Management of Treatment-Experienced Patients: A Summary of Key CROI 2008 Research Management of...

Management of Treatment-Experienced Patients: A Summary of Key CROI 2008 Research

Management of Treatment-Experienced Patients

The Body PRO Coverage of the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008)

February 3-6, 2008Boston, Mass.

Faculty:Kathryn Anastos, M.D.Cal Cohen, M.D., M.S.David Wohl, M.D.

Cal Cohen, M.D., M.S.

CROI 2008:Coverage From

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Kathryn Anastos, M.D.Kathryn Anastos, M.D., is the Executive Co-Director for Clinical and Scientific Programs of WE-ACTx (Women's Equity in Access to Care and Treatment, a community-based organization committed to providing HIV primary care, including antiretroviral therapy, to female survivors of genocidal rape in Rwanda. She has also developed and serves as the Principal Investigator of the Rwandan Women's Cohort Study (RWISA), funded by the U.S. National Institutes of Health (NIH). She is currently Professor of Medicine, Epidemiology and Population Health at Albert Einstein College of Medicine, Bronx, N.Y. Additionally, since 1993, Dr. Anastos has served as the Principal Investigator for the New York City/Bronx Consortium of the Women's Interagency HIV Study (WIHS), also funded by NIH.

Cal Cohen, M.D., M.S.Dr. Cal Cohen is the research director of Harvard Vanguard Medical Associates and Community Research Initiative of New England in Boston, Mass. He is also a clinical instructor at Harvard Medical School. In addition, he works as an HIV clinical management consultant and internist at Harvard Pilgrim Health Care. Dr. Cohen holds appointments at Brigham and Women's Hospital and Beth Israel Hospital, both in Boston, Mass. In addition to caring for HIV-infected patients and directing clinical research at a large HIV community-based research site, Dr. Cohen is actively involved in evaluating new antiretroviral therapies, the durability and longevity of the benefits from such therapies and issues regarding compliance and adherence. Dr. Cohen has served as a consultant to or has received honoraria or research support from Abbott Laboratories, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and Tibotec.

David Wohl, M.D. Dr. Wohl is an associate professor of medicine at the University of North Carolina at Chapel Hill, and co-directs HIV services for the North Carolina Department of Corrections. Dr. Wohl is an investigator in the NIAID-sponsored AIDS Clinical Trials Group (ACTG) and a member of the ACTG Complications of HIV Disease Research Agenda Committee. His research focuses on metabolic and infectious complications of HIV and its therapies, as well as issues related to medication adherence and access to care—particularly among incarcerated inmates with HIV infection. Dr. Wohl has served as a consultant to or has received honoraria or research support from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck & Co, Roche Laboratories and Tibotec.

This activity is supported by an educational grant from

Faculty


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About This Slide Presentation

• This presentation was created to accompany The Body PRO's summary of key research presented at CROI 2008, featuring reports by Kathryn Anastos, M.D., Cal Cohen, M.D., M.S., and David Wohl, M.D. For more information about this program, please visit us on the Web at: TheBodyPRO.com/CROI2008

• Please feel free to use this slide presentation for personal reference or for your own presentations; however, we ask that you not modify any aspects of the slides contained within this presentation, so proper attribution can be retained. If you would like to publish all or part of this presentation, or repost any of these slides online, permission must first be obtained from Body Health Resources Corporation.

• Our gratitude goes out to all the researchers who granted permission for their slides to be adapted for this presentation.


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HIV Resistance Incidence on a Province-Wide Basis

0

100

200

300

400

500

600

1996

1998

2000

2002

2004

2006

2008

3TC

NRTI

NNRTI

PI

Any

Number of New Cases

of Resistance Detected

Viviane Lima et al. CROI 2008; abstract 895. Reprinted with permission.


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VICTOR-E1: Mean Change in HIV-1 RNA From Baseline at Week 48 All ITT Subjects

*Comparing VCV to Control based on ANOVAMissing values of change from baseline imputed by the average of immediately preceeding and following non-missing values; in other cases, missing values imputed by zero.

-1.77 -1.75

-0.79

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Me

an

Ch

an

ge

in

HIV

-1 R

NA

Fro

m

Ba

se

lin

e (

log

10

co

pie

s/m

L)

VCV 20 mg + OBTn = 40


Placebo + OBTn = 35

Difference: -0.98P = 0.0017*

Difference: -0.98P = 0.0026*

Primary Study Endpoint Overall Population

-1.75

-1.47

-1.14

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0



Placebo + OBTn = 10

Difference: -0.61

Difference: -0.33 M

ea

n C

ha

ng

e i

n H

IV-1

RN

A F

rom

B

as

eli

ne

(lo

g 1

0 c

op

ies

/mL

)

Subjects Baseline HIV-1 RNA > 100,000

copies/mL

Barry Zingman et al. CROI 2008; abstract 39LB. Reprinted with permission.


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VICTOR-E1: Percentage of Subjects With HIV-1 RNA < 400 Copies/mL at Week 48

24 9 7 6 6 6 13 11 16 13 11

Overall By No. Active Drugs in OBT*

n = 26

% o

f Sub

ject

s

67%71%

83%

69%

57%60%

83%

85%

46%

25%26%

33%

45%

18%

0%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%VCV 30 mg + OBT

VCV 20 mg + OBT

Placebo + OBT

7 8 7

≥3 2 1 0

P = 0.0004 30 mg

* OSS: Defined as fully sensitive

treatment in OBT by Monogram PhenoSense.

Partially sensitive patients

were designated as resistant.



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VICTOR-E1: Adverse Event Rate by Time on Study

*Rate > 10/100 person-years.

All Casualties and SeveritiesAll Patients Receiving One Dose

VCV 30 mg + OBTRate

VCV 20 mg + OBTRate

Placebo + OBT Rate

Total Exposure in Person-Years (P-Y)* 33.2 34.67 22.39

SAE’s n (P-Y) 4 (12) 5 (14.4) 5 (22.3)

Any Adverse Event 111.4 112.5 147.4Diarrhea 45.2 31.7 40.2Respiratory Symptoms 24.1 51.9 22.3

Nausea 15.1 8.7 22.3Pyrexia 15.1 11.5 17.9Dizziness 15.1 2.9 17.9Headache 15.1 8.7 31.2Tinea Pedis 12.1 0 4.5Lymphadenopathy 9.0 20.2 8.9Depression 9.0 11.5 26.8Musculoskeletal Pain 9.0 8.7 40.2Asthenia 6.0 2.9 13.4Fatigue 6.0 14.4 13.4Upper Abdominal Pain 3.0 14.4 0Flatulence 3.0 5.8 17.9Anorexia 0 0 13.4



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MOTIVATE: Percentage of Patients With HIV-1 RNA < 50 Copies/mL at Week 48 by Screening HIV-1 RNA* and by Baseline† CD4+ Cell Count

David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.


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MOTIVATE: Percentage of Adverse Events Occurring in ≥ 5% of Patients in Any Group (Unadjusted for Study Treatment Exposure)

David Hardy et al. CROI 2008; abstract 792. Reprinted with permission.


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Screen and Baseline Tropism Reclassifications Amongst Subjects With R5 Virus Only by Standard Trofile

Jacqueline Reeves et al. CROI 2008; abstract 869. Reprinted with permission.


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BENCHMRK-1 & 2: Combined EfficacyPercent of Patients With HIV RNA < 50 Copies/mL at Week 48 by Genotypic Sensitivity Score (GSS)

For patients with GSS = 1, 4 ART agents represented at least 80% of the active agents in OBT: darunavir (52%, 52% in raltegravir and placebo groups, respectively), enfuvirtide (8%, 16%), tenofovir (12%, 6%), and tipranavir (11%, 11%).

David Cooper et al. CROI 2008; abstract 788. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Stations, New Jersey, USA, All Rights Reserved


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BENCHMRK-1 & 2: Combined EfficacyPercent of Patients HIV RNA < 50 Copies/mL At Week 48 by PSS Based on Upper and Lower Cutoffs

The analysis by PSS score has been reanalyzed using the upper cutoff to better account for the impact of partial ART activity.Isolates with fold-change IC50 above the lower but below the upper cutoff are now reported as "partially sensitive." The upper cutoff was developed as the lower

cutoff may underestimate partial ART activity in a regimen. At the time the BENCHMRK studies were initiated, only the lower cutoff was reported. The efficacy by PSS has been reanalyzed using the upper cutoffs, where

available, to better account for the impact of partial ART activity.Conclusion: At all levels of PSS, the results using the upper and lower cutoffs are similar, confirming the contribution of raltegravir in the treatment regimen.


1

BENCHMRK-1 & 2 Combined Efficacy Percent of Patients With HIV RNA <50 copies/mL

at Week 48 by PSS Based on Upper and Lower cutoffs

Percent of PatientsNPSS

PSS = 0 (Based on lower cutoff )

PSS = 1 (Based on lower cutoff)

Raltegravir + OBT Placebo + OBT

0 20 40 60 80 100

51

52

61

48

71

70

2

8

29

13

48

43

m518p18p19bar50PSScutoffs012wk48

65

33

137

71

221

313

44

12

69

54

108

153


PSS = 0 (Based on upper cutoff)

PSS = 1 (Based on upper cutoff)

PSS >= 2 (Based on lower cutoff)

PSS >= 2 (Based on upper cutoff)

Virological failures carried forward

n


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BENCHMRK-1: Summary of Clinical Adverse Events (AEs)


(n = 232) (n = 118) Difference From Placebo†

% % % (95% CI) P-Value

Mean Follow-Up (Weeks)

% Patients With: Any AE

54.5

90.9

38.6

84.7

6.20 (-0.7, 14.4)

0.105

Drug-related‡ AE

48.7 54.2 -5.53 (-16.4, 5.6)

0.366

Serious AE

19.8 17.8 2.03 (-7.1, 10.2)

0.774

Serious Drug-Related AE 3.0 0.8 2.17 (-1.8, 5.4)

0.275

Deaths

1.3 2.5 -1.25 (-6.0, 1.7)

0.409

Discontinued Due to AE

1.7 3.4 -1.67 (-6.8, 1.6)

nps§

†Tests of significance were performed on the percentage of patients with at least one adverse event in the category. The 95% CIs were calculated using Miettinen and Nurminen's method. P-Values were generated using the Fisher exact test.

‡Determined by the investigator to be possibly, probably, or definitely drug related.

§nps=not pre-specified for statistical analysis.



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DUET-1: Response (< 50 Copies/mL) By PSS (DRV FC < 10)* at Week 48

Richard Haubrich et al. CROI 2008; abstract 790. Reprinted with permission.


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DUET-1: Response (< 50 Copies/mL) By PSS (DRV FC < 40)* at Week 48

Richard Haubrich et al. CROI 2008; abstract 790. Reprinted with permission.


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TITAN: Number of VFs and Resistance Development in VFs

Sandra De Meyer et al. CROI 2008; abstract 874. Reprinted with permission.


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TITAN: Proportion of Isolates Remaining Susceptible to PIs Upon VF (Phenotypic Antivirogram Data)

Sandra De Meyer et al. CROI 2008; abstract 874. Reprinted with permission.

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