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New and Emerging Therapies for the Clinical Management of HIV Infection

New and Emerging Therapies for the Clinical Management of HIV Infection. Sponsored for CME credit by Rush University Medical Center. Supported by an independent educational grant from Gilead Sciences Medical Affairs. CME Disclaimer, Disclosure Information, and Slide Handouts. CME Disclaimer

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New and Emerging Therapies for the Clinical Management of HIV Infection

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  1. New and Emerging Therapies for the Clinical Management of HIV Infection Sponsored for CME credit by Rush University Medical Center Supported by an independent educational grant from Gilead Sciences Medical Affairs

  2. CME Disclaimer, Disclosure Information, and Slide Handouts • CME Disclaimer • These slides may not be videotaped, published, posted online, and/or presented for Continuing Medical Education credit without written permission from Rush University Medical Center and Practice Point Communications • Disclosure Information • It is the policy of the Rush University Medical Center Office of Continuing Medical Education to ensure that its CME activities are independent, free of commercial bias and beyond the control of persons or organizations with an economic interest in influencing the content of CME • Everyone who is in a position to control the content of an educational activity must disclose all relevant financial relationships with any commercial interest (including but not limited to pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the presentation topic) within the preceding 12 months • If there are relationships that create a conflict of interest, these must be resolved by the CME Course Director in consultation with the Office of Continuing Medical Education prior to the participation of the faculty member in the development or presentation of course content • Slide Handouts • The enclosed slide handouts are provided for reference purposes only • The faculty presenter may have customized the slides through reordering or deleting and thus the handouts may not exactly match the presentation

  3. Educator Lisa Hightow-Weidman, MD, MPH Associate Professor University of North Carolina at Chapel Hill • Disclosures • Grants/Research Support: n/a • Consultant: n/a • Speakers’ Bureau: Gilead, Janssen • Stock Shareholder: n/a • Other Financial or Material Support: n/a

  4. Accreditation and Designation Rush University Medical Center is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Rush University Medical Center designates this live activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only credit commensurate with the extent of their participation in the activity. ANAC is an approved provider of continuing nursing education (CNE) by the Virginia Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. This activity is approved for 1.0 contact hour by the Association of Nurses in AIDS Care. The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UAN #0012-9999-13-043-L02-P). This activity is accredited for 1 hour of continuing pharmacy education (CPE) credit. The University of Florida College of Pharmacy will report all credit to CPE Monitor within 30 working days after receiving evidence of successful completion of the course. Successful completion means that you must attend the entire program and complete an evaluation form. Supported by an independent educational grant from Gilead Sciences Medical Affairs.

  5. Faculty CME Course Director Harold A. Kessler, MD Professor of Medicine and Immunology/Microbiology Associate Director, Section of Infectious Diseases Rush University Medical Center Chicago, Illinois Content Development and Training Eric S. Daar, MD Chief, Division of HIV Medicine Harbor-UCLA Medical Center Torrance, California Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California CME Reviewer David M. Simon, MD, PhD Associate Professor Section of Infectious Diseases Rush University Medical Center Chicago, Illinois CNE Reviewer Allison R. Webel, RN, PhD Instructor and KL2 Clinical Research Scholar Frances Payne Bolton School of Nursing Case Western Reserve University Cleveland, Ohio

  6. Faculty Disclosures

  7. Faculty Disclosures

  8. Opinions and Off-Label Discussions The opinions or views expressed in this educational program are those of the participants and do not necessarily reflect the opinions or recommendations of Gilead Sciences Medical Affairs, Rush University Medical Center, the Association of Nurses in AIDS Care, or the University of Florida College of Pharmacy The faculty may have included discussion on unlabeled uses of a commercial product or an investigational use of a product not yet approved for this purpose Please consult the full prescribing information before using any medication mentioned in this program

  9. New Electronic Evaluation Process • Please clearly print your information on the Sign-in Sheet • You will receive an electronic evaluation to the email address provided within 1 business day • Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed • Completion Is Required for CME/CNE/CPE credit and future attendance • Incomplete evaluations will preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area

  10. Learning Objectives(CME/CNE and CPE) • Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine and/or advance practice nursing: • Appropriately select antiretroviral therapy for my HIV-infected patients according to the guideline recommendations by the Department of Health and Human Services • Counsel my HIV-infected patients on the benefits and risks associated with antiretroviral therapy • Counsel my HIV-infected patients on new potential drug targets against HIV infection • Counsel my HIV-infected patients how HIV agents in late-stage clinical development may impact future management of HIV-infected patients • Upon completion of this activity, the pharmacist should be able to: • Recommend antiretroviral therapy for my HIV-infected patients according to the guideline recommendations by the Department of Health and Human Services • Counsel my HIV-infected patients on the benefits and risks associated with antiretroviral therapy • Counsel my HIV-infected patients on new potential drug targets against HIV infection • Counsel my HIV-infected patients how HIV agents in late-stage clinical development may impact future management of HIV-infected patients CPE CME/CNE

  11. Program Overview • Treatment challenges/clinical needs • New antiviral drugs/formulations

  12. Worldwide Treatment andPrevention Gaps (2011) • On ART: 8 million • Number needing ART: 15 million • New infections: 2 million • People were waiting to become treatment-eligible, sicken, or die: ~24 million • Estimated coverage of ART in low- and middle-income countries: 36% Granich R, et al. Curr Opin HIV AIDS. 2013;8:41-49.

  13. Chronic HIV in the US:Underdiagnosed and Undertreated 1,106,400- 1,200,000 ~80% Diagnosed 874,056- 960,000 Number (in ‘000s) ~40% Treated ~20% of All HIV-Infected Are HIV RNA <50 copies/mL 437,028- 489,600 209,773- 376,992 Treated Diagnosed Viral Suppression Prevalence Smith MK, et al. PLoS One. 2012;9:e1001260. Gardner EM, et al. Clin Infect Dis. 2011;52:793-800. Burns DN, et al. Clin Infect Dis. 2010;51:725-731.

  14. No Single, Stand-Alone HIV Prevention Intervention Will Halt the HIV Pandemic • Over the past 30 years, existing prevention strategies have had limited to no success • Education about risks • Behavioral interventions to decrease risk • Harm reduction • Vaccines

  15. The Shift Towards EarlierInitiation of Antiretroviral Therapy • Newer ART regimens • Generally better tolerated, more convenient, and more potent than older regimens • Survival benefit • Randomized controlled trials • Observational cohort data • Untreated HIV • Maybe associated the development of non-AIDS-defining illness • Biologic rationale • Effective ART reduces HIV transmission

  16. Simultaneous Use of Different Classes of Prevention Strategies Biomedical Interventions Structural Interventions HIV Testing, Linkage to Care, Expanded ART Coverage Combination HIV Prevention Individual and Small Group Behavioral Interventions Community Interventions

  17. FDA Approves First Drug for Reducing the Risk of Sexually Acquired HIV Infection (July 16, 2012) • Emtricitabine/tenofovir DF • Indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection in adults at high risk • Other prevention methods (eg, safe sex practices, risk reduction counseling, and regular HIV testing) • Revised PrEP Boxed Warning • Use in those who are confirmed HIV-negative prior to prescribing the drug and at least every 3 months during use • Contraindicated in those with unknown or positive HIV status • Gilead Sciences conditions of PrEP approval • Collect viral isolates from individuals who acquire HIV while taking emtricitabine/tenofovir DF and to evaluate these isolates for the presence of resistance • Collect pregnancy outcomes data for women who become pregnant while taking emtricitabine/tenofovir DF for PrEP • Conduct a trial to evaluate drug adherence and its relationship to adverse events, risk of seroconversion, and resistance development in seroconverters Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312210.htm.

  18. CDC Interim Guidance: PrEP in Heterosexually Active Adults and MSM • Interim guidance as part of a comprehensive set of HIV prevention services • PrEP has the potential to contribute to effective and safe HIV prevention for if it is: • Targeted to those at high risk for HIV acquisition • Delivered as part of a comprehensive set of prevention services • Risk reduction and PrEP adherence counseling • Ready access to condoms • Diagnosis and treatment of STIs • Accompanied by monitoring HIV status, side effects, adherence, and risk behavior CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68. CDC. MMWR Morb Mortal Wkly Rep. 2012;61:586-589.

  19. PrEP Trial Results • Proof of efficacy study of topical tenofovir gel in women • CAPRISA 004 • First oral PrEP study of emtricitabine/tenofovir DF for MSM • iPrEx • Proof of efficacy studies in young, heterosexual adults in Africa • Partners PrEP • TDF2 (CDC4940) • Early termination due to futility of PrEP in women • FEM-PrEP • VOICE (oral tenofovir DF and topical tenofovir arms only)

  20. CDC Interim Guidance for HealthcareProviders: Beginning PrEP Medication Regimen • Prescribe emtricitabine/tenofovir DF (200/300 mg) • 1 tablet daily • In general, prescribe no more than a 90-day supply • Renew only after confirming patient remains HIV uninfected • If HBV infected • Consider emtricitabine/tenofovir DF for HBV and HIV prevention • Provide risk-reduction and PrEP medication adherence counseling and condoms CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68. CDC. MMWR Morb Mortal Wkly Rep. 2012;61:586-589.

  21. CDC Interim Guidance for HealthcareProviders: Follow-Up While on PrEP • Evaluate and support PrEP medication adherence at each follow-up visit (more often if needed) • For women, conduct pregnancy test • Every 2 to 3 months • HIV antibody test (document negative result) • Assess • Risk behaviors and provide risk-reduction counseling and condoms • STI symptoms (if present, test and treat as needed) • Every 6 months • Test for STI regardless of symptomatology (treat as needed) • Every 3 months after initiation, then yearly while on PrEP • Blood urea nitrogen • Serum creatinine CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68. CDC. MMWR Morb Mortal Wkly Rep. 2012;61:586-589.

  22. CDC Interim Guidance for HealthcareProviders: Discontinuing PrEP • Perform HIV test(s) to confirm HIV status • If positive • Order and document results of resistance testing • Establish linkage to care • For pregnant women, inform prenatal-care provider and coordinate care to maintain HIV prevention during pregnancy and breastfeeding • If negative • Establish linkage to risk-reduction support services as indicated • If active HBV infection at initiation of PrEP • Consider appropriate medication for continued treatment of HBV infection CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68. CDC. MMWR Morb Mortal Wkly Rep. 2012;61:586-589.

  23. Program Overview • Treatment challenges/clinical needs • New antiviral drugs/formulations

  24. DHHS Guidelines:When To Start Perspectives • Untreated HIV infection may have detrimental effects at all stages of infection • Effects of immune deficiency, direct effects of HIV on specific end organs, and the indirect effects of HIV-associated inflammation on these organs • Earlier treatment may prevent the damage associated with HIV replication during early stages of infection • Sustaining viral suppression and maintaining higher CD4 count via ART delays or prevents some non-AIDS-defining complications and disorders • Success of ART hinges on avoiding treatment interruptions DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013.

  25. When to Start Treatment The IAS-USA guidelines also recommends initiating antiretroviral therapy in HIV-infected patients with active hepatitis C virus infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection. DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013; Thompson MA, et al. JAMA. 2012;308:387-402.

  26. DHHS Guidelines: Preferred Regimens INSTI: Integrase strand transfer inhibitors. 1Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2Lamivudine may substitute for emtricitabine or visa versa. 3Tenofovir DF should be used with caution in patients with renal insufficiency. 4Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day. DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013.

  27. DHHS Guidelines: Alternative Regimens 1Abacavir should not be used in patients who test positive for HLA-B*5701. Use abacavir with caution in patients with high risk of cardiovascular disease or pretreatment HIV RNA >100,000 copies/mL. 2Lamivudine may substitute for emtricitabine or visa versa. 3Use rilpivirine with caution in patients with pretreatment HIV RNA >100,000 copies/mL. 4Once-daily lopinavir/r is not recommended in pregnant women. 5Patients with creatinine clearance >70 mL/min. DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013.

  28. No One Right Option for Everyone:Limitations of Current First-Line Regimens • Efavirenz-based regimens • Not recommended for women at risk of becoming pregnant • CNS toxicity • Rash • Low barrier to resistance • Raltegravir-based regimens • Twice-daily administration • Relatively low barrier to resistance • Lack of second-line integrase inhibitor option • Ritonavir-boosted PI-based regimens • Higher pill count • Gastrointestinal toxicity

  29. Simplified and Convenient ART:Achieving Goals of Therapy • Treatment goals • Reduce HIV-associated morbidity and prolong the duration and quality of survival • Restore and preserve immunologic function • Maximally and durably suppress plasma HIV viral load • Prevent HIV transmission • Individualize strategies to achieve goals • Tailor regimens to enhance adherence • Pretreatment genotypic resistance testing • Maximize conditions to promote ART adherence DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013.

  30. Potential Therapeutic Targets CCR5 Inhibitors Fusion Inhibitors Cytoplasm Reverse Transcriptase Inhibitors Protease Inhibitors Integrase Inhibitors Nucleus

  31. Program Overview • Treatment challenges/clinical needs • New antiviral drugs/formulations

  32. Study 102: QUAD Versus Efavirenz/Emtricitabine/Tenofovir DF Single-Tablet, Once-Daily Regimens Phase 3 study (192 weeks) Treatment-naïve Double-blind HIV RNA >5000 copies/mL Any CD4 count Non-inferiority (12% margin) Elvitegravir 150 mg/Cobicistat 150 mg/ Emtricitabine/Tenofovir DF (n=348) Randomization 1:1 Efavirenz 600 mg/ Emtricitabine/Tenofovir DF (n=352) Primary Endpoint Week 48 HIV RNA <50 Copies/mL Sax PE, et al. Lancet. 2012;379:2439-2448. Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.

  33. Study 102:Baseline Demographics Sax PE, et al. Lancet. 2012;379:2439-2448. Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.

  34. Study 102:Virologic and Immunologic Outcomes CD4 Cell Gain HIV RNA <50 Copies/mL EVG/COBI/FTC/TDF EFV/FTC/TDF EVG/COBI/FTC/TDF EFV/FTC/TDF Difference (%): 3.6 (-1.6, 8.8) 295 Difference (%): 2.7 (-2.9, 8.3) 273 88% 84% 84% 82% 239* 206 Patients (%) CD4 Gain (cells/mm3) 96 (n=307/302) 96 (n=348/352) 48 (n=325/315) 48 (n=348/352) Week Week *P=0.009. Sax PE, et al. Lancet. 2012;379:2439-2448. Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.

  35. Study 102: Virologic Outcomesby Baseline HIV RNA Baseline HIV RNA >100K Copies/mL Baseline HIV RNA <100K Copies/mL EVG/COBI/FTC/TDF EFV/FTC/TDF EVG/COBI/FTC/TDF EFV/FTC/TDF 90% 86% 85% 84% 83% 82% 81% 81% Patients (%) Patients (%) 96 (n=230/236) 96 (n=230/236) 48 (n=348/352) 48 (n=348/352) Week Week Sax PE, et al. Lancet. 2012;379:2439-2448. Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.

  36. Study 102 (Week 96):NNRTI, Integrase, and NRTI Resistance Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.

  37. Study 102 (Week 96):Safety and Tolerability Week 96 Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4):18219. Abstract O424a.

  38. Study 103: QUAD VersusAtazanavir/r + Emtricitabine/Tenofovir DF Once-Daily Regimens Phase 3 study (192 weeks) Treatment-naïve Double-blind HIV RNA >5000 copies/mL Any CD4 count Non-inferiority (12% margin) Elvitegravir/Cobicistat/ Emtricitabine/Tenofovir DF (n=353) Randomization 1:1 Atazanavir/r + Emtricitabine/Tenofovir DF (n=355) Primary Endpoint Week 48 HIV RNA <50 Copies/mL DeJesus E, et al. Lancet. 2012;379:2429-2438. Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.

  39. Study 103:Baseline Demographics DeJesus E, et al. Lancet. 2012;379:2429-2438. Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.

  40. Study 103:Virologic and Immunologic Outcomes CD4 Cell Gain HIV RNA <50 Copies/mL EVG/COBI/FTC/TDF ATV/r + FTC/TDF EVG/COBI/FTC/TDF ATV/r + FTC/TDF Difference (%): 2.7 (-2.1, 7.5) Difference (%): 1.1 (-4.5, 6.7) 90% 261 87% 256 83% 82% 211 207 Patients (%) CD4 Gain (cells/mm3) 96 (n=316/315) 96 (n=353/355) 48 (n=334/321) 48 (n=353/355) Week Week DeJesus E, et al. Lancet. 2012;379:2429-2438. Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.

  41. Study 103: Virologic Outcomesby Baseline HIV RNA Baseline HIV RNA >100K Copies/mL Baseline HIV RNA <100K Copies/mL EVG/COBI/FTC/TDF ATV/r + FTC/TDF EVG/COBI/FTC/TDF ATV/r + FTC/TDF 93% 90% 85% 84% 84% 82% 82% 80% Patients (%) Patients (%) 96 (n=150/141) 96 (n=203/214) 48 (n=150/141) 48 (n=203/214) Week Week DeJesus E, et al. Lancet. 2012;379:2429-2438. Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.

  42. Study 103 (Week 96):Resistance Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.

  43. Study 103 (Week 96):Safety and Tolerability Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4):18220. Abstract O424b.

  44. Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF:Dosing and Safety Considerations • Meal restrictions • Take with meal • Adverse events • Diarrhea, nausea • Comparable with ATV/r, usually mild and rarely leads to drug discontinuation • Early decrease in estimated GFR from cobicistat • Generally benign if <0.4 mg/dL increase in creatinine • Drug-drug interactions: may be similar to ritonavir-boosted PI, do not use with other PIs • Elvitegravir and raltegravir share similar resistance pathways (cross resistant) DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 12, 2013. Johnson VA, et al. Top Antivir Med. 2011;19:156-164.

  45. ECHO and THRIVE Studies:Study Design (96 Weeks) Phase 3 Studies Treatment-naïve, HIV RNA >5000 copies/mL, no NNRTI resistance-associated mutations Rilpivirine 25 mg qd + Emtricitabine/Tenofovir DF qd Randomization 1:1 ECHO (n=690) Efavirenz 600 mg qd + Emtricitabine/Tenofovir DF qd Rilpivirine 25 mg qd + 2 NRTIs* Randomization 1:1 THRIVE (n=678) Efavirenz 600 mg qd + 2 NRTIs Primary endpoint: non-inferiority at week 48 (lower confidence interval <12%). *Investigator’s choice: emtricitabine/tenofovir DF, zidovudine/lamivudine, abacavir/lamivudine. Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print]. Molina J-M, et al. Lancet. 2011;378:238-246. Cohen CJ, et al. Lancet. 2011;378:229-237.

  46. ECHO and THRIVE Studies:Baseline Demographics ECHO THRIVE Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print]. Molina J-M, et al. Lancet. 2011;378:238-246. Cohen CJ, et al. Lancet. 2011;378:229-237.

  47. ECHO and THRIVE Studies:HIV RNA <50 Copies/mL(ITT-TLOVR) Rilpivirine Efavirenz 86% 83% 83% 82% 78% 78% Patients (%) CD4 +189 cells/µL CD4 +171 cells/µL CD4 +196 cells/µL CD4 +182 cells/µL CD4 +228 cells/µL CD4 +219 cells/µL ECHO (n=346/344) THRIVE (n=340/338) Pooled Data (n=686/682) Week 48 Week 96 Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print]. Molina J-M, et al. Lancet. 2011;378:238-246. Cohen CJ, et al. Lancet. 2011;378:229-237.

  48. Rilpivirine Efavirenz Rilpivirine Efavirenz Pooled ECHO/THRIVE Post-Hoc Analysis:HIV RNA <50 Copies/mL (Week 96) By Baseline HIV RNA (copies/mL) By Baseline CD4 (cells/mm3) 85% 84% 81% 80% 79% 79% 75% 75% 71% 70% 69% 56% HIV RNA <50 Copies/mL (%) HIV RNA <50 Copies/mL (%) <50 (n=34/36) 50-<200 (n=194/175) 200-<350 (n=313/307) >350 (n=144/164) <100K (n=368/329) >100K (n=318/353) All patients received emtricitabine/tenofovir DF. Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].

  49. Pooled ECHO/THRIVE (Week 96):Discontinuations and Virologic Failure Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].

  50. Pooled ECHO/THRIVE (Week 96):Safety *P<0.0001 and †P=0.0039 versus rilpivirine. Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].

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