# Presentation: 714305

## RESIST Trials - Grade 3 or 4 AST, ALT or Total Bilirubin:Actions and Outcomes

| 
Action Taken: | TPV/r
N=748 | CPI/r
N=737 |
| --- | --- | --- |
| Total Number of Grade 3 or 4  ALT, AST, or Bilirubin | 74 (9.9) | 26 (3.5) |
|  |  |  |
| Continued treatment | 57 (7.6%) | 26 (3.5%) |
| No interruption | 47 (6.3%) | 23 (3.1%) |
| Interrupted | 10 (1.3%) | 3 (0.4%) |
| Discontinued treatment | 17 (22.7%) | 0 (0%)   |
| With Grade 3  | 7 (0.9%) |  |
| With Grade 4 | 10 (1.3%) |  |

## Lipid Lowering Agent Use Among RESIST Participants

- Note: agents included are statins, fibrates, and omega-3 fatty acids

## Effect of LLD on triglycerides: RESIST

## Risk Confirmed (3 times) Triglycerides Above 500 mg/dl for RESIST Patients

- Probability of event (%)

- Note: Included are RESIST participants who had baseline triglycerides <500 and developed at least 3 determinations above 500 mg/dL

## RTV-boosted drug interaction assessments

## Reduced GSS as Key Mutations Increase

## Hypertriglyceridemia:Relative Contribution of TPV and RTV 

- Median baseline and maximal increase in serum triglycerides accordingto dose among Trial 1182.52 participants

| 
Dose | n | Median (Q25, Q75) baseline (mg/dL) | Median (Q25, Q75) maximum increase (mg/dL) |
| --- | --- | --- | --- |
| 500/100 | 73 | 263 (168, 430) | 161 (58, 403) |
| 500/200 | 72 | 221 (172, 332) | 271 (99, 558) |
| 750/200 | 71 | 223 (173, 416) | 196 (72, 421) |

## Analysis of Treatment Response at Week 48

- n = Number of responders
- N = Number of evaluable patients
- Treatment difference and confidence interval weighted for the size of enfuvirtide and PI strata

|  | RESIST-1 |  |  |  |  |  | RESIST-2 |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | Treatment Group |  |  |  |  |  |  |  |  |  |  |  |
|  | TPV/r |  |  | CPI/r |  |  | TPV/r |  |  | CPI/r |  |  |
|  | n | (%) | N | n | (%) | N | n | (%) | N | n | (%) | N |
| Key analysis |  |  |  |  |  |  |  |  |  |  |  |  |
| FAS (week 24) (NCF, as randomised) | 130 | (41.8) | 311 | 74 | (23.9) | 309 | 177 | (40.7) | 435 | 76 | (17.8) | 428 |
| FAS (week 48) (NCF, as randomised) | 103 | (33.1) | 311 | 49 | (15.9) | 309 | 148 | (34.0) | 435 | 64 | (15.0) | 428 |
| Sensitivity analysis |  |  |  |  |  |  |  |  |  |  |  |  |
| PPS (week 48) (NCF, as randomised) | 66 | (35.7) | 185 | 38 | (19.7) | 193 | 102 | (37.4) | 273 | 41 | (16.1) | 254 |

## K-M Probabilities for Grade 3 or 4 ALT and/or ASTThrough 120 Weeks in 8 HIV+ Integrated Trials*

| 29 | 25 | 6 | 2 | 1 | 0 |
| --- | --- | --- | --- | --- | --- |
| 1870 | 1445 | 1019 | 417 | 148 | 133 |

**# At Risk-**

**Events-**

- * Includes TPV/r patients from 1182.2, 1182.4, 1182.6, 1182.17, 1182.51, 1182.52, and CPI/r patients who switched to TPV/r 500/200 from RESIST trials 1182.12 and 1182.48

## RESIST StudiesCox Regression Model for Risk of Grade 3 or 4 ALT/AST

- Baseline risk factors for Grade 34 ALT/AST are similar in TPV/r  and CPI/r
- Independent variables: age, gender, race, ΔCD4, baseline triglycerides, NRTI, NNRTI, viral load, CDC HIV stage, duration of HIV infection

| Factor/Comparison |  |  |
| --- | --- | --- |
|  |     Risk Ratio |      95% CI |
| Treatment Group:TPV/r vs CPI/r | 2.4 | 1.5 – 3.8 |
| Baseline ALT,AST Total Bilirubin:(Grade > 1 vs Grade < 1) | 2.5 | 1.3 – 4.8 |
| CD4+ Cell Count at Baseline:     >200 vs ≤200 cells/mm3 | 2.0 | 1.3 – 2.5 |
| HBV or HCV Co-infection:Co-infected vs not co-infected | 2.3 | 1.4 – 3.7 |

## Predictors of TPV/r Antiviral Response Multiple Regression Model

***P***** Value**

**Estimate**

- <0.01

**0.17**

**TPV Score **
**(per mutation)**

- <0.01

**-0.24**

**Per Available Drug****in OBR**

- <0.01

**-0.91**

**Enfuvirtide Use**

- <0.01

**-1.25**

**Tipranavir/r**

**24 Weeks**

**Parameter**

## Tipranavir trough concentrations with proton pump inhibitors

## Trial 1182.52Impact of IQ on 14-Day Viral Load Response 

- Change from baseline at 2 weeks (log10)

- Inhibitory quotient

- 30

- -3

- -2

- -1

- 0

- 1

- 0.1

- 1

- 10

- 100

- 1000

- 10,000

## 1182.52Impact of IQ on 14-Day Viral Load Response 

- 0.05

- -0.13

- -1.03

- -1.16

- -0.98

- -1.25

- -1.4

- -1.2

- -1

- -0.8

- -0.6

- -0.4

- -0.2

- 0

- ≤5

- >5–30

- >30–50

- >50–100

- >100–150

- >150

- Inhibitory quotient

- HIV RNA log10 change from baseline

**7**

**27**

**14**

**34**

**25**

**58**

- 0.2

## RESIST Trials24 Week VL Change according to IQ in Patients not using Enfuvirtide

## RESIST Trials24 Week VL Change according to IQ in Patients using Enfuvirtide

## Antiviral activity of tipranavir (ViroLogic)Non-clade B isolates

- Antiviral activity of tipranavir (ViroLogic)Non-clade B isolates

- Mean EC50 (nM)

**102**
**74**
**116**

**38**
**124**

**Ref. NL4-3 (B virus)**
**EC****50**** = 62 nM**

- EC50 values measured at ViroLogic Inc (South San Francisco) using the PhenoSense assay

- No evidence that other HIV-1 clades and circulating recombinant forms
- have lower susceptibility to TPV than HIV-1 clade B

- Clade B biological cutoff value for TPV not yet determined
- (1.6X LPV or 99nM)*

- * Parkin et al, AAC, **2004**, *48*, 437-443

- (three isolates each except two for clade H)

## VIRCO / ViroLogic in Tipranavir Phenotype

## Mutations Which Increase Susceptibility to TPV

| Amino acid | Median FC IC50 |  | N | Parameter Estimate | P-value |
| --- | --- | --- | --- | --- | --- |
|  | Wild type | Mutated |  |  |  |
| 18L | 1.00 | 0.50 | 5 | -0.55 | 0.035 |
| 30N | 1.20 | 0.50 | 26 | -0.54 | <0.001 |
| 50V | 1.10 | 0.70 | 19 | -0.31 | 0.021 |
| 54L | 1.10 | 0.70 | 21 | -0.31 | 0.018 |
| 77I | 1.20 | 1.00 | 102 | -0.18 | 0.011 |
| 88D | 1.10 | 0.60 | 26 | -0.38 | 0.001 |