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Risk of Osteoporotic Fractures Associated with Cumulative Exposure to Tenofovir and Other Antiretroviral Agents
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6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
Mark Mascolini
Cumulative use of tenofovir or lopinavir/ritonavir independently raised the risk of osteoporotic fracture, but only in the combination antiretroviral therapy (cART) era, according to results of a 27,000-person analysis of the Veterans Affairs' (VA) Clinical Case Registry [1]. HCV coinfection, low body mass index, tobacco use, older age, and white race also independently boosted osteoporotic fracture risk.
Two earlier cohort studies found a higher fracture prevalence in people with HIV than in the general US population [2,3]. But the Women's Interagency HIV Study found equivalent fracture risk in HIV-positive US women and women at risk of HIV [4]. An Australian study identified a strong correlation between a sub-200 CD4 count and fragility fracture risk [5].
Several studies, including AIDS Clinical Trials Group protocol A5224s [6], link tenofovir to low bone mineral density. But whether cumulative use of tenofovir or other individual antiretrovirals raise the risk of osteoporotic fracture remained unaddressed until the VA study by Roger Bedimo and colleagues [1].
Defining osteoporotic fractures as those involving the wrist, vertebrae, or hip, the VA investigators assessed fracture rates (by ICD-9 code) in HIV-positive VA beneficiaries identified in the Veterans Affairs' Clinical Case Registry from 1998 through 2009. They conducted two analyses, one in all 39,277 patients enrolled in the Clinical Case Registry from 1988 to 2009, the other in 27,107 patients seen only during the cART era: 1996 to 2009. By analyzing pharmacy records, the investigators calculated cumulative exposure to individual antiretrovirals and antiretroviral classes until a fracture diagnosis or the end of follow-up.
The study group averaged 44 years in age; 98% were men, 45% white, and 33% smokers. While 15% had diabetes, 31% had a positive HCV assay, 33% had a body mass index below 20 kg/m(2). The VA team identified at least one fracture in 951 people for the entire period, 486 affecting the wrist, 341 the hip, and 124 the spine. There were 572 fractures in the cART era, 296 affecting the wrist, 200 the hip, and 76 the spine.
Univariate analysis determined that every year of antiretroviral use upped the osteoporotic fracture risk 5% (hazard ratio 1.05, 95% confidence interval [CI] 1.01 to 1.10, P = 0.02). But this correlation did not endure in a multivariate analysis considering other fracture risk factors. Five factors did boost fracture risk in the multivariate analysis at the following odds hazard ratios (HR) (and 95% CIs):
--White race: HR 1.88 (1.54 to 2.30), P < 0.0001
--Every 10 years of age: HR 1.50 (1.37 to 1.64), P < 0.0001
--Tobacco use: HR 1.31 (1.09 to 1.56), P = 0.003
--Body mass index below 20 kg/m(2): HR 1.48 (1.18 to 1.87), P = 0.007
--HCV coinfection: HR 1.49 (1.25 to 1.77), P < 0.0001
For the entire study period, 1988 through 2009, none of the individual antiretrovirals or antiretroviral classes examined made osteoporotic fractures more likely in analyses that considered age, race, tobacco use, chronic kidney disease, diabetes, body mass index, and concomitant exposure to other antiretrovirals.
When Bedimo and coworkers looked at specific boosted PIs, they found a heightened fracture risk only with lopinavir/ritonavir (HR 1.13, 95% CI 1.04 to 1.22, P = 0.005 in model 1; HR 1.09, 95% CI 1.00 to 1.20, P = 0.051), and not with nelfinavir, indinavir/ritonavir, atazanavir, atazanavir/ritonavir, or ritonavir alone. (from Jules: to be clear, using Model 2 adjusts for concomitant ARV use and TDF remains associated with fracture [each yr of TDF use HR 1.12] but Kaletra does not remain associated with fractures in model 2 after adjusting for concomitant exposure to other ARTs)
Model 1
--Each year of tenofovir use: HR 1.13 (1.05 to 1.21), P = 0.001
--Each year of boosted PI use: HR 1.08 (1.01 to 1.15), P = 0.026
Model 2
--Each year of tenofovir use: HR 1.12 (1.03 to 1.21), P = 0.011
--Each year of boosted PI use: no association
Years of exposure to abacavir, to zidovudine or stavudine, or to nonnucleosides did not affect fracture risk in these analyses.
When Bedimo and coworkers looked at specific boosted PIs, they found a heightened fracture risk only with lopinavir/ritonavir (HR 1.13, 95% CI 1.04 to 1.22, P = 0.005 in model 1; HR 1.09, 95% CI 1.00 to 1.20, P = 0.051), and not with nelfinavir, indinavir/ritonavir, atazanavir, atazanavir/ritonavir, or ritonavir alone. (from Jules: to be clear, using Model 2 adjusts for concomitant ARV use and TDF remains associated with fracture [each yr of TDF use HR 1.12] but Kaletra does not remain associated with fractures in model 2 after adjusting for concomitant exposure to other ARTs)
The VA team surmised that tenofovir and lopinavir/ritonavir raised osteoporotic fracture risk only in the cART era because of longer survival of cohort members in that era and exclusion of most people not treated with antiretrovirals or treated with only one or two antiretrovirals. Bedimo noted that this retrospective analysis did not evaluate bone mineral density, so it could not ensure that the fractures (identified by ICD-9 codes) were osteoporotic. The VA team did not conduct separate analyses of older versus younger cohort members.
References
1. Bedimo R, Zhang S, Drechsler H, Tebas P, Maalouf N. Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract MOAB0101.
2. Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. 2008;93:3499-3504.
3. Young B, Dao CN, Buchacz K, Baker R, Brooks JT; HIV Outpatient Study (HOPS) Investigators. Increased rates of bone fracture among HIV-infected persons in the HIV Outpatient Study (HOPS) compared with the US general population, 2000-2006. Clin Infect Dis. 2011;52:1061-1068.
4. Yin MT, Shi Q, Hoover DR, et al. Fracture incidence in HIV-infected women: results from the Women's Interagency HIV Study. AIDS. 2010;24:2679-2686.
5. Yong MK, Elliott JH, Woolley IJ, Hoy JF. Low CD4 count is associated with an increased risk of fragility fracture in HIV-infected patients. J Acquir Immune Defic Syndr. 2011 Apr 23. Epub ahead of print.
6. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203:1791-1801.
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