Patient Self-Reported Adherence to Ritonavir-Boosted Darunavir Combined With Either Raltegravir or Tenofovir Disoproxil Fumarate/Emtricitabine in the NEAT001/ANRS143 Trial

Adriana Ammassari, MD; Wolfgang Stöhr, PhD; Andrea Antinori, MD; Jean-Michel Molina, PhD; Christine Schwimmer, PhD; Pere Domingo, MD; Anders Thalme, MD, PhD; Massimo Di Pietro, MD; Cedrick Wallet, MSc; Anton Pozniak, MD; Laura Richert, PhD; François Raffi, MD, PhD

Disclosures

J Acquir Immune Defic Syndr. 2018;79(4):481-490. 

In This Article

Abstract and Introduction

Abstract

Background: The NEAT001/ANRS143 trial demonstrated noninferiority of ritonavir-boosted darunavir combined with either raltegravir (RAL + DRV/r) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC + DRV/r) in HIV-positive, antiretroviral-naive adults. In post hoc analyses, however, RAL + DRV/r showed inferiority in patients with baseline CD4+ <200/mm3 and HIV-1 RNA ≥100,000 copies per milliliter. This preplanned ancillary study was conducted to assess whether differences in adherence might explain efficacy results.

Setting: Phase III, open-label, randomized, multicenter study in 15 European countries (ClinicalTrials.gov, NCT01066962).

Methods: Seven hundred seventy-four participants self-reported adherence (modified AIDS Clinical Trials Group questionnaire) over 96 weeks [383 RAL + DRV/r (twice daily; 5 pills/day), 391 TDF/FTC + DRV/r (once daily; 4 pills/day)]. Primary endpoint was ≥95% versus <95% adherence to prescribed doses recorded (1) over the last 4 days or (2) on the visual analogue scale over the last 30 days.

Results: Characteristics, except age, were similar between arms; 9% had CD4+ <200 cells/mm3 and HIV-1 RNA ≥100,000 copies per milliliter. Adherence ≥95% in the last 4 days (P = 0.029) or at the visual analogue scale (P = 0.0072) was higher with TDF/FTC + DRV/r than with RAL + DRV/r. Adherence ≥95% over the last 4 days was associated with lower probability of virological failure (P = 0.015). Adherence in patients with baseline CD4+ <200 cells/mm3 and HIV-1 RNA ≥100,000 copies per milliliter was similar to the rest of the population, and not significantly associated with efficacy measures, with no significant differences between arms.

Conclusion: Adherence was high and slightly better in the TDF/FTC + DRV/r than in the RAL + DRV/r arm. No convincing evidence was found that higher failure rate in the RAL + DRV/r arm in the subgroup with worse baseline viroimmunological status is caused by adherence differences.

Introduction

Treatment of HIV infection relies on combination antiretroviral therapy (ART), which is highly effective in achieving control of HIV replication, in recovering immune deficiency and thus in allowing for improved life expectancy.[1] Nevertheless, effectiveness of ART may be hampered by suboptimal adherence to medication intake.[2] Many factors, which may be related to the patient, the circumstances and the treatment, may impede drug intake exactly as prescribed. It has been widely demonstrated that a negative impact on medication adherence is mainly driven by 2 factors: complexity of the regimen, determined by repeated daily dosing and number of pills, and treatment side effects.[3,4] In an era with more convenient antiretroviral (ARV) regimens, patients' perceived side effects and treatment convenience or satisfaction are becoming the most important factors for sustained adherence.[5]

Also, in clinical trials, adherence to study medications is essential for reaching study outcomes and may influence trial results. ARVs are highly efficacious in suppressing HIV but associated with low adherence rates and may eventually lead to low virologic efficacy and selection of drug resistance compromising future treatment options. The NEAT001/ANRS143 study was a phase 3, open-label, noninferiority, randomized, multicenter clinical trial comparing the efficacy and safety of the nucleotide reverse-transcriptase inhibitor (NtRTI)-sparing regimen of ritonavir-boosted darunavir (DRV/r) plus raltegravir (RAL) with the standard triple drug regimen of DRV/r plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for first-line combination ART in HIV adults naive to ARVs.[6] Notably, the 2 study arms were different in respect to number of daily dosages and pills with a higher complexity burden in the RAL + DRV/r than in the TDF/FTC + DRV/r arm. The final results, obtained in 805 patients with a median of 123 weeks of follow-up, showed noninferiority of the NtRTI-sparing regimen compared with the standard treatment. In prespecified subgroup analysis, this finding was confirmed for patients with CD4+ cells >200 cells/mm3, whereas in patients with <200 cells/mm3, the RAL + DRV/r arm was inferior to the standard triple regimen. A nonsignificant difference toward more failures in the NtRTI-sparing treatment group was also observed in patients with baseline HIV-1 RNA of 100,000 copies per milliliter or more. A post hoc analysis indicated that the inferiority of the NtRTI-sparing regimen was restricted to patients with baseline CD4+ cell count <200/mm3 and HIV-1 RNA ≥100,000 copies per milliliter. It may be possible that in this patient subgroup, composed of more difficult-to-treat patients with advanced HIV disease, nonadherence behaviors may have played a relevant role.

The preplanned ancillary study on patient self-reported adherence to ARVs was conducted to compare levels and time trends of different adherence measures by treatment arms, to evaluate association of adherence with virological failure, and particularly to assess whether differences in adherence to RAL + DRV/r or TDF/FTC + DRV/r might explain subgroup efficacy results in the NEAT001/ANRS143 trial.

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