Institutionally chartered Data and Safety Monitoring Boards: structured approaches to assuring participant safety in clinical research.

Data and Safety Monitoring Boards (DSMBs) derived from the need to monitor large federally funded multi-center clinical trials and evolved to include commercial and other large and complex trials. Eventually, academic health centers also created institutionally focused trial monitoring mechanisms. The basic general principles that define traditional DSMBs extend to the institutional level. The primary responsibilities are assuring safety of the participants, preserving the integrity of the trial, and ensuring the reliability of the results. Institutionally chartered DSMBs meet these responsibilities but usually have fewer members, have a structure specific to the needs of the trial, are more focused and/or have different scope reviewing smaller, single site, higher risk, and investigator-initiated studies and are flexible to accommodate institution-specific requirements and approaches. Their purpose is to meet the responsibilities of oversight for safety and data integrity, ensure proper study design, rigor and conduct, as well as provide statistical support appropriate to the setting of the research. Academic health centers should recognize the importance and existence of institution level safety and data monitoring and provide support as much as possible. Investigators should have sufficient resources available to assemble DSMBs. The Clinical and Translational Science Awards Collaborative DSMB Workgroup provides an online manual to assist investigators.

"I'm not gonna be able to do anything about it, then what's the point?": A broad group of stakeholders identify barriers and facilitators to HCV testing in a Massachusetts jail.

BACKGROUND: Despite national guidelines promoting hepatitis C virus (HCV) testing in prisons, there is substantial heterogeneity on the implementation of HCV testing in jails. We sought to better understand barriers and opportunities for HCV testing by interviewing a broad group of stakeholders involved in HCV testing and treatment policies and procedures in Massachusetts jails. METHODS: We conducted semi-structured interviews with people incarcerated in Middlesex County Jail (North Billerica, MA), clinicians working in jail and community settings, corrections administrators, and representatives from public health, government, and industry between November 2018-April 2019. RESULTS: 51/120 (42%) of people agreed to be interviewed including 21 incarcerated men (mean age 32 [IQR 25, 39], 60% non-White). Themes that emerged from these interviews included gaps in knowledge about HCV testing and treatment opportunities in jail, the impact of captivity and transience, and interest in improving linkage to HCV care after release. Many stakeholders discussed stigma around HCV infection as a factor in reluctance to provide HCV testing or treatment in the jail setting. Some stakeholders expressed that stigma often led decisionmakers to estimate a lower "worth" of incarcerated individuals living with HCV and therefore to decide against paying for HCV testing.". CONCLUSION: All stakeholders agreed that HCV in the jail setting is a public health issue that needs to be addressed. Exploring stakeholders' many ideas about how HCV testing and treatment can be approached is the first step in developing feasible and acceptable strategies.

Via media: Role and responsibilities of the independent safety officer.

Every research study that includes volunteer participants requires safety assurances in proportion to the risks of the study. Investigator-initiated clinical research can present unique regulatory challenges particularly for studies with a risk profile that warrants more oversight than minimal risk but less than for large, commercial, or high-risk research. The use of an independent safety officer (ISO) offers a middle way of right-sizing oversight to match the risk. ISOs are clinicians or researchers with relevant expertise who are independent of the investigator and the research study. Their relationship to the study is defined by a formal charter which is aligned with the protocol and Data and Safety Monitoring Plan to address the oversight process, responsibilities of the ISO, and clearly describe the variables to be monitored. The ISO responsibilities include reviewing safety data, adverse events, recruitment, demographics, study progress, data quality, protocol changes, and any new scientific information that pertains to the trial. Finally, the ISO reports in their review on any significant findings may propose modifications to the study or a need to stop the trial.

The Burden of Untreated HCV Infection in Hospitalized Inmates: a Hospital Utilization and Cost Analysis.

Hepatitis C virus (HCV) is highly prevalent in incarcerated populations. The high cost of HCV therapy places a major burden on correctional system healthcare budgets, but the burden of untreated HCV is not known. We investigated the economic impact of HCV through comparison of length of stay (LOS), frequency of 30-day readmission, and costs of hospitalizations in inmates with and without HCV using a 2004-2014 administrative claims database. Inmates with HCV had longer LOS, higher frequency of 30-day readmission, and increased cost of hospitalizations. Costs were higher in inmates with HCV even without advanced liver disease and in inmates with HIV/HCV compared to HCV alone. We conclude that although HCV treatment may not avert all of the observed increases in hospitalization, modest reductions in hospital utilization with HCV cure could help offset treatment costs. Policy discussions on HCV treatment in corrections should be informed by the costs of untreated HCV infection.

"Tweak Your Order Set!" Implementation of Modified Laboratory Order Set Improves Hepatitis C Virus Screening Rates in People Living With Human Immunodeficiency Virus.

There are several barriers to annual hepatitis C virus antibody (HCVAb) testing, including lack of provider knowledge of the changing HCV epidemic and provider underestimation of a patient's risk. We identified low rates of testing for HCVAb in people living with human immunodeficiency virus (HIV) in our outpatient HIV Infectious Diseases clinic, and we developed a quality improvement project to increase rates of HCVAb screening.

Increasing Infectious Endocarditis Admissions Among Young People Who Inject Drugs.

People who inject drugs (PWID) are at risk for infective endocarditis (IE). Hospitalization rates related to misuse of prescription opioids and heroin have increased in recent years, but there are no recent investigations into rates of hospitalizations from injection drug use-related IE (IDU-IE). Using the Health Care and Utilization Project National Inpatient Sample (HCUP-NIS) dataset, we found that the proportion of IE hospitalizations from IDU-IE increased from 7% to 12.1% between 2000 and 2013. Over this time period, we detected a significant increase in the percentages of IDU-IE hospitalizations among 15- to 34-year-olds (27.1%-42.0%; P < .001) and among whites (40.2%-68.9%; P < .001). Female gender was less common when examining all the IDU-IE (40.9%), but it was more common in the 15- to 34-year-old age group (53%). Our findings suggest that the demographics of inpatients hospitalized with IDU-IE are shifting to reflect younger PWID who are more likely to be white and female than previously reported. Future studies to investigate risk behaviors associated with IDU-IE and targeted harm reduction strategies are needed to avoid further increases in morbidity and mortality in this rapidly growing population of young PWID.

Hepatitis C Screening in People With Human Immunodeficiency Virus: Lessons Learned From Syphilis Screening.

Background. The incidence of hepatitis C virus (HCV) infection is increasing in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). New guidelines recommend annual screening for HCV, similar to recommendations for syphilis screening with rapid plasma reagin (RPR). Methods. This study compares the frequency of repeat HCV antibody (Ab) testing to repeat RPR testing in a retrospective chart review of 359 HCVAb-negative people living with HIV (PLWH) observed in an Infectious Diseases clinic. Patients were classified into risk groups based on sexual risk factors. Results. Although 85% of PLWH had repeat syphilis screening, less than two thirds had repeat HCVAb screening. The MSM status was associated with increased HCVAb and RPR testing (adjusted odds ratio, 2.6 and 5.9, respectively). Seven persons had incident HCV infection: 3 were MSM, and 4 had symptoms or abnormal laboratory results to prompt testing. Conclusions. Failure to find incident HCV infection in PLWH represents missed opportunities to cure HCV infection and prevent progressive liver disease. Further quality improvement studies are necessary to develop physician-focused interventions to increase HCV screening rates in PLWH.

Metabolic syndrome predicts all-cause mortality in persons with human immunodeficiency virus.

We examined the association between metabolic syndrome (MS) and its individual defining criteria on all-cause mortality in human immunodeficiency virus (HIV)-infected persons. We used data from 567 HIV-infected participants of the Nutrition for Healthy Living study with study visits between 9/1/2000 and 1/31/2004 and determined mortality through 12/31/2006. MS was defined using modified National Cholesterol Education Program guidelines. Cox proportional hazards for all-cause mortality were estimated for baseline MS status and for its individual defining criteria. There were 83 deaths with median follow-up of 63 months. Baseline characteristics associated with increased risk of mortality were: older age in years (univariate hazard ratio [HR] 1.04, p<0.01), current smoking (HR 1.99, p=0.02), current heroin use (HR 1.97, p=0.02), living in poverty (HR 2.0, p<0.01), higher mean HIV viral load (HR 1.81, p<0.01), and having a BMI <18 (HR 5.84, p<0.01). For MS and its criteria, only low HDL was associated with increased risk of mortality on univariate analysis (HR 1.84, p=0.01). However, metabolic syndrome (adjusted HR 2.31, p=0.02) and high triglycerides (adjusted HR 3.97, p<0.01) were significantly associated with mortality beyond 36 months follow-up. MS, low HDL, and high triglycerides are associated with an increased risk of mortality in HIV-infected individuals.

Effect of a dietary intervention and n-3 fatty acid supplementation on measures of serum lipid and insulin sensitivity in persons with HIV.

BACKGROUND: Elevated serum triglyceride and low HDL-cholesterol concentrations have been reported in persons with HIV. OBJECTIVE: The effect of a dietary intervention plus n-3 (omega-3) fatty acid supplementation on serum triglycerides and markers of insulin sensitivity was investigated. DESIGN: Fifty-four persons with HIV and elevated serum triglycerides (>150 mg/dL) and/or abnormal Quantitative Insulin Sensitivity Check Index values (<0.35 but >0.30) were recruited for a dietary intervention in which total fat, type of fat, fiber, and glycemic load were controlled along with supplementation with n-3 fatty acids to achieve an intake of 6 g/d. The subjects were randomly assigned to an intervention or control group, and serum lipids, markers of insulin sensitivity, and serum phospholipid fatty acids were measured in both groups at baseline, 3 wk, and 13 wk. RESULTS: Triglycerides in the intervention group decreased from a median of 180 mg/dL (interquartile range: 141, 396) to 114 mg/dL (interquartile range: 84, 169) from baseline to 3 wk, whereas they remained stable in the control group (P = 0.003). Serum phospholipid fatty acids indicated a decrease in de novo lipogenesis and a decrease in arachidonic acid (% nmol; P

Factors associated with serum retinol, alpha-tocopherol, carotenoids, and selenium in Hispanics with problems of HIV, chronic hepatitis C, and drug use.

The effects of hepatitis and drug use on nutritional problems in HIV infection have rarely been examined despite the importance of drug use in the global HIV pandemic. We examined the effects of HIV, hepatitis C, and drug use on serum micronutrients in 300 US Hispanic adults. Chronic hepatitis C infection was associated with lower serum retinol (-8.2 microg/dl, P < 0.0001), alpha-tocopherol (-0.10 ln microg/dl, P = 0.024), and carotenoids (-19.8 microg/dl, P < 0.0001). HIV infection was associated with lower selenium (-6.1 microg/l, P = 0.028). Elevated triglycerides in HIV infection were associated with higher serum retinol and alpha-tocopherol. Drug use was not independently associated with micronutrient alterations. We conclude that hepatitis C is an important determinant of low serum micronutrients, and should be considered in any nutritional assessment of HIV infected populations. As the safety of micronutrient supplementation is not established, policy for appropriate HIV clinical care should distinguish between populations with and without hepatitis coinfection.

Cystatin C and creatinine in an HIV cohort: the nutrition for healthy living study.

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons have an increased risk of chronic kidney disease (CKD). Serum creatinine level may underestimate the prevalence of CKD in subjects with decreased lean body mass or liver disease. Level of serum cystatin C, an alternative kidney function marker, is independent of lean body mass. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 250 HIV-infected subjects on highly active antiretroviral therapy in the Nutrition for Healthy Living (NFHL) cohort; 2,628 National Health and Nutrition Examination Survey (NHANES) 2001-2002 subjects. PREDICTORS & OUTCOMES: Comparison of serum creatinine levels in NFHL to those in NHANES subjects; comparison of CKD in NFHL subjects ascertained using serum creatinine versus cystatin C levels. MEASUREMENTS: Standardized serum creatinine, serum cystatin C, glomerular filtration rate (GFR) estimated from serum creatinine and cystatin C levels. RESULTS: Creatinine levels were lower in NFHL than NHANES subjects despite greater rates of hepatitis, diabetes, and drug use (mean difference, -0.18 mg/dL; P < 0.001 adjusted for age, sex, and race). Of NFHL subjects, only 2.4% had a creatinine-based estimated GFR less than 60 mL/min/1.73 m(2), but 15.2% had a cystatin-based estimated GFR less than 60 mL/min/1.73 m(2). LIMITATIONS: GFR was estimated rather than measured. Other factors in addition to GFR may affect creatinine and cystatin C levels. Measurements of proteinuria were not available. CONCLUSIONS: Serum creatinine levels may overestimate GFRs in HIV-infected subjects. Kidney disease prevalence may be greater than previously appreciated.

Declines in dietary macronutrient intake in persons with HIV infection who develop depression.

BACKGROUND: The effect of depression on dietary intake has not, to our knowledge, been examined in persons with HIV infection. METHODS: We conducted a longitudinal analysis of participants in the Nutrition for Healthy Living Study (NFHL). We measured changes in dietary macronutrient intake in participants who developed depression and, using multiple regression analysis, compared the changes with a control group of patients who did not become depressed. RESULTS: Ninety patients developed depression during the observation period, and we compared these with 152 non-depressed controls. The two groups had similar age and body mass index (BMI) at baseline, but those who developed depression were more likely to be female, less educated and had lower incomes. After adjustment, compared with non-depressed participants, those who developed depression had significantly greater decreases in the following daily intakes: total energy (-341 kcal, P = 0.006), protein (-12.3 g, P = 0.02), total fat (-18.5 g, P = 0.008), carbohydrate (-36.8 g, P = 0.02), total fibre (-4.3 g, P = 0.001) and saturated fat (-6.7 g, P = 0.01). There were no significant differences in the daily intakes of simple sugars and long-chain n-3 fatty acids, or BMI. CONCLUSION: Depression is associated with decreases in total daily energy intake and in six of the eight dietary components we measured. Clinicians should be aware that depression-associated nutritional deficiencies may complicate the care of persons with HIV.

Ritonavir greatly impairs CYP3A activity in HIV infection with chronic viral hepatitis.

PURPOSE: Ritonavir is a powerful inhibitor of cytochrome P450 3A (CYP3A) that metabolizes many antiretrovirals. We examined the effect of ritonavir and of chronic viral hepatitis (CVH) status on CYP3A activity. METHODS: Twenty-six HIV-positive men (13 with CVH, 16 on chronic ritonavir-based highly active antiretroviral therapy) received oral and intravenous midazolam, a probe for CYP3A phenotypic activity. RESULTS: CYP3A activity was expressed as oral clearance of the midazolam probe. In HIV-positive subjects not on ritonavir, CYP3A activity (mean +/- SD) did not differ between subjects by CVH (no CVH, controls: 28.5 +/- 9.0 vs. CVH+: 23.2 +/- 6.2 mL/min/kg, not significant). In those on ritonavir (R), CYP3A activity was 7% of controls (R: 2.1 +/- 0.8 vs. no R 28.5 +/- 9.0 mL/min/kg, P < 0.0004). CYP3A activity in subjects on ritonavir and with CVH was further reduced to 4% of controls (no CVH, R+ 2.1 +/- 0.8 vs. R+, CVH+ 1.0 +/- 0.4 mL/min/kg, P < 0.006). CONCLUSIONS: Ritonavir markedly decreases CYP3A activity. In the presence of CVH, ritonavir-based therapy further reduces CYP3A activity by half. Coinfection with CVH impairs CYP3A activity in the presence of the CYP3A inhibitor ritonavir.

The impact of cirrhosis on CD4+ T cell counts in HIV-seronegative patients.

BACKGROUND: Studies of the progression liver fibrosis in human immunodeficiency virus (HIV) and hepatitis C virus-coinfected patients suggest that cirrhosis is associated with immunosuppression, as measured by low absolute CD4(+) T cell counts. However, we hypothesized that, in patients with advanced liver disease, low CD4(+) T cell counts may occur secondary to portal hypertension and splenic sequestration, regardless of the presence or absence of HIV infection. METHODS: Sixty HIV-seronegative outpatients with cirrhosis were enrolled during the period 2001-2003 in a prospective, cross-sectional study of the association between liver disease and CD4(+) T cell counts and percentages. Demographic characteristics, liver disease-related characteristics, and laboratory results--including CD4(+) T cell parameters--were collected. RESULTS: A total of 39 patients (65%) had a low CD4(+) T cell count; 26 patients (43%) and 4 patients (7%) had CD4(+) T cell counts <350 and <200 cells/mm(3), respectively. Abnormal CD4(+) T cell counts were associated with splenomegaly (P=.03), thrombocytopenia (P=.002), and leukopenia (P<.001). The percentage of CD4(+) T cells was normal in 95% of patients who had a low absolute CD4(+) T cell count. CD4(+) T cell counts were significantly lower among cirrhotic patients than among 7638 HIV-seronegative historic control subjects without liver disease. CONCLUSIONS: Cirrhosis is associated with low CD4(+) T cell counts in the absence of HIV infection. Discordance between low absolute CD4(+) T cell counts and normal CD4(+) T cell percentages may be attributable to portal hypertension and splenic sequestration. Our findings have significant implications for the use and interpretation of absolute CD4(+) T cell counts in HIV-infected patients with advanced liver disease.

Micronutrient levels and HIV disease status in HIV-infected patients on highly active antiretroviral therapy in the Nutrition for Healthy Living cohort.

BACKGROUND: Low serum micronutrient levels were common before widespread use of highly active antiretroviral therapy (HAART) and were associated with adverse outcomes. Few data are available on micronutrient levels in subjects taking HAART. OBJECTIVE: To determine the prevalence of low serum retinol, alpha-tocopherol, zinc, and selenium in HIV-infected subjects taking HAART and to assess the association of micronutrient levels with HIV disease status. DESIGN: Cross-sectional. SETTING: Nutrition for Healthy Living (NFHL) study. PARTICIPANTS: HIV-infected subjects on HAART. METHODS: Retinol, alpha-tocopherol, zinc, and selenium were determined in frozen serum samples from 171 men and 117 women. Low serum levels were defined as retinol <30 microg/dL, selenium <85 microg/L, alpha-tocopherol <500 microg/dL, and zinc <670 microg/L. Association of micronutrient quartiles with CD4 cell count, CD4 count <200 cells/mm, HIV viral load (VL), and undetectable VL was assessed using adjusted multivariate regression. RESULTS: Five percent of men and 14% of women had low retinol, 8% of men and 3% of women had low selenium, and 7% of men and no women had low alpha-tocopherol. Forty percent of men and 36% of women had low zinc, however. Subjects in the upper quartiles of zinc had lower log VL levels than those in the lowest quartile (significant for women). Subjects in the upper quartiles of selenium also tended to have lower VL levels compared with those in the lowest quartile. Surprisingly, women in the upper quartiles of retinol had higher log VLs than those in the lowest quartile. There was no significant association of any micronutrient with CD4 cell count or likelihood of CD4 count <200 cells/mm. The level of CD4 cell count influenced the association of retinol with log VL in men, however. In men with CD4 counts >350 cells/mm, those with higher retinol had higher log VLs compared with the lowest quartile, whereas in men with CD4 counts <350, those with higher retinol levels had lower log VLs compared with the lowest quartile. CONCLUSIONS: Low retinol, alpha-tocopherol, and selenium are uncommon in HIV-infected subjects on HAART. Zinc deficiency remains common, however. Decreased retinol levels in women and in men with CD4 counts >350 cells/mm and increased zinc and selenium levels in both genders may be associated with improved virologic control.

Insulin resistance in HIV-infected men and women in the nutrition for healthy living cohort.

OBJECTIVE: We evaluated insulin resistance (IR) in an HIV-infected cohort and compared our results with those of the National Health and Nutrition Examination Survey III (NHANES III). METHODS: Using a cross-sectional study design, we determined the Quantitative Insulin Sensitivity Check Index (QUICKI) in 378 nondiabetic participants in the Nutrition for Healthy Living (NFHL) study and evaluated the association of the QUICKI with demographic, socioeconomic, body composition, lipid, liver function, HIV-associated factors (CD4 cell count, viral load, highly active antiretroviral therapy type, and years infected), and injection drug use. The prevalence of IR (QUICKI <0.350) and the mean QUICKI were ascertained for nondiabetic persons aged 25 to 65 years in the NHANES III and compared with those in the NFHL study. RESULTS: Protease inhibitor (PI) highly active antiretroviral therapy (HAART) and nonnucleoside reverse transcriptase inhibitor (NNRTI) HAART were associated with worse IR in HIV-infected men. Greater waist circumference, triglycerides, age, and alanine aminotransferase were associated with worse IR, and higher high-density lipoprotein, low-density lipoprotein, and smoking were associated with less IR in the NFHL study; CD4 cell count, viral load, and years HIV infected were not associated with IR. There was no significant difference in the prevalence of IR in the NFHL study versus the NHANES III (51% vs. 47%; P = 0.27). NFHL participants were not more IR than NHANES III participants. CONCLUSIONS: IR in the NFHL study was quite common but not significantly different than in the NHANES III and was associated with similar factors as in the general population. PI HAART and NNRTI HAART were associated with worse IR in men.

Increasing risk of 5% or greater unintentional weight loss in a cohort of HIV-infected patients, 1995 to 2003.

Although the incidence of most AIDS-defining opportunistic infections, including HIV wasting syndrome, has dramatically decreased since the introduction of highly active antiretroviral therapy (HAART), previous studies have shown that weight loss and wasting are still common in HIV-infected persons. We examined the 6-month risk and determinants of > or =5% weight loss during the period when the use of combination antiretroviral therapy and HAART was commonplace among 713 participants enrolled in the Nutrition for Healthy Living cohort in Boston, Massachusetts between 1995 and 2003. There was a significant 50% increase in the 6-month risk of > or =5% weight loss in the later HAART years (1998-2003) compared with the early HAART years (1995-1997) among most of the participants who reported they were not trying to lose weight (P = 0.002). In addition to calendar time, several other variables were significantly independently associated with risk of > or =5% weight loss, including use of injection drugs; living below the federal poverty level; higher body mass index (BMI; > or =25 kg/m(2)); lower CD4 cell count; higher HIV viral load; and presence of diarrhea, nausea, or fever. The characteristics of weight loss in the later HAART years did not differ from the early HAART years with respect to initial body composition (eg, weight, BMI, triceps skinfold thickness) or changes in body composition during the periods of weight loss. In summary, we have found that the risk of > or =5% unintentional weight loss over 6-month intervals is on the rise in our cohort of HIV-infected participants, despite better control of HIV infection in recent years. Although we still do not know the exact cause of this increase, the fact that it exists indicates the need for clinicians who take care of HIV-infected patients to continue to pay attention to weight loss among particular segments of their patient population. This is particularly important because recent studies have shown that even a 5% weight loss in 6 months markedly increases the risk of death.

Dietary intake in HIV-positive persons with and without malabsorption.

This review examines the relationship among malabsorption, diarrhea, dietary intake, and body composition in an outpatient cohort of individuals with HIV infection. Twenty-three percent of the participants had malabsorption, which was not associated with the presence of current or chronic diarrhea. In this "outpatient" HIV cohort with a mean body-mass index (BMI) of 25 kg/m2, the presence of malabsorption did not have adverse nutritional outcomes in terms of body weight, lean body mass, hemoglobin, or albumin. The diets of those with or without malabsorption did not meet the goals of the Dietary Guidelines for Americans. Median dietary intake was high in percentage of total fat and saturated fat and low in total fiber intake and some key micronutrients.