IAS 2015: Return to Vancouver

IAS 2015: Return to Vancouver Paul E. Sax, M.D. Clinical Director, Division of Infectious Diseases Brigham and Women s Hospital Professor of Medicine Harvard Medical School NEAETC

Memories from 1996 First realization for many that combination ART could suppress viral replication indefinitely? Panel of HIV researchers drenched in blood by ACT- UP activists; Marty Hirsch s new suit ruined Hospital installed high-speed internet access for all Elsewhere: Atlanta Olympics (and bombing), Clinton vs Dole, Fargo, Alanis Morissette Gulick R, et al. NEJM 1997;337:734

Kicking over chairs, throwing microphones, smashing glasses and overturning conference tables, protesters demanded an immediate end to the practice of treating AIDS patients with dangerous chemotherapeutic agents. The activists asserted that the therapies hyped during the week-long conference such as AZT, ddi, ddc and protease inhibitors impair the immune system's natural ability to fight HIV and control the opportunistic infections that kill people with AIDS. http://www.virusmyth.com/aids/news/actupsfpr2.htm

December 30, 1996

IAS Vancouver 2015: Outline START: A landmark study Antiretroviral therapy

The biggest news out of Vancouver IAS 2015 was: 1. Teenager cured of HIV. 2. Results of the START study. 3. A clinical trial of ART with 100% of the participants women. 4. Largest switch study ever in stably suppressed patients. 5. Marty Hirsch got a new suit. 0% 0% 0% 0% 0% 1 2 3 4 5

START Study: Study Design HIV-infected individuals who are ART-naïve with CD4+ count >500 cells/mm 3 Immediate ART Group Initiated ART immediately Following randomization N=2,326 Deferred ART Group Defer ART until the CD4+ count declines to <350 cells/mm 3 N=2,359 Primary Composite Endpoint, Target =213 Serious AIDS or death from AIDS Serious Non-AIDS Events and death not attributable to AIDS CVD, ESRD, decompensated live disease, & non-aids defining cancers DSMB Stopped Study on May 27, 2015 Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

START Study: Baseline Characteristics Characteristics Immediate-Initiation Group (N=2326) Deferred-Initiation Group (N=2359) All Patients (N=4685) Median Age (IRQ)-yr 36 (29-44) 36 (29-44) 36 (29-44) Female Sex no. (%) 624 (26.8) 633 (26.8) 1,257 (26.8) Mode of Infection with HIV no. (%) Sexual Contact Men Having Sex with Men 1,300 (55.9) 1,286 (54.5) 2,586 (55.2) With Person of Opposite Sex 873 (37.5) 917 (38.9) 1,790 (38.2) Injection-drug Use 37 (1.6) 27 (1.1) 37 (1.6) Blood Products, Other, or Unknown 116 (5.0) 129 (5.5) 116 (5.0) Median Time Since HIV Diagnosis (IQR) yr 1.0 (0.4-3.0) 1.1 (0.4-3.1) 1.0 (0.4-3.0) Median CD4+ count (IQR) cells/mm 651 (585-765) 651 (582-764) 651 (585-765) Median HIV RNA (IQR) copies/ml 13,000 (3133-43,808) 12,550 (2963-42,567) 13,000 (3133-43,808) Median CHD Risk at 10yr (IQR) - % 1.9 (0.5-5.0) 1.9 (0.5-5.3) 1.9 (0.5-5.0) Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301. No significant differences between groups

Mean CD4+Count (cells/mm 3 ) START Study: B CD4+ Count 1000 950 900 850 800 750 700 650 600 550 500 450 CD4 Cell Counts Immediate Initiation Deferred Initiation 12 24 36 48 60 Months CD4 at the start of ART in deferred. Median 408 Estimated difference 194 cells Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

START Study: Initial ART Combinations Immediate Deferred TDF/FTC/EFV TDF/FTC/ATV/r ZDV/3TC/EFV TDF/FTC/DRV/r TDF/FTC/RPV TDF/FTC/RAL Other N=2287 (98%) N=1134 (48%) EFV: 73% vs 51% TDF: 89% in both groups Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

Cumulative Percent with an Event START Study: Primary Endpoint Immediate ART Deferred ART No. with Event (%) 42 (1.8%) 96 (4.1%) Rate/100PY 0.60 1.38 HR (Imm/Def) 0.43 (95% CI: 0.30 to 0.62, p<0.001) 10 8 Immediate ART Deferred ART 6 4 5.3 2 0 2.5 0 6 12 18 24 30 36 42 48 54 60 Months Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

Cumulative Percent with an Event START Study: Serious AIDS Events Immediate ART Deferred ART No. with Event (%) 14 50 Rate/100PY 0.20 0.72 HR (Imm/Def) 0.28 (95% CI: 0.15 to 0.50, p<0.001) 10 8 Immediate ART Deferred ART 6 4 2 0 0 6 12 18 24 30 36 42 48 54 60 Months Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

Cumulative Percent with an Event START Study: Serious NON-AIDS Events Immediate ART Deferred ART No. with Event (%) 29 47 Rate/100PY 0.42 0.67 HR (Imm/Def) 0.61 (95% CI: 0.38 to 0.97, p=0.04) 10 8 Immediate ART Deferred ART 6 4 2 0 0 6 12 18 24 30 36 42 48 54 60 Months Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

START Study: Primary and Secondary Endpoints End Point Immediate- Initiation Group (N=2326) Deferred- Initiation Group (N=2359) Hazard Ratio (95% CI) P Value No. No. /100 person-yr No. No. /100 person-yr Composite Primary End Point 42 0.60 96 1.38 0.43 (0.30-0.62) <0.001 Components of the Primary End Point Serious AIDS-Related Event 14 0.20 50 0.72 0.28 (0.15-0.50) <0.001 Serious Non-AIDS-Related Event 29 0.42 47 0.67 0.61 (0.38-0.97) 0.04 Death From Any Cause 12 0.17 21 0.30 0.58 (0.28-1.17) 0.13 Tuberculosis 6 0.09 20 0.28 0.29 (0.12-0.73) 0.008 Kaposi s Sarcoma 1 0.01 11 0.16 0.09 (0.01-0.71) 0.02 Malignant Lymphoma 3 0.04 10 0.14 0.30 (0.08-1.10) 0.07 Cancer Not Related to AIDS 9 0.13 18 0.26 0.50 (0.22-1.11) 0.09 Cardiovascular Disease 12 0.17 14 0.20 0.84 (0.39-1.81) 0.65 Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

Primary Endpoint Subgroup Analysis Subgroup Percentage in Group Immediate Initiation Deferred Initiation no. of patients with event (rote per 100 person-yr) Hazard Ratio (95% CI) Age 0.98 35yr 48.8 I5 (0.43) 31 (0.91) 0.47 >35yr 51.2 27 (0.78) 65 (1.85) 0.42 Sex 0.38 Male 73.2 35 (0.66) 74 (1.40) 0.47 Female 26.8 7 (0.42) 22 (1.34) 0.31 Race 0.65 Black 30.1 I5 (0.82) 28 (1.52) 0.57 White 44.5 21 (0.63) 53 (1.54) 0.40 Other 25.4 6 (0.34) 15 (0.91) 0.37 Geographic region 0.55 High income 46.0 20 (0.56) 51 (1.42) 0.39 Low or moderate income 54.0 22 (0.65) 45 (1.35) 0.48 Baseline CD4+ 0.71 <600 cells/mm 3 31.5 10 (0.44) 35 (1.54) 0.28 600-800 cells/mm 3 48.6 24 (0.70) 46 (1.38) 0.50 >800 cells/mm 3 19.9 8 (0.63) 15 (1.14) 0.56 Baseline HIV RNA 0.25 <5000 copies/ml 31.8 12 (0.56) 18 (0.83) 0.66 5000-30,000 copies/ml 35.5 13 (0.53) 36 (1.41) 0.38 >30.000 copies/ml 32.5 17 (0.72) 42 (1.92) 0.37 Smoker 0.93 Yes 31.9 18 (0.78) 43 (1.81) 0.43 No 68.1 24 (0.52) 53 (1.16) 0.44 Framingham 10-yr CHD risk 0.56 <0.8 32.7 8 (0.35) 17 (0.77) 0.46 0.8-3.6 32.3 11 (0.48) 27 (1.23) 0.39 >3.6 33.5 23 (1.00) 50 (2.05) 0.50 0.25 0.50 1.00 2.00 P Value for Interaction Immediate Initiation Better Deferred Initiation Better Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

Percent of Follow-up Time START Study: CD4 at Event 60 Immediate ART 2 3 6 11 20 (4.7) (0.8) (0.4) (0.6) (0.6) Deferred ART No. of Participants with Events (Rates per 100 PY) 5 34 34 9 14 (1.8) (2.0) (1.5) (0.6) (1.1) 50 40 30 20 10 0 <350 350-499 500-649 650-799 800 <350 350-499 500-649 650-799 Latest CD4+ Count (Cells per Cubic Millimeter) Primary Events at Latest CD4 count >500 c/mm 3 800 Immediate Defer Percent 88% 59% Rate (/100 PY) 0.6 1.1 Lundgren J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOSY0301.

The START study results will profoundly influence clinical practice. 1. True now it is proven that HIV treatment is beneficial for all. 2. False we have been treating everyone regardless of CD4 for years anyway. 0% 0% 1 2 ART is recommended for all HIV-infected individuals. --DHHS Guidelines, 2012 https://aidsinfo.nih.gov/contentfiles/adultandadolescentgl003093.pdf

IAS Vancouver 2015: Outline START: A landmark study Antiretroviral therapy

WAVES : Initial ART in Women Baseline Week 48 WAVES 1:1 (n=575) EVG/COBI/FTC/TDF QD ATV+RTV+FTC/TDF Placebo QD ATV+RTV+FTC/TDF QD EVG/COBI/FTC/TDF Placebo QD Open Label Extension Key Eligibility Criteria: HIV infected womem HIV-1 RNA 500 copies/ml Estimated GFR 70 ml/min No history of prior antiretroviral therapy Sensitivity to FTC, TDF, and ATV Stratification: HIV-1 RNA (<=100,000, >100,000-<=400,000, >400,000 copies/ml) Race (Black or non-black) Squires K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOLBPE08.

WAVES: Study Enrollment Squires K, et al. IAS 2015, #MOLBPE08 21

STB (n=289) ATV+RTV+TVD (n=286) Age (years), median (Q1,Q3) 34 (28,43) 35 (29,42) Race White Black Asian Mode of Infection Heterosexual 96% 94% HIV Disease Asymptomatic AIDS 44% 49% 3% 81% 4.2% 42% 47% 6% 75% 4.5% Body Mass Index (BMI), Mean (SD) 26 (7.02) 26 (5.69) Positive HBsAg 3.1% 2.4% Positive HCV Antibody 7.6% 8.7% HIV-1 RNA (log 10 copies/ml), Median (Q1,Q3) < 100,000 c/ml >100,000-400,000 c/ml > 400,000 c/ml 4.46 (4.09,4.97) 76% 15% 9% CD4 cell count (cells/mm 3 ), Median (Q1,Q3) 344 (246,466) <200 cells/mm 3 17% Squires K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOLBPE08. WAVES Study: Baseline Characteristics 4.56 (4.02,5.00) 75% 17% 8% 370 (244,489) 18%

HIV-1 RNA < 50 c/ml, % WAVES Study: Primary Endpoint EVG/COBI/FTC/TDF (n=289) 100 80 87 81 ATV+ RTV + FTC/TDF (n=286) Treatment Difference (95% CI) Favors ATV+ RTV Favors STB 60 40 6.5% 20 0 9 12 Virologic Success Virologic Failure No Virologic Data 4-12% +12% Mean CD4 Cell Increase (cells/mm 3 ) was 196 (EVG/COBI/FTC/TDF & ATV/RTV + FTC/TDF) 7 0 0.4% 12.6% RESISTANCE STB: Only on pt with emergent D67D/N ATV/r: 3 with M184V/I Squires K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOLBPE08.

Virologic Success (%) WAVES Study: Efficacy by Baseline HIV-1 RNA & CD4 Count EVG/COBI/FTC/TDF ATV+RTV+FTC/TDF 100 80 87 86 81 82 90 88 82 86 78 79 60 40 20 0 Overall VL 100,000 VL > 100,000 CD4 350 N 289 286 220 214 69 72 146 131 143 154 CD4 > 350 Squires K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. MOLBPE08. HIV-1 RNA (c/ml) CD4 Cell Count (/µl) AERs leading to d/c: E/C/F/T - 7 vs ATV/r - 20

Integrase-Based First-Line Therapy: It s Better WAVES: EVG/COBI/TDF/FTC better than ATV/r SPRING-2: DTG better than EFV FLAMINGO: DTG better than DRV/r ACTG 5257: RAL better than DRV/r and ATV/r

Probability of Suicidality 0.00 0.01 0.02 0.03 0.04 0.05 ACTG: Risk of EFV Suicidality May Be Associated with CYP2B6 and 2A6 Metabolizer Genotypes Extensive (levels: 1-2) Intermediate (3-7) Slow (8-12) 7 events* 18 events * Hazard ratio (95% CI): 1.85 (1.05, 3.26), P= 0.03 9 events 0 48 96 144 192 Weeks Since EFV Initiation Unweighted No. at risk: Extensive 623 506 435 233 52 Mid 838 659 566 276 45 Slow 195 152 124 62 8 Mollan K, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUPEB273.

TDF/FTC + Doravirine vs EFV: Results by Baseline HIV RNA 100,000 c/ml >100,000 c/ml 100 80 60 40 20 83.3 85.7 92.4 92.1 60.5 65.8 92.1 94.7 0 n/n: 55/66 54/63 25: 51/66 58/63 11: 23/38 25/38 35/38 36/38 % <40 c/ml % <200 c/ml % <40 c/ml % <200 c/ml Doravirine 100 mg q.d. Efavirenz 600 mg q.d. Virologic failures: DRV 17, EFV 11 -- mostly due to low-level viremia at week 24 (no resistance detected) 1 or more CNS adverse events: DRV 27%, EFV 46% -- difference -19.4% (95% CI -31.7, -6.6) Gatell J, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB04.

Three ECF-TAF Switch Studies 1. From first regimens TDF/FTC/EFV, TDF/FTC + ATV/r or ATV/c, or TDF/FTC/EVG/c 2. In chronic renal insufficiency 3. In hepatitis B/HIV co-infection

Tenofovir Alafenamide (TAF) GI TRACT PLASMA Tenofovir (TFV) Parent Nucleotide DIANION TFV TFV HIV TARGET CELL Tenofovir disoproxil fumarate (TDF) Tenofovir alafenamide (TAF) ESTER TDF 300 mg TAF 25 mg T 1/2 = 0.4 min T 1/2 = 90 min TFV HIV TFV AMIDATE 91% lower plasma TFV levels minimize renal and bone effects while maintaining high potency for suppressing HIV T 1/2 based on in vitro plasma data. 1. Lee W et. Antimicr Agents Chemo 2005;49(5):1898-1906. 2. Birkus G et al. Antimicr Agents Chemo 2007;51(2):543-550. 3. Babusis D, et al. Mol Pharm 2013;10(2):459-66. 4. Ruane P, et al. J Acquir Immune Defic Syndr 2013; 63:449-5. 5. Sax P, et al. JAIDS 2014. 2014;67(1):52-8. 6. Sax P, et al. Lancet 2015;385:2606-15.

Switch to E/C/F/TAF from First Regimen Primary Endpoint HIV-1 RNA <50 c/ml Randomized (2:1), active-controlled, open-label study Virologically Suppressed Adults Baseline Characteristics E/C/F/TDF (n=459) EFV/FTC/TDF (n=376) Boosted ATV + FTC/TDF (n=601) Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102. Week 0 n=959 n=477 E/C/F/TAF n=959 4 8 Switch to E/C/F/TAF Continue TDF-Based Regimen TDF-Based Regimen n=477 Median age, years 41 40 Female, % 11 11 Race, % White 68 66 Black or African descent 18 21 Hispanic/Latino ethnicity 26 17 Median CD4 count, cells/mm 3 675 662 Patients with <200 cells/mm 3, % 0.5 0.8 Median estimated GFR, ml/min* 106 108 Dipstick proteinuria, % Grade 1 8.5 9.2 Grade 2 0.4 0.6 9 6

HIV-1 RNA <50 c/ml, % Switch to E/C/F/TAF from First Regimen: Results Virologic Outcome Treatment Difference (95% CI) E/C/F/TAF TDF-Based Regimen n=477 100 97 93 TDF Based E/C/F/TAF 80 60 40 4.1 20 1.6 6.7 0 6 1 1 2 Success Failure No Virologic Data n= 932 444 10 6 17 27 12% 0 +12% Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102. 31

Patients With HIV-1 RNA <50 c/ml, % Virologic Outcome By Prior Treatment Primary Endpoint E/C/F/TAF TDF-Based Regimen p <0.001 p=0.02 p=0.02 p=ns 100 97 96 97 98 93 90 92 97 80 60 40 20 0 95% CI = 932 959 444 477 All Prior Regimens 1.6 6.7 241 251 112 125 Prior EFV/FTC/TDF Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102. 390 402 183 199 Prior Boosted ATV + FTC/TDF 301 306 149 153 Prior E/C/F/TDF 0.5 12.3 0.9 9.2-1.9 3.9 32

Median % Change Switch to E/C/F/TAF in Suppressed Adults: Effect on Tubular Proteinuria 30 20 10 0-10 -20-30 -40-50 -60 Urine Urine Urine Retinol Urine Beta 2 Protein:Creatinine UPCR Albumin:Creatinine UACR Binding RBP: Protein:Creat Ratio Microglobulin:Creatinine B2MG: Ratio 18 19 10 9-18 -21-33 -52 Switch to E/C/F/TAF associated with: Improvement in spine and hip BMD Reduction in proportion classified as osteopenia or osteoporosis Reduction in tubular proteinuria; no change in egfr Increase in fasting lipids E/C/F/TAF TDF-Based Regimen Mills A, et al; 8th IAS, Vancouver, Canada, July 19-22, 2015; Abst. TUAB0102.

Study 112: Switch to E/C/F/TAF in Patients With Renal Impairment Phase 3 study (96 weeks) Treatment-experienced Open-label HIV RNA <50 copies/ml egfr 30-69 ml/min Switch to E/C/F/TAF (n=242) Primary Endpoint Week 24 Change From Baseline in egfr E/C/F/TAF: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. TAF 25 mg. Pre-switch ART regimens: NRTI: tenofovir DF (65%), abacavir (22%), other (7%), none (5%). Third agent (some regimens included >1 third agent): PI (44%), NNRTI (42%), INSTI (24%), CCR5 antagonist (3%). Baseline characteristics: Median age: 58 years. Hypertension/diabetes: 40%/14%. Median CD4: 632 cells/mm 3. Median egfr: 56 ml/min (<60 ml/min: 66%). Dipstick proteinuria grade 1/2/3-4: 23%/10%/0%. Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35-36. Abstract TUAB0103..

Actual GFR (ml/min) Change in egfr (ml/min) Study 112: Change in GFR After Switch to E/C/F/TAF in Patients With Renal Impairment Actual GFR at Week 24 (Iohexol Clearance) Mean Change in egfr at Week 48 (Cockcroft-Gault) 80 Baseline 6 70 60 Week 24 59 58 63 63 4 50 50 49 2 40 0 0.2 30 20-2 -0.6-1.8 10 0 All Patients Yes No TDF in Previous Regimen -4-6 Baseline egfr (ml/min): 56 58 53 All Patients Yes No TDF in Previous Regimen Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35-36. Abstract TUAB0103..

Study 112: Change in GFR and Other Outcomes After Switch to E/C/F/TAF Actual GFR was unaffected by E/C/F/TAF switch, regardless of previous regimen egfr remained unchanged through week 48 Significant improvements after E/C/F/TAF switch (P<0.05) Spine and hip bone mineral density Urinary tubular proteins and fractional excretion of uric acid Albuminuria and proteinuria Cholesterol fractions in patients not on a TDF-based regimen at time of switch Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35-36. Abstract TUAB0103..

Mother at delivery HIV-1 Remission for >12 ddc since 13 weeks gestation Years After Early ART HIV RNA 4.63 log 10 copies/ml and CD4 81 cells/mm 3 Infant (delivery 37 weeks, 5 days of gestation) At birth Zidovudine prophylaxis, HIV RNA undetectable at day 3 HIV DNA undetectable at days 3 and 14, detected at week 4 Week 6: zidovudine interrupted, HIV RNA rose sharply to 2.17 million copies/ml Month 3: initiate ART (zidovudine, didanosine, abacavir, ritonavir) Loss to follow-up between 5.8 and 6.8 years ART interrupted by mother at approximately year 6.5 Remains HIV RNA undetectable after returning to care Unknown if HIV-1 remission in this infant represents early treatment translating into long-term control or if long-term control is related to other factors Frange P, et al. J Int AIDS Soc. 2015;18(suppl 4):3-4. Abstract MOAA0105LB.

Thank you! February 12, 1996