pablo tebas, md. actg 5202/5224s startmrk metabolic study steal (abacavir and inflammatory...
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Pablo Tebas, MD
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ACTG 5202/5224sSTARTMRK Metabolic StudySTEAL (abacavir and inflammatory
markers)EUROSIDA and risk of CKDHOPS and risk of fracturesVitamin D studiesCancer studiesHepatitis
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A5224s
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A5224s
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A5224s
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In low HIV RNA stratum, in comparison between ABC/3TC vs. TDF/FTC: significantly greater increase in TC, LDL, HDL with both EFV and ATV/r; greater increase in TG with ATV/r
Median Change in Fasting Lipids (Week 48, mg/dL)
Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.
Change in Calculated Creatinine Clearance, (mL/min)
TC LDL HDL TG
ABC/3TC
ATV/r 29 13 8 24
EFV 40 21 12 15
P-value <0.001 0.002 <0.001 0.26
TDF/FTC
ATV/r 10 2 5 14
EFV 22 10 8 13
P-value <0.001 0.002 <0.001 0.26
Week 48 Week 96
ABC/3TC
ATV/r 3.1 6.1
EFV 4.3 7.8
P-value 0.17 0.33
TDF/FTC
ATV/r -0.9 -2.6
EFV 4.1 4.9
P-value 0.001 <0.001
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A5224s
* -linear regressionNo significant interaction of NRTI and NNRTI/PI components (p=0.63)
**
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A5224s
*
*
* -linear regressionNo significant interaction of NRTI and NNRTI/PI components (p=0.69)
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A5224s (n=269) 5.6% had ≥ 1 fracture (all traumatic) No statistically significant differences between NRTI
components or NNRTI/PI components in fracture rate (Fisher’s exact) or time to first fracture (log-rank test)
A5202 (n=1857) 4.3% fracture rate (12.7% of those atraumatic) No statistically significant differences between NRTI
components or NNRTI/PI components in fracture rate (Fisher’s exact), incidence or time to first fracture (log-rank test) TDF/
FTC+EFV
(n=464)
TDF/FTC+AT
V/r(n=465)
ABC/3TC+EFV(n=465)
ABC/3TC+ATV/
r(n=463)
Total(n=1857)
% with ≥ 1 fractures
4.5% 4.5% 4.7% 3.4% 4.3%
Incidence per 100 pt-year
1.8 1.8 1.9 1.4 1.7A5224s
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No statistically significant differences between NRTI components and NNRTI/PI components (Fisher’s exact test)
% Limb fat loss from 0 to 96 weeks
TDF/FTC+EFV(n=56)
TDF/FTC+ATV/r(n=45)
ABC/3TC+EFV(n=53)
ABC/3TC+ATV/r(n=49)
Total(n=203)
≥ 10%Primary
14.3%
(6.4%,25.3%)
15.6%
(7.0%,28.6%)
18.9%
(9.4%, 31.6%)
16.3% (7.5%,28.8%)
16.3%
(11.8%, 22.0%)
≥ 20% Post hoc
8.9% 0% 3.8% 6.1% 4.9%
A5224s
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A5224s
**
* -linear regressionNo significant interaction of NRTI and NNRTI/PI components (p=0.67)
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A5224s
*
*
* -linear regressionNo significant interaction of NRTI and NNRTI/PI components (p=0.66)
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Bone All regimens appeared to produce an initial bone loss with
subsequent stabilization or even improvement after week 48 TDF/FTC led to greater BMD loss in hip and lumbar spine than
ABC/3TC ATV/r led to greater BMD loss in lumbar spine (but not hip) than
EFV Fractures were similarly distributed among study arms
Fat Regimens containing TDF/FTC or ABC/3TC increased limb fat and
trunk fat and were not significantly different ATV/r led to greater gain in limb fat and trunk fat than EFV Lipoatrophy, even the mild protocol-defined form, occurred in
16% (95% CI 12-22 %) of the participants and was not significantly different between TDF/FTC and ABC/3TC or between EFV and ATV/r
A5224s
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Randomized, double-blind study comparing RAL vs EFV, both with TDF/FTC
Week 96 lipids (all pts, n=563) EFV increased TC, HDL-C,
LDL-C, TG, and glucose sig more than EFV
No sig difference in total/HDL chol ratio
Dexa substudy (n=111) Overall, limb fat increased
over time By week 96, 3/37 pts on
RAL, 2/38 on EFV had >20% loss of limb fat
DeJesus E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 720.
‡ p <0.001* P =0.025
‡‡
‡
‡
*
18.2
17.0
18.1
17.7
Raltegravir Group 55 4037
Efavirenz Group 56 4638
Number of Contributing Patients
Mean Percent (%) Change (SE) in Appendicular Fat Over Time
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VA cohort 19424 patients 278 MIsNo association with ABC
Quebec nested case control 125 MIs 1084 ControlMild association
Bedimo et al.MOAB202
Durand et al.TUPEB175
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Primary Results: Similar virologic results Increased risk of CV events in ABC/3TC group (8 ABC/3TC vs 1
TDF/FTC, p=0.48) not explained by lipid changes No difference in renal outcomes Loss of bone density in TDF/FTC vs gain in ABC/3TC group
Inflammatory Marker Substudy 14 biomarkers (inflammatory/renal, thrombotic, endothelial function)
measured at weeks 0, 12, 24, and 48 Primary analysis (change from week 0-12): No significant association
between use of ABC/3TC and change in markers Alternative explanation for ABC/3TC association with CVD needed
HIV +Suppressed
on 2 NRTI + PI or NNRTI
(N=357)
T DF/FTC FDCn=179
ABC/3TC FDCn=178
Martin A, et al. Clin Infect Dis. 2009 Nov 15;49(10):1591-601; Emery S, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 718.
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Analysis of patients with ≥3 creatinine measurements + body weight, 2004 6,842 patients with 21,482 person-years of follow-up
Definition of CKD (eGRF by Cockcroft-Gault) If baseline eGFR ≥60 mL/min/1.73 m2, fall to <60 If baseline eGFR <60 mL/min/1.73 m2, fall by 25%
225 (3.3%) progressed to CKD
• Risk factors for CKD on TDF: age, HTN, HCV, lower eGFR, lower CD4+ count
Cumulative Exposure to ARVs and Risk of CKD
Kirk O, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 107LB.
Univariable Multivariables
IRR/year 95% CIP-
valueIRR/year
95% CI P-value
Tenofovir 1.32 1.21-1.41<0.00
011.16
1.06-1.25
<0.0001
Indinavir 1.18 1.13-1.24<0.00
011.12
1.06-1.18
<0.0001
Atazanavir 1.48 1.35-1.62<0.00
011.21
1.09-1.34
0.0003
Lopinavir/r 1.15 1.07-1.23<0.00
011.08
1.01-1.16
0.030
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Comparison of HOPS cohort (n=8456) vs National Hospital Discharge Survey and National Hospital Ambulatory Care Medical Survey Adjusted for age and gender
Fractures: 276 during median 4.8 yrs follow-up
Risk factors for fractures Age >47 Nadir CD4+ count <200 HCV co-infection Diabetes Substance use
Conclusion: Fracture rates are higher in HIV infected population and rate is increasing with age
* Indirectly standarized using rtes from NHAMCS-OPD data
Dao C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 128.
Gender-adjusted rates of fracture among adults aged
25-54 years
HOPS*P = 0.01
NHAMCS-OPDP = 0.32
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Retrospective seasonal analysis of Vitamin D deficiency within Swiss cohort
Started ARV in: Fall (n=108); Spring (n=103) 75% men; age = 37;
White = 87%; CD4+ 227; BMI = 22.9
ARVs: TDF – 17%; NNRTIs – 43%; PI -56%
Conclusions Vitamin D deficiency is
common, but seasonal Blacks are at increased risk NNRTI use a risk factor
Vitamin D Deficiency is Not Influenced By ART
Mueller N, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 752.
Baseline before cART Fall (n=108)
Spring (n=103)
Vitamin D Deficiency 14% 42%
Insufficiency 62% 53%
Target Level 24% 5%
12 Months after cART Start
Vitamin D Deficiency 14% 47%
Insufficiency 63% 48%
Target Level 23% 5%
18 Months after cART Start
Vitamin D Deficiency 18% 52%
Insufficiency 59% 38%
Target Level 23% 10%
Deficiency <30 nmol/LTarget ≥75 nmol/L
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Study of cancer risk in AIDS patients from 1980-2006 (n=372,364)
Predominantly male (79%), non-hispanic black (42%), MSM (42%)
Median age of 36 years at the onset of AIDS
Cancer risk in years 3 - 5 after AIDS onset increased for AIDS but also Non-AIDS defining cancers
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.
Cancer typeNo
cases SIR 95% CI
AIDS-defining cancers
Kaposi sarcoma 3136 53215137 - 5511
Non-Hodgkin lymphoma
3345 32 31 - 33
Cervical cancer 101 5.6 5.5 - 6.8
Non-AIDS-defining cancers
Anal cancer 219 27 24 - 31
Liver cancer 86 3.7 3.0 - 4.6
Lung cancer 531 3.0 2.8 - 3.3
Hodgkin lymphoma
184 9.1 7.7 - 11
All non-AIDS related cancers
2155 1.7 1.5 - 1.8
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VA-Cohort (3,707 HIV-positive patients)
Predominantly male (98%), white (43%)
Median age of 47 years
Lung cancer risk factors- smoking and drug abuse
more often among HIV+- Similar rates of COPD
Sigel K, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 30.
26 cases per 10,000 pt-yrs
15 cases per 10,000 pt-yrs
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Berenguer, J. et al. Hepatology 2009;50:407-413; Berenguer, J, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 167.
0 1 10 100
0 1 10
Crude Adjusted
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Recent studies demonstrate polymorphisms near interleukin 28 B (IL28B) gen predict sustained virological response (SVR) to treatment with Peg-IFN + RBV in HCV-monoinfected pts harboring genotype 1
Study assessing potential role of theIL-28B treatment induced clearance of rs12979860 polymorphism in acute and chronic hepatitis C in HIV-positive patients
0
25
50
75
100
C/C C/T T/T
IL28B genotype
P=0.008
%S
VR
HIV(-)/HCV(+)
P=0.039
IL28B genotype
HIV(+)/chronic hepatitis C
C/C C/T T/T
0
25
50
75
100%
SV
R
P=n.s.
IL28B genotype
HIV(+)/acute hepatitis C
C/C C/T T/T
0
25
50
75
100
%S
VR
Rauch A. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 162; Natterman J, et al. ibid., Abst. 164; Rallon N, et al. ibid. , Abst. 165LB.
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Rs12979860 and SVR Predictors of SVR
Rauch A. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 162; Natterman J, et al. ibid., Abst. 164; Rallon N, et al. ibid. , Abst. 165LB.
P = 0.684
P=0.009
P=0.002
P <0.001
P <0.001
3.5
3.7
8.0
11.9HCV-RNA
<500,000 IU/mlHCV
Genotype 3
Rs12979860CC Genotype
Liver Fibrosis Stage F0-F2