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Overall benefit of antiretroviral treatment on the risk of fracture in HIV: nested case control analysis in a health-insured population
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Download the PDF here
AIDS: POST ACCEPTANCE, 1 February 2012
Mundy, Linda M.; Youk, Ada O.; McComsey, Grace A.; Bowlin, Steve J.
2nd Bone Study Published-
from Jules: there have been a number of different studies that find different results, sometimes appearing conflicting. But I think often these studies are conducted in a vacuum situation unable to assess the full spectrum of causations. In bone disease, it is a complicated situation when you try to assess the relationships between bone loss, fractures & HIV & the impact of various ARTs: This study appeared to find a reduced risk for fracture associated with efavirenz.
[From Jules: prior studies have reported initial declines in bone mineral density immediately after starting HAART]: "Significant decreases in BMD were especially noted during the first year of exposure in patients randomized to abacavir/lamivudine and to tenofovir/emtricitabine, with either ritonavir-boosted atazanavir or efavirenz; reported fractures were all associated with trauma and not different between study arms [9]."....this study reports: "Exposure to antiretroviral (ARV) therapy by drug class and by duration (any drug/class) was associated with reduced risk for fracture".....and "Drug-specific ARV exposures over time identified an increased risk for fracture associated with darunavir, delavirdine and saquinavir while reduced risk was associated with efavirenz, emtricitabine, lamivudine, tenofovir, and zidovudine. An initial null risk became a reduced risk with increased duration for nevirapine. In a similar pattern, abacavir, didanosine, nelfinavir, ritonavir and stavudine were initially associated with increased risk for fracture, after which the risk became null with increased duration of exposure. Null or uncertain risk for fracture was associated with amprenavir, atazanavir, enfuvirtide, fosamprenavir, indinavir, lopinavir, tipranavir, and zalcitabine."
"Together, these drug-specific exposure-response relationships suggest an overall benefit of ARV treatment relative to estimates of risk for fracture in subjects without ARV treatment. While it is clinically relevant to discern distinctions in studies that assess changes in BMD versus fracture, our findings are consistent with several longitudinal studies of stable BMD in ARV-exposedpatients [5,7,25,26]. As BMD decreases with age, the mechanisms of bone modeling are not unidirectional and untreated HIV infection has been associated with uncoupled bone formation and bone resorption that seems attributed to both viral and inflammatory effects [27]. An undefined direct mechanism for bone remodeling is plausible in treated HIV infection and an indirect mechanism for bone remodeling is supported by lower levels of calcitrol (1,25-dihydroxyvitamin D) as reported in patients with advanced HIV infection compared to patients with early HIV infection [28]. Such changes in calcitrol may promote intestinal calcium absorption and regulation of osteoblast function. While there is theoretical biological plausibility that increased fat-free mass and decreased inflammation evident via changes in C reactive protein, interleukin-6, soluble tumor necrosis factor receptor (sTNFR) I and sTNFR II are linked to ARV treatment and altered BMD, such measures are beyond the scope of an observational database analysis [11,28,29]."
Abstract
Objectives: Fractures are common and associated with multiple risk factors. We assessed the risks for fracture associated with time-dependent, differential antiretroviral drug exposures among a cohort of persons with human immunodeficiency virus (HIV) infection.
Design: Nested case-control study from an HIV cohort of 59,594 medically-insured persons with HIV infection enrolled in a medical care between January 1997 and March 2008.
Methods: Cases were subjects with a low-impact, non-traumatic fracture identified by ICD-9-CM codes; non-cases were 1:4 matched and without fracture.
Results: Cases comprised 2,411 persons with HIV infection with fractures who were risk-set matched to 9,144 persons with HIV infection without fractures. Exposure to antiretroviral (ARV) therapy by drug class and by duration (any drug/class) was associated with reduced risk for fracture. Drug-specific ARV exposures over time identified an increased risk for fracture associated with darunavir, delavirdine and saquinavir while reduced risk was associated with efavirenz, emtricitabine, lamivudine, tenofovir, and zidovudine. An initial null risk became a reduced risk with increased duration for nevirapine. In a similar pattern, abacavir, didanosine, nelfinavir, ritonavir and stavudine were initially associated with increased risk for fracture, after which the risk became null with increased duration of exposure. Null or uncertain risk for fracture was associated with amprenavir, atazanavir, enfuvirtide, fosamprenavir, indinavir, lopinavir, tipranavir, and zalcitabine.
Conclusions: Our findings suggest an overall reduced risk for facture in persons treated versus not treated with ARV drugs for HIV infection. Differential drug-specific exposure-response relationships for fracture will need to be further evaluated in other study populations.
Discussion
Our study identified an overall reduced risk for fracture in persons treated versus not treated with ARV drugs forHIV infection. The study design and analysis highlights the complexity of estimating time-dependent, ARV drug-specific risks for fracture among persons on combination ARV regimens over different intervals of time for the treatment of HIVinfection [22]. Given the known dynamic complexity of bone metabolism in aging populations with HIV infection and differential ARV exposure, we emphasize three noteworthy findings from this nested case-control study.
First, exposures to ARV treatment by drug class, duration, and most drug-specific exposures were associated with reduced risk for fracture among persons with HIV infection. Second, beyond ARV drug class estimates of risk, the ARV drug-specific risk estimates for fracture revealed three different risk categories, with increased risk for fracture identified for three drugs (Table 4). For darunavir, although the number of fracture events were low, the estimate of risk was substantial (aOR 1.93, 95% CI 1.05Ð3.56; pg=0.043), and further assessment of this PI in other study populations seems justified. For delavirdine, the number of fracture events was low, the estimate of risk was moderate (aOR 1.59, 95% CI 0.94Ð2.71; pg=0.095), and future comparisons of risk in other populations may not be feasible given low prescribed use of delavirdine in current practice. For saquinivir, there were 115 exposed cases and although the approximate quartiles of risk varied, the global and trend values were consistent with increased risk. With two of these three drugs in the PI class, these data support some findings from two randomized trials that have identified an association of reducedBMDin the spine and PI exposures [11,12]. The potential correlations of reduced BMD short-term versus clinical benefits and risks of various PI-based regimens will require additional evaluation. Third, our time-censored subset analysis of abacavir versus tenofovir exposures revealed null risk in adjusted models for known risk variables and other ARV drug exposures (Table 5). Prior comparative analyses of abacavir versus tenofovir have been inconsistent, yet a significantly larger reduction in BMD has been consistently associated with tenofovir versus other NRTI agents [23Ð25]. Significant decreases in BMD were especially noted during the first year of exposure in patients randomized to abacavir/lamivudine and to tenofovir/emtricitabine, with either ritonavir-boosted atazanavir or efavirenz; reported fractures were all associated with trauma and not different between study arms [9].
Together, these drug-specific exposure-response relationships suggest an overall benefit of ARV treatment relative to estimates of risk for fracture in subjects without ARV treatment. While it is clinically relevant to discern distinctions in studies that assess changes in BMD versus fracture, our findings are consistent with several longitudinal studies of stable BMD in ARV-exposedpatients [5,7,25,26]. As BMD decreases with age, the mechanisms of bone modeling are not unidirectional and untreated HIV infection has been associated with uncoupled bone formation and bone resorption that seems attributed to both viral and inflammatory effects [27]. An undefined direct mechanism for bone remodeling is plausible in treated HIV infection and an indirect mechanism for bone remodeling is supported by lower levels of calcitrol (1,25-dihydroxyvitamin D) as reported in patients with advanced HIV infection compared to patients with early HIV infection [28]. Such changes in calcitrol may promote intestinal calcium absorption and regulation of osteoblast function. While there is theoretical biological plausibility that increased fat-free mass and decreased inflammation evident via changes in C reactive protein, interleukin-6, soluble tumor necrosis factor receptor (sTNFR) I and sTNFR II are linked to ARV treatment and altered BMD, such measures are beyond the scope of an observational database analysis [11,28,29].
As noted in a recent study by the HIV Outpatient Study investigators, our findings are consistent with several established risk factors for fracture [30Ð34]. Despite consistencies in established risks among numerous studies, reported exposure-response relationships for ARV treatment and fracture among persons with HIV infection have varied based on study design, execution, and
analyses. Such distinctions are notable by population when restricted to either men or women, covariates such as age when assessed by year or by decade, and quantification of antiretroviral drug exposure when assessed as a dichotomous variable, drug class, or cumulative drug-specific exposure. As an example, a recent study among US women and a case-control study from Australia have each reported that tenofovir was not associated with fracture [31,34]. Given the inconsistencies in reported studies to date, additional investigations of exposure to protease inhibitors and to tenofovir remain important and clinically-relevant for future investigations.
We acknowledge several limitations associated with the report of these study findings. First, as a retrospective study executed with administrative claims data, ascertainment bias for both information and measurement exists inclusive of the assumption that a prescription claim equated with administration of the ARV drug as prescribed and the population is likely differential from randomized trial populations. We were unable to assess race (not available in INBD) or tobacco exposure (less than 5% identified in pre-study feasibility assessment), did not include a covariate for opiate use, testosterone use, or untreated hypogonadism, and likely underestimated the severity of advanced HIV infection or AIDS based on available CD4 counts and ICD-9-CM claims for opportunistic infections and malignancies. We were able to create claims-based variables for low body weight, low physical activity, and advanced HIV infection. Second, by design, we grouped all subjects with low-impact and nontraumatic fracture as cases and did not estimate risks specific for the lumbar spine, hip, and other bone. As such, we are not able to associate with findings with studies that have had BMD loss as the outcome of interest. Third, our study population was restricted to fractures in adults and the findings are not able to be generalized to children or to longitudinal changes in BMD [35]. Fourth, almost all subjects with ARV exposure in our study were on NRTI-containing regimens, and we are unable to expand upon findings from a recent report of greater changes in BMD for subjects randomized to NRTI containing ARV regimens versus NRTI-sparing regimens [12]. Lastly, we were unable to assess ARV exposure prior to membership in the insured plan that was captured by INBD. It is nevertheless noteworthy that the study design, execution, and analysis combined the restructure of over 1.9 million ARV prescription claims using occupational epidemiology methods to estimate drug-specific exposure-response relationships.
In summary, bone fractures are common and risks for fracture seem multifactorial among persons with HIV infection.We report significantly reduced risk of fracture in a dichotomous analysis of ARV drug exposure, with a similar exposure-response relationship identified for ARV drug class and for cumulative duration of exposure. Differential ARV drug-specific risks for fracture suggest further assessment of individual drug exposures in other populations is warranted. Given the complexity of ARV treatment for long-term survival among aging populations with HIV infection, our findings contribute evidence to and support for future robust analysis of observational cohort data to assess and identify modifiable risk factors associated with aging and drug exposure-response relationships. Such comparative research efforts will be integral to optimizing incremental net health benefits with tailored ARV treatment in the years to come.
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