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.



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Switching ARVs in Virologically Suppressed Patients.

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