Effects Of Serostatus Research Articles

Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis

Prior studies suggest increased cytomegalovirus (CMV) infection after haploidentical donor transplantation with posttransplant cyclophosphamide (HaploCy). The role of allograft source and posttransplant cyclophosphamide (PTCy) in CMV infection is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection, and effects of serostatus and CMV infection on transplant outcomes. We examined patients reported to the Center for International Blood and Marrow Transplantation Research between 2012 and 2017 who had received HaploCy (n = 757), matched related (Sib) with PTCy (SibCy, n = 403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n = 1605). Cumulative incidences of CMV infection by day 180 were 42%, 37%, and 23%, respectively (P < .001). CMV disease was statistically comparable. CMV infection risk was highest for CMV-seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor (HaploCy [n = 545]: hazard ratio [HR], 50.3; SibCy [n = 279]: HR, 47.7; SibCNI [n = 1065]: HR, 24.4; P < .001). D+/R− patients also had increased risk for CMV infection. Among R+ or those developing CMV infection, HaploCy had worse overall survival and nonrelapse mortality. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic graft-versus-host disease (GVHD) overall, but CMV infection in PTCy recipients was associated with higher chronic GVHD (P = .006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally, CMV infection may negate the chronic GVHD protection of PTCy. This study supports aggressive prevention strategies in all receiving PTCy.

Potential Biases Arising From Epidemic Dynamics in Observational Seroprotection Studies.

The extent and duration of immunity following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are critical outstanding questions about the epidemiology of this novel virus, and studies are needed to evaluate the effects of serostatus on reinfection. Understanding the potential sources of bias and methods for alleviating biases in these studies is important for informing their design and analysis. Confounding by individual-level risk factors in observational studies like these is relatively well appreciated. Here, we show how geographic structure and the underlying, natural dynamics of epidemics can also induce noncausal associations. We take the approach of simulating serological studies in the context of an uncontrolled or controlled epidemic, under different assumptions about whether prior infection does or does not protect an individual against subsequent infection, and using various designs and analytical approaches to analyze the simulated data. We find that in studies assessing whether seropositivity confers protection against future infection, comparing seropositive persons with seronegative persons with similar time-dependent patterns of exposure to infection by stratifying or matching on geographic location and time of enrollment is essential in order to prevent bias.

HIV infection and age effects on striatal structure are additive.

The age of the HIV-infected population is increasing. Although many studies document gray matter volume (GMV) changes following HIV infection, GMV also declines with age. Findings have been inconsistent concerning interactions between HIV infection and age on brain structure. Effects of age, substance use, and inadequate viral suppression may confound identification of GMV serostatus effects using quantitative structural measures. In a cross-sectional study of HIV infection, including 97 seropositive and 84 seronegative, demographically matched participants, ages 30-70, we examined serostatus and age effects on GMV and neuropsychological measures. Ninety-eight percent of seropositive participants were currently treated with anti-retroviral therapies and all were virally suppressed. Gray, white, and CSF volumes were estimated using high-resolution T1-weighted MRI. Linear regression modeled effects of serostatus, age, education, comorbidities, and magneticfield strength on brain structure, using both a priori regions and voxel-based morphometry. Although seropositive participants exhibited significant bilateral decreases in striatal GMV, no serostatus effects were detected in the thalamus, hippocampus, or cerebellum. Age was associated with cortical, striatal, thalamic, hippocampal, and cerebellar GMV reductions. Effects of age and serostatus on striatal GMV were additive. Although no main effects of serostatus on neuropsychological performance were observed, serostatus moderated the relationship between pegboard performance and striatal volume. Both HIV infection and age were associated with reduced striatal volume. The lack of interaction of these two predictors suggests that HIV infection is associated with premature, but not accelerated, brain age. In serostatus groups matched on demographic and clinical variables, there were no observed differences in neuropsychological performance. Striatal GMV measures may be promising biomarker for use in studies of treated HIV infection.

Verbal and spatial working memory among drug-using HIV-infected men and women.

Working memory (WM) is a critical component of many neurocognitive functions. The literature has demonstrated consistently that WM impairment is more frequent and severe among substance-dependent individuals (SDIs) infected with HIV compared with uninfected SDIs; however, the SDIs who participated in these previous studies were primarily male. There are few published data on WM performance among HIV+ women with or without substance use disorders, and essentially no direct comparisons of WM performance between HIV+ men and women, regardless of substance use. We investigated potential sex and serostatus effects on WM among a sample of 360 SDIs (114 with HIV; 66% female) verified abstinent from alcohol and drugs of abuse at testing and generally comparable on substance use and comorbid characteristics. Participants were tested with the n-back task, a well-established WM measure that is sensitive to HIV-associated cognitive impairment. HIV+ men and women performed spatial and verbal versions of the n-back significantly less accurately compared with HIV- participants. Women showed slower response times compared with men on both versions, regardless of HIV serostatus. Individuals dependent on cocaine showed faster RTs compared with non-dependent users, but this effect was not apparent among opioid- or alcohol-dependent groups. Findings on n-back accuracy are consistent with our previous proposal that WM impairment represents a signature deficit among HIV+ SDIs; however, WM impairment appears less common among HIV+ women without a substance use history. The pattern of sex differences in response speed but serostatus effects on response accuracy is comparable to a recent report by our group of sex differences in learning speed but serostatus effects on delayed recall.

A Study of the Longitudinal Patterns of Stimulant and Amyl Nitrite Use and Sexual Behavior Pre- and Post-HIV Seroconversion Among MSM.

The use of stimulant drugs alone or in combination with amyl nitrites (stimulant/nitrites) has been associated with higher rates of risky sexual behavior and predictive of HIV infection among men who have sex with men. However, the temporal pattern of stimulant/nitrite use pre- and post-seroconversion has not been well established. This study assessed changes in stimulant/nitrite use and risky sexual behavior among seroconverting MSM over time. Data were collected in the Baltimore-Washington, DC; Pittsburgh; Chicago; and Los Angeles sites of the Multicenter AIDS Cohort Study (MACS), a longitudinal study of the natural history of HIV infection among MSM. We used propensity scores to select 1044 MSM from 7087 MACS participants composed of 348 seroconverting, 348 seronegative, and 348 seroprevalent participants matched on demographics, recruitment cohort, and study visits. We centered up to four-years of semi-annual data around the seroconversion visit of the seroconverting case within each matched group of participants. Mixed effects regressions estimated the effects of serostatus, recruitment cohort, and time on self-reported stimulant/nitrite use, numbers of male intercourse partners, and numbers of unprotected receptive anal intercourse (URAI) partners. Covariates included demographics, binge drinking, and marijuana use. Seroconverters had the highest odds of stimulant/inhaled nitrite use (AOR 10.3, CI 4.8-22.0), incident rates of intercourse (IRR 1.6, CI 1.3-2.1), and URAI partners (IRR 5.1, CI 3.5-7.3). All participants decreased drug use and sexual risk behavior over time. However, the decreases were largest for seroconverters who nevertheless maintained the highest rates of stimulant/nitrite use and sexual risk. Cohort-related effects were associated with sharp reductions in stimulant/nitrite use and URAI in the early 1990s that rebounded considerably within the first decade of the 2000s. Although all participants decreased risky sexual behavior and stimulant and/or nitrite use over time, seroconverters had the largest decreases. There was no evidence for abrupt or substantial increases in drug use or risky sex post-seroconversion. However, there was substantial variation at the individual level, with the factors underlying this variation not well understood and worth further study. Moreover, stimulant/nitrite use and risky sexual behavior appear to have been strongly influenced by contextual historical and socio-cultural effects. The manner in which contextual factors influence individual behavior is also not well understood and also warrants further study.

Brain Structural Changes following HIV Infection: Meta-Analysis.

Numerous studies have used structural neuroimaging to measure HIV effects on brain macroarchitecture. While many have reported changes in total brain volume, gray matter volume, white matter volume, CSF volume, and basal ganglia volume following HIV infection, quantitative inconsistencies observed across studies are large. Our aim was to evaluate the consistency and temporal stability of serostatus effects on a range of structural neuroimaging measures. PubMed, reference lists, and corresponding authors. The meta-analysis included 19 cross-sectional studies reporting HIV effects on cortical and subcortical volume from 1993 to 2016. Random-effects meta-analysis was used to estimate individual study standardized mean differences and study heterogeneity. Meta-regression was used to examine the effects of the study publication year. Meta-analysis revealed standardized mean differences related to the serostatus of -0.65 (P = .002) for total brain volume, -0.28 for gray matter volume (P = .008), -0.24 (P = .076) for white matter volume, and 0.56 (P = .001) for CSF volume. Basal ganglia volume differences related to serostatus were not significant. Nevertheless, estimates of between-study heterogeneity suggested that much of the observed variance was between studies. Publication year was associated with recent reductions in many neurostructural effects. Many studies pooled participants with varying durations of treatment, disease, and comorbidities. Image-acquisition methods changed with time. While published studies of HIV effects on brain structure had substantial variations that are likely to result from changes in HIV treatment practice during the study period, quantitative neurostructural measures can reliably detect the effects of HIV infection during treatment, serving as reliable biomarkers.

Effects of sex and HIV serostatus on spatial navigational learning and memory among cocaine users.

Spatial learning and memory are critically dependent on the integrity of hippocampal systems. Functional MRI and neuropathological studies show that hippocampal circuitry is prominently affected among HIV-seropositive individuals, but potential spatial learning and memory deficits have not been studied in detail in this population. We investigated the independent and interactive effects of sex and HIV serostatus on performance of a spatial learning and memory task in a sample of 181 individuals with a history of cocaine dependence. We found that men showed faster times to completion on immediate recall trials compared with women and that delayed recall was significantly poorer among HIV-infected compared with HIV-uninfected participants. Additionally, a sex × serostatus effect was found on the total number of completed learning trials. Specifically, HIV-infected men successfully completed more learning trials compared with HIV-infected women. Results are discussed in the context of recent reports of sex and HIV serostatus effects on episodic memory performance.

Effects of serostatus and gender on the HRV-16-induced local immune response

The “experimental cold model” is widely used to investigate effects of HRV infection. However, effects of serostatus and gender on the HRV-induced immune response have not been clarified.40 healthy seropositive and seronegative (1:1) male and female (1:1) subjects were inoculated with HRV-16.HRV infection increased viral load in nasal wash, which tended to be more pronounced in seronegative subjects. Furthermore, HRV infection increased levels of IP-10, IL-6, and IL-10 and leukocyte numbers in nasal wash of seronegative, but not of seropositive subjects. No differences in any of the parameters were found between both sexes.The HRV-induced local immune response is diminished in seropositive subjects compared with seronegative subjects, while gender does not influence this response. These results have important implications for the design of future experimental cold studies: seronegative subjects, from both sexes can be included.

Sex and HIV serostatus effects on high-risk decision making

the effects of quinpirole (QUIN), a preferential DRD3 agonist, in drug-naive male and female rhesus monkeys. Next, we examined the effects of chronic COC (n=3) and MA (n=3) exposure on sensitivity to QUIN in male monkeys. Finally, using PET imaging with the radioligand [11C]PHNO,weexamined the relationshipbetween DRD3 availability and (1) QUIN-elicited yawning and (2) simple discrimination and reversal performance – a measure of cognitive flexibility. Methods: Cumulative doses of QUIN (0.01–0.3mg/kg) were injected i.m. in30-minbinsand the totalnumberof yawnsobserved were recorded for each bin. QUIN-elicited yawning was characterized as an inverted U-shaped function of dose. Results: Significant sex differences were noted with QUIN being less potent and eliciting fewer yawns in females. Additionally, monkeys with a MA SA history were more sensitive to the behavioral effects of low doses of QUIN vs. controls, whereas COC SA monkeys were not significantly different than controls. Finally, analyses revealed significant relationships between DRD3 availability and both QUIN-elicited yawning and acquisition of discrimination in several regions of the brain. Future studies will extend these results to females. Conclusions: These findings suggest that QUIN-elicited yawning is an excellent tool for examining DRD3 activity, that this receptor is critical in discrimination learning, and that both sex and drug history influence individual sensitivity to the behavioral effects of DRD3 preferring compounds. Such information will be critical in developing sex-specific treatments for drug abuse. Financial support: Supported by DA012460.

Altered functional response to risky choice in HIV infection.

BackgroundRisky decision-making is commonly observed in persons at risk for and infected with HIV and is associated with executive dysfunction. Yet it is currently unknown whether HIV alters brain processing of risk-taking decision-making.MethodsThis study examined the neural substrate of a risky decision-making task in 21 HIV seropositive (HIV+) and 19 seronegative (HIV-) comparison participants. Functional magnetic resonance imaging was conducted while participants performed the risky-gains task, which involves choosing among safe (20 cents) and risky (40/80 cent win or loss) choices. Linear mixed effects analyses examining group and decision type were conducted. Robust regressions were performed to examine the relationship between nadir CD4 count and Kalichman sexual compulsivity and brain activation in the HIV+ group. The overlap between the task effects and robust regressions was explored.ResultsAlthough there were no serostatus effects in behavioral performance on the risky-gains task, HIV+ individuals exhibited greater activation for risky choices in the basal ganglia, i.e. the caudate nucleus, but also in the anterior cingulate, dorsolateral prefrontal cortex, and insula relative to the HIV- group. The HIV+ group also demonstrated reduced functional responses to safe choices in the anterior cingulate and dorsolateral prefrontal cortex relative to the HIV- group. HIV+ individuals with higher nadir CD4 count and greater sexual compulsivity displayed lower differential responses to safe versus risky choices in many of these regions.ConclusionsThis study demonstrated fronto-striatal loop dysfunction associated with HIV infection during risky decision-making. Combined with similar between-group task behavior, this suggests an adaptive functional response in regions critical to reward and behavioral control in the HIV+ group. HIV-infected individuals with higher CD4 nadirs demonstrated activation patterns more similar to seronegative individuals. This suggests that the severity of past immunosuppression (CD4 nadir) may exert a legacy effect on processing of risky choices in the HIV-infected brain.

Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter

We evaluated regional brain volumes and cerebral metabolite levels as correlates of HIV DNA in peripheral blood mononuclear cells (PBMCs). In this cross-sectional study, 35 HIV+ subjects aged ≥40 years (25 with detectable PBMC HIV DNA; 10 with HIV DNA <10 copies/10(6) cells, the threshold of detection) and 12 seronegative controls underwent structural brain MRI and magnetic resonance spectroscopy at 3 T. HIV+ subjects were on combination antiretroviral therapy ≥1 year; all but 1 had plasma HIV RNA <50 copies/mL. We used logistic regression to evaluate relationships of likely predictor variables to the outcome of PBMC HIV DNA detectability in the HIV+ subjects. Effects of serostatus and HIV DNA on regional brain volumes (normalized to intracranial volume) and on metabolite ratios over creatine were evaluated by analyses of covariance, controlling for age. Relative to the HIV+ group with undetectable HIV DNA, subjects with detectable HIV DNA demonstrated decreased volumes of cerebellar (-14%, p = 0.020) and total subcortical (-10%, p = 0.024) gray matter. Compared to healthy controls, only the detectable HIV DNA group showed significant (p < 0.05) enlargement of lateral ventricles and volumetric reductions of caudate, putamen, thalamus, hippocampus, nucleus accumbens, brainstem, total cortical gray matter, and cerebral white matter. Detectable HIV DNA was not associated with significantly altered cerebral metabolite levels. Inability to clear peripheral blood of HIV DNA is associated with regional brain atrophy in well-controlled HIV infection, supporting the involvement of peripheral viral reservoirs in the neuropathogenesis of persistent HIV-related neurocognitive disorders.

Effects of Depressed Mood versus Clinical Depression on Neuropsychological Test Performance among African American Men Impacted by HIV/AIDS

The utility of self-report measures in identifying those at risk for depressive disorder and the adverse impact of depression versus depressed mood and HIV serostatus on neuropsychological (NP) test performance were examined in a large sample (N = 243) of gay and bisexual African American men. Results indicate high rates of depression relative to recent population estimates, regardless of methodology, but that the use of standard cut-scores for self-report inventories may significantly overestimate psychiatric morbidity. Limited independent effects of serostatus or depression on NP test performance were observed. More importantly, a complex set of adverse effects of depression and its interaction with serostatus which varied according to the methodology used to assess depression were observed. These findings are discussed in light of ongoing controversy regarding the relative influence of depression on neuropsychological functioning among people living with HIV/AIDS.

Low Education as a Possible Risk Factor for Cognitive Abnormalities in HIV-1

The present study reports new and unexpected results of cognitive abnormalities among human immunodeficiency virus type 1 (HIV-1) asymptomatic subjects in the Multicenter AIDS Cohort Study. The major purpose of our analyses is to estimate the separate and combined effects of serostatus and education level on the prevalence of cognitive abnormality. Cognitive "abnormality" was defined as performance that deviated > or = 2 SDs below the mean of the total seronegative group on at least one of the five neuropsychological screening tests (Grooved Pegboard, Verbal Fluency, Digit Span, Symbol Digit Modalities, Rey Auditory Verbal Learning). The predicted prevalence of cognitive abnormality was 38% in seropositive individuals with no more than 12 years of education, compared with < 17% in the other education-serostatus groups. This interaction between education level and serostatus remained after controlling for the possible confounding effects of age, ethnicity, CD4 level, depression, prior drug history, and learning disability using logistic regression. To account for these findings, we suggest that low education might reflect an indirect index of lower reserve capacity (i.e., a risk factor) that lowers the threshold for neuropsychological abnormalities in cases of early HIV-1 infection.