Switching ARVs in Virologically Suppressed Patients.
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Switching ARVs in Virologically Suppressed Patients
Switching ARVs in Virologically Suppressed Patients
Switching ARVs in Virologically Suppressed Patients
Switching ARVs in Virologically Suppressed Patients
Data PresentationData Presentation
AI-073: Switching Suppressed Patients to EFV/FTC/TDF
DeJesus E, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-1234
Phase IV, multicenter (55 US sites), open-label study (N=300)
Primary Endpoint: Non-inferiority of STR vs. SBR for HIV-1 RNA <200 c/mL
through Week 48 by TLOVR analysis
Randomization2:1
Stratify byPI or NNRTI
Continue
Switch• VL<200 c/mL
• Stable ARV Regimen • On 1st regimen or
suppressed on previous PI regimen
• No H/O VF
STR=EFV/FTC/TDF QD (n=203)
SBR=Stay on Baseline Regimen (n=97)
AI-073: Results at 48 Weeks
Virologic Failure STR 3 , SBR 1
AE’s all grades
STR: Higher incidence
-Sleep disturbance 14% vs 0
-Dizziness 11% vs 1%
-GI (nauseas, diarrhea) 6% vs 2%
DC due to AE’s STR 10 (5%), SBR 1 (1%)
GFR (CG, MDRD) No significant changes
Change TG (mg/dl) STR -20, SBR -3 (P=0.035)
Pt preference STR 91%, SBR 9% (P=0.001)
% w
ith H
IV R
NA
<50
c/m
L (T
LOVR
)
Treatment Difference (STR – SBR)95% CI:2.6% (5.9%, 11.1%)
DeJesus E, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-1234
ANRS 138: Enfuvirtide to Raltegravir Switch in Highly Experienced Patients
• Patients with triple-class resistance and HIV RNA <400 c/mL
• Randomized to continue ENF (n=85) or switch to RAL (n=84)
• Median of 13.6 years prior ART and 2.3 years on ENF
• Week 24 Results:• 89% <50 c/mL in both arms• Virologic Failure: 1 in each arm (∆ = 0.01%, 95% CI -4.4, +4.5)• No significant CD4 changes in either arm• Grade 3/4 AE: 11% ENF arm, 19% RAL arm (P=0.12)
• Conclusion: Raltegravir maintains suppression when substituted for ENF in fully suppressive regimens
De Castro N, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 572.
STARTMRK:RAL vs. EFV in ARV-Naïve Patients
Lennox J, et al. 48th ICAAC/46th IDSA, 2008. Abst. H-896a
RAL + TDF/FTC EFV + TDF/FTC
Me
an
Ch
an
ge
(m
g/d
L)
Weeks
Pe
rce
nt
<5
0 C
op
ies
/mL
0 2 4 8 12 16 24 32 40 48
0
20
40
60
80
100
82%
Non-inferiorityP-Value <0.001
86%
CD4 Count Increase:189 vs. 163 (p<0.05)
STARTMRK: Predictors of Success
Subgroup analyses support consistent efficacy across multiple virologic and immunologic parameters
% of Patients with HIV RNALevels <50 copies/mL
Subgroup Raltegravir Efavirenz
Overall 92% 89%
Baseline Plasma HIV RNA (c/mL) ≤50,000 95% 87%
>50,000 90% 90%
≤100,000 93% 89%
>100,000 91% 89%
Baseline CD4 Cell Counts (cells/mm3) ≤50 84% 86%
>50 to ≤200 89% 86%
>200 94% 92%
Lennox J, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 573.
D:A:D Study: PIs and Risk of MI
0.9 1 1.1 1.3 1.4
Primary model
Dyslipidemia
Elevated blood pressure
Diabetes mellitus
Lipodystrophy
Glucose
All above + lipid-lowering and antihypertensive medication
Lopinavir/r Indinavir
RR of MI (95% CI)
Effect of Adjustment for Latest Metabolic Factors
* Approximate test for heterogeneity: P=0.02
IDV NFV LPV/r SAQ #PYFU: 68,469 56,529 37,136 44,657#MI: 298 197 150 221
1.2
1.13
1
0.9
RR
/ye
ar
(95
% C
I)
Risk with Cumulative Exposure to PI
Lundgren JD, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 42LB.
SWITCHMRK 1 & 2:Study Design
• Identical, multicenter, double-blind, randomized, active-controlled studies
• Enrolled pts with HIV RNA <50 c/mL on LPV/r BID regimen in combination with at least 2 NRTIs
• No limit on number of prior ART regimens
• Prior virologic failure not an exclusion
• No lipid lowering therapy for at least 12 weeks
• Randomized (1:1) to continue LPV/r or switch to RAL
Eron J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 70aLB.
SWITCHMRK 1 SWITCHMRK 2
RAL
(N=174)
LPV/r
(N=174)
RAL
(N=176)
LPV/r
(N=178)
HIV RNA
≤ 50 c/mL94.3% 92.5% 96.0% 95.5%
Mean CD4 (cells/mm3)
478 508 471 482
LPV/r ≤ 1 yr 16.7% 17.8% 17.6% 18.5%
Median yrs prior ART(min, max)
3.3
(0.3, 22.3)3.6
(0.5, 20.2) 3.7
(0.5,19.2)4.6
(0.6,16.3)
Median # prior ART(min, max)
5.0
(4.0, 16.0)5.0
(2.0, 5.0)5.5
(3.0,13.0)6.0
(4.0,14.0)
*Median Percent Change **Not prespecified for test
SWITCHMRK 1 and 2:Mean Change in Lipids at Week 12
Eron J, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 70aLB.
FastingCholesterol
NonHDL-C
FastingTriglycerides*
Fasting LDL-C
FastingHDL-C
2%1% 2%
-15%
-2%4%
-41%
1%-1%
-13%
P<0.001P<0.001
P<0.001
P=0.704 nps**
RAL + ARTsLPV/r + ARTs
-50
-40
-30
-20
-10
0
10
20
1%1% 3%
-15%
4%8%
-43%
-3%-1%
-12%
P<0.001P<0.001
P<0.001
P=0.269 nps**
FastingCholesterol
NonHDL-C
FastingTriglycerides*
Fasting LDL-C
FastingHDL-C
Cha
nge
from
bas
elin
e at
wee
k 12
, m
ean%
SWITCHMRK 1 SWITCHMRK 2
• RAL not non-inferior to maintaining LPV/r
• Further Analysis underway to assess affect of Tx experience on results• 84% with confirmed HIV RNA >50 c/mL) in the RAL group were not on
1st ART regimen; 66% with history of VF on prior regimen(s)
SWITCHMRK 1 and 2:Virologic Outcomes (NC = F)
Eron J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 70aLB.
Per
cent
H
IV R
NA
<50
Cop
ies/
mL
50
60
70
80
90
100SWITCHMRK 1
0 4 8 12 24Weeks
81%
87%
(95% CI) : -6.6 (-14.4, 1.2)
0 4 8 12 24Weeks
94%
88%
(95% CI) : -5.8 (-12.2, 0.2)
SWITCHMRK 1 & 2: Resistance Summary at Time of Failure
Study DrugVirologic Failures
(>400 c/mL) Study drug mutations RTI mutations
RAL12
N155H K103N
None V118I, M184V; V179D
None V179E
G140G/S, Q148R, Q148Q/H, N155N/H D67D/G, M184V, T215T/I; Y181C
N155H M184M/V; K103R
N155H, Q148Q/R, Y143Y/C D67D/N, K70K/R, M184V, K219Q
Q148H, G140S M184V; K103N, P225H
G140G/S, Q148R, Q148Q/H, N155N/H, Q148Q/R None
N155H None
Y143Y/S, Q148Q/R None
None None
Not done Not done
LPV/r4
L10I/V, G16G/E, L63S, A71A/T, V77I None
Not done Not done
L10I, K20R, M36I, M46L, I54V, L63P, A71V, V82A, L90M K65R, D67N, K219E; K103R, Y181C
V11V/I, L63P, V77I None
Eron J, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 70aLB.
Switching ARVs in Virologically Suppressed Patients
Switching ARVs in Virologically Suppressed Patients
Debate/DiscussionDebate/Discussion
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