Depression and all-cause mortality risk in HIV-infected and HIV-uninfected US veterans: a cohort study.

OBJECTIVES: The contribution of depression to mortality in adults with and without HIV infection is unclear. We hypothesized that depression increases mortality risk and that this association is stronger among those with HIV infection. METHODS: Veterans Aging Cohort Study (VACS) data were analysed from the first clinic visit on or after 1 April 2003 (baseline) to 30 September 2015. Depression definitions were: (1) major depressive disorder defined using International Classification of Diseases, Ninth Revision (ICD-9) codes; (2) depressive symptoms defined as Patient Health Questionnaire (PHQ)-9 scores ≥ 10. The outcome was all-cause mortality. Covariates were demographics, comorbid conditions and health behaviours. RESULTS: Among 129 140 eligible participants, 30% had HIV infection, 16% had a major depressive disorder diagnosis, and 24% died over a median follow-up time of 11 years. The death rate was 25.3 [95% confidence interval (CI) 25.0-25.6] deaths per 1000 person-years. Major depressive disorder was associated with mortality [hazard ratio (HR) 1.04; 95% CI 1.01, 1.07]. This association was modified by HIV status (interaction P-value = 0.02). In HIV-stratified analyses, depression was significantly associated with mortality among HIV-uninfected veterans but not among those with HIV infection. Among those with PHQ-9 data (n = 7372), 50% had HIV infection, 22% had PHQ-9 scores ≥ 10, and 28% died over a median follow-up time of 12 years. The death rate was 27.3 (95% CI 26.1-28.5) per 1000 person-years. Depressive symptoms were associated with mortality (HR 1.16; 95% CI 1.04, 1.28). This association was modified by HIV status (interaction P-value = 0.05). In HIV-stratified analyses, depressive symptoms were significantly associated with mortality among veterans with HIV infection but not among those without HIV infection. CONCLUSIONS: Depression was associated with all-cause mortality. This association was modified by HIV status and method of depression ascertainment.

Acute and chronic immune biomarker changes during interferon/ribavirin treatment in HIV/HCV co-infected patients.

Chronic viral infections lead to persistent immune activation, which is alleviated by eradicating or suppressing the infection. To understand the effects of interferon treatment on immune system activation by chronic infections, we evaluated kinetic patterns of a broad spectrum of serum biomarkers during HCV treatment in HIV/HCV co-infected patients. HCV viral load and 50 biomarkers were analysed at baseline and 27 time points during pegylated interferon-alpha and ribavirin (IFN/RBV) treatment of 12 HIV/HCV co-infected patients. We evaluated biomarker changes from baseline for each time point and biomarker correlations with clinical parameters, treatment response and liver histopathology. IL-1α, IL-12p40, IL-1RA, IP-10, MIG, MIP-1α/1ß, HGF, sCD40L, TRAIL and leptin increased in the first day. IL-12p70, IL-17A, IL-10, GROα, IL-8, MCP-3, IL-4 and M-CSF peaked later during week 1. IL-1α, HGF, IP-10, MIP-1α, TRAIL, sCD40L, IL-10, IL-12p70, MCP-3, FGFb, ENA-78, TGF-ß, IL-2, IFN-γ, IL-6, IL-15, IL-7 and PDGF-BB decreased below baseline over the course of treatment. Higher BMI, baseline HCV viral load and leptin levels were associated with lack of sustained virologic response. ENA-78 was associated with sustained viral response. Positive correlations were found between liver inflammation and baseline CD4 count, sVCAM and HGF; fibrosis stage and HGF; liver steatosis, BMI and leptin. Our findings suggest IFN/RBV treatment initially increases levels of several biomarkers, but eventually leads to a decline in many immune markers. These findings shed light on the relationship between IFN treatment and immune activation by chronic viral infections, such as HCV.

Impact of empiric weight-based vancomycin dosing on nephrotoxicity and mortality in geriatric patients with methicillin-resistant Staphylococcus aureus bacteraemia.

WHAT IS KNOWN AND OBJECTIVE: Few studies have evaluated the effect of vancomycin dosing on the health outcomes in geriatric patients. Data are needed to determine whether higher vancomycin dosing strategies are more effective in geriatric patients and/or lead to excessive rates of adverse events. METHODS: This study used a subset of patients aged ≥65 years from a multicentre, retrospective, cohort study of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. Patients received ≥ 48 h of empiric vancomycin between 1 July 2002 and 30 June 2008. We compared the incidence of nephrotoxicity and in-hospital mortality in patients who received guideline-recommended dosing (at least 15 mg/kg/dose) to patients who received lower dosing. Multivariable generalized mixed-effect models were constructed to determine independent risk factors for nephrotoxicity and in-hospital mortality. RESULTS AND DISCUSSION: Half of the cohort (46% of 92 patients) received guideline-recommended dosing. Empiric use of weight-based dosing did increase the percentage of patients achieving a vancomycin trough ≥ 15 mg/L (57% vs. 42%). Nephrotoxicity occurred in 32% of patients and 26% died during their hospitalization. Guideline-recommended dosing was not associated with significant changes in nephrotoxicity (OR 1·13; 95% CI 0·40-3·19) or in-hospital mortality (OR 1·14; 95% CI 0·41-3·18) in the multivariable analysis. WHAT IS NEW AND CONCLUSION: In this study of geriatric patients, guideline-recommended dosing was not associated with significant changes in nephrotoxicity or mortality. As 40% of the patients who received guideline-recommended dosing failed to achieve a target vancomycin trough of ≥ 15 mg/L, future studies should focus on dosing strategies to increase target attainment rate.

Adverse outcome analyses of observational data: assessing cardiovascular risk in HIV disease.

Clinical decisions are ideally based on randomized trials but must often rely on observational data analyses, which are less straightforward and more influenced by methodology. The authors, from a series of expert roundtables convened by the Forum for Collaborative HIV Research on the use of observational studies to assess cardiovascular disease risk in human immunodeficiency virus infection, recommend that clinicians who review or interpret epidemiological publications consider 7 key statistical issues: (1) clear explanation of confounding and adjustment; (2) handling and impact of missing data; (3) consistency and clinical relevance of outcome measurements and covariate risk factors; (4) multivariate modeling techniques including time-dependent variables; (5) how multiple testing is addressed; (6) distinction between statistical and clinical significance; and (7) need for confirmation from independent databases. Recommendations to permit better understanding of potential methodological limitations include both responsible public access to de-identified source data, where permitted, and exploration of novel statistical methods.

Predictive value of HIV-1 replication capacity and phenotypic susceptibility scores in antiretroviral treatment-experienced patients.

OBJECTIVES: The aim of the study was to determine the prognostic value of HIV replication capacity (RC) for subsequent antiretroviral (ARV) treatment response in ARV-experienced patients. METHODS: RC and phenotypic resistance testing were performed at baseline and week 12 on plasma samples from patients randomized to undergo a 12-week ARV drug-free period (ARDFP) or initiate immediate salvage therapy (no-ARDFP group) in the Options in Management with Antiretrovirals (OPTIMA) trial. Dichotomous and incremental phenotypic susceptibility scores (dPSSs and iPSSs, respectively) were calculated. The predictive value of RC and PSS for ARV therapy response and/or ARDFP was evaluated using multivariate regression analysis and Pearson correlations. RESULTS: In 146 no-ARDFP subjects, baseline RC (50.8%) did not change at week 12 and was not correlated with CD4 cell count or viral load changes at week 12 (P=0.33 and P=0.79, respectively) or at week 24 (P=0.96 and P=0.14, respectively). dPSS predicted virological but not CD4 cell count response to ARV therapy at weeks 12, 24 and 48 (P=0.002, P<0.001 and P=0.005, respectively). RC was significantly correlated with dPSS and iPSS at baseline, but did not increase their predictive value. In the 137 ARDFP patients, RC increased significantly (from 52.4 to 85.8%), but did not predict CD4 cell count and viral load changes during ARDFP (P=0.92 and P=0.26, respectively). RC after ARDFP did not predict subsequent CD4 cell count and viral load changes 12 weeks following ARV treatment reinitiation (P=0.90 and P=0.29, respectively). CONCLUSIONS: We found no additional predictive value of replication capacity for virological or immunological responses (above what PSS provides) in patients undergoing salvage ARV treatment.

Hepatitis C virus coinfection and the risk of cardiovascular disease among HIV-infected patients.

BACKGROUND: Among HIV-infected patients, hepatitis C virus (HCV) coinfection is associated with lower cholesterol levels, but it remains unclear how it affects cardiovascular outcomes. METHODS: We performed logistic regression to evaluate acute myocardial infarction (AMI) and cerebrovascular disease (CVD) events by HCV status among HIV-infected US veterans in the highly active antiretroviral therapy (HAART) era (1996-2004). We then performed survival analyses to evaluate incident AMI and CVD, exploring antiretroviral therapy (ART) as a time-dependent variable. RESULTS: A total of 19 424 HIV-infected patients [31.6% of whom were HCV-coinfected (HIV/HCV)] contributed 76 376 patient-years of follow-up. HCV coinfection was associated with lower rates of hypercholesterolaemia (18.0% in HIV/HCV vs. 30.7% in HIV-only patients; P<0.001), but higher rates of hypertension (43.8%vs. 35.6%; P<0.0001), type 2 diabetes mellitus (16.2%vs. 11.1%; P<0.0001) and smoking (36.7%vs. 24.7%; P=0.009). Rates of AMI and CVD were significantly higher among HIV/HCV than HIV-only patients: 4.19 vs. 3.36 events/1000 patient-years, respectively (P<0.001), for AMI; and 12.47 vs. 11.12 events/1000 patient-years, respectively (P<0.001), for CVD. When analyses were controlled for diabetes mellitus, hypertension, age and duration of ART, hazard ratios (HRs) among those with HIV/HCV (vs. HIV only) were 1.25 [95% confidence interval (CI) 0.98-1.61; P=0.072] for AMI and 1.20 (CI 1.04-1.38; P=0.013) for CVD. Hypertension (HR 2.05; P<0.001), greater age (HR 1.79; P<0.001) and longer duration (cumulative years) of antiretroviral use (HR 1.12; P=0.0411) were also associated with increased risk of AMI in the adjusted model. CONCLUSIONS: In the HAART era, HCV coinfection was associated with a significantly increased risk of CVD and a trend towards an increased risk of AMI among HIV-infected patients.

Phenytoin hypersensitivity syndrome masquerading as fever and systemic illness of unknown origin in an HIV-infected patient.

A 32-year-old HIV-infected woman developed fever and systemic illness of unknown origin after being placed on phenytoin for seizures. Her clinical syndrome, skin biopsy findings, and clinical response to steroids were consistent with phenytoin hypersensitivity syndrome.

Lipid abnormalities in HIV/hepatitis C virus-coinfected patients.

BACKGROUND: Among HIV-infected patients, hepatitis C virus (HCV) coinfection is associated with increased rates of lipodystrophy and insulin resistance. Its impact on HIV-associated dyslipidaemia is less clear. METHODS: The lipid profiles of all HIV-infected patients and a subset of HCV-infected patients seen at the VA Medical Center in Dallas from January 2003 to March 2004 were analysed. Demographic data, HCV serostatus, and HIV treatment history were recorded. Lipid profiles of HIV/HCV-coinfected patients were compared with those of HIV-monoinfected and HCV-monoinfected patients. RESULTS: A total of 359 HIV-infected patients, 91 (25.3%) of whom were HCV coinfected, and 112 HCV-infected patients were included in the analysis. Among the HIV-infected patients, HCV coinfection was associated with a reduced risk of hypercholesterolaemia [9.9% vs 24.8%; relative risk (RR)=0.333; 95% confidence interval (CI)=0.158-0.699; P<0.001] and hypertriglyceridaemia (48.4% vs 60.3%; RR=0.616; 95% CI=0.382-0.994; P=0.031). After controlling for duration of protease inhibitor (PI) therapy, race, alanine aminotransferase (ALT) concentration and platelet count, HCV remained an independent predictor of hypercholesterolaemia (RR=0.369; P=0.01) and any dyslipidaemia (RR=0.531; P=0.019). In addition, the rate of dyslipidaemias was lower among HCV-monoinfected than HIV/HCV-coinfected patients (29.5% vs 50.5; P=0.002). White race was also an independent predictor of dyslipidaemia (73.8% vs 50.7%; RR=2.32; 95% CI=1.44-3.76; P=0.001). CONCLUSIONS: HCV coinfection independently predicted lower rates of dyslipidaemia among HIV-infected patients. An analysis of lipid kinetics among mono- and coinfected patients may elucidate the mechanisms of the apparent protective effect of HCV infection.

Cost as a barrier to condom use: the evidence for condom subsidies in the United States.

OBJECTIVES: This study sought to determine the impact of price on condom use. METHODS: A program based on distribution of condoms at no charge was replaced with one providing low-cost condoms (25 cents). Pretest and posttest surveys asked about condom use among persons reporting 2 or more sex partners. RESULTS: At pretest, 57% of respondents had obtained free condoms, and 77% had used a condom during their most recent sexual encounter. When the price was raised to 25 cents, the respective percentages decreased to 30% and 64%. CONCLUSIONS: Cost is a barrier to condom use. Free condoms should be distributed to encourage their use by persons at risk for HIV and other sexually transmitted diseases.