1. TITAN = TMC114/r In Treatment-experienced pAtients Naïve to lopinavir
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Influence of Baseline Factors on Virologic Response to PREZISTA/Ritonavir (PREZISTA/r) vs Lopinavir/r (LPV/r): Week 48 Outcome in TITAN
 W. David Hardy, MD1; Daniel Berger, MD2; Els De Paepe, MSc3; Sandra De Meyer, PhD3; David Moriarty, PhD4; Joseph Mrus, MD5; Sabrina Spinosa-Guzman, MD3
1Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Northstar Medical Center, Chicago, IL, USA; 3Tibotec BVBA, Mechelen, Belgium; 4Tibotec Inc., Yardley, PA, USA; and 5Tibotec Therapeutics, Bridgewater, NJ, USA
TITAN = TMC114/r In Treatment-experienced pAtients Naïve to lopinavir
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

2. TITAN (TMC114-C214): Study Design
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Phase III randomized, controlled trial with primary analysis at Week 48
Screening phase (4 weeks)
Treatment phase (96 weeks)
PREZISTA/r 600/100mg bid + OBR
Treatment-experienced, LPV-naïve
VL ≥1,000 copies/mL
Stable HAART (≥12 wks) or STI (≥4 wks)
LPV/r * 400/100mg bid + OBR
785 patients screened, 595 randomized and treated
TITAN is an ongoing, randomised, controlled trial. It is an international 96-week study, with primary analysis at Week 48.
Patients were screened for eligibility and had to be:
treatment experienced but naïve to lopinavir
have documented HIV infection
have a viral load of greater than one thousand copies per mL
to have been on stable HAART therapy or off treatment for 12 weeks or more.
A total of 595 patients were randomised to treatment of either, PREZISTA 600mg with 100mg ritonavir or lopinavir 400mg, again with the same low dose of ritonavir.
Both treatments were administered twice daily, and all patients also received an optimised background regimen. This consisted of at least 2 to 3 antiretrovirals from the NRTI and NNRTI classes.
LPV/r patients were allowed to switch to new formulation upon its approval by the regulatory authorities. At the time of this analysis 18% had switched top the new formulation.
Background
Patients co-infected with chronic hepatitis B or C were allowed to enter the trial if their condition was clinically stable and they were not expected to require hepatitis treatment during the study period.
Randomisation was performed using a centralised system to ensure balance across treatments groups and across two stratification factors (the use of an NNRTI in the OBR and screening plasma viral load of <50,000 or 50,000 copies/mL).
PREZISTA was administered as 300-mg tablets, ritonavir as 100-mg capsules and lopinavir-ritonavir as 133.3/33.3-mg capsules. During the study, a new formulation of lopinavir-ritonavir (200/50-mg tablet) became available. The study protocol was amended to allow patients randomised to lopinavir-ritonavir to switch to the new formulation as soon as it was approved by local regulatory authorities; subsequently, all patients on this arm would be switched to the new formulation.
Patients who experienced virological failure (defined as plasma viral load >400 copies by week 16 or beyond) or a treatment-related grade 4 AE or a confirmed grade 4 laboratory abnormality were eligible to participate in the planned rollover phase. Results of the 48-week primary analysis are reported here.
All patients received optimized background therapy (OBR)
Two to three ARVs from approved NRTI and/or NNRTI classes
Enfuvirtide disallowed
Stratification factors: Baseline VL and use of NNRTI in OBR
*LPV/r patients were allowed to switch to new formulation upon its approval by the regulatory authorities
VL = viral load; PREZISTA/r = PREZISTA with low-dose ritonavir, LPV/r = lopinavir with low-dose ritonavir
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

3. Summary of Previous Findings from TITAN
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Overall, in treatment-experienced, LPV-naïve patients:
PREZISTA/r was virologically non-inferior and superior to LPV/r (VL <400 and VL<50 copies/mL)
Twice as many patients receiving LPV/r experienced virologic failure (VF) compared with patients receiving PREZISTA/r
Following VF and compared with LPV/r, PREZISTA/r-based therapy was associated with lower rates of development of
Primary PI mutations or NRTI RAMs
Phenotypic resistance to the PI or NRTI(s) in the study regimen
PREZISTA/r was safe and well tolerated, with a lower rate of diarrhea and lower increases in triglycerides than LPV/r, and a higher rate of rash
VL, viral load; RAM, resistance-associated mutation
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

4. TITAN: Virologic Response through Week 48 (ITT-TLOVR) – All Patients
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VL <400 copies/mL
VL <50 copies/mL
100
100 90
P =.008* 90
P =.005* 80
77%* 80 70 70
71%
67% 60 60
60%
Patients with VL <400 and <50 copies/mL (% [95% CI]) 50 50
PREZISTA/r (n=298) 40 40
PREZISTA/r (n=298)
LPV/r (n=297) 30 30
LPV/r (n=297) 20 20 10 10
BAS 4 8 12 16 24 36 48
BAS 4 8 12 16 24 36 48
Time (weeks)
Time (weeks)
PREZISTA/r was non-inferior and superior to LPV/r
*P value for superiority derived from logistic regression model including treatment and stratification factors: baseline log10 VL and use of NNRTI in the optimized background regimen
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

5. TITAN: Baseline Characteristics
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PREZISTA/r (n=298)
LPV/r (n=297)
Demographics
Male, n (%)
Mean (±SD) age (years)
229 (77)
41  9.0
241 (81)
41  8.6
Disease characteristics
Mean (± SD) baseline log10 VL
Median CD4 (cells/mm3 [range])
4.33 0.79
235 (3–831)
4.28 0.81
230 (2–1,096)
History of ARV treatment
Structured treatment interruption, n (%)
Previous ARV experience, n (%)
NRTIs: ≥4
NNRTIs: ≥1
PIs: 0
PIs: 1
PIs: ≥2
64 (21)
156 (52)
225 (76)
94 (32)
108 (36)
96 (32)
71 (24)
151 (51)
93 (31)
115 (39)
89 (30)
Optimized background therapy
Number of active NRTIs used, n (%)* 1 ≥2
Active NNRTI used, n (%)†
30 (10)
70 (24)
188 (65)
31 (10)
42 (15)
75 (26)
171 (59)
21 (7)
Baseline fold change in EC50 (FC) to PI
PREZISTA FC ≤10
LPV FC ≤10
287 (98)‡
263 (90)‡
286 (99)‡
261 (90)‡
The demographic, disease characteristics and treatment history were well balanced across both treatment arms
Patients had an average age of 41 years. Mean plasma viral load was 4.3 log10 copies/mL and median CD4 cell count was 232 cells/mm3
The population of patients in this trial were representative of those we see failing in clinical practice
Baseline resistance characteristics were also well balanced between treatment arms.
Background
The mean duration of study treatment was similar in both groups (53·5 weeks for PREZISTA-ritonavir and 51·5 weeks for lopinavir-ritonavir).
Activity of ARVs assessed by baseline phenotype (Antivirogram®); 576 of 582 patients with phenotype data used ≥1 NRTI in the OBR; †54 patients used an NNRTI, irrespective of activity; ‡582 (PREZISTA/r=292; LPV/r=290) patients had baseline phenotype available
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

6. TITAN: Baseline Characteristics
TTCA
PREZISTA/r (n=298)
LPV/r (n=297)
Demographics
Male, n (%)
Mean (±SD) age (years)
229 (77)
41  9.0
241 (81)
41  8.6
Disease characteristics
Mean (± SD) baseline log10 VL
Median CD4 (cells/mm3 [range])
4.33 0.79
235 (3–831)
4.28 0.81
230 (2–1,096)
History of ARV treatment
Structured treatment interruption, n (%)
Previous ARV experience, n (%)
NRTIs: ≥4
NNRTIs: ≥1
PIs: 0
PIs: 1
PIs: ≥2
64 (21)
156 (52)
225 (76)
94 (32)
108 (36)
96 (32)
71 (24)
151 (51)
93 (31)
115 (39)
89 (30)
Optimized background therapy
Number of active NRTIs used, n (%)* 1 ≥2
Active NNRTI used, n (%)†
30 (10)
70 (24)
188 (65)
31 (10)
42 (15)
75 (26)
171 (59)
21 (7)
Baseline fold change in EC50 (FC) to PI
PREZISTA FC ≤10
LPV FC ≤10
287 (98)‡
263 (90)‡
286 (99)‡
261 (90)‡
The demographic, disease characteristics and treatment history were well balanced across both treatment arms
Patients had an average age of 41 years. Mean plasma viral load was 4.3 log10 copies/mL and median CD4 cell count was 232 cells/mm3
The population of patients in this trial were representative of those we see failing in clinical practice
Baseline resistance characteristics were also well balanced between treatment arms.
Background
The mean duration of study treatment was similar in both groups (53·5 weeks for PREZISTA-ritonavir and 51·5 weeks for lopinavir-ritonavir).
Activity of ARVs assessed by baseline phenotype (Antivirogram®); 576 of 582 patients with phenotype data used ≥1 NRTI in the OBR; †54 patients used an NNRTI, irrespective of activity; ‡582 (PREZISTA/r=292; LPV/r=290) patients had baseline phenotype available
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

7. Difference in VL <50 copies/mL, % (95% CI)
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TITAN: Difference in Virologic Response (VL <50 copies/mL) at Week 48: Univariate Analysis
Difference in VL <50 copies/mL, % (95% CI)
n [PREZISTA/r −LPV/r] (%)
Overall (ITT)
Gender
Male
Female
Baseline CD4 (cells/mm3)
<
100– <
200– < ³
Baseline VL (copies/mL)
<100,
³100,
LPV/r
FAVORS
PREZISTA/r
Active ARVs* in OBR ≥
Active NRTIs* in OBR ≥
Active NNRTI* in OBR
Yes
No†
−50
−40
−30
−20
−10 10 20 30 40 50
*Activity assessed by BL phenotype (Antivirogram®); † 522 patients did not use an NNRTI and 2 patients used an inactive NNRTI ITT, intent-to-treat; VL, viral load; OBR, optimized background regimen
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

8. TITAN: NRTIs and NNRTIs Used in the OBR
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TITAN: NRTIs and NNRTIs Used in the OBR
PREZISTA/r arm (N=298)
NRTI/NNRTI sensitive
NRTI/NNRTI resistant
LPV/r arm (N=297)
NRTI/NNRTI sensitive
NRTI/NNRTI resistant 80 60 58 54
Patients (%) 47 44 41 38 40 28 26 26 22 18 20 15 13 12 9 5 2 3
TDF
3TC
ZDV
ddI
ABC
FTC
d4T
EFV
NVP
NRTIs
NNRTIs
NRTI use was generally well-balanced between treatment groups and consistent with current practice
NRTI/NNRTI activity assessed by baseline phenotype (Antivirogram®)
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

9. TITAN: Baseline Characteristics
TTCA
PREZISTA/r (n=298)
LPV/r (n=297)
Demographics
Male, n (%)
Mean (±SD) age (years)
229 (77)
41  9.0
241 (81)
41  8.6
Disease characteristics
Mean (± SD) baseline log10 VL
Median CD4 (cells/mm3 [range])
4.33 0.79
235 (3–831)
4.28 0.81
230 (2–1,096)
History of ARV treatment
Structured treatment interruption, n (%)
Previous ARV experience, n (%)
NRTIs: ≥4
NNRTIs: ≥1
PIs: 0
PIs: 1
PIs: ≥2
64 (21)
156 (52)
225 (76)
94 (32)
108 (36)
96 (32)
71 (24)
151 (51)
93 (31)
115 (39)
89 (30)
Optimized background therapy
Number of active NRTIs used, n (%)* 1 ≥2
Active NNRTI used, n (%)†
30 (10)
70 (24)
188 (65)
31 (10)
42 (15)
75 (26)
171 (59)
21 (7)
Baseline fold change in EC50 (FC) to PI
PREZISTA FC ≤10
LPV FC ≤10
287 (98)‡
263 (90)‡
286 (99)‡
261 (90)‡
The demographic, disease characteristics and treatment history were well balanced across both treatment arms
Patients had an average age of 41 years. Mean plasma viral load was 4.3 log10 copies/mL and median CD4 cell count was 232 cells/mm3
The population of patients in this trial were representative of those we see failing in clinical practice
Baseline resistance characteristics were also well balanced between treatment arms.
Background
The mean duration of study treatment was similar in both groups (53·5 weeks for PREZISTA-ritonavir and 51·5 weeks for lopinavir-ritonavir).
Activity of ARVs assessed by baseline phenotype (Antivirogram®); 576 of 582 patients with phenotype data used ≥1 NRTI in the OBR; †54 patients used an NNRTI, irrespective of activity; ‡582 (PREZISTA/r=292; LPV/r=290) patients had baseline phenotype available
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

10. Difference in VL <50 copies/mL, % (95% CI)
TTCA
TITAN: Difference in Virologic Response (VL <50 copies/mL) at Week 48: Univariate Analysis
n [PREZISTA/r −LPV/r] (%)
Overall (ITT)
Difference in VL <50 copies/mL, % (95% CI)
LPV/r
FAVORS
PREZISTA/r
Previous PI experience 
Baseline LPV FC ≤
>
Baseline PREZISTA FC ≤
>
No. of LPV RAMs1
< ≥
No. of PREZISTA RAMs1 ≥
Baseline IAS-USA primary PI mutations1 ≥
ITT, intent-to-treat; FC, fold change in EC50; RAM, resistance-associated mutation
−50
−40
−30
−20
−10 10 20 30 40 50
1Johnson VA et al. Top in HIV Med 2006; 14:
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

11. TITAN: Impact of IAS-USA Primary PI Mutations
TITAN: Impact of IAS-USA Primary PI Mutations* at Baseline on VL <50 Copies/mL at Week 48
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All Patients
Patients with Prior PI Experience † 69 78 68 62 53 42 31 10 20 30 40 50 60 70 80 90 1 2 ≥3
% HIV RNA <50 copies/mL (ITT-TLOVR)
PREZISTA/r (n=203)
LPV/r (n=204)
PREZISTA/r (n=296)
LPV/r (n=297) 90 79 80 70 68 69 70 67 58 44 33 60 50
% HIV RNA <50 copies/mL (ITT-TLOVR) 40 30 20 10 1 2 ≥3
Number of IAS-USA primary PI mutations n= n=
Patients with non-missing genotype data; †Excludes patients with missing LPV FC at baseline
*D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, or L90M1
1Johnson VA et al. Top in HIV Med 2007;15:
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

12. All Patients with LPV FC ≤10
TITAN: Impact of IAS-USA Primary PI Mutations* at BL on VL <50 Copies/mL at Week 48—Patients with LPV FC ≤10 at BL
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All Patients with LPV FC ≤10
PREZISTA/r (n=172)
LPV/r (n=174)
Patients with Prior PI Experience and LPV FC ≤10† 69 77 68 63 61 55 47 43 10 20 30 40 50 60 70 80 90 1 2 ≥3
% HIV RNA <50 copies/mL (ITT-TLOVR)
n =
PREZISTA/r (n=263)
LPV/r (n=261) 90 78 80 69 68 70 66 65 59 60 50 50
% HIV RNA <50 copies/mL (ITT-TLOVR) 43 40 30 20 10 1 2 ≥3
Number of IAS-USA primary PI mutations
n =
Patients with non-missing genotype data; †Excludes patients with missing LPV FC at baseline
*D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, or L90M1
1Johnson VA et al. Top in HIV Med 2007;15:
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

13. Difference in VL <50 copies/mL, % (95% CI)
TITAN: Difference in Virologic Response (VL <50 copies/mL, ITT-TLOVR): Multivariate Analyses
TTCA
Difference in VL <50 copies/mL, % (95% CI)
Factors in Multivariate Logistic Regression Model
LPV/r
FAVORS
PREZISTA/r
None (Unadjusted Result)
Model A
- Baseline VL,
NNRTI in OBR
- Baseline VL,
- Baseline CD4,
- NNRTI in OBR,
- Number of prior PIs*
Model B
- Baseline VL,
Baseline CD4,
Number of active ARVs in OBR
- Baseline log10 FC to PREZISTA or LPV*
Model C
- Baseline VL,
- Baseline CD4,
- Number of active ARVs in OBR
- Number of PREZISTA resistance-associated mutations
Model D
How the different covariates were modeled in the multivariate analyses:
log10 baseline HIV RNA - continuous
baseline CD4 count (cells/mm3) - continuous
log 10 FC PREZISTA - continuous
log10 FC LPV - continuous
NNRTI in OB (yes=1/no=0)
number of active ARVs: 0, 1, >=2
number of PREZISTA/LPV mutations: 0, 1, 2, >=3
Number of primary PI mutations (IAS): 0, >=1
- Baseline VL,
Baseline CD4,
Number of active ARVs in OBR
- Number of LPV resistance-associated mutations*
Model E
- Baseline VL,
Baseline CD4,
Number of active ARVs in OBR
- Number of IAS-USA primary PI mutations*
Model F
−50
−40
−30
−20
−10 10 20 30 40 50
Treatment, BL VL, number of prior PIs, and BL resistance to treatment PI were significantly associated with response, P <.05
Activity of ARVs assessed by baseline phenotype (Antivirogram®); *Includes interactions with treatment
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.

14. TITAN Conclusions In treatment-experienced, LPV-naïve patients:
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In treatment-experienced, LPV-naïve patients:
The difference in virologic response (VL <50 copies/mL) favoring PREZISTA/r was generally consistent across subgroups
Multivariate analyses demonstrated that the difference in response favoring PREZISTA/r was maintained after adjusting for baseline characteristics including VL and CD4, activity of OBR, PI resistance, and prior PI experience
Overall, and in patients phenotypically sensitive to both PIs at baseline (FC ≤10), the presence of 1 or more IAS-USA primary PI mutations affected the response to LPV/r but not PREZISTA/r
As the number of IAS-USA primary PI mutations increased, the difference in virologic response favoring PREZISTA/r increased
VL, viral load; OBR, optimized background regimen; PI, protease inhibitor
Hardy WD, et al. Oral presentation presented at IDSA Abst 1209.