HIV Treatment and Clinical Trials 2014 Eric S. Daar, M.D. Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Grants Consultant Disclosures Bristol Myers Squibb, Gilead, Merck, ViiV Abbvie, Bristol Myers Squibb, Gilead, Janssen, Merck, Teva, ViiV Overview • Pathogenesis • Treatment – When to start – What to start – When to switch • Treatment as prevention • Future Viral Dynamics Productively Infected CD4+ Lymphocytes Infected Resting Memory CD4+ Lymphocytes Activated Uninfected CD4+ Lymphocytes Activated Uninfected CD4+ Lymphocytes Perelson A, et al. 1995 Long-lived Cells Viral Dynamics Productively Infected CD4+ Lymphocytes Infected Resting Memory CD4+ Lymphocytes >95% Log10 RNA T1/2~1 day Activated Uninfected CD4+ Lymphocytes Weeks Activated Uninfected CD4+ Lymphocytes T1/2~20 min. Long-lived Cells 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% Log10 RNA T1/2~2-4 weeks Activated Uninfected CD4+ Lymphocytes Long-lived Cells Weeks Viral Dynamics Productively Infected CD4+ Lymphocytes Infected Resting Memory CD4+ Lymphocytes <1% Log10 RNA >95% T1/2~6 monthsyears T1/2~1 day Weeks --- Year T1/2~20 min. Activated Uninfected CD4+ Lymphocytes <5% T1/2~2-4 weeks Activated Uninfected CD4+ Lymphocytes Long-lived Cells 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 Antiretroviral Activity: An Historical Perspective HIV RNA change (log10 c/mL) 1987: AZT Monotherapy 1994: Two-Drug Therapy 1997: HAART 0 0 0 -0.5 -0.5 -0.5 -1 -1 -1 -1.5 -1.5 -1.5 -2 -2 -2 -2.5 -2.5 -2.5 -3 24-week response -3 24-week response Fischl, NEJM, 1987 Katzenstein, NEJM, 1996 Eron, NEJM, 1995; Hammer, NEJM, 1996 -3 24-week response Gulick, NEJM, 1997; Cameron, Lancet, 1998 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 Age at time of death Remaining life years – 52.7 for asymptomatic HIV+ patients General population Asymptomatic HIV+ patients van Sighem A, et al. AIDS 2010; 24:1527-1535 Awareness of Serostatus Among People with HIV and Estimates of Transmission ~25% Unaware of Infection ~54% New Infections Accounting for: ~75% Aware of Infection People Living with HIV Marks, et al, AIDS 2006;20:1447-50 ~46% New Infections New Sexual Infections 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. Rapid HIV Testing HIV Cascade When to Start? 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 crossresistance • Limited evidence for earlier therapy being associated with better outcomes than delayed therapy Physical Manifestations of Fat Redistribution Syndromes Case for earlier therapy 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 Baseline Characteristics Early (n=408) Standard (n=408) 40 40 Male (%) 41% 44% Median CD4+ (cells/mm3) 280 282 Body Mass Index (kg/m2) 21.4 21.0 Median age (years) Severe P, et al. NEJM 2010 363:257-265. CIPRAHT001: Clinical Endpoints May 2009: DSMB review stopped study due to excess deaths in Defer Treatment arm Early Standard Hazards Ratio (p value) Death 6 23 4.0 (.0011 ) Incident Tuberculosis 18 36 2.0 (.0125 ) 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. NA-ACCORD: Risk of Death with ART Deferral 351-500 CD4+ >500 CD4+ RR 95% CI P RR 95% CI P Deferral of ART 1.7 1.3, 2.3 <0.001 1.9 1.4, 2.8 <0.001 Female Sex 1.2 0.9, 1.6 0.24 1.9 1.3, 2.6 <0.001 Older Age (per 10 years) 1.7 1.5, 1.9 <0.001 1.8 1.6, 2.1 <0.001 Baseline CD4 count (per 100 cells/mm3) 1.1 0.7, 1.8 0.59 0.9 0.9, 1.0 0.03 Kitahata M, et al. New Engl J Med 2009;360:1815-26. 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 48 96 144 192 240 Weeks From Starting ART Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192. 288 336 Neurocognitive disorders associated with CD4 nadir Odds Ratio for Cognitive Impairment by CD4 Nadir 1.1 1 Odds Ratio 0.9 0.8 0.7 0.6 0.5 0.4 0.3 <50 50-199 200-349 CD4 Nadir Odds Ratios for NP Impairment Ellis R, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 429. ≥350 Consequences of stopping ARVs: SMART Trial HIV-1-infected patients with CD4+ cell count > 350 cells/mm3 (N = 5472) 95.4% treatment experienced 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) El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296. SMART: Primary endpoint and components Endpoints #Pts w/ Events Relative Risk (95% CI) 2.5 Progression of Disease or Death 164 Death 84 Serious HIV Events 21 1.9 6.1 > 1.5 Severe Complications* 114 *CVD, Renal, Hepatic Events (fatal/nonfatal) ► 0.1 El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296. 1 Favors DC Favors VS ► 10 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 0.3 0.3 ∆ IL-6 (pg/mL) 0.2 0.11 0.04 0 0 ≤400 40110,000 10,00050,000 >50,000 Month 1 HIV RNA (c/mL) • Suggests HIV viremia effect on endothelium, leading to increased tissue factors and initiation of coagulation cascade P=.0003 for trend 0.3 0.2 0.2 0.1 0.1 0 0 -0.1 -0.1 -0.2 -0.2 P<.0001 for trend -0.3 -0.4 ≤400 401-10,000 10,000-50,000 >50,000 Month 1 HIV RNA Level (copies/mL) *DC patients on ART at baseline with HIV RNA ≤400 copies/mL 1Kuller 0.4 L, et al. PLoS 2008;10:1496-1508. 2SMART/INSIGHT: Duprez et al, CROI, 2009. -0.3 -0.4 ∆ HDL (μmol/L) μg/mL P=.0005 for trend 0.1 ∆ IL-6 ∆ HDL 0.4 0.28 HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm3 (N = 1763 couples) Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3 (n = 886 couples) Delayed ART Initiate ART at CD4+ cell count ≤ 250 cells/mm3* (n = 877 couples) *Based on 2 consecutive values ≤ 250 cells/mm3. • 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 Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print] 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. 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-AIDSdefining 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. When to Start Treatment Clinical Category CD4 Count (cells/mm3) DHHS 2013 IAS-USA 2012 EACS 2012 BHIV 2012 WHO 2013 AIDS/Severe Sx Any value R R R R R Asymptomatic ≤350 R R R R R 350 to ≤500 R R C D R >500 R R D D D Pregnant women Any value R R R R R HIV-associated nephropathy Any value R R R R R HIV/HBV Any value R R R R R HIV-neg partner Any value R R C C R DHHS Mar 2013: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf; IAS-USA: Thompson MA, et al. JAMA. 2012; 308: 387-402; EACS Nov 2012. http://www.eacsociety.org/Portals/0/files/pdf%20files/EacsGuidelines-v6.1-2edition.pdf; BHIV 2012: http://www.bhiva.org/TreatmentofHIV1_2012.aspx; WHO June 2013: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf What to start? HIV replication cycle and sites of drug activity NRTIs AZT (Zidovudine-Retrovir) ddI (Didanosine-Videx) ddC (Zalcitabine-Hivid) d4T (Stavudine-Zerit) 3TC (Lamivudine-Epivir) ABC(Abacavir-Ziagen) FTC (Emtricitabine, Emtriva) NNRTIs Efavirenz (Sustiva) Delavirdine (Rescriptor) Nevirapine (Viramune) (XR) Etravirine (Intelense) Rilpivirine (Edurant) nRTI Cellular DNA Tenofovir DF (Viread) Nucleus Protease Inhibitors Indinavir (Crixivan) Ritonavir (Norvir) Saquinavir (Fortovase) Nelfinavir (Viracept) Lopinavir/ritonavir (Kaletra) Atazanavir (Reyataz) Fos Amprenavir (Lexiva) Tipranavir (Aptivus) Darunavir (Prezista) HIV Virions New HIV particles Reverse Integrase Transcriptase Protease Capsid proteins and viral RNA CD4 Receptor Fusion Inhibitor T-20 (Enfuvirtide, Fuzeon) Viral RNA Integrase Inhibitor Raltegravir (Isentress) Elvitegravir /COBI Dolutegravir (Tivicay) CCR5 Antagonist Maraviroc (Celsentri) 1 Attachment Unintegrated double stranded Viral DNA 3 2 Uncoating Integrated viral DNA Reverse Transcription Viral mRNA 4 Integration Transcription gag-pol polyprotein 5 Translation 6 Assembly and Release Factors to consider in choosing firstline therapy • Patients willingness to commit to therapy • Baseline resistance • Efficacy data • Tolerability • Convenience • Comorbid conditions • Consequences of failure (resistance) • Since the introduction of potent ARV therapy preferred regimens all include NRTIs + third drug Which Nucleoside Reverse Transcriptase Inhibitor? A5202: Study Design HIV-1 RNA ≥1000 c/mL Arm A Any CD4+ count > 16 years of age ART-naïve 1857 N=1858 enrolled B Randomized Randomized 1:1:1:1 1:1:1:1 C Stratified by screening HIV-1 RNA TDF/FTC QD ABC/3TC Placebo QD ABC/3TC QD TDF/FTC Placebo QD TDF/FTC QD ABC/3TC Placebo QD EFV QD EFV QD ATV/r QD (< or ≥ 100,000 c/mL) Enrolled 2005-2007 Followed through Sept 2009, 96 wks after last pt enrolled D ABC/3TC QD TDF/FTC Placebo QD ATV/r QD A5202: Time to Virologic Failure in Patients with HIV RNA >100,000 c/mL Probability of No Virologic Failure 100 Probability of No Virologic Failure (%) TDF-FTC (26 events) 80 ABC-3TC (57 events) 60 40 P<0.001, log-rank test Hazard ratio, 2.33 (95% CI, 1.46-3.72) 20 0 0 12 24 36 48 60 72 84 96 108 Weeks since Randomization No. at Risk ABC-3TC 398 363 313 267 222 188 137 87 49 20 TDF-FTC 399 361 321 284 236 204 160 104 65 23 Sax PE, et al. NEJM 2009;361:2230-2240. ABC/3TC vs. TDF/FTC Time to Virologic Failure (End of Study: Low Viral Load Stratum) Sax P, et al. JID 2011 Which third drug to combine with NRTIs? Boosted-Protease Inhibitors KLEAN1 (ITT-E, TLOVR) 48 weeks 100 100 66 80 CASTLE3 (ITT, NC=F) 96 weeks ARTEMIS2 (ITT, TLOVR) 96 weeks 100 79 80 71 65 80 68 60 60 60 40 40 40 20 20 20 n=434 0 n=346 N=444 LPV/r FPV/r 400/100 700/100 BID BID 0 74 n=343 LPV/r DRV/r QD or 800/100 BID QD n=443 0 n=440 LPV/r ATV/r 400/100 300/100 BID QD 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 ATV/r vs. EFV Primary Endpoint Daar ES, et al. Ann Intern Med 2011 A5202: Overall ITT Percent of Failures with Emergence of Major Resistance Mutations* ABC/3TC TDF/FTC p=0.0003 p=0.046 Percent p<0.0001 A N Y M A J O R Viral failures No baseline resistance N= p<0.0001 A N Y N N R T I N R T I P I p-values: ATV/r vs. EFV (amongst failures) M A J O R A N Y A N Y N N R T I N R T I P I M A J O R N N R T I N R T I P I M A J O R N N R T I N R T I ATV/r EFV ATV/r EFV 76 63 54 48 P I mutations defined by IAS-USA (2008) list plus T69D, L74I, G190C/E/Q/T/V for RT and Daar ES, et al. AIM 2011 L24I, F53L, I54V/A/T/S and G73C/S/T/A for PR *Major STARTMRK: RAL vs. EFV ITT, NC=F Percentage of Patients with HIV RNA Levels <50 Copies/mL 100 86 81 76 75 71 80 82 60 79 69 Twice per day vs. Once per 67 day BUT Less side effects 40 20 61 CD4 Change: RAL +374 vs. EFV +312 0 Weeks 0 12 24 48 72 96 120 144 168 192 216 240 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. 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) THRIVE (TMC278-C215) 2 N=678 patients 1:1 RPV 25 mg QD + 2 NRTIs* (n=340) EFV 600 mg QD + 2 NRTIs* (n=338) Baseline parameter Median log10 VL, copies/mL (min–max) Baseline VL >100,000 copies/mL Median CD4 cells/mm3 (min–max) Hepatitis B or C co-infection RPV N=686 EFV N=682 5 (2–7) 5 (3–7) 46% 249 (1–888) 7% 52% 260 (1–1,137) 9% * 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, ECHO and THRIVE Studies: HIV RNA <50 Copies/mL(ITT-TLOVR) Rilpivirine 83% 86% CD4 +196 cells/µL CD4 +182 cells/µL CD4 +189 cells/µL 82% Efavirenz 78% 78% CD4 +228 cells/µL CD4 +219 cells/µL Patients (%) 83% ECHO CD4 +171 cells/µL THRIVE (n=346/344) (n=340/338) Week 48 Cohen M, et al. 6th IAS Conference. Rome, 2011. Abstract TuLBPE032. Molina J-M, et al. Lancet. 2011;378:238-246. Cohen CJ, et al. Lancet. 2011;378:229-237. Pooled Data (n=686/682) Week 96 Pooled ECHO/THRIVE (Week 96): Discontinuations and Virologic Failure Rilpivirine (n=686) Efavirenz (n=682) HIV RNA <50 copies/mL (%) 78 78 Virologic failure (%) Overall Rebounder Never suppressed 12 6 5 6 4 2 Discontinued due to (%) Adverse events Other reasons 4 7 8 8 0.1 1.0 Death (%) Cohen M, et al. 6th IAS Conference. Rome, 2011. Abstract TuLBPE032. 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) 17 8 16 8 4 38* 27* 22* 13† 15* Grade 2-4 laboratory abnormality (%) Total cholesterol LDL-C AST ALT 7 7 6 6 22* 18* 10 11 *P<0.0001 and †P=0.0039 versus rilpivirine. Cohen M, et al. 6th IAS Conference. Rome, 2011. Abstract TuLBPE032. GS102 & GS103: EVG/COBI/TDF/FTC vs. EFV/TDF/FTC or ATV/RTV + TDF/FTC Randomized, Phase III, Double-blind, Double Dummy, Active-controlled, International Studies GS 102 Quad QD ~89% men 33% >105 c/mL CD4= ~385 c/uL EFV/FTC/TDF Placebo QD EFV/FTC/TDF QD Treatment Naïve Quad Placebo QD HIV-1 RNA ≥5,000 c/mL Any CD4 cell count eGFR ≥70 mL/min Quad QD ATV/r +TDF/FTC Placebo QD GS 103 ~90% men ~41% >105 c/mL CD4= ~370 c/uL QUAD Placebo QD ATV/r +TD/FTC QD 48 weeks Sax P, et al, Lancet 2012: 379::2439-48; DeJesus E, et al, Lancet 2012; 379: 2429-38 192 weeks Study 236-102: Primary Endpoint: HIV-1 RNA < 50 copies/mL +3.6%, 95% CI 3.6 (-1.6% to +8.8%) CD4+ change: Quad +239 vs. EFV +206 c/mm3 (p=0.009) No difference by baseline characteristics Sax P, et al, Lancet 2012: 379::2439-48 Study 236-102: Common Adverse Events Quad EFV/FTC/TDF (n=348) (n=352) Treatment Emergent Adverse Events in ≥ 10% of subjects (%) Diarrhea 23% 19% Nausea * 21% 14% Abnormal Dreams ^ 15% 27% Upper Respiratory Infection 14% 11% Headache 14% 9% Fatigue 12% 13% Insomnia * 9% 14% Depression 9% 11% Dizziness ^ 7% 24% Rash # * p<0.05; ^ p<0.001; # p=0.009 Sax P, et al, Lancet 2012: 379::2439-48 6% 12% Study 236-102: Primary Endpoint: HIV-1 RNA < 50 copies/mL +3.6%, 95% CI 3.6 (-1.6% to +8.8%) CD4+ change: Quad +239 vs. EFV +206 c/mm3 (p=0.009) No difference by baseline characteristics Sax P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 101. Study 236-102: Common Adverse Events Quad EFV/FTC/TDF (n=348) (n=352) Treatment Emergent Adverse Events in ≥ 10% of subjects (%) Diarrhea 23% 19% Nausea * 21% 14% Abnormal Dreams ^ 15% 27% Upper Respiratory Infection 14% 11% Headache 14% 9% Fatigue 12% 13% Insomnia * 9% 14% Depression 9% 11% Dizziness ^ 7% 24% Rash # * p<0.05; ^ p<0.001; # p=0.009 Sax P, et al, Lancet 2012: 379::2439-48 6% 12% Dolutegravir vs Currently “Preferred” Regimens in Treatment-Naive Pts • Randomized, noninferiority phase III studies • Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 48 SPRING-2[1] (active controlled) SINGLE[2] (placebo controlled) FLAMINGO[3] (open label) ART-naive pts VL ≥ 1000 c/mL (N = 822) ART-naive pts VL ≥ 1000 c/mL HLA-B*5701-neg CrCL > 50 mL/min (N = 833) ART-naive pts VL ≥ 1000 c/mL (N = 484) DTG 50 mg QD + 2 NRTIs* (n = 411) RAL 400 mg BID + 2 NRTIs* (n = 411) DTG 50 mg QD + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) DTG 50 mg QD + 2 NRTIs* (n = 242) DRV/RTV 800/100 mg QD + 2 NRTIs* (n = 242) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. 1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Walmsley S, et al. ICAAC 2012. Abstract H-556b. 3. Feinberg J, et al. ICAAC 2013. Abstract H1464a. SPRING-2: DTG vs RAL + 2 NRTIs in Naive Patients HIV-1 RNA < 50 copies/mL (%) DTG 50 mg QD (n = 411) 100 Δ2. 5% (-2.2% to 7.1%) 88 85 80 RAL 400 mg BID (n = 411) Δ4.4% (-1.1% to 10.0%) 81 76 • VF at Wk 96[2]: 5% (22/411) in DTG arm and 7% (29/411) in RAL arm 60 • CD4+ cell count increase at Wk 96 similar: 40 20 0 • DTG noninferior to RAL at both Wk 48 primary endpoint[1] and Wk 96[2] Treatment-related study d/c: 2% in each arm at Wk 96 361/ 411 351/ 411 Wk 48 333/ 411 314/ 411 – +276 cells/mm3 (DTG) vs +264 cells/mm3 (RAL) Wk 96 1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17. HIV-1 RNA < 50 copies/mL at Wk 48 (%) SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC in Naive Pts at Wk 48 Δ +7.4% 95% CI (+2.5% to +12.3%; P = .003) 100 88 81 80 • Treatment-related study d/c: 2% in DTG vs 10% in EFV arm • VF at Wk 48: 4% (18/414) in DTG arm and 4% (17/419) in EFV arm 60 40 • CD4+ cell count increase at Wk 48 greater with DTG: 20 0 • DTG superior to EFV at Wk 48 primary efficacy endpoint 364/ 414 340/ 419 DTG 50 mg + ABC/3TC QD EFV/TDF/ FTC QD Walmsley S, et al. NEJM 2013 – +267 cells/mm3 (DTG) vs – +208 cells/mm3 (EFV) (P < .001) HIV-1 RNA < 50 copies/mL at Wk 48 (%) FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Naive Patients at Wk 48 Δ +7.1% (95% CI: +0.9% to +13.2%; P = .025) 100 90 83 80 60 – Treatment-related study d/c: 2% in DTG arm vs 4% in DRV/RTV arm • VF at Wk 48: < 1% (n = 2) in each arm 40 20 0 • DTG superior to DRV/RTV at Wk 48 primary efficacy endpoint 217/ 242 200/ 242 DTG 50 mg QD + NRTIs DRV/RTV 800/100 mg QD + NRTIs Feinberg J, et al. ICAAC 2013. Abstract H1464a. • CD4+ cell count increase at Wk 48 similar: – +210 cells/mm³ in each arm DHHS Guidelines: What to Start Preferred Regimens • EFV/TDF/FTC • ATV/r + TDF/FTC • DRV/r (once daily) + TDF/FTC • RAL + TDF/FTC • EVG/COBI/TDF/FTC October 30, 2013 • DTG + TDF/FTC • DTG + ABC/3TC [Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC] Alternative Regimens • EFV + ABC/3TC • RPV + (TDF or ABC)/(FTC or 3TC) • ATV/r or DRV/r + ABC/3TC • FPV/r or LPV/r (qd or bid) ABC/3TC or TDF/FTC • RAL + ABC/3TC Acceptable Regimens • EFV or RPV + ZDV/3TC • NVP + TDF/FTC or ZDV/3TC or ABC/3TC • ATV + (ABC or ZDV)/3TC • ATV/r, DRV/r, LPV/r, FPV/r , RAL + ZDV/3TC • MVC + ZDV or ABC/3TC • SQV/r + TDF/FTC or ABC/3TC or ZDV/3TC (with caution) DHHS Guidelines. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf . Revision March 27, 2012. Individualizing First-line Therapy: Specific Circumstances Circumstance Agents No genotype Use boosted PI High HIV-1 RNA Caution with ABC, RPV Renal disease Caution with TDF, ATV/RTV; monitoring complicated with COBI and DTG Dyslipidemia RAL, DTG, RPV most lipid neutral CV risk factors Possible association with ABC, ddI, LPV/RTV No data for DRV/RTV, INSTIs, MVC Pregnancy Preferred: ZDV/3TC + NVP, LPV/RTV, or ATV/RTV EFV can be used after first 5-6 wks Chronic HBV Preferred TDF + 3TC or FTC Alternative is entecavir Decreased BMD Caution with TDF CNS effects Caution with EFV for at least first month When to Consider ARV Switch • ARV intolerance • Difficulty with adherence • Treatment failure • Incomplete virologic response • Two consecutive HIV RNA>400 or >50 copies/mL after 24 and 48 weeks, respectively • Virologic rebound • After virologic suppression HIV RNA repeatedly above assay limit of detection Adapted from US Department of Health and Human Services Guidelines; Revised January 10, 2011. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf Treatment-Experienced Patients: Full Virologic Suppression is Often Achievable? Thorough assessment of level of resistance Assess ability to adhere with future treatment options Treatment history Current resistance testing Available active agents Preferably at least two fully active agents needed In general adding a single drug should be avoided Genotypic Interpretation SUSCEPTIBILITY Slide 62 BENCHMRK-1 & -2: Raltegravir in Treatment-Experienced Patients Current Analysis: Week 48 HIV-infected patients with triple-class resistance and HIV-1 RNA > 1000 copies/mL (BENCHMRK-1: N = 352; BENCHMRK-2: N = 351) Planned follow-up: Week 156 Raltegravir 400 mg twice daily + OBR* (BENCHMRK-1: n = 232; BENCHMRK-2: n = 230) Placebo + OBR* (BENCHMRK-1: n = 118; BENCHMRK-2: n = 119) *Investigator-selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir permitted. 1. Cooper DA, et al. CROI 2008. Abstract 788. 2. Steigbigel R, et al. CROI 2008. Abstract 789. BENCHMRK-1: Patients With HIV-1 RNA < 50 c/mL at Week 48 RAL + OBR BENCHMRK-1[1] Placebo + OBR 100 62%* 65%* 33% 31% Patients (%) Patients (%) 80 60 40 20 0 n= n= 0 2 4 8 12 16 24 Weeks 232 118 231 118 231 118 230 118 229 117 232 118 32 229 118 40 230 118 48 231 118 *P < .001 for RAL vs placebo, derived from a logistic regression model adjusted for baseline HIV-1 RNA level (log10), first ENF use in OBR, first DRV use in OBR, active PI in OBR. 1. Cooper DA, et al. CROI 2008. Abstract 788. 2. Steigbigel R, et al. CROI 2008. Abstract 789. Antiretrovirals for prevention and future directions HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: 350-550 cells/mm3 (N = 1763 couples) Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3 (n = 886 couples) Delayed ART Initiate ART at CD4+ cell count ≤ 250 cells/mm3* (n = 877 couples) *Based on 2 consecutive values ≤ 250 cells/mm3. • 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 Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print] 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. Scienceexpress, July 19th 2010. 18th IAC 2010, Vienna, Austria, Abst. TUS505 68 (N=444) (N=445) Scienceexpress, July 19th 2010. 18th IAC 2010, Vienna, Austria, Abst. TUS505 High adherers (>80%) effectiveness = 54% 69 Cumulative Probability of HIV Infection iPrEx Study (n=2499) Grant R. et al. NEJM 2010; 363:2587-2599. N=64 N=36 Risk Reduction 44% (95% CI: 15, 63) P=0.005 Weeks iPrEx Protection and Adherence Overall Grant R. et al. NEJM 2010; 363:2587-2599. >90% Adherence Detectable Drug Levels Efficacy Rates of Prevention Trials Effect Size, Percent (95% CI) Study ART for prevention; HPTN 052, Africa, Asia, Americas PrEP for discordant couples; Partners PrEP, Uganda, Kenya PrEP for heterosexual men and women; TDF2, Botswana Medical male circumcision; Orange Farm, Rakai, Kisumu PrEP for MSMs; iPrEX, Americas, Thailand, South Africa Sexually transmitted diseases treatment; Mwanza, Tanzania Microbicide; CAPRISA 004, South Africa HIV vaccine; RV144, Thailand PrEP for women; FEM-PrEP, Kenya, SA, Tanzania 0 20 96 (73-99) 73 (49-85) 63 (21-84) 54 (38-66) 44 (15-63) 42 (21-58) 39 (6-60) 31 (1-51) 0 (-69-41) 40 60 Efficacy (Percent) 80 100 Adapted from: Abdool Karim SS and Karim QA. Lancet 2011; 378(9809):e23-5 and Celum C and Baeten JM. Curr Opinion Infect Dis 2012; 25:51-57 Obstacle to cure: At least one…. Siliciano JD, et al. Nature Med 2003;9:727-8 Hutter G, et al. N Engl J Med 2009; 360:692-8. Procedure and Events • • • • Ablative chemotherapy Total body XRT Graft vs. host Transplant with CCR5∆32 homozygous donor Persaud D, et al. N Engl J Med 2013; 369: 1828-35 Hypotheses: • Early treatment as PEP • Early treatment and neonatal immune system prevented/limited reservoir and allowed for clearance • Reservoir small and will take longer for rebound • Child destined to be elite controller • Other Thank You and Questions