1. Comparison of PI vs PI ATV vs ATV/r BMS 089
ARV-trial.com
Comparison of PI vs PI
ATV vs ATV/r BMS 089
LPV/r mono vs LPV/r + ZDV/3TC MONARK
LPV/r QD vs BID M M A5073
LPV/r + 3TC vs LPV/r + 2 NRTI GARDEL
ATV/r vs FPV/r ALERT
ATV/r vs DRV/r ATADAR
FPV/r vs LPV/r KLEAN
SQV/r vs LPV/r GEMINI
ATV/r vs LPV/r CASTLE
DRV/r vs LPV/r ARTEMIS 1

2. CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
ARV-trial.com
CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
Design
Randomisation*
1 : 1
Open-label
W48
W96
N = 440
ATV/r 300/100 mg QD
TDF/FTC fdc QD
> 18 years
ARV-naïve or < 1 week of
prior ARV exposure
HIV RNA > 5,000 c/mL
Any CD4 cell count
N = 443
LPV/r 400/100 mg BID
TDF/FTC fdc QD
*Randomisation was stratified by HIV RNA (< or > 100,000 c/mL)
at screening and geographic region
Objective
Non inferiority of ATV/r vs LPV/r at W48: % HIV RNA < 50 c/mL by intention to treat, confirmed virologic response, non completer equals failure (CVR, NC = F) (lower margin of the 2-sided 95% CI for the difference = - 10%, 90% power)
CASTLE
Molina JM. Lancet 2008;372:646-55 2

3. CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
ARV-trial.com
CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
Baseline characteristics and patient disposition
ATV/r N = 440
LPV/r N = 443
Median age, years 34 36
Female
31%
HIV RNA (log10 c/mL), median
5.01
4.96
HIV RNA > 100,000 c/mL
51%
47%
CD4 cell count (/mm3), median
205
204
CD4 < 50 per mm3
13%
11%
Hepatitis B / hepatitis C coinfection
5% / 9%
5% / 7%
Discontinuation by W48 9%
For lack of efficacy
N = 5
N = 8
For adverse event
N = 10
N = 14
Discontinuation on or after W48 3%
N = 7
N = 1
LPV/r was administered as soft-gel capsules during the first 48 weeks
CASTLE
Molina JM. Lancet 2008;372:646-55 3

4. CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
ARV-trial.com
CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
Response to treatment at week 48
HIV RNA < 50 c/mL (ITT) 25 50
100 75 78 76 %
95% CI for the difference
= - 3.8; 7.1
Primary analysis
= - 3.6; 7.4
ATV/r (N = 440)
LPV/r (N = 443)
CVR, NC = F
TLOVR
HIV RNA < 50 c/mL at W48 (CVR, NC = F) by baseline HIV RNA
Baseline
ATV/r
LPV/r
RNA < 5 log10 c/mL
RNA > 5 log10 c/mL
82%
74%
81%
72%
Post hoc analysis: lower virologic response rate associated with lower CD4 counts for LPV/r (p = ) but not for ATV/r (p = 0.51)
Mean CD4/mm3 increase at W48 (observed values):
203 (ATV/r) vs 219 (LPV/r)
CVR, NC = F : confirmed virologic response, non completer equals failure
CASTLE
Molina JM. Lancet 2008;372:646-55 4

5. CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
ARV-trial.com
CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
Virologic failure
Definition: failure to achieve confirmed HIV RNA < 400 c/mL by W48, or rebound of HIV RNA > 400 c/mL after achieving confirmed HIV RNA < 400 c/mL without re-suppression, or discontinuation due to insufficient HIV RNA response before W48
Emergence of resistance in virologic failure
ATV/r N = 440
LPV/r N = 443
Confirmed virologic response-defined virologic failure
25 (6%)
26 (6%)
Failure to achieve confirmed HIV RNA < 400 c/mL 11 3
Rebound after confirmed HIV RNA < 400 c/mL 10 17
Discontinuation due to insufficient HIV RNA response 4 6
Assessed for emergence of resistance mutations 19 20
Any PI-resistance mutation
Polymorphic mutations
Major mutations 8
2 *
M184I/V / TDF-resistance mutation / TAM
5 / 1 / 1
4 / 0 / 1
* 1 patient with M46I and N88S; 1 patient with L10F, V32I, K43T, M46I, A71I, G73S, L90M
CASTLE
Molina JM. Lancet 2008;372:646-55 5

6. CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
ARV-trial.com
CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
Safety at W48: ATV/r vs LPV/r
Serious adverse events occurred in similar proportions: 12% vs 10%
Grade 2 to 4 treatment-related nausea and diarrhoea were less frequent with ATV/r: 4% vs 8% and 2% vs 11%, respectively
Initiation of anti-diarrhoeal medication: 9% vs 22%
Grade 2 to 4 jaundice: 4% of ATV/r patients vs none of LPV/r patients
Grade 3/4 hyperbilirubinaemia: 34% vs < 1%
Grade 3/4 elevations in triglycerides and total cholesterol were significantly less frequent with ATV/r: < 1% vs 4% and 7% vs 18%, respectively
Median change in calculated creatinine clearance (Cockroft) was similar in both groups = - 1%
Mean increases in total cholesterol, non-HDL cholesterol and triglycerides were significantly lower on ATV/r (p < for the 3)
Use of lipid-lowering agents through W48: 2% vs 8%
CASTLE
Molina JM. Lancet 2008;372:646-55 6

7. CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
ARV-trial.com
CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
Summary
ATV/r QD was non inferior to LPV/r BID, when co-administered with TDF/FTC
Similar virologic reponse of the 2 PI/r in patients with high HIV RNA at enrolment
Results suggest reduced virologic response to LPV/r in patients with baseline CD4 < 50/mm3 mainly because of intolerance to LPV/r in this highly immunosuppressed subgroup
Development of major PI-associated resistance mutations occurred in 2 ATV/r patients and no LPV/r patients
Incidence of diarrhoea and nausea was lower with ATV/r than with LPV/r
Incidence of hyper bilirubinemia with ATV/r was high, but less than 1% of patients discontinued due to jaundice
Lipid elevations were less pronounced with ATV/r
CASTLE
Molina JM. Lancet 2008;372:646-55 7

8. CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
ARV-trial.com
CASTLE Study: ATV/r QD vs LPV/r BID, in combination with TDF/FTC
Conclusion
ATV/r QD demonstrated similar antiviral efficacy to LPV/r BID, when coadministered with TDF/FTC (1)
With less gastrointestinal toxicity
But with a higher rate of hyperbilirubinemia
At W96 (2), HIV RNA < 50 c/mL was obtained in 74% of ATV/r patients vs 68% of LPV/r patients (p < 0.05 in the intent-to-treat analysis) confirming non-inferiority of ATV/r to LPV/r
Safety analysis at W96 confirmed W48 results
Treatment-related gastrointestinal adverse events were more frequent with LPV/r
Hyperbilirubinemia and/or jaundice was the most frequent ATV/r-related adverse event
Lipid elevations were significantly higher with LPV/r
These results support current recommendation of ATV/r + TDF + FTC QD as a preferred first-line regimen for the treatment of HIV-infected patients
CASTLE
(1) Molina JM. Lancet 2008;372: ; (2) Molina JM. JAIDS 2010;53:323-32 8