Maraviroc (MVC) Once Daily With
Darunavir/Ritonavir (DRV/r) Compared
to Tenofovir/Emtricitabine (TDF/FTC)
With DRV/r: 48-Week Results From
MODERN (Study A4001095)
H.-J. Stellbrink,1 P. Pulik,2 J. Szlavik,3 D. Murphy,4
A. Lazzarin,5 J. Portilla,6 A. Rinehart,7
E. Le Fevre,8 A. Fang,9 S. Valluri,9 G. Mukwaya,10 J. Heera11
1ICH-Study
Center, Hamburg, Germany; 2SPZOZ Wojewodzki Szpital Zakazny, Warsaw, Poland; 3Egyesittet Szent
Istvan es Szent Laszio Korhaz-Rendelointezet, Budapest, Hungary; 4Clinique Medicale L'Actuel, Montreal, Canada;
5Ospedale San Raffaele, Divisione di Malattie Infettive, Milan, Italy; 6Hospital General Universitario de Alicante,
Unidad de VIH, Alicante, Spain; 7-8ViiV Healthcare, 7Research Triangle Park, NC, USA; 8Brentford, United Kingdom;
9-11Pfizer Inc., 9New York, NY, USA; 10Medicines Development Group, New York, NY, USA; 11Groton, CT, USA
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Rationale for MVC + Boosted PI Regimen
• Nucleoside toxicity-sparing
• QD regimen/improved adherence
• Low risk of resistance and preservation of treatment options if
virologic failure occurs1
• Good penetration of MVC in CSF and genital secretions2-4
• MOTIVATE5 and PK studies support use of MVC 150 mg QD
with selected ritonavir-boosted PIs6-8
• Prevalence of CCR5 tropic virus is greatest in treatment-naive
individuals9
1. Portsmouth et al. IAC 2011. Abstract TUAB0103. 2. Tiraboschi et al. J Acquir Immune Defic Syndr.
2010;55:e35-e36. 3. Dumond et al. J Acquir Immune Defic Syndr. 2009;51:546-543. 4. Brown et al. J Infect Dis.
2011;203:1484-1490. 5. Jacqmin et al. CPT Pharmacometrics Syst Pharmacol. 2013;2:e64. 6. Vourvahis et al.
IWCPHHT 2010, Abstract 37. 7. Calcagno et al. J Antimicrob Chemother. 2013;68:1686-1688. 8. Mora-Peris et
al. J Antimicrob Chemother. 2013;68:1348-1353. 9. Hoffmann. Eur J Med Res. 2007;12:385-390.
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
.
Study Design
Trofile™ Phenotypic
Assay
(Monogram
Biosciences)
CCR5
tropic
1:1
randomization
to treatment
n≈402
TDF/FTC + MVC QD PBO
+ DRV/r (800/100 mg QD)
1:1
randomization
to treatment
n≈402
TDF/FTC + MVC QD PBO
+ DRV/r (800/100 mg QD)
MVC (150 mg QD) + TDF/FTC QD PBO
+ DRV/r (800/100 mg QD)
Screening Visit
1:1 randomization
to tropism assay
N≈1608
Genotypic Tropism
Assaya
(Siemens Healthcare
Diagnostics)
CCR5
tropic
Screening
(6 weeks)
Eligibility Criteria
• Antiretroviral treatment naive
• Plasma HIV-1 ≥ 1000 c/mL
• CD4 ≥ 100 cells/mm3
• No evidence of resistance to
DRV, TDF, FTC
• ≥ 18 years of age
MVC (150 mg QD) + TDF/FTC QD PBO
+ DRV/r (800/100 mg QD)
0
48 wk
Primary analysis
96 wk
• Phase 3, randomized, double-blind
• Primary endpoint: proportion of subjects with HIV-1 RNA <50 c/mL
at wk 48 (MSDF)b by FDA snapshot algorithm
• Non-inferiority study (NI margin of 10% between treatment groups)
• 195 sites in 22 countries
• Study was terminated on 04 Oct 2013 upon recommendation of IDMC
aSiemens
bMSDF:
HIV-1 Coreceptor Tropism Assay is for research use only.
Missing, Switch, Discontinuation = Failure.
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Subject Disposition
Screening Visit
1:1 randomization to
tropism assay
N=1423
CCR5
tropic
Received
≥ 1 dose of
study drug
n=797
TDF/FTC + DRV/r
n=401
351 ongoing at
48-week analysis
MVC + DRV/r
n=396
323 ongoing at
48-week analysis
Discontinuation
All Screen Failures
n=610a
• 552 did not meet entrance criteria
• 220 non-R5 virus
• 264 tropism not reportable
• 68 other criteria not met
• 57 other reasons for screening failureb
MVC
TDF/FTC
Adverse events
19
18
Insufficient clinical response
33
8
Lost to follow-up
8
7
No longer willing to participate
6
8
Other
7
9
73
50
TOTAL
Screening
(6 weeks)
0
48 wk
Primary analysis
96 wk
*Siemens HIV-1 Coreceptor Tropism Assay is for research use only.
aAn additional 16 subjects were excluded from the study after the first randomization,
but did not receive any study drug (total exclusions, n=626). bIncluded AE (n=1), lost to
follow up (n=7), no longer willing to participate (n=20), protocol deviations (n=3), other
(n=27).
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Baseline Characteristics
MVC + DRV/r
(n=396)
TDF/FTC+ DRV/r
(n=401)
37.0 (18–72)
35.0 (18–70)
Male, n (%)
360 (90.9)
367 (91.5)
Race, n (%)
White
Black
Other
322 (81.3)
60 (15.2)
14 (3.5)
326 (81.3)
55 (13.7)
20 (5.0)
Median CD4+ count,
cells/mm3 (range)
352
(86–1295)
345
(34–1177)
38 (9.5)
45 (11.2)
4.42 (2.93–6.36)
4.42 (2.68–6.47)
HIV-1 RNA ≥100,000 copies/mL, n (%)
81 (20.5)
83 (20.7)
Clade, n (%)
B
Non-B
342 (86.4)
54 (13.6)
354 (88.3)
47 (11.7)
Median age, years (range)
CD4+ count <200 cells/mm3, n (%)
Mean HIV-1 RNA, log10 copies/mL (range)
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Virologic and Immunologic Response
Proportion of subjects with
HIV-1 RNA <50 copies/mL
TDF/FTC 86.8%
348/401 subjects
MVC 77.3%
306/396 subjects
Adjusted treatment difference (95% CI):
-9.5% (-14.8%, -4.2%)
BL
4
8
12
16
20
24
36
48
Week
Mean CD4+ cell count changes at Week 48 (mean ± SD, cells/mm3)
MVC + DRV/r
195.3 ± 175.7
TDF/FTC + DRV/r
193.9 ± 175.7
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Proportion of subjects with
HIV-1 RNA <50 copies/mL (%)
Treatment Response at Week 48
by Key Subgroups
No. of subjects
Total
253 282
315 318
Baseline
HIV-1 RNA
53 66
81 83
25 40
38 45
121 142
159 161
101 100
127 118
59 66
72 77
Baseline
CD4+ Cell Count
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Comparable MVC Responses Were Observed in
Populations Screened by Genotype and Trofile™
146/181
(80.7%)
160/215
(74.4%)
Genotype
Trofile
• The adjusted difference was 6.9% in the MVC arm in favor of the genotype assay
(95% CI -1.3%, 15%)
• There was no difference in response rate between assays in the TDF/FTC arm
(160/185 [86.5%], genotype; 188/216 [87.0%], Trofile)
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Subjects with Protocol-Defined Treatment
Failure (PDTF: Time of Failure)
Subjects with PDTF, n (%)a
HIV-1 RNA copies/mL at PDTF, n
50 to 200
201 to 400
401 to 1000
1001 to 10,000
10,001 to 50,000
MVC + DRV/r TDF/FTC + DRV/r
(n=396)
(n=401)
40 (10.1)
13 (3.2)
22
5
8
4
1
10
0
1
0
2
• Majority of subjects with PDTF (MVC + DRV/r, 68%; TDF/FTC + DRV/r, 77%) had
HIV-1 RNA <400 copies/mL at PDTF
• 7 subjects in both arms achieved HIV-1 RNA <50 copies/mL at last dose
• No treatment-emergent resistance to any study drug was observed
a
•
•
•
•
•
•
Protocol-defined treatment failure criteria:
Decrease in plasma HIV-1 RNA <1 log10 from baseline after Week 4, unless plasma HIV-1 RNA is <50 copies/mL, or
Plasma HIV-1 RNA >1.0 log10 above the nadir value after Week 4, where the nadir is the lowest plasma HIV-1 RNA concentration, or
Plasma HIV-1 RNA ≥50 copies/mL at any time after Week 24, or
Plasma HIV-1 RNA ≥50 copies/mL after suppression to <50 copies/mL on two consecutive visits, or
Decrease in plasma HIV-1 RNA <2 log10 from baseline on or after Week 12, unless plasma HIV-1 RNA is <50 copies/mL (post Amendment 2) and <400 copies/mL
(post Amendment 3)
All PDTFs required confirmation within 28 days of the initial event.
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract #.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Treatment-Emergent Adverse Events,
Malignancies, and Laboratory Abnormalities
MVC + DRV/r
Most common AEs (>5% of subjects), n (%)
Diarrhea
Nasopharyngitis
Upper respiratory tract infection
Rash
Nausea
Fatigue
Cough
Bronchitis
Gastroenteritis
Depression
Insomnia
Malignancies, n (%)
Grade 3/4 laboratory abnormalities, n (%)
Alanine aminotransferase (ALT)
Total bilirubin
Creatine kinase
Cholesterol
(n=396)
TDF/FTC + DRV/r
(n=401)
81 (20.5)
40 (10.1)
36 (9.1)
32 (8.1)
29 (7.3)
26 (6.6)
24 (6.1)
23 (5.8)
20 (5.1)
18 (4.5)
14 (3.5)
7 (2.0)a
130 (32.4)
47 (11.7)
33 (8.2)
25 (6.2)
42 (10.5)
40 (10.0)
26 (6.5)
21 (5.2)
15 (3.7)
26 (6.5)
25 (6.2)
2 (0.7)b
7 (1.8)
3 (0.8)
13 (3.3)
8 (2.0)
5 (1.3)
1 (0.2)
14 (3.5)
6 (1.5)
aMVC:
Kaposi’s Sarcoma (n = 3), Castleman’s Disease (n = 1), Basal Cell Carcinoma (n = 1), Hodgkin’s Lymphoma (n = 2; one case assessed as possibly
treatment-related by investigator).
bTDF/FTC: Kaposi’s Sarcoma (n=1), Testis Cancer (n=1)
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Summary and Conclusions
• MVC 150 mg QD in 2-drug therapy regimen demonstrated statistically lower
•
•
•
•
rates of viral suppression when compared to a 3-drug regimen of TDF/FTC +
DRV/r in antiretroviral-naive subjects over 48 weeks
– IDMC recommended that the study be terminated in October 2013
Within each arm, there was comparable efficacy by tropism assay used for
screening
The majority of PDTFs failed with HIV-1 viral load <400 copies/mL
There was no treatment-emergent resistance in either arm
There was comparable safety and no unexpected safety findings
• The efficacy of MVC + PI/r as stable switch therapy is under evaluation in
the ongoing MARCH study
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Acknowledgments
• Subjects and their supporters
• Charles Craig, Research Virology Consulting and The Research
Network
• Marilyn Lewis, The Research Network
• Colleagues at ViiV Healthcare and Pfizer
Stellbrink et al. IAC 2014; Melbourne, Australia. Abstract TUAB0101.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Acknowledgments:
MODERN Study Investigators
Dr Jose Maria Gatell Artigas
Daniel Podzamczer Palter
Dr Joaquin Portilla Sogorb
Dr Juan Julian Gonzalez Garcia
Assoc Prof Antonio Rivero Roman
Prof Dr Gerd Faetkenheuer
Dr Andreas Plettenberg
Prof Dr Johannes Richard Bogner
Prof Dr Juergen K Rockstroh
Prof Dr Jan van Lunzen
Dr Heiko Karcher
Prof Dr Hans-Juergen Stellbrink
Dr Howard Alan Grossman
Dr Javier Osvaldo Morales-Ramirez
Dr David Michael Asmuth
Dr David Michael Mushatt
Dr Melanie Ann Thompson
Dr Joan M. Duggan
Dr Christopher Michael Polk
Dr William Keith Henry
Dr Miguel M. Mogyoros
Catherine Butkus Small
Dr Shubha J. Kerkar
Dr Carl Jack Fichtenbaum
Dr Paul Alan Benson
Dr William David Hardy
Dr Roberto Baun Corales
Dr Armin Rieger
Dr Gordon Elwood Crofoot Jr.
Dr Michael Grant Sension
Dr Jihad Slim
Dr Jacek Gasiorowski
Professor. Dr Waldemar Halota
Dr Rodger David MacArthur
Dr Jan Sven Fehr
Dr Marcel Stoeckle
Eugénio Teofilo
Dra. Rosário Serrao
Dr Teresa Branco
Dr Emanuel G. Vlahakis
Stephen Kegg
Dr Christoph Stephan
Dr Edmund Lydons Wilkins
Dr Jason Andrew Flamm
Dr Janos Szlavik
Dr Chloe Meave Orkin
Dr Stephen Eliot Follansbee
Dr Alan Hinwai Man
Dr Keikawus Arasteh
Dr Gabriele L. Knecht
Dr Hans Jaeger
Dr Dushyantha Thilak Jayaweera
Dr Robin Henry Dretler
Dr Lizette Santiago
Dr Jennifer Christy Bartczak
Dr Steven Santiago
Dr Jose Andres Montero
Dr Gary Blick
Dr Bienvenido Gamulo Yangco
Dr Norman Peter Markowitz
Dr David Michael Parenti
Dr Margaret Ann Fischl
Alyssa Shon
Dr Dawd Said Siraj
Dr Mamta K. Jain
Dr Barbara Heeter Wade
Dr Bruce Stephen Rashbaum
Dr Barbara J. Hanna
Dr Catherine Maria Creticos
Dr Shannon Ray Schrader
Dr Louis Marshall Sloan
Dr Craig Allan Dietz
Dr Jerome A. Ernst
Dr Carmen D. Zorrilla
Dr Michael Bruce Wohlfeiler
Dr Ruth Soto-Malave
Dr Thomas Bryan Campbell
Dr Jeffery Linn Meier
Dr Julia Betzabe Garcia-Diaz
Dr Peter Gregory Gulick
Dr Michael John Kozal
Dr Susan Swindells
Dr Sharon Lynn Walmsley
Dr Daniel B. Murphy
Dr Jean-Guy Baril
Dr Jason Brunetta
Dr Jonathan Benjamin Angel
Dr Brian Conway
Dr David Philip Wright
Dr Anthony Martin Mills
Dr Ivan Melendez-Rivera
Dr Clifford Arbery Kinder
Dr Kathleen King Casey
Dr Joseph Clayton Gathe Jr
Dr Donna Mildvan
Dr Jorge Ernesto Rodriguez
Dr Babafemi Olapoju Taiwo
Dr Michael Switow Saag
Dr Peter P. Shalit
Dr Daniel Jay Skiest
Prof Dr Hansjakob Furrer
Prof Dr Pietro Vernazza
Dr Jan Gerstoft
Svend Stenvang Pedersen
Matti Ristola
Prof Jacques Reynes
Dr Antoine Cheret
Dr Jean-Michel Molina
Prof Christine Katlama
Prof Pierre-Marie Girard
Dr Lelia Escaut
Prof Francois Raffi
Dr Laurent Cotte
Prof Clifford L. Leen
Dr Christiane Cordes
Dr David Rey
Dr Gilles Olivier Pialoux
Dr Mark T. Bloch
Prof Ilja Mohandas Hoepelman
Dr Mark Richard Nelson
Dr Piotr Pulik
Dr Lars R. Mathiesen
Dr David Alfred Baker
Dr Mark Denis Kelly
Prof Margaret Anne Johnson
Dr Manuela Doroana
Dr Daniel Benjamin Klein
Prof Yves Levy
Prof Philippe Morlat
Dr Thierry Prazuck
Dr Ian Geoffrey Williams
Dr Stephen Taylor
Juan Berenguer Berenguer
Dr Martin J. Fisher
Dr Anders Thalme
Dr Hernando Knobel Freud
Prof Nathan Clumeck
Prof Bernard Vandercam
Prof Dr Michel Moutschen
Dr Kinda Schepers
Prof Dr Linos Vandekerckhove
Dr Eric Florence
Prof Magnus Gisslen
Prof Andrew Carr
Dr Tim Read
Dr Leo Flamholc
Dr Pere Domingo Pedrol
Dr Julian HJ Elliott
Dr Anders Blaxhult
Maria Jose Rios Villegas
Prof Patrick Yeni
Prof Adriano Lazzarin
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia