Transcript Abacavir Use and Risk of Acute Myocardial Infarction and

Risk of Osteoporotic Fractures
Associated with Cumulative
Exposure to Tenofovir and Other
Antiretroviral Agents
Roger Bedimo, MD; Song Zhang, PhD;
Henning Drechsler, MD; Pablo Tebas, MD;
Naim Maalouf, MD
Osteoporotic Fractures among HIVInfected Patients: Role of ART
 Decreased bone mineral density is increasingly
reported in the aging HIV-positive population.
 Odds of osteoporosis are elevated in HIV-infected vs.
uninfected1,2, and in ART users vs. non-users1
 Tenofovir exposure was shown to be associated with
a significantly greater decrease in bone mineral
density than stavudine3, and abacavir4
 The risk of osteoporotic fractures (OF) associated
with cumulative (PY) exposure to tenofovir vs. other
antiretroviral agents has never been explored
1Brown
and Qaqish AIDS 2006,20:2165-2174.; 2Triant et al, JCEM. 2008,93:3499-3504
3Gallant et al., JAMA. 2004;292(2):191-201. 4McComsey G. JID 2011;203(12):1791-801
Methods: Data Source, Predictors and
Outcome Measures
• Data Source: Veterans Affairs’ Clinical Case Registry; HIV
patients in pre-HAART (’88-’95) and HAART eras (’96-’09).
• Predictors:
– Antiretroviral exposure: PY of exposure to NRTIs (TDF, ABC,
AZT or D4T), NNRTI, boosted PI.
– Age, Race, Smoking, BMI, type 2 diabetes, HCV co-infection
(by ICD-9 codes or antibody +), Chronic kidney disease:
Estimated GFR<60 by MDRD
• Gender not included in the model; The population is >98% male.
• Outcome: Incident osteoporotic fracture defined as any:
– Vertebral fractures (ICD-9 codes 805.2 through 805.7), Hip
fractures (820.0 through 820.9), or Wrist fractures (814.0,
814.1, 813.4 and 813.5)
Results: Study Population,
Treatment Exposure and Events
• Two separate analyses were conducted, including:
1. All patients enrolled in CCR from 1988 to 2009.
2. Patients enrolled in the HAART era only: from 1996 to 2009.
• Cumulative exposure to each separate ARV or ARV class,
from first administration to censure date:
–
1) development of the first OF episode ; 2) discontinuation of
the ARV; 3) last recorded patient encounter; 4) December 31st,
2009 (date of censure of the dataset).
• Cox survival models of association of ARV exposure & OF:
–
–
1) Univariate analysis;
2) MV Model 1: Controlling for CKD, age, race, tobacco use, DM,
BMI & HCV; 3) MV Model 2: Controlling for Model 1 variables +
concomitant exposure to other ARVs.
Results: Study Population,
Follow-Up Time and Events
Entire Period:
1988 - 2009
HAART Era Only:
1996-2009
(n =56,660)
(n =32,439)
39,277 (69.4%)
27,107 (83.6%)
305,237
191,258
164,414
122,364
Vertebral Fractures
124
77
Wrist Fractures
486
296
Hip Fractures
341
200
All Osteoporotic Fractures*
951
572
Number of Patients with ART
Exposure (%)
Total PY of Observation
Total PY of ART Exposure
*defined for this study as first vertebral, wrist or hip fracture during follow-up
Risk Factors among Patients with
and without Osteoporotic Fracture
Baseline
Characteristics
Total
(n =56,660)
Fracture
(n =951)
No Fracture
(n =55,709)
P-value
44 (10)
46 (10)
44 (10)
P<0.0001
% Male
98
98
98
P=0.91
% Whites
45
57
45
P<0.0001
% Smokers
33
56
32
P<0.0001
% Diabetes*
15
25
15
P<0.0001
% BMI<20
33
49
33
P<0.0001
% HCV Positive
31
51
31
P<0.0001
Age in Yrs; median
(SD)
*Classified only by ICD-9 codes. Laboratory values not extracted
Fracture Rate (per 1,000 patient-years)
Age-adjusted Rates of Osteoporotic
Fractures (Entire Cohort)
8
7
6
Vertebral
5
Hip
4
Wrist
3
Total
General population1
2
1Data
from Triant V, et al.,
JCEM 2008;93: 3499–3504
1
0
18-29
30-39
40-49
50-59
60-69
Age at Cohort Entry (Years)
≥70
Factors Predicting Osteoporotic
Fracture in HIV Patients
Factors
Hazard Ratio (95% Confidence Interval; p value)
Univariate Analysis
Multi-variable Analysis
Cumulative ART
Use (per year)
1.05 (1.01 – 1.10; p=0.02)
0.99 (0.95 – 1.04; p=0.77)
CKD (eGFR <60)
1.48 (1.04 – 2.09; p=0.03)
1.05 (0.72 – 1.53; p = 0.79)
White Race
1.76 (1.46 – 2.13; p < 0.0001)
1.88 (1.54 – 2.30; p< 0.0001)
Age (per 10 year
increase)
1.51 (1.39 – 1.63; p <0.0001)
1.50 (1.37 – 1.64; p< 0.0001)
Tobacco Use
1.25 (1.06 – 1.47; p=0.01)
1.31 (1.09 – 1.56; p=0.003)
Diabetes
1.27 (1.05 – 1.53; p=0.01)
1.10 (0.90 – 1.34; p=0.34)
BMI < 20
1.61 (1.29 – 2.00; p<0.0001)
1.48 (1.18 – 1.87; p=0.007)
HCV Co-infection
1.43 (1.21 – 1.69; p<0.0001)
1.49 (1.25 – 1.77; p< 0.0001)
Antiretroviral Exposure and Risk of
Osteoporotic Fractures: 1988-2009
Drug or Drug
Category
PY of
Exposure
Hazard Ratio per Year of Exposure (95% Confidence Interval; p
value)
Univariate Analysis
Multi-variable Model 1 Multi-variable Model 2
Tenofovir (TDF)
46,062
1.08 (1.02-1.15;
<0.001)
1.06 (0.99-1.12;
0.079)
1.06 (0.99-1.14;
0.106)
Abacavir (ABC)
24,251
0.99 (0.93-1.05;
0.989)
0.96 (0.90-1.03;
0.245)
0.96 (0.90-1.03;
0.224)
Thymidines
(AZT or D4T)
94,595
1.02 (0.99-1.05;
0.199)
0.96 (0.95-1.02;
0.311)
0.99 (0.95-1.02;
0.520)
boosted PI
(rPI)
41,336
1.06 (1.01-1.12;
0.015)
1.04 (0.99-1.10;
0.142)
1.03 (0.97-1.09;
0.349)
NNRTI
59,857
0.99 (0.95-1.03;
0.655)
0.96 (0.92-1.01;
0.094)
0.96 (0.92-1.01;
0.112)
MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI;
MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.
Antiretroviral Exposure and Risk of
Osteoporotic Fractures: 1988-2009
Hazard Ratio
1.2
1.1
1.0
0.9
0.8
MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI;
MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.
What Happened in the HAART Era?
• Higher % of patients on ARVs, low viremia.
• Increased survival (and time at risk) and increased
fracture rates
Fracture Rate per 1000 Patient-Years
Fracture Rate by Year
4.5
4
3.5
Pre-HAART Era:
1.61 Events/1000 PY
3
2.5
2
1.5
1
HAART Era:
4.09 Events/1000 PY
0.5
0
Year of Fracture Diagnosis
Antiretroviral Exposure and Risk of
Osteoporotic Fractures: HAART Era
Drug or Drug
Category
PY of
Exposure
Hazard Ratio per Year of Exposure (95% Confidence Interval; p
value)
Univariate Analysis
Multi-variable Model 1 Multi-variable Model 2
Tenofovir (TDF)
38,009
1.16 (1.08-1.24;
<0.0001)
1.13 (1.05-1.21;
0.001)
1.12 (1.03-1.21;
0.011)
Abacavir (ABC)
18,885
0.99 (0.92-1.07;
0.842)
0.96 (0.88-1.04;
0.313)
0.95 (0.87 -1.03;
0.194)
AZT or D4T
68,376
1.02 (0.97-1.06;
0.489)
0.98 (0.93-1.02;
0.289)
0.99 (0.94-1.04;
0.600)
boosted PI
(rPI)
32,109
1.11 (1.05-1.18;
0.001)
1.08 (1.01-1.15;
0.026)
1.05 (0.97-1.13;
0.237)
NNRTI
48,943
1.01 (0.96-1.06;
0.771)
0.98 (0.93-1.03;
0.409)
0.98 (0.92-1.03;
0.386)
MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI;
MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.
Antiretroviral Exposure and Risk of
Osteoporotic Fractures: HAART Era
1.3
Hazard Ratio
1.2
1.1
1.0
0.9
0.8
MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI;
MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.
Interaction Between TDF and PI
Exposure for OF Risk: HAART Era
• Concomitant exposure to both TDF and rPI associated with a
greater OF risk than exposure to either TDF without rPI or
rPI without TDF
1.4
Hazard Ratio
1.30
1.2
1.0
1.21
1.22
1.16
1.11
1.10
1.01
1.01
1.04
0.8
0.6
TDF
rPI
TDF + rPI
Exposure to Specific Protease
Inhibitors and OF Risk: HAART Era
Drug
PY of
Exposure
Hazard Ratio per Year of Exposure (95% Confidence Interval; p value)
Univariate Analysis
Multi-variable Model 1
Multi-variable Model 2
IDV
12,124
1.00 (0.93 - 1.07; 0.947) 0.98 (0.91 - 1.05; 0.579) 0.99 (0.92 - 1.07; 0.755)
ATV
12,685
1.12 (0.98 - 1.27; 0.097) 1.08 (0.95 - 1.24; 0.233) 1.03 (0.89 - 1.18; 0.713)
NFV
14,356
1.00 (0.93 - 1.07; 0.977) 0.98 (0.91 -1.05; 0.509) 0.98 (0.91 - 1.05; 0.512)
LPV/RTV 15,319
1.17 (1.08 - 1.26;
<0.0001)
1.13 (1.04 - 1.22; 0.005) 1.09 (1.00 -1.20; 0.051)
MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI;
MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.
Exposure to Specific Protease
Inhibitors and OF Risk: HAART Era
Drug
PY of
Exposure
Hazard Ratio per Year of Exposure (95% Confidence Interval; p value)
Univariate Analysis
Multi-variable Model 1
Multi-variable Model 2
IDV
12,124
1.00 (0.93 - 1.07; 0.947) 0.98 (0.91 - 1.05; 0.579) 0.99 (0.92 - 1.07; 0.755)
ATV
12,685
1.12 (0.98 - 1.27; 0.097) 1.08 (0.95 - 1.24; 0.233) 1.03 (0.89 - 1.18; 0.713)
NFV
14,356
1.00 (0.93 - 1.07; 0.977) 0.98 (0.91 -1.05; 0.509) 0.98 (0.91 - 1.05; 0.512)
LPV/RTV 15,319
1.17 (1.08 - 1.26;
<0.0001)
1.13 (1.04 - 1.22; 0.005) 1.09 (1.00 -1.20; 0.051)
RTV
1.06 (0.97 - 1.15; 0.2)
1.04 (0.96 - 1.14; 0.349) 1.01 (0.92 - 1.11; 0.79)
1.11 (0.95 - 1.31; 0.18)
1.08 (0.91 - 1.27; 0.378) 0.99 (0.84 - 1.18; 0.946)
18,691
ATV/RTV 9546
MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI;
MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.
Exposure to Specific Protease
Inhibitors and OF Risk: HAART Era
Hazard Ratio
1.4
1.2
1.0
0.8
0.6
MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI;
MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs.
Discussion – Entire Study Period
• Overall, antiretroviral exposure is associated with a nonsignificant OF risk after controlling for OF risk factors.
– HR for cumulative ART exposure is modest compared to other
fracture risk factors: White race, advancing age and smoking
• Cumulative exposure to TDF and boosted PI are each
associated with modest increase in fracture risk in
univariate analysis, but not after controlling for fracture
risk factors.
• Significant increase in fracture rates in the HAART era
– Cumulative ART exposure likely does not account for the
increased risk in the HAART era
Discussion – HAART Era - I
• Fracture risk associated with cumulative exposure to TDF
remains significant after controlling for other OF risk
factors and concomitant ARV used.
• Cumulative exposure to boosted PI is also associated with
increased OF risk after controlling for other OF risk
factors, but not after controlling for concomitant ARVs.
– There was an interaction between TDF and boosted PI use.
• Greater fracture rates, higher (significant) HR for TDF
and rPI in the HAART era could be due to longer survival,
and exclusion of most patients with no Rx, mono-dual Rx
Discussion – HAART Era - II
• Among PIs, LPV/RTV is associated with an increased OF
risk. Exposure to ATV, NFV or IDV were not associated
with increased OF risk.
– While these could be explained by concomitant use of RTV with
LPV, neither RTV alone nor boosted ATV or IDV were associated
with increased risk.
Strengths and Limitations
• Large sample size (more than 56,000 patients; more than
900 with fracture events)
• Uniform data collection on exposures and outcomes across
VA system, including pre-HAART and HAART eras.
• Our study is a retrospective cohort study.
• Osteoporotic fracture events not ascertained (only ICD-9
code used – validated in other VA studies)
• Bone mineral density is not evaluated. Fractures cannot be
proven to be osteoporotic in nature.
Acknowledgements
• Study funded by VA MERIT grant I01 CX00041801A1
• Thanks to the VA Center for Quality
Management for access to CCR data and
material support
• Thanks to IAS for giving us the opportunity to
share our work