# Presentation: 738593

## Response Rates in Heavily Pretreated HIV+ Patients

- Roy M. Gulick, MD, MPH
- Cornell 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

## GART: HIV RNA Changes by Number of Active Drugs

- 0

- -0.25

- -0.50

- -0.75

- -1.00

- -1.25

- No. of active drugs

- Change (log)

- % of patients

- HIV RNAchanges(log)

- GART  n=78
- No GART  n=75

****

****

- Baxter, et al., AIDS 2000

## Therapeutic Drug Monitoring:  VIRADAPT

**Time, mo**
**0****	****3****	****6**

**0.05**
**-0.15**
**-0.35**
**-0.55**
**-0.75**
**-0.95**
**-1.05**
**-1.35**
**-1.55**

**HIV RNA, log decrease**

- 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

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

- Deeks, et al, J Infect Dis 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

- Percent alive and AIDS-free

- Grabar, et al, Ann Intern Med 2000

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

| Regimen
Cohort | Virologic failure
(VL >500) | Immune + clinical failure | Clinical events |
| --- | --- | --- | --- |
| 1st HAART | 40% | 20% | 5% |
| 2nd HAART | 50% | 30% | 24% |
| 3rd HAART | 67% | 40% | 25% |

- Mocroft, et al.  3rd Salvage Workshop, 2000

## Prospective Studies of Salvage Rx:  First Failures

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

## 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% | none |
| SQVsgc | -0.2 logs | 10% | +37 |
| IDV | -0.6 logs | 37% | +22 |

- Para, et al.  J Infect Dis 2000

## 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)

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

## 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)

- Gulick, et al, J Infect Dis 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)

- Feinberg, et al.  Glasgow Meeting, 2000

## M97-765: HIV RNA Mean Change from Baseline

**log****10**** copies/mL**

**Week**

**At Week 2, NRTIs were **
**switched and NVP added **

**At Baseline, PI was**
**switched to lopinavir/r**

- Feinberg, et al.  Glasgow Meeting, 2000

**Notes:**
The primary analysis for this study was to look at the proportion of subjects with an HIV RNA < LOD at Week 24.

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

**Percent**

**Week**

-    _Sample Size_
-    400/100 mg	36
-    400/200 mg	34

**65%**
**61%**

- Feinberg, et al.  Glasgow Meeting, 2000

**Notes:**
The primary analysis for this study was to look at the proportion of subjects with an HIV RNA < LOD at Week 24.

## 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)

- Rockstroh, Glasgow Meeting, 2000

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

**Percentage of patients**

**71%**** **
**59%**

**Week:**

**400/100mg n = 29****	**
**533/133mg****	**** n = 28****	**

## 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)

## 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

- Mocroft, et al.  3rd Salvage Workshop 2000

## 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-experiencedResults

- 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%)

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

## 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-experiencedResults

- 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)

- Hammer, et al, 7th CROI, #LB7

## 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

- Raffi, et al., Glasgow Meeting 2000

## 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 RNA Median Change from BL**

- 200 mg BID
- 300 mg BID
- 500 mg BID
- 500 mg BID
- Add-On

## 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

- Schooley, et al, Glasgow Meeting 2000

## Tenofovir:  Gilead 902 Study 

**Notes:**
Abstrct 740a Wednesday
Baseline resistance mutations to NRTI were very common.
Further selection of NRTI mutations occurred usually consistent with concomittant nuleoside therapy. 3 subjects developed HIV with K65R mutations (still  blinded).

## 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

## T20-205: Phase I follow-upViral Load Reduction -- Week 32 

- <date/time>

- n=71

- n=66

- n=64

- n=50

- n=46

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

**Viral Load Change from Baseline**
**(log****10 ****copies / mL)**

## 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.