xviii international aids conference ● vienna, austria ●18-23 july 2010
DESCRIPTION
Lopinavir/ritonavir (LPV/r) Combined with Raltegravir (RAL) Demonstrated Similar Antiviral Efficacy and Safety as LPV/r Combined with Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC) in Treatment-Naïve HIV-1-Infected Subjects: PROGRESS 48 week results. - PowerPoint PPT PresentationTRANSCRIPT
Jacques Reynes1, Adebayo Lawal2, Federico Pulido3, Ruth Soto-Malave4, Joseph Gathe5, Min Tian2, Linda Fredrick2, Todd Correll2, Thomas Podsadecki2, Angela Nilius2
XVIII International AIDS Conference ● Vienna, Austria ●18-23 July 2010
1. Department of Infectious and Tropical Diseases, Montpellier University Hospital, Montpellier, France 2. Abbott, Abbott Park, Illinois 3. Unidad VIH. Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Madrid Spain 4. University of Puerto Rico, School of Medicine, Infectious
Diseases Section, San Juan, Puerto Rico and Innovative Care PSC, Bayamon, Puerto Rico 5. Therapeutic Concepts, Houston, Texas
MOAB0101
Lopinavir/ritonavir (LPV/r) Combined with Raltegravir (RAL) Demonstrated Similar Antiviral Efficacy and Safety as LPV/r Combined with Tenofovir Disoproxil Fumarate/Emtricitabine
(TDF/FTC) in Treatment-Naïve HIV-1-Infected Subjects:
PROGRESS 48 week results
2PROGRESS 48 week results – XVIII IAC19-Jul-10
Background• The standard ARV therapy of a PI or NNRTI + 2 NRTIs is effective,
though 15-20% of patients on long-term therapy experience toxicity related to NRTI use1-4
• Combinations of drugs from other classes can be effective while avoiding NRTI-associated toxicity5
• LPV/r, a PI with durable antiviral activity, is approved for use in ARV-naïve and experienced patients in combination with NRTIs6-8
• RAL is an integrase inhibitor that quickly suppresses viral replication and is approved for use in ARV-naïve and experienced patients9-10
• The PROGRESS trial is the first phase III study designed to test the efficacy and safety of a novel NRTI-sparing strategy using RAL and LPV/r in naïve patients
1. Hogg, RS et al., Lancet, 1997; 349:1294; 2. Lewis, W et al., Nat. Rev. Drug Discov., 2003;2:812-22; 3. Shikuma, CM et al., AIDS, 2001;15:1801-9; 4. Nolan, D et al., Sex Health, 2005;2:153-63; 5. Riddler, SA et al., N. Engl. J. Med., 2008;358:2095-106; 6. Gathe JR et al., JAIDS, 2009;50:474-481; 7. Zajdenverg, R., et al., JAIDS, 2010;54:143-51; 8 Kaletra US prescribing Information, 2010; 9. Lennox, J et al., Lancet, 2009; 374:796-806. 10. Isentress US prescribing Information, 2009.
3PROGRESS 48 week results – XVIII IAC19-Jul-10
LPV/r + RAL vs. LPV/r + TDF/FTC in Treatment-Naive Subjects: PROGRESS Study Design
• Primary endpoint: plasma HIV-1 RNA <40 copies/mL at week 48 (FDA ITT TLOVR)
• Non-inferiority assessed by 95% CI for the difference ([LPV/r + RAL] – [LPV/r + TDF/FTC]) using a -20% threshold
• If non-inferiority with respect to the -20% margin was demonstrated, then non-inferiority with respect to a -12% margin was to be evaluated
LPV/r 400/100 mg BID + TDF/FTC 300/200 mg QD
(n=105)
Inclusion Criteria for PROGRESS (M10-336)• HIV-1 infection• ARV-naïve • Plasma HIV-1 RNA >1000 copies/mL• Any CD4+ T-cell count
ScreeningWeek 96
LPV/r 400/100 mg BID
+ RAL 400 mg BID
(n=101)
Week 48PrimaryEfficacyEndpoint
4PROGRESS 48 week results – XVIII IAC19-Jul-10
Baseline Demographics and HIV Disease Characteristics*
* Excludes randomized but not dosed, n=3† Plasma HIV-1 viral loads determined using automated, quantitative RT-PCR assay
Variable LPV/r + RAL(N=101)
LPV/ + TDF/FTC(N=105)
Total(N=206)
Males, n (%) 88 (87.1) 86 (81.9) 174 (84.5)
White, n (%) 74 (73.3) 81 (77.1) 155 (75.2)
Black, n (%)Other, n (%)
22 (21.8) 5 (4.9)
22 (21.0)2 (1.9)
44 (21.4) 7 (3.4)
Mean age ± SD, years 39.8 ± 9.9 39.4 ± 11.2 39.6 ± 10.6
Mean BL HIV-1 RNA, log10 copies/mL (range)†
4.24(2.0-6.0)
4.25(2.7 – 6.0)
4.25 (2.0 – 6.0)
Mean BL CD4, cells/μL (range)
289.3(5 – 668)
297.6(5 – 743)
293.5 (5 – 743)
5PROGRESS 48 week results – XVIII IAC19-Jul-10
Subject Disposition at Week 48
Reasons for Discontinuations
LPV/r + RAL(N=101)n, (%)
LPV/ + TDF/FTC(N=105)n, (%)
Total (N=206)n, (%)
All Reasons* 8 (7.9) † 11 (10.5) ** 19 (9.2)
AE/HIV-related Event 2 (2.0) 2 (1.9) 4 (1.9)
Withdrew Consent 1 (1.0) 3 (2.9) 4 (1.9)
Lost to Follow-Up 3 (3.0) 3 (2.9) 6 (2.9)
Noncompliance║ 1 (1.0) 0 (0) 1 (0.5)
Virologic Failure 1 (1.0) 2 (1.9) 3 (1.5)
Other║ 1 (1.0) 1 (1.0) 2 (1.0)
On treatment beyond week 48 93 (92.1) 94 (89.5) 187 (90.8)
*P >0.100 for LPV/r + RAL vs. LPV/r + TDF/FTC comparison for each reason † 4 subjects discontinued prior to week 48 and 4 subjects discontinued after week 48 visit ** 9 subjects discontinued prior to week 48 and 2 subjects discontinued after week 48 visit ║ 1 LPV/r + RAL subject discontinued due to two reasons: Noncompliance and Other
6PROGRESS 48 week results – XVIII IAC19-Jul-10
Primary Efficacy Endpoint at Week 48: Proportion of Subjects Responding (FDA ITT TLOVR)
LPV/r + RAL was non-inferior to LPV/r + TDF/FTC in treatment-naïve subjects at 48 weeks
7PROGRESS 48 week results – XVIII IAC19-Jul-10
Mean CD4+ T-cell Count Change from Baseline to Week 48 (cells/mm3)
8PROGRESS 48 week results – XVIII IAC19-Jul-10
Emergence of Resistance Mutations*
Study DrugNumber of subjects with new mutations
LPV/r + RAL LPV/r + TDF/FTC
LPV 0/4 0/3
RAL † 1/3 N/A
TDF 0/4 0/3
FTC 0/4 1/3
*LPV-associated mutations: Major: V32I, I47V/A, L76V, V82A/F/T/S. Minor: L10F/I/R/V, K20M/R, L24I, L33F, M46I/L, I50V, F53L, I54/V/L/A/M/T/S, L63P, A71V/T, G73S, I84V, or L90M RAL-associated mutations: Y143R/H/C, Q148H/K/R, or N155H TDF-associated mutations: K65R or K70EFTC-associated mutations: K65R or M184V/I † 1 RAL sample not available for testing after meeting protocol-defined criteriaN/A-not applicable
• 7 subjects (4 LPV/r + RAL and 3 LPV/r + TDF/FTC) met the protocol-defined criteria for resistance testing – N155H mutation detected in 1 LPV/r + RAL subject– M184V mutation detected in 1 LPV/r + TDF/FTC subject
9PROGRESS 48 week results – XVIII IAC19-Jul-10
Percentages of Subjects with Moderate or Severe Drug-related Adverse Events*
LPV/r + RAL(N=101)n (%)
LPV/r + TDF/FTC
(N=105)n (%)
Any Adverse Event 28 (27.7) 29 (27.6)
Diarrhea Hypercholesterolemia
8 (7.9)8 (7.9)
14 (13.3)5 (4.8)
Hypertriglyceridemia 6 (5.9) 2 (1.9)
Hyperlipidemia 3 (3.0) 1 (1.0)
Blood triglycerides increased Alanine aminotransferase increased
3 (3.0)
2 (2.0)
1 (1.0)
1 (1.0)
*Occurring in ≥2.0% in either treatment groupP>0.100 for LPV/r + RAL vs. LPV/r + TDF/FTC comparison for each adverse event
10PROGRESS 48 week results – XVIII IAC19-Jul-10
Number and % of Subjects with Grade 3+ Laboratory Values*
*Occurring in ≥2.0% in either treatment group† P=0.023 for LPV/r + RAL vs. LPV/r + TDF/FTC comparison
LPV/r + RAL(N=101)n (%)
LPV/r + TDF/FTC
(N=105)n (%)
SGPT/ALT >5X ULN, n (%)SGOT/AST >5X ULNCreatine phosphokinase
>4X ULN † Calcium <1.75 mmol/L Cholesterol >7.77 mmol/L Triglycerides >8.475 mmol/L Calculated creatinine clearance <50 mL/min Lipase >2X ULN
3 (3.0) 5 (5.0)
13 (12.9)
2 (2.0) 16 (15.8) 10 (9.9) 1 (1.0)
4 (4.0)
1 (1.0) 1 (1.0)4 (3.8)
0 14 (13.5)
5 (4.8) 4 (3.8)
7 (6.7)
11PROGRESS 48 week results – XVIII IAC19-Jul-10
Lipid Changes From Baseline to Week 48
Variable LPV/r + RAL N=97
LPV/r + TDF/FTC N=97 P-value#
# P-values based on one-way ANOVA
12PROGRESS 48 week results – XVIII IAC19-Jul-10
Study Conclusions 1• Through 48 weeks, LPV/r + RAL and LPV/r + TDF/FTC had
similar efficacy in treatment-naïve subjects– LPV/r + RAL was non-inferior to LPV/r + TDF/FTC at week 48
• Proportion of subjects responding [FDA ITT TLOVR, P=0.850] – LPV/r + RAL: 83.2% – LPV/r + TDF/FTC: 84.8%
– Similar mean increases in CD4+ T-cell counts at week 48 (P=0.237)• LPV/r + RAL: 214.9 cells/mm3
• LPV/r + TDF/FTC: 245.0 cells/mm3
• No new protease mutations associated with lopinavir resistance developed on study in either treatment arm– A RAL associated resistance mutation was observed in one subject receiving
LPV/r + RAL– A FTC associated resistance mutation was observed in one subject receiving
LPV/r + TDF/FTC
13PROGRESS 48 week results – XVIII IAC19-Jul-10
• Both regimens were generally well tolerated with few study drug-related discontinuations– Discontinuations for AEs or HIV-related events: LPV/r + RAL=2.0% and
LPV/r + TDF/FTC=1.9%
– AE profile and laboratory abnormalities were generally similar with statistically greater mean increases in TC, TG, and HDL and more reports of at least moderate lipid elevations in the LPV/r + RAL group
• Outcomes that will be available after 96 weeks include: – Adherence – DEXA scans – Anthropometric measurements– Patient reported outcomes
Study Conclusions 2
14PROGRESS 48 week results – XVIII IAC19-Jul-10
PROGRESS: AcknowledgementsThe authors express their gratitude • To the patients and their families for their participation and support during the
study• To the PROGRESS (M10-336) Study Team at Abbott and the clinical research
personnel who worked on this study• To Merck for providing raltegravir• To the PROGRESS investigators:
– USA• Larry M. Bush• Frederick A. Cruickshank• Edwin DeJesus• Robin Henry Dretler• Joseph Gathe• Cynthia Mayer• Igho Ofotokun• Moti Ramgopal• Louis Marshall Sloan• Lawrence F. Waldman
– Canada• Jonathan B. Angel• Mona Loutfy• Anita Rachlis
– France• Laurent Cotte• Pierre-Marie Girard• Jacques Reynes• Dominique Salmon
– Italy• Fiorella DiSora• Adriano Lazzarin• Andrea Antinori
– Poland• Marcin Czarnecki
– Puerto Rico• Ivan Melendez-Rivera• Ruth Soto-Malave
– Spain• Bonaventura Clotet• Daniel Podzamczer• Federico Pulido• Jesus Sanz• Pompeyo Viciana
Back-up slides
16PROGRESS 48 week results – XVIII IAC19-Jul-10
Efficacy Analyses Utilized For PROGRESS Study
– FDA ITT TLOVR: Time to loss of virological response. Subjects are considered responders when they achieve two consecutive HIV-1 RNA values <40 copies/mL. Subjects are classified as non-responders at all subsequent visits if they demonstrate 2 consecutive rebound HIV-1 RNA values ≥40 copies/mL, or if they discontinue the study for any reason prior to week 48
– ITT NC=F: Non-completer equals failure. Subjects with missing data were considered failures unless values from the visits directly before and after the missing data were <40 copies/mL (these subjects were considered responders)
– ITT M=F: Missing equals failure. Subjects with missing data were considered failures
– ITT LOCF: Last observation carried forward. For each subject, missing values were replaced by the most recent non-missing value
– OD: Observed data. Subjects with missing data were excluded
– ITT Subjects: All randomized subjects who had both a baseline value and at least one post-baseline value were included in efficacy analyses.
17PROGRESS 48 week results – XVIII IAC19-Jul-10
LPV/r + RAL N=101
n/N(%)
LPV/r + TDF/FTC
N=105 n/N(%)
Difference[95% CI] P-value
FDA ITT TLOVR 84/101 (83.2) 89/105 (84.8) -1.6%
[-12.0%, 8.8% ]0.850
ITT NC=F 82/101 (81.2) 90/105 (85.7) -4.5%
[-15.1%, 5.9% ]0.454
ITT M=F 82/101 (81.2) 90/105 (85.7) -4.5%
[-15.1%, 5.9% ]0.454
ITT LOCF 85/101 (84.2) 93/105 (88.6)-5.4%
[-15.2%, 4.4% ]0.418
OD 82/97 (84.5) 90/96 (93.8) -9.3%
[-18.9%, -0.3% ]0.062
Proportion of Subjects with Plasma HIV-1 RNA <40 Copies/mL at Week 48
P-values calculated using Fisher’s exact test