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Innovative Strategies for the Managementof HIV Infection
Dual therapies without NRTIs
Jean-Guy Baril, MDClinique médicale du Quartier Latin
CHUMThis activity is supported byan educational grant from:
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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
DisclosuresDr. Jean-Guy Baril
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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.
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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, anti-
HCV negative
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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
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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
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
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)
As patients live longer on therapy…
new therapeutic options which lessen the impact of ARV therapy on their bodies are especially important.
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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 suppression1. 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
NRTI-sparing approach:Findings to date
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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
Innovative strategies for HIV care
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.
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•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
Methods
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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
Trial selection
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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)
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PROGRESS:LPV/r + RAL vs. LPV/r + TDF/FTC in ARV-naïve patients
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
LPV/r 400/100 mg BID + TDF/FTC 300/200 mg QD
(n=105)
ScreeningWeek 96
LPV/r 400/100 mg BID
+ RAL 400 mg BID (n=101)
Week 48PrimaryEfficacyEndpoint
* 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].
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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].
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LPV/r + RAL and LPV/r + TDF/FTC groups were compared using one-way ANOVA
PROGRESS:Mean percent change from baseline to weeks 48 and 96 in body fat parameters
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].
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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.
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PROGRESS Bone Mineral DensityJuly 14, 2011
Proportion of Subjects with ≥5% Decrease from Baseline in Total Bone Mineral Density
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Results from a Single Arm Study of Darunavir/Ritonavir Plus Raltegravir inTreatment-Naïve HIV-1-Infected Patients (ACTG A5262)
Babafemi Taiwo et al. , Northwestern Univ., Chicago, IL, US
Presented as poster no 551 at CROIYear 2011
ACTG A5262
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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
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RADAR study: Raltegravir combined with boosted Darunavir has similar safety and antiviral efficacy astenofovir/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, RomeYear 2011
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Radar study
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RADAR study, 24 weeks : Key Findings
Working Group on Innovative Strategies for HIV Care, 2012.
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
Other outcomes
Mean TC +21.6 +8.8 0.20
conclusion Similar safety and efficacy
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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, ViennaYear 2010
The SPARTAN study
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Atazanavir/r + TDF/FTC or Maraviroc in Treatment-naïve Patients (Study A4001078)
• Primary Patient Eligibility Criteria:− 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
Open-label, 96-week Phase 2b Pilot Study
Mills T, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0102.
Randomization1 : 1
N = 121 MVC (150 mg QD) + ATV/r (300/100 mg QD)
FTC/TDF + ATV/r (300/100 mg QD)
48wk
Screening(6 weeks)
0 24wk
16wk
PrimaryEndpoint
96wk
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A4001078: Virologic Outcomes
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 subjectsMills T, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0102.
82.0%
67.8%
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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
A4001078: Adverse Events and SafetyMVC + ATV/r
n=60FTC/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)
Discontinued due to AE, n (%) 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)
Mills T, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0102.
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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)
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Humphries A, et al. CROI 2013. Abstract 180LB.
LPV/r 400/100 mg BID +RAL 400 mg BID
(n = 270)
LPV/r 400/100 mg BID + 2-3 NRTIs QD or BID
(n = 271)
HIV-infected pts with virologic failure on first-line regimen of 2
NRTIs + NNRTI(N = 541)
Stratified by clinical site, baseline HIV-1 RNA
(≤ or > 100,000 copies/mL)
Wk 48 primary endpoint
PRESENTED AT CROI 2013
SECOND LINE:LPV/r +RAL vs. LPV/r + NRTIs after first-line virologic failure
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Design:Randomized, open-label study conducted at 38 sites in 15 countries
Subjects: 541 HIV-1 positive adults (≥16 years) with virologic failure with first-line ART (NNRTI + 2N(t)RTIs) for ≥24 weeks
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)
0
20
40
80
100
Wk
LPV/RTV + RALLPV/RTV + 2-3 NRTIs
60
0 12 24 36 48
HIV
-1 R
NA
< 2
00 c
/mL
(%)
Similar high levels of virologic suppression with each strategy in primary mITT analysis
82.6
80.8
P = .59
Humphries A, et al. CROI 2013. Abstract 180LB. Graphic used with permission.Zheng Y, et al. CROI 2013. Abstract 558.
SECOND LINE:Non-inferiority of LPV/r + RAL vs. LPV/r + NRTIs
PRESENTED AT CROI 2013
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CROI 2013, Abstract #566
ROCnRAL ANRS 157:Switch to MVC+RAL in lipodystrophic patients with suppressed viral load
Key inclusion criteria:HIV RNA < 50 copies/mLCD4 cell count nadir >100 cells/mm3
Clinical lipodystrophy
RAL 400 mg BID + MVC 300 mg BID
(n=44)
Switched from suppressive
HAART
Primary endpointProportion 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)
24 weeksPrimaryendpoint
48 weeks
PRESENTED AT CROI 2013
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CROI 2013, Abstract #566
7 patients discontinued therapy
• 5 had virologic failure; 3 due to adverse events
• 3/5 failures had resistance to RAL (A. F121Y, Y143C, N155HPremature discontinuation of study advised by DSMB
ROCnRAL ANRS 157:Switch to MVC+RAL in lipodystrophic patients with suppressed viral load
PRESENTED AT CROI 2013
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Maraviroc + Raltegravir Dual Therapy in Aviremic HIV+
Patients with Lipodystrophy: Virologic Failures and Resistance
Katlama C, et al. Presented at CROI 2013; poster #566.
Patient
W-4 screening Baseline Virological Failure
cART prior entry
Duration of suppressed viremia (yrs)
CD4 count (mm3)
Viral tropism
(on DNA)
HIV-1 viral load (c/mL)
Time of failure
Drug concen-trations
plasma Cmin (ng/mL)
Integrase mutation
resistance
Viral tropism on HIV-RNA
1TDF / FTC /
EFV9.5 477 CCR5
1052973598
W4W8
W12
RAL: 21MVC: 13
No mut. to RAL
CCR5
2 DRV/r 7.5 832 CCR5
897218101453204
W16W18W20W24
RAL: 1960
MVC: 160
RAL: VT2I,
Y143CCXCR4
3TDF / FTC /
DRV/r9.8 893 CCR5
698070
W16W20
RAL: 56MVC: 104
RAL: VT2I,
N155HCCR5
4TDF / FTC /
DRV/r3.6 601 CCR5
27434259
W12W16
RAL: 121MVC: 28
RAL: VT2I
CCR5
5TDF / FTC /
EFV6.6 954 CCR5
3752820
W20W22
RAL: 87MVC: 105
RAL: F121Y
CCR5
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Maraviroc + Raltegravir Dual Therapy in Aviremic HIV+ Patients with Lipodystrophy: Serious AEs Leading to Discontinuation
Katlama C, et al. Presented at CROI 2013; poster #566.
Patient Characteristics Serious AETiming of
SAE
Patient 6
• CCR5 tropism• cART: ABC/3TC/ATV• Suppressed viremia: 6.2 yrs• CD4 cell count: 715/mm3
• HBsAg-, HBsAb-, HBcAb+
HBV reactivationAST/ALT > 20xN (grade 4)Related to lamivudine discontinuation
W16
Patient 7
• CCR5 tropism• cARTL: TDF/FTC/RTV• Suppressed viremia: 5.6
years• CD4 cell count: 594/mm3
Cutaneous rash and diarrhea possibly related to raltegravir and maraviroc
W4
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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).
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2013 2014 TOTAL
STUDY N STUDY N N
LPV/r + RALEARNEST
(treatment failure)400
SELECT(treatment failure)
350 750
LPV/r + 3TCGARDEL
(ARV-naïve)205
OLE(simplification)
168 372
DRV/r + RALNEAT001
(ARV-naïve)400 400
DRV/r + MVCMODERN
(ARV-naïve)402 402
GUSTA(Switch)
165 165
PK 15 15
DRV + ETVINROADSPhase 2
(treatment failure)54 54
ATV + RALHARNESS
(Switch)60 60
N= dual therapy arm
ONGOING STUDIES OF PI-BASED NRTI-SPARING REGIMENS
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•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.
CONCLUSIONS
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ACKNOWLEDGEMENTSThe Working Group on Innovative Strategies for HIV Care