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Worse HIV Control--Not Antiretrovirals--Linked to Low Bone Density in Vancouver; ART risk factor in 2nd study
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(Vancouver poster online at
http://www.retroconference.org/2008/PDFs/969.pdf.)
(Lopinavir-vs-efavirenz poster online at
http://www.retroconference.org/2008/PDFs/966.pdf.)
15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
Mark Mascolini
from Jules Levin: several studies over the past 2 years report 70% with HIV had reduced bone mineral density, a French study reported 80%; 60% have osteopenia and 10-15% have osteoporosis. These are high rates of bone disease and most noteworthy is the average age of patients in these studies is often in their 40s, raising the concern if fractures will start emerging in large numbers among HIV+. Among the general population, osteopenia is associated with fractures and fractures are associated with mortality. Standard risk factors include many which are prevalent in HIV: alcohol, smoking, HCV, perhaps diabetes, and low weight. Striking is that there are no guidelines for performing bone DEXAs among HIV+, little prospective study, and little understanding of the risk factors and their prevalence in HIV. There is little discussion and education regarding bone disease for care providers and patients. Our research institutions the ACTG and the NIH deprioritize bone disease. There are good reasons and some research to support that HIV's dysregulation of the immune system leads to reduced bone mineral density, and perhaps reconfiguration of the immune system by HAART may again dysregulate bone metabolism. I speculate to suggest that NRTIs dysregulate bone metabolism perhaps by affecting mitochondria in bone cells, but little research has been conducted regarding this. One study found hypercholesteremia in Japan could reduce bone mineral density.
Contradicting an earlier meta-analysis that found low bone mineral density more often in HIV-infected people taking antiretrovirals than in untreated people with HIV [1], analysis of the Vancouver HIV cohort linked only longer tenofovir therapy to a higher risk of thinning bones [2]. In fact, a higher CD4 count and a lower viral load independently predicted a lower risk of thin bone among men in this cross-sectional study. Several non-HIV risk factors, including lower weight, nonwhite race, and alcohol use, raised the risk of weaker bones.
On the other hand, analysis of data from a trial comparing lopinavir/ritonavir with efavirenz in previously untreated people found equivalent and significant drops in bone mineral density with the two regimens through 96 weeks [3]. These investigators did not report if more people had osteopenia or osteoporosis at the end of follow-up.
Vancouver clinicians analyzed DEXA-measured rates of reduced bone mineral density, osteopenia, and osteoporosis in 285 people seen once between January 2005 and July 2007; 80% were white and 89% men. Median age stood at 48 years (interquartile range 43 to 55 years). Antiretroviral therapy and HIV care are free in Vancouver.
Two thirds of the study group had abnormal bone mineral density, 54% had osteopenia, and 13% had osteoporosis. (The investigators did not say how they defined "abnormal"; they defined osteopenia and osteoporosis by World Health Organization criteria.) Lower body mass index (P < 0.01) and more alcohol use (P = 0.01) were more frequent in people with than without abnormal bone density. Abnormal bone density rates did not vary significantly by gender, ethnicity (white versus nonwhite), age, smoking status, family history of osteoporosis, or injecting drug use (no versus yes).
Among HIV-related factors, higher current CD4 count correlated with normal bone mineral density (P = 0.03), and the investigators saw a trend toward an association between higher nadir CD4 count and normal bones (P = 0.10). Current viral load did not correlate with bone thickness in this analysis. Neither cumulative time on antiretrovirals nor cumulative time on protease inhibitors (PIs) affected bone mineral density, although longer PI therapy correlated with thinner bones in the earlier meta-analysis [1]. Six or more months taking tenofovir (versus fewer than 6 months) favored thinner bones in a comparison that approached statistical significance (P = 0.08). Among people taking tenofovir at least 6 months, 56% had abnormal bone density, while 44% taking tenofovir fewer than 6 months had low bone density.
Multivariate analysis picked out four factors that independently affected bone mineral density in all 285 people, at the following odds ratios (OR) and 95% confidence intervals (CI):
· Higher body mass index lowered the risk of abnormal bone density 15%: OR 0.85, 95% CI 0.78 to 0.91, P < 0.01.
· White versus nonwhite ethnicity more than doubled the risk: OR 2.52, 95% CI 1.09 to 5.84, P = 0.03.
· Every 100-cell higher current CD4 count lowered the risk 13%: OR 0.87, 95% CI 0.77 to 0.98, P = 0.03.
· Fewer than versus more than 6 months on tenofovir doubled the risk: OR 2.01, 95% CI 1.11 to 3.62, P = 0.02.
Alcohol use raised the risk of low bone density almost 75% (OR 1.73), but this correlation fell just short of statistical significance (95% CI 0.93 to 3.20, P = 0.08).
Limiting the analysis to the 253 men, the Vancouver team found five factors that affected the risk of low bone density:
· Higher body mass index lowered the risk almost 20%: OR 0.81, 95% CI 0.74 to 0.89, P < 0.01.
· Low or moderate versus high self-reported physical activity more than doubled the risk: OR 2.16, 95% CI 1.09 to 4.27, P = 0.03.
· Alcohol use more than doubled the risk: OR 2.08, 95% CI 1.01 to 4.29, P = 0.04.
· Every 100-cell higher current CD4 count lowered the risk 20%: OR 0.80, 95% CI 0.69 to 0.94, P = 0.01.
· Current viral load below 10,000 copies lowered the risk 76% (OR 0.24, 95% CI 0.06 to 0.86, P = 0.02.
The investigators caution that the analysis of antiretroviral impact on bone density suffers from their inability to make statistical adjustments for adherence. But why the Vancouver antiretroviral results differ from those in the meta-analysis [1] or in the lopinavir-efavirenz study (described below) remains unclear.
The lopinavir-versus-efavirenz trial involved 155 antiretroviral-naive people randomized to one drug or the other, plus AZT/3TC [3]. People who reined in HIV with lopinavir triple therapy could simplify their regimen to lopinavir monotherapy. The bone analysis involved 74 people taking lopinavir and 32 taking efavirenz who had DEXA scans on study entry and at 96 weeks. The two groups matched closely in bone density when the study began.
Multivariate analysis linked higher pretreatment bone mineral density to higher weight, black race, and higher pretreatment viral load (P = 0.003 for each correlation), but not with age, smoking status, alcohol use, CD4 count, or higher TNF-alpha soluble receptor levels.
After 96 weeks the average decrease from pretreatment bone density measured 2.5% in the lopinavir group and 2.3% in the efavirenz group. These declines from baseline were significant for each regimen (P < 0.01), but the difference between regimens was not significant (P = 0.86). Switching to lopinavir/ritonavir monotherapy had no impact on rates of bone density change. Three factors predicted more than a 5% drop in bone mineral density through 96 weeks: lower pretreatment CD4 count, nonblack race, and higher pretreatment fasting glucose.
Comparing results of these three studies is chancy because the patient populations, methods, and outcome measures differed among them. Still, the disparate antiretroviral risk results will perpetuate concerns over the impact of HIV and anti-HIV drugs on bone health. The three studies are consistent in showing that traditional risk factors for low bone density certainly affect people with HIV.
References
1. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS. 2006;20:2165-2174.
2. Guillemi S, Ng F, Zhang W, et al. Risk factors for reduced bone mineral density in HIV-infected individuals in the modern HAART era. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 969.
3. Brown T, McComsey G, King M, et al. Bone mineral density 96 weeks after ART initiation: a randomized trial comparing efavirenz-based therapy with a lopinavir/ritonavir-containing regimen with simplification to LPV/r monotherapy. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 966.
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