Integrating HIV Cluster Analysis in Everyday Public Health Practice: Lessons Learned From a Public Health--Academic Partnership.

BACKGROUND: The use of molecular HIV cluster analysis to supplement public health contact tracing has shown promise in addressing HIV outbreaks. However, the potential of HIV cluster analysis as an adjunct to daily, person-by-person HIV prevention efforts remains unknown. We documented lessons learned within a unique public health-academic partnership while guiding workaday HIV prevention efforts with near-real-time molecular cluster analysis. SETTING: A public health-academic partnership in the State of Rhode Island, the United States. METHODS: We recorded perceptions of our team of academicians and public health practitioners that were encountered in an 18-month study evaluating the integration of molecular cluster analysis with HIV contact tracing for public health benefit. The focus was on monthly conferences where molecular clustering of each new statewide diagnosis was discussed to facilitate targeted interventions and on attempted reinterviews of all newly HIV-diagnosed persons statewide whose HIV sequences clustered to increase partner naming. RESULTS: Three main themes emerged: First, multidisciplinary conferences are substantially beneficial for gleaning actionable inferences from integrating molecular cluster analysis and public health data. Second, universal reinterviews were perceived to potentially have negative consequences but may be selectively beneficial. Third, the translation of cluster analysis into public health action is hampered by jurisdictional surveillance boundaries and within-jurisdictional data silos, across which data sharing is problematic. CONCLUSIONS: Insights from a statewide public health-academic partnership support integration of molecular HIV cluster analyses with public health efforts, which can guide public health activities to prevent transmission while identifying substantial barriers to integration, informing continued research.

Acquired Human Immunodeficiency Virus Type 1 Drug Resistance in Rhode Island, USA, 2004-2021.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) acquired drug resistance (ADR) compromises antiretroviral therapy (ART). METHODS: We aggregated all HIV-1 protease-reverse transcriptase-integrase sequences over 2004-2021 at the largest HIV center in Rhode Island and evaluated ADR extent, trends, and impact using Stanford Database tools. Trends were measured with Mann-Kendall statistic, and multivariable regressions evaluated resistance predictors. RESULTS: Sequences were available for 914 ART-experienced persons. Overall ADR to any drug decreased from 77% to 49% (-0.66 Mann-Kendall statistic); nucleoside reverse transcriptase inhibitors 65% to 32%, nonnucleoside reverse transcriptase inhibitors 53% to 43%, and protease inhibitors 28% to 7% (2004-2021), and integrase strand transfer inhibitors 16% to 13% (2017-2021). Multiclass resistance decreased from 44% to 12% (2-class) and 12% to 6% (3-class). In 2021, 94% had at least one 3-drug or 2-drug one-pill-once-daily (OPOD) option. Males and those exposed to more ART regimens were more likely to have ≥2-class resistance, and higher regimen exposure was also associated with fewer OPOD options. CONCLUSIONS: Comprehensive analyses within a densely-sampled HIV epidemic over 2004-2021 demonstrated decreasing ADR. Continued ADR monitoring is important to maintain ART success, particularly with rising INSTI use in all lines of therapy and 2-drug and long-acting formulations.

An Automated Bioinformatics Pipeline Informing Near-Real-Time Public Health Responses to New HIV Diagnoses in a Statewide HIV Epidemic.

Molecular HIV cluster data can guide public health responses towards ending the HIV epidemic. Currently, real-time data integration, analysis, and interpretation are challenging, leading to a delayed public health response. We present a comprehensive methodology for addressing these challenges through data integration, analysis, and reporting. We integrated heterogeneous data sources across systems and developed an open-source, automatic bioinformatics pipeline that provides molecular HIV cluster data to inform public health responses to new statewide HIV-1 diagnoses, overcoming data management, computational, and analytical challenges. We demonstrate implementation of this pipeline in a statewide HIV epidemic and use it to compare the impact of specific phylogenetic and distance-only methods and datasets on molecular HIV cluster analyses. The pipeline was applied to 18 monthly datasets generated between January 2020 and June 2022 in Rhode Island, USA, that provide statewide molecular HIV data to support routine public health case management by a multi-disciplinary team. The resulting cluster analyses and near-real-time reporting guided public health actions in 37 phylogenetically clustered cases out of 57 new HIV-1 diagnoses. Of the 37, only 21 (57%) clustered by distance-only methods. Through a unique academic-public health partnership, an automated open-source pipeline was developed and applied to prospective, routine analysis of statewide molecular HIV data in near-real-time. This collaboration informed public health actions to optimize disruption of HIV transmission.

Not all clusters are equal: dynamics of molecular HIV-1 clusters in a statewide Rhode Island epidemic.

OBJECTIVES: Molecular epidemiology is a powerful tool to characterize HIV epidemics and prioritize public health interventions. Typically, HIV clusters are assumed to have uniform patterns over time. We hypothesized that assessment of cluster evolution would reveal distinct cluster behavior, possibly improving molecular epidemic characterization, towards disrupting HIV transmission. DESIGN: Retrospective cohort. METHODS: Annual phylogenies were inferred by cumulative aggregation of all available HIV-1 pol sequences of individuals with HIV-1 in Rhode Island (RI) between 1990 and 2020, representing a statewide epidemic. Molecular clusters were detected in annual phylogenies by strict and relaxed cluster definition criteria, and the impact of annual newly-diagnosed HIV-1 cases to the structure of individual clusters was examined over time. RESULTS: Of 2153 individuals, 31% (strict criteria) - 47% (relaxed criteria) clustered. Longitudinal tracking of individual clusters identified three cluster types: normal, semi-normal and abnormal. Normal clusters (83-87% of all identified clusters) showed predicted growing/plateauing dynamics, with approximately three-fold higher growth rates in large (15-18%) vs. small (∼5%) clusters. Semi-normal clusters (1-2% of all clusters) temporarily fluctuated in size and composition. Abnormal clusters (11-16% of all clusters) demonstrated collapses and re-arrangements over time. Borderline values of cluster-defining parameters explained dynamics of non-normal clusters. CONCLUSIONS: Comprehensive tracing of molecular HIV clusters over time in a statewide epidemic identified distinct cluster types, likely missed in cross-sectional analyses, demonstrating that not all clusters are equal. This knowledge challenges current perceptions of consistent cluster behavior over time and could improve molecular surveillance of local HIV epidemics to better inform public health strategies.

Beyond HIV outbreaks: protocol, rationale and implementation of a prospective study quantifying the benefit of incorporating viral sequence clustering analysis into routine public health interventions.

INTRODUCTION: HIV continues to have great impact on millions of lives. Novel methods are needed to disrupt HIV transmission networks. In the USA, public health departments routinely conduct contact tracing and partner services and interview newly HIV-diagnosed index cases to obtain information on social networks and guide prevention interventions. Sequence clustering methods able to infer HIV networks have been used to investigate and halt outbreaks. Incorporation of such methods into routine, not only outbreak-driven, contact tracing and partner services holds promise for further disruption of HIV transmissions. METHODS AND ANALYSIS: Building on a strong academic-public health collaboration in Rhode Island, we designed and have implemented a state-wide prospective study to evaluate an intervention that incorporates real-time HIV molecular clustering information with routine contact tracing and partner services. We present the rationale and study design of our approach to integrate sequence clustering methods into routine public health interventions as well as related important ethical considerations. This prospective study addresses key questions about the benefit of incorporating a clustering analysis triggered intervention into the routine workflow of public health departments, going beyond outbreak-only circumstances. By developing an intervention triggered by, and incorporating information from, viral sequence clustering analysis, and evaluating it with a novel design that avoids randomisation while allowing for methods comparison, we are confident that this study will inform how viral sequence clustering analysis can be routinely integrated into public health to support the ending of the HIV pandemic in the USA and beyond. ETHICS AND DISSEMINATION: The study was approved by both the Lifespan and Rhode Island Department of Health Human Subjects Research Institutional Review Boards and study results will be published in peer-reviewed journals.

Statewide Longitudinal Trends in Transmitted HIV-1 Drug Resistance in Rhode Island, USA.

BACKGROUND: HIV-1 transmitted drug resistance (TDR) remains a global challenge that can impact care, yet its comprehensive assessment is limited and heterogenous. We longitudinally characterized statewide TDR in Rhode Island. METHODS: Demographic and clinical data from treatment-naïve individuals were linked to protease, reverse transcriptase, and integrase sequences routinely obtained over 2004-2020. TDR extent, trends, impact on first-line regimens, and association with transmission networks were assessed using the Stanford Database, Mann-Kendall statistic, and phylogenetic tools. RESULTS: In 1123 individuals, TDR to any antiretroviral increased from 8% (2004) to 26% (2020), driven by non-nucleotide reverse transcriptase inhibitor (NNRTI; 5%-18%) and, to a lesser extent, nucleotide reverse transcriptase inhibitor (NRTI; 2%-8%) TDR. Dual- and triple-class TDR rates were low, and major integrase strand transfer inhibitor resistance was absent. Predicted intermediate to high resistance was in 77% of those with TDR, with differential suppression patterns. Among all individuals, 34% were in molecular clusters, some only with members with TDR who shared mutations. Among clustered individuals, people with TDR were more likely in small clusters. CONCLUSIONS: In a unique (statewide) assessment over 2004-2020, TDR increased; this was primarily, but not solely, driven by NNRTIs, impacting antiretroviral regimens. Limited TDR to multiclass regimens and pre-exposure prophylaxis are encouraging; however, surveillance and its integration with molecular epidemiology should continue in order to potentially improve care and prevention interventions.

Low Seroprevalence of SARS-CoV-2 in Rhode Island blood donors during may 2020 as determined using multiple serological assay formats.

BACKGROUND: Epidemic projections and public health policies addressing Coronavirus disease (COVID)-19 have been implemented without data reporting on the seroconversion of the population since scalable antibody testing has only recently become available. METHODS: We measured the percentage of severe acute respiratory syndrome- Coronavirus-2 (SARS-CoV-2) seropositive individuals from 2008 blood donors drawn in the state of Rhode Island (RI). We utilized multiple antibody testing platforms, including lateral flow immunoassays (LFAs), enzyme-linked immunosorbent assays (ELISAs) and high throughput serological assays (HTSAs). To estimate seroprevalence, we utilized the Bayesian statistical method to adjust for sensitivity and specificity of the commercial tests used. RESULTS: We report than an estimated seropositive rate of RI blood donors of approximately 0.6% existed in April-May of 2020. Daily new case rates peaked in RI in late April 2020. We found HTSAs and LFAs were positively correlated with ELISA assays to detect antibodies specific to SARS-CoV-2 in blood donors. CONCLUSIONS: These data imply that seroconversion, and thus infection, is likely not widespread within this population. We conclude that IgG LFAs and HTSAs are suitable to conduct seroprevalence assays in random populations. More studies will be needed using validated serological tests to improve the precision and report the kinetic progression of seroprevalence estimates.

Longitudinal typing of molecular HIV clusters in a statewide epidemic.

BACKGROUND: HIV molecular epidemiology is increasingly integrated into public health prevention. We conducted cluster typing to enhance characterization of a densely sampled statewide epidemic towards informing public health. METHODS: We identified HIV clusters, categorized them into types, and evaluated their dynamics between 2004 and 2019 in Rhode Island. We grouped sequences by diagnosis year, assessed cluster changes between paired phylogenies, t0 and t1, representing adjacent years and categorized clusters as stable (cluster in t0 phylogeny = cluster in t1 phylogeny) or unstable (cluster in t0 ≠ cluster in t1). Unstable clusters were further categorized as emerging (t1 phylogeny only) or growing (larger in t1 phylogeny). We determined proportions of each cluster type, of individuals in each cluster type, and of newly diagnosed individuals in each cluster type, and assessed trends over time. RESULTS: A total of 1727 individuals with available HIV-1 subtype B pol sequences were diagnosed in Rhode Island by 2019. Over time, stable clusters and individuals in them dominated the epidemic, increasing over time, with reciprocally decreasing unstable clusters and individuals in them. Conversely, proportions of newly diagnosed individuals in unstable clusters significantly increased. Within unstable clusters, proportions of emerging clusters and of individuals in them declined; whereas proportions of newly diagnosed individuals in growing clusters significantly increased over time. CONCLUSION: Distinct molecular cluster types were identified in the Rhode Island epidemic. Cluster dynamics demonstrated increasing stable and decreasing unstable clusters driven by growing, rather than emerging clusters, suggesting consistent in-state transmission networks. Cluster typing could inform public health beyond conventional approaches and direct interventions.

Seroprevalence of SARS-CoV-2 Antibodies in Rhode Island From a Statewide Random Sample.

Objectives. To characterize statewide seroprevalence and point prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Rhode Island.Methods. We conducted a cross-sectional survey of randomly selected households across Rhode Island in May 2020. Antibody-based and polymerase chain reaction (PCR)-based tests for SARS-CoV-2 were offered. Hispanics/Latinos and African Americans/Blacks were oversampled to ensure adequate representation. Seroprevalence estimations accounted for test sensitivity and specificity and were compared according to age, race/ethnicity, gender, housing environment, and transportation mode.Results. Overall, 1043 individuals from 554 households were tested (1032 antibody tests, 988 PCR tests). The estimated seroprevalence of SARS-CoV-2 antibodies was 2.1% (95% credible interval [CI] = 0.6, 4.1). Seroprevalence was 7.5% (95% CI = 1.3, 17.5) among Hispanics/Latinos, 3.8% (95% CI = 0.0, 15.0) among African Americans/Blacks, and 0.8% (95% CI = 0.0, 2.4) among non-Hispanic Whites. Overall PCR-based prevalence was 1.5% (95% CI = 0.5, 3.1).Conclusions. Rhode Island had low seroprevalence relative to other settings, but seroprevalence was substantially higher among African Americans/Blacks and Hispanics/Latinos. Rhode Island sits along the highly populated northeast corridor, making our findings broadly relevant to this region of the country. Continued monitoring via population-based sampling is needed to quantify these impacts going forward.

Empirical comparison of analytical approaches for identifying molecular HIV-1 clusters.

Public health interventions guided by clustering of HIV-1 molecular sequences may be impacted by choices of analytical approaches. We identified commonly-used clustering analytical approaches, applied them to 1886 HIV-1 Rhode Island sequences from 2004-2018, and compared concordance in identifying molecular HIV-1 clusters within and between approaches. We used strict (topological support ≥ 0.95; distance 0.015 substitutions/site) and relaxed (topological support 0.80-0.95; distance 0.030-0.045 substitutions/site) thresholds to reflect different epidemiological scenarios. We found that clustering differed by method and threshold and depended more on distance than topological support thresholds. Clustering concordance analyses demonstrated some differences across analytical approaches, with RAxML having the highest (91%) mean summary percent concordance when strict thresholds were applied, and three (RAxML-, FastTree regular bootstrap- and IQ-Tree regular bootstrap-based) analytical approaches having the highest (86%) mean summary percent concordance when relaxed thresholds were applied. We conclude that different analytical approaches can yield diverse HIV-1 clustering outcomes and may need to be differentially used in diverse public health scenarios. Recognizing the variability and limitations of commonly-used methods in cluster identification is important for guiding clustering-triggered interventions to disrupt new transmissions and end the HIV epidemic.

Adolescent with COVID-19 as the Source of an Outbreak at a 3-Week Family Gathering - Four States, June-July 2020.

There is increasing evidence that children and adolescents can efficiently transmit SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1-3). During July-August 2020, four state health departments and CDC investigated a COVID-19 outbreak that occurred during a 3-week family gathering of five households in which an adolescent aged 13 years was the index and suspected primary patient; 11 subsequent cases occurred.

Limited Secondary Transmission of SARS-CoV-2 in Child Care Programs - Rhode Island, June 1-July 31, 2020.

On June 1, 2020, with declines in coronavirus disease 2019 (COVID-19) cases and hospitalizations in Rhode Island,* child care programs in the state reopened after a nearly 3-month closure implemented as part of mitigation efforts. To reopen safely, the Rhode Island Department of Human Services (RIDHS) required licensed center- and home-based child care programs to reduce enrollment, initially to a maximum of 12 persons, including staff members, in stable groups (i.e., staff members and students not switching between groups) in physically separated spaces, increasing to a maximum of 20 persons on June 29. Additional requirements included universal use of masks for adults, daily symptom screening of adults and children, and enhanced cleaning and disinfection according to CDC guidelines.† As of July 31, 666 of 891 (75%) programs were approved to reopen, with capacity for 18,945 children, representing 74% of the state's January 2020 child care program population (25,749 children).

Post-exposure rabies prophylaxis for mass bat exposures: Case series and systematic review.

To assess and describe the use of rabies post-exposure prophylaxis (PEP) related to mass bat exposures (MBEs) in the literature and in the state of Rhode Island. Data on MBE events occurring between 2010 and 2016 from the Rhode Island Department of Health (RIDOH) were reviewed to determine PEP usage. For comparison, a systematic review was also performed by searching PubMed, EMBASE, Cochrane Library and Web of Science using the keywords 'rabies,' 'bat' and 'exposure.' There were three MBE events in Rhode Island between 2010 and 2016 in which groups of individuals were asleep during the potential exposure. As a result, RIDOH provided PEP to those involved in the event. In a systematic review of 12 published reports, a variety of settings were involved in MBEs: camping sites, a domestic flight, a neonatal intensive care unit and dormitories. The number of potential rabies exposures ranged from five to 1,429 people. PEP recommendations for assessed persons ranged from 0% to 100% across events (median 21%). The variation in PEP recommendations following a MBE may be dependent on medical need, past precedent or preference. Federal guidance for MBE is needed to add clarity and to minimize the variability in PEP recommendations for such events in the future.

Challenges in evaluating the use of viral sequence data to identify HIV transmission networks for public health.

Great efforts are devoted to end the HIV epidemic as it continues to have profound public health consequences in the United States and throughout the world, and new interventions and strategies are continuously needed. The use of HIV sequence data to infer transmission networks holds much promise to direct public heath interventions where they are most needed. As these new methods are being implemented, evaluating their benefits is essential. In this paper, we recognize challenges associated with such evaluation, and make the case that overcoming these challenges is key to the use of HIV sequence data in routine public health actions to disrupt HIV transmission networks.

Overview of Antimicrobial Stewardship Activities in Rhode Island.

Due to the rise of antibiotic resistance, and the decrease of novel antibiotics coming to market, the Centers for Disease Control and Prevention (CDC) has formally recognized that action must take place to ensure appropriate antibiotic use, and maintain public health. The RI Department of Health (RIDOH) Director responded by initiating the RI Antimicrobial Stewardship and Environmental Cleaning Task Force (RIAMSEC), a multidisciplinary team that set in motion a set of tasks for RIDOH. As a result, a survey of antibiotic stewardship programs (ASP) at the RI acute care hospitals (ACHs) and long-term care (LTC) facilities revealed gaps in addressing HAI prevention and AMS goals for the state. RIDOH has therefore expanded statewide coordination efforts to form the RI Healthcare-Associated Infection Prevention and Antimicrobial Stewardship Coalition which is intended to effectively prevent HAI and ultimate improve the Centers for Medicare and Medicaid Services Hospital-acquired Condition (HAC) Reduction scores in Rhode Island.[Full article available at http://rimed.org/rimedicaljournal-2018-06.asp].

Meningococcal carriage among a university student population - United States, 2015.

OBJECTIVES: Several outbreaks of serogroup B meningococcal disease have occurred among university students in recent years. In the setting of high coverage of the quadrivalent meningococcal conjugate vaccine and prior to widespread use of serogroup B meningococcal vaccines among adolescents, we conducted surveys to characterize the prevalence and molecular characteristics of meningococcal carriage among university students. METHODS: Two cross-sectional oropharyngeal carriage surveys were conducted among undergraduates at a Rhode Island university. Isolates were characterized using slide agglutination, real-time polymerase chain reaction (rt-PCR), and whole genome sequencing. Adjusted prevalence ratios and 95% confidence intervals were calculated using Poisson regression to determine risk factors for carriage. RESULTS: A total of 1837 oropharyngeal specimens were obtained from 1478 unique participants. Overall carriage prevalence was 12.7-14.6% during the two survey rounds, with 1.8-2.6% for capsular genotype B, 0.9-1.0% for capsular genotypes C, W, or Y, and 9.9-10.8% for nongroupable strains by rt-PCR. Meningococcal carriage was associated with being male, smoking, party or club attendance, recent antibiotic use (inverse correlation), and recent respiratory infections. CONCLUSIONS: In this university setting, the majority of meningococcal carriage was due to nongroupable strains, followed by serogroup B. Further evaluation is needed to understand the dynamics of serogroup B carriage and disease among university students.