1. HCV Co-infection is Associated with a High Risk of Osteoporotic Fractures Among HIV Patients Roger Bedimo, MD; Henning Drechsler, MD; Song Zhang, PhD; Andrew Westfall, MS; Naim Maalouf, MD

2. Osteoporotic Fractures among HIV- Infected Patients: Incidence  Decreased bone mineral density is increasingly reported in the aging HIV-positive population.  Interaction b/w low BMD and  bone turnover in predicting fracture risk 1  15-30% of HIV-infected patients are co-infected with hepatitis C, which by itself is associated with osteoporosis and  bone turnover 2  The aging of the HIV population suggests that fracture risk will increase in HAART vs. pre-HAART era. 1 Gamero. J Bone Miner Res 1996,11:1531-1538; 2 Gastroenterology 2003,125:937-940

3. Osteoporotic Fractures among HIV- Infected Patients: Mortality  Fracture prevalence is increased in HIV-infected compared with non-HIV-infected patients. 1  The HIV population in the US is predominantly male.  Although the overall prevalence of fragility fractures is higher in women, men generally have higher rates of fracture-related mortality. 2,3  The overall mortality is about 20% in the first 12 months after hip fracture and is higher in men than women 2 Center JR, et al. Lancet 1999; 353:878; 3 Hasserius R, et al.. Osteoporos Int 2003;14:61. 1 Triant V, et al., JCEM 2008;93: 3499–3504;

4. Factors Likely Associated with Decreased Bone Health in HIV OSTEOPOROSIS and  FRACTURE RISK Inflammatory Cytokines HIVHAART Hypogonadism Glucocorticoids HCV Malnutrition, low BMI Tobacco, Alcohol Vitamin D deficiency Chronic kidney disease Aims:  To evaluate the impact of HCV co-infection on the risk of osteoporotic fractures among HIV-infected patients.  To evaluate the impact of osteoporotic fractures on all- cause mortality

5. 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: –HCV co-infection: ICD-9 codes for HCV or HCV antibody + –Chronic kidney disease: Estimated GFR<60 by MDRD –BMI, Age, Race, Antiretroviral exposure, Smoking Outcomes: –Osteoporotic fractures: Vertebral fractures (ICD-9 codes 805.2 through 805.7), Hip fractures (820.0 through 820.9), and Wrist fractures (814.0, 814.1, 813.4 and 813.5) –All-cause mortality: Cox survival model

6. Results: Study Population, Treatment Exposure and Events Patients: 56,660 included in the analysis; 98.1% male; 17,281 (31.2%) HCV+; Mean age at entry: 45.0 (SD:10.4) Follow-up: 305,237 patient-years; mean: 5.4 yrs/patient (range: 0 – 23.8 years) ARV exposure: 64.2% of patients exposed for ≥ 30 days. Mean Rx duration: 4.08 years (range: 0 – 18.7; SD: 3.92). Osteoporotic fractures during period of observation: –951 individual patients sustained at least one osteoporotic fracture (106 vertebral, 451 wrist and 308 hip). –Rate/1000 patient-years for HIV and HIV/HCV patients were 2.54 and 3.25 respectively.

7. Risk Factors among Patients with and without Osteoporotic Fracture Total (n =56,660) Fracture (n =951) No Fracture (n =55,709) P-value Age in Yrs; mean ( SD) 45.01 (10.36)47.48 (10.08)44.97 (10.36)P<0.0001 % Male 98.0597.9198.05P=0.91 % Whites 45.1457.1044.83P<0.0001 % with Tobacco Use 32.8556.4732.39P<0.0001 % Diabetes 15.2824.8615.10P<0.0001 % BMI<20 33.2448.8132.88P<0.0001 % HCV Positive 31.4050.531.02P<0.0001

8. Age-adjusted Rates of Osteoporotic Fractures (Entire Cohort) 0 1 2 3 4 5 6 7 8 18-2930-3940-4950-5960-69 ≥70 Age at Diagnosis (Years) Fracture Rate (per 1,000 patient-years) Vertebral Hip Wrist Total General population 1 1 Data from Triant V, et al., JCEM 2008;93: 3499–3504

9. Rates of Osteoporotic Fractures by Year of Diagnosis and HCV Status

10. Factors Predicting Osteoporotic Fracture in HIV Patients FactorsHazard Ratio (95% Confidence Interval; p value) Univariate AnalysisMulti-variable Analysis HCV Co-infection1.27 (1.11 - 1.44; p = 0.0003)1.43 (1.22 - 1.69; p< 0.0001) CKD (eGFR <60)1.34 (1.03 – 1.74; p=0.03)1.10 (0.77 – 1.58; p = 0.61) White Race1.64 (1.41 – 1.89; p < 0.0001)1.75 (1.49 – 2.04; p< 0.0001) Age (per 10 year increase) 1.49 (1.40 – 1.59; p <0.0001)1.50 (1.38 – 1.63; p< 0.0001) ART Use0.57 (0.48 – 0.67; p<0.0001)0.44 (0.35 – 0.56; p<0.0001) Tobacco Use1.30 (1.14 – 1.48; p<0.0001)1.48 (1.26 – 1.75; p<0.0001) Diabetes1.18 (1.02 – 1.37; p=0.02)1.02 (0.85 – 1.22; p=0.85) BMI < 201.54 (1.29 – 1.82; p<0.0001)1.40 (1.13 – 1.73; p=0.002)

11. Fracture Rates in HIV and HIV/HCV Patients Fracture Rate (per 1,000 patient-years)

12. Predictors of Death of Patients with HIV in the HAART era FactorsHazard Ratio (95% Confidence Interval; p value) Univariate AnalysisMulti-variable Analysis Osteoporotic Fracture2.29 (2.05 – 2.56; p<0.0001)1.77 (1.52 – 2.06; p<0.001) HCV Co-infection1.12 (1.08 – 1.16; p<0.0001)1.41 (1.32 - 1.50; p<0.0001) CKD (eGFR <60)1.89 (1.39 – 2.56; p<0.0001)2.17 (1.96 – 2.41; p < 0.0001) Black Race1.16 (1.10 – 1.22; p<0.0001)1.12 (1.05 – 1.19; p=0.0003) Age (per 10 year increase) 1.40 (1.37 – 1.42; p<0.0001)1.60 (1.55 – 1.65; p < 0.0001) ART Use0.46 (0.44 – 0.48; p<0.0001)0.50 (0.45 – 0.54; p< 0.0001) Diabetes0.89 (0.85 – 0.93; p<0.0001)1.04 (0.97 – 1.11; p=0.28) BMI<202.55 (2.44 – 2.67; p<0.0001)2.27 (2.12 – 2.44; p<0.0001)

13. Discussion - I HCV co-infection is associated with a higher risk of osteoporotic fractures among HIV-infected patients. Risk of osteoporotic fractures appears to be increasing in the HAART era among HIV/HCV patients. Exposure to antiretroviral therapy appears to be protective of osteoporotic fractures. –Higher overall mortality in the pre-HAART era might not have allowed time to develop osteoporotic fractures –It is possible that HAART is not protective, but a surrogate measure of patients with better care

14. Discussion - II Patients with HIV have a higher incidence of fractures than the general population, in spite of HAART therapy which may reduce fracture risk Other factors associated with increased risk of osteoporotic fractures include White race, advancing age and smoking. CKD and diabetes were not associated with osteoporotic fracture Osteoporotic fracture is an independent predictor of all- cause mortality.

15. Strengths and Limitations Our study is a retrospective cohort study. 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. 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. Impact of type (HAART and non-HAART) and duration of antiretroviral exposure not completed (in progress)

16. Acknowledgements VA Center for Quality Management for access to CCR data and material support Dr. Pablo Tebas for great insight, critical review and comments IAS for giving us the opportunity to share our work