Modifying Therapy in the Treatment-experienced Patient: When should it be done? Joseph J. Eron, Jr., MD Professor of Medicine UNC Chapel Hill School of Medicine

Disclosures Principal Investigator (Research Grants to University of North Carolina): GlaxoSmithKline/ViiV Ad hoc Consultant: Abbvie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Merck, Tibotec/Janssen, Tobira Data and Safety Monitoring Board: Vertex (Inactive 2/1/2014)

Treatment-experienced Patient Two broad categories Suppressed HIV RNA; candidates for regimen modification Convenience, tolerability, toxicity, cost Virologic failure, usually in the context of poor medication adherence Reestablish virologic suppression while avoiding complex or poorly tolerated therapy (whenever possible)

Changing Therapy when HIV RNA Is Suppressed Switching the regimen may improve safety, tolerability, convenience, or cost. Pro – My job as a clinician is to make sure each patient is on an optimal regimen weighing multiple factors Con – Any switch could lead to unanticipated toxicity, medication error, drug-drug interactions, and subsequent HIV RNA rebound

Regimen Switching with Virologic Suppression The vast majority of patients in care on ART have HIV RNA below the limit of detection Example: 87% of Hopkins Cohort, 85% UNC Clinical Cohort Possible reasons to change treatment Reduce pill burden and dosing frequency Enhance tolerability Decrease anticipated short-term or long-term toxicity Decrease food requirements Optimize treatment in anticipation of pregnancy Reduce costs Improve immunologic response (?) Moore R, et al. Clin Infect Dis. 2011; 53:600-604. DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.

Disadvantages of Regimen Switching A new agent may lead to new adverse event Virologic rebound may lead to resistance Risk increased if previous resistance testing not done or unavailable or Complete treatment history is not known Increased monitoring in the short term What is said is not always what is heard Medication errors occur including DDI Cost of new regimen may be higher

Candidates for Regimen Switching Optimal: Patients with no suspected drug-resistant virus Selected patients with documented or suspected drug resistance may also be candidates Focus on those who changed regimens when treatment options were much more limited Similar agents with better formulation, frequency, or potency; FDCs; and dosing simplification Key is to review treatment history, treatment responses, tolerance, and resistance test results Maintaining virologic suppression a priority Slide: Candidates for Regimen Simplification Candidates for regimen simplification include: No suspected drug-resistant virus. Selected patients with documented or suspected drug resistance. Patients on regimens that were selected when treatment options were limited. For such patients it is important to review treatment history, treatment responses, tolerance, and resistance test results, as well as consider expert consultation.1 Reference Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013;1-267. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.

SPIRIT: Switching from PI/r to Rilpivirine RPV/FTC/TDF STR HIV-1 RNA <50 copies/mL Stable PI/r + 2 NRTIs ≥ 6 months On 1st or 2nd regimen No prior NNRTIs No known genotypic resistance to study ARVs 24 weeks 48 weeks n=317 n=159 2:1 n=476 PI/r +2 NRTIs Primary Endpoint: Noninferiority (12% margin) to PI + RTV + 2 NRTIs by FDA snapshot analysis HIV-1 RNA <50 c/mL at 24 weeks Palella F, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0104. 8

SPIRIT: Virologic Suppression at Weeks 24 and 48 (Immediate switch, Day 1 to W24) (delayed, Day 1 to W24) (delayed switch, W24 to W48) (Immediate switch, Day 1 to W48) 23/24 subjects with preexisting K103N maintain virologic suppression Pretherapy VL NOT associated with rebound Fewer adverse events on rilpivirine-based therapy Lipid levels improved substantially 3 patients on RPV failed with resistance Fisher M, et al. HIV11; Glasgow, Scotland; November 11-15, 2012; Abst. P285.

STRATEGY-PI: Switch from PI/r to TDF/FTC/EVG/c CORE_Efficacy_Safety_Feb-14_SLB.ppt 4/22/2017 STRATEGY-PI: Switch from PI/r to TDF/FTC/EVG/c n =293 n =140 2:1 PI + RTV + FTC/TDF EVG/C/FTC/TDF Week 96 Week 48 STRATEGY-PI Study EVG/C/FTC/TDF: coformulated elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg. PI + RTV + FTC/TDF: ritonavir-boosted PI and emtricitabine/tenofovir DF. Reasons subjects chose to enroll in study Desire to simplify current regimen 86% Concerned about long-term side effects of current regimen 12% Arribas J, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 551LB. Gilead 10

STRATEGY-PI: Virologic Outcome at Week 48 EVG/C/FTC/TDF (n=290) PI + RTV + FTC/TDF (n=139) Virologic success at week 48 HIV-1 RNA <50 copies/mL* 272 (93.8%) 121 (87.1%) Virologic failure (VF) at week 48 2 (0.7%) 2 (1.4%) HIV-1 RNA ≥ 50 copies/mL 2 1 Discontinued study drug due to lack of efficacy Discontinued study drug due to other reasons and last available HIV-1 RNA ≥50 copies/mL No virologic data in week 48 window 16 (5.5%) 16 (11.5%) Discontinued study drug due to AE 5 Discontinued study drug due to other reasons and last available HIV-1 RNA <50 copies/mL 11 (3.7%) 14 (10.1%) Missing data during window but on study drug No subject met the protocol-defined criteria for treatment-emergent resistance testing with virologic rebound ≥400 c/mL Modest/significant improvement in diarrhea and bloating * 6.7% (+0.4%, +13.7%) P=0.025 for superiority Arribas J, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 551LB.

SPIRAL Study Switch to RAL vs Continue PI/r Very low rates of VF Patients with NRTI experience Similar success ABC/3TC vs TDF/FTC Similar results Improvement in lipids Including TC/HDL Not in endothelial function hsCRP IL-6 Insulin D-Dimer Change after switch from PI/r to RAL -40% -46% -26% -8% P value <0.0001 0.018 Martinez E, et al. AIDS. 2010. AIDS 2012, AHR 2013 and Masia, et al. J Antimicrob Chemother. 2013.

Novel Strategies for Switch Simplification from 3-drug therapy to 2 drugs PI/r plus 3TC alone GARDEL study (in treatment naïve), AtLaS study PI/r plus integrase inhibitor Integrase inhibitor plus NNRTI Multiple small studies NVP plus raltegravir Etravirine plus raltegravir Beware of noncomparative studies RAL plus maraviroc – stopped due to VF RPV plus DTG vs continued NNRTI plus 2NRTI Cahn P, et al. Lancet Infect Dis. 2014;14:572-580. Monteiro P, et al. J Antimicrob Chemother. 2014;69:742-748. Reliquet V, et al. Antivir Ther. 2014;19:117-123. Calin R, et al. Antivir Ther. 2012;17:1601-1604. Di Giambenedetto S, et al. J Antimicrob Chemother. 2013;68:1364-1372. van Lelyveld S, et al. Presented at: CROI. Atlanta, GA; March 3-6, 2013.

Oral maintenance phase** stratified by VL and NRTI LATTE: Study Design Phase 2b randomized, multicenter, partially blind, dose-ranging study comparing S/GSK744 plus RPV to EFV plus NRTIs 744 30 mg + 2 NRTIs* 744 10 mg + 2 NRTIs* Oral induction phase 744 60 mg + 2 NRTIs* Oral maintenance phase** 744 10 mg + RPV 25 mg HIV ART-naïve HIV RNA >1,000 c/mL 1:1:1:1 Randomization stratified by VL and NRTI 744 30 mg + RPV 25 mg 744 60 mg + RPV 25 mg 24 16 20 48 96 72 EFV 600 mg + 2 NRTIs* Week D1 *ABC/3TC or TDF/FTC **Patients on 744 + NRTI: If week 20 VL <50 c/mL - simplify to 744/RPV at week 24 Margolis D, et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. PS7/1.

Median (IQR) change from baseline CD4+ cell count (cells/mm3) Two-drug 744 + RPV Maintained Suppression Comparable to EFV-based Therapy 744 overall response W24 87% 744 overall response W48 82% Induction Phase Maintenance Phase Proportion, % EFV response W24 74% EFV response W48 71% Median (IQR) change from baseline CD4+ cell count (cells/mm3) Week 48 744 overall +219 (141,343) EFV +227 (134,369) BL 2 4 8 12 16 24 26 28 32 36 40 48 Week Margolis D, et al. CROI 2014; Boston, MA. Abstract 91LB.

Long-acting Injectable Study LATTE 2 Rilpivirine LA plus 744 LA monthly or every other month vs Oral 744 + 2NRTI Margolis D, et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. PS7/1; Margolis D, et al. CROI 2014; Boston, MA. Abstract 91LB; Levin J. Presented at 21st Conference on Retroviruses and Opportunistic Infections. Boston, MA. March 3 - 6, 2014.

Treatment Experienced Patient with Virologic Failure Selected Factors Associated with Virologic Failure Patient factors ART factors Higher baseline HIV RNA Side effects and toxicities Lower nadir CD4 cell count Suboptimal pharmacokinetics Prior AIDS diagnosis Food/fasting requirements Substance use, depression Drug-drug interactions Presence of drug-resistant virus Suboptimal virologic potency Prior treatment failure Prescription errors Suboptimal ART adherence/missed clinic appointments DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.

Virologic Failure: Next Steps Assess patient’s past medication history, adherence, and potential medication intolerance, previous resistance tests Order drug resistance test For patients on an integrase inhibitor, specific testing for integrase inhibitor resistance should be performed if available The goal of ART is to reestablish virologic suppression At least 2 (preferably 3) fully active drugs as part of new regimen Eron Corollary: 3 fully active drugs – may increase complexity, decrease tolerability, and increase cost – partially active drugs likely contribute DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.

Second-line: LPV/RTV + RAL vs LPV/RTV + NRTIs after First-line VF Randomized, open-label, international, multicenter trial Week 48 primary endpoint Stratified by clinical site, baseline HIV-1 RNA (≤ or > 100,000 copies/mL) Lopinavir/ritonavir 400/100 mg BID + Raltegravir 400 mg BID (n=270) HIV-infected patients with virologic failure on first-line regimen of 2 NRTIs + NNRTI (n=541) TDF + FTC/3TC: 46% AZT + FTC/3TC: 18% For more detailed information about this study go to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202013/ART/Capsules/180LB.aspx. Lopinavir/ritonavir 400/100 mg BID + 2-3 NRTIs QD or BID (n=271) Of 492 participants with baseline GRT: 89% had ≥1 N(t)RTI resistance mutation 60% had M184V plus 1 or more additional N(t)RTI mutations Boyd MA, et al. Lancet. 2013;381:2091-2099.

Second-line Study: Results P-value=0.59 80.8% (76.1 – 85.5) 82.6% (78.1 – 87.1) Percent Patients Boyd M, et al. 20th CROI; Atlanta, GA; March 3-6, 2013. Abst. 180LB.

Therapy for Later Treatment Failure Adherence remains the most common cause For patients who initiated therapy in the ART era – multiclass, high-level resistance is rare Resistance testing is critical Use at least 2 fully active drugs if possible Partially active drugs likely add benefit NRTI may not be necessary Knowledge of a drug’s barrier to resistance and activity against resistant virus is essential

Modifying Antiretroviral Therapy in Treatment-experienced Patients: Summary Patients with HIV RNA suppression Goals include: simplify, improve tolerability, reduce toxicity, sustain virologic suppression Need: Treatment history, resistance data, clear patient understanding and follow-up Patients with virologic failure Adherence must be addressed Resistance testing is critical At least 2 fully active agents – most patients have several options Full suppression is the goal.