Prostate Cancer Screening and Incidence among Aging Persons Living with HIV.

PURPOSE: The risk of prostate cancer among persons living with human immunodeficiency virus (PWH) is not well understood and may be obscured by different opportunities for detection. MATERIALS AND METHODS: We identified 123,472 (37,819 PWH and 85,653 comparators) men enrolled in the Veterans Aging Cohort Study, a prospective national cohort of PWH and demographically matched, uninfected comparators in 2000-2015. We calculated rates of prostate specific antigen (PSA) testing by human immunodeficiency virus (HIV) status and fit multivariable Poisson models comparing the rates of PSA testing, prostate biopsy, and cancer incidence. RESULTS: The mean age at enrollment was 52 years. Rates of PSA testing were lower in PWH versus uninfected comparators (0.58 versus 0.63 tests per person-year). Adjusted rates of PSA screening and prostate biopsy were lower among PWH (incidence rate ratio [IRR] 0.87, 95% CI 0.75-0.84 and IRR 0.79 95% CI 0.74-0.83, respectively). The crude IRR for prostate cancer was lower in PWH versus controls (IRR 0.90, 95% CI 0.83-0.97). However, in a multivariable model adjusting for PSA testing, cancer incidence was similar by HIV status (IRR=0.93, 95% CI 0.86-1.01, p=0.08). Among patients who received a prostate biopsy, incidence of prostate cancer did not differ significantly by HIV status (IRR 1.06, 95% CI 0.98-1.15, p=0.15). Among incident cancers, there were significant differences in the distributions of Gleason grade (p=0.05), but not cancer stage (p=0.14) by HIV status. CONCLUSIONS: When accounting for less PSA testing among PWH, the incidence of prostate cancer was similar by HIV status. These findings suggest that less screening contributed to lower observed incidence of prostate cancer in PWH.

Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial.

BACKGROUND: Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity. METHODS: This is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3-5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated. DISCUSSION: In this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04397718. Registered on May 21, 2020.

A Telephone and Mail Outreach Program Successfully Increases Uptake of Hepatocellular Carcinoma Surveillance.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Society guidelines recommend surveillance with abdominal ultrasound with or without serum alpha-fetoprotein every 6 months for adults at increased risk of developing HCC. However, adherence is often suboptimal. We assessed the feasibility of a coordinated telephone outreach program for unscreened patients with cirrhosis within the Veteran's Affairs (VA) health care system. Using a patient care dashboard of advanced chronic liver disease in the VA Greater Los Angeles Healthcare System, we identified veterans with a diagnosis of cirrhosis, a platelet count ≤ 150,000/uL, and no documented HCC surveillance in the previous 8 months. Eligible veterans received a telephone call from a patient navigator to describe the risks and benefits of HCC surveillance. Orders for an abdominal ultrasound and alpha-fetoprotein were placed for veterans who agreed to surveillance. Veterans who were not reached by telephone received an informational letter by mail to encourage participation. Of the 129 veterans who met the eligibility criteria, most were male (96.9%). The most common etiology for cirrhosis was hepatitis C (64.3%), and most of the patients had compensated cirrhosis (68.2%). The patient navigators reached 32.5% of patients by phone. Patients in each group were similar across clinical and demographic characteristics. Patients who were called were more likely to undergo surveillance (adjusted odds ratio = 2.56, 95% confidence interval: 1.03-6.33). Most of the patients (72.1%) completed abdominal imaging when reached by phone. Conclusion: Targeted outreach increased uptake of HCC surveillance among patients with cirrhosis in a large, integrated, VA health care system.

Long term surgical outcomes for infective endocarditis in people who inject drugs: a systematic review and meta-analysis.

BACKGROUND: In recent years, the number of infective endocarditis (IE) cases associated with injection drug use has increased. Clinical guidelines suggest deferring surgery for IE in people who inject drugs (PWID) due to a concern for worse outcomes in comparison to non-injectors (non-PWID). We performed a systematic review and meta-analysis of long-term outcomes in PWID who underwent cardiac surgery and compared these outcomes to non-PWID. METHODS: We systematically searched for studies reported between 1965 and 2018. We used an algorithm to estimate individual patient data (eIPD) from Kaplan-Meier (KM) curves and combined it with published individual patient data (IPD) to analyze long-term outcomes after cardiac surgery for IE in PWID. Our primary outcome was survival. Secondary outcomes were reoperation and mortality at 30-days, one-, five-, and 10-years. Random effects Cox regression was used for estimating survival. RESULTS: We included 27 studies in the systematic review and 19 provided data (KM or IPD) for the meta-analysis. PWID were younger and more likely to have S. aureus than non-PWID. Survival at 30-days, one-, five-, and 10-years was 94.3, 81.0, 62.1, and 56.6% in PWID, respectively; and 96.4, 85.0, 70.3, and 63.4% in non-PWID. PWID had 47% greater hazard of death (HR 1.47, 95% CI, 1.05-2.05) and more than twice the hazard of reoperation (HR 2.37, 95% CI, 1.25-4.50) than non-PWID. CONCLUSION: PWID had shorter survival that non-PWID. Implementing evidence-based interventions and testing new modalities are urgently needed to improve outcomes in PWID after cardiac surgery.

HIV and Age Do Not Synergistically Affect Age-Related T-Cell Markers.

INTRODUCTION: Despite major progress in controlling HIV disease through antiretroviral therapy, changes in immune phenotype and function persist in individuals with chronic HIV, raising questions about accelerated aging of the immune system. METHODS: We conducted a cross-sectional study (2005-2007) of HIV-infected (n = 111) and uninfected (n = 114) men from the Veterans Aging Cohort Study. All HIV-infected subjects were on antiretroviral therapy with VL <400 copies/mL for at least 3 years. T-cell markers were examined using flow cytometry. We evaluated the impact of HIV serostatus and age on T-cell phenotypes (expressed as percentages of the total CD4 and CD8 T-cell population) using multivariate linear regression, adjusted for smoking, alcohol, and race/ethnicity. We tested for interactions between HIV and age by including interaction terms. RESULTS: Among both HIV-infected and uninfected subjects, increasing age was associated with a decreased proportion of naive CD4 T cells (P = 0.014) and CD8 T cells (P < 0.0001). Both HIV infection and increasing age were associated with higher proportions of effector memory CD4 T cells (P < 0.0001 for HIV; P = 0.04 for age) and CD8 T cells (P = 0.0001 for HIV; P = 0.0004 for age). HIV infection, but not age, was associated with a higher proportion of activated CD8 T cells (P < 0.0001). For all T-cell subsets tested, there were no significant interactions between HIV infection and age. CONCLUSIONS: Age and HIV status independently altered the immune system, but we found no conclusive evidence that HIV infection and advancing age synergistically result in accelerated changes in age-associated T-cell markers among virally suppressed individuals.

HIV and Obesity Comorbidity Increase Interleukin 6 but Not Soluble CD14 or D-Dimer.

OBJECTIVES: Obesity prevalence among people living with HIV (HIV+) is rising. HIV and obesity are proinflammatory states, but their combined effect on inflammation (measured by interleukin 6, IL-6), altered coagulation (D-dimer), and monocyte activation (soluble CD14, sCD14) is unknown. We hypothesized inflammation increases when obesity and HIV infection co-occur. METHODS: The Veterans Aging Cohort Study survey cohort is a prospective, observational study of predominantly male HIV+ veterans and veterans uninfected with HIV; a subset provided blood samples. Inclusion criteria for this analysis were body mass index ≥ 18.5 kg/m and biomarker measurement. Dependent variables were IL-6, sCD14, and D-dimer quartiles. Obesity/HIV status was the primary predictor. Unadjusted and adjusted logistic regression models were constructed. RESULTS: Data were analyzed for 1477 HIV+ and 823 uninfected participants. Unadjusted median IL-6 levels were significantly higher and sCD14 levels significantly lower in obese/HIV+ compared with nonobese/uninfected (P <0.01 for both). In adjusted analyses, the odds ratio for increased IL-6 in obese/HIV+ patients was 1.76 (95% confidence interval: 1.18 to 2.47) compared with nonobese/uninfected, and obesity/HIV+ remained associated with lower odds of elevated sCD14. We did not detect a synergistic association of co-occurring HIV and obesity on IL-6 or sCD14 elevation. D-dimer levels did not differ significantly between body mass index/HIV status groups. CONCLUSIONS: HIV-obesity comorbidity is associated with elevated IL-6, decreases in sCD14, and no significant difference in D-dimer. These findings are clinically significant, as previous studies associated these biomarkers with mortality. Future studies should assess whether other biomarkers show similar trends and potential mechanisms for unanticipated sCD14 and D-dimer findings.

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 with 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 from 1996 to 2009. Using International Classification of Diseases, Ninth Revision 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 2 years after baseline. We used multivariable Poisson regression to determine incidence rate ratios (IRRs) 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 1000 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% confidence interval [CI]: 1.64 to 2.30; IRR: 2.60, 95% CI: 1.70 to 3.97; and IRR: 1.48, 95% CI: 1.10 to 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.

HIV infection, cardiovascular disease risk factor profile, and risk for acute myocardial infarction.

BACKGROUND: Traditional cardiovascular disease risk factors (CVDRFs) increase the risk of acute myocardial infarction (AMI) among HIV-infected (HIV+) participants. We assessed the association between HIV and incident AMI within CVDRF strata. METHODS: Cohort-81,322 participants (33% HIV+) without prevalent CVD from the Veterans Aging Cohort Study Virtual Cohort (prospective study of HIV+ and matched HIV- veterans) participated in this study. Veterans were followed from first clinical encounter on/after April 1, 2003, until AMI/death/last follow-up date (December 31, 2009). Predictors-HIV, CVDRFs (total cholesterol, cholesterol-lowering agents, blood pressure, blood pressure medication, smoking, diabetes) used to create 6 mutually exclusive profiles: all CVDRFs optimal, 1+ nonoptimal CVDRFs, 1+ elevated CVDRFs, and 1, 2, 3+ major CVDRFs. Outcome-Incident AMI [defined using enzyme, electrocardiogram (EKG) clinical data, 410 inpatient ICD-9 (Medicare), and/or death certificates]. Statistics-Cox models adjusted for demographics, comorbidity, and substance use. RESULTS: Of note, 858 AMIs (42% HIV+) occurred over 5.9 years (median). Prevalence of optimal cardiac health was <2%. Optimal CVDRF profile was associated with the lowest adjusted AMI rates. Compared with HIV- veterans, AMI rates among HIV+ veterans with similar CVDRF profiles were higher. Compared with HIV- veterans without major CVDRFs, HIV+ veterans without major CVDRFs had a 2-fold increased risk of AMI (HR: 2.0; 95% confidence interval: 1.0 to 3.9; P = 0.044). CONCLUSIONS: The prevalence of optimal cardiac health is low in this cohort. Among those without major CVDRFs, HIV+ veterans have twice the AMI risk. Compared with HIV- veterans with high CVDRF burden, AMI rates were still higher in HIV+ veterans. Preventing/reducing CVDRF burden may reduce excess AMI risk among HIV+ people.

Liver fibrosis progression in hepatitis C virus infection after seroconversion.

IMPORTANCE: Knowing the rate of liver fibrosis progression in hepatitis C virus (HCV)-infected persons can help inform patients and providers (clinicians, medical institutions or organizations, and third-party payers) in making treatment decisions. OBJECTIVE: To determine the rate and factors associated with liver fibrosis progression and hepatic decompensation in persons after acquiring HCV infection. DESIGN, SETTING, AND PARTICIPANTS: Secondary data analysis of persons in the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), a national Veterans Affairs (VA) database, between 2002 and 2012. Among 610 514 persons in ERCHIVES (half were HCV positive), we identified those with an initial negative and subsequent positive test result for HCV antibody and positive HCV RNA test result (HCV+). Controls had 2 negative HCV antibody test results (HCV-) in a comparable time frame and were matched 1:1 on age (in 5-year blocks), race, and sex. We excluded persons with human immunodeficiency virus, hepatitis B, less than 24 months of follow-up, hepatocellular carcinoma, and cirrhosis at baseline. MAIN OUTCOMES AND MEASURES: Progression of liver fibrosis as estimated by the Fibrosis-4 (FIB-4) index; development of cirrhosis, defined by a FIB-4 score greater than 3.5; and development of hepatic decompensation. RESULTS: The evaluable data set consisted of 1840 persons who were HCV+ and 1840 HCV- controls. The HCV+ persons were younger and had a lower mean (SD) body mass index (27.39 [5.51] vs 29.49 [6.16]; P < .001), a higher prevalence of alcohol and drug abuse and dependence diagnoses, and higher serum aminotransferase levels, but had a lower prevalence of diabetes and hypertension. Fibrosis progression started early after infection among HCV+ persons and tapered off after 5 years. A total of 452 cirrhosis and 85 hepatic decompensation events were recorded. After 10 years of follow-up, HCV+ persons were more likely to have a diagnosis of cirrhosis compared with HCV- controls (18.4% vs 6.1%). Nine years after diagnosis of cirrhosis, hepatic decompensation events were uncommon but had a higher rate in the HCV+ group (1.79% vs 0.33%). CONCLUSIONS AND RELEVANCE: Persons who seroconverted for HCV have a more rapid progression of liver fibrosis and accelerated time to development of cirrhosis after seroconversion compared with HCV- controls. Fibrosis progression occurs early after infection; however, hepatic decompensation is uncommon after diagnosis of cirrhosis.

Relationship between health insurance and medical care for patients hospitalized with human immunodeficiency virus-related Pneumocystis carinii pneumonia, 1995-1997: Medicaid, bronchoscopy, and survival.

In the late 1980s, Medicaid-insured human immunodeficiency virus (HIV)-infected patients with Pneumocystis carinii pneumonia (PCP) were 40% less likely to undergo diagnostic bronchoscopy and 75% more likely to die than were privately insured patients, whereas rates of use of other, less resource-intensive aspects of PCP care were similar. We reviewed 1395 medical records at 59 hospitals in 6 cities for the period 1995-1997 to examine the impact of insurance status on PCP-related care. Medicaid patients were only one-half as likely to undergo diagnostic bronchoscopy as were privately insured patients, yet we found no evidence that mortality was greater among patients who received empirical treatment. The bronchoscopy rates were primarily related to patients' personal insurance status. A weaker hospital-level effect was seen that was related to hospitals' Medicaid/private insurance case mix ratios. The situation has evolved from one in which Medicaid coverage was associated with underuse of bronchoscopy and poorer survival among empirically treated persons with HIV-related PCP to one in which empirical therapy is effective in treating this disease and expensive diagnostic procedures may be overused for privately insured patients.