icon- folder.gif   Conference Reports for NATAP  
 
  16th CROI
Conference on Retroviruses and Opportunistic Infections Montreal, Canada
February 8-11, 2009
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Factors affecting virologic response to darunavir/ritonavir and lopinavir/ritonavir in treatment-naïve HIV-1-infected patients in ARTEMIS at 96 weeks
 
 
  Reported by Jules Levin
CROI 2009 Feb 8-12 2009, Montreal
 
Mark Nelson,1 Patrick Yeni,2 Michael Sension,3 Prudence Ive,4 Liddy Chen,5 Andrew Hill,6 Ralph DeMasi,5 Sabrina Spinosa-Guzman7 1Chelsea and Westminster Hospital, London, UK; 2Hopital Bichat and University of Paris, Paris, France; 3Comprehensive Care Center, Fort Lauderdale, Florida, USA; 4Clinical HIV Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa; 5Tibotec Inc., Yardley, PA, USA; 6University of Liverpool, Liverpool, UK; 7Tibotec BVBA, Mechelen, Belgium
 
AUTHOR CONCLUSIONS
In ARTEMIS at 96 weeks, significantly more treatment-naïve patients achieved HIV-1 RNA <50 copies/mL with once-daily DRV/r 800/100mg compared with LPV/r 800/200mg total daily dose, even after adjusting for baseline predictors of response (i.e. adherence, age, race and baseline HIV-1 RNA).
 
These results were also seen when patients who discontinued for adverse events or other reasons were excluded from the analysis (non-VF censored population).
 
Sub-optimal adherence to DRV/r did not compromise virologic response, whereas patients receiving LPV/r who had sub-optimal adherence were significantly more likely to fail therapy.
 
The efficacy benefit of DRV/r over LPV/r in the ARTEMIS trial was driven primarily by virologic endpoints. This efficacy benefit was not primarily caused by differences in discontinuations for adverse events or other reasons.
 
Introduction
 
ARTEMIS (TMC114-C211; AntiRetroviral Therapy with TMC114 ExaMined In naïve Subjects) is an ongoing, randomized, controlled, Phase III trial evaluating the efficacy and safety of darunavir (DRV;TMC114) with low-dose ritonavir (DRV/r) versus lopinavir (LPV)/r in treatment-naïve HIV-1-infected patients.1
 
In the 96-week analysis,2 79% of DRV/r compared with 71% of LPV/r patients achieved HIV-1 RNA <50 copies/mL; intent-to-treat/time-to-loss of virologic response (ITT-TLOVR), p value for superiority = 0.012.
 
Once-daily DRV/r was generally safe and well tolerated in the Week 96 analysis2 -- grade 2-4 diarrhea at least possibly related to treatment occurred less frequently with DRV/r than LPV/r (4% vs 11%; p<0.001)
-- grade 2-4 triglyceride and total cholesterol laboratory abnormalities were reported less frequently with DRV/r than LPV/r (18% vs 28%, p=0.0016 and 4% vs 13%, p<0.0001, respectively).
 
DRV/r at a dose of 800/100mg qd has been approved in both Europe and the US3 for the treatment of HIV-1 infection in treatment-naïve adult patients.
 
To determine the factors influencing virologic response to DRV/r in ARTEMIS, we examined the effect of different baseline and treatment factors (such as adherence) on HIV-1 RNA reduction to <50 copies/mL at Week 96 in different subgroups of patients in the trial.
 
Methods
 
Patients and study design

♦ Adult, HIV-1-infected, treatment-naïve patients with HIV-1 RNA 35000 copies/mL were randomized to receive DRV/r 800/100mg qd or LPV/r 800/200mg total daily dose
-- all patients receive a fixed-dose background regimen of tenofovir disoproxil fumarate (TDF) 300mg qd and emtricitabine (FTC) 200mg qd (TDF/FTC was provided by Gilead).
♦ The primary objective of the ARTEMIS study was to demonstrate non-inferiority of DRV/r qd versus LPV/r based on the primary endpoint, which was the proportion of patients with confirmed HIV-1 RNA <50 copies/mL.
♦ Detailed methodology of the ARTEMIS study has been reported previously.1
♦ For comparing proportions, unless otherwise stated (eg. using a model with certain covariates), chi-squared tests were used.
 
Definition of virologic response
 
ITT-TLOVR was used to define virologic response <50 copies/mL at Week 96
♦ In the TLOVR algorithm, a patient's response is considered to be >50 copies/mL at Week 96 if he/she
-- discontinued randomized treatment before Week 96, for any reason
-- had not achieved HIV-1 RNA levels below 50 copies/mL for at least two consecutive visits before Week 96 (never suppressed)
-- showed a rebound in HIV-1 RNA above 50 copies/mL for two consecutive visits by Week 96, after intitial suppression. Even if this rebound in HIV-1 RNA was temporary, this patient is still a failure by TLOVR.
 
Confirmed virologic response (CVR) NC=F
♦ CVR is the same as the standard ITT-TLOVR analysis, but does not include any temporary blips in HIV-1 RNA as failures. This method was used in the CASTLE study.4 If a patient shows two consecutive HIV-1 RNA >50 copies/mL values during treatment, but then there is resuppression to <50 copies/mL on two consecutive visits, the patient is still classified as a success by this method.
 
Non-VF censored
♦ This analysis excludes patients who discontinued randomized treatment for any reason other than VF.
 
Multivariate analysis models
♦ Logistic regression models were implemented to investigate the associations between achieving HIV-RNA <50 copies/mL at Week 96 and treatment and prognostic covariates.
♦ Potential prognostic covariates included age, sex, race, region, adherence, baseline log10 HIV-1 RNA and baseline CD4 cell count.
♦ Treatment effect was measured by differences in the unadjusted and model-adjusted responses using TLOVR and TLOVR non-VF censored algorithms (excluding discontinuations for reasons other than VF to determine response).
 
Adherence
♦ The Modified Medication Adherence Self-Report Inventory (M-MASRI) questionnaire assessed adherence with trial medication by percentages of doses taken from Week 0 to Week 96
-- average adherence from Week 4 to Week 96 was used to assess overall adherence up to Week 96 or time of withdrawal in early terminations (mean adherence >95% [adherent] vs 295% [sub-optimally adherent]).
 
Results
 
Patient disposition and baseline characteristics

 
Demographic data and disease characteristics were well balanced across the treatment arms at baseline (Table 1).
 

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Overall response and response by adherence
 
The overall response rate and the percentage of responders are shown in Figure 1 and Table 2, respectively.
 

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When response was assessed by adherence, there was no statistically significant difference in response (HIV-1 RNA <50 copies/mL) at Week 96 between adherent patients in the DRV/r and LPV/r treatment groups.
 

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However, in sub-optimally adherent patients, those receiving DRV/r had a greater response at Week 96 than those receiving LPV/r (Figure 2).
 

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In the DRV/r group, sub-optimally adherent patients had similar rates of response (76%) compared with adherent patients (82%; p=0.3312).
 
In the LPV/r group, sub-optimally adherent patients had statistically lower rates of response (53%) than adherent patients (78%; p<0.0001).
 
Multivariate analysis
 
In the multivariate analyses, the difference in response (HIV-1 RNA <50 copies/mL) favoring DRV/r was maintained after adjusting for baseline and treatment factors (Figure 3).
 

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In the multivariate analysis, the full model (N=643) included treatment, adherence, age, race, baseline log10 HIV-1 RNA, and baseline CD4 cell count
-- region was initially included in the model, but was found to be significantly correlated with race, and therefore was removed.
 
In the final reduced model, treatment effect was also examined; the analysis of main effects is shown (Table 3a). The response and difference in response was calculated for the final reduced model (Table 3b)
-- significantly more treatment-naïve patients achieved HIV-1 RNA <50 copies/mL with once-daily DRV/r compared with LPV/r.
 

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Repeat analysis in the non-VF censored population
 
Multivariate analysis

The analysis of main effects was performed in non-VF censored patients (excludes all patients who discontinued for reasons other than true VF), and the reduced model results are shown (Table 4a)
-- significantly more treatment-naïve patients achieved HIV-1 RNA <50 copies/mL with once-daily DRV/r compared with LPV/r (Table 4b).
 

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REFERENCE
1. Ortiz R, et al. AIDS 2008;22:1389-97.
2. Mills A, et al. 48th ICAAC/46th IDSA, Washington, DC, USA, 25-28 October 2008. Abstract H-1250c.
3. Tibotec Inc. PREZISTATM (darunavir) Prescribing Information. Revised October 2008 [accessed 22 December 2008]. Available from: http://www.prezista.com.
4. Molina J-M, et al. 48th Annual ICAAC/IDSA 46th Annual Meeting, Washington, DC, USA, 25-28 October 2008. Abstract H-1250d.