Janet P. Tate

Increased Risk of Fragility Fractures among HIV Infected Compared to Uninfected Male Veterans

Background HIV infection has been associated with an increased risk of fragility fracture. We explored whether or not this increased risk persisted in HIV infected and uninfected men when controlling for traditional fragility fracture risk factors. Methodology/Principal Findings Cox regression models were used to assess the association of HIV infection with the risk for incident hip, vertebral, or upper arm fracture in male Veterans enrolled in the Veterans Aging Cohort Study Virtual Cohort (VACS-VC). We calculated adjusted hazard ratios comparing HIV status and controlling for demographics and other established risk factors. The sample consisted of 119,318 men, 33% of whom were HIV infected (34% aged 50 years or older at baseline, and 55% black or Hispanic). Median body mass index (BMI) was lower in HIV infected compared with uninfected men (25 vs. 28 kg/m2; p<0.0001). Unadjusted risk for fracture was higher among HIV infected compared with uninfected men [HR: 1.32 (95% CI: 1.20, 1.47)]. After adjusting for demographics, comorbid disease, smoking and alcohol abuse, HIV infection remained associated with an increased fracture risk [HR: 1.24 (95% CI: 1.11, 1.39)]. However, adjusting for BMI attenuated this association [HR: 1.10 (95% CI: 0.97, 1.25)]. The only HIV-specific factor associated with fragility fracture was current protease inhibitor use [HR: 1.41 (95% CI: 1.16, 1.70)]. Conclusions/Significance HIV infection is associated with fragility fracture risk. This risk is attenuated by BMI.

Hepatic Decompensation in Antiretroviral-Treated Patients Co-Infected With HIV and Hepatitis C Virus Compared With Hepatitis C Virus–Monoinfected Patients: A Cohort Study

Context Patients with HIV are often co-infected with hepatitis C virus (HCV). Whether treatment of HIV with antiretroviral therapy (ART) can improve HCV outcomes is a topic of interest. Contribution In a Veterans Affairs study, patients co-infected with HIV and HCV who had HIV RNA levels less than 1000 copies/mL had a lower rate of hepatic decompensation than those with less HIV suppression. However, the rate was still higher than that in HCV-monoinfected patients. Caution Few women were studied. Implication Patients co-infected with HIV and HCV remain at greater risk for poor outcomes from HCV infection than HCV-monoinfected patients despite viral suppression by ART. The Editors Co-infection with chronic hepatitis C virus (HCV) occurs in 10% to 30% of HIV-infected patients (14). The course of chronic HCV is accelerated in patients co-infected with HIV, with more rapid progression of liver fibrosis than in HCV-monoinfected patients (57). Consequently, HCV-related liver complications, particularly hepatic decompensation (defined by the presence of ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatic encephalopathy [8]), have emerged as important causes of illness in co-infected patients (9, 10). Despite the importance of HCV-related end-stage liver disease, few longitudinal studies have evaluated the incidence and determinants of hepatic decompensation among patients co-infected with HIV and HCV during the antiretroviral therapy (ART) era. Previous studies suggest that ART slows progression of HCV-associated liver fibrosis, possibly by reducing HIV-related inflammation and immune dysfunction and inhibiting the ability of HIV to directly infect hepatocytes (1013). However, whether rates of hepatic decompensation and other severe liver events (for example, hepatocellular carcinoma [HCC] or liver-related death) in co-infected patients receiving ART are similar to those in HCV-monoinfected patients remains unclear. Furthermore, the determinants of hepatic decompensation among co-infected patients receiving ART are unknown. Determination of these factors could help define the mechanisms of decompensation in co-infected patients and could suggest interventions to reduce the risk for end-stage liver disease in this population. We first compared the incidence of hepatic decompensation between antiretroviral-treated patients co-infected with HIV and HCV and HCV-monoinfected patients. We hypothesized that rates of decompensation would remain higher in co-infected patients despite ART. We then evaluated host and viral factors associated with decompensation among co-infected patients. Methods Study Design and Data Source We conducted a retrospective cohort study among antiretroviral-treated patients co-infected with HIV and HCV and HCV-monoinfected patients in the VACS-VC (Veterans Aging Cohort Study Virtual Cohort) between 1 January 1997 and 30 September 2010 (14). The VACS-VC consists of electronic medical record data from HIV-infected patients receiving care at Veterans Affairs (VA) medical facilities across the United States. Each HIV-infected patient is matched on age, sex, race/ethnicity, and site to 2 HIV-uninfected persons. Data include hospital and outpatient diagnoses (recorded using International Classification of Diseases, Ninth Revision [ICD-9], codes), procedures (recorded using CPT [Current Procedural Terminology] codes), laboratory results, and pharmacy data. Clinically confirmed cancer diagnoses are available from the VA Central Cancer Registry. Deaths are identified from the VA Vital Status file, which uses data from the Social Security Death Master File, Medicare Vital Status Files, and VA Beneficiary Identification and Records Locator Subsystem. For patients who died, principal cause of death can be determined by linkage with the National Death Index (15). In addition, U.S. Medicare and Medicaid claims data are available for veterans also enrolled in these programs and have been merged with VACS-VC data. Study Patients Co-infected patients were included if they had detectable HCV RNA, had recently initiated ART (defined as use of 3 antiretrovirals from 2 classes [16] or 3 nucleoside analogues [a previously accepted ART regimen] [17]) within the VA system, had an HIV RNA level greater than 500 copies/mL within 180 days before starting ART (to identify those who newly initiated ART [18]), and had been observed for at least 12 months in the VACS-VC after starting ART. Monoinfected patients had detectable HCV RNA, no recorded HIV ICD-9 diagnosis or antiretroviral prescriptions, and at least 12 months of observation in the VACS-VC. Patients were excluded if, during the baseline period (defined in the Statistical Analysis section), they had hepatic decompensation, HCC, or liver transplantation or received interferon-based HCV therapy (because treatment reduces the risk for hepatic decompensation [19, 20]). Study Outcomes The primary outcome was incident hepatic decompensation, which was defined by 1 ICD-9 diagnosis of ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage at hospital discharge or 2 such outpatient diagnoses in the VACS-VC (Supplement 1). A prior study validated this determination, with 91% of events confirmed by medical records (21). The requirement of 2 outpatient diagnoses aimed to exclude events that were suspected but not subsequently confirmed at follow-up visits. On the basis of the results of the prior validation study (21), we did not include ICD-9 diagnoses for hepatic encephalopathy and jaundice, which could indicate decompensation, because these diagnoses frequently were linked to unrelated conditions (for example, narcotic overuse, stroke recorded as encephalopathy, or biliary obstruction or atazanavir-associated hyperbilirubinemia recorded as jaundice). Date of decompensation was defined as the hospital discharge date (if identified by hospital diagnosis) or initial outpatient diagnosis date (if identified by outpatient diagnosis). Supplement 1. ICD-9, ICD-10, and CPT Codes Secondary outcomes included incident hepatic decompensation (determined by the aforementioned ICD-9based definition) within the VACS-VC, Medicare, or Medicaid data (to capture outcomes occurring at non-VA hospitals that did not result in transfer to a VA facility; this outcome was secondary because non-VA events have not been validated); HCC; and severe liver events, a composite outcome of hepatic decompensation within the VACS-VC, HCC, or liver-related death. Hepatocellular carcinoma was determined using the VA Central Cancer Registry, which confirmed diagnoses by histologic or cytologic evaluation or consistent radiography. We classified deaths as liver-related if the underlying cause from the National Death Index was recorded as hepatic decompensation, liver cancer, alcoholic liver disease, viral hepatitis, or nonalcoholic liver disease (Supplement 1) (15). Data Collection Baseline data (Table 1) included age, sex, race/ethnicity, VA center patient volume, body mass index (BMI), diabetes mellitus, alcohol dependence or abuse, injection or noninjection drug use, hepatitis B surface antigen status, HCV genotype, HCV RNA level, pre-ART CD4 cell count, pre-ART plasma HIV RNA level, and baseline antiretroviral regimen. Diabetes was defined as a random glucose level of at least 200 mg/dL or antidiabetic medication use (22, 23). Alcohol dependence or abuse (24) and injection or noninjection drug use (24, 25) were defined by previously validated ICD-9 diagnoses (Supplement 1). Baseline serum creatinine, hemoglobin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels and platelet count were collected from dates closest to but before the start of follow-up. Baseline FIB-4 score, a noninvasive measure of advanced hepatic fibrosis, was determined as follows: [age in yearsAST level in U/L] / [(platelet count in109/L)(ALT level in U/L)1/2] (26). Because liver fibrosis can progress by 1 stage as early as within 4 years for antiretroviral-treated patients co-infected with HIV and HCV (7) and within 5 years for HCV-monoinfected persons (27), we determined baseline FIB-4 scores by using ALT levels, AST levels, and platelet counts within a 2-year period around the start of follow-up. Scores less than 1.45 indicate no or minimal fibrosis, and scores greater than 3.25 indicate advanced hepatic fibrosis or cirrhosis in co-infected (26) and HCV-monoinfected patients (28). Table 1. Characteristics of the Study Cohorts Longitudinal data included hepatitis B surface antigen status, plasma HIV RNA level, diabetes, and liver transplantation (determined by diagnosis and procedural codes) (Supplement 1). Statistical Analysis The 12 months before the start of follow-up represented the baseline period for both cohorts. Follow-up began 12 months after ART initiation for co-infected patients and after 12 months in the VACS-VC for monoinfected patients. The rationale for defining the baseline period as the first year of receipt of ART for co-infected patients was that many of these patients initially entered care at the time of ART initiation, which was shortly after their HIV diagnosis. Follow-up continued until a study end point, death, initiation of HCV therapy, or the last visit before 30 September 2010, whichever came first. For descriptive purposes, we estimated incidence rates (events per 1000 person-years) of end points with 95% CIs, standardized by the age and race/ethnicity distribution of co-infected patients (29). We then used Cox models to estimate adjusted hazard ratios (HRs) for outcomes in co-infected compared with monoinfected patients (30). We controlled for all available clinically relevant variables in Table 1. The proportionality of hazards was evaluated by plots of Schoenfeld residuals (31). In a sensitivity analysis, we addressed the potential for informative censoring by using inverse probability of censoring weights and Cox regression (Supplement

Does an Index Composed of Clinical Data Reflect Effects of Inflammation, Coagulation, and Monocyte Activation on Mortality Among Those Aging With HIV?

BACKGROUND When added to age, CD4 count and human immunodeficiency virus type 1 (HIV-1) RNA alone (Restricted Index), hemoglobin, FIB-4 Index, hepatitis C virus (HCV), and estimated glomerular filtration rate improve prediction of mortality. Weighted and combined, these 7 routine clinical variables constitute the Veterans Aging Cohort Study (VACS) Index. Because nonroutine biomarkers of inflammation (interleukin 6 [IL-6]), coagulation (D-dimer), and monocyte activation (sCD14) also predict mortality, we test the association of these indices and biomarkers with each other and with mortality. METHODS Samples from 1302 HIV-infected veterans on antiretroviral therapy were analyzed. Indices were calculated closest to date of collection. We calculated Spearman correlations stratified by HIV-1 RNA and HCV status and measured association with mortality using C statistics and net reclassification improvement (NRI). RESULTS Of 1302 subjects, 915 had HIV-1 RNA <500 copies/mL and 154 died. The VACS Index was more correlated with IL-6, D-dimer, and sCD14 than the Restricted Index (P < .001). It was also more predictive of mortality (C statistic, 0.76; 95% confidence interval [CI], .72-.80) than any biomarker (C statistic, 0.66-0.70) or the Restricted Index (C statistic, 0.71; 95% CI, .67-.75). Compared to the Restricted Index alone, NRI resulted from incremental addition of VACS Index components (10%), D-dimer (7%), and sCD14 (4%), but not from IL-6 (0%). CONCLUSIONS Among HIV-infected individuals, independent of CD4, HIV-1 RNA, and age, hemoglobin and markers of liver and renal injury are associated with inflammation. Addition of D-dimer and sCD14, but not IL-6, improves the predictive accuracy of the VACS Index for mortality.

Predictive accuracy of the veterans aging cohort study index for mortality with HIV infection: A north american cross cohort analysis

Background:By supplementing an index composed of HIV biomarkers and age (restricted index) with measures of organ injury, the Veterans Aging Cohort Study (VACS) index more completely reflects risk of mortality. We compare the accuracy of the VACS and restricted indices (1) among subjects outside the Veterans Affairs Healthcare System, (2) more than 1–5 years of prior exposure to antiretroviral therapy (ART), and (3) within important patient subgroups. Methods:We used data from 13 cohorts in the North American AIDS Cohort Collaboration (n = 10, 835) limiting analyses to HIV-infected subjects with at least 12 months exposure to ART. Variables included demographic, laboratory (CD4 count, HIV-1 RNA, hemoglobin, platelets, aspartate and alanine transaminase, creatinine, and hepatitis C status), and survival. We used C-statistics and net reclassification improvement (NRI) to test discrimination varying prior ART exposure from 1 to 5 years. We then combined Veterans Affairs Healthcare System (n = 5066) and North American AIDS Cohort Collaboration data, fit a parametric survival model, and compared predicted to observed mortality by cohort, gender, age, race, and HIV-1 RNA level. Results:Mean follow-up was 3.3 years (655 deaths). Compared with the restricted index, the VACS index showed greater discrimination (C-statistics: 0.77 vs. 0.74; NRI: 12%; P < 0.0001). NRI was highest among those with HIV-1 RNA <500 copies per milliliter (25%) and age ≥50 years (20%). Predictions were similar to observed mortality among all subgroups. Conclusions:VACS index scores discriminate risk and translate into accurate mortality estimates over 1–5 years of exposure to ART and for diverse patient subgroups from North American.

An internationally generalizable risk index for mortality after one year of antiretroviral therapy.

Objective:Despite the success of antiretroviral therapy (ART), excess mortality continues for those with HIV infection. A comprehensive approach to risk assessment, addressing multiorgan system injury on ART, is needed. We sought to develop and validate a practical and generalizable mortality risk index for HIV-infected individuals on ART. Design and methods:The Veterans Aging Cohort Study (VACS) was used to develop the VACS Index, based on age, CD4 cell count, HIV-1 RNA, hemoglobin, aspartate and alanine transaminase, platelets, creatinine and hepatitis C status, and a Restricted Index based on age, CD4 cell count and HIV-1 RNA with an outcome of death up to 6 years after ART initiation. Validation was in six independent cohorts participating in the ART Cohort Collaboration (ART-CC). Results:In both the development (4932 patients, 656 deaths) and validation cohorts (3146 patients, 86 deaths) the VACS Index had better discrimination than the Restricted Index (c-statistics 0.78 and 0.72 in VACS, 0.82 and 0.78 in ART-CC). The VACS Index also demonstrated better discrimination than the Restricted Index for HIV deaths and non-HIV deaths, in men and women, those younger and older than 50 years, with and without detectable HIV-1 RNA, and with or without HCV coinfection. Conclusions:Among HIV-infected patients treated with ART, the VACS Index more accurately discriminates mortality risk than traditional HIV markers and age alone. By accounting for multiorgan system injury, the VACS Index may prove a useful tool in clinical care and research.

Validity of diagnostic codes and liver-related laboratory abnormalities to identify hepatic decompensation events in the Veterans Aging Cohort Study

The absence of validated methods to identify hepatic decompensation in cohort studies has prevented a full understanding of the natural history of chronic liver diseases and impact of medications on this outcome. We determined the ability of diagnostic codes and liver‐related laboratory abnormalities to identify hepatic decompensation events within the Veterans Aging Cohort Study (VACS).

Physiologic Frailty and Fragility Fracture in HIV-Infected Male Veterans

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

Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions

Objective: The link between CNS penetration of antiretrovirals and AIDS-defining neurologic disorders remains largely unknown. Methods: HIV-infected, antiretroviral therapy–naive individuals in the HIV-CAUSAL Collaboration who started an antiretroviral regimen were classified according to the CNS Penetration Effectiveness (CPE) score of their initial regimen into low (<8), medium (8–9), or high (>9) CPE score. We estimated “intention-to-treat” hazard ratios of 4 neuroAIDS conditions for baseline regimens with high and medium CPE scores compared with regimens with a low score. We used inverse probability weighting to adjust for potential bias due to infrequent follow-up. Results: A total of 61,938 individuals were followed for a median (interquartile range) of 37 (18, 70) months. During follow-up, there were 235 cases of HIV dementia, 169 cases of toxoplasmosis, 128 cases of cryptococcal meningitis, and 141 cases of progressive multifocal leukoencephalopathy. The hazard ratio (95% confidence interval) for initiating a combined antiretroviral therapy regimen with a high vs low CPE score was 1.74 (1.15, 2.65) for HIV dementia, 0.90 (0.50, 1.62) for toxoplasmosis, 1.13 (0.61, 2.11) for cryptococcal meningitis, and 1.32 (0.71, 2.47) for progressive multifocal leukoencephalopathy. The respective hazard ratios (95% confidence intervals) for a medium vs low CPE score were 1.01 (0.73, 1.39), 0.80 (0.56, 1.15), 1.08 (0.73, 1.62), and 1.08 (0.73, 1.58). Conclusions: We estimated that initiation of a combined antiretroviral therapy regimen with a high CPE score increases the risk of HIV dementia, but not of other neuroAIDS conditions.

Risk of mortality and physiologic injury evident with lower alcohol exposure among HIV infected compared with uninfected men.

BACKGROUND HIV infected (HIV+) individuals may be more susceptible to alcohol-related harm than uninfected individuals. METHODS We analyzed data on HIV+ and uninfected individuals in the Veterans Aging Cohort Study (VACS) with an Alcohol Use Disorders Identification Test-Consumption AUDIT-C score from 2008 to 2012. We used Cox proportional hazards models to examine the association between alcohol exposure and mortality through July, 2014; and linear regression models to assess the association between alcohol exposure and physiologic injury based on VACS Index Scores. Models were adjusted for age, race/ethnicity, smoking, and hepatitis C infection. RESULTS The sample included 18,145 HIV+ and 42,228 uninfected individuals. Among HIV+ individuals, 76% had undetectable HIV-1 RNA (<500 copies/ml). The threshold for an association of alcohol use with mortality and physiologic injury differed by HIV status. Among HIV+ individuals, AUDIT-C score ≥4 (hazard ratio [HR] 1.25, 95% CI 1.09-1.44) and ≥30 drinks per month (HR, 1.30, 95% CI 1.14-1.50) were associated with increased risk of mortality. Among uninfected individuals, AUDIT-C score ≥5 (HR, 1.19, 95% CI 1.07-1.32) and ≥70 drinks per month (HR 1.13, 95% CI 1.00-1.28) were associated with increased risk. Similarly, AUDIT-C threshold scores of 5-7 were associated with physiologic injury among HIV+ individuals (beta 0.47, 95% CI 0.22, 0.73) and a score of 8 or more was associated with injury in uninfected (beta 0.29, 95% CI 0.16, 0.42) individuals. CONCLUSIONS Despite antiretroviral therapy, HIV+ individuals experienced increased mortality and physiologic injury at lower levels of alcohol use compared with uninfected individuals. Alcohol consumption limits should be lower among HIV+ individuals.

Risk factors for hospitalization and medical intensive care unit (MICU) admission among HIV infected Veterans

Objective:With improved survival of HIV-infected persons on antiretroviral therapy and growing prevalence of non-AIDS diseases, we asked whether the VACS Index, a composite measure of HIV-associated and general organ dysfunction predictive of all-cause mortality, predicts hospitalization and medical intensive care unit (MICU) admission. We also asked whether AIDS and non-AIDS conditions increased risk after accounting for VACS Index score. Methods:We analyzed data from the Veterans Aging Cohort Study (VACS), a prospective study of HIV-infected Veterans receiving care between 2002 and 2008. Data were obtained from the electronic medical record, VA administrative databases, and patient questionnaires and were used to identify comorbidities and calculate baseline VACS Index scores. The primary outcome was first hospitalization within 2 years of VACS enrollment. We used multivariable Cox regression to determine risk factors associated with hospitalization and logistic regression to determine risk factors for MICU admission, given hospitalization. Results:Of 3410 patients, 1141 were hospitalized within 2 years; 203 (17.8%)/1141 patients included an MICU admission. Median VACS Index scores were 25 (no hospitalization), 34 (hospitalization only), and 51 (MICU). In adjusted analyses, a 5-point increment in VACS Index score was associated with 10% higher risk of hospitalization and MICU admission. In addition to VACS Index score, Hispanic ethnicity, current smoking, hazardous alcohol use, chronic obstructive pulmonary disease, hypertension, diabetes, and prior AIDS-defining event predicted hospitalization. Among those hospitalized, VACS Index score, cardiac disease, and prior cancer predicted MICU admission. Conclusions:The VACS Index predicted hospitalization and MICU admission as did current smoking, hazardous alcohol use, and AIDS and certain non-AIDS diagnoses.