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Modifying Therapy in the Treatment-experienced Patient: When should it be done?

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

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Modifying Therapy in the Treatment-experienced Patient: When should it be done?

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  1. 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

  2. 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)

  3. 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)

  4. Changing Therapy when HIV RNAIs 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

  5. 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.

  6. Disadvantages ofRegimen 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

  7. 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 DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.

  8. SPIRIT: Switching from PI/r to Rilpivirine Primary Endpoint: • Noninferiority (12% margin) to PI + RTV + 2 NRTIs by FDA snapshot analysis HIV-1 RNA <50 c/mL at 24 weeks RPV/FTC/TDF STR RPV/FTC/TDF STR n=317 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 2:1 PI/r +2 NRTIs RPV/FTC/TDF STR n=159 n=476 24 weeks 48 weeks Palella F, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0104.

  9. SPIRIT: Virologic Suppressionat Weeks 24 and 48 • 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 (Immediate switch, Day 1 to W24) (delayed, Day 1 to W24) (delayed switch, W24 to W48) (Immediate switch, Day 1 to W48) Fisher M, et al. HIV11; Glasgow, Scotland; November 11-15, 2012; Abst. P285.

  10. STRATEGY-PI: Switch from PI/r to TDF/FTC/EVG/c STRATEGY-PI Study n =293 EVG/C/FTC/TDF PI + RTV + FTC/TDF 2:1 PI + RTV + FTC/TDF n =140 Week 48 Week 96 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. Arribas J, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 551LB.

  11. STRATEGY-PI: Virologic Outcome at Week 48 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 Arribas J, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 551LB. * 6.7% (+0.4%, +13.7%) P=0.025 for superiority

  12. SPIRAL StudySwitch 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 Martinez E, et al. AIDS. 2010. AIDS 2012, AHR 2013 and Masia, et al. J AntimicrobChemother. 2013.

  13. 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 AntimicrobChemother. 2014;69:742-748. Reliquet V, et al. AntivirTher. 2014;19:117-123. Calin R, et al. AntivirTher. 2012;17:1601-1604. Di Giambenedetto S, et al. J AntimicrobChemother. 2013;68:1364-1372. van Lelyveld S, et al. Presented at: CROI. Atlanta, GA; March 3-6, 2013.

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

  15. Two-drug 744 + RPV Maintained Suppression Comparable to EFV-based Therapy 744 overall response W48 82% 744 overall response W24 87% Induction Phase Maintenance Phase Proportion, % EFV response W24 74% EFV response W48 71% BL 2 4 8 12 16 24 26 28 32 36 40 48 Week Margolis D, et al. CROI 2014; Boston, MA. Abstract 91LB.

  16. 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.

  17. Treatment Experienced Patientwith Virologic Failure Selected Factors Associated with Virologic Failure DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.

  18. 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.

  19. Second-line: LPV/RTV + RAL vs LPV/RTV + NRTIs after First-line VF 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% Lopinavir/ritonavir 400/100 mg BID + 2-3 NRTIs QD or BID(n=271) • Of 492 participantswithbaseline GRT: • 89% had ≥1 N(t)RTI resistancemutation • 60% had M184V plus 1 or more additional N(t)RTI mutations Boyd MA, et al.Lancet. 2013;381:2091-2099. Randomized, open-label, international, multicenter trial

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

  21. 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

  22. 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.

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