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:

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 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, 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 showed 1 … higher rates of treatment failure poorer tolerability (i.e. DMP-006; IDV+EFV) Recent (2011) meta-analysis of 10 PI monotherapy trials showed 2 … 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, (25): pp Mathis, S., et al. Effectiveness of protease inhibitor monotherapy versus combination antiretroviral maintenance therapy: a meta-analysis. PLoS One, (7): p. e 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) and Conference on Retroviruses and Opportunistic Infections (CROI) 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 RegimenARV-naïveARV-experienced PI/r + RALPROGRESS (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 + MVCA (ATV/r + MVC) VEMAN (LPV/r + MVC) MIDAS (DRV/r + MVC PI/r + 3TCLOREDA (LPV/r + 3TC)ATLAS (ATV/r + 3TC) PI/r + NNRTIACTG 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 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 6 th IAS conference, Rome Year 2011

Radar study

RADAR study, 24 weeks : Key Findings Working Group on Innovative Strategies for HIV Care, Key Findings OutcomeRAL 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 Other outcomes Mean TC conclusionSimilar 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 XVIII th IAC conference, Vienna Year 2010 The SPARTAN study

Atazanavir/r + TDF/FTC or Maraviroc in Treatment-naïve Patients (Study A ) Primary Patient Eligibility Criteria: −R5 HIV at screening −HIV-1 RNA ≥1,000 copies/mL −CD4 ≥100 cells/mm 3 −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 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

A : 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. TUAB % 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 A : 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 RegimenARV-naïveARV-experienced PI/r + RALPROGRESS (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 + MVCA (ATV/r + MVC) VEMAN (LPV/r + MVC) MIDAS (DRV/r + MVC PI/r + 3TCLOREDA (LPV/r + 3TC)ATLAS (ATV/r + 3TC) PI/r + NNRTIACTG 5142 (LPV/r + EFV)A5116 (LPV/r + EFV) NEKA (LPV/r + NVP)

Humphries A, et al. CROI Abstract 180LB. LPV/r 400/100 mg BID + RAL 400 mg BID (n = 270) LPV/r 400/100 mg BID 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 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) Wk LPV/RTV + RAL LPV/RTV NRTIs HIV-1 RNA < 200 c/mL (%) Similar high levels of virologic suppression with each strategy in primary mITT analysis P =.59 Humphries A, et al. CROI Abstract 180LB. Graphic used with permission. Zheng Y, et al. CROI 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 CD 4 cell count nadir >100 cells/mm 3 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 screeningBaselineVirological Failure cART prior entry Duration of suppressed viremia (yrs) CD4 count (mm 3 ) Viral tropism (on DNA) HIV-1 viral load (c/mL) Time of failure Drug concen- trations plasma C min (ng/mL) Integrase mutation resistance Viral tropism on HIV-RNA 1 TDF / FTC / EFV CCR W4 W8 W12 RAL: 21 MVC: 13 No mut. to RAL CCR5 2DRV/r7.5832CCR W16 W18 W20 W24 RAL: 1960 MVC: 160 RAL: VT2I, Y143C CXCR4 3 TDF / FTC / DRV/r CCR W16 W20 RAL: 56 MVC: 104 RAL: VT2I, N155H CCR5 4 TDF / FTC / DRV/r CCR W12 W16 RAL: 121 MVC: 28 RAL: VT2I CCR5 5 TDF / FTC / EFV CCR 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. PatientCharacteristicsSerious AE Timing of SAE Patient 6 CCR5 tropism cART: ABC/3TC/ATV Suppressed viremia: 6.2 yrs CD4 cell count: 715/mm 3 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/mm 3 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 (A ) 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).

TOTAL STUDYN NN LPV/r + RAL EARNEST (treatment failure) 400 SELECT (treatment failure) LPV/r + 3TC GARDEL (ARV-naïve) 205 OLE (simplification) DRV/r + RAL NEAT001 (ARV-naïve) 400 DRV/r + MVC MODERN (ARV-naïve) 402 GUSTA (Switch) 165 PK 15 DRV + ETV INROADS Phase 2 (treatment failure) 54 ATV + RAL HARNESS (Switch) 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