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1.  Comparative Effectiveness of Diabetic Oral Medications Among HIV-Infected and HIV-Uninfected Veterans 
Diabetes Care  2016;40(2):218-225.
OBJECTIVE
Type 2 diabetes is increasingly common in HIV-infected individuals. The objective of this study was to compare the glycemic effectiveness of oral diabetic medications among patients with and without HIV infection.
RESEARCH DESIGN AND METHODS
A longitudinal cohort study was conducted among HIV-infected and uninfected veterans with type 2 diabetes initiating diabetic medications between 1999 and 2010. Generalized estimating equations were used to compare changes in hemoglobin A1c (HbA1c) through the year after medication initiation, adjusting for baseline HbA1c level and clinical covariates. A subanalysis using propensity scores was conducted to account for confounding by indication.
RESULTS
A total of 2,454 HIV-infected patients and 8,892 HIV-uninfected patients initiated diabetic medications during the study period. The most commonly prescribed medication was metformin (n = 5,647, 50%), followed by a sulfonylurea (n = 5,554, 49%) and a thiazolidinedione (n = 145, 1%). After adjustment for potential confounders, there was no significant difference in the change in HbA1c level among the three groups of new users. HIV infection was not significantly associated with glycemic response (P = 0.24). Black and Hispanic patients had a poorer response to therapy compared with white patients, with a relative increase in HbA1c level of 0.16% (95% CI 0.08, 0.24) [1.7 mmol/mol (0.9, 2.6)] (P < 0.001) and 0.25% (0.11, 0.39) [2.7 mmol/mol (1.2, 4.3)] (P = 0.001), respectively.
CONCLUSIONS
We found that glycemic response was independent of the initial class of diabetic medication prescribed among HIV-uninfected and HIV-infected adults with type 2 diabetes. The mechanisms leading to poorer response among black and Hispanic patients, who make up a substantial proportion of those with HIV infection and type 2 diabetes, require further investigation.
doi:10.2337/dc16-0718
PMCID: PMC5250696  PMID: 27634393
2.  Immunological and infectious risk factors for lung cancer in US veterans with HIV: a longitudinal cohort study 
The lancet. HIV  2016;4(2):e67-e73.
Summary
Background
HIV infection is independently associated with risk of lung cancer, but few data exist for the relation between longitudinal measurements of immune function and lung-cancer risk in people living with HIV.
Methods
We followed up participants with HIV from the Veterans Aging Cohort Study for a minimum of 3 years between Jan 1, 1998, and Dec 31, 2012, and used cancer registry data to identify incident cases of lung cancer. The index date for each patient was the later of the date HIV care began or Jan 1, 1998. We excluded patients with less than 3 years’ follow-up, prevalent diagnoses of lung cancer, or incomplete laboratory data. We used Cox regression models to investigate the relation between different time-updated lagged and cumulative exposures (CD4 cell count, CD8 cell count, CD4/CD8 ratio, HIV RNA, and bacterial pneumonia) and risk of lung cancer. Models were adjusted for age, race or ethnicity, smoking, hepatitis C virus infection, alcohol use disorders, drug use disorders, and history of chronic obstructive pulmonary disease and occupational lung disease.
Findings
We identified 277 cases of incident lung cancer in 21 666 participants with HIV. In separate models for each time-updated 12 month lagged, 24 month simple moving average cumulative exposure, increased risk of lung cancer was associated with low CD4 cell count (p trend=0·001), low CD4/CD8 ratio (p trend=0·0001), high HIV RNA concentration (p=0·004), and more cumulative bacterial pneumonia episodes (12 month lag only; p trend=0·0004). In a mutually adjusted model including these factors, CD4/CD8 ratio and cumulative bacterial pneumonia episodes remained significant (p trends 0·003 and 0·004, respectively).
Interpretation
In our large HIV cohort in the antiretroviral therapy era, we found evidence that dysfunctional immune activation and chronic inflammation contribute to the development of lung cancer in the setting of HIV infection. These findings could be used to target lung-cancer prevention measures to high-risk groups.
Funding
US National Institutes of Health.
doi:10.1016/S2352-3018(16)30215-6
PMCID: PMC5444465  PMID: 27916584
3.  The Starting Treatment for Ethanol in Primary care Trials (STEP Trials): Protocol for Three Parallel Multi-Site Stepped Care Effectiveness Studies for Unhealthy Alcohol Use in HIV-Positive Patients 
Unhealthy alcohol use is common among HIV-positive patients, yet effective evidence-based treatments are rarely provided in clinical settings providing HIV care. Further, given patient variability in response to initial treatments, stepped care approaches may be beneficial. We describe the rationale, aims and study design for the current Starting Treatment for Ethanol in Primary care Trials (STEP Trials); three parallel randomized controlled effectiveness trials being conducted in five Infectious Disease Clinics. Participants meeting criteria for: 1) at-risk drinking, 2) moderate alcohol use with liver disease (MALD), or 3) alcohol use disorder (AUD) are randomized to integrated stepped care versus treatment as usual. For those with at-risk drinking or MALD, integrated stepped care starts with a one session brief intervention and follow-up 2-week telephone booster. Based on pre-specified nonresponse criteria, participants may be “stepped up” at week 4 to receive four sessions of motivational enhancement therapy (MET) and “stepped up” again at week 12 for addiction physician management (APM) and consideration of alcohol pharmacotherapy. For those with AUD, integrated stepped care begins with APM. Non-responders may be “stepped up” at week 4 to receive MET and again at week 12 for a higher level of care (e.g. intensive outpatient program). The primary outcome is alcohol consumption assessed at 24 weeks, and secondary outcome is the VACS Index, a validated measure of HIV morbidity and mortality risk. Results from the STEP Trials should inform future research and the implementation of interventions to address unhealthy alcohol use among HIV-positive individuals.
doi:10.1016/j.cct.2016.11.008
PMCID: PMC5253227  PMID: 27876616
Multicenter study; Randomized controlled trial; Algorithms; HIV; Alcohol
4.  Baseline, Time-Updated, and Cumulative HIV Care Metrics for Predicting Acute Myocardial Infarction and All-Cause Mortality 
Six human immunodeficiency virus (HIV) care metrics predicted acute myocardial infarction (AMI) and mortality among HIV-infected individuals. Time-updated Veterans Aging Cohort Study Index provided the best prediction for both AMI and mortality.
Background. After adjustment for cardiovascular risk factors and despite higher mortality, those with human immunodeficiency virus (HIV+) have a greater risk of acute myocardial infarction (AMI) than uninfected individuals.
Methods. We included HIV+ individuals who started combination antiretroviral therapy (cART) in the Veterans Aging Cohort Study (VACS) from 1996 to 2012. We fit multivariable proportional hazards models for baseline, time-updated and cumulative measures of HIV-1 RNA, CD4 counts, and the VACS Index. We used the trapezoidal rule to build the following cumulative measures: viremia copy-years, CD4-years, and VACS Index score-years, captured 180 days after cART initiation until AMI, death, last clinic visit, or 30 September 2012. The primary outcomes were incident AMI (Medicaid, Medicare, and Veterans Affairs International Classification of Diseases-9 codes) and death.
Results. A total of 8168 HIV+ individuals (53 861 person-years) were analyzed with 196 incident AMIs and 1710 deaths. Controlling for known cardiovascular risk factors, 6 of the 9 metrics predicted AMI and all metrics predicted mortality. Time-updated VACS Index had the lowest Akaike information criterion among all models for both outcomes. A time-updated VACS Index score of 55+ was associated with a hazard ratio (HR) of 3.31 (95% confidence interval [CI], 2.11–5.20) for AMI and a HR of 31.77 (95% CI, 26.17–38.57) for mortality.
Conclusions. Time-updated VACS Index provided better AMI and mortality prediction than CD4 count and HIV-1 RNA, suggesting that current health determines risk more accurately than prior history and that risk assessment can be improved by biomarkers of organ injury.
doi:10.1093/cid/ciw564
PMCID: PMC5106607  PMID: 27539575
acute myocardial infarction; HIV; mortality; VACS Index
5.  The Impact of Prescribed Opioids on CD4 Cell Count Recovery among HIV-Infected Patients Newly Initiating Antiretroviral Therapy 
HIV medicine  2016;17(10):728-739.
Objectives
Certain prescribed opioids have immunosuppressive properties, yet their impact on clinically relevant outcomes, including antiretroviral therapy (ART) response among HIV-infected patients, remains understudied.
Methods
Using the Veterans Aging Cohort Study data, we conducted a longitudinal analysis of 4,358 HIV-infected patients initiating ART between 2002 and 2010 and then followed them for 24 months. The primary independent variable was prescribed opioid duration, categorized using pharmacy data as none prescribed, short-term (<90 days), and long-term (≥90 days). Outcomes included CD4 cell count over time. Analyses adjusted for demographics, comorbid conditions, ART type and year of initiation, and overall disease severity (ascertained with the VACS index). Sensitivity analyses examined whether effects varied according to baseline CD4 cell count, achievement of viral load suppression, and opioid properties (i.e., dose and known immunosuppressive properties).
Results
Compared to those with none, patients with short-term prescribed opioids had a similar increase in CD4 cell count (rise per year: 74 vs. 68 cells/mm3, p=0.11), as did those with long-term prescribed opioids (rise per year: 74 vs. 75 cells/mm3, p=0.98). In sensitivity analysis, compared to those with none, short-term prescribed opioid effects were statistically significant among those with baseline CD4 cell count ≥500 cells/mm3 (rise per year: 52 vs. 20 cells/mm3, p=0.04); findings were otherwise unchanged.
Conclusions
Despite immunosuppressive properties intrinsic to opioids, prescribed opioids appeared to have no effect on CD4 cell counts over 24 months among HIV-infected patients initiating antiretroviral therapy.
doi:10.1111/hiv.12377
PMCID: PMC5053822  PMID: 27186715
HIV; analgesics; opioid; CD4 lymphocyte count; disease progression; antiretroviral therapy
6.  Active Surveillance to Quantify the Burden of Norovirus in a U.S. Veterans Affairs (VA) Patient Population, Houston, 2015–2016 
Open Forum Infectious Diseases  2017;4(Suppl 1):S317.
Abstract
Background
Norovirus is the leading cause of acute gastroenteritis (AGE) outbreaks in the United States; however, little data exist on the burden of endemic norovirus disease among adults. Robust estimates of the norovirus disease burden among US adults are needed to inform assessment of potential norovirus vaccines, which are currently in development.
Methods
We conducted active surveillance for AGE at the Michael E. DeBakey Veteran’s Affairs (VA) Medical Center, where approximately 104,000 unique patients were served in 2016. Cases were defined as veterans with symptoms of AGE (≥3 loose stools, ≥2 vomiting episodes, or ≥1 episodes of both loose stool and vomiting, within 24 hours) occurring in the previous 10 days, who presented to the emergency department or outpatient clinics (outpatients), or were admitted to the hospital (inpatients). Patients without AGE symptoms in the prior 14 days were enrolled as controls. Demographic data and illness characteristics were collected from enrolled subjects, and stool samples were collected and tested using the FilmArray gastrointestinal panel. Norovirus positives were confirmed by real-time RT-PCR and genotyped after sequencing of conventional PCR products.
Results
From November 1, 2015–November 30, 2016, 130 inpatient and 85 outpatient AGE cases, along with 20 inpatient and 37 outpatient controls, were enrolled and provided a stool specimen. Among cases, 201 (93%) were male, and 94 (44%) were ≥65 years; median duration of illness was 3 days (range, 1–10 days). Norovirus was detected in 12 (9%) inpatient and 15 (18%) outpatient cases; norovirus was not detected in any controls. Incidence of norovirus-associated hospitalization was 15/100,000 population, and was similar in hospitalized cases aged <65 years (14/100,000) and ≥65 years (15/100,000). Of 22 norovirus positive specimens genotyped, 13 (59%) were GII.4 Sydney.
Conclusion
This robust, active surveillance platform employed screening and enrollment of patients in a VA population meeting a standardized AGE case definition, as well as asymptomatic controls. Data from this study highlight the burden of norovirus in adults and importance of a norovirus vaccine.
Disclosures
R. L. Atmar, Takeda Vaccines, Inc.: Research Support, Research support. B. Lopman, HHS/NIH/NIAID: Grant Investigator, Grant recipient. Bill & Melinda Gates Foundation: Grant Investigator, Grant recipient.
doi:10.1093/ofid/ofx163.741
PMCID: PMC5632071
7.  Weight Gain and Incident Diabetes among HIV Infected-Veterans Initiating Antiretroviral Therapy Compared to Uninfected Individuals 
Background
The health implications of weight gain after antiretroviral therapy (ART) for HIV infection are not well characterized and may differ from weight gain among uninfected individuals. We use data from the Veterans Aging Cohort Study (VACS) to determine whether weight gain after ART has a similar association with incident type-2 diabetes mellitus (DM) as weight gained among HIV-uninfected (uninfected) individuals.
Methods
We explored associations of weight gain and incident diabetes (A1c ≥ 6.5 %), in VACS, a national observational study of HIV infected (HIV+) individuals demographically matched 1:2 to uninfected controls. From 2000 to 2011, weight change was assessed in the year following ART initiation for HIV+ individuals and date of first available BMI for uninfected individuals. We estimated hazard ratios (HR) and 95% CI adjusted for baseline BMI using Cox regression.
Results
HIV+ individuals had lower prevalence of DM at baseline (12%, HIV+, 23% uninfected) and lower incident diabetes (5% HIV+, 11% uninfected). The association of weight gain with risk of DM was linear for HIV+ and uninfected but the slope of the association was steeper for HIV+. For each 5 pounds of weight gained, HIV+ had 14% increased risk of DM (HR, 1.14; 95% CI, 1.10–1.17) and uninfected individuals had 8% increased risk (HR: 1.08; 95% CI, 1.07–1.10) (p<0.01 for interaction).
Conclusion
Weight gained in the first year after ART initiation is associated with greater risk of DM than that among uninfected individuals. HIV+ individuals initiating ART who are not underweight should avoid substantial weight gain.
doi:10.1097/QAI.0000000000001071
PMCID: PMC5023454  PMID: 27171741
Diabetes; HIV; weight gain; obesity; Veterans; Inflammation
8.  Proceedings of the 14th annual conference of INEBRIA 
Holloway, Aisha S. | Ferguson, Jennifer | Landale, Sarah | Cariola, Laura | Newbury-Birch, Dorothy | Flynn, Amy | Knight, John R. | Sherritt, Lon | Harris, Sion K. | O’Donnell, Amy J. | Kaner, Eileen | Hanratty, Barbara | Loree, Amy M. | Yonkers, Kimberly A. | Ondersma, Steven J. | Gilstead-Hayden, Kate | Martino, Steve | Adam, Angeline | Schwartz, Robert P. | Wu, Li-Tzy | Subramaniam, Geetha | Sharma, Gaurav | McNeely, Jennifer | Berman, Anne H. | Kolaas, Karoline | Petersén, Elisabeth | Bendtsen, Preben | Hedman, Erik | Linderoth, Catharina | Müssener, Ulrika | Sinadinovic, Kristina | Spak, Fredrik | Gremyr, Ida | Thurang, Anna | Mitchell, Ann M. | Finnell, Deborah | Savage, Christine L. | Mahmoud, Khadejah F. | Riordan, Benjamin C. | Conner, Tamlin S. | Flett, Jayde A. M. | Scarf, Damian | McRee, Bonnie | Vendetti, Janice | Gallucci, Karen Steinberg | Robaina, Kate | Clark, Brendan J. | Jones, Jacqueline | Reed, Kathryne D. | Hodapp, Rachel M. | Douglas, Ivor | Burnham, Ellen L. | Aagaard, Laura | Cook, Paul F. | Harris, Brett R. | Yu, Jiang | Wolff, Margaret | Rogers, Meighan | Barbosa, Carolina | Wedehase, Brendan J. | Dunlap, Laura J. | Mitchell, Shannon G. | Dusek, Kristi A. | Gryczynski, Jan | Kirk, Arethusa S. | Oros, Marla T. | Hosler, Colleen | O’Grady, Kevin E. | Brown, Barry S. | Angus, Colin | Sherborne, Sidney | Gillespie, Duncan | Meier, Petra | Brennan, Alan | de Vargas, Divane | Soares, Janaina | Castelblanco, Donna | Doran, Kelly M. | Wittman, Ian | Shelley, Donna | Rotrosen, John | Gelberg, Lillian | Edelman, E. Jennifer | Maisto, Stephen A. | Hansen, Nathan B. | Cutter, Christopher J. | Deng, Yanhong | Dziura, James | Fiellin, Lynn E. | O’Connor, Patrick G. | Bedimo, Roger | Gibert, Cynthia | Marconi, Vincent C. | Rimland, David | Rodriguez-Barradas, Maria C. | Simberkoff, Michael S. | Justice, Amy C. | Bryant, Kendall J. | Fiellin, David A. | Giles, Emma L. | Coulton, Simon | Deluca, Paolo | Drummond, Colin | Howel, Denise | McColl, Elaine | McGovern, Ruth | Scott, Stephanie | Stamp, Elaine | Sumnall, Harry | Vale, Luke | Alabani, Viviana | Atkinson, Amanda | Boniface, Sadie | Frankham, Jo | Gilvarry, Eilish | Hendrie, Nadine | Howe, Nicola | McGeechan, Grant J. | Ramsey, Amy | Stanley, Grant | Clephane, Justine | Gardiner, David | Holmes, John | Martin, Neil | Shevills, Colin | Soutar, Melanie | Chi, Felicia W. | Weisner, Constance | Ross, Thekla B. | Mertens, Jennifer | Sterling, Stacy A. | Shorter, Gillian W. | Heather, Nick | Bray, Jeremy | Cohen, Hildie A. | McPherson, Tracy L. | Adam, Cyrille | López-Pelayo, Hugo | Gual, Antoni | Segura-Garcia, Lidia | Colom, Joan | Ornelas, India J. | Doyle, Suzanne | Donovan, Dennis | Duran, Bonnie | Torres, Vanessa | Gaume, Jacques | Grazioli, Véronique | Fortini, Cristiana | Paroz, Sophie | Bertholet, Nicolas | Daeppen, Jean-Bernard | Satterfield, Jason M. | Gregorich, Steven | Alvarado, Nicholas J. | Muñoz, Ricardo | Kulieva, Gozel | Vijayaraghavan, Maya | Adam, Angéline | Cunningham, John A. | Díaz, Estela | Palacio-Vieira, Jorge | Godinho, Alexandra | Kushir, Vladyslav | O’Brien, Kimberly H. M. | Aguinaldo, Laika D. | Sellers, Christina M. | Spirito, Anthony | Chang, Grace | Blake-Lamb, Tiffany | LaFave, Lea R. Ayers | Thies, Kathleen M. | Pepin, Amy L. | Sprangers, Kara E. | Bradley, Martha | Jorgensen, Shasta | Catano, Nico A. | Murray, Adelaide R. | Schachter, Deborah | Andersen, Ronald M. | Rey, Guillermina Natera | Vahidi, Mani | Rico, Melvin W. | Baumeister, Sebastian E. | Johansson, Magnus | Sinadinovic, Christina | Hermansson, Ulric | Andreasson, Sven | O’Grady, Megan A. | Kapoor, Sandeep | Akkari, Cherine | Bernal, Camila | Pappacena, Kristen | Morley, Jeanne | Auerbach, Mark | Neighbors, Charles J. | Kwon, Nancy | Conigliaro, Joseph | Morgenstern, Jon | Magill, Molly | Apodaca, Timothy R. | Borsari, Brian | Hoadley, Ariel | Scott Tonigan, J. | Moyers, Theresa | Fitzgerald, Niamh M. | Schölin, Lisa | Barticevic, Nicolas | Zuzulich, Soledad | Poblete, Fernando | Norambuena, Pablo | Sacco, Paul | Ting, Laura | Beaulieu, Michele | Wallace, Paul George | Andrews, Matthew | Daley, Kate | Shenker, Don | Gallagher, Louise | Watson, Rod | Weaver, Tim | Bruguera, Pol | Oliveras, Clara | Gavotti, Carolina | Barrio, Pablo | Braddick, Fleur | Miquel, Laia | Suárez, Montse | Bruguera, Carla | Brown, Richard L. | Capell, Julie Whelan | Paul Moberg, D. | Maslowsky, Julie | Saunders, Laura A. | McCormack, Ryan P. | Scheidell, Joy | Gonzalez, Mirelis | Bauroth, Sabrina | Liu, Weiwei | Lindsay, Dawn L. | Lincoln, Piper | Hagle, Holly | Wallhed Finn, Sara | Hammarberg, Anders | Andréasson, Sven | King, Sarah E. | Vargo, Rachael | Kameg, Brayden N. | Acquavita, Shauna P. | Van Loon, Ruth Anne | Smith, Rachel | Brehm, Bonnie J. | Diers, Tiffiny | Kim, Karissa | Barker, Andrea | Jones, Ashley L. | Skinner, Asheley C. | Hinman, Agatha | Svikis, Dace S. | Thacker, Casey L. | Resnicow, Ken | Beatty, Jessica R. | Janisse, James | Puder, Karoline | Bakshi, Ann-Sofie | Milward, Joanna M. | Kimergard, Andreas | Garnett, Claire V. | Crane, David | Brown, Jamie | West, Robert | Michie, Susan | Rosendahl, Ingvar | Andersson, Claes | Gajecki, Mikael | Blankers, Matthijs | Donoghue, Kim | Lynch, Ellen | Maconochie, Ian | Phillips, Ceri | Pockett, Rhys | Phillips, Tom | Patton, R. | Russell, Ian | Strang, John | Stewart, Maureen T. | Quinn, Amity E. | Brolin, Mary | Evans, Brooke | Horgan, Constance M. | Liu, Junqing | McCree, Fern | Kanovsky, Doug | Oberlander, Tyler | Zhang, Huan | Hamlin, Ben | Saunders, Robert | Barton, Mary B. | Scholle, Sarah H. | Santora, Patricia | Bhatt, Chirag | Ahmed, Kazi | Hodgkin, Dominic | Gao, Wenwu | Merrick, Elizabeth L. | Drebing, Charles E. | Larson, Mary Jo | Sharma, Monica | Petry, Nancy M. | Saitz, Richard | Weisner, Constance M. | Young-Wolff, Kelly C. | Lu, Wendy Y. | Blosnich, John R. | Lehavot, Keren | Glass, Joseph E. | Williams, Emily C. | Bensley, Kara M. | Chan, Gary | Dombrowski, Julie | Fortney, John | Rubinsky, Anna D. | Lapham, Gwen T. | Forray, Ariadna | Olmstead, Todd A. | Gilstad-Hayden, Kathryn | Kershaw, Trace | Dillon, Pamela | Weaver, Michael F. | Grekin, Emily R. | Ellis, Jennifer D. | McGoron, Lucy | McGoron, Lucy
doi:10.1186/s13722-017-0087-8
PMCID: PMC5606215
9.  Hepatic safety of buprenorphine in HIV-infected and uninfected patients with opioid use disorder: The role of HCV-infection 
Introduction
Individuals with HIV and hepatitis C (HCV) infection, alcohol use disorder, or who are prescribed potentially hepatotoxic medications may be at increased risk for buprenorphine (BUP) associated hepatotoxicity.
Materials and methods
We examined a cohort of HIV-infected and uninfected patients receiving an initial BUP prescription between 2003 and 2012. We compared changes in alanine and aspartate aminotransferases (ALT and AST) and total bilirubin (TB) stratified by HIV status. We identified cases of liver enzyme elevation (LEE), TB elevation (TBE), and conducted chart review to assess for cases of drug induced liver injury (DILI) and death. We examined associations between age, sex, race, HIV-infection, HCV-infection, alcohol use disorder, and prescription of other potentially heptatotoxic medications with the composite endpoint of LEE, TBE, and DILI.
Results
Of 666 patients prescribed BUP, 36% were HIV-infected, 98% were male, 60% had RNA-confirmed HCV infection, 50% had a recent diagnosis of alcohol use disorder, and 64% were prescribed other potentially hepatotoxic medications. No clinically significant changes were observed in median ALT, AST and TB and these changes did not differ between HIV-infected and uninfected patients. Compared with uninfected patients, HIV-infected (OR 7.3, 95% CI 2.1-26.1, p=0.002), HCV-infected (OR 4.9 95% CI 1.6-15.2, p=0.007) or HIV/HCV co-infected patients (OR 6.9, 95%CI 2.1-22.2, p=0.001) were more likely to have the composite endpoint of LEE, TB elevation or DILI, in analyses that excluded 60 patients with evidence of pre-existing liver injury. 31 patients had LEE, 14/187 HIV-infected and 17/340 uninfected (p = 0.25); 11 had TBE, including 9/186 HIV-infected and 2/329 uninfected (p = 0.002); 8 experienced DILI, 4/202 HIV-infected and 2/404 uninfected (p = 0.45). There were no significant associations with alcohol use disorder or prescription of other potentially hepatotoxic medications after adjustment for HIV/HCV status.
Conclusions
Liver enzymes and TB are rarely elevated in HIV-infected and uninfected patients receiving BUP. Risk of hepatotoxicity was greater in individuals infected with HIV, HCV, or HIV/HCV co-infection, who may benefit from increased monitoring.
doi:10.1016/j.jsat.2016.06.002
PMCID: PMC4976086  PMID: 27431048
buprenorphine; HIV; Hepatitis C; drug induced liver injury
10.  Fracture prediction with modified-FRAX in older HIV-infected and uninfected men 
Background
FRAX® is a validated, computer-based clinical fracture risk calculator that estimates 10-year risk of major osteoporotic (clinical spine, forearm, hip or shoulder) fracture, and hip fracture alone. It is widely used for decision-making in fracture prevention, but may underestimate risk in HIV-infected individuals. Some experts recommend considering HIV a cause of secondary osteoporosis when calculating FRAX in HIV-infected individuals.
Methods
From the Veterans Aging Study Virtual Cohort (VACS-VC), we included 24451 HIV-infected and uninfected 50-70 year old men with complete data in year 2000 to approximate all but two factors (i.e. history of secondary osteoporosis and parental hip fracture) for modified-FRAX calculation without bone density and 10-year observational data for incident fragility fracture. Accuracy of the modified-FRAX calculation was compared by observed/estimated (O/E) ratios of fracture by HIV status.
Results
Accuracy of modified-FRAX was less for HIV-infected (O/E=1.62, 95%CI: 1.45, 1.81) than uninfected men (O/E=1.29, 95%CI: 1.19, 1.40), but improved when HIV was included as a cause of secondary osteoporosis (O/E=1.20, 95%CI: 1.08, 1.34). However, only 3-6% of men with incident fractures were correctly identified by the modified-FRAX using accepted FRAX thresholds for pharmacologic therapy.
Conclusions
Modified-FRAX underestimated fracture rates more in older HIV-infected than otherwise similar uninfected men. Accuracy improved when HIV was included as a cause of secondary osteoporosis, but it still performed poorly for case-finding. Further studies are necessary to determine how to use FRAX or define an HIV-specific index to risk stratify for screening and treatment in older HIV-infected individuals.
doi:10.1097/QAI.0000000000000998
PMCID: PMC4942335  PMID: 27003493
fracture incidence; HIV; men; FRAX
11.  Time trends in cancer incidence in persons living with HIV/AIDS in the antiretroviral therapy era: 1997–2012 
AIDS (London, England)  2016;30(11):1795-1806.
Objective
Utilizing the Veterans Aging Cohort Study, the largest HIV cohort in North America, we conducted one of the few comprehensive comparisons of cancer incidence time trends in HIV-infected (HIV+) versus uninfected persons during the antiretroviral therapy (ART) era.
Design
Prospective cohort study.
Methods
We followed 44,787 HIV+ and 96,852 demographically-matched uninfected persons during 1997–2012. We calculated age-, sex-, and race/ethnicity-standardized incidence rates (IR) and incidence rate ratios (IRR, HIV+ versus uninfected) over four calendar periods with IR and IRR period trend p-values for cancer groupings and specific cancer types.
Results
We observed 3,714 incident cancer diagnoses in HIV+ and 5,760 in uninfected persons. The HIV+ all cancer crude IR increased between 1997–2000 and 2009–2012 (p-trend=0.0019). However, after standardization, we observed highly significant HIV+ IR declines for all cancer (25% decline; p-trend<0.0001), AIDS-defining cancers (ADC; 55% decline; p-trend<0.0001), non-AIDS-defining cancers (NADC; 15% decline; p-trend=0.0003), and non-virus-related NADC (20% decline; p-trend<0.0001); significant IRR declines for all cancer (from 2.0 to 1.6; p-trend<0.0001), ADC (from 19 to 5.5; p-trend<0.0001), and non-virus-related NADC (from 1.4 to 1.2; p-trend=0.049); and borderline significant IRR declines for NADC (from 1.6 to 1.4; p-trend=0.078) and virus-related NADC (from 4.9 to 3.5; p-trend=0.071).
Conclusion
Improved HIV care resulting in improved immune function most likely contributed to the HIV+ IR and the IRR declines. Further promotion of early and sustained ART, improved ART regimens, reduction of traditional cancer risk factor (e.g., smoking) prevalence, and evidence-based screening could contribute to future cancer incidence declines among HIV+ persons.
doi:10.1097/QAD.0000000000001112
PMCID: PMC4925286  PMID: 27064994
acquired immunodeficiency syndrome; HIV infections; neoplasms; cancer; Veterans
12.  Do Biomarkers Of Inflammation, Monocyte Activation And Altered Coagulation Explain Excess Mortality Between HIV Infected and Uninfected People? 
Background
HIV infection and biomarkers of inflammation (measured by interleukin-6 [IL-6]), monocyte activation (soluble CD14 [sCD14]), and coagulation (D-dimer) are associated with morbidity and mortality. We hypothesized that these immunologic processes mediate (explain) some of the excess risk of mortality among HIV infected (HIV+) versus uninfected people independently of co-morbid diseases.
Methods
Among 2350 (1521 HIV+) participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS BC) we investigated whether the association between HIV and mortality was altered by adjustment for IL-6, sCD14 and D-dimer, accounting for confounders. Participants were followed from date of blood draw for biomarker assays (baseline) until death or 7/25/2013. Analyses included ordered logistic regression and Cox Proportional Hazards regression.
Results
During 6·9 years (median), 414 deaths occurred. The proportional odds of being in a higher quartile of IL-6, sCD14 or D-dimer was 2-3 fold higher for viremic HIV+ versus uninfected people. Mortality rates were higher among HIV+ compared to uninfected people (incidence rate ratio (95% CI): 1·31 (1·06-1·62). Mortality risk increased with increasing quartiles of IL-6, sCD14 and D-dimer regardless of HIV status. Adjustment for IL-6, sCD14 and D-dimer partially attenuated mortality risk among HIV+ people with unsuppressed viremia (HIV-1 RNA≥10000 copies/mL) compared to uninfected people – hazard ratio (95% CI) decreased from 2·18 (1·60-2·99) to 2·00 (1·45-2·76).
Conclusions
HIV infection is associated with elevated IL-6, sCD14 and D-dimer, which are in turn associated with mortality. Baseline measures of these biomarkers partially mediate excess mortality risk among HIV+ versus uninfected people.
doi:10.1097/QAI.0000000000000954
PMCID: PMC4867134  PMID: 26885807
HIV; mortality; inflammation; monocyte activation; coagulation
13.  Isolated Hepatitis B Core Antibody is Associated with Advanced Hepatic Fibrosis in HIV/HCV Infection but not in HIV infection alone 
Summary
HIV+/HCV+ persons with isolated HBcAb have a higher prevalence of advanced fibrosis than persons who are non-immune to HBV, who have resolved HBV, or who are HbsAb+ only.
doi:10.1097/QAI.0000000000000941
PMCID: PMC4837046  PMID: 26829660
Hepatitis B Core Antibody; HIV; hepatitis C
14.  Quantitative and Qualitative Antibody Responses to Immunization With the Pneumococcal Polysaccharide Vaccine in HIV-Infected Patients After Initiation of Antiretroviral Treatment: Results From a Randomized Clinical Trial 
The Journal of Infectious Diseases  2014;211(11):1703-1711.
Background. Pneumococcal vaccination is recommended for human immunodeficiency virus-infected (HIV+) persons; the best timing for immunization with respect to initiation of antiretroviral therapy (ART) is unknown.
Methods. Double-blind, placebo-controlled trial in HIV+ with CD4+ T cells/µL (CD4) ≥ 200 randomized to receive the 23-valent pneumococcal polysaccharide vaccine (PPV23) or placebo at enrollment, followed by placebo or PPV23, respectively, 9–12 months later (after ≥6 months of ART). Capsular polysaccharide-specific immunoglobin (Ig) G and IgM levels to serotypes 1, 3, 4, 6B, and 23F, and opsonophagocytic killing activity (OPA) to serotypes 6B and 23F were evaluated 1 month postvaccination.
Results. One hundred seven subjects were enrolled, 72 (67.3%) were evaluable (36/group). Both groups had significant increases in pre- to 1-month postvaccination IgG levels, but negligible to IgM, and significant increases in OPA titers to serotype 6B but not to 23F. There were no significant differences between groups in serotype-specific IgM or IgG levels or OPA titers. For the combined groups, there was a significant correlation between serotype-specific IgG and OPA titers to 23F but not to 6B. There was no correlation between CD4, viral load and IgG responses.
Conclusions. In HIV+ with CD4 ≥ 200, delaying PPV23 until ≥6 months of ART does not improve responses and may lead to missed opportunities for immunization.
doi:10.1093/infdis/jiu819
PMCID: PMC4471434  PMID: 25538270
antibody; HIV; pneumococcal vaccine; pneumococcal capsular polysaccharides; antiretroviral treatment
15.  HIV status and the risk of ischemic stroke among men 
Neurology  2015;84(19):1933-1940.
Objective:
Given conflicting data regarding the association of HIV infection and ischemic stroke risk, we sought to determine whether HIV infection conferred an increased ischemic stroke risk among male veterans.
Methods:
The Veterans Aging Cohort Study–Virtual Cohort consists of HIV-infected and uninfected veterans in care matched (1:2) for age, sex, race/ethnicity, and clinical site. We analyzed data on 76,835 male participants in the Veterans Aging Cohort Study–Virtual Cohort who were free of baseline cardiovascular disease. We assessed demographics, ischemic stroke risk factors, comorbid diseases, substance use, HIV biomarkers, and incidence of ischemic stroke from October 1, 2003, to December 31, 2009.
Results:
During a median follow-up period of 5.9 (interquartile range 3.5–6.6) years, there were 910 stroke events (37.4% HIV-infected). Ischemic stroke rates per 1,000 person-years were higher for HIV-infected (2.79, 95% confidence interval 2.51–3.10) than for uninfected veterans (2.24 [2.06–2.43]) (incidence rate ratio 1.25 [1.09–1.43]; p < 0.01). After adjusting for demographics, ischemic stroke risk factors, comorbid diseases, and substance use, the risk of ischemic stroke was higher among male veterans with HIV infection compared with uninfected veterans (hazard ratio 1.17 [1.01–1.36]; p = 0.04).
Conclusions:
HIV infection is associated with an increased ischemic stroke risk among HIV-infected compared with demographically and behaviorally similar uninfected male veterans.
doi:10.1212/WNL.0000000000001560
PMCID: PMC4433456  PMID: 25862803
16.  Cost-effectiveness of Collaborative Care for Depression in Human Immunodeficiency Virus Clinics 
Objective
To examine the cost-effectiveness of the HITIDES intervention.
Design
Randomized controlled effectiveness and implementation trial comparing depression collaborative care with enhanced usual care.
Setting
Three Veterans Health Administration (VHA) HIV clinics in the Southern US.
Subjects
249 HIV-infected patients completed the baseline interview; 123 were randomized to the intervention and 126 to usual care.
Intervention
HITIDES consisted of an off-site HIV depression care team that delivered up to 12 months of collaborative care. The intervention used a stepped-care model for depression treatment and specific recommendations were based on the Texas Medication Algorithm Project and the VA/Department of Defense Depression Treatment Guidelines.
Main outcome measure(s)
Quality-adjusted life years (QALYs) were calculated using the 12-Item Short Form Health Survey, the Quality of Well Being Scale, and by converting depression-free days to QALYs. The base case analysis used outpatient, pharmacy, patient, and intervention costs. Cost-effectiveness was calculated using incremental cost effectiveness ratios (ICERs) and net health benefit (NHB). ICER distributions were generated using nonparametric bootstrap with replacement sampling.
Results
The HITIDES intervention was more effective and cost-saving compared to usual care in 78% of bootstrapped samples. The intervention NHB was positive and therefore deemed cost-effective using an ICER threshold of $50,000/QALY.
Conclusions
In HIV clinic settings this intervention was more effective and cost-saving compared to usual care. Implementation of off-site depression collaborative care programs in specialty care settings may be a strategy that not only improves outcomes for patients, but also maximizes the efficient use of limited healthcare resources.
doi:10.1097/QAI.0000000000000732
PMCID: PMC4626259  PMID: 26102447
17.  Association of COPD with risk for pulmonary infections requiring hospitalization in HIV-infected Veterans 
Background
Pulmonary infections remain more common in HIV-infected (HIV+) compared to uninfected individuals. The increase in chronic lung diseases among aging HIV+ individuals may contribute to this persistent risk. We sought to determine whether chronic obstructive pulmonary disease (COPD) is an independent risk factor for different pulmonary infections requiring hospitalization among HIV+ patients.
Methods
We analyzed data from 41,993 HIV+ Veterans in the nationwide Veterans Aging Cohort Study Virtual Cohort (VACS-VC) from 1996–2009. Using ICD-9 codes, we identified baseline comorbid conditions, including COPD, and incident community-acquired pneumonia (CAP), pulmonary tuberculosis (TB) and Pneumocystis jirovecii pneumonia (PCP) requiring hospitalization within two years after baseline. We used multivariable Poisson regression to determine incidence rate ratios (IRR) associated with COPD for each type of pulmonary infection, adjusting for comorbidities, CD4+ cell count, HIV viral load, smoking status, substance use, vaccinations and calendar year at baseline.
Results
Unadjusted incidence rates of CAP, TB and PCP requiring hospitalization were significantly higher among persons with COPD compared to those without COPD (CAP: 53.9 vs. 19.4 per 1,000 person-years; TB: 8.7 vs. 2.8; PCP: 15.5 vs. 9.2; p ≤0.001). In multivariable Poisson regression models, COPD was independently associated with increased risk of CAP, TB and PCP (IRR 1.94, 95% CI 1.64–2.30; IRR 2.60, 95% CI 1.70–3.97; and IRR 1.48, 95% CI 1.10–2.01, respectively).
Conclusions
COPD is an independent risk factor for CAP, TB and PCP requiring hospitalization among HIV+ individuals. As the HIV+ population ages, the growing burden of COPD may confer substantial risk for pulmonary infections.
doi:10.1097/QAI.0000000000000751
PMCID: PMC4607625  PMID: 26181820
COPD; pulmonary infection; pneumonia; HIV; comorbidities
18.  Depression and HIV Infection are Risk Factors for Incident Heart Failure Among Veterans: Veterans Aging Cohort Study 
Circulation  2015;132(17):1630-1638.
Background
Both HIV and depression are associated with increased heart failure (HF) risk. Depression, a common comorbidity, may further increase the risk of HF among HIV+ adults. We assessed the association between HIV, depression and incident HF.
Methods and Results
Veterans Aging Cohort Study (VACS) participants free from cardiovascular disease at baseline (N = 81,427; 26,908 HIV+, 54,519 HIV-) were categorized into four groups: HIV- without major depressive disorder (MDD) [reference]; HIV- with MDD; HIV+ without MDD; and HIV+ with MDD. ICD-9 codes from medical records were used to determine MDD and the primary outcome, HF. After 5.8 follow-up years, HF rates per 1000 person-years were highest among HIV+ participants with MDD (9.32; 95% CI, 8.20–10.6). In Cox proportional hazards models, HIV+ participants with MDD had significantly higher risk of HF [adjusted hazard ratio (aHR) = 1.68; 95% CI, 1.45–1.95] compared to HIV- participants without MDD. MDD was associated with HF in separate fully adjusted models for HIV- and HIV+ participants (aHR = 1.21; 1.06–1.37 and 1.29; 1.11–1.51, respectively). Among those with MDD, baseline antidepressant use was associated with lower risk of incident HF events (aHR = 0.76; 0.58–0.99).
Conclusions
Our study is the first to suggest MDD is an independent risk factor for HF in HIV+ adults. These results reinforce the importance of identifying and managing MDD among HIV+ patients. Future studies must clarify mechanisms linking HIV, MDD, antidepressants, and HF; and identify interventions to reduce HF morbidity and mortality in those with both HIV and MDD.
doi:10.1161/CIRCULATIONAHA.114.014443
PMCID: PMC4624488  PMID: 26358261
HIV infection; depression; psychiatric comorbidity; heart failure; epidemiology
19.  Thirty-Day Postoperative Mortality Among Individuals With HIV Infection Receiving Antiretroviral Therapy and Procedure-Matched, Uninfected Comparators 
JAMA surgery  2015;150(4):343-351.
IMPORTANCE
Antiretroviral therapy (ART) has converted human immunodeficiency virus (HIV) infection into a chronic condition, and patients now undergo a variety of surgical procedures, but current surgical outcomes are inadequately characterized.
OBJECTIVE
To compare 30-day postoperative mortality in patients with HIV infection receiving ART with the rates in uninfected individuals.
DESIGN, SETTING, AND PARTICIPANTS
Retrospective analysis of nationwide electronic medical record data from the US Veterans Health Administration Healthcare System, October 1, 1996, to September 30, 2010. Common inpatient surgical procedures were grouped using the Healthcare Cost and Utilization Project Clinical Classification System to match HIV-infected and uninfected patients in a 1:2 ratio. Data on 1641 patients with HIV infection receiving combination ART who were undergoing inpatient surgery were compared with data on 3282 procedure-matched, uninfected comparators. Poisson regression models of 30-day postoperative mortality were adjusted for procedure year, age, Charlson Comorbidity Index score, hemoglobin level, albumin level, HIV infection, CD4 cell count, and HIV-1 RNA level.
MAIN OUTCOMES AND MEASURES
All-cause 30-day postoperative mortality.
RESULTS
The most common procedures in both groups were cholecystectomy (10.5%), hip arthroplasty (10.5%), spine surgery (9.8%), herniorrhaphy (7.4%), and coronary artery bypass grafting (7.0%). In patients with HIV infection, CD4 cell distributions were 80.0% with 200/µL or more, 16.3% with 50/µL to 199/µL, and 3.7% with less than 50/µL; 74.1% of patients with HIV infection had undetectable HIV-1 RNA. Human immunodeficiency virus infection was associated with higher 30-day postoperative mortality compared with the mortality in uninfected patients (3.4% [56 patients]) vs 1.6% [53]); incidence rate ratio [IRR], 2.11; 95% CI, 1.41–3.17; P < .001). CD4 cell count was inversely associated with mortality, but HIV-1 RNA provided no additional information. After adjustment, patients with HIV infection had increased mortality compared with uninfected patients at all CD4 cell count strata (≥500/µL: IRR, 1.92; 95% CI, 1.02–3.60; P = .04; 200–499/µL: IRR, 1.89; 95% CI, 1.20–2.98; P = .01; 50–199/µL: IRR, 2.66; 95% CI, 1.29–5.47; P = .01; and <50/µL: IRR, 6.21; 95% CI, 3.55–10.85; P < .001). Hypoalbuminemia (IRR, 4.35; 95% CI, 2.78–6.81; P < .001) and age in decades (IRR, 1.47; 95% CI, 1.23–1.76; P < .001) were also strongly associated with mortality.
CONCLUSIONS AND RELEVANCE
Current postoperative mortality rates among individuals with HIV infection who are receiving ART are low and are influenced as much by hypoalbuminemia and age as by CD4 cell status. Human immunodeficiency virus infection and CD4 cell count are only 2 of many factors associated with surgical outcomes that should be incorporated into surgical decision making.
doi:10.1001/jamasurg.2014.2257
PMCID: PMC5015449  PMID: 25714794
20.  Adherence and HIV RNA Suppression in the Current Era of Highly Active Antiretroviral Therapy (HAART) 
Background
We examined trends in adherence to highly active antiretroviral therapy (HAART) and HIV RNA suppression, and estimated the minimum cutoff of adherence to newer HAART formulations needed for HIV RNA suppression by regimen type.
Methods
We used VA pharmacy dispensing data from the Veterans Aging Cohort Study Virtual Cohort between October 2000 and September 2010, and defined adherence as the duration of time the patient had the medications available, relative to the total number of days between refills for all antiretrovirals in a year. Temporal trends in adherence and viral load suppression were examined by the patient's most frequently used HAART regimen in the year. The minimum needed adherence was defined as the level at which the odds of suppression was not significantly different than that observed with ≥95% adherence using repeated measures logistic regression.
Results
21,865 HAART users contributed 82,217 person-years of follow-up. There was a significant increase (ptrend<0.001) in the proportion virally suppressed even among those with <95% adherence (2001: 38% to 2010: 84%) and the trend was similar when restricting to their first HAART regimen. For NNRTI multi-pill users, the odds of suppression did not differ for 85-89% adherence compared to those with ≥95% adherence, odds ratios: 0.82 (0.64,1.04), but for PI users, the odds of suppression significantly differed if adherence levels were <95% compared to ≥95% adherence.
Conclusions
Although all HIV-infected persons should be instructed to achieve perfect adherence, concerns of slightly lower adherence should not hinder prescribing new HAART regimens early in HIV infection.
doi:10.1097/QAI.0000000000000643
PMCID: PMC4482798  PMID: 25886923
Adherence; current HAART; HIV RNA suppression; Veterans Health Administration Center
21.  Impact of Defined Clinical Population and Missing Data on Temporal Trends in HIV Viral Load Estimation within a Healthcare System 
HIV medicine  2015;16(6):346-354.
Background
Community viral load (CVL) estimates vary based on analytic methods. We extended the CVL concept and used data from the Veterans Affairs Healthcare System (VA) to determine trends in the healthcare system viral load (HSVL), sensitivity to varying definitions of the clinical population, and assumptions regarding missing data.
Methods
We included HIV-infected patients in the Veterans Aging Cohort Study, 2000-2010, with >1 documented CD4 count, HIV-1 RNA or antiretroviral prescription (N=37,318). We created 6-month intervals including patients with ≥1 visit in the past 2 years. We assessed temporal trends in clinical population size, patient clinical status and mean HSVL and explored the impact of varying definitions of the clinical population and assumptions about missing viral load.
Results
The clinical population size varied by definition, increasing from 16,000–19,000 patients in 2000 to 23,000–26,000 in 2010. The proportion of patients with suppressed HIV-1 RNA increased over time. Over 20% of patients had no viral load measured in a given interval or prior two years. Among patients with a current HIV-1 RNA, mean HSVL decreased from 97,800 in 2000 to 2,000 copies/mL in 2010. When current HIV-1 RNA data were unavailable and the HSVL was recalculated using the last available HIV-1 RNA, HSVL decreased from 322,300 to 9,900 copies/mL. HSVL was underestimated when using only current data in each interval.
Conclusion
The CVL concept can be applied to a healthcare system, providing a measure of healthcare quality. Like CVL, HSVL estimates depend on definitions of the clinical population and assumptions about missing data.
doi:10.1111/hiv.12219
PMCID: PMC4478104  PMID: 25688937
HIV; community viral load; population surveillance; quality of health care; epidemiologic methods
22.  Weight Change After Antiretroviral Therapy and Mortality 
This study examines weight change in human immunodeficiency virus-infected veterans after 1 year of antiretroviral therapy (ART). Survival benefits of weight gain after ART initiation depended on baseline body mass index, and markers of disease severity predicted weight gain.
Background. Weight gain after antiretroviral therapy (ART) initiation is common, but its implication for mortality is unknown. We evaluated weight change in the first year after ART initiation and its association with subsequent mortality.
Methods. Human immunodeficiency virus-infected patients from the Veterans Aging Cohort Study (VACS) who initiated ART between 2000 and 2008, with weight recorded at baseline and 1 year later, were followed another 5 years for mortality. Baseline body mass index (BMI) was classified as underweight (<18.5 kg/m2), normal (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), and obese (≥30 kg/m2). We used multivariable Cox models to assess mortality risk with adjustment for disease severity using the VACS Index.
Results. The sample consisted of 4184 men and 127 women with a mean age of 47.9 ± 10.0 years. After 1 year of ART, median weight change was 5.9 pounds (2.7 kg) (interquartile range, −2.9 to 17.0 pounds, −1.3 to 7.7 kg). Weight gain after ART initiation was associated with lower mortality among underweight and normal-weight patients. A minimum threshold of 10- to 19.9-pound (4.5 to 9.0 kg) weight gain was beneficial for normal-weight patients (hazard ratio, 0.56; 95% confidence interval, .41–.78), but there was no clear benefit to weight gain for overweight/obese patients. Baseline weight, CD4 cell count status, and hemoglobin level were strongly associated with weight gain. Risk for weight gain was higher among those with greater disease severity, regardless of weight at initiation.
Conclusions. The survival benefits of weight gain after ART initiation are dependent on starting BMI. Weight gain after ART is associated with lower mortality for those who are not initially overweight.
doi:10.1093/cid/civ192
PMCID: PMC4542664  PMID: 25761868
HIV; veterans; weight; antiretroviral therapy; BMI
23.  Do Biomarkers of Inflammation, Monocyte Activation, and Altered Coagulation Explain Excess Mortality Between HIV Infected and Uninfected People? 
Supplemental Digital Content is Available in the Text.
Background:
HIV infection and biomarkers of inflammation [measured by interleukin-6 (IL-6)], monocyte activation [soluble CD14 (sCD14)], and coagulation (D-dimer) are associated with morbidity and mortality. We hypothesized that these immunologic processes mediate (explain) some of the excess risk of mortality among HIV infected (HIV+) versus uninfected people independently of comorbid diseases.
Methods:
Among 2350 (1521 HIV+) participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS BC), we investigated whether the association between HIV and mortality was altered by adjustment for IL-6, sCD14, and D-dimer, accounting for confounders. Participants were followed from date of blood draw for biomarker assays (baseline) until death or July 25, 2013. Analyses included ordered logistic regression and Cox Proportional Hazards regression.
Results:
During 6.9 years (median), 414 deaths occurred. The proportional odds of being in a higher quartile of IL-6, sCD14, or D-dimer were 2–3 fold higher for viremic HIV+ versus uninfected people. Mortality rates were higher among HIV+ compared with uninfected people [incidence rate ratio (95% CI): 1.31 (1.06 to 1.62)]. Mortality risk increased with increasing quartiles of IL-6, sCD14, and D-dimer regardless of HIV status. Adjustment for IL-6, sCD14, and D-dimer partially attenuated mortality risk among HIV+ people with unsuppressed viremia (HIV-1 RNA ≥10,000 copies per milliliter) compared with uninfected people—hazard ratio (95% CI) decreased from 2.18 (1.60 to 2.99) to 2.00 (1.45 to 2.76).
Conclusions:
HIV infection is associated with elevated IL-6, sCD14, and D-dimer, which are in turn associated with mortality. Baseline measures of these biomarkers partially mediate excess mortality risk among HIV+ versus uninfected people.
doi:10.1097/QAI.0000000000000954
PMCID: PMC4867134  PMID: 26885807
HIV; mortality; inflammation; monocyte activation; coagulation
24.  Health outcomes among HIV-positive Latinos initiating antiretroviral therapy in North America versus Central and South America 
Introduction
Latinos living with HIV in the Americas share a common ethnic and cultural heritage. In North America, Latinos have a relatively high rate of new HIV infections but lower rates of engagement at all stages of the care continuum, whereas in Latin America antiretroviral therapy (ART) services continue to expand to meet treatment needs. In this analysis, we compare HIV treatment outcomes between Latinos receiving ART in North America versus Latin America.
Methods
HIV-positive adults initiating ART at Caribbean, Central and South America Network for HIV (CCASAnet) sites were compared to Latino patients (based on country of origin or ethnic identity) starting treatment at North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) sites in the United States and Canada between 2000 and 2011. Cox proportional hazards models compared mortality, treatment interruption, antiretroviral regimen change, virologic failure and loss to follow-up between cohorts.
Results
The study included 8400 CCASAnet and 2786 NA-ACCORD patients initiating ART. CCASAnet patients were younger (median 35 vs. 37 years), more likely to be female (27% vs. 20%) and had lower nadir CD4 count (median 148 vs. 195 cells/µL, p<0.001 for all). In multivariable analyses, CCASAnet patients had a higher risk of mortality after ART initiation (adjusted hazard ratio (AHR) 1.61; 95% confidence interval (CI): 1.32 to 1.96), particularly during the first year, but a lower hazard of treatment interruption (AHR: 0.46; 95% CI: 0.42 to 0.50), change to second-line ART (AHR: 0.56; 95% CI: 0.51 to 0.62) and virologic failure (AHR: 0.52; 95% CI: 0.48 to 0.57).
Conclusions
HIV-positive Latinos initiating ART in Latin America have greater continuity of treatment but are at higher risk of death than Latinos in North America. Factors underlying these differences, such as HIV testing, linkage and access to care, warrant further investigation.
doi:10.7448/IAS.19.1.20684
PMCID: PMC4800379  PMID: 26996992
HIV; antiretroviral therapy; highly active; mortality; Latin America; North America; cohort studies

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