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NORTHWEST AIDS EDUCATION AND TRAINING CENTER
Novel Antiretroviral Studies and Strategies
Bob Harrington, MD
University of Washington
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Early Vs Deferred HAART
Strategic Timing of AntiRetroviral Treatment (START) Study
START: 2015
• 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 nonAIDS events and death
INSIGHT START Study Group, New Engl J Med, July, 2015
Early Vs Deferred HAART
Strategic Timing of AntiRetroviral Treatment (START) Study
START: 2015
• 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
Early Vs Deferred HAART
Strategic Timing of AntiRetroviral Treatment (START) Study
End Point
Immediate Rx
#
Composite primary
endpoint
Deferred Rx
START:
2015
#/100 py
#
#/100 py
HR
P value
42
0.60
96
1.38
0.43
< 0.001
Serious AIDS event
14
0.20
50
0.72
0.28
< 0.001
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
0.28
0.29
0.008
Kaposi’s sarcoma
1
0.01
11
0.16
0.09
0.02
Lymphoma
3
0.04
10
0.14
0.30
0.07
Non-AIDS cancer
9
0.13
18
0.26
0.50
0.09
Cardiovascular disease
12
0.17
14
0.20
0.84
0.65
Components of endpoint
INSIGHT START Study Group, New Engl J Med, July, 2015
Early Vs Deferred HAART
TEMPRANO ANRS 12136 STUDY
TEMPRANO: 2015
• 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 12136 Study Group, New Engl J Med, July, 2015
Early Vs Deferred HAART
TEMPRANO ANRS 12136 STUDY
TEMPRANO: 2015
• TB and invasive bacterial
disease accounted for 42%
and 27% of the primary
endpoints
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 (0.41-0.76)
0.65 (0.48-0.88)
Patients with
CD4 > 500
0.56 (0.33-0.94)
0.61 (0.36-1.01)
• No difference in grade 3,4 AEs
between the groups
TEMPRANO ANRS 12136 Study Group, New Engl J Med, July, 2015
All patients
CD4 > 500
CD4 < 500
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
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%])
Perez-Molina, Lancet Infect Disease, 2015
< 50 at 48 Weeks
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
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%)
65
88
AEs
All pts
> 100,000
Cahn, Lancet Infect Disease, 2014
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
OLE Study
r/LPV + 3TC Vs r/LPV + 2 nRTIs
48 Weeks
Arribas, Lancet Infect Disease, 2015
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
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) + EFV (600 mg) +
TDF/FTC
TDF/FTC
< 200
< 40
< 200
< 40
All patients
90%
73%
88%
72%
BL < 100,000
92%
95%
BL > 100,000
AEs
IAS 2015 Vancouver
60%
28%
66%
56%