Response Rates in Heavily Pretreated HIV+ Patients

Roy M. Gulick, MD, MPHCornell Clinical Trials Unit

Clinical Cohort Studies: Virologic Failure Rates

Cohort N (% above LD, time)Amsterdam(Wit JID 99)

271 40% , 48 wks

Cleveland(Valdez Arch IM 99)

310 53%, 1 yr

Hopkins(Lucas Ann IM 99)

273 63%, 1 yr

Swiss(Ledergerber Lancet 99)

1517 38%, 2 yrs

UCSF (Deeks AIDS 99) 337 50%, 48 wks

Clinical Cohort Studies: Predictors of Virologic Failure

• prior antiretroviral treatment• higher baseline/peak viral load level• lower baseline/nadir CD4 cell count• specific antiretroviral regimen used• more missed clinic appointments

Baxter, et al., AIDS 2000

-0.10

-0.58

-1.02-1.25

0102030405060708090

100

1 2 3 4

0-0.25-0.50-0.75-1.00-1.25

No. of active drugs

Change (log)

% of patients

HIV RNAchanges

(log)

GART n=78No GART n=75

GART: HIV RNA Changes by Number of Active Drugs

Therapeutic Drug Monitoring: VIRADAPT

Time, mo0 3

60.05-0.15-0.35-0.55-0.75-0.95-1.05-1.35-1.55

HIV

RN

A, l

og d

ecre

ase

Control = Standard of care.Source: Garraffo. Antiviral Ther; 1999;4(1):75.

HIV RNA Decreases in PI-Treated Patients

SOC

SOC + GT

OC

OC + GT

S/OC = suboptimal/optimal drug concentration GT = genotypic testing done

Clinical Cohort Studies: Limitations

• Heterogeneous patient populations (e.g., prior antiretroviral experience)

• Reflects antiretroviral rx use in 1996-98– Fewer antiretrovirals available– More complex regimens– Sequential monotherapy

• ?virologic = immunologic = clinical failure

Deeks, et al, J Infect Dis 2000

UCSF Cohort (N=380):Virologic +Immunologic Responses

Grabar, et al, Ann Intern Med 2000

French Cohort (N=2236):Viro., Immun. + Clinical Responses

IR+/VR+

IR-/VR-

IR-/VR+IR+/VR-

.6 12 18 24 30 Months since introduction of PI

100

95

90

85

75

80

Perc

ent a

live

and

AID

S-fr

ee

Mocroft, et al. 3rd Salvage Workshop, 2000

Treatment Failure at 2 years: EuroSIDA Cohort (N=8507)

RegimenCohort

Virologic failure(VL >500)

Immune + clinical failure

Clinical events

1st HAART 40% 20% 5%

2nd HAART 50% 30% 24%

3rd HAART 67% 40% 25%

Prospective Studies of Salvage Rx: First Failures

• ACTG 333: SQV-experienced• ACTG 372b: IDV-experienced• ACTG 359: IDV-experienced• ABT-765: Single PI-experienced

Para, et al. J Infect Dis 2000

ACTG 333: SQV-experienced• Study population: >48 wks SQVhc, no

other PI, stable antivirals X 2 mos (N=72) • Baseline: HIV RNA 21K, CD4 222• Results (interim analysis at 8 wks):

Rx VL change

% <200 cps/ml

CD4 change

SQVhc none 9% noneSQVsgc -0.2 logs 10% +37IDV -0.6 logs 37% +22

Hammer, et al, 6th CROI, #490.

ACTG 372b: IDV-experienced• Population: HIV+, on AZT or d4T + 3TC + IDV

with VL >500 cps/ml (N = 84)• Duration: 48 weeks• Rx: EFV + ADV + ABC (or new NRTI) +/- NFV• Results: Overall, 29 (35%) had HIV RNA <500

copies/ml at week 16• Factorial analyses:

– ABC (37%) vs. 1-2 new NRTI’s (32%) (p=0.62)– NFV (45%) vs. placebo (24%)

• favored nelfinavir group (p=0.046)

Gulick, et al, J Infect Dis 2000

ACTG 359: IDV-experienced• Population: HIV+, > 6 mo prior IDV, HIV RNA 2-

200K, naïve to other PI and NNRTI, (N = 277)• Baseline: VL 32K, CD4 229• Rx: SQVsgc + RTV or NFV + DLV, ADV, or both• Overall, 77 (30%) had HIV RNA <500 copies/ml at

week 16• Factorial analyses:

– SQV/RTV (28%) vs. SQV/NFV (33%) (p=0.50)– DLV (40%) vs. ADV (18%) vs. both (33%)

• favored DLV-containing regimens (p=0.006)

Feinberg, et al. Glasgow Meeting, 2000

Abbott M97-765: PI-experienced

• Study population: HIV+, single PI failure, NNRTI naïve, HIV RNA 1-100K (N=70)

• Baseline: VL 4.1 logs, CD4 372• Study treatment: lopinavir 400 mg bid +

ritonavir 100 or 200 mg bid + NVP + nucs X 96 weeks

• Preliminary results: 4 d/c for rx-related effects (3 GI, 1 rash)

-1.5

-1.0

-0.5

0.0

0 24 48 72 96

log 1

0 cop

ies/

mL

Week

M97-765: HIV RNA Mean Change from Baseline

At Week 2, NRTIs were switched and NVP added

At Baseline, PI wasswitched to lopinavir/r

0

20

40

60

80

100

0 24 48 72 96

400/100 mg400/200 mg

Perc

ent

Week

M97-765: HIV RNA <400 copies/mL (ITT M=F)

Sample Size 400/100 mg 36 400/200 mg 34

65%61%

Rockstroh, Glasgow Meeting, 2000

Abbott M97-957: >2 PI-experienced• Study population: HIV+, >2 PI failure,

NNRTI naïve, HIV RNA >1000 (N=57)• Baseline: VL ~4.5 logs, CD4 ~245• Study treatment: lopinavir 400 or 533 mg

bid + ritonavir 100 or 133 mg bid + EFV + nucs X 48 weeks

• Preliminary results: 3 d/c for rx-related effects (2 CNS sx, 1 lactic acidosis)

0

20

40

60

80

100

0 2 5 8 12 16 20 24 32 40 48

Perc

enta

ge o

f pat

ient

s

71%71%

59%59%

Week:

400/100mg n = 29533/133mg n = 28

M98-957: Proportion <400 copies/mL (ITT M=F)

400/100mg BID 533/133mg BID

Heavily Pretreated Patients:A Definition

• Patients with:– a loss/lack of virologic response to at least 2

HAART regimens– have taken at least one member of each of the

approved antiretroviral drug classes (NRTI, NNRTI, PI)

Mocroft, et al. 3rd Salvage Workshop 2000

Heavily Pretreated Patients:EuroSIDA Cohort (1)

• 266 pts had 3-class experience; had taken >2 HAART regimens and started new salvage rx:– 40% decreased VL <1000, and 30% maintained

this decrease at 6 months– 55% had >1 log decrease and 45% maintained this

decrease at 6 months(55-70% virologic failure at 6 months)

– 55% decreased CD4 below baseline (imm.failure at 1 year)

– 5% had a new AIDS event/death (clinical failure at 1 year)

Mocroft, et al. 3rd Salvage Workshop 2000

Heavily Pretreated Patients:EuroSIDA Cohort (2)

• Predictors of virologic response:– Prior VL <500 cps/ml– Less prior rx (28% decline in probability/year rx)– Higher latest CD4 count– Central Europe resident

• Predictors of immunologic/clinical response:– Female– Lower latest VL – Fewer prior antiretrovirals

Eron, et al, AIDS 1998, #OP5.2

CNAA 2007: PI-experienced• Population: HIV+, >20 weeks combination

therapy with a PI; HIV RNA >500 cps/ml (N=99)

• Baseline experience: 72% 4-5 NRTI, 44% NNRTI; 60% 3-4 PI

• Duration: 48 weeks• Treatment: open label ABC + EFV + APV• Primary endpoint: safety/tolerability, antiviral

activity at 16 weeks

Eron, et al, AIDS 1998, #OP5.2

CNAA 2007: PI-experiencedResults

• Overall, 19 (26%) had HIV RNA <400 copies/ml at week 16

• Subgroup analyses:– NNRTI naïve, VL <40K (53%)– NNRTI naïve, VL >40K (23%)– NNTRI experienced, VL <40K (33%)– NNRTI experienced, VL >40K (7%)

Hammer, et al, 7th CROI, #LB7

ACTG 398: PI-experienced• Population: HIV+, >4 months of up to 3 prior PI;

HIV RNA >1000; prior NNRTI OK; (N=481)• Duration: 72+ weeks• Treatment:

– open label APV + ABC + EFV + ADV with • SQV sgc 1600 mg bid • IDV 1200 mg bid• NFV 1250 mg bid or• matching placebo (for 2nd PI)

• Primary endpoint: safety/antiviral activity/24 wks

Hammer, et al, 7th CROI, #LB7

ACTG 398: PI-experiencedResults

• Overall, 149 (31%) had HIV RNA <200 copies/ml at week 24

• Subgroup analyses:– NNRTI-naïve (43%) vs. experienced (16%)

• favors naïve subjects (p<0.001)– 1 PI exp (37%) vs. >2 PI exp (29%)

• no difference (p=0.16)– Dual PI rx (35%) vs. APV alone rx (23%)

• favors dual PI rx (p=0.002)

Raffi, et al., Glasgow Meeting 2000

New Drug in Experienced Pts: DAPD (nucleoside analog)

DAPD-101 Study• Study population: Failed prior ZDV or d4T + 3TC;

VL 5-250K cps/ml, CD4 >50 (N=24)• Baseline: VL 5 logs, CD4 ~350• Prior treatment experience:

– average number of antivirals – 6– average prior length of rx -- 4 years– 100% NRTI, >60% NNRTI, >80% PI

• Rx: DAPD at 200, 300, 500 mg bid; 3 groups washed out X 7d, 1 group added on X 15 days

DAPD-101: Median Change in HIV-1 RNA Treatment Experienced Cohorts

Study Day

DAPD BID TREATMENT WASHOUT

-2

-1.5

-1

-0.5

0

0.5

0 5 10 15 20

HIV

-1 R

NA

Med

ian

Cha

nge

from

BL

200 mg BID300 mg BID500 mg BID500 mg BIDAdd-On

Schooley, et al, Glasgow Meeting 2000

New Drug in Experienced Pts: Tenofovir (nucleotide analog)

Gilead 902 Study• Study population: On stable antiretroviral

regimen with VL >5K (N=189)• Baseline: VL 3.7 logs; CD4 ~350• Prior treatment experience:

– average prior length of rx – 4.6 years– Baseline mutations: 97% NRTI, 32% NNRTI, 57% PI

• Rx: tenofovir at 75, 150, or 300 mg qd (or placebo) X 48 weeks

Tenofovir: Gilead 902 Study

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0 4 8 12 16 20 24 28 32

Placebo 75 mg150 mg300 mg

Mean HIV RNA Change

(log10

copies./mL) from Baseline

300 mg TDF started

Weeks:

N = 189 175 181 176 170 164 164 105

Lalezari, et al, Durban AIDS Meeting 2000

New Drug in Experienced Pts: T-20 (fusion inhibitor)

T-20 205 Study• Study population: Prior T-20 experience (N=71)• Baseline: VL 4.8 logs, CD4 133• Prior treatment experience:

– average number of antivirals – 10– 80% were three-drug class experienced

• Rx: T-20 50 mg bid sq + other antiretrovirals chosen by hx and genotype X 48 wks

• Results: 14/71 (20%) had <0.5 log reduction;• 23/70 (33%) had >1 log reduction or VL <400

Lalezari, et al, Durban AIDS Meeting 2000

2.5

3

3.5

4

4.5

5

5.5

Baseline Week 8 Week 16 Week 24 Week 32

n=71

n=66 n=64

n=50

n=46

T20-205: Phase I follow-upViral Load Reduction -- Week 32

Vir a

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Salvage Therapy: Conclusions• Virologic failure occurs commonly; immunologic and

clinical failure also occur; all should be evaluated.• Predictors of response include adherence, VL, CD4,

resistance profile, number of active drugs, drug levels.• Newer drugs with novel resistance patterns and/or

mechanisms demonstrate activity, even in heavily pretreated patients.

• Novel study design may demonstrate activity AND provide benefit for the subjects.

• Further clinical research is needed.