icon- folder.gif   Conference Reports for NATAP  
 
  4th IAS (Intl AIDS Society) Conference on HIV Pathogenesis, Treatment and Prevention
Sydney, Australia
22-25 July 2007
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Comparison of 48-week efficacy and safety of darunavir/ritonavir (DRV/r) with lopinavir/ritonavir (LPV/r) in LPV/r-naive, treatment-experienced, patients: a randomised, controlled Phase III trial (TITAN)
 
 
  Valdez-Madruga J, Berger DS, McMurchie M, Suter F, Banhegyi D, Ruxrungtham K, Lefebvre E, De Paepe E, Tomaka F, De Pauw M, Vandevoorde A, Vangeneugden T, Spinosa-Guzman S
 
TITAN = TMC114/r In Treatment-experienced pAtients Naive to lopinavir
 
AUTHOR'S SUMMARY:
--DRV/r was not only non-inferior, but virologically superior to LPV/r
--DRV/r was safe and well tolerated
--DRV/r provided better protection of the NRTI and the PI classes upon failure versus LPV/r
 
TITAN (TMC114-C214): Study Design
(595 patients randomized and treated)
 

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All patients received optimised background therapy
- at least two or three ARVs from approved NRTI and/or NNRTI classes;
enfuvirtide disallowed
 
*LPV/r patients were allowed to switch to new formulation upon its approval by the regulatory authorities;
VL = viral load; DRV/r = darunavir with low-dose ritonavir, LPV/r = lopinavir with low-dose ritonavir
 
TITAN Study Objectives
 
Primary objective
--demonstrate non-inferiority in confirmed VL <400 copies/mL with DRV/r vs LPV/r at Week 48
 
Secondary objectives
--test for superiority of DRV/r over LPV/r in the event that the primary objective was achieved
--evaluate other virological and immunological parameters
VL <50 copies/mL
change in CD4 cell count
--evaluate efficacy, safety and tolerability over 96 weeks
 
TITAN: baseline characteristics
80% men. Mean viral load at baseline: 4.3 log; CD4: 230.
PREVIOUS ART EXPERIENCE:
NRTIs >/= 4: 52% DRV/r, 51% LPV/r
NNRTIs >/=1: 76% DRV/r, 77% LPV/r
PIs (0): 32% DRV/r, 31% LPV/r
PIs (1): 36% DRV/r, 39% LPV/r
PIs >/=2: 32% DRV/r, 30% LPV/r
Optimized background regimen:
Number of sensitive agentsÑ
0 - 10% DRV, 15% LPV
1 - 24% DRV, 26% LPV
>/= 2 - 65% DRV, 51% LPV

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TITAN: study completion/withdrawal
20.8% discontinued treatment in the DRV/r arm, 1.3% due to viral failure; and 29% in the LPV/r arm discontinued, 11.4% due to viral failure. Discontinuation due to AE/HIV-related event was 6.7% in DRV/r & 7.1% in LPV/r.

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TITAN: viral load <400 copies/mL to Week 48 (TLOVR)
77% on DRV/r and 67% on Kaletra achieved <400 c/ml (ITT) p=0.008. Estimated LSM difference in response vs LPV/r for: ITT: 77-67 = 10% (95% CI 2;17) PP: 77-68 = 9% (95% CI 2;16)

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TITAN: difference (DRV/r-LPV/r) in viral load <400 copies/mL to Week 48 (TLOVR)
Estimated* LSM difference in response vs LPV/r for superiority (ITT) = 10% (95% CI 2;17); p=0.008
Estimated* LSM difference in response vs LPV/r for non-inferiority (PP) = 9% (95% CI 2;16) p<0.001.

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*Estimated from a logistic regression model including treatment and stratification factors: baseline log10 VL and use of NNRTIs in the optimised background regimen
 
TITAN: viral load <50 copies/mL to
Week 48 (TLOVR) - all patients

71% taking DRV/r were <50 c/ml; 60% raking LPV/r are <50 c/ml (ITT).
--Estimated LSM difference in response vs LPV/r = 11% (95% CI 3;19), p=0.005.

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TITAN: viral load <50 copies/mL at
Week 48 by baseline LPV FC (TLOVR)

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TITAN: development of primary PI mutations and NRTI RAMs upon treatment failure
 
Development of IAS-USA* mutations in VF patients at endpoint

For all viral failures 21% on DRV/r had Primary PI mutations & 36% taking Kaletra. 14% on DRV/r had NRTI RAMs and 27% on Kaletra.
--Viral failures with LPV FC LPVNRt-11.gif

TITAN: most common AEs
Diarrhea: 31.9% DRV, 41.8% LPV.
Nausea: 18.5% DRV, 20.9% Kaletra;
Rash (all types): 16.1% on DRV; 6.7% on Kaletra.
Grade 2-4 diarrhea: 7.7% DRV, 14.5% LPV.
Grand 2-4 nausea: 4% DRV, 4.4% LPV. Grade 2-4 rash (all types): 3% DRV, 1% LPV.

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