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New and Emerging Therapies for the Clinical Management of HIV Infection Sponsored for CME credit by Rush University Medical Center Supported by an independent.

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Presentation on theme: "New and Emerging Therapies for the Clinical Management of HIV Infection Sponsored for CME credit by Rush University Medical Center Supported by an independent."— Presentation transcript:

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

4 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. The University of Florida College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education (UAN # 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. 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.

5 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 6 Faculty Disclosures CME Course Director: Harold A. Kessler, MD Content Development and Training: Eric S. Daar, MD Grants/research support NoneAbbott, Gilead Sciences, Merck, Pfizer, ViiV ConsultantNoneBristol-Myers Squibb, Gilead Sciences, Merck, ViiV Speakers’ bureauNone Stock shareholder Abbott Laboratories, GlaxoSmithKline, Merck None Other financial or material support None

7 7 Faculty Disclosures CME Reviewer: David M. Simon, MD, PhD CNE Reviewer: Allison R. Webel, RN, PhD Medical Editor: Peter Pinkowish Grants/research support None ConsultantNone Speakers’ bureau None Stock shareholder None Other financial or material support None

8 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 9 New Electronic Evaluation Process ●Please clearly print your information on the Sign-in Sheet ●You will receive an electronic evaluation to the address provided within 1 business day ●Reminder 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 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 CME/CNE ●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

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

12 12 Worldwide Treatment and Prevention 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 13 Chronic HIV in the US: Underdiagnosed and Undertreated Number (in ‘000s) Prevalence Diagnosed Treated 1,106,400- 1,200, , , , ,600 ~80% Diagnosed ~40% Treated Smith MK, et al. PLoS One. 2012;9:e Gardner EM, et al. Clin Infect Dis. 2011;52: Burns DN, et al. Clin Infect Dis. 2010;51: ~20% of All HIV-Infected Are HIV RNA <50 copies/mL 209, ,992 Viral Suppression

14 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 15 The Shift Towards Earlier Initiation 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 16 Simultaneous Use of Different Classes of Prevention Strategies Biomedical Interventions Structural Interventions Community Interventions Individual and Small Group Behavioral Interventions HIV Testing, Linkage to Care, Expanded ART Coverage Combination HIV Prevention

17 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:

18 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: CDC. MMWR Morb Mortal Wkly Rep. 2012;61:

19 19 ●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) PrEP Trial Results

20 20 CDC Interim Guidance for Healthcare Providers: 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: CDC. MMWR Morb Mortal Wkly Rep. 2012;61:

21 21 CDC Interim Guidance for Healthcare Providers: 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: CDC. MMWR Morb Mortal Wkly Rep. 2012;61:

22 22 CDC Interim Guidance for Healthcare Providers: 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: CDC. MMWR Morb Mortal Wkly Rep. 2012;61:

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

24 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: Revision February 12, 2013.

25 25 When to Start Treatment Clinical Category CD4 Count (cells/mm 3 ) HIV RNA (copies/mL) 2/2013 DHHS Guidelines 2012 IAS-USA Guidelines AIDS-defining illness or severe symptoms Any value Treat Asymptomatic<500Any valueTreat >500Any valueTreat Pregnant womenAny value Treat HIV-associated nephropathyAny value Treat HIV/HBV coinfection when HBV treatment is indicated Any value Treat DHHS. Available at: Revision February 12, 2013; Thompson MA, et al. JAMA. 2012;308: 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.

26 26 DHHS Guidelines: Preferred Regimens NNRTIEfavirenz 1 /emtricitabine 2 /tenofovir DF 3 PIAtazanavir 4 + ritonavir + emtricitabine 2 /tenofovir DF 3 Darunavir + ritonavir (qd) + emtricitabine 2 /tenofovir DF 3 INSTIRaltegravir + emtricitabine 2 /tenofovir DF 3 Pregnant women Lopinavir/r bid + zidovudine/lamivudine 2 INSTI: Integrase strand transfer inhibitors. 1 Efavirenz should not be used during the first trimester of pregnancy or in women trying to conceive or not using effective and consistent contraception. 2 Lamivudine may substitute for emtricitabine or visa versa. 3 Tenofovir DF should be used with caution in patients with renal insufficiency. 4 Atazanavir + RTV should not be used in patients who require >20 mg omeprazole equivalent/day. DHHS. Available at: Revision February 12, 2013.

27 27 DHHS Guidelines: Alternative Regimens NNRTIEfavirenz + (abacavir 1 or zidovudine)/lamivudine 2 Rilpivirine 3 /emtricitabine 2 /tenofovir DF Rilpivirine 3 + abacavir/lamivudine 2 PIAtazanavir + ritonavir + abacavir/lamivudine 2 Darunavir + ritonavir + abacavir/lamivudine 2 Fosamprenavir + ritonavir (qd or bid) + abacavir/lamivudine 2 or emtricitabine 2 /tenofovir DF Lopinavir/r 4 (qd or bid) + abacavir/lamivudine 2 or emtricitabine 2 /tenofovir DF INSTIRaltegravir + abacavir/lamivudine 2 Elvitegravir/cobicistat/emtricitabine/tenofovir DF 5 1 Abacavir 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. 2 Lamivudine may substitute for emtricitabine or visa versa. 3 Use rilpivirine with caution in patients with pretreatment HIV RNA >100,000 copies/mL. 4 Once-daily lopinavir/r is not recommended in pregnant women. 5 Patients with creatinine clearance >70 mL/min. DHHS. Available at: Revision February 12, 2013.

28 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 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: Revision February 12, 2013.

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

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

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

33 33 Study 102: Baseline Demographics EVG/COBI/FTC/TDF (n=348) EFV/FTC/TDF (n=352) Males (%)8890 Mean age (years)38 Race (%) White Black HIV RNA Median (log 10 copies/mL) >100K copies/mL (%) Median CD4 (cells/mm 3 ) <200 cells/mm 3 (%) 200 to 350 cells/mm 3 (%) 351 to 500 cells/mm 3 (%) >500 cells/mm 3 (%) Sax PE, et al. Lancet. 2012;379: Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424a.

34 34 Study 102: Virologic and Immunologic Outcomes Patients (%) HIV RNA <50 Copies/mL CD4 Cell Gain 88% 48 (n=348/352) 96 (n=348/352) 84% CD4 Gain (cells/mm 3 ) 239* 295 *P= Difference (%): 3.6 (-1.6, 8.8) 84% 82% Difference (%): 2.7 (-2.9, 8.3) EVG/COBI/FTC/TDF EFV/FTC/TDF Week EVG/COBI/FTC/TDF EFV/FTC/TDF Sax PE, et al. Lancet. 2012;379: Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424a. 48 (n=325/315) 96 (n=307/302) Week

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

36 36 Study 102 (Week 96): NNRTI, Integrase, and NRTI Resistance EVG/COBI/FTC/TDF (n=348) EFV/FTC/TDF (n=352) Number of patients analyzed for resistance With resistance to ART regimen Any primary integrase resistance (number of patients) E92Q T66I Q148R N155H Any primary NNRTI resistance (number of patients) K103N K101E/K Y188Y/F/H/L G190A/S Any primary NRTI resistance (number of patients) M184V/I K65R Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424a.

37 37 Study 102 (Week 96): Safety and Tolerability EVG/COBI/FTC/TDF (n=348) EFV/FTC/TDF (n=352) Treatment-emergent adverse events (%) Nausea Abnormal dreams Insomnia Dizziness Rash Grade 3/4 creatine kinase abnormality (%)714 Median change in eGFR (mL/min) (C-G) Mean change in lipids (mg/dL) Total cholesterol LDL-C HDL-C Triglycerides Week 96 Zolopa A, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424a.

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

39 39 Study 103: Baseline Demographics EVG/COBI/FTC/TDF (n=353) ATV/r + FTC/TDF (n=355) Males (%)9289 Mean age (years)38 Race (%) White Black HIV RNA Median (log 10 copies/mL) >100K copies/mL (%) Median CD4 (cells/mm 3 ) <200 cells/mm 3 (%) 200 to 350 cells/mm 3 (%) 351 to 500 cells/mm 3 (%) >500 cells/mm 3 (%) DeJesus E, et al. Lancet. 2012;379: Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424b.

40 40 Study 103: Virologic and Immunologic Outcomes Patients (%) HIV RNA <50 Copies/mL CD4 Cell Gain 90% 48 (n=353/355) 96 (n=353/355) 87% CD4 Gain (cells/mm 3 ) Difference (%): 2.7 (-2.1, 7.5) 83% 82% Difference (%): 1.1 (-4.5, 6.7) EVG/COBI/FTC/TDF ATV/r + FTC/TDF Week 48 (n=334/321) 96 (n=316/315) Week EVG/COBI/FTC/TDF ATV/r + FTC/TDF DeJesus E, et al. Lancet. 2012;379: Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424b.

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

42 42 Study 103 (Week 96): Resistance EVG/COBI/FTC/TDF (n=353) ATV/r + FTC/TDF (n=355) Number of patients Analyzed for resistance With resistance to ART regimen Any primary integrase resistance (number of patients) E92Q T66I Q148R N155H Any primary NRTI resistance (number of patients) M184V/I K65R Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424b.

43 43 Study 103 (Week 96): Safety and Tolerability EVG/COBI/FTC/TDF (n=353) ATV/r + FTC/TDF (n=355) Treatment-emergent adverse events (%) Diarrhea Nausea Upper respiratory infection Headache Fatigue Ocular icterus Grade 3/4 creatine kinase abnormality (%)710 Median change in eGFR (mL/min) (C-G) Mean change in lipids (mg/dL) Total cholesterol LDL-C HDL-C Triglycerides Rockstroh J, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O424b.

44 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: Revision February 12, Johnson VA, et al. Top Antivir Med. 2011;19:

45 45 ECHO and THRIVE Studies: Study Design (96 Weeks) Phase 3 Studies Treatment-naïve, HIV RNA >5000 copies/mL, no NNRTI resistance-associated mutations Randomization 1:1 Efavirenz 600 mg qd + Emtricitabine/Tenofovir DF qd 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: Cohen CJ, et al. Lancet. 2011;378: Rilpivirine 25 mg qd + Emtricitabine/Tenofovir DF qd ECHO (n=690) Randomization 1:1 Efavirenz 600 mg qd + 2 NRTIs Rilpivirine 25 mg qd + 2 NRTIs* THRIVE (n=678)

46 46 ECHO and THRIVE Studies: Baseline Demographics Rilpivirine (n=346) Placebo (n=344) Rilpivirine (n=340) Placebo (n=338) Males (%) Ethnicity (%) White Black HIV RNA Median (log 10 copies/mL) <100K copies/mL (%) >100K copies/mL (%) Median CD4 (cells/mm 3 ) Emtricitabine/tenofovir DF (%) Zidovudine/lamivudine (%) Abacavir/lamivudine (%) ECHO THRIVE Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print]. Molina J-M, et al. Lancet. 2011;378: Cohen CJ, et al. Lancet. 2011;378:

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

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

49 49 Pooled ECHO/THRIVE (Week 96): Discontinuations and Virologic Failure Rilpivirine (n=686) Efavirenz (n=682) HIV RNA <50 copies/mL (%)78 Virologic failure (%) Overall Rebounder Never suppressed Discontinued due to (%) Adverse events Other reasons Death (%) Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print].

50 50 Pooled ECHO/THRIVE (Week 96): Safety Rilpivirine (n=686) Efavirenz (n=682) Most common adverse events of interest (%) Any neurologic Dizziness Any psychiatric Abnormal dreams/nightmares Rash (any type) * 27* 22* 13 † 15* Grade 2-4 laboratory abnormality (%) Total cholesterol LDL-C AST ALT * 18* Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print]. *P< and † P= versus rilpivirine.

51 51 ECHO/THRIVE: Conclusions ●Efficacy - Week 0-48: rilpivirine was non-inferior to efavirenz - Week 48-96: comparable between rilpivirine and efavirenz arms - Better rilpivirine response: baseline HIV RNA 100K copies/mL ●Overall virologic failure rate - Week 0-48: higher in the rilpivirine arm - Weeks 48-96: similar increases in rilpivirine and efavirenz arms ●Resistance with virologic failure - Rilpivirine: 6.4%; efavirenz: 2.3% ●Safety - Lower incidence of adverse events of interest compared with efavirenz - Most adverse events emerge during the first 4 weeks of therapy Cohen M, et al. AIDS. 2012;Dec 3. [Epub ahead of print]. Molina J-M, et al. Lancet. 2011;378: Cohen CJ, et al. Lancet. 2011;378: Rashbaum B, et al. 51 st ICAAC. Chicago, Abstract H Rimsky L, et al. JAIDS. 2012;59:39-46.

52 52 STAR Study: Design (96 Weeks) Randomization 1:1 Efavirenz/Emtricitabine/Tenofovir DF Once Daily Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O425. Emtricitabine/Rilpivirine/Tenofovir DF Once Daily Phase 3b study (96 weeks) Treatment-naïve Open-label HIV RNA >2500 copies/mL Any CD4 count Genotypic sensitivity (EFV, FTC, RPV, TDF) Non-inferiority (12% margin) Single-Tablet, Once-Daily Regimens Primary Endpoint Week 48 HIV RNA <50 Copies/mL

53 53 STAR Study: Baseline Demographics FTC/RPV/TDF (n=394) EFV/FTC/TDF (n=392) Males (%)93 Mean age (years)3735 Race (%) White Black Latino HIV RNA Median (log 10 copies/mL) >100K copies/mL (%) Median CD4 (cells/mm 3 ) Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O425.

54 54 STAR Study (Week 48): Virologic and Immunologic Outcomes Patients (%) HIV RNA <50 Copies/mLCD4 Cell Gain 85.8% FTC/RPV/TDF (n=394) EFV/FTC/TDF (n=392) 81.6% CD4 Gain (cells/mm 3 ) P=0.34 Difference (%): 4.1 (-1.1, 9.2) Non-inferiority criteria met. FTC/RPV/TDF (n=394) EFV/FTC/TDF (n=392) Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O425.

55 55 STAR Study (Week 48): Virologic Outcomes By Baseline HIV RNA Patients (%) HIV RNA <50 Copies/mL)Virologic Failure 89% 80% <100K (n=260/250) FTC/RPV/TDF EFV/FTC/TDF 82% >100K (n=134/142) Cohen C, et al. J Int AIDS Soc. 2012;15(suppl 4): Abstract O425. Baseline HIV RNA Difference (%): 7.2 (1.1, 13.4) Difference (%): -1.8 (-11.1, 7.5) Patients (%) 5% 10% <100K (n=260/250) FTC/RPV/TDF EFV/FTC/TDF 3% 9% > K (n=98/117) Baseline HIV RNA >500K* (n=36/25) 25% 16% *Analysis of the >500K stratum was a post-hoc.

56 56 Emtricitabine/Rilpivirine/Tenofovir DF: Dosing and Safety Considerations ●Meal restrictions - Take with meal ●Drugs that increase gastric pH (eg, proton-pump inhibitors) may decrease plasma concentrations of rilpivirine ●Adverse events (less common with rilpivirine compared with efavirenz) - Rash - Neuropsychiatric symptoms ●Resistance (rilpivirine) - Most common RAM is E138K (leads to cross resistance to etravirine) DHHS. Available at: Revision February 12, Johnson VA, et al. Top Antivir Med. 2011;19:

57 57 Evidence Supports Combination ART for Prevention of HIV Transmission ●Transmission only occurs from persons with HIV ●HIV RNA level is single greatest risk factor for HIV transmission ●Combination ART can lower HIV RNA level to undetectable levels ●Observational evidence in heterosexual couples ●Previous modeling work suggests considerable potential ●Knowing one’s HIV status is key to prevention with combination ART ●When to start combination ART is not known for certainty

58 58 New Electronic Evaluation Process ●Please clearly print your information on the Sign-in Sheet ●You will receive an electronic evaluation to the address provided within 1 business day ●Reminder 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

59 59 Outcomes Measurement Reminder ●We are required to assess “changes in learners’ competence, performance or patient outcomes achieved as a result of their participation in a CME/CNE/CPE sponsored educational activity” ●As a result of this requirement you will receive a short survey via 8 to 12 weeks after completing this course - We consider the survey to be an additional component of your overall participation in this educational activity and would urge you to reflect on what you learned in the activity and then complete this survey


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