Innovative Strategies for the Managementof 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:

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

Disclosures Dr. Jean-Guy Baril"

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, anti-

HCV 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

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."

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"

NRTI-sparing approach: Findings to date"

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."

• 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"

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"

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"

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)"

Screening"Week 96"

LPV/r 400/100 mg BID + RAL 400 mg BID (n=101)" Week 48

Primary Efficacy Endpoint"

* 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]."

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]."

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."

PROGRESS Bone Mineral Density July 14, 2011

Proportion of Subjects with ≥5% Decrease from Baseline in Total Bone Mineral Density"

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 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

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"

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)

•  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."

Randomization 1 : 1

N = 121 MVC (150 mg QD) + ATV/r (300/100 mg QD)

FTC/TDF + ATV/r (300/100 mg QD)

48 wk

Screening (6 weeks)

0 24 wk

16 wk

Primary Endpoint

96 wk

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 subjects"Mills T, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0102."

82.0%"

67.8%"

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 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)

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."

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)

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"

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 + RAL LPV/RTV + 2-3 NRTIs"

60"

0" 12" 24" 36" 48"

HIV

-1 R

NA

< 20

0 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"

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/mL CD4 cell count nadir >100 cells/mm3

Clinical lipodystrophy"

RAL 400 mg BID + MVC 300 mg BID

(n=44)"

Switched from suppressive

HAART"

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)"

24 weeks Primary endpoint"

48 weeks"

PRESENTED AT CROI 2013"

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, N155H Premature discontinuation of study advised by DSMB"

ROCnRAL ANRS 157: Switch to MVC+RAL in lipodystrophic patients with suppressed viral load "

PRESENTED AT CROI 2013"

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

1 TDF / FTC / EFV

9.5 477 CCR5 105

2973 598

W4 W8

W12

RAL: 21 MVC: 13

No mut. to RAL

CCR5

2 DRV/r 7.5 832 CCR5

8972 1810 1453 204

W16 W18 W20 W24

RAL: 1960

MVC: 160

RAL: VT2I, Y143C

CXCR4

3 TDF / FTC / DRV/r 9.8 893 CCR5 69

8070 W16 W20

RAL: 56 MVC: 104

RAL: VT2I, N155H

CCR5

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

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 AE Timing of

SAE

Patient 6

• 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

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

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).

2013 2014 TOTAL STUDY N STUDY N N

LPV/r + RAL EARNEST

(treatment failure) 400 SELECT (treatment failure) 350 750

LPV/r + 3TC GARDEL

(ARV-naïve) 205 OLE

(simplification) 168 372

DRV/r + RAL NEAT001

(ARV-naïve) 400 400

DRV/r + MVC MODERN

(ARV-naïve) 402 402

GUSTA (Switch)

165 165

PK 15 15

DRV + ETV INROADS Phase 2

(treatment failure) 54 54

ATV + RAL HARNESS

(Switch) 60 60

N= dual therapy arm"

ONGOING STUDIES OF PI-BASED NRTI-SPARING REGIMENS"

• 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"

ACKNOWLEDGEMENTS"The Working Group on Innovative Strategies for HIV Care"