Michael T. Yin

Bone Disease in HIV Infection: A Practical Review and Recommendations for HIV Care Providers

Low bone mineral density (BMD) is prevalent in human immunodeficiency virus (HIV)-infected subjects. Initiation of antiretroviral therapy is associated with a 2%-6% decrease in BMD over the first 2 years, a decrease that is similar in magnitude to that sustained during the first 2 years of menopause. Recent studies have also described increased fracture rates in the HIV-infected population. The causes of low BMD in individuals with HIV infection appear to be multifactorial and likely represent a complex interaction between HIV infection, traditional osteoporosis risk factors, and antiretroviral-related factors. In this review, we make the point that HIV infection should be considered as a risk factor for bone disease. We recommend screening patients with fragility fractures, all HIV-infected post-menopausal women, and all HIV-infected men ⩾50 years of age. We also discuss the importance of considering secondary causes of osteoporosis. Finally, we discuss treatment of the more severe cases of bone disease, while outlining the caveats and gaps in our knowledge.

Discriminants of Prevalent Fractures in Chronic Kidney Disease

Patients with chronic kidney disease (CKD) have higher rates of fracture than the general population. Increased bone remodeling, leading to microarchitectural deterioration and increased fragility, may accompany declining kidney function, but there are no reliable methods to identify patients at increased risk for fracture. In this cross-sectional study of 82 patients with predialysis CKD, high-resolution imaging revealed that the 23 patients with current fractures had significantly lower areal density at the femoral neck; total, cortical, and trabecular volumetric bone density; cortical area and thickness; and trabecular thickness. Compared with levels in the lowest tertile, higher levels of osteocalcin, procollagen type-1 N-terminal propeptide, and tartrate-resistant acid phosphatase 5b were associated with higher odds of fracture, even after adjustment for femoral neck T-score. Discrimination of fracture prevalence was best with a femoral neck T-score of -2.0 or less and a value in the upper two tertiles for osteocalcin, procollagen type-1 N-terminal propeptide, or tartrate-resistant acid phosphatase 5b; these values corresponded to the upper half of the normal premenopausal reference range. In summary, these cross-sectional data suggest that measurement of bone turnover markers may increase the diagnostic accuracy of densitometry to identify patients with CKD at high risk for fracture.

Short-term bone loss in HIV-infected premenopausal women.

Background:Low bone mineral density (BMD) has been reported in HIV+ women, but less is known about the longitudinal evolution of BMD and fracture incidence. Methods:In 100 HIV+ and 68 HIV− premenopausal women in the Womens Interagency HIV Study, BMD was measured by dual energy x-ray absorptiometry at the femoral neck (FN) and lumbar spine (LS) at index visit and after a median of 2.5 years. Results:In HIV+ women, BMD at index visit was normal but 5% lower at the LS and FN than in HIV− women. Annual percent decrease in BMD did not differ between HIV+ and HIV− women at the LS (−0.8% ± 0.2% vs −0.4% ± 0.2%, P = 0.20) or FN (−0.8% ± 0.3% vs −0.6% ± 0.3%, P = 0.56) and remained similar after adjustment for age, weight, and BMD at index visit. Among HIV+ women, bone loss was associated with vitamin D deficiency and opiate use but not with use or class of antiretrovirals. Incidence of self-reported fracture was 0.74 per 100 person-years in HIV+ women and similar in HIV− women. Conclusions:In premenopausal HIV+ women, index BMD was lower than comparable HIV− women; however, rates of bone loss at the LS and FN were similar over 2.5 years of observation, irrespective of antiretroviral therapy.

Incident fractures in HIV-infected individuals: a systematic review and meta-analysis

Objective(s):Some but not all studies indicate that individuals with HIV infection are at an increased risk of fracture. We systematically reviewed the literature to investigate whether incidence of fracture (both overall and fragility) differs between individuals with and without HIV. Design:A systematic review and meta-analysis. Methods:Medline, Scopus and the Cochrane Library databases for all studies ever published up to 28 September 2012 and electronically available conference abstracts from CROI, ASBMR, IAS and AIDS were searched. All studies reporting incidence of all fracture and fragility fracture in HIV-infected adults were included. A random effects model was used to calculate pooled estimates of incidence rate ratios (IRRs) for studies that presented data for HIV-infected and controls. For all studies, incidence rates of fracture and predictors of fracture among HIV-infected individuals were summarized. Results:Thirteen eligible studies were analysed, of which seven included controls. Nine studies reported all incident fractures and 10 presented incident fragility fractures. The pooled IRR was 1.58 [95% confidence interval (CI) 1.25–2.00] for all fracture and 1.35 (95% CI 1.10–1.65) for fragility fracture. Smoking, white race and older age were consistent predictors for fragility fractures. Conclusion:Our results indicate that HIV infection is associated with a modest increase in incident fracture. Future research should focus on clarifying risk factors, designing appropriate interventions and the long-term implications of this increased risk for an ageing HIV-infected population.

Low Bone Mass and High Bone Turnover in Postmenopausal Human Immunodeficiency Virus-Infected Women

CONTEXT Low bone mineral density (BMD) is commonly reported in young men and women with HIV infection, and fracture rates may be higher. With effective antiretroviral therapy (ART), the HIV population is aging. However, little is known about the skeletal status of postmenopausal women. OBJECTIVE We aimed to assess the effects of HIV infection and ART on BMD and bone turnover in postmenopausal minority women. DESIGN, SETTING, AND PATIENTS A prospective cohort study was performed in 92 HIV+ and 95 HIV- postmenopausal Hispanic and African-American women. MAIN OUTCOME MEASURES We measured BMD by dual-energy x-ray absorptiometry, fracture prevalence, serum levels of inflammatory cytokines (TNFalpha, IL-6), bone turnover markers, calciotropic hormones, and estrone. RESULTS HIV+ women were younger (56 +/- 1 vs. 60 +/- 1 yr; P < 0.01) and had lower BMI (28 +/- 1 vs. 30 +/- 1 kg/m(2); P < 0.01) and estrone levels. Prevalence of T scores below -1.0 was greater in HIV+ women at the spine (78 vs. 64%; P < 0.05), total hip (45 vs. 29%; P < 0.05), and femoral neck (64 vs. 46%; P < 0.05), and Z scores adjusted for BMI were lower in HIV+ women at the same sites. Serum TNFalpha, N-telopeptide, and C-telopeptide were significantly higher in HIV+ than HIV- women, particularly those receiving ART. HIV+ status was independently and negatively associated with spine and hip BMD after adjustment for age, ethnicity, BMI, and alcohol. CONCLUSION The lower BMD, higher prevalence of low BMD, and higher levels of bone turnover markers detected in HIV+ postmenopausal minority women could place them at high risk for future fractures.

Fracture incidence in HIV-infected women: results from the Women's Interagency HIV Study

Background:The clinical importance of the association of HIV infection and antiretroviral therapy (ART) with low bone mineral density (BMD) in premenopausal women is uncertain because BMD stabilizes on established ART and fracture data are limited. Methods:We measured time to first new fracture at any site with median follow-up of 5.4 years in 2391 (1728 HIV-infected, 663 HIV-uninfected) participants in the Womens Interagency HIV Study (WIHS). Self-report of fracture was recorded at semiannual visits. Proportional hazard models assessed predictors of incident fracture. Results:At baseline, HIV-infected women were older (40 ± 9 vs. 36 ± 10 years, P < 0.0001), more likely to report postmenopausal status and be hepatitis C virus-infected, and weighed less than HIV-uninfected women. Among HIV-infected women, mean CD4+ cell count was 482 cells/μl; 66% were taking ART. Unadjusted incidence of fracture did not differ between HIV-infected and uninfected women (1.8 vs. 1.4/100 person-years, respectively, P = 0.18). In multivariate models, white (vs. African-American) race, hepatitis C virus infection, and higher serum creatinine, but not HIV serostatus, were statistically significant predictors of incident fracture. Among HIV-infected women, older age, white race, current cigarette use, and history of AIDS-defining illness were associated with incidence of new fracture. Conclusion:Among predominantly premenopausal women, there was little difference in fracture incidence rates by HIV status, rather traditional risk factors were important predictors. Further research is necessary to characterize fracture risk in HIV-infected women during and after the menopausal transition.

Incidence and predictors of acute kidney injury associated with intravenous polymyxin B therapy

BACKGROUND Increases in multidrug-resistance among gram-negative organisms have necessitated the use of polymyxins. To date, the incidence of acute kidney injury (AKI) associated with polymyxin B has not been evaluated using RIFLE criteria. METHODS Adult patients who received polymyxin B were retrospectively evaluated to determine the incidence of AKI during polymyxin B therapy using RIFLE criteria. Predictors of AKI were identified by comparing characteristics of patients with and without AKI. RESULTS A total of 73 patients were included. The incidence of AKI was 60%. Ten (14%) patients discontinued therapy due to nephrotoxicity. Median duration of polymyxin B was 11 days with a median cumulative dose of 18 mg/kg. Concomitant nephrotoxins were received in 69 (95%). Patients with AKI had a higher median cumulative dose (1578 mg vs. 800 mg; p = 0.02), a higher body mass index (BMI) (27.2 vs. 24.5 kg/m(2); p = 0.03), and were more likely to receive vancomycin (82% vs. 55%; p = 0.03) compared to those without AKI. After controlling for polymyxin B duration, independent predictors of AKI were higher BMI and concomitant vancomycin. CONCLUSIONS The incidence of AKI during polymyxin B therapy was 60%. Further studies are needed to define dosing parameters that maximize efficacy and minimize nephrotoxicity.

Higher Rates of Bone Loss in Postmenopausal HIV-Infected Women: A Longitudinal Study

CONTEXT AND OBJECTIVE The objective of the study was to assess the effects of HIV infection and antiretroviral therapy on change in bone mineral density (BMD) in postmenopausal minority women. DESIGN, SETTING, AND PATIENTS We report a longitudinal analysis of change in BMD with a median duration of 15.4 (interquartile range 13.1, 20.7) months in a prospective cohort study of 128 (73 HIV+, 55 HIV-) postmenopausal Hispanic and African-American women. MAIN OUTCOME MEASURES Annualized change in BMD by dual-energy x-ray absorptiometry and correlation with baseline markers of bone turnover and serum levels of inflammatory cytokines were measured. RESULTS HIV+ women were younger (56 ± 1 vs. 59 ± 1 yr, P < 0.05) and had lower body mass index (BMI; 28 ± 1 vs. 31 ± 1 kg/m(2), P < 0.01). The majority of HIV+ women were on established antiretroviral therapy for more than 3 yr. At baseline, BMD, adjusted for age, race, and BMI, was lower in HIV+ women at the lumbar spine (LS), total hip, and radius and serum C-telopeptide was higher. Annualized rates of bone loss adjusted for baseline BMD were higher in HIV+ women by 2.4-fold at the LS (-1.2 ± 0.3% vs. -0.5 ± 0.3%, P = 0.0009), 3.7-fold at the one third radius (-1.1 ± 0.2% vs. -0.3 ± 0.2, P = 0.006) and 1.7-fold at the ultradistal radius (-1.2 ± 0.2% vs. -0.7 ± 0.2%, P = 0.02). In multivariate analysis, HIV+ status predicted bone loss at the LS, total hip, and ultradistal radius. Among HIV+ women, lower BMI, higher markers of bone turnover levels, and tenofovir were associated with more bone loss. CONCLUSION HIV+ postmenopausal minority women had lower BMD, increased bone turnover, and higher rates of bone loss than HIV- women. These features may place these women at increased risk for fracture as they age.

Recommendations for Evaluation and Management of Bone Disease in HIV

Thirty-four human immunodeficiency virus (HIV) specialists from 16 countries contributed to this project, whose primary aim was to provide guidance on the screening, diagnosis, and monitoring of bone disease in HIV-infected patients. Four clinically important questions in bone disease management were identified, and recommendations, based on literature review and expert opinion, were agreed upon. Risk of fragility fracture should be assessed primarily using the Fracture Risk Assessment Tool (FRAX), without dual-energy X-ray absorptiometry (DXA), in all HIV-infected men aged 40-49 years and HIV-infected premenopausal women aged ≥40 years. DXA should be performed in men aged ≥50 years, postmenopausal women, patients with a history of fragility fracture, patients receiving chronic glucocorticoid treatment, and patients at high risk of falls. In resource-limited settings, FRAX without bone mineral density can be substituted for DXA. Guidelines for antiretroviral therapy should be followed; adjustment should avoid tenofovir disoproxil fumarate or boosted protease inhibitors in at-risk patients. Dietary and lifestyle management strategies for high-risk patients should be employed and antiosteoporosis treatment initiated.

Physiologic Frailty and Fragility Fracture in HIV-Infected Male Veterans

BACKGROUND The Veterans Aging Cohort Study (VACS) Index is associated with all-cause mortality in individuals infected with human immunodeficiency virus (HIV). It is also associated with markers of inflammation and may thus reflect physiologic frailty. This analysis explores the association between physiologic frailty, as assessed by the VACS Index, and fragility fracture. METHODS HIV-infected men from VACS were included. We identified hip, vertebral, and upper arm fractures using ICD-9-CM codes. We used Cox regression models to assess fragility fracture risk factors including the VACS Index, its components (age, hepatitis C status, FIB-4 score, estimated glomerular filtration rate, hemoglobin, HIV RNA, CD4 count), and previously identified risk factors for fragility fractures. RESULTS We included 40 115 HIV-infected male Veterans. They experienced 588 first fragility fractures over 6.0 ± 3.9 years. The VACS Index score (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.11-1.19), white race (HR, 1.92; 95% CI, 1.63-2.28), body mass index (HR, 0.94; 95% CI, .92-.96), alcohol-related diagnoses (HR, 1.65; 95% CI, 1.26-2.17), cerebrovascular disease (HR, 1.95; 95% CI, 1.14-3.33), proton pump inhibitor use (HR, 1.87; 95% CI, 1.54-2.27), and protease inhibitor use (HR, 1.25; 95% CI, 1.04-1.50) were associated with fracture risk. Components of the VACS Index score most strongly associated with fracture risk were age (HR, 1.40; 95% CI, 1.27-1.54), log HIV RNA (HR, 0.91; 95% CI, .88-.94), and hemoglobin level (HR, 0.82; 95% CI, .78-.86). CONCLUSIONS Frailty, as measured by the VACS Index, is an important predictor of fragility fractures among HIV-infected male Veterans.