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.

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 > 10,000 copies/mL Primary endpoint

– % patients with HIV RNA < 50 copies/mL at week 48

– Planned interim analysis of first150 patients completing week 24

1:1 randomization

Saquinavir/r 1000/100 mg bid

+ TDF/FTC

Lopinavir/r 400/100 mg bid

+ TDF/FTC

Study Design

Baseline Demographics

Baseline Characteristic Saquinavir/r n = 74

Lopinavir/rn = 76

Sex, male: n (%) 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)

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

Subject Disposition Through Week 24

72 included in 1st interim analysisITT population

2 protocol deviations

73 included in 1st interim analysisITT population

3 protocol deviations

64 on therapy at week 24

13 discontinued prior to wk 244 safety†

9 non-safety

63 on therapy at week 24

14 discontinued prior to wk 242 safety11 non-safety1 death*

* Death due to boating accident† 1 case of fatal hepatic failure occurred

337 subjects randomized

167 subjects randomized to SQV/r 170 subjects randomized to LPV/r

76 included in 1st interim analysis

94 remainder of study population

93 remainder of study population

74 included in 1st interim analysis

0%

20%

40%

60%

80%

100%

Wk 2 Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24

HIV RNA Suppression at Week 24, ITT

SQV/r < 400 copies/mL LPV/r < 400 copies/mL

SQV/r < 50 copies/mL LPV/r < 50 copies/mL

69.4%75.3%

83.6%80.6%

Perc

ent o

f pat

ient

s

p = 0.637

p = 0.427

At all time points, comparisons between SQV/r and LPV/r are not statistically significant

n = 72n = 73

0%

20%

40%

60%

80%

100%

Wk 2 Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24

HIV RNA Suppression at Week 24, Observed

79.4%85.9%

95.3%92.1% p = 0.328

p = 0.492

SQV/rLPV/r

6769

6970

6967

6967

6665

6565

6364

Perc

ent o

f pat

ient

s

SQV/r < 400 copies/mL LPV/r < 400 copies/mL

SQV/r < 50 copies/mL LPV/r < 50 copies/mL

At all time points, comparisons between SQV/r and LPV/r are not statistically significant

n =n =

0

50

100

150

200

250

300

350

Wk 0 Wk 2 Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24

Mean CD4 Count, ObservedC

D4

coun

t (ce

lls/m

m3 ) +157 cells/mm3

+140 cells/mm3

p = 0.7546SQV/r LPV/r

SQV/rLPV/r

6871

7070

6868

6866

6564

6563

6364

7169

At all time points, comparisons between SQV/r and LPV/r are not statistically significant

n =n =

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

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

Virologic failure defined as 2 consecutive HIV RNA > 400 copies/mL at Week 16 or thereafterBL, baseline; VF, virologic failure; PI, protease inhibitor; RT, reverse transcriptase inhibitor

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

Virologic failure defined as 2 consecutive HIV RNA > 400 copies/mL at Week 16 or thereafterBL, baseline; VF, virologic failure; PI, protease inhibitor; RT, reverse transcriptase inhibitor

Adverse EventsGrade II–IV

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 GII–GIV AEs reported in ≥ 2% of patientsGastrointestinal disorders: pts with ≥ 1 GII–GIV AE, n (%)

Nausea, n Vomiting, n Diarrhea, n

10 (14)65 2

17 (23)1057

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 Lopinavir/r1 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 2–16: HIV RNA < 50 copies/mL, CD4 42 cells/mm3; only concomitant medications TMP–SMX 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 > 100,000 copies/mL– Week 24: patient died

1 acute psychotic episode

– Resolved with sequelae

*As indicated by the investigator

0

50

100

150

200

250

Totalcholesterol

LDL HDL Triglycerides

Change in Lipids at Week 24M

ean

lipid

val

ues

(mg/

dL)

SQV/r BaselineSQV/r Week 24

LPV/r BaselineLPV/r Week 24

+ 21 + 29

+ 12 + 10

+ 9 + 9

+ 29

+ 88p = 0.182

p = 0.779

p = 0.602

p = 0.020

0%

10%

20%

30%

40%

50%

Percent of Patients with Elevated Lipidsat Baseline and Week 24

Fasting cholesterol ≥ grade 1(≥ 200 mg/dL; ≥ 5.2 mmol/L)

Fasting triglycerides ≥ grade 2(≥ 400 mg/dL; ≥ 4.5 mmol/L)

17%13%

21%

38%

0% 1% 4%

p = 0.009

13%

SQV/r BaselineSQV/r Week 24

LPV/r BaselineLPV/r Week 24

p = 0.036

n = 63 n = 64 n = 72n = 73n = 71n = 72 n = 73 n = 72

Perc

ent o

f pat

ient

s

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

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

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

The Roche study management team Gilead for provision of Truvada®