF (Figure 1). Because of slow recruitment, the trial steering committee decided to terminate inclusions after a 7 month extension of the initial 12 month inclusion period.

The primary analysis included 195 participants: 98 in the lopinavir/r arm and 97 in the EFV/FTC/TDF arm (two exclusions by the trial steering committee for non-fulfilment of regulatory criteria and previous efavirenz toxicity).

The patients' baseline characteristics are summarized in Table 1.

Efficacy

The primary outcome was reached by 64% of patients in the lopinavir/r arm and 71% in the EFV/FTC/TDF arm [difference between arms –6.8% (95% CI –19.9; 6.2)].

The main reasons for treatment failure were trial strategy discontinuation (71% with lopinavir/r, 68% with EFV/FTC/TDF) and virological failure (23% versus 32%, respectively) at week 96. The other reasons for failure were AIDS-defining events and death (3% for both in the lopinavir/r arm, no cases in the EFV/FTC/TDF arm).

When re-intensification was not considered to represent failure in the lopinavir/r arm, the percentage of patients without treatment failure reached 70% in this arm [difference between arms –0.7% (95% CI –13.5; 12.0)].

The CD4 cell count remained stable from week 0 to 96 in both arms. The proportion of patients with VL <1 copy/mL was significantly higher in the EFV/FTC/TDF arm at both week 48 and 96. The only predictor of success was VL <1 copy/mL at baseline, in both arms.

Resistance

Sanger and UltraDeep sequencing showed the occurrence of PI mutations in the lopinavir/r arm (n = 4) and of NNRTI and/or NRTI mutations in the EFV/FTC/TDF arm (n = 2).

Ancillary studies

No clinically significant changes were observed in fat distribution and bone mineral density in the DXA substudy (Tables S1 and S2, available as Supplementary data at JAC Online) and the neurocognitive functions explored remained stable (Tables S3–S5) from week 0 to 96.

Safety

At least one grade 3 or 4 clinical event occurred in 22 participants (22%) in the lopinavir/r arms and 21 patients (22%) in the EFV/FTC/TDF arm. In 10 patients (5 in each arm), these events were considered drug-related (gastrointestinal disorders and asthenia with lopinavir/r, and insomnia/depression, vertigo and hot flush with EFV/FTC/TDF).

Discussion

As in previous trials of boosted PI-based maintenance monotherapy, we observed more virological failures and episodes of low-level viraemia with lopinavir/r than with EFV/FTC/TDF.^4–13 Nevertheless, as in a previous trial, re-intensification was similarly successful in the two arms.^4,8 The proportion of participants in whom PI mutations occurred on lopinavir/r was low (4 of 98, 4%; albeit significantly higher than reported elsewhere with darunavir/r monotherapy), but this had no impact on future PI options, as in the PIVOT trial.^3,14,15

A recent meta-analysis showed no significant deleterious impact of lopinavir/r or darunavir/r monotherapy in terms of CNS disorders.⁹

In two trials, with NNRTIs as the control arm, ultrasensitive VL values were similar in the two arms among patients with VL <50 copies/mL, whereas in our study, VL was more frequently <1 copy/mL in the EFV/FTC/TDF arm.^16,17 The only predictor of success at week 96 was VL <1 copy/mL at baseline, regardless of the randomization arm, as in the MONOI study.¹⁶

Conclusions

This study failed to demonstrate the non-inferiority of lopinavir/r maintenance monotherapy versus EFV/FTC/TDF. Ultrasensitive VL assay may help to select the best candidates for drug-saving maintenance therapy.

Acknowledgements

We thank the ANRS 140 DREAM study participants, their partners, families and caregivers, and all the staff of the participating sites.

Other members of the ANRS 140 DREAM Study Group

Members of the Steering Committee (Prof. Pierre-Marie Girard, Dr Jean-Luc Meynard, Prof. Geneviève Chêne, Dr Sami Kolta, Dr Roland Landman, Prof. Patrick Mercié, Dr Laetitia Moinot, Dr Laurence Morand-Joubert, Dr Isabelle Cohen-Codar, Sandrine Couffin-Cadiergues, Dr Jean-Marie Poirier, Dr Isabelle Poizot, Dr Cécile Rabian, Prof. Bruno Spire, Dr Anne-Marie Taburet and Prof. Yazdan Yazdanpanah), the Data Safety Monitoring Board (Prof. Eric Bellissant, Dr Isabelle Pellegrin, Sybilla Peron and Prof. Stéphane De Wit), the Event Review Committee (Dr Olivier Patey, Prof. Elisabeth Rouveix and Prof. Yazdan Yazdanpanah), IMEA (Karine Amat, Aïda Benalycherif and Babacar Sylla) and INSERM U1219 (Valérie Boilet, Vincent Bouteloup, Françoise Couturier, Adélaïde Perrier, Dr Caroline Roussillon and Monique Termote).

Funding

This study was sponsored and funded by the French National Institute for Health and Medical Research–France Recherche Nord&Sud Sida-HIV Hepatites (Inserm-ANRS), Paris, France. Gilead provided efavirenz/emtricitabine/tenofovir and AbbVie provided lopinavir/ritonavir and study funding.

Transparency declarations

J.-L. M. has received honoraria from Gilead, Abbott, ViiV and BMS. B. S. has received support for seminars from MSD, Gilead and Janssen, honoraria for participation on scientific boards from Gilead and MSD and non-financial support from MSD. O. B. has received participation for employment and logistic of the search team from ANRS, honoraria for participation in training in the field of social sciences from Gilead and MSD, and non-financial support from Janssen. The institution headed by G. C. has received grant support from INSERM-ANRS, Gilead and AbbVie. G. C. has also received grant support for INSERM-ANRS ongoing clinical trials from Gilead, Tibotec-Janssen, Merck laboratories, Boehringer Ingelheim and Abbott. P.-M. G. has received grant support from BMS and Janssen, personal fees from BMS and Abbvie, and honoraria for participation on international boards from Gilead and ViiV. The remaining authors have none to declare.

 This work was presented at the 20th International AIDS Conference, Melbourne, 23 July 2014 (poster WEPE 088).

Supplementary data

Tables S1–S5 are available as Supplementary data at JAC Online.

References

Author notes