Saquinavir/r bid vs Lopinavir/r bid plus Emtricitabine/Tenofovir qd in ARV-naive HIV-1-Infected Patients: Gemini Study

1
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.

2
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. IASUSA Guidelines, Hammer et al. JAMA 2006
296827-843.
3
Study Design

• Prospective, Phase IIIb, randomized,
  multi-center, open-label, 2-arm study
• N 337
• USA, Canada, Puerto Rico, France,
  Thailand
• Duration 48 weeks
• Inclusion criteria
• Treatment naive
• CD4 350 cells/mm3
• HIV RNA gt 10,000 copies/mL
• Primary endpoint
• patients with HIV RNA lt 50 copies/mL at week
  48
• Planned interim analysis of first150 patients
  completing week 24

Saquinavir/r 1000/100 mg bid TDF/FTC

• 11 randomization

Lopinavir/r 400/100 mg bid TDF/FTC
4
Baseline Demographics
Baseline Characteristic Saquinavir/r n 74 Lopinavir/r n 76
Sex, male n () 58 (78) 53 (70)
Age, years median (range) 36.0 (2162) 36.5 (2063)
Weight, kg median (range) 65.7 (43111.8) 64.1 (34.5128.5)
HIV RNA, log10 copies/mL mean SD 5.1 0.63 5.2 0.60
HIV RNA gt 100,000 copies/mL n () 43 (58) 57 (75)
CD4 count, cells/mm3 mean SD 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)
HCV n () 8 (11) 8 (11)
Prior AIDS-defining event n () 21 (28) 28 (37)
Data unavailable for one patient
5
Subject Disposition Through Week 24
6
HIV RNA Suppression at Week 24, ITT
n 72
SQV/r lt 400 copies/mL
SQV/r lt 50 copies/mL
LPV/r lt 400 copies/mL
LPV/r lt 50 copies/mL
n 73
83.6
p 0.637
80.6
75.3
p 0.427
69.4
Percent of patients
At all time points, comparisons between SQV/r and
LPV/r are not statistically significant
7
HIV RNA Suppression at Week 24, Observed
SQV/r lt 400 copies/mL
SQV/r lt 50 copies/mL
LPV/r lt 400 copies/mL
LPV/r lt 50 copies/mL
95.3
p 0.328
92.1
85.9
p 0.492
79.4
Percent of patients
SQV/r
67
69
69
69
66
65
63
n
LPV/r
69
70
67
67
65
65
64
n
At all time points, comparisons between SQV/r and
LPV/r are not statistically significant
8
Mean CD4 Count, Observed
SQV/r
LPV/r
p 0.7546
157 cells/mm3
140 cells/mm3
CD4 count (cells/mm3)
SQV/r
68
70
68
68
65
65
63
71
n
LPV/r
71
70
68
66
64
63
64
69
n
At all time points, comparisons between SQV/r and
LPV/r are not statistically significant
9
Discontinuations
Reason for Withdrawal Saquinavir/r (n 74) Lopinavir/r (n 76)
Overall discontinuations, n () 14 (19) 13 (17)
Safety, n () 3 (4) 4 (5)
Adverse event, n () 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
Death, n 1 1
Non-safety, n () 11 (15) 9 (12)
Not related to study drug Same subject who
discontinued due to hepatic failure
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LPV/r Arm Virologic Failures No Acquisition of
PI Mutations
Pt BL VL copies/mL Lowest VL copies/mL VL at VF copies/mL BL CD4 cells/mm3 CD4 at VF cells/mm3 Comments (including all identified RT and PI mutations)
1 200,000 315Wk 16 655Wk 24 133 355 No genotypic mutations at BL and VF significant diarrhea
2 21,700 1,890Wk 8 8,020Wk 20 3 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 gt 400 copies/mL at Week 16 or thereafter
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SQV/r Arm Virologic Failures No Acquisition of
PI Mutations
Pt BL VL copies/mL Lowest VL copies/mL VL at VF copies/mL BL CD4 cells/mm3 CD4 at VF cells/mm3 Comments (including all identified RT and PI mutations)
1 78,800 32,000Wk 2 345,000Wk 20 126 224 No genotypic mutations at BL and VF no notable intercurrent illness.
2 628,000 1,290Wk 16 4,410Wk 20 82 296 PI mutations K20R, L63P at BL and VF poor adherence
3 902,000 1,150Wk 8 1,270Wk 20 115 247 Missing BL genotype nausea, poor adherence RT mutation M184V at VF
4 63,100 15,000Wk 20 15,000Wk 20 4 41 PI mutations L10I, I13V, L63P, V77I at BL and VF poor adherence CMV esophagitis
5 2.4 x 107 816,000Wk 4 3,410,000Wk 19 13 167 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 gt 400 copies/mL at Week 16 or thereafter
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Adverse EventsGrade IIIV
n () Saquinavir/r (n 73) Lopinavir/r (n 73)
Total pts with 1 AE, n () Total number of AEs 35 (48) 85 42 (58) 94
Individual GIIGIV AEs reported in 2 of patients Individual GIIGIV AEs reported in 2 of patients Individual GIIGIV AEs reported in 2 of patients
Gastrointestinal disorders pts with 1 GIIGIV 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
13
Study Drug-Related Serious Adverse Events and
Deaths
Saquinavir/r Lopinavir/r
1 hypokalemia Resolved without sequelae 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, albumin 3.6 g/dL, total bilirubin 1.09 mg/dL Week 216 HIV RNA lt 50 copies/mL, CD4 42 cells/mm3 only concomitant medications TMPSMX and fluconazole Week 17 study medications stopped due to jaundice, ascites, and pitting edema deteriorating albumin and increasing bilirubin negative work-up for new viral infections or autoimmune disease Week 20 HIV RNA gt 100,000 copies/mL Week 24 patient died
1 acute psychotic episode Resolved with sequelae 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, albumin 3.6 g/dL, total bilirubin 1.09 mg/dL Week 216 HIV RNA lt 50 copies/mL, CD4 42 cells/mm3 only concomitant medications TMPSMX and fluconazole Week 17 study medications stopped due to jaundice, ascites, and pitting edema deteriorating albumin and increasing bilirubin negative work-up for new viral infections or autoimmune disease Week 20 HIV RNA gt 100,000 copies/mL Week 24 patient died
As indicated by the investigator
14
Change in Lipids at Week 24
p 0.020
p 0.182
88
p 0.779
29
21
29
p 0.602
Mean lipid values (mg/dL)
12
10
9
9
SQV/r Baseline
LPV/r Baseline
SQV/r Week 24
LPV/r Week 24
15
Percent of Patients with Elevated Lipidsat
Baseline and Week 24
p 0.036
38
p 0.009
Percent of patients
21
17
13
13
4
0
1
n 73
n 73
n 63
n 64
n 72
n 71
n 72
n 72
Fasting cholesterol grade 1 ( 200 mg/dL 5.2
mmol/L)
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
16
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

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Acknowledgements

• 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

• 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