Sex Differences in Human Immunodeficiency Virus Persistence and Reservoir Size During Aging.

BACKGROUND: Sex differences in human immunodeficiency virus (HIV) reservoir dynamics remain underexplored. METHODS: Longitudinal samples from virally suppressed midlife women (n = 59, median age 45 years) and age-matched men (n = 31) were analyzed retrospectively. At each time point, we measured sex hormones (by means of enzyme-linked immunosorbent assay) and cellular HIV DNA and RNA (by means of digital droplet polymerase chain reaction). Number of inducible HIV RNA+ cells, which provides an upper estimate of the replication-competent reservoir, was quantified longitudinally in a different subset of 14 women, across well-defined reproductive stages. Mixed-effects models included normalized reservoir outcomes and sex, time since antiretroviral therapy (ART) initiation, and the sex-by-time interaction as predictors. RESULTS: At ART initiation, women and men had median (interquartile range [IQR]) CD4+ T-cell counts of 204/µL (83-306/µL) versus 238/µL (120-284/µL), respectively; median ages of 45 (42-48) versus 47 (43-51) years; and median follow-up times of 79.2/µL (60.5-121.1/µL) versus 66.2/µL (43.2-80.6/µL) months. We observed a significant decline of total HIV DNA over time in both men and women (P < .01). However, the rates of change differed significantly between the sexes (P < .01), with women having a significantly slower rate of decline than men, more pronounced with age. By contrast, the levels of inducible HIV RNA increased incrementally over time in women during reproductive aging (P < .01). CONCLUSIONS: In contrast to men, in whom the HIV reservoir steadily declines with aging, the HIV reservoir in women is more dynamic. Total HIV DNA (including intact and defective genomes) declines more slowly in women than in men, while the inducible HIV RNA+ reservoir, which is highly enriched in replication-competent virus, increases in women after menopause.

Can't Work From Home: Pooled Nucleic Acid Testing of Laboratory Workers During the COVID-19 Pandemic.

Together with protective measures, routine screening for severe acute respiratory syndrome coronavirus 2 infection helps provide a safe working environment. We evaluated a pooled nucleic acid testing strategy in a research laboratory. It allowed lab activity to be maintained and would save 25 920 person-hours and $1 684 800/year by increasing the margin of safety for returning to work.

Spreading the Veterans Health Administration's emergency department rapid access clinics (ED-RAC) innovation: Role of champions and local contexts.

BACKGROUND: Champions frequently facilitate change in healthcare, but the literature lacks specificity regarding champion activities and interactions with local contexts. The Veterans' Health Administration (VA) Emergency Department (ED) Rapid Access Clinic (ED-RAC) initiative used champions to spread an innovation aimed at achieving timely specialty follow-up care for ED patients. We assessed the roles champions and local contexts played in successful ED-RAC spread in the initiative's first year. METHODS: Our mixed method formative evaluation included serial questionnaires, fieldnotes from meetings, and champion interviews. We analyzed qualitative data from spread site rapid and non-rapid implementers, assessing champion and contextual factors. RESULTS: Among 24 participating VA sites, 11 were rapid implementers (i.e., implemented ED-RAC in first year), 13 were not. Site champions at rapid sites described crossing multiple organizational units to get tasks accomplished (e.g., gaining buy-in, requesting resources); champions at non-rapid sites experienced inter-departmental communication challenges and competing demands. Champions at rapid and non-rapid sites encountered similar context-related barriers (e.g. scheduling complexities) and facilitators (e.g. enthusiastic buy-in), but differed in leadership and resource barriers. CONCLUSIONS: Identifying site champions was not enough to assure rapid innovation spread. Interdependencies between ED-RAC implementation requirements (e.g., boundary spanning, resources) and champion and contextual factors helped explain variations in progress. IMPLICATIONS: Tailoring spread support to champion and contextual factors may facilitate more rapid spread of innovations.

Subclinical Cytomegalovirus and Epstein-Barr Virus Shedding Is Associated with Increasing HIV DNA Molecular Diversity in Peripheral Blood during Suppressive Antiretroviral Therapy.

Cytomegalovirus (CMV) almost universally infects persons with HIV (PWH), and it is a driver of persistent inflammation and HIV persistence. The mechanisms underlying the association between CMV (and possibly other herpesviruses) and HIV persistence are unclear. Serially collected blood samples were obtained from men who have sex with men (MSM) who started antiretroviral therapy (ART) within 1 year of their estimated date of HIV infection (EDI). Total CMV and Epstein-Barr virus (EBV) DNA were quantified in peripheral blood mononuclear cells by droplet digital PCR (ddPCR). Deep sequencing of the HIV DNA partial env gene was performed, and the dynamics of viral diversity over time were analyzed in relation to CMV and EBV shedding status. In total, 37 MSM PWH were included and followed for a median of 23 months (IQR, 22 to 28). Participants started ART within a median of 3.1 months (IQR, 1.5 to 6.5) after EDI and remained virally suppressed thereafter. A total of 18 participants (48.6%) were classified as high EBV shedders, while 19 (51.4%) were classified as CMV shedders. In longitudinal analyses, normalized molecular diversity levels tended to increase over time among participants with detectable CMV and high EBV DNA (0.03 ± 0.02, P = 0.08), while they significantly declined among participants with no/low viral shedding (-0.04 ± 0.02, P = 0.047, interaction P < 0.01). Subclinical CMV and EBV shedding could contribute to the dynamics of the HIV DNA reservoir during suppressive ART. Whether persistent CMV/EBV replication could be targeted as a strategy to reduce the size of the latent HIV reservoir is an avenue that should be explored.IMPORTANCE As part of this study, we evaluated the molecular characteristics of the HIV DNA reservoir over time during antiretroviral treatment (ART) in relation to those of other chronic viral infections (i.e., cytomegalovirus [CMV] and Epstein-Barr virus [EBV]). We demonstrated that the presence of CMV and high-level EBV DNA in peripheral blood cells was associated with changes in HIV DNA molecular diversity. Specifically, HIV DNA molecular diversity increased over time among participants with detectable CMV and high-level EBV DNA, while it significantly declined among participants with no/low viral shedding. Although the current study design does not allow causality to be inferred, it does support the theory that persistent CMV and EBV shedding could contribute to the dynamics of the HIV DNA reservoir during suppressive ART, even when ART is initiated during the earliest phases of HIV infection.

Modeling Patient No-Show History and Predicting Future Appointment Behavior at the Veterans Administration's Outpatient Mental Health Clinics: NIRMO-2.

INTRODUCTION: No-shows are detrimental to both patients' health and health care systems. Literature documents no-show rates ranging from 10% in primary care clinics to over 60% in mental health clinics. Our model predicts the probability that a mental health clinic outpatient appointment will not be completed and identifies actionable variables associated with lowering the probability of no-show. MATERIALS AND METHODS: We were granted access to de-identified administrative data from the Veterans Administration Corporate Data Warehouse related to appointments at 13 Veterans Administration Medical Centers. Our modeling data set included 1,206,271 unique appointment records scheduled to occur between January 1, 2013 and February 28, 2017. The training set included 846,668 appointment records scheduled between January 1, 2013 and December 31, 2015. The testing set included 359,603 appointment records scheduled between January 1, 2016 and February 28, 2017. The dependent binary variable was whether the appointment was completed or not. Independent variables were categorized into seven clusters: patient's demographics, appointment characteristics, patient's attendance history, alcohol use screening score, medications and medication possession ratios, prior diagnoses, and past utilization of Veterans Health Administration services. We used a forward stepwise selection, based on the likelihood ratio, to choose the variables in the model. The predictive model was built using the SAS HPLOGISTIC procedure. RESULTS: The best indicator of whether someone will miss an appointment is their historical attendance behavior. The top three variables associated with higher probabilities of a no-show were: the no-show rate over the previous 2 years before the current appointment, the no-show probability derived from the Markov model, and the age of the appointment. The top three variables that decrease the chance of no-showing were: the appointment was a new consult, the appointment was an overbook, and the patient had multiple appointments on the same day. The average of the areas under the receiver operating characteristic curves was 0.7577 for the training dataset, and 0.7513 for the test set. CONCLUSIONS: The National Initiative to Reduce Missed Opportunities-2 confirmed findings that previous patient attendance is one of the key predictors of a future attendance and provides an additional layer of complexity for analyzing the effect of a patient's past behavior on future attendance. The National Initiative to Reduce Missed Opportunities-2 establishes that appointment attendance is related to medication adherence, particularly for medications used for treatment of mood disorders or to block the effects of opioids. However, there is no way to confirm whether a patient is actually taking medications as prescribed. Thus, a low medication possession ratio is an informative, albeit not a perfect, measure. It is our intention to further explore how diagnosis and medications can be better captured and used in predictive modeling of no-shows. Our findings on the effects of different factors on no-show rates can be used to predict individual no-show probabilities, and to identify patients who are high risk for missing appointments. The ability to predict a patient's risk of missing an appointment would allow for both advanced interventions to decrease no-shows and for more efficient scheduling.

Performing rapid autopsy for the interrogation of HIV reservoirs.

: Rapid autopsy at the end of life in people with HIV (PWH) permits the preservation of valuable tissue specimens for subsequent study of HIV reservoirs. At our institution, we have developed a cohort of PWH who consent to a rapid autopsy to gather a wide range of fluids and tissues with the goal of advancing HIV cure research. The protocol for successfully performing these autopsies has required careful thought and development over months and years. We have now successfully performed six rapid autopsies and detail here our steps to build the study cohort, train and staff a team of more than a dozen personnel, and process and preserve hundreds of samples from each autopsy.

Presence of asymptomatic cytomegalovirus and Epstein--Barr virus DNA in blood of persons with HIV starting antiretroviral therapy is associated with non-AIDS clinical events.

BACKGROUND: Even with antiretroviral therapy (ART), persons with HIV (PWH) experience increased morbidity and mortality. Cytomegalovirus (CMV) and Epstein--Barr virus (EBV) co-infections likely exacerbate inflammatory-related diseases. OBJECTIVE: To determine if presence of detectable CMV or EBV DNA in peripheral blood mononuclear cells (PBMC) is associated with non-AIDS events among PWH receiving modern ART. DESIGN: We performed a case--control study of PWH starting ART and HIV-suppressed at year 1 and thereafter, 140 cases who experienced non-AIDS events and 305 matched controls. Events included myocardial infarction, stroke, malignancy, serious bacterial infection or death. METHODS: Blood samples were studied pre-ART, 1-year post-ART and pre-event. Controls had an event-free follow-up equal or greater than cases. CMV and EBV DNA levels were measured in PBMC. Conditional logistic regression analysis assessed associations and adjusted for relevant covariates; Spearman's correlations compared CMV and EBV DNA levels with other biomarkers. RESULTS: CMV DNA was detected in PBMC of 25% of participants, EBV DNA was detected in more than 90%. Higher EBV DNA levels were associated with increased risk of events at all time points (odds ratio (OR) per one IQR = 1.5-1.7, all P < 0.009). At year 1, detectable CMV DNA was associated with increased risk of events in most adjusted models (OR = 1.4-1.8, P values ranging 0.03-0.17). Higher levels of CMV and EBV DNA correlated with multiple inflammatory markers and lower CD4/CD8 ratio. CONCLUSION: In PWH starting ART, detection of CMV and EBV DNA in PBMC was associated with development of non-AIDS events. Clinical trials will be needed to understand causal mechanisms and ways to interrupt them.

Herd Immunity Likely Protected the Men Who Have Sex With Men in the Recent Hepatitis A Outbreak in San Diego, California.

A high seroprevalence of hepatitis A virus (81%) among human immunodeficiency virus-negative high-risk men who have sex with men is likely why this community was largely spared from a recent hepatitis A virus outbreak in San Diego, California.

Impact of Public Safety Policies on Human Immunodeficiency Virus Transmission Dynamics in Tijuana, Mexico.

Background: North Tijuana, Mexico is home to many individuals at high risk for transmitting and acquiring human immunodeficiency virus (HIV). Recently, policy shifts by local government impacted how these individuals were handled by authorities. Here we examined how this affected regional HIV transmission dynamics. Methods: HIV pol sequences and associated demographic information were collected from 8 research studies enrolling persons in Tijuana and were used to infer viral transmission patterns. To evaluate the impact of recent policy changes on HIV transmission dynamics, qualitative interviews were performed on a subset of recently infected individuals. Results: Between 2004 and 2016, 288 unique HIV pol sequences were obtained from individuals in Tijuana, including 46.4% from men who have sex with men, 42.1% from individuals reporting transactional sex, and 27.8% from persons who inject drugs (some individuals had >1 risk factor). Forty-two percent of sequences linked to at least 1 other sequence, forming 37 transmission clusters. Thirty-two individuals seroconverted during the observation period, including 8 between April and July 2016. Three of these individuals were putatively linked together. Qualitative interviews suggested changes in policing led individuals to shift locations of residence and injection drug use, leading to increased risk taking (eg, sharing needles). Conclusions: Near real-time molecular epidemiologic analyses identified a cluster of linked transmissions temporally associated with policy shifts. Interviews suggested these shifts may have led to increased risk taking among individuals at high risk for HIV acquisition. With all public policy shifts, downstream impacts need to be carefully considered, as even well-intentioned policies can have major public health consequences.