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 TGABC/3TC

ATV/r 29 13 8 24EFV 40 21 12 15P-value <0.001 0.002 <0.001 0.26

TDF/FTCATV/r 10 2 5 14EFV 22 10 8 13P-value <0.001 0.002 <0.001 0.26

Week 48 Week 96ABC/3TC

ATV/r 3.1 6.1EFV 4.3 7.8P-value 0.17 0.33

TDF/FTCATV/r -0.9 -2.6EFV 4.1 4.9P-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% CI P-value

IRR/year 95% CI P-value

Tenofovir 1.32 1.21-1.41 <0.0001 1.16 1.06-

1.25<0.000

1

Indinavir 1.18 1.13-1.24 <0.0001 1.12 1.06-

1.18<0.000

1

Atazanavir 1.48 1.35-1.62 <0.0001 1.21 1.09-

1.34 0.0003

Lopinavir/r 1.15 1.07-1.23 <0.0001 1.08 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% CIAIDS-defining cancers

Kaposi sarcoma 3136 5321 5137 - 5511

Non-Hodgkin lymphoma 3345 32 31 - 33

Cervical cancer 101 5.6 5.5 - 6.8Non-AIDS-defining cancersAnal cancer 219 27 24 - 31Liver cancer 86 3.7 3.0 - 4.6Lung cancer 531 3.0 2.8 - 3.3Hodgkin 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/TIL28B genotype

P=0.008

%SV

R

HIV(-)/HCV(+)

P=0.039

IL28B genotype

HIV(+)/chronic hepatitis C

C/C C/T T/T0

25

50

75

100%

SVR

P=n.s.

IL28B genotype

HIV(+)/acute hepatitis C

C/C C/T T/T0

25

50

75

100

%SV

R

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