jean-guy baril md clinique médicale du quartier latin

Report
Innovative Strategies for the Management
of HIV Infection
Dual therapies without NRTIs
Jean-Guy Baril, MD
Clinique médicale du Quartier Latin
CHUM
This activity is supported by
an educational grant from:
Disclosures
Dr. Jean-Guy Baril
Received consultant, investigator or speaker honoraria/grants from
the following companies
•AbbVie
•Bristol-Myers Squibb
•GlaxoSmithKline
•Boehringer Ingelheim
•Pfizer
•Roche
•Tibotec
•Merck Frosst
•Gilead
ANTIBODY Healthcare Communications received an unconditional grant from
AbbVie Canada for the literature review
Objectives
•
•
•
Review the data from studies supporting the use of
dual therapy on treatment-naive or experienced
patients with an undetectable viral load.
Know the studies done with a protease inhibitor in
combination with another single agent such as an
integrase inhibitor, maraviroc, 3TC or an NNRTI.
Discuss the role of these options in clinical practice.
Denis’ Case
•
Patient has never been treated for his HIV. Suffers
from diabetes but is well controlled. He also has
renal insufficiency.
• Accepted to begin treatment because of a drop in
his CD4 to 370 and a viral load of 150 000
Lab results:
• Creatinine: 133; eGFR: 55; Urinalysis: N; MAU: 4.6 mg/mmol
(N<2.1)
• HLAB5701: Positive for genotype: no mutation.
• HBsAG negative, anti-HBs positive, anti-HBc negative, antiHCV negative
Which treatment to start with?
•
•
•
•
•
•
1) Atripla
2) Truvada + PI/r
3) Kivexa + Efavirenz
4) Combivir + Efavirenz
5) PI/r + Raltegravir
6) PI/r + Efavirenz
The ongoing need for novel regimens
“A person starting combination therapy can expect
to live about 43 years at 20 years of age…”
The Lancet, 20081
As patients live
longer on therapy…
new therapeutic options
which lessen the impact of
ARV therapy on their bodies
are especially important.
What are the goals of NRTI-free therapy?2
•Maintain efficacy
•Prevent resistance
•Reduce toxicities
•Maintain and improve adherence
•Reduce costs
(including the total cost of care)
1. The Antiretroviral Therapy Cohort Collaboration. Lancet 2008;372:293-99;
2. 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
Department of Health and Human Services
NRTI-sparing approach:
Findings to date
Initial studies showed1…
• higher rates of treatment failure
• poorer tolerability
(i.e. DMP-006; IDV+EFV)
Recent (2011) meta-analysis of 10 PI
monotherapy trials showed2…
• increase in the risk of virologic failure
• decrease in viral suppression
1. Staszewski, S., et al. Efavirenz plus Zidovudine and Lamivudine, Efavirenz plus Indinavir, and Indinavir plus Zidovudine and Lamivudine in the
Treatment of HIV-1 Infection in Adults. New England Journal of Medicine, 1999. 341(25): pp. 1865-1873.
2. Mathis, S., et al. Effectiveness of protease inhibitor monotherapy versus combination antiretroviral maintenance therapy: a meta-analysis. PLoS One,
2011. 6(7): p. e22003.0
Innovative strategies for HIV care
The working group:
• Dr. S. Walmsley, ON (Co-chair)
• Dr. J.G. Baril, QC (Co-chair)
•
•
•
•
•
Dr. C. Murphy, BC
Dr. J. Angel, ON
Dr. J. Gill, AB
Dr. G. Smith, ON
Sandra Blitz, ON
What did the working group do?
Reviewed the current and available
evidence on innovative dual
therapies(PI/r + RAL or MVC or NNRTI
or 3TC) for ARV-naïve and
-experienced patients.
Methods
• Literature search using PubMed was done from 2002 through
February 2012
• International AIDS Society Conference on HIV Pathogenesis and Treatment
and Prevention (WAC/IAS) 2009-2011 and Conference on Retroviruses and
Opportunistic Infections (CROI) 2009-2012 abstracts search
• Additionally, an expert review committee consisting of HIV specialists reviewed
and rated all identified trials and was queried around their knowledge of any
other potentially relevant studies in existence, including those cited in the
reference lists of identified studies
Trial selection
INCLUSION CRITERIA
•randomized controlled or prospectively designed single-arm trials
•minimum duration 24 weeks
•naive or switch of virologically suppressed patients
•primary outcome of suppression of viral load, change in viral load or virologic failure was
acceptable
–other virologic outcomes were acceptable as a primary endpoint, if they were supplemented by
secondary endpoints which looked at the above criteria
•secondary outcome data were included if available (toxicities and-or co-morbidities
outcome)
•considered acceptable: pilot/proof-of-concept studies, abstracts.
EXCLUSION CRITERIA
•Case reports, reviews, correspondences and research letters
•Phase I trials, laboratory studies , pharmacokinetic/pharmacodynamic studies,
retrospective or included patients who were ARV-experienced but not suppressed or
were pediatric, pregnancy/pMTCT or co-infection studies
NRTI-sparing trials:
ARV-naïve and – experienced patients
Regimen
ARV-naïve
ARV-experienced
PI/r + RAL
PROGRESS (LPV/r + RAL)
ACTG 5262 (DRV/r + RAL)
RADAR (DRV/r + RAL)
SPARTAN (ATV + RAL)
CCTG 589 (LPV/r + RAL)
KITE (LPV/r + RAL)
PI/r + MVC
A4001076 (ATV/r + MVC)
VEMAN (LPV/r + MVC)
MIDAS (DRV/r + MVC
PI/r + 3TC
LOREDA (LPV/r + 3TC)
ATLAS (ATV/r + 3TC)
PI/r + NNRTI
ACTG 5142 (LPV/r + EFV)
A5116 (LPV/r + EFV)
NEKA (LPV/r + NVP)
PROGRESS:
LPV/r + RAL vs. LPV/r + TDF/FTC in ARV-naïve patients
LPV/r 400/100 mg BID
+ RAL 400 mg BID (n=101)
Screening
LPV/r 400/100 mg BID
+ TDF/FTC 300/200 mg QD
(n=105)
Week 48
Primary
Efficacy
Endpoint
Week 96
Met Primary Endpoint of Non-inferiority
Primary endpoint: plasma HIV-1 RNA <40 copies/mL at week 48 (FDA-TLOVR)
•LPV/r + RAL=83.2%,
•LPV/r + TDF/FTC=84.8%
Difference -1.6%, 95% exact confidence interval (CI) -12.0%, 8.8%; P=0.850,
Safety and tolerability were similar at week 48
* 3 subjects were randomized but not dosed
Reynes J, Trinh R, Pulido F, et al. Lopinavir/ritonavir (LPV/r) combined with raltegravir (RAL) or tenofovir/emtricitabine (TDF/FTC) in antiretroviral-naive
subjects: 96-week results of the PROGRESS study. AIDS Res Hum Retroviruses. 2012;[epub ahead of print].
PROGRESS:
Week 96 (TLOVR)
(88.9% obs)
(85.2% obs)
RAL-TDF/FTC= 3.7% (95% CI: -7.5%, 14.3%) obs
Reynes J, Trinh R, Pulido F, et al. Lopinavir/ritonavir (LPV/r) combined with raltegravir (RAL) or tenofovir/emtricitabine (TDF/FTC) in antiretroviral-naive
subjects: 96-week results of the PROGRESS study. AIDS Res Hum Retroviruses. 2012;[epub ahead of print].
PROGRESS:
Mean percent change from baseline to weeks 48 and 96 in body fat parameters
LPV/r + RAL and LPV/r + TDF/FTC groups were compared using one-way ANOVA
Reynes J, Trinh R, Pulido F, et al. Lopinavir/ritonavir (LPV/r) combined with raltegravir (RAL) or tenofovir/emtricitabine (TDF/FTC) in antiretroviral-naive
subjects: 96-week results of the PROGRESS study. AIDS Res Hum Retroviruses. 2012;[epub ahead of print].
PROGRESS:
Mean percent change in bone mineral density analyzed using DXA through 96
weeks of treatment
van Wyk J. Body fat distribution changes after 96 weeks of therapy with lopinavir/ritonavir (LPV/r) plus raltegravir (RAL) compared with LPV/r plus
tenofovir/emtricitabine (TDF/FTC) in antiretroviral (ARV)-naive, HIV-1-infected subjects from the PROGRESS study. Presented at: 13th European AIDS
Conference; October 12-14, 2011; Belgrade, Serbia.
Proportion of Subjects with ≥5% Decrease
from Baseline in Total Bone Mineral Density
PROGRESS Bone Mineral Density
July 14, 2011
Results from a Single Arm Study
of Darunavir/Ritonavir Plus
Raltegravir in
Treatment-Naïve HIV-1-Infected
Patients (ACTG A5262)
Babafemi Taiwo et al. ,
Northwestern Univ.,
Chicago, IL, US
Presented as poster no 551 at CROI
Year 2011
ACTG A5262
ACTG 5262 Aims, method and design
Aim
• To assess the efficacy and safety of DRV/r plus RAL in antiretroviral-naïve
subjects
Methods and design
• A multicentre, single arm, open label, 52-week pilot study of RAL 400mg
BID plus DRV/r 800mg/100mg QD
RADAR study: Raltegravir combined
with boosted Darunavir has similar
safety and antiviral efficacy as
tenofovir/emtricitabine combined with
boosted darunavir in antiretroviral-naive
patients
Author, R. Bedimo et al. VA North Texas Health
Care System, Medicine, Dallas, United States
Presented as poster no MOPE214 at the 6th
IAS conference, Rome
Year 2011
Radar study
RADAR study, 24 weeks : Key Findings
Key Findings
Outcome
RAL with
DRV/RTV
TDF/FTC with
DRV/RTV
P value
Undetectable
viral load, (% < 50)
88.9 %
81.0 %
0.41
Change in CD4
cell count
+123
+174
0.19
Mean TC
+21.6
+8.8
0.20
conclusion
Similar safety and efficacy
Other outcomes
Working Group on Innovative Strategies for HIV Care, 2012.
The SPARTAN study: a pilot study to
assess the safety and efficacy of an
investigational NRTI- and RTV-sparing
regimen of atazanavir (ATV)
experimental dose of 300mg BID plus
raltegravir (RAL) 400mg BID (ATV+RAL)
in treatment-naïve HIV-infected subjects
M.J. Kozal et al. Yale University School of Medicine
and VA CT Healthcare System, New Haven, United States
Presented as LB no : THLBB204 at the
XVIIIth IAC conference, Vienna
Year 2010
The SPARTAN study
Atazanavir/r + TDF/FTC or Maraviroc in
Treatment-naïve Patients (Study A4001078)
Open-label, 96-week Phase 2b Pilot Study
FTC/TDF + ATV/r (300/100 mg QD)
Randomization
1:1
N = 121
Screening
(6 weeks)
MVC (150 mg QD) + ATV/r (300/100 mg QD)
0
16
wk
24
wk
• Primary Patient Eligibility Criteria:
−
−
−
−
48
wk
Primary
Endpoint
R5 HIV at screening
HIV-1 RNA ≥1,000 copies/mL
CD4 ≥100 cells/mm3
No evidence of resistance to ATV/r, TDF, or FTC
Mills T, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0102.
96
wk
A4001078: Virologic Outcomes
82.0%
67.8%
ITT, NC=F
•
•
MVC arm: 6/8 with detectable viremia at week 96 had VL <250 cps/mL
No genotypic, phenotypic resistance or tropism changes detected in any failing subjects
Mills T, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0102.
A4001078: Adverse Events and Safety
MVC + ATV/r
n=60
FTC/TDF + ATV/r
n=61
Any AE, n (%)
58 (96.7)
61 (100.0)
Serious AE, n (%)
13 (21.7)
11 (18.0)
Grade 3 or 4 AE, n (%)
32 (53.3)
20 (32.8)
2 (3.3)
0
Hyperbilirubinemia, n (%)
AE-related
Grade 3 or 4 AE-related
Grade 3 or 4 laboratory
18 (30.0)
10 (16.7)
42 (70.0)
16 (26.2)
8 (13.1)
34 (55.7)
Jaundice, n (%)
AE-related
Grade 3 or 4 AE related
10 (16.7)
5 (8.3)
6 (9.8)
1 (1.6)
Discontinued due to AE, n (%)
Mean change in creatinine clearance from baseline to week 96:
• MVC + ATV/r = ↓1.5 mL/min
• TDF/FTC + ATV/r = ↓21.5 mL/min
Mills T, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0102.
NRTI-sparing trials:
ARV-naïve and – experienced patients
Regimen
ARV-naïve
ARV-experienced
PI/r + RAL
PROGRESS (LPV/r + RAL)
ACTG 5262 (DRV/r + RAL)
RADAR (DRV/r + RAL)
SPARTAN (ATV + RAL)
CCTG 589 (LPV/r + RAL)
KITE (LPV/r + RAL)
PI/r + MVC
A4001076 (ATV/r + MVC)
VEMAN (LPV/r + MVC)
MIDAS (DRV/r + MVC
PI/r + 3TC
LOREDA (LPV/r + 3TC)
ATLAS (ATV/r + 3TC)
PI/r + NNRTI
ACTG 5142 (LPV/r + EFV)
A5116 (LPV/r + EFV)
NEKA (LPV/r + NVP)
PRESENTED AT CROI 2013
SECOND LINE:
LPV/r +RAL vs. LPV/r + NRTIs after first-line virologic failure
Wk 48
primary endpoint
Stratified by clinical site,
baseline HIV-1 RNA
(≤ or > 100,000 copies/mL)
LPV/r 400/100 mg BID +
RAL 400 mg BID
(n = 270)
HIV-infected pts with virologic
failure on first-line regimen of 2
NRTIs + NNRTI
(N = 541)
Humphries A, et al. CROI 2013. Abstract 180LB.
LPV/r 400/100 mg BID +
2-3 NRTIs QD or BID
(n = 271)
PRESENTED AT CROI 2013
SECOND LINE:
Non-inferiority of LPV/r + RAL vs. LPV/r + NRTIs
Similar high levels of virologic suppression
with each strategy in primary mITT analysis
Design:
Randomized, open-label study conducted
at 38 sites in 15 countries
Treatment arms (1:1 randomization):
•LPV/r + 2-2 N(t)RTIs (control)
•LPV/r + RAL [N(t)RTI-sparing]
Primary objective:
Comparison of the antiviral efficacy of
second-line ART regimens (% with plasma
HIV RNA <200 copies/mL after 48 weeks)
100
HIV-1 RNA < 200 c/mL (%)
Subjects:
541 HIV-1 positive adults (≥16 years) with
virologic failure with first-line ART (NNRTI
+ 2N(t)RTIs) for ≥24 weeks
82.6
80
80.8
P = .59
60
40
LPV/RTV + RAL
LPV/RTV + 2-3 NRTIs
20
0
Humphries A, et al. CROI 2013. Abstract 180LB. Graphic used with permission.
Zheng Y, et al. CROI 2013. Abstract 558.
0
12
24
Wk
36
48
PRESENTED AT CROI 2013
ROCnRAL ANRS 157:
Switch to MVC+RAL in lipodystrophic patients with suppressed viral load
Key inclusion criteria:
HIV RNA < 50 copies/mL
CD4 cell count nadir >100
cells/mm3
Clinical lipodystrophy
Switched from
suppressive
HAART
24 weeks
Primary
endpoint
RAL 400 mg BID
+ MVC 300 mg BID
(n=44)
48 weeks
Primary endpoint
Proportion of patients with treatment failure at week 24 (ITT)
(Defined as either virological failure with 2 consecutive plasma HIV RNA >50
copies/mL or treatment discontinuation)
CROI 2013, Abstract #566
PRESENTED AT CROI 2013
ROCnRAL ANRS 157:
Switch to MVC+RAL in lipodystrophic patients with suppressed viral load
7 patients discontinued therapy
•5 had virologic failure; 3 due to adverse events
•3/5 failures had resistance to RAL (A. F121Y, Y143C, N155H
Premature discontinuation of study advised by DSMB
CROI 2013, Abstract #566
Maraviroc + Raltegravir Dual Therapy in Aviremic HIV+
Patients with Lipodystrophy: Virologic Failures and Resistance
W-4 screening
Patient
1
cART prior
entry
TDF / FTC /
EFV
Duration of
suppressed
viremia (yrs)
9.5
7.5
Baseline
CD4 count
(mm3)
477
832
Virological Failure
Time of
failure
Drug
concentrations
plasma Cmin
(ng/mL)
Integrase
mutation
resistance
Viral
tropism on
HIV-RNA
CCR5
105
2973
598
W4
W8
W12
RAL: 21
MVC: 13
No mut.
to RAL
CCR5
CCR5
8972
1810
1453
204
W16
W18
W20
W24
RAL:
1960
MVC: 160
RAL:
VT2I,
Y143C
CXCR4
W16
W20
RAL: 56
MVC: 104
RAL:
VT2I,
N155H
CCR5
Viral
tropism
(on DNA)
HIV-1 viral
load (c/mL)
2
DRV/r
3
TDF / FTC /
DRV/r
9.8
893
CCR5
69
8070
4
TDF / FTC /
DRV/r
3.6
601
CCR5
27434
259
W12
W16
RAL: 121
MVC: 28
RAL:
VT2I
CCR5
5
TDF / FTC /
EFV
6.6
954
CCR5
375
2820
W20
W22
RAL: 87
MVC: 105
RAL:
F121Y
CCR5
Katlama C, et al. Presented at CROI 2013; poster #566.
Maraviroc + Raltegravir Dual Therapy in Aviremic HIV+
Patients with Lipodystrophy: Serious AEs Leading to Discontinuation
Patient
Characteristics
Serious AE
Timing of
SAE
CCR5 tropism
cART: ABC/3TC/ATV
Suppressed viremia: 6.2 yrs
CD4 cell count: 715/mm3
HBsAg-, HBsAb-, HBcAb+
HBV reactivation
AST/ALT > 20xN
(grade 4)
Related to
lamivudine
discontinuation
W16
Cutaneous rash
and diarrhea
possibly related
to raltegravir
and maraviroc
W4
Patient 6
•
•
•
•
•
Patient 7
• CCR5 tropism
• cARTL: TDF/FTC/RTV
• Suppressed viremia: 5.6
years
• CD4 cell count: 594/mm3
Katlama C, et al. Presented at CROI 2013; poster #566.
Ongoing Studies
• ANRS 143 Study:
Study to determine whether the combination regimen of DRV/r and RAL is not inferior to
the combination therapy involving the DRV/r and TDF-FTC combination in 800 adults
infected with HIV-1 without a history of ARV treatment, for at least 96 weeks.
• MODERN Study:
– Phase III study (A4001095) comparing a CCR5 antagonist (maraviroc) with the
combination regimen TDF-FTC (Truvada®) both taken in combination with DRV/r for 96
weeks, in 804 patients.
• LPV/r and lamivudine (3TC):
– Comparison of the tolerability and efficacy of LPV/r taken with 3TC and LPV taken with two
NRTIs in 407 subjects with no history of ARV treatment for 96 weeks.
• HARNESS Study
– Phase IV study comparing the switch from a treatment with atazanavir 300 mg/ritonavir
100 mg QD combined with either raltegravir BID or tenofovir/emtricitabine QD in patients
with an undetectable viral load under tri-therapy (120 patients).
ONGOING STUDIES OF PI-BASED
NRTI-SPARING REGIMENS
2013
STUDY
LPV/r + RAL
LPV/r + 3TC
DRV/r + RAL
EARNEST
(treatment failure)
GARDEL
(ARV-naïve)
NEAT001
(ARV-naïve)
MODERN
(ARV-naïve)
GUSTA
(Switch)
PK
2014
N
400
205
STUDY
SELECT
(treatment failure)
OLE
(simplification)
TOTAL
N
N
350
750
168
372
400
400
402
402
165
165
15
15
DRV + ETV
INROADS
Phase 2
(treatment failure)
54
54
ATV + RAL
HARNESS
(Switch)
60
60
DRV/r + MVC
N= dual therapy arm
CONCLUSIONS
• Despite the numerous available ARV combinations, no treatment regimen is
free of adverse effects.
• Most PLHIV are now treated and will be so for most of their lives. The following
should be taken into consideration:
– Long-term toxicities
– Existing co-morbidities
– Cross toxicities
– Drug interactions
• Treatments should be individualized to take each patient’s circumstances into
account. There is a need for NRTI-sparing treatments:
– Patients who are intolerant of NRTIs
– Resistance to NRTIs
– Co-morbidities exacerbated by NRTIs
• Studies are underway of PI/r combinations with raltegravir, maraviroc and 3TC
and will be able to better support this practice in the future. For now, the
preliminary results show that not all of these combinations are equivalent.
ACKNOWLEDGEMENTS
The Working Group on Innovative
Strategies for HIV Care

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