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HIV Treatment and Clinical Trials

HIV Treatment and Clinical Trials. Eric S. Daar, MD Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA. Overview. Pathogenesis Testing Treatment When to start What to start When to switch Treatment as prevention

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HIV Treatment and Clinical Trials

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  1. HIV Treatment and Clinical Trials Eric S. Daar, MDChief, Division of HIV MedicineHarbor-UCLA Medical Center Professor of MedicineDavid Geffen School of Medicine at UCLA

  2. Overview • Pathogenesis • Testing • Treatment • When to start • What to start • When to switch • Treatment as prevention • Future

  3. Viral Dynamics Productively Infected CD4+ Lymphocytes Infected Resting Memory CD4+ Lymphocytes Activated Uninfected CD4+ Lymphocytes Antiretroviral Therapy Long-lived Cells Activated Uninfected CD4+ Lymphocytes Perelson A, et al. 1995

  4. Viral Dynamics Productively Infected CD4+ Lymphocytes Infected Resting Memory CD4+ Lymphocytes >95% T1/2~1 day Activated Uninfected CD4+ Lymphocytes Log10 RNA T1/2~20 min. Weeks Antiretroviral Therapy Activated Uninfected CD4+ Lymphocytes Long-lived Cells

  5. Viral Dynamics Productively Infected CD4+ Lymphocytes Infected Resting Memory CD4+ Lymphocytes >95% T1/2~1 day T1/2~20 min. Activated Uninfected CD4+ Lymphocytes <5% T1/2~2-4 weeks Antiretroviral Therapy Log10 RNA Activated Uninfected CD4+ Lymphocytes Long-lived Cells Weeks

  6. Viral Dynamics Productively Infected CD4+ Lymphocytes Infected Resting Memory CD4+ Lymphocytes T1/2~6 months-years >95% <1% Log10 RNA T1/2~1 day Weeks --- Year T1/2~20 min. Activated Uninfected CD4+ Lymphocytes <5% T1/2~2-4 weeks Antiretroviral Therapy Activated Uninfected CD4+ Lymphocytes Long-lived Cells

  7. Lessons From Pathogenesis • High levels viral replication makes mutations (resistance) inevitable if detectable viremia • Persistent cellular reservoirs of infection established early in course of infection • Source of archived virus throughout course of disease • Viral rebound likely regardless of duration of viral suppression with current therapeutic options

  8. 0 -0.5 -1 -1.5 -2 -2.5 -3 Antiretroviral Activity:An Historical Perspective 1987: AZT Monotherapy 1994: Two-Drug Therapy 1997: HAART 0 0 -0.5 -0.5 -1 -1 -1.5 -1.5 HIV RNA change (log10 c/mL) -2 -2 -2.5 -2.5 -3 -3 24-week response 24-week response 24-week response Fischl, NEJM, 1987 Katzenstein, NEJM, 1996 Eron, NEJM, 1995;Hammer, NEJM, 1996 Gulick, NEJM, 1997; Cameron, Lancet, 1998

  9. Life Expectancy of HIV-Infected Patients • Life expectancy of Athena cohort to general population (n=4,174) • Expected life years remaining at age 25 • 53.1 (44.9-59.5) for general population • 52.7 for asymptomatic HIV+ patients Years of Life Remaining Age at time of death Years lived Remaining Life Years Age at 24 weeks (years) General Population Asymptomatic HIV+ Patients van Sighem A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 526.

  10. Awareness of Serostatus Among People with HIV and Estimates of Transmission ~25% Unaware of Infection ~54% New Infections Accounting for: ~75% Aware of Infection ~46% New Infections People Living with HIV New Sexual Infections Marks, et al, AIDS 2006;20:1447-50

  11. Revised CDC Recommendations for HIV Testing in Healthcare Settings • Routine voluntary testing for patients ages 13 to 64 years in healthcare settings • Not based on patient risk • Opt-out testing • No separate consent for HIV • Pretest counseling not required • Repeat HIV testing left to discretion of provider • Based on patient risk Branson BM, et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.

  12. Rapid HIV Testing

  13. Rapid Home HIV Testing(Approved July 2012)

  14. Impact of Expanded HIV Testing in Washington, DC • 3.7-fold increase in number of publicly funded HIV tests performed in Washington, DC, from 2004-2008 • 2004: 19,766 • 2008: 72,866 • 17% increase in number of new HIV/AIDS name-based case reports from 2004-2007 • Significant reduction in time to progression to AIDS following HIV diagnosis from 2004-2008 (P < .0001) • Time interval between diagnosis to entry into care significantly improved from 2004-2008 Median CD4+ cell count at time of HIV diagnosis between 2004-2008 P < .05 for trend 400 343 336 296 275 300 216 Median CD4+ cell count 200 100 0 2004 2005 2006 2007 2008 Year of Diagnosis Castel A, et al. CROI 2010. Abstract 34.

  15. HIV Cascade

  16. When to Start?

  17. Why not treat everyone? • Not ready to commit to treatment • Short-term and long-term toxicity • Need for life long therapy • Risk of virologic failure, resistance and cross-resistance • Limited evidence for earlier therapy being associated with better outcomes than delayed therapy

  18. Physical Manifestations of Fat Redistribution Syndromes

  19. Case for Earlier Therapy

  20. CIPRAHT001: Randomized Trial of When to Start ART in Haiti Randomized clinical endpoint study of when to start therapy • Treatment-naive • No hx AIDS-defining illness • CD4 200-350 Early Treatment (Immediate ZDV/3TC + EFV) Primary endpoint: Survival Standard Treatment(Delay until CD4+ <200 or AIDS Severe P, et al. NEJM 2010 363:257-265.

  21. CIPRAHT001: Clinical Endpoints May 2009: DSMB review stopped study due to excess deaths in Defer Treatment arm Clinical Endpoints • Infectious causes of death • Early: 1 (gastroenteritis) • Standard: 17 (7 gastroenteritis, 5 TB, 4 pneumonia, 1 cholangitis/sepsis) • More toxicity from ART and intensive need for lab f/u for deferred grp • WHO start guidelines now modified to <350 cells/uL Severe P, et al. NEJM 2010 363:257-265.

  22. NA-ACCORD: Risk of Death with ART Deferral Kitahata M, et al. New Engl J Med 2009;360:1815-26.

  23. Ultimate CD4 Cell Count Depends on Where You Start ATHENA National Cohort2 1000 800 600 400 ≥500 350-500 200 200-350 50-200 <50 0 0 240 144 48 96 192 288 336 Weeks From Starting ART Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

  24. Neurocognitive disorders associated with CD4 nadir 1.1 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 Odds Ratio for Cognitive Impairment by CD4 Nadir Odds Ratio <50 50-199 200-349 ≥350 CD4 Nadir Odds Ratios for NP Impairment Ellis R, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 429.

  25. Continuous antiretroviral therapy throughout follow-up (n = 2752) ART stopped/deferred until CD4+ <250 cells/mm3 then started to increase CD4+ to >350 cells/mm3 (n = 2720) Consequences of stopping ARVs: SMART Trial HIV-1-infected patients with CD4+ cell count > 350 cells/mm3 (N = 5472) 95.4% treatment experienced El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.

  26. ► Favors DC SMART: Primary endpoint and components #Pts w/ Events Relative Risk (95% CI) Endpoints Progression of Disease or Death 164 2.5 1.9 Death 84 6.1 Serious HIV Events 21 > 1.5 Severe Complications* 114 *CVD, Renal, Hepatic Events (fatal/nonfatal) 0.1 1 10 Favors VS ► El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.

  27. SMART: Changes in D-Dimer and IL-6 Levels Change in Log IL-6 (pg/mL) and HDL (μmol/L) BL to 1 Month2* Change in D-Dimer*, BL to 1 Month ∆ IL-6 P=.0003 for trend 0.4 0.4 ∆ HDL 0.3 0.3 0.3 0.28 P=.0005 for trend 0.2 0.2 0.2 μg/mL 0.1 0.1 ∆ IL-6 (pg/mL) ∆ HDL (μmol/L) 0.11 0 0 0.1 0.04 -0.1 -0.1 0 0 -0.2 -0.2 ≤400 401-10,000 10,000-50,000 >50,000 P<.0001 for trend -0.3 -0.3 Month 1 HIV RNA (c/mL) ≤400 401-10,000 10,000-50,000 >50,000 -0.4 -0.4 • Suggests HIV viremia effect on endothelium, leading to increased tissue factors and initiation of coagulation cascade Month 1 HIV RNA Level (copies/mL) *DC patients on ART at baseline with HIV RNA ≤400 copies/mL 1Kuller L, et al. PLoS 2008;10:1496-1508. 2SMART/INSIGHT: Duprez et al, CROI, 2009.

  28. HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples • Primary efficacy endpoint: virologically linked HIV transmission • Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death • Couples received intensive counseling on risk reduction and use of condoms Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3 (n = 886 couples) HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm3 (N = 1763 couples) Delayed ARTInitiate ART at CD4+ cell count ≤ 250 cells/mm3* (n = 877 couples) *Based on 2 consecutive values ≤ 250 cells/mm3. Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print]

  29. Linked HIV Transmission Events n=27; incidence rate 1.7 per 100 p-y (95% CI 1.1, 2.5) n=1; incidence rate 0.1 per 100 p-y (95% CI 0.0, 0.4) Cohen M, et al. NEJM July 18, 2011.

  30. When to Start Treatment *Unless elite controller (HIV RNA <50 copies/mL) or has stable CD4 cell count and low-level viremia in absence of therapy. 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 March 27, 2012; Thompson MA, et al. JAMA. 2012;308:387-402.

  31. Rationale for Recommending Therapy for Those with >350 CD4 cells/uL • Recent cohort studies (4 for 350-500 cells/uL and 1 for >500 cells/uL) • HIV replication associated with non-AIDS-defining diseases (e.g. cardiovascular, renal, liver, malignancy) • Evidence that ARVs may reduce risk of transmission • ARV more effective, convenient, better tolerated than in the past US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Guidelines.

  32. What to Start

  33. HIV replication cycle and sites of drug activity Protease New HIV particles Capsid proteins and viral RNA CD4 Receptor Viral RNA Fusion Inhibitor T-20 (Enfuvirtide, Fuzeon) Integrase Inhibitor Raltegravir (Isentress) Elvitegravir (as QUAD) CCR5 Antagonist Maraviroc (Celsentri) Reverse Transcription Attachment Translation Uncoating Integration Transcription • NNRTIs • Efavirenz (Sustiva) • Delavirdine (Rescriptor) • Nevirapine (Viramune) • Etravirine (Intelense) • Rilpivirine (Edurant) • Protease Inhibitors • Indinavir (Crixivan) • Ritonavir (Norvir) • Saquinavir (Fortovase) • Nelfinavir (Viracept) • Lopinavir/ritonavir (Kaletra) • Atazanavir (Reyataz) • Fos Amprenavir (Lexiva) • Tipranavir (Aptivus) • Darunavir (Prezista) • NRTIs • AZT (Zidovudine-Retrovir) • ddI (Didanosine-Videx) • ddC (Zalcitabine-Hivid) • d4T (Stavudine-Zerit) • 3TC (Lamivudine-Epivir) • ABC(Abacavir-Ziagen) • FTC (Emtricitabine, Emtriva) • nRTI • Tenofovir DF • (Viread) Cellular DNA Nucleus HIV Virions Reverse Transcriptase Integrase Unintegrated double stranded Viral DNA gag-pol polyprotein Integrated viral DNA Viral mRNA 6 5 1 3 4 2 Assembly and Release

  34. Factors to consider in choosing first-line therapy • Patients willingness to commit to therapy • Baseline resistance • Comorbid conditions • Efficacy data • Tolerability • Convenience • Consequences of failure (resistance) • Since the introduction of potent ARV therapy preferred regimens all include NRTIs + third drug

  35. Nucleoside Reverse Transcriptase Inhibitors

  36. HIV RNA <400 c/mL (n=456) 100 80 71% 58% 60 p=0.004 (95% CI: 4.2%, 21.6%) Responders (%) 40 TDF/FTC* ZDV/3TC 20 0 0 8 16 32 48 72 96 120 144 Weeks GS 934: Efficacy of ZDV/3TC vs. TDF/FTC with Efavirenz (ITT) *Fixed dose FTC/TDF used from Wks 96-144 Arribas JR, et al.4th IAS, Sydney 2007, #WEPEB029

  37. A5202: Study Design Arm TDF/FTC QD TDF/FTC QD EFV EFV HIV-1 RNA ≥1000 c/mL Any CD4+ count > 16 years of age A QD QD ABC/3TC Placebo QD ABC/3TCQD ABC/3TC QD EFV EFV B QD QD TDF/FTC Placebo QD TDF/FTC Placebo QD ART ART - - naïve naïve 1857 enrolled N=1858 Randomized 1:1:1:1 Randomized 1:1:1:1 TDF/FTCQD TDF/FTC QD ATV/r ATV/r C QD QD Stratified by screening HIV-1 RNA(< or ≥ 100,000 c/mL) Enrolled 2005-2007 Followed through Sept 2009, 96 wks after last pt enrolled ABC/3TC Placebo QD ABC/3TC Placebo QD ABC/3TC QD ABC/3TCQD ATV/r ATV/r D QD QD TDF/FTC Placebo QD TDF/FTC Placebo QD

  38. A5202: Time to Virologic Failure in Patients with HIV RNA >100,000 c/mL Probability of No Virologic Failure TDF-FTC (26 events) ABC-3TC (57 events) P<0.001, log-rank testHazard ratio, 2.33 (95% CI, 1.46-3.72) Sax PE, et al. NEJM 2009;361:2230-2240.

  39. ABC/3TC vs. TDF/FTCTime to Virologic Failure(End of Study: Low Viral Load Stratum) Sax P, et al. JID 2011

  40. Third Drug to Combine with NRTIs

  41. Boosted-Protease Inhibitors KLEAN1 (ITT-E, TLOVR) 48 weeks CASTLE3 (ITT, NC=F) 96 weeks ARTEMIS2 (ITT, TLOVR) 96 weeks 100 100 100 79 66 80 80 74 80 71 65 68 60 60 60 40 40 40 20 20 20 n=346 n=343 n=443 n=440 n=434 N=444 0 0 0 LPV/r QD or BID DRV/r 800/100 QD LPV/r 400/100 BID ATV/r 300/100 QD LPV/r 400/100 BID FPV/r 700/100 BID Adapted from: 1. Eron J, et al. Lancet 2006; 368:476-482; 2. Mills A, et al. AIDS May 29, 2009 3. Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d

  42. ATV/r vs. EFVPrimary Endpoint Daar ES, et al. Ann Intern Med 2011

  43. A5202: Overall ITT Percent of Failures with Emergence of Major Resistance Mutations* ABC/3TC TDF/FTC p=0.0003 p=0.046 p-values: ATV/r vs. EFV (amongst failures) p<0.0001 p<0.0001 ANY MA J OR ANY MA J OR ANY MA J OR ANY MA J OR Percent N N R T I N N R T I N N R T I N N R T I N R T I N R T I N R T I N R T I P I P I P I P I ATV/r EFV ATV/r EFV Viral failures No baseline resistance N= 76 63 54 48 Daar ES, et al. AIM 2011 *Major mutations defined by IAS-USA (2008) list plus T69D, L74I, G190C/E/Q/T/V for RT and L24I, F53L, I54V/A/T/S and G73C/S/T/A for PR

  44. STARTMRK: RAL vs. EFV ITT, NC=F 86 81 76 75 71 100 82 79 80 69 67 61 60 Twice per day vs. Once per day BUT Less side effects Percentage of Patients withHIV RNA Levels <50 Copies/mL 40 20 CD4 Change: RAL +374 vs. EFV +312 0 0 12 24 48 72 96 120 144 168 192 216 240 Weeks Number of Contributing Patients Raltegravir 400 mg BID 281 278 279 280 281 281 277 280 281 281 277 279 Efavirenz 600 mg QHS 282 282 282 281 282 282 281 281 282 282 282 279 Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. LBPE19.

  45. Pooled ECHO and THRIVE: Virologic Response (ITT-TLOVR) 84.3% 82.3% Rimsky L, et al. 50th ICAAC 2010, Boston, MA. Abst. H-1810

  46. Pooled ECHO and THRIVE: Virologic Response (ITT-TLOVR) Rimsky L, et al. 50th ICAAC 2010, Boston, MA. Abst. H-1810

  47. THRIVE (TMC278-C215) 2 RPV 25 mg QD + 2 NRTIs* (n=340) N=678 patients 1:1 EFV 600 mg QD + 2 NRTIs* (n=338) ECHO and THRIVE: Rilpivirine ECHO (TMC278-C209)1 RPV 25 mg QD + TDF/FTC (n=346) N=690 patients 1:1 EFV 600 mg QD + TDF/FTC (n=344) * Investigator’s choice: TDF/FTC; AZT/3TC; ABC/3TC Cohen C, et al. 18th IAC; Vienna, July 18-23, 2010. Abst. THLBB206. 1. Molina JM, et al. Lancet 2011; 378:238-46; 2. Cohen CJ, et al. Lancet 2011; 378:229-37,

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