This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
THE BODY PROThe HIV Resource for Health Professionals
The Body PRO Covers the XVII International AIDS Conference (AIDS 2008)Mexico City; August 3-8, 2008
This activity is supported by educational grants from
Faculty: David Wohl, M.D.Associate Professor of Medicine at the University of North Carolina at Chapel Hill
This activity is jointly sponsored by Postgraduate Institute for Medicine and The Body PRO.
David Wohl, M.D.
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
2
Faculty for This ActivityFaculty for This Activity
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.
DisclosuresDr. Wohl has been a consultant for Abbott Laboratories, Tibotec and Merck & Co. He has served on speakers bureaus for Abbott, Gilead, Roche Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, Tibotec and Merck. In addition, he has received research support from Abbott, Roche and Merck.
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
3
ACTG 5202: Study DesignACTG 5202: Study Design
• 96-Week, Randomized, Partially Blinded Study
• Comparing efficacy, safety and tolerability of regimens shown below as initial therapy for HIV-1 infection
Any CD4+ CountHIV-1 RNA ≥ 1,000 Copies/mL
≥ 16 Years of Age
Stratified by HIV-1 RNA (< or ≥ 100,000 Copies/mL)
ART-naïve N=1858
Randomized 1:1:1:1EFV
EFV QD
ATV/rQD
ATV/rQDART-Naïve
N = 1,858Randomized 1:1:1:1
QDTDF/FTC QD
ABC/3TC Placebo QD
ABC/3TC QD
TDF/FTC Placebo QD
TDF/FTC QD
ABC/3TC Placebo QD
ABC/3TC QD
TDF/FTC Placebo QD
Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303.
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
4
ACTG 5202: NIAID Therapeutic DSMB Findings and RecommendationsACTG 5202: NIAID Therapeutic DSMB Findings and Recommendations
Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303.
January 29, 2008: First Efficacy Review
• ABC/3TC showed excess virologic failures
Data Combined and Analyzed as Two Arms (ABC/3TC vs. TDF/FTC) Per DSMB Request
• Found highly significant differences
• ABC/3TC: Excess virologic failures occurred in patients with viral load ≥ 100,000 copies/mL
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
5
ACTG 5202: Primary Study End PointsACTG 5202: Primary Study End Points
Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303.
EfficacyTime to Virologic Failure
Early FailureWeeks 16 to 24
Confirmed Viral Load ≥ 1,000 Copies/mL
Later FailureWeek 24 On
Confirmed Viral Load ≥ 200 Copies/mL
Safety
Lab Abnormality at Least One Grade Higher Than Baseline
OR
Time to First Grade 3 or 4 Sign/Symptom
Tolerability Time to Modification of Originally Randomized Regimen
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
6
ACTG 5202: Timing and Type of Virologic FailureACTG 5202: Timing and Type of Virologic Failure
Tenofovir/Emtricitabine
(N = 399)
Abacavir/Lamivudine
(N = 398)
Total With VF* 26 (7%) 57 (14%)≥ 200 Copies/mL
≥ 24 Weeks
Prior < 200 Copies/mL
15 29
≥ 200 Copies/mL
≥ 24 Weeks
No Prior < 200 Copies/mL
2 9
≥ 1,000 Copies/mL
< 24 Weeks
No Prior < 200 Copies/mL
9 19
Post hoc analysis: There was no
significant difference in the risk of virologic rebound (P = 0.247)
for subjects achieving two
< 50 copies/mL on therapy.
Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303.
*VF = virologic failure
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
Adapted from Martin Markowitz et al. AIDS 2008; abstract TUAB0102.
Group VF* Type 3TC EFV RAL TDF
RAL 100 NR† M184M/I/V K65K/R
V151I, N155H D232D/N, G163R/G
K65K/R
RAL 100 REL¹ M184M/I/V Y143C‡
RAL 200 NR† M184M/I/V N155H
RAL 200 NR† M184V
RAL 200 REL¹
RAL 200/400 REL¹,²
EFV NR† K65R G190E S230S/N∞ K65R
EFV REL¹,² M184VY188L
K103K/N
NOTE: Percentage of virologic failures in RAL 6/160 (3.8%) and in EFV 2/38 (5.3%).*VF = virologic failure†NR = non-response; > 400 copies/mL at week 24 or early discontinuation; All achieved > log10 decrease in HIV RNA at nadir.¹REL = virologic relapse; > 400 copies/mL after initial response of < 400 copies/mL or 1.0 log10 increase above nadir level.2Failure occurred after week 48.‡Mutation developed after patient was a virologic failure.∞A common polymorphism that does not affect raltegravir sensitivity in phenotypic assays. All other mutations listed were associated with reduced drug sensitivity.
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
22Protocol 004: Percent of Patients With Grade 3 / 4* Laboratory Abnormalities
Protocol 004: Percent of Patients With Grade 3 / 4* Laboratory Abnormalities
Fasting Total Cholesterol > 300 mg/dL 2 (5.3) 0 (0.0)
Fasting Triglycerides > 750 mg/dL 3 (7.9) 0 (0.0)
Lipase > 3 x ULN 0 (0.0) 2 (1.3)
Pancreatic Amylase > 2 x ULN 0 (0.0) 4 (2.5)
Adapted from Martin Markowitz et al. AIDS 2008; abstract TUAB0102.
*No grade 3 or 4 abnormalities were reported in either treatment group for the following parameters: hemoglobin, platelet count, fasting glucose, creatinine, and total bilirubin.
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
23
EFV vs. LPV/r: Study DesignEFV vs. LPV/r: Study Design
Juan Sierra Madero et al. AIDS 2008; abstract TUAB0104. Reprinted with permission.
Screened (N = 264)
ZDV/ 3TC 300/150 mg BIDZDV/ 3TC 300/150 mg BIDSubstitution of AZT for ABC allowedSubstitution of AZT for ABC allowed
(N = 14; EFV 6 and LPV/r 8)(N = 14; EFV 6 and LPV/r 8)
(1:1)
National Multicenter, Open-Label, Randomized, 48-Week Study to Compare the Virological Success of EFV vs. LPV/r in Treatment-Naïve HIV-1 Infected Subjects
Antiretroviral Strategy Update: Highlights From AIDS 2008
25
EFV vs. LPV/r: Proportion of Patients With HIV RNA < 400 Copies/mLEFV vs. LPV/r: Proportion of Patients With HIV RNA < 400 Copies/mL
Juan Sierra Madero et al. AIDS 2008; abstract TUAB0104. Reprinted with permission.
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
26
EFV vs. LPV/r: Change of Median CD4+ Cell CountsEFV vs. LPV/r: Change of Median CD4+ Cell Counts
Juan Sierra Madero et al. AIDS 2008; abstract TUAB0104. Reprinted with permission.
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
27
TMC278–C204: Study DesignTMC278–C204: Study Design
Mario Santoscoy et al. AIDS 2008; abstract TUAB0103. Reprinted with permission.
Ongoing (extended to 5 years), randomized, active-controlled, dose-ranging Phase IIb study in ARV-naïve patients.
Primary objective to evaluate the TMC278 efficacy (ITT-TLOVR) and safety dose-response relationship at Week 48.
EFV = efavirenz; ITT = intent to treat; TLOVR = time to loss of virologic response NRTI backbone chosen by investigator and is either AZT/3TC or TDF/FTC administered as fixed-dose combinations where available
Screening and Randomization
1:1:1:1
ARV-Naïve Patients (N = 368)
HIV RNA 5,000 Copies/mL
Primary Analysis at 48 Weeks
Analysis at 96 Weeks
96 weeks
TMC278 25 mg QD + 2 NRTIs N = 93
TMC278 75 mg QD + 2 NRTIs N = 95
TMC278 150 mg QD + 2 NRTIs N = 91
EFV 600 mg QD + 2 NRTIs N = 89
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
28TMC278–C204: High Response Rate and Sustained Virologic Response Over 96 Weeks Similar to EFV
TMC278–C204: High Response Rate and Sustained Virologic Response Over 96 Weeks Similar to EFV
Mario Santoscoy et al. AIDS 2008; abstract TUAB0103. Reprinted with permission.
HIV-1 RNA < 50 Copies/mL to Week 96 (ITT-TLOVR Algorithm)
• No clinically relevant changes in adrenal and thyroid parameters were observed
ECG
• Increases in QTc interval were seen with all TMC278 doses and EFV up to 48 weeks, which then stabilizedup to Week 96– increases were primarily seen with the AZT/3TC backbone– mean increase was lowest with TMC278 25 mg
Mario Santoscoy et al. AIDS 2008; abstract TUAB0103. Reprinted with permission.
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
32
GRACE: Study Design andBaseline CharacteristicsGRACE: Study Design andBaseline Characteristics
Judith Currier et al. AIDS 2008; abstract THPDB202. Reprinted with permission.
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
33
GRACE: 24-Week Interim Analysis: Efficacy and SafetyGRACE: 24-Week Interim Analysis: Efficacy and Safety
Virologic Response (VL < 50 Copies/mL)
• At Week 24, mean increase in CD4 cell count in women was 86 cells/mm3 (ITT-NC=F)
• At Week 24, discontinuation rate for women was 24.4% -- Discontinuations were generally unrelated to VF (0.6%) or AEs (7.8%)
Safety and Tolerability in Women
• Most common grade 2-4 adverse events at least possibly related to study drug:
—Nausea (6.1%)— Diarrhea (5.6%)— Rash (2.8%)— Weight gain (2.8%)
• Serious AEs were reported in 16.7% (N = 30) of women
— Most common was pneumonia, reported in 4.4% (N = 8) of women
• No major issues with Grade 2-4 laboratory abnormalities were noted
ITT, intention-to-treat;TLOVR, time to loss of virologic response algorithm;TLOVR-non-VF, algorithm excluded patients who discontinued for reasons other than virologic failure;NC=F, non-completer=failure
Judith Currier et al. AIDS 2008; abstract THPDB202. Reprinted with permission.
The Body PRO
Antiretroviral Strategy Update: Highlights From AIDS 2008
34
• Visit The Body PRO for comprehensive coverage of AIDS 2008.This presentation was created to accompany The Body PRO's summaries of key research presented at AIDS 2008, by David Wohl, M.D. Learn more at: TheBodyPRO.com/AIDS2008
• In addition, be sure to browse through The Body PRO's extensive coverage of AIDS 2008, which includes:– Summaries and analyses of research on a wide array of clinical
subjects.– Interviews with top researchers discussing the results of noteworthy
studies.– Audio podcasts you can play online or download to your computer or
MP3 player.– Narrated, online slide presentations highlighting major study results.
• Visit TheBodyPRO.com/AIDS2008 today for a full listing of our conference materials!