Transcript Saquinavir/r bid vs Lopinavir/r bid plus Emtricitabine/Tenofovir qd in ARV-naive HIV-1-Infected Patients: Gemini Study J Slim, MD1, A Avihingsanon, MD2, K Ruxrungtham, MD2, M.

Saquinavir/r bid vs Lopinavir/r bid plus
Emtricitabine/Tenofovir qd in ARV-naive
HIV-1-Infected Patients: Gemini Study
J Slim, MD1, A Avihingsanon, MD2, K Ruxrungtham, MD2,
M Schutz, MD3 and S Walmsley, MD, MSc, FRCPC4
1St
Michael's Medical Center, Newark, United States;
2HIV-NAT, Thai Red Cross AIDS Research Centre and Chulalongkorn
University Hospital, Bangkok, Thailand; 3Roche, Nutley, United States and
4University of Toronto, Toronto, Canada.
Rationale for the Gemini Trial
 HAART containing a boosted protease inhibitor
(PI) is recommended in first-line treatment1

Guidelines recommend four boosted PIs –
atazanavir, fosamprenavir, lopinavir, or saquinavir
– as preferred PI therapy1

Head-to-head comparative trials can provide
information, guiding the decision between the
preferred PI options
1. IAS–USA Guidelines, Hammer et al. JAMA 2006; 296:827-843.
Study Design
 Prospective, Phase IIIb, randomized, multi-center,

open-label, 2-arm study
N = 337
–
USA, Canada, Puerto Rico, France,
Thailand
Saquinavir/r
1000/100 mg bid
+ TDF/FTC
 Duration = 48 weeks
 Inclusion criteria
– Treatment naive
1:1 randomization
– CD4 ≤ 350 cells/mm3
Lopinavir/r
– HIV RNA > 10,000 copies/mL
400/100 mg bid
 Primary endpoint
+ TDF/FTC
– % patients with HIV
–
RNA < 50 copies/mL at week 48
Planned interim analysis of first
150 patients completing week 24
Baseline Demographics
Baseline Characteristic
Saquinavir/r
Lopinavir/r
n = 74
n = 76
58 (78)
53 (70)
Age, years: median (range)
36.0 (21–62)
36.5 (20–63)
Weight, kg: median (range)
65.7 (43–111.8)
64.1 (34.5–128.5)
HIV RNA, log10 copies/mL: mean ± SD
5.1 ± 0.63
5.2 ± 0.60
HIV RNA > 100,000 copies/mL: n (%)
43 (58)
57 (75)
134.1 ± 111.4
121.1 ± 111.1*
CD4 count ≤ 50 cells/mm3: n (%)
24 (32)
30 (40)*
CD4 count ≤ 100 cells/mm3: n (%)
35 (47)
42 (56)*
8 (11)
8 (11)
21 (28)
28 (37)
Sex, male: n (%)
CD4 count, cells/mm3: mean ± SD
HCV+: n (%)
Prior AIDS-defining event: n (%)
*Data unavailable for one patient
Subject Disposition Through Week 24
337 subjects randomized
167 subjects randomized to SQV/r
74 included in 1st
interim analysis
93 remainder of
study population
170 subjects randomized to LPV/r
76 included in 1st
interim analysis
2 protocol deviations
72 included in 1st
interim analysis
ITT population
94 remainder of
study population
3 protocol deviations
73 included in 1st
interim analysis
ITT population
14 discontinued prior to wk 24
2 safety
11 non-safety
1 death*
63 on therapy
at week 24
* Death due to boating accident
† 1 case of fatal hepatic failure occurred
13 discontinued prior to wk 24
4 safety†
9 non-safety
64 on therapy
at week 24
HIV RNA Suppression at Week 24, ITT
Percent of patients
100%
SQV/r < 400 copies/mL
SQV/r < 50 copies/mL
n = 72
LPV/r < 400 copies/mL
LPV/r < 50 copies/mL
n = 73
83.6% p = 0.637
80.6%
80%
75.3% p = 0.427
69.4%
60%
40%
20%
0%
Wk 2
Wk 4
Wk 8
Wk 12
Wk 16
Wk 20
Wk 24
At all time points, comparisons between SQV/r and LPV/r are not statistically significant
HIV RNA Suppression at Week 24,
Observed
Percent of patients
100%
SQV/r < 400 copies/mL
SQV/r < 50 copies/mL
LPV/r < 400 copies/mL
LPV/r < 50 copies/mL
95.3% p = 0.328
92.1%
80%
85.9%
79.4% p = 0.492
60%
40%
20%
0%
Wk 2
SQV/r n = 67
LPV/r n = 69
Wk 4
Wk 8
Wk 12
Wk 16
69
70
69
67
69
67
66
65
Wk 20
65
65
Wk 24
63
64
At all time points, comparisons between SQV/r and LPV/r are not statistically significant
Mean CD4 Count, Observed
SQV/r
LPV/r
p = 0.7546
CD4 count (cells/mm3)
350
+157 cells/mm3
300
+140 cells/mm3
250
200
150
100
50
0
Wk 0
SQV/r n = 71
LPV/r n = 69
Wk 2
Wk 4
Wk 8
68
71
70
70
68
68
Wk 12 Wk 16 Wk 20 Wk 24
68
66
65
64
65
63
63
64
At all time points, comparisons between SQV/r and LPV/r are not statistically significant
Discontinuations
Reason for Withdrawal
Saquinavir/r
Lopinavir/r
(n = 74)
(n = 76)
14 (19)
13 (17)
3 (4)
4 (5)
2 (3)
4 (5)
Nausea, n
0
1
Vomiting, n
0
1
Hepatic failure, n
0
1†
Weight decreased, n
1
0
Pregnancy, n
0
1
Psychotic disorder, n
1
0
1*
1†
11 (15)
9 (12)
Overall discontinuations, n (%)
Safety, n (%)
Adverse event, n (%)
Death, n
Non-safety, n (%)
*Not related to study drug
†Same subject who discontinued due to hepatic failure
LPV/r Arm Virologic Failures:
No Acquisition of PI Mutations
Pt
BL VL
copies/mL copies/mL copies/mL cells/mm3
1 200,000
2
Lowest VL VL at VF BL CD4 CD4 at VF
21,700
315
Wk 16
1,890
Wk 8
655
Wk 24
8,020
Wk 20
133
3
Comments
cells/mm3
(including all identified
RT and PI mutations)
355
No genotypic mutations at BL
and VF; significant diarrhea
3
BL RT mutations Y181C,
T215C, K219E; missed visits;
additional RT mutation M184V
at VF
BL, baseline; VF, virologic failure; PI, protease inhibitor; RT, reverse transcriptase inhibitor
Virologic failure defined as 2 consecutive HIV RNA > 400 copies/mL at Week 16 or thereafter
SQV/r Arm Virologic Failures:
No Acquisition of PI Mutations
Pt BL VL
Lowest VL VL at VF BL CD4 CD4 at VF
copies/mL copies/mL
copies/mL cells/mm3
1 78,800
32,000
345,000
Wk 2
Wk 20
2 628,000
1,290
Wk 16
4,410
Wk 20
3 902,000
1,150
1,270
Wk 8
Wk 20
4 63,100
15,000
Wk 20
15,000
5 2.4 x 107
816,000 3,410,000
Wk 4
Wk 20
Wk 19
cells/mm3
126
224
82
296
115
247
4
41
13
167
Comments
(including all identified
RT and PI mutations)
No genotypic mutations at BL
and VF; no notable intercurrent
illness.
PI mutations K20R, L63P at BL
and VF; poor adherence
Missing BL genotype; nausea,
poor adherence; RT mutation
M184V at VF
PI mutations L10I, I13V, L63P,
V77I at BL and VF; poor
adherence; CMV esophagitis
PI mutation L63P at BL and
VF; no notable intercurrent
illness
BL, baseline; VF, virologic failure; PI, protease inhibitor; RT, reverse transcriptase inhibitor
Virologic failure defined as 2 consecutive HIV RNA > 400 copies/mL at Week 16 or thereafter
Adverse Events
Grade II–IV
Saquinavir/r
Lopinavir/r
n (%)*
(n = 73)
(n = 73)
Total pts with ≥ 1 AE, n (%)
Total number of AEs
35 (48)
85
42 (58)
94
Individual GII–GIV AEs reported in ≥ 2% of patients
Gastrointestinal disorders: pts with ≥ 1 GII–GIV AE, n (%)
Nausea, n
Vomiting, n
Diarrhea, n
10 (14)
6
5
2
17 (23)
10
5
7
Upper respiratory tract infection, n
2
5
Headache, n
3
4
Dizziness, n
2
1
Pyrexia, n
1
2
Decreased appetite, n
2
1
Hypokalemia, n
2
0
Arthralgia, n
2
2
Back pain, n
2
2
*Multiple occurrences of the same adverse event in one individual counted only once
Study Drug-Related* Serious
Adverse Events and Deaths
Saquinavir/r
1 hypokalemia
Lopinavir/r
1 death due to hepatic failure
– Female Thai; BL HIV RNA 52,300 copies/mL,
CD4 5 cells/mm3, HBV/HCV neg, ALT 61 U/L,
– Resolved without
albumin 3.6 g/dL, total bilirubin 1.09 mg/dL
sequelae
– Week 2–16: HIV RNA < 50 copies/mL,
CD4 42 cells/mm3; only concomitant
medications TMP–SMX and fluconazole
1 acute psychotic
– Week 17: study medications stopped due to
episode
jaundice, ascites, and pitting edema;
deteriorating albumin and increasing bilirubin;
negative work-up for new viral infections or
– Resolved with
autoimmune disease
sequelae
– Week 20: HIV RNA > 100,000 copies/mL
– Week 24: patient died
*As indicated by the investigator
Change in Lipids at Week 24
p = 0.020
Mean lipid values (mg/dL)
p = 0.182
+ 88
250
p = 0.779
200
+ 21
+ 29
p = 0.602
150
+ 12
100
+ 29
+ 10
+9
+9
50
0
Total
LDL
cholesterol
SQV/r Baseline
SQV/r Week 24
HDL
LPV/r Baseline
LPV/r Week 24
Triglycerides
Percent of Patients with Elevated Lipids
at Baseline and Week 24
p = 0.036
Percent of patients
50%
40%
38%
p = 0.009
30%
21%
20%
17%
13%
13%
10%
0%
n = 72 n = 63
n = 71 n = 64
Fasting cholesterol ≥ grade 1
(≥ 200 mg/dL; ≥ 5.2 mmol/L)
0%
1%
n = 73
n = 73
4%
n = 72 n = 72
Fasting triglycerides ≥ grade 2
(≥ 400 mg/dL; ≥ 4.5 mmol/L)
SQV/r Baseline
LPV/r Baseline
SQV/r Week 24
LPV/r Week 24
Conclusions
 In this interim analysis, saquinavir/r produced
similar rates of HIV RNA suppression and similar
CD4 cell count increases to lopinavir/r in
treatment-naive patients
 More gastrointestinal adverse events were
experienced by patients treated with lopinavir/r
than with saquinavir/r
 Significantly more patients developed
hyperlipidemia with lopinavir/r than with
saquinavir/r
Acknowledgements
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Jonathan B. Angel, MD
Christian Aquilina, MD
Jean-François Bergmann, MD, PhD
Robert Bolan, MD
Philip Brachman, MD
U. Fritz Bredeek, MD, PhD
Jason Brunetta, MD
Robert Catalla, MD
Catherine Creticos, MD
Charles P. Craig, MD
Yasmine Debab, MD
Edwin Dejesus, MD
Pierre Dellamonica, MD
Serge Dufresne, MD
Joseph Gathe, Jr, MD
Barbara Hanna, MD
Dushyantha Jayaweera, MD
Joseph G. Jemsek, MD
Harold Katner, MD
Richard Lalonde, MD
Jean-Marie Lang, MD, PhD
Caroline Lascoux-Combe
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Jean-Michel Livrozet, MD
Mona Loutfy, MD, MPH
Ivan Melendez, MD
Karam Mounzer, MD
Gerald Pierone, MD
Isabelle Poizot-Martin, MD, PhD
David Prelutsky, MD
Anita R. Rachlis, MD, MEd
Isabelle Ravaux, MD
Kiat Ruxrungtham, MD
Dominique Salmon, MD, PhD
Anne Simon, MD
Jihad Slim, MD
Fiona M. Smaill, MD
Christian Trepo, MD, PhD
Benoit Trottier, MD
Sharon Walmsley, MSc, MD
Douglas J. Ward, MD
Yazdan Yazdanpanah, MD, MSc
David Zucman, MD
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The Roche study management team
Gilead for provision of Truvada®