1. Novel Antiretroviral Studies and Strategies
Bob Harrington, MD
University of Washington
Presentation prepared by:
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Last Updated: Date

2. Early Vs Deferred HAART Strategic Timing of AntiRetroviral Treatment (START) Study
Randomized study to start ART immediately (when CD4 > 500) or defer until CD4 < 350
215 sites in 35 countries, opened enrollment March 2011
N = 4685 men and women > 18 (median age 36), all with CD4 > 500
Median age 36, M:F 63%:27%, median CD4 651, VL 12,759
Median follow-up: 2.8 years
Countries include low, middle and high income
Outcome: combination of serious AIDS events, serious non-AIDS events and death
INSIGHT START Study Group, New Engl J Med, July, 2015

3. Early Vs Deferred HAART Strategic Timing of AntiRetroviral Treatment (START) Study
DSMB analysis of data from March 2015:
Early Rx group: 42 events
Deferred group: 96 events
57% reduction in the primary endpoint in the early Rx group
Benefit regardless of age, sex, race, country, CD4 count, smoking status and FRS
INSIGHT START Study Group, New Engl J Med, July, 2015

4. Early Vs Deferred HAART Strategic Timing of AntiRetroviral Treatment (START) Study
End Point
Immediate Rx
Deferred Rx HR
P value #
#/100 py
Composite primary endpoint 42
0.60 96
1.38
0.43
< 0.001
Components of endpoint
Serious AIDS event 14
0.20 50
0.72
0.28
Serious non-AIDS event 29
0.42 47
0.67
0.61
0.04
Death 12
0.17 21
0.30
0.58
0.13
Tuberculosis 6
0.09 20
0.29
0.008
Kaposi’s sarcoma 1
0.01 11
0.16
0.02
Lymphoma 3 10
0.14
0.07
Non-AIDS cancer 9 18
0.26
0.50
Cardiovascular disease
0.84
0.65
INSIGHT START Study Group, New Engl J Med, July, 2015

5. Early Vs Deferred HAART TEMPRANO ANRS 12136 STUDY
Unblinded, multicenter, randomized, controlled, 2 X 2 factorial trial conducted in 9 care centers in the Ivory Coast
N = 2056 men and women > 18, with CD4 < 800 who met no criteria for starting ART. Randomized to:
Deferred ART (until meeting WHO criteria)
Deferred ART + IPT
Immediate ART
Immediate ART + IPT
Primary endpoint: composite of AIDS illness OR non-AIDS cancer OR non-AIDS invasive bacterial infection OR death at 30 months
Median age 35, F 79%, median CD4 ~ 460 (40% > 500)
TEMPRANO ANRS Study Group, New Engl J Med, July, 2015

6. Early Vs Deferred HAART TEMPRANO ANRS 12136 STUDY
TB and invasive bacterial disease accounted for 42% and 27% of the primary endpoints
No difference in grade 3,4 AEs between the groups
All patients
HR for death or severe HIV disease (Early Vs late ART)
HR for death or severe HIV disease (IPT Vs no IPT)
All patients
0.56 ( )
0.65 ( )
Patients with CD4 > 500
0.56 ( )
0.61 ( )
CD4 > 500
CD4 < 500
TEMPRANO ANRS Study Group, New Engl J Med, July, 2015

7. SALT Study r/ATZ + 3TC Vs r/ATZ + 2 nRTIs
Randomized, open label study, N = 286, Spain
No h/o drug failure or drug resistance
No chronic HBV
HIV RNA < 50 copies/mL for at least 6 months
Randomized to:
r/ATZ + 3TC
r/ATZ + 2 nRTIs (chosen by investigators)
Primary endpoint: HIV RNA < 50 copies/mL at 48 weeks
Perez-Molina, Lancet Infect Disease, 2015

8. SALT Study r/ATZ + 3TC Vs r/ATZ + 2 nRTIs
Dual therapy not inferior to triple therapy
Toxicity similar between regimens
Fewer patients in the dual therapy arm discontinued treatment (3 [2%] Vs 10 [7%])
< 50 at 48 Weeks
Perez-Molina, Lancet Infect Disease, 2015

9. GARDEL Study r/LPV + 3TC Vs r/LPV + 2 nRTIs
Randomized, controlled, open label study, N = 426, Argentina, Chile, Mexico, Peru, Spain and the US
>18 years, ART naïve, VL > 1000, no CD4 criteria
No h/o drug failure or drug resistance
No chronic HBV
Baseline characteristics
Median CD4 ~ 320
Median HIV RNA 4.87 logs (44% > 100,000 copies)
Randomized to:
r/LPV + 3TC
r/LPV + 2 nRTIs (chosen by investigators FTC/3TC + ABC or TDF or AZT)
Primary endpoint: HIV RNA < 50 copies/mL at 48 weeks
Cahn, Lancet Infect Disease, 2014

10. GARDEL Study r/LPV + 3TC Vs r/LPV + 2 nRTIs
Results
Dual Rx
Triple Rx
< 50: all patients
88.3%
83.7%
< 50 (BL VL > 100,000)
87.2%
77.9%
Toxicity - discontinuations 1
(0.4%)
10 (4.9%)
AEs 65 88
All pts
> 100,000
Cahn, Lancet Infect Disease, 2014

11. OLE Study r/LPV + 3TC Vs r/LPV + 2 nRTIs
Randomized, open label study, N = 250, Spain and France
No h/o drug failure or drug resistance
No chronic HBV
HIV RNA < 50 copies/mL for at least 6 months on r/LPV + 2 nRTIs
Randomized to:
r/LPV + 3TC
r/LPV + 2 nRTIs (chosen by investigators)
Primary endpoint: HIV RNA < 50 copies/mL at 48 weeks
Arribas, Lancet Infect Disease, 2015

12. OLE Study r/LPV + 3TC Vs r/LPV + 2 nRTIs
48 Weeks
Arribas, Lancet Infect Disease, 2015

13. Notes from IAS 2015: TAF
A. Mills: Switching from TDF to TAF based regimens: data from suppressed patients at 48 weeks
~1200 patients, < 50 for 96 weeks on Stribild, Atripla or r/ATZ + TRU
Switched to TAF + FTC + c/ELV or stayed on original regimen
VL < 50 at 48 weeks: 97% (TAF) Vs 93% (TDF) (TAF superior to TDF)
Increased BMD and less renal effects in TAF treated patients
S. Gupta: Subjects with renal impairment switching from TDF to TAF: improved renal and bone safety at 48 weeks
Single arm, open label study
N = 242, CrCl 30-69
At 48 weeks:
No change in GFR, reduced urine RBP, B2MG and protein excretion
Improved BMD
Increased TG, TC and LDL
IAS 2015 Vancouver

14. Notes from IAS 2015: Doravirine
J Gatell: Efficacy and safety of Doravirine + TDF/FTC Vs Efavirenz + TDF/FTC in ART naïve patients (24 weeks)
Doravirine – unique R profile, is metabolized by CYP3A4 but does not induce or inhibit the enzyme
N = 216 patients, 24 week analysis
DRV (100 mg) + TDF/FTC
EFV (600 mg) + TDF/FTC
< 200
< 40
All patients
90%
73%
88%
72%
BL < 100,000
92%
95%
BL > 100,000
60%
66%
AEs
28%
56%
IAS 2015 Vancouver