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Pablo Tebas, MD
ACTG 5202/5224sSTARTMRK Metabolic StudySTEAL (abacavir and inflammatory
markers)EUROSIDA and risk of CKDHOPS and risk of fracturesVitamin D studiesCancer studiesHepatitis
A5224s
A5224s
A5224s
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
A5224s
* -linear regressionNo significant interaction of NRTI and NNRTI/PI components (p=0.63)
**
A5224s
*
*
* -linear regressionNo significant interaction of NRTI and NNRTI/PI components (p=0.69)
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
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
A5224s
**
* -linear regressionNo significant interaction of NRTI and NNRTI/PI components (p=0.67)
A5224s
*
*
* -linear regressionNo significant interaction of NRTI and NNRTI/PI components (p=0.66)
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
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
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
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.
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
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
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
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
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
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
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.
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