CROI 2016 Abstract eBook

Abstract Listing

Oral Abstracts

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Antiretrovirals, Fractures, and Osteonecrosis in a Large European HIV Cohort Alvaro H. Borges 1 ; Jennifer Hoy 2 ; Eric Florence 3 ; Dalibor Sedlacek 4 ; Hans-Jürgen Stellbrink 5 ;Vilma Uzdaviniene 6 ;Tomazic Janez 7 ; Panagiotis Gargalianos-Kakolyris 8 ; Jens D. Lundgren 9 ; Amanda Mocroft 10 ; for the EuroSIDA in EuroCOORD 1 CHIP, Rigshospitalet, Univ of Copenhagen, Copenhagen, Denmark; 2 Alfred Hosp, Melbourne, Australia; 3 Inst of Trop Med Antwerp, Antwerp, Belgium; 4 Charles Univ Hosp Plzen, Plzen, Czech Republic; 5 ICH Study Cntr, Hamburg, Germany; 6 Vilnius Univ Hosp Santariskiu Klinikos, Vilnius, Lithuania; 7 Univ Med Cntr Ljubljana, Ljubljana, Slovenia; 8 General Hosp of Athens “G. Gennimatas”, Athens, Greece; 9 Rigshospitalet, Univ of Copenhagen, Copenhagen, Denmark; 10 Univ Coll London, London, UK Background: It is well established that antiretrovirals (ARVs) affect markers of bone turnover, but less is known about their effect on risk of fractures and femoral osteonecrosis. We hypothesized exposure to ARVs including tenofovir (TDF) would increase the risk of both outcomes. Methods: EuroSIDA participants were prospectively followed from baseline (Jan 2004) until last visit or death to assess fractures and femoral osteonecrosis. Poisson regression was used to identify clinical, laboratory and demographic factors associated with either bone endpoint. Ever, current and cumulative exposures to each ARV were added to the multivariate model. Results: During 86118 person-years of follow up (PYFU) among 11820 eligible persons (median age 41y, 75%male, 86%white, median baseline CD4 440/mm 3 and 70.4% virologically suppressed), there were 618 incident fractures (incidence/1000PYFU 7.2; 95%CI 6.6-7.7) and 89 incident cases of osteonecrosis (1.0;0.8-1.3). After adjustment, higher risk of fractures was associated with older age, white race, lower BMI, IV drug use, lower baseline CD4, HCV-coinfection, prior osteonecrosis, prior fracture, recent non-AIDS cancer and recent cardiovascular disease (last 12 months) (Figure). The crude incidence of fracture was 8.1/1000PYFU (7.3-8.9) in those ever exposed to TDF compared to 4.7 (4.1-5.4) in those never exposed; corresponding figures for persons currently on and off TDF were 7.8 (6.8-8.7) and 5.6 (5.0-6.3). After adjustment, persons who had ever used TDF (1.40; 1.15-1.70) or who were currently on TDF (1.25; 1.05-1.49) had a significantly higher incidence of fractures. There was no association between longer exposure to TDF and fractures (1.02/5y exposure; 0.94-1.25). No other ARV was associated with fractures (all p>0.1). Risk of osteonecrosis was associated with white race, lower nadir CD4, prior osteonecrosis, prior fracture and prior AIDS (Figure). Persons who had ever used didanosine, indinavir, saquinavir, lopinavir/r, or TDF had higher risk of osteonecrosis, but this association was no longer observed in models adjusted for confounders (not shown). Conclusions: In HIV infection, host factors, HIV-specific variables and co-morbidities contribute to risk of fractures and osteonecrosis. TDF but not other ARVs was an independent risk factor for fractures. There was no association between the use of any of the ARVs and risk of osteonecrosis.

Oral Abstracts

47

A Single Dose Zoledronic Acid Prevents Antiretroviral-Induced Bone Loss Ighovwerha Ofotokun 1 ; KehmiaTitanji 1 ; AswaniVunnava 1 ; Antonina Foster 1 ; Anandi N. Sheth 1 ; Cecile D. Lahiri 1 ; Jeffrey L. Lennox 1 ; Andrea Knezevic 2 ; Kirk A. Easley 2 ; M. N. Weitzmann 1 1 Emory Univ Sch of Med, Atlanta, GA, USA; 2 Emory Univ Rollins Sch of PH, Atlanta, GA, USA Background: HIV enhances bone loss, and close to 2/3 of HIV patients are osteopenic and 15% osteoporotic, leading to 2-9 fold higher fracture prevalence in the aging HIV population. Antiretroviral therapy (ART) further worsens this loss, inducing an additional 2-6% loss in bone mineral density (BMD), mostly within the first 48 weeks, providing a window for prophylaxis with long-acting antiresorptives such as zoledronic acid (ZA). Methods: We randomized non-osteoporotic, viremic ART-naïve adult HIV-patients initiating ART with atazanavir/ritonavir+tenofovir/emtricitabine to a single ZA (5mg) vs . placebo (PL) infusion in a double-blinded placebo controlled phase 2 trial. Laboratory and safety measures, plasma bone turnover markers including C-terminal telopeptide of collagen (CTx), a sensitive marker of bone resorption, and BMD were performed at weeks 0, 12, 24, and 48. Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints. Results: Of the 63 subjects enrolled, 84%were black, 16%white, and 21%women with a mean age of 39.6 years. Treatment with ZA was associated with a 74% reduction in bone resorption relative to PL at 12 weeks [CTx: 0.08 ng/ml (ZA) vs. 0.31 ng/ml (PL), p <0.001; mean difference= -0.23 ng/ml (95% CI: -0.31, -0.14)] with 65% and 56% relative reduction at 24 and 48 weeks respectively. ZA led to an 8% increase in lumbar spine BMD at 12 weeks relative to PL [1.305 g/cm 2 vs. 1.204 g/cm 2 , p =0.003; mean difference=0.101 g/cm 2 (95% CI: 0.035, 0.168)], with a greater increase of 11% at 24 and 48 weeks. Of note, BMD at the lumbar spine increased 1.9% (95% CI: 0.39, 4.22) from baseline to 48 weeks in the ZA arm but decreased 4.4% (95% CI: 2.63, 6.24) in the PL arm. Lumbar spine T- and Z-scores were significantly higher in patients receiving ZA vs . PL at weeks 12, 24, and 48 (all p <0.05). Significant trends were also observed at the hip and femoral neck. The rate of virologic suppression and mean CD4 T cell increase over 48 weeks were similar between the arms. ZA was well tolerated without major side effects. Conclusions: In this single center proof-of-concept study, a single infusion of ZA at the time of ART initiation prevented ART-induced bone resorption and bone loss at key fracture-prone anatomical sites. These effects were observed as early as 12 weeks and persisted through 48 weeks, the period when ART-induced bone loss is most intense. Replication of these results in a confirmatory multicenter randomized clinical trial is warranted.

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CROI 2016