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1.  Increased fracture incidence in middle-aged HIV-infected and uninfected women: updated results from the Women’s Interagency HIV Study 
Background
We previously reported that fracture incidence rates did not differ by HIV status among predominantly premenopausal Women's Interagency HIV Study (WIHS) participants. We now conduct a follow-up study with 5 additional observation years, to further characterize fracture risk associated with HIV infection in women as they age.
Methods
We measured time to first new fracture at any site in 2375 (1713 HIV-infected, 662 HIV-uninfected) WIHS participants, with median 10 years follow-up. Fractures were self-reported semiannually. Proportional Hazards models assessed predictors of incident fracture.
Results
At index visit, HIV-infected women were older (median age 40 yrs (IQR 34–46) vs. 35 (27–43), p<0.0001) and more likely to be postmenopausal, HCV-infected, and weigh less than HIV-uninfected women. Among HIV-infected women, mean CD4+ count was 480 cells/µL and 63% were taking HAART. Unadjusted incidence rates of any fracture were higher in HIV-infected than uninfected women (2.19/100 person-years (py) vs 1.54/100py, p=0.002). In multivariate models, HIV status, older age, white (vs. black) race, prior fracture, history of cocaine use, and history of injection drug use were significant predictors of incident fracture. Among HIV-infected women, age, white race, prior fracture, smoking, and prior AIDS were predictors of new fracture.
Conclusion
Middle-aged HIV-infected women had a higher adjusted fracture rate than uninfected women. Cocaine use and injection drug use were also associated with a greater risk of incident fracture. Further research is needed to understand whether the risk of fracture associated with cocaine use relates to increased rate of falls, or direct effects on bone metabolism.
doi:10.1097/QAI.0000000000000674
PMCID: PMC4557627  PMID: 26322667
HIV; women; bone; fracture; fragility fracture
2.  Plasma IL-6/IL-10 Ratio and IL-8, LDH, and HBDH Level Predict the Severity and the Risk of Death in AIDS Patients with Pneumocystis Pneumonia 
Journal of Immunology Research  2016;2016:1583951.
Objective. To identify blood biomarkers to predict severity and mortality in AIDS PCP patients. Methods. Biomarkers including clinical parameters and plasma inflammatory cytokines were assessed in 32 HIV-infected patients with Pneumocystis pneumonia (PCP) at time of admission. Predictive value of the biomarkers for clinical severity and in-hospital mortality was evaluated by corresponding ROC curve. Results. Levels of CRP, WBC, LDH, HBDH, and Ferritin were significantly higher in the severe and nonsurvivor AIDS PCP patients. These important biochemical indicators have inverse correlation with oxygenation index, especially levels of LDH (P = 0.008, R2 = 0.258), HBDH (P = 0.001, R2 = 0.335), and Ferritin (P = 0.005, R2 = 0.237). Plasma IL-8 and IL-6 levels were significantly higher in patients with PaO2/FiO2 ≤ 200 mmHg and nonsurvivors than in those with PaO2/FiO2 > 200 mmHg and survivors. Severe and nonsurvival groups showed higher ratio of mean IL-6/IL-10 level (1.78 ± 1.56, P < 0.001; 1.11 ± 0.72, P = 0.043), larger AUC (95% CI 0.781–1.000, P < 0.001; 95% CI 0.592–0.917, P = 0.043), and more significantly inverse correlation with the oxygenation index. Conclusion. Plasma IL-8, LDH, and HBDH levels and IL-6/IL-10 ratio could be helpful for early evaluation of the severity and predicting fatal outcomes in AIDS PCP patients.
doi:10.1155/2016/1583951
PMCID: PMC4992515  PMID: 27579328
4.  Osteoporosis and fractures in HIV/hepatitis C virus coinfection: a systematic review and meta-analysis 
AIDS (London, England)  2014;28(14):2119-2131.
Objective
There is growing evidence that fracture risk is increased in individuals with HIV and/or hepatitis C virus (HCV) infection. We systematically reviewed the literature to determine whether prevalence of osteoporosis and incidence of fracture is increased in HIV/HCV-coinfected individuals.
Design
A systematic review and meta-analysis.
Methods
A search was performed of Medline, Scopus and the Cochrane Library databases, as well as of abstracts from annual retroviral, liver and bone meetings (up to 2013) for studies with bone mineral density (BMD) or bone fracture data for HIV/HCV-coinfected individuals. Osteoporosis odds ratios (ORs) and fracture incidence rate ratios (IRRs) were estimated from studies with data on HIV-monoinfected or HIV/HCV-uninfected comparison groups.
Results
Of 15 included studies, nine reported BMD data and six reported fracture data. For HIV/HCV-coinfected, the estimated osteoporosis prevalence was 22% [95% confidence interval (95% CI) 12–31] and the crude OR for osteoporosis compared with HIV-monoinfected was 1.63 (95% CI 1.27–2.11). The pooled IRR of overall fracture risk for HIV/HCV-coinfected individuals was 1.77 (95% CI 1.44–2.18) compared with HIV-monoinfected and 2.95 (95% CI 2.17–4.01) compared with uninfected individuals. In addition to HIV/HCV-coinfection, older age, lower BMI, smoking, alcohol and substance use were significant predictors of osteoporosis and fractures across studies.
Conclusion
HIV/HCV coinfection is associated with a greater risk of osteoporosis and fracture than HIV monoinfection; fracture risk is even greater than uninfected controls. These data suggest that HIV/HCV-coinfected individuals should be targeted for fracture prevention through risk factor modification at all ages and DXA screening at age 50.
doi:10.1097/QAD.0000000000000363
PMCID: PMC4940983  PMID: 24977441
bone; coinfection; fracture; hepatitis C virus; HIV; osteoporosis
5.  Recommendations for Evaluation and Management of Bone Disease in HIV 
We provide guidance and recommendations on clinically relevant questions regarding the screening, monitoring, and management of bone disease in HIV-infected patients using the best available data from a comprehensive literature search.
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.
doi:10.1093/cid/civ010
PMCID: PMC4400413  PMID: 25609682
bone disease; fragility fracture; human immunodeficiency virus; osteoporosis
6.  Increased Bone Resorption During Tenofovir Plus Lopinavir/Ritonavir Therapy in Chinese Individuals with HIV 
Purpose
Few studies have evaluated the effects of anti-retroviral therapy on skeletal metabolism in Asian populations infected with human immunodeficiency virus (HIV).
Methods
We performed a secondary analysis of bone turnover markers (BTM) at baseline and two years in stored plasma samples collected from 2/2009 – 1/2013 as part of a multi-center trial. Two groups were compared: 1) treatment-naïve patients initiated on zidovudine (AZT)/lamivudine (3TC) plus nevirapine (NVP), and 2) patients who failed first-line therapy and were switched to tenofovir (TDF)/3TC plus lopinavir/ritonavir (LPVr). Tests included the bone resorption marker, C-terminal cross-linking telopeptide of type-1 collagen (CTX) and the bone formation marker procollagen type 1 N-terminal propeptide (P1NP).
Results
In the TDF/3TC+LPVr group, samples were available from 59 patients at baseline and 56 patients at two years. Of these, 36 patients had samples available from both time points. In the AZT/3TC+NVP group, plasma samples were analyzed from 82 participants at baseline and of those, 61 had samples at two years. Median change over two years was greater in the TDF/3TC+LPVr group for both CTX (+0.24 ng/mL, IQR 0.10–0.43 vs. +0.09ng/mL, IQR −0.03 to 0.18, p=0.001) and P1NP (+25.5ng/mL, IQR 2.4–51.3 vs. +7.11 ng/mL, IQR −4.3 to 21.6, p=0.012). Differences remained after adjusting for age, sex, and body mass index.
Conclusions
Switching to TDF/3TC+LPVr after treatment failure resulted in greater increases in BTMs than initiation with AZT/3TC+NVP in Chinese patients with HIV. Following this change, bone resorption marker levels increased by nearly 60%, which is greater than the 25–35% increase from baseline described previously in non-Chinese populations. Further studies are warranted to elucidate these findings.
doi:10.1007/s00198-014-2874-3
PMCID: PMC4334679  PMID: 25224293
Bone Turnover; Resorption; HIV; Chinese; Tenofovir
7.  Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy – ACTG A5286 
Tenorio, Allan R. | Chan, Ellen S. | Bosch, Ronald J. | Macatangay, Bernard J. C. | Read, Sarah W. | Yesmin, Suria | Taiwo, Babafemi | Margolis, David M. | Jacobson, Jeffrey M. | Landay, Alan L. | Wilson, Cara C. | Mellors, John W. | Keshavarzian, Ali | Rodriguez, Benigno | Aziz, Mariam | Presti, Rachel | Deeks, Steven | Ebiasah, Ruth | Myers, Laurie | Borowski, LuAnn | Plants, Jill | Palm, David A. | Weibel, Derek | Putnam, Beverly | Lindsey, Elizabeth | Player, Amy | Albrecht, Mary | Kershaw, Andrea | Sax, Paul | Keenan, Cheryl | Walton, Patricia | Baum, Jane | Stroberg, Todd | Hughes, Valery | Coster, Laura | Kumar, Princy N. | Yin, Michael T. | Noel-Connor, Jolene | Tebas, Pablo | Thomas, Aleshia | Davis, Charles E. | Redfield, Robert R. | Sbrolla, Amy | Flynn, Teri | Davis, Traci | Whitely, Kim | Singh, Baljinder | Swaminathan, Shobha | McGregor, Donna | Palella, Frank | Aberg, Judith | Cavanagh, Karen | Santana Bagur, Jorge L. | Flores, Olga Méndez | Fritsche, Janice | Sha, Beverly | Slamowitz, Debbie | Valle, Sandra | Tashima, Karen | Patterson, Helen | Harber, Heather | Para, Michael | Eaton, Molly | Maddox, Dale | Currier, Judith | Cajahuaringa, Vanessa | Luetkemeyer, Annie | Dwyer, Jay | Fichtenbaum, Carl J. | Saemann, Michelle | Ray, Graham | Campbell, Thomas | Fischl, Margaret A. | Bolivar, Hector | Oakes, Jonathan | Chicurel-Bayard, Miriam | Tripoli, Christine | Weinman, D. Renee | Adams, Mary | Hurley, Christine | Dunaway, Shelia | Storey, Sheryl | Klebert, Michael | Royal, Michael
The Journal of Infectious Diseases  2014;211(5):780-790.
Background. Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART).
Methods. HIV-positive adults receiving ART for ≥96 weeks with undetectable viremia for ≥48 weeks and CD4+ T-cell counts <350 cells/mm3 were randomized 2:1 to rifaximin versus no study treatment for 4 weeks. T-cell activation, LPS, and soluble CD14 were measured at baseline and at weeks 2, 4, and 8. Wilcoxon rank sum tests compared changes between arms.
Results. Compared with no study treatment (n = 22), rifaximin (n = 43) use was associated with a significant difference between study arms in the change from baseline to week 4 for CD8+T-cell activation (median change, 0.0% with rifaximin vs +0.6% with no treatment; P = .03). This difference was driven by an increase in the no-study-treatment arm because there was no significant change within the rifaximin arm. Similarly, although there were significant differences between study arms in change from baseline to week 2 for LPS and soluble CD14, there were no significant changes within the rifaximin arm.
Conclusions. In immune nonresponders to ART, rifaximin minimally affected microbial translocation and CD8+T-cell activation.
Trial registration number. NCT01466595.
doi:10.1093/infdis/jiu515
PMCID: PMC4334803  PMID: 25214516
HIV; immune nonresponders to ART; microbial translocation; immune activation; inflammation; rifaximin
8.  High-Dose Vitamin D and Calcium Attenuates Bone Loss with Antiretroviral Therapy Initiation 
Annals of internal medicine  2015;162(12):815-824.
Background
Antiretroviral therapy (ART) initiation for HIV-1 infection is associated with 2-6% loss in bone mineral density (BMD).
Objective
To evaluate vitamin D3 (4000 IU daily) plus calcium (1000 mg calcium carbonate daily) supplementation on bone loss associated with ART initiation.
Design
48-week prospective, randomized, double-blind, placebo-controlled study.
Setting
Thirty nine AIDS Clinical Trials Network research units.
Participants
ART-naïve HIV-infected adults.
Measurements
BMD by dual-energy X-ray absorptiometry (DXA); 25-hydroxy vitamin D (25(OH)D) levels, parathyroid hormone (PTH), phosphate metabolism, markers of bone turnover and systemic inflammation.
Results
165 eligible subjects were randomized (79 Vitamin D/calcium (VitD/Cal); 86 placebo); 142 subjects with evaluable DXA data were included in the primary analysis. The study arms were well-balanced at baseline: median age 33 years; 90% male; 33% non-Hispanic black; median CD4 count 341 cells/mm3; and median 25(OH)D 23 ng/mL (57 nmol/L). At 48 weeks, subjects receiving placebo had greater decline in total hip BMD than VitD/Cal: −3.19% median change (1st-3rd quartile (Q1, Q3) −5.12%, −1.02%) vs. (−1.46% −3.16%,−0.40%). respectively (p=0.001). Lumbar spine BMD loss for the two groups was similar: −2.91% (−4.84%, −1.06%) vs. −1.41% (−3.78%, 0.00%), (p=0.085). At week 48, 90% of participants achieved HIV-1 RNA <50 copies/mL. Levels of 25(OH)D3 increased in the VitD/Cal but not the placebo group: median change of 24.5 (14.6, 37.8) vs. 0.7 (−5.3, 4.3) ng/mL, respectively (p<0.001). Additionally, increases in markers of bone turnover were blunted in the VitD/Cal group.
Limitations
No international sites were included; only 48 weeks of follow up
Conclusion
Vitamin D/calcium supplementation mitigates the loss of BMD seen with initiation of efavirenz/emtricitabine/tenofovir, particularly at the total hip, which is the site of greatest concern for fragility fracture.
Primary Funding Source
National Institute of Allergy and Infectious Diseases, Bristol-Meyers Squibb, Gilead Sciences.
doi:10.7326/M14-1409
PMCID: PMC4608553  PMID: 26075752
9.  Bone health in HIV-infected children, adolescents and young adults: a systematic review 
Background
Children and adolescents, who either acquire HIV infection perinatally, from contaminated blood products or via sexual transmission early in life, have the greatest cumulative exposure to the negative direct and indirect effects of HIV infection and ART on bone, which may lead to increased lifetime risk for osteoporosis and fracture. We conducted a systematic review to evaluate the literature on bone health in children and adolescents with HIV.
Methods
We performed a comprehensive search of the Medline, Scopus, and Cochrane Library databases (up to April 1, 2014) for studies that reported on bone imaging or bone fractures in HIV-infected children, adolescents, or young adults.
Results
A total of 32 publications met our inclusion criteria. Seventeen studies were cross-sectional and 15 were longitudinal. The majority of studies were conducted in high-income countries, three in middle-income countries and none in low-income countries. Overall, the studies we reviewed indicate that measures of bone mass are reduced, with increased prevalence of low BMD in children and adolescents with HIV. However, the studies are highly variable with respect to comparison sources, measurement methods, adjustment techniques for body size or growth retardation, and highlighted risk factors, including aspects related to medication exposures as well as the effects of HIV infection per se.
Conclusion
HIV infection appears to be associated with decreased bone accrual throughout childhood and adolescence. Initial studies indicate that sub-optimal bone accrual may be persistent and result in reduced peak bone mass, an important determinant of future risk of osteoporosis and fracture. Important areas for future research include evaluation of bone mass, bone quality and fracture risk across the life course among those with early-life infection with HIV, particularly in resource-limited settings where the majority of children with HIV live.
doi:10.4172/2155-6113.1000374
PMCID: PMC4618404  PMID: 26504618
10.  Bone Density and Fractures in HIV-infected Postmenopausal Women: A Systematic Review 
With the development of effective antiretroviral therapy, HIV-infected women are living longer and transitioning through menopause. The purpose of our study was to systematically examine the evidence that menopause is an additional risk predictor for osteoporosis and fractures in HIV-infected women. Electronic databases were searched for studies of low bone density or fractures in HIV-infected postmenopausal women. Studies that met the inclusion criteria (n = 10) were appraised using a validated quality assessment tool. The majority of studies were rated as good quality and the remaining were fair. The prevalence of osteoporosis reported in these studies ranged from 7.3% to 84% and 0.7% to 23% in HIV-infected and uninfected postmenopausal women, respectively. In the two qualifying studies, postmenopausal status was not a predictor of fractures in HIV-infected women. Findings suggest that HIV care providers should accurately assess postmenopausal status and modifiable risk factors for osteoporosis in all older HIV-infected women.
doi:10.1016/j.jana.2015.03.005
PMCID: PMC4573531  PMID: 26066693
bone mineral density (BMD); fractures; HIV; menopause
11.  A Multicenter Study of Initiation of Antiretroviral Therapy and Transmitted Drug Resistance in Antiretroviral-Naive Adolescents and Young Adults With HIV in New York City 
This multicenter study demonstrates uptake in recently changed HIV guidelines for initiation of antiretroviral therapy (ART) in HIV-infected youths in New York City. Our results also demonstrate a high proportion of ART resistance in ART-naive youths newly diagnosed with HIV.
Background. In December 2009, the Department of Health and Human Services guidelines for initiation of antiretroviral therapy (ART) changed to include patients with CD4 counts between 350 and 500 cells/µL. The aims of this study were to assess uptake of this recommendation in ART-naive youth with human immunodeficiency virus (HIV) and to describe the epidemiology of transmitted genotypic drug resistance mutations (DRMs) in this population.
Methods. A multicenter, retrospective cohort study of ART initiation in ART-naive youth was performed. Eligible subjects were 13–25 years of age, were diagnosed with HIV within 1 year of presentation to care at the study sites, and presented to care from January 2007 to June 2011.
Results. Of 685 potential subjects identified, 331 (49%) fulfilled inclusion criteria. Mean CD4 count at presentation to care was 452 cells/µL. Overall, 191 (58%) subjects started ART. The mean CD4 count at ART initiation was 261 cells/µL before and 363 cells/µL after the 2009 guideline change (P < .0001). Of 212 (64%) subjects with resistance testing available prior to ART initiation, 38 (18%) subjects had a major DRM and an increased proportion of resistance was seen in later study years.
Conclusions. Our study demonstrated an uptake in recently changed guideline recommendations to treat HIV-infected individuals at higher CD4 counts and reinforces the importance of performing resistance testing at entry into care, as 18% of our population had major DRMs prior to initiation of ART.
doi:10.1093/cid/ciu003
PMCID: PMC3988426  PMID: 24429431
HIV; adolescents; youth; genotypic resistance; antiretroviral therapy
12.  Outcomes by Sex Following Treatment Initiation With Atazanavir Plus Ritonavir or Efavirenz With Abacavir/Lamivudine or Tenofovir/Emtricitabine 
Smith, Kimberly Y. | Tierney, Camlin | Mollan, Katie | Venuto, Charles S. | Budhathoki, Chakra | Ma, Qing | Morse, Gene D. | Sax, Paul | Katzenstein, David | Godfrey, Catherine | Fischl, Margaret | Daar, Eric S. | Collier, Ann C. | Bolivar, Hector H. | Navarro, Sandra | Koletar, Susan L. | Gochnour, Diane | Seefried, Edward | Hoffman, Julie | Feinberg, Judith | Saemann, Michelle | Patterson, Kristine | Pittard, Donna | Currin, David | Upton, Kerry | Saag, Michael | Ray, Graham | Johnson, Steven | Santos, Bartolo | Funk, Connie A. | Morgan, Michael | Jackson, Brenda | Tebas, Pablo | Thomas, Aleshia | Kim, Ge-Youl | Klebert, Michael K. | Santana, Jorge L. | Marrero, Santiago | Norris, Jane | Valle, Sandra | Cox, Gary Matthew | Silberman, Martha | Shaik, Sadia | Lopez, Ruben | Vasquez, Margie | Daskalakis, Demetre | Megill, Christina | Shore, Jessica | Taiwo, Babafemi | Goldman, Mitchell | Boston, Molly | Lennox, Jeffrey | del Rio, Carlos | Lane, Timothy W. | Epperson, Kim | Luetkemeyer, Annie | Payne, Mary | Gripshover, Barbara | Antosh, Dawn | Reid, Jane | Adams, Mary | Storey, Sheryl S. | Dunaway, Shelia B. | Gallant, Joel | Wiggins, Ilene | Smith, Kimberly Y. | Swiatek, Joan A. | Timpone, Joseph | Kumar, Princy | Moe, Ardis | Palmer, Maria | Gothing, Jon | Delaney, Joanne | Whitely, Kim | Anderson, Ann Marie | Hammer, Scott M. | Yin, Michael T. | Jain, Mamta | Petersen, Tianna | Corales, Roberto | Hurley, Christine | Henry, Keith | Bordenave, Bette | Youmans, Amanda | Albrecht, Mary | Pollard, Richard B. | Olusanya, Abimbola | Skolnik, Paul R. | Adams, Betsy | Tashima, Karen T. | Patterson, Helen | Ukwu, Michelle | Rogers, Lauren | Balfour, Henry H. | Fox, Kathy A. | Swindells, Susan | Van Meter, Frances | Robbins, Gregory | Burgett-Yandow, Nicole | Davis, Charles E. | Boyce, Colleen | O'Brien, William A. | Casey, Gerianne | Morse, Gene D. | Hsaio, Chiu-Bin | Meier, Jeffrey L. | Stapleton, Jack T. | Mildvan, Donna | Revuelta, Manuel | Currin, David | El Sadr, Wafaa | Loquere, Avelino | El-Daher, Nyef | Johnson, Tina | Gross, Robert | Maffei, Kathyrn | Hughes, Valery | Sturge, Glenn | McMahon, Deborah | Rutecki, Barbara | Wulfsohn, Michael | Cheng, Andrew | Dix, Lynn | Liao, Qiming
This clinical trial identifies a significantly earlier time to virologic failure in women randomized to atazanavir/ritonavir compared to women randomized to efavirenz.
Background. We aimed to evaluate treatment responses to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) in initial antiretroviral regimens among women and men, and determine if treatment outcomes differ by sex.
Methods. We performed a randomized trial of open-label ATV/r or EFV combined with abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) in 1857 human immunodeficiency virus type 1–infected, treatment-naive persons enrolled between September 2005 and November 2007 at 59 sites in the United States and Puerto Rico. Associations of sex with 3 primary study endpoints of time to virologic failure, safety, and tolerability events were analyzed using Cox proportional hazards models. Model-based population pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM version VII).
Results. Of 1857 participants, 322 were women. Women assigned to ATV/r had a higher risk of virologic failure with either nucleoside reverse transcriptase inhibitor backbone than women assigned to EFV, or men assigned to ATV/r. The effects of ATV/r and EFV upon safety and tolerability risk did not differ significantly by sex. With ABC/3TC, women had a significantly higher (32%) safety risk compared to men; with TDF/FTC, the safety risk was 20% larger for women compared to men, but not statistically significant. Women had slower ATV clearance and higher predose levels of ATV compared to men. Self-reported adherence did not differ significantly by sex.
Conclusions. This is the first randomized clinical trial to identify a significantly earlier time to virologic failure in women randomized to ATV/r compared to women randomized to EFV. This finding has important clinical implications given that boosted protease inhibitors are often favored over EFV in women of childbearing potential.
Clinical Trials Registration NCT00118898.
doi:10.1093/cid/cit747
PMCID: PMC3905755  PMID: 24253247
sex; atazanavir; efavirenz; abacavir; tenofovir
13.  The Association of Self-perception of Body Fat Changes and Quality of Life in the Women’s Interagency HIV Study 
AIDS care  2013;25(12):10.1080/09540121.2013.793265.
Body fat changes are of concern to HIV-seropositive adults on highly active antiretroviral therapy (HAART). Studies examining the association of body fat changes and quality of life (QOL) in the setting of HIV infection have been conducted predominately in men. We examined the relationship of self-perceived body fat change with QOL among 1,671 HAART-using HIV-seropositive women (mean age 40 ± 8 years; 54% African American, 24% reporting ≤ 95% HAART adherence) from the Women’s Interagency HIV Study. Self-perception of any fat loss was associated with lower overall QOL. Report of any peripheral fat loss was strongly associated with nearly all QOL domains (i.e., physical functioning, role functioning, energy/fatigue, social functioning, pain, emotional well-being, health perception, and perceived health index) except cognitive functioning, whereas report of any central fat loss was significantly associated with lower social and cognitive functioning. Report of any central fat gain was associated with lower overall QOL, but only physical functioning, energy/fatigue, and cognitive functioning were significantly affected. A significant association of report of any peripheral fat gain with overall QOL was not observed, however peripheral fat gain was significantly associated with lower physical functioning and pain. We found that any report of fat loss, especially in peripheral body sites is associated with lower QOL, as was any report of central fat gain. Ultimately health providers and patients need to be informed of these associations so as to better support HIV-seropositive women who live with these effects.
doi:10.1080/09540121.2013.793265
PMCID: PMC3769511  PMID: 23656440
body image perception; lipoatrophy; lipohypertrophy; Quality of life; HIV-seropositive women; HAART
14.  Trabecular and cortical microarchitecture in postmenopausal HIV-infected women 
Calcified tissue international  2013;92(6):557-565.
Objective
To assess the effects of HIV infection and antiretroviral therapy (ART) on trabecular and cortical microarchitecture in postmenopausal minority women.
Methods
A subgroup of 106 (46 HIV-infected, 60 uninfected) postmenopausal Hispanic and African American women from an established cohort had areal bone mineral density (aBMD) measured by dual-energy x-ray absorptiometry, and trabecular and cortical volumetric BMD (vBMD) and microarchitecture measured by high-resolution peripheral quantitative computed tomography (HRpQCT) at the radius and tibia.
Results
HIV-infected women were slightly younger (58±1 versus 61±1 yrs, p=0.08), and had lower body mass index (BMI, 28±1 versus 32±1 kg/m2, p<0.01). BMI-adjusted aBMD Z scores were lower in HIV-infected women at the lumbar spine, total hip and ultradistal radius. Serum N-telopeptide and C-telopeptide levels were also higher in HIV-infected women. Trabecular and cortical vBMD were similar at the radius, but cortical area (105.5±2.4 versus 120.6±2.0mm2, p<0.01) and thickness (956±33 versus 1075±28 m, p<0.01) at the tibia were approximately 11–12% lower in HIV-infected women. Differences remained significant after adjusting for age, BMI and race/ethnicity. In contrast, cortical porosity was similar in both groups.
Conclusion
Although HIV-infected postmenopausal women had lower aBMD at the spine, total hip and ultradistal radius and higher levels of bone resorption markers, the only differences detected by HRpQCT were lower cortical thickness and area at the tibia.
doi:10.1007/s00223-013-9716-8
PMCID: PMC3656136  PMID: 23460340
HIV; microarchitecture; cortical structure; osteoporosis; postmenopausal women
15.  Relationship of vitamin D, HIV, HIV treatment and lipid levels in the Women’s Interagency HIV study (WIHS) of HIV-infected and un-infected women in the US 
Relationships between vitamin D, lipids, HIV infection, and HIV treatment (±ART) were investigated with Women’s Interagency HIV Study data (n=1758 middle-aged women) using multivariable regression. 63 % had vitamin D deficiency. Median 25-OH vitamin D was highest in HIV-infected +ART-treated women (17 ng/mL, p<0.001), but the same in HIV-uninfected or HIV-infected without ART (14 ng/mL). Vitamin D levels were lower if ART included efavirenz (15 vs 19 ng/mL, p<0.001). The most common lipid abnormality was high triglycerides (≥200 mg/dL) in HIV-infected +ART, (13%, vs 7% of HIV-infected without ART and 5% of HIV-uninfected (p<0.001) with a positive relationship between 25-OH-D and triglycerides (95% confidence interval 0.32 to 1.69, p<.01). No relationships between 25-OH-D and cholesterol were detected. Vitamin D deficiency is common irrespective of HIV status but influenced by HIV treatment. Similarly, vitamin D levels were positively related to triglycerides only in ART treated HIV infected, and unrelated to cholesterol.
doi:10.1177/2325957413506748
PMCID: PMC4016117  PMID: 24668135
Vitamin D; lipids; HIV infected; HIV uninfected; 25-OH vitamin D; cholesterol; LDL-cholesterol; triglycerides; lipids; WIHS
16.  Incident fractures in HIV-infected individuals: a systematic review and meta-analysis 
AIDS (London, England)  2013;27(12):1949-1957.
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.
doi:10.1097/QAD.0b013e328361d241
PMCID: PMC4030545  PMID: 24126140
bone; fracture; fracture incidence; fragility fracture; HIV
17.  Physiologic Frailty and Fragility Fracture in HIV-Infected Male Veterans 
Frailty, as measured by the Veterans Aging Cohort Study Index, is an important predictor of fragility fracture in the context of established fracture risk factors. Anemia and increasing age drive this association in a male veteran population.
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.
doi:10.1093/cid/cit056
PMCID: PMC3634308  PMID: 23378285
HIV; frailty; fragility fractures; Veterans
18.  Vitamin D, Bone, and HIV Infection 
Topics in antiviral medicine  2012;20(5):168-172.
Vitamin D deficiency has been associated with increased risk for falls and fractures, diabetes and obesity, cardiovascular disease, some malignancies, and tuberculosis. Observational data have suggested benefit of higher vitamin D levels in many of these settings. However, data from randomized trials supporting the benefit of vitamin D supplementation are generally lacking, apart from data showing benefit in preventing falls and fractures in the elderly. HIV-infected persons have a high prevalence of vitamin D deficiency and insufficiency, and some antiretroviral drugs are known to interfere with vitamin D metabolism. However, as in the general population, there are currently few data from clinical trials to identify benefits of vitamin D screening and supplementation in the HIV-infected population. A rational approach is to screen at-risk patients (eg, those aged 50 years and older and those with osteoporosis, prior fracture, or high risk for falls); supplementation may be considered in specific subgroups of patients.
PMCID: PMC4019218  PMID: 23363695
19.  Lower peak bone mass and abnormal trabecular and cortical microarchitecture in young men infected with HIV early in life 
AIDS (London, England)  2014;28(3):345-353.
Introduction
HIV infection and antiretroviral therapy (ART) early in life may interfere with acquisition of peak bone mass, thereby increasing fracture risk in adulthood.
Methods
We conducted a cross-sectional study of dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) in 30 HIV-infected African–American or Hispanic Tanner stage 5 men aged 20–25 on ART (15 perinatally infected and 15 infected during adolescence) and 15 HIV-uninfected controls.
Results
HIV-infected men were similar in age and BMI, but were more likely to be African–American (P = 0.01) than uninfected men. DXA-derived areal bone mineral density (aBMD) Z-scores were 0.4–1.2 lower in HIV-infected men at the spine, hip, and radius (all P < 0.05). At the radius and tibia, total and trabecular volumetric BMD (vBMD), and cortical and trabecular thickness were between 6 and 19% lower in HIV-infected than uninfected men (P <0.05). HIV-infected men had dramatic deficiencies in plate-related parameters by individual trabeculae segmentation (ITS) analyses and 14–17% lower bone stiffness by finite element analysis revealed. Differences in most HR-pQCT parameters remained significant after adjustment for race/ethnicity. No DXA or HR-pQCT parameters differed between men infected perinatally or during adolescence.
Conclusion
At an age by which young men have typically acquired peak bone mass, HIV-infected men on ART have lower BMD, markedly abnormal trabecular plate and cortical microarchitecture, and decreased whole bone stiffness, whether infected perinatally or during adolescence. Reduced bone strength in young adults infected with HIV early in life may place them at higher risk for fractures as they age.
doi:10.1097/QAD.0000000000000070
PMCID: PMC4019223  PMID: 24072196
bone microarchitecture; bone mineral density; bone strength; high-resolution peripheral quantitative computed tomography; peak bone mass; perinatal HIV infection
20.  Association of Regional Body Composition with Bone Mineral Density in HIV-infected and Uninfected Women: Women's Interagency HIV Study 
Objective
To understand how regional body composition affects bone mineral density (BMD) in HIV-infected and uninfected women.
Methods
Dual energy X-ray absorptiometry was used to measure regional lean and fat mass and BMD at lumbar spine (LS), total hip (TH), and femoral neck (FN) in 318 HIV-infected and 122 HIV-uninfected Women's Interagency HIV Study participants at baseline and 2 and 5 years later. Total lean and fat mass were measured using bioimpedance analysis. Multivariate marginal linear regression models assessed the association of HIV status and body composition on BMD change.
Results
Compared to HIV-uninfected women, HIV-infected women were older (44 vs. 37 yrs), more likely to be HCV-infected (32% vs. 14%), and post-menopausal (26% vs. 3%), and had lower baseline total fat mass, trunk fat and leg fat. In multivariate models, increased total lean mass was independently associated with increased BMD at LS, TH and FN and total fat mass was associated with increased BMD at TH and FN (all p<0.05). When total fat was replaced in multivariate models with trunk fat and leg fat, increased trunk fat (and not leg fat) was associated with increased TH and FN BMD (p<0.001).
Conclusions
Total fat and lean mass are strong, independent predictors of TH and FN BMD, and lean mass was associated with greater LS BMD. Regardless of HIV status, greater trunk fat (and not leg fat) was associated with increased TH and FN BMD, suggesting that weight bearing fat may be a more important predictor of BMD in the hip.
doi:10.1097/QAI.0b013e31826cba6c
PMCID: PMC3494812  PMID: 22895436
Body composition; fat redistribution; bone mineral density; HIV; women
21.  Klebsiella pneumoniae K1 Liver Abscess and Septic Endophthalmitis in a U.S. Resident 
Journal of Clinical Microbiology  2013;51(3):1049-1051.
Klebsiella pneumoniae K1 is a major agent of hepatic abscess with metastatic disease in East Asia, with sporadic reports originating elsewhere. We report a case of abscess complicated by septic endophthalmitis caused by a wzyAKpK1-positive Klebsiella strain in a U.S. resident, raising concern for global emergence.
doi:10.1128/JCM.02853-12
PMCID: PMC3592058  PMID: 23303492
22.  High Performance Liquid Chromatography-Mass Spectrometry (LC-MS) assay for polymyxin B1 and B2 in human plasma 
Therapeutic Drug Monitoring  2012;34(4):398-405.
Background
Polymyxin B is an old antibiotic with increasing clinical relevance in the treatment of multi-drug resistant Gram-negative bacterial infections. However, current dosing regimens are largely empiric as clinical pharmacological characterization of the drug has been hindered by the lack of assays to measure polymyxin B in human plasma.
Methods
A high performance liquid chromatography-mass spectrometry (LC-MS) assay was developed to quantify polymyxin B1 and B2 in human plasma using pure calibrators. After purification with a solid-phase extraction column, polymyxin B1 and B2 were separated on a C18 column by gradient chromatography with an overall runtime of 12 minutes. Polymyxin B1 and B2 were ionized by positive electron spray ionization and the resulting ions specific to polymyxin B1 and B2 were monitored (selected ion recording).
Results
The dominant ions produced were [M + 2H]2+ at m/z 602.6 and 595.5 for polymyxin B1 and polymyxin B2, respectively. The assay was linear between concentrations of 100 and 2500 ng/ml, with inter-day precision of 5.9% and 3.4% at 100 ng/mL and 5.3% and 4.0% at 2000 ng/ml for polymyxin B1 and polymyxin B2, respectively. Accuracy was 80.2% and 82.2% at 100 ng/mL and 99.9% and 109.6% at 2000 ng/ml for polymyxin B1 and polymyxin B2, respectively. No interference from other drugs commonly administered with polymyxin B was detected. The performance of the assay is affected by gross hemolysis and hyperlipemia. The method was successfully applied to patient samples. Interestingly, in a single patient the ratio of B1 and B2 did not change over a period of 12 hours after administration of the drug.
Conclusions
A simple method for the simultaneous measurement of polymyxin B1 and polymyxin B2 in human plasma is described, which has the potential to optimize clinical use of this valuable antibiotic by permitting pharmacokinetic studies and therapeutic drug monitoring.
doi:10.1097/FTD.0b013e31825c827a
PMCID: PMC3394890  PMID: 22735673
Polymyxin B; liquid chromatography-mass spectrometry; pharmacokinetics; therapeutic drug monitoring; multidrug-resistant gram-negative bacterial infections
23.  Fractures after antiretroviral initiation 
AIDS (London, England)  2012;26(17):2175-2184.
Background
Bone mineral density declines by 2–6% within 1–2 years after initiation of antiretroviral therapy (ART); however, it is uncertain whether this results in an immediate or cumulative increase in fracture rates.
Methods
We evaluated the incidence and predictors of fracture in 4640 HIV-positive participants from 26 randomized ART studies followed in the AIDS Clinical Trials Group (ACTG) Longitudinal-Linked Randomized Trial study for a median of 5 years. Fragility and nonfragility fractures were recorded prospectively at semiannual visits. Incidence was calculated as fractures/total person-years. Cox proportional hazards models evaluated effects of traditional fracture risks, HIV disease characteristics, and ART exposure on fracture incidence.
Results
Median (interquartile range) age was 39 (33, 45) years; 83% were men, 48% white, and median nadir CD4 cell count was 187 (65, 308) cells/μl. Overall, 116 fractures were reported in 106 participants with median time-to-first fracture of 2.3 years. Fracture incidence was 0.40 of 100 person-years among all participants and 0.38 of 100 person-years among 3398 participants who were ART naive at enrollment into ACTG parent studies. Among ART-naive participants, fracture rates were higher within the first 2 years after ART initiation (0.53/100 person-years) than subsequent years (0.30/100 person-years). In a multivariate analysis of ART-naive participants, increased hazard of fracture was associated with current smoking and glucocorticoid use but not with exposure to specific antiretrovirals.
Conclusion
Fracture rates were higher within the first 2 years after ART initiation, relative to subsequent years. However, continuation of ART was not associated with increasing fracture rates in these relatively young HIV-positive individuals.
doi:10.1097/QAD.0b013e328359a8ca
PMCID: PMC3652631  PMID: 22951635
antiretroviral initiation; bone loss; fracture; fracture incidence; HIV
24.  The Association of HIV Status with Bacterial Vaginosis and Vitamin D in the United States 
Journal of Women's Health  2011;20(10):1497-1503.
Abstract
Objective
To estimate the association between vitamin D deficiency and bacterial vaginosis (BV) among nonpregnant HIV-infected and uninfected women.
Methods
In a substudy of the Women's Interagency HIV Study, including women from Chicago and New York, the association between BV and vitamin D deficiency, demographics, and disease characteristics was tested using generalized estimating equations. Deficiency was defined as <20 ng/mL 25 (OH) vitamin D and insufficiency as >20 and ≤30 ng/mL. BV was defined by the Amsel criteria.
Results
Among 602 observations of nonpregnant women (480 HIV infected and 122 uninfected), BV was found in 19%. Vitamin D deficiency was found in 59.4%, and insufficiency was found in 24.4%. In multivariable analysis, black race was the most significant predictor of BV (adjusted odds ratio [AOR] 5.90, (95% confidence interval [CI] 2.52-13.8). Vitamin D deficiency was independently associated with BV among HIV-infected women (AOR 3.12, 95% CI 1.16-8.38) but not among HIV-uninfected women. There was a negative linear correlation between vitamin D concentration and prevalence of BV in HIV-infected women (r=−0.15, p=0.001).
Conclusions
Vitamin D deficiency was very common in this cohort and significantly associated with BV among HIV-infected women. These preliminary findings suggest that further epidemiologic and mechanistic exploration of the relationship between vitamin D and BV in HIV-infected women is warranted.
doi:10.1089/jwh.2010.2685
PMCID: PMC3233211  PMID: 21875343
25.  Associations of Education Level and Bone Density Tests among Cognitively Intact Elderly White Women in Managed Medicare 
Objectives. To examine associations between having bone density tests and level of education among white elderly women in managed Medicare. Method. Data from the ninth through twelfth cohort (2006–2009) of the Medicare Health Outcome Survey (HOS) of managed Medicare plans were analyzed; 239331 white elderly women were included. Respondents were grouped by education level and the percentages of respondents who had lifetime bone density testing done among each group were analyzed. Results. 62.7% of respondents with less than a high school education reported previously taking a bone density test. This was lower than the 73.8% for respondents who completed high school and the 81.0% for respondents with more than a high school education. When potential confounding factors such as age, body mass index, marital status, smoking history, year of HOS survey, and region were factored in, the odds ratios of having a bone density test when compared to respondents with less than a high school education were 1.61 and 2.39, respectively, for those with just a high school education and more than a high school education (P < 0.001). Conclusion. Higher education was independently associated with greater use of bone density test in these elderly white women.
doi:10.1155/2012/179150
PMCID: PMC3463901  PMID: 23056041

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