High HIV diversity, recombination, and superinfection revealed in a large outbreak among persons who inject drugs in Kentucky and Ohio, USA.

We investigated transmission dynamics of a large human immunodeficiency virus (HIV) outbreak among persons who inject drugs (PWID) in KY and OH during 2017-20 by using detailed phylogenetic, network, recombination, and cluster dating analyses. Using polymerase (pol) sequences from 193 people associated with the investigation, we document high HIV-1 diversity, including Subtype B (44.6 per cent); numerous circulating recombinant forms (CRFs) including CRF02_AG (2.5 per cent) and CRF02_AG-like (21.8 per cent); and many unique recombinant forms composed of CRFs with major subtypes and sub-subtypes [CRF02_AG/B (24.3 per cent), B/CRF02_AG/B (0.5 per cent), and A6/D/B (6.4 per cent)]. Cluster analysis of sequences using a 1.5 per cent genetic distance identified thirteen clusters, including a seventy-five-member cluster composed of CRF02_AG-like and CRF02_AG/B, an eighteen-member CRF02_AG/B cluster, Subtype B clusters of sizes ranging from two to twenty-three, and a nine-member A6/D and A6/D/B cluster. Recombination and phylogenetic analyses identified CRF02_AG/B variants with ten unique breakpoints likely originating from Subtype B and CRF02_AG-like viruses in the largest clusters. The addition of contact tracing results from OH to the genetic networks identified linkage between persons with Subtype B, CRF02_AG, and CRF02_AG/B sequences in the clusters supporting de novo recombinant generation. Superinfection prevalence was 13.3 per cent (8/60) in persons with multiple specimens and included infection with B and CRF02_AG; B and CRF02_AG/B; or B and A6/D/B. In addition to the presence of multiple, distinct molecular clusters associated with this outbreak, cluster dating inferred transmission associated with the largest molecular cluster occurred as early as 2006, with high transmission rates during 2017-8 in certain other molecular clusters. This outbreak among PWID in KY and OH was likely driven by rapid transmission of multiple HIV-1 variants including de novo viral recombinants from circulating viruses within the community. Our findings documenting the high HIV-1 transmission rate and clustering through partner services and molecular clusters emphasize the importance of leveraging multiple different data sources and analyses, including those from disease intervention specialist investigations, to better understand outbreak dynamics and interrupt HIV spread.

Simulation of Full HIV Cluster Networks in a Nationally Representative Model Indicates Intervention Opportunities.

BACKGROUND: Clusters of rapid HIV transmission in the United States are increasingly recognized through analysis of HIV molecular sequence data reported to the National HIV Surveillance System. Understanding the full extent of cluster networks is important to assess intervention opportunities. However, full cluster networks include undiagnosed and other infections that cannot be systematically observed in real life. METHODS: We replicated HIV molecular cluster networks during 2015-2017 in the United States using a stochastic dynamic network simulation model of sexual transmission of HIV. Clusters were defined at the 0.5% genetic distance threshold. Ongoing priority clusters had growth of ≥3 diagnoses/year in multiple years; new priority clusters first had ≥3 diagnoses/year in 2017. We assessed the full extent, composition, and transmission rates of new and ongoing priority clusters. RESULTS: Full clusters were 3-9 times larger than detected clusters, with median detected cluster sizes in new and ongoing priority clusters of 4 (range 3-9) and 11 (range 3-33), respectively, corresponding to full cluster sizes with a median of 14 (3-74) and 94 (7-318), respectively. A median of 36.3% (range 11.1%-72.6%) of infections in the full new priority clusters were undiagnosed. HIV transmission rates in these clusters were >4 times the overall rate observed in the entire simulation. CONCLUSIONS: Priority clusters reflect networks with rapid HIV transmission. The substantially larger full extent of these clusters, high proportion of undiagnosed infections, and high transmission rates indicate opportunities for public health intervention and impact.

Clusters of Rapid HIV Transmission Among Gay, Bisexual, and Other Men Who Have Sex with Men - United States, 2018-2021.

Gay, bisexual, and other men who have sex with men (MSM) accounted for 68% of new HIV diagnoses in the United States in 2020* (1). Despite advances in treatment and prevention, HIV transmission among MSM continues, in part because of stigma and barriers to accessing prevention and treatment services (2). HIV cluster detection and response, a core strategy of the Ending the HIV Epidemic in the United States initiative,† is an important tool for early identification and response to rapid HIV transmission, including among MSM. To better understand rapid HIV transmission among this population, CDC characterized large HIV molecular clusters detected using analysis of HIV-1 nucleotide sequence data from the National HIV Surveillance System (NHSS).§ Among 38 such clusters first detected during 2018-2019 that had grown to include more than 25 persons by December 2021, 29 occurred primarily among MSM. Clusters primarily among MSM occurred in all geographic regions, and 97% involved multiple states. Clusters were heterogeneous in age, gender identity, and race and ethnicity and had rapid growth rates (median = nine persons added per year). The overall transmission rate at cluster detection was 22 transmission events per 100 person-years, more than six times that of previously estimated national transmission rates (3). Most clusters of rapid HIV transmission occur among MSM. Swift response to reach diverse persons and communities with early, tailored, and focused interventions is essential to reducing HIV transmission (4).

Assessing concordance of HIV risk behaviors collected by different surveillance systems.

OBJECTIVES: Assess concordance of assigned transmission category between National HIV Surveillance System (NHSS) and Medical Monitoring Project (MMP); assess persistence of behaviors by comparing transmission category to current behavior. DESIGN: Retrospective analysis of HIV surveillance data. METHODS: For 4034 participants in the 2016 MMP cycle, transmission category was assigned in NHSS and MMP by applying a hierarchy to acquisition risk behaviors and selecting the most likely risk behavior that led to HIV acquisition. We assessed concordance of transmission category between systems, the number of persons with an updated transmission category in NHSS after incorporating MMP data, and concordance of transmission category and current behavior. RESULTS: Concordance of transmission category between NHSS and MMP was 87% for men with evidence of male-to-male sexual contact and ranged from 27% to 62% in persons with other transmission categories. Transmission category in NHSS was updated for 9% of persons after incorporating MMP data, mostly affecting those with no identified risk in NHSS. Current behavior aligned with updated NHSS transmission category in 56% of men with a transmission category of male-to-male sexual contact. However, only 8% of men and 5% of women with a transmission category of injection drug use had recently injected drugs. CONCLUSION: HIV surveillance systems can better inform prevention efforts with more complete risk information. Sexual behaviors are more persistent over time than injection drug use. In addition to promoting viral suppression, routinely assessing risk and tailoring prevention activities accordingly can improve health outcomes.

HIV Cluster and Outbreak Detection and Response: The Science and Experience.

The Respond pillar of the Ending the HIV Epidemic in the U.S. initiative, which consists of activities also known as cluster and outbreak detection and response, offers a framework to guide tailored implementation of proven HIV prevention strategies where transmission is occurring most rapidly. Cluster and outbreak response involves understanding the networks in which rapid transmission is occurring; linking people in the network to essential services; and identifying and addressing gaps in programs and services such as testing, HIV and other medical care, pre-exposure prophylaxis, and syringe services programs. This article reviews the experience gained through 30 HIV cluster and outbreak responses in North America during 2000-2020 to describe approaches for implementing these core response strategies. Numerous jurisdictions that have implemented these response strategies have demonstrated success in improving outcomes related to HIV care and viral suppression, testing, use of prevention services, and reductions in transmission or new diagnoses. Efforts to address important gaps in service delivery revealed by cluster and outbreak detection and response can strengthen prevention efforts broadly through multidisciplinary, multisector collaboration. In this way, the Respond pillar embodies the collaborative, data-guided approach that is critical to the overall success of the Ending the HIV Epidemic in the U.S. initiative.

Response to a Large HIV Outbreak, Cabell County, West Virginia, 2018-2019.

INTRODUCTION: In January 2019, the West Virginia Bureau for Public Health detected increased HIV diagnoses among people who inject drugs in Cabell County. Responding to HIV clusters and outbreaks is 1 of the 4 pillars of the Ending the HIV Epidemic in the U.S. initiative and requires activities from the Diagnose, Treat, and Prevent pillars. This article describes the design and implementation of a comprehensive response, featuring interventions from all pillars. METHODS: This study used West Virginia Bureau for Public Health data to identify HIV diagnoses during January 1, 2018-October 9, 2019 among (1) people who inject drugs linked to Cabell County, (2) their sex or injecting partners, or (3) others with an HIV sequence linked to Cabell County people who inject drugs. Surveillance data, including HIV-1 polymerase sequences, were analyzed to estimate the transmission rate and timing of infections using molecular clock phylogenetic analysis. Federal, state, and local partners designed and implemented a comprehensive response during January 2019-October 2019. RESULTS: Of 82 people identified in the outbreak, most were male (60%), were White (91%), and reported unstable housing (80%). In a large molecular cluster containing 56 of 60 (93%) available sequences, 93% of inferred transmissions occurred after January 1, 2018. HIV testing, HIV pre-exposure prophylaxis, and syringe services were rapidly expanded, leading to improved linkage to HIV care and viral suppression. CONCLUSIONS: Evidence of rapid transmission in this outbreak galvanized robust collaboration among federal, state, and local partners, leading to critical improvements in HIV prevention and care services. HIV outbreak response requires increased coordination and creativity to improve service delivery to people affected by rapid HIV transmission.

Increasing Capacity to Detect Clusters of Rapid HIV Transmission in Varied Populations-United States.

Molecular cluster detection analyzes HIV sequences to identify rapid HIV transmission and inform public health responses. We describe changes in the capability to detect molecular clusters and in geographic variation in transmission dynamics. We examined the reporting completeness of HIV-1 polymerase sequences in quarterly National HIV Surveillance System datasets from December 2015 to December 2019. Priority clusters were identified quarterly. To understand populations recently affected by rapid transmission, we described the transmission risk and race/ethnicity of people in clusters first detected in 2018-2019. During December 2015 to December 2019, national sequence completeness increased from 26% to 45%. Of the 1212 people in the 136 clusters first detected in 2018-2019, 69% were men who have sex with men (MSM) and 11% were people who inject drugs (PWID). State-by-state analysis showed substantial variation in transmission risk and racial/ethnic groups in clusters of rapid transmission. HIV sequence reporting has increased nationwide. Molecular cluster analysis identifies rapid transmission in varied populations and identifies emerging patterns of rapid transmission in specific population groups, such as PWID, who, in 2015-2016, comprised only 1% of people in such molecular clusters. These data can guide efforts to focus, tailor, and scale up prevention and care services for these populations.

Human Immunodeficiency Virus (HIV) Outbreak Investigation Among Persons Who Inject Drugs in Massachusetts Enhanced by HIV Sequence Data.

BACKGROUND: The Massachusetts Department of Public Health and the Centers for Disease Control and Prevention collaborated to characterize a human immunodeficiency virus (HIV) outbreak in northeastern Massachusetts and prevent further transmission. We determined the contributions of HIV sequence data to defining the outbreak. METHODS: Human immunodeficiency virus surveillance and partner services data were analyzed to understand social and molecular links within the outbreak. Cases were defined as HIV infections diagnosed during 2015-2018 among people who inject drugs with connections to northeastern Massachusetts or HIV infections among other persons named as partners of a case or whose HIV polymerase sequence linked to another case, regardless of diagnosis date or geography. RESULTS: Of 184 cases, 65 (35%) were first identified as part of the outbreak through molecular analysis. Twenty-nine cases outside of northeastern Massachusetts were molecularly linked to the outbreak. Large molecular clusters (75, 28, and 11 persons) were identified. Among 161 named partners, 106 had HIV; of those, 40 (38%) diagnoses occurred through partner services. CONCLUSIONS: Human immunodeficiency virus sequence data increased the case count by 55% and expanded the geographic scope of the outbreak. Human immunodeficiency virus sequence and partner services data each identified cases that the other method would not have, maximizing prevention and care opportunities for HIV-infected persons and their partners.

Incident infection in high-priority HIV molecular transmission clusters in the United States.

OBJECTIVE: To identify correlates of incident HIV infection in rapidly growing HIV molecular clusters. DESIGN: Phylogenetic analysis of HIV public health surveillance data. METHODS: High-priority HIV genetic transmission clusters with evidence of rapid growth in 2012 (i.e. clusters with a pairwise genetic distance ≤0.005 substitutions/site and at least three cases diagnosed in 2012) were identified using HIV-TRACE. Then, we investigated cluster growth, defined as HIV cases diagnosed in the following 5 years that were genetically linked to these clusters. For clusters that grew during the follow-up period, Bayesian molecular clock phylogenetic inference was performed to identify clusters with evidence of incident HIV infection (as opposed to diagnosis of previously infected cases) during this follow-up period. RESULTS: Of the 116 rapidly growing clusters identified, 73 (63%) had phylogenetic evidence for an incident HIV case during the 5-year follow-up period. Correlates of an incident HIV case arising in clusters included a greater number of diagnosed but virally unsuppressed cases in 2012, a greater number of inferred undiagnosed cases in the cluster in 2012, and a younger time of most recent common ancestor for the cluster. CONCLUSION: These findings suggest that incident infections in rapidly growing clusters originate equally from diagnosed but unsuppressed cases and undiagnosed infections. These results highlight the importance of promoting retention in care and viral suppression as well as partner notification and other case-finding activities when investigating and intervening on high-priority molecular transmission clusters.

Brief Report: Temporal Changes in HIV Transmission Patterns Among Young Men Who Have Sex With Men, United States, 2009-2016.

BACKGROUND: In the United States, young men (aged 13-24 years) who have sex with men (MSM) bear a disproportionate burden of HIV. Transmission among MSM has been found to be disassortative by age. METHODS: We analyzed HIV-1 pol sequences reported to the US National HIV Surveillance System from MSM with HIV diagnosed during 2009-2016. Using an HIV genetic transmission network, we identified persons with closely related viruses (ie, genetic distance ≤1.5%) and used multivariable logistic regression to examine changes from 2009-2012 to 2013-2016 in proportions of MSM linked to young MSM who were >5 years older or of the same race/ethnicity. RESULTS: Among 9510 young MSM linked to another MSM with a closely related virus, 37% linked to an older MSM and 62% linked to an MSM of the same race/ethnicity. Comparing 2013-2016 with 2009-2012, we found increases in linkage of older MSM to young MSM, with the most substantial increases seen in Hispanic/Latinos aged 13-19 [adjusted prevalence ratio (APR) = 1.31, 95% confidence interval (CI) = 1.11 to 1.56] and blacks aged 13-19 (APR = 1.23, CI = 1.06 to 1.41) and 20-24 years (APR = 1.14, CI = 1.02 to 1.28). By contrast, change in linkage patterns among racial/ethnic groups was unremarkable. CONCLUSIONS: We found evidence of increased age mixing among MSM with respect to HIV transmission over time, which coincides temporally with changes in partner-seeking behavior such as increased use of mobile applications. These findings indicate the importance of social factors on HIV sexual and transmission networks and suggest that prevention efforts need to effectively reach MSM of all ages.

HIV Diagnoses and Viral Suppression Among US Women in Rural and Nonrural Areas, 2010-2017.

BACKGROUND: Women in rural areas face challenges to HIV diagnosis and care, including limited access to testing and treatment facilities. Recent declines in HIV diagnosis rates among women in the United States are encouraging. However, few studies have addressed how HIV diagnosis and care differ by rurality. METHODS: We analyzed National HIV Surveillance System data for women aged ≥13 years with diagnosed HIV infection. We examined diagnoses in the United States during 2010-2017. Then, for women living with diagnosed HIV in 40 jurisdictions with complete laboratory reporting, we assessed viral suppression (viral load <200 copies/mL). Analyses were stratified by rural-urban category: rural (population <50,000), metropolitan (population 50,000-499,000), and metropolitan statistical areas (MSA, population ≥500,000). RESULTS: Among 64,004 women who received a diagnosis of HIV infection during 2010-2017, 4.2% resided in a rural area, 15% resided in a metropolitan area, and 80% resided in an MSA. Rural women had the highest percentage of stage 3 infection (acquired immune deficiency syndrome) at diagnosis (rural 30%, metropolitan 27%, MSA 25%). Of 190,735 women living with diagnosed HIV, viral suppression was lower in rural areas (rural 55%, metropolitan 59%, MSA 58%). CONCLUSIONS: During 2010-2017, most HIV diagnoses occurred among women residing in nonrural areas. However, women in rural areas had slightly higher levels of late diagnosis and lower levels of viral suppression, which might have resulted from differences in access to testing and treatment services. Interventions are needed to increase HIV testing, care, and viral suppression among women in rural areas.

Opioid Use Fueling HIV Transmission in an Urban Setting: An Outbreak of HIV Infection Among People Who Inject Drugs-Massachusetts, 2015-2018.

Objectives. To describe and control an outbreak of HIV infection among people who inject drugs (PWID).Methods. The investigation included people diagnosed with HIV infection during 2015 to 2018 linked to 2 cities in northeastern Massachusetts epidemiologically or through molecular analysis. Field activities included qualitative interviews regarding service availability and HIV risk behaviors.Results. We identified 129 people meeting the case definition; 116 (90%) reported injection drug use. Molecular surveillance added 36 cases to the outbreak not otherwise linked. The 2 largest molecular groups contained 56 and 23 cases. Most interviewed PWID were homeless. Control measures, including enhanced field epidemiology, syringe services programming, and community outreach, resulted in a significant decline in new HIV diagnoses.Conclusions. We illustrate difficulties with identification and characterization of an outbreak of HIV infection among a population of PWID and the value of an intensive response.Public Health Implications. Responding to and preventing outbreaks requires ongoing surveillance, with timely detection of increases in HIV diagnoses, community partnerships, and coordinated services, all critical to achieving the goal of the national Ending the HIV Epidemic initiative.

Natural selection favoring more transmissible HIV detected in United States molecular transmission network.

HIV molecular epidemiology can identify clusters of individuals with elevated rates of HIV transmission. These variable transmission rates are primarily driven by host risk behavior; however, the effect of viral traits on variable transmission rates is poorly understood. Viral load, the concentration of HIV in blood, is a heritable viral trait that influences HIV infectiousness and disease progression. Here, we reconstruct HIV genetic transmission clusters using data from the United States National HIV Surveillance System and report that viruses in clusters, inferred to be frequently transmitted, have higher viral loads at diagnosis. Further, viral load is higher in people in larger clusters and with increased network connectivity, suggesting that HIV in the United States is experiencing natural selection to be more infectious and virulent. We also observe a concurrent increase in viral load at diagnosis over the last decade. This evolutionary trajectory may be slowed by prevention strategies prioritized toward rapidly growing transmission clusters.

Estimating Effects of HIV Sequencing Data Completeness on Transmission Network Patterns and Detection of Growing HIV Transmission Clusters.

HIV nucleotide sequence data can identify clusters of persons with genetically similar strains suggesting transmission. We simulated the effect of lowered data completeness, defined by the percent of persons with diagnosed HIV with a reported sequence, on transmission patterns and detection of growing HIV transmission clusters. We analyzed HIV surveillance data for persons with HIV diagnosed during 2008-2014 who resided in Michigan or Washington. We calculated genetic distances, constructed the inferred transmission network for each jurisdiction, and compared transmission network characteristics and detection of growing transmission clusters in the full dataset with artificially reduced datasets. Simulating lower levels of completeness resulted in decreased percentages of persons linked to a cluster from high completeness (full dataset) to low completeness (5%) (Michigan: 54%-18%; Washington, 46%-16%). Patterns of transmission between certain populations remained robust as data completeness level was reduced. As data completeness was artificially decreased, sensitivity of cluster detection substantially diminished in both states. In Michigan, sensitivity decreased from 100% with the full dataset, to 62% at 50% completeness and 21% at 25% completeness. In Washington, sensitivity decreased from 100% with the full dataset, to 71% at 50% completeness and 29% at 25% completeness. Lower sequence data completeness limits the ability to detect clusters that may benefit from investigation; however, inferences can be made about transmission patterns even with low data completeness, given sufficient numbers. Data completeness should be prioritized, as lack of or delays in detection of transmission clusters could result in additional infections.

Identifying Clusters of Recent and Rapid HIV Transmission Through Analysis of Molecular Surveillance Data.

BACKGROUND: Detecting recent and rapid spread of HIV can help prioritize prevention and early treatment for those at highest risk of transmission. HIV genetic sequence data can identify transmission clusters, but previous approaches have not distinguished clusters of recent, rapid transmission. We assessed an analytic approach to identify such clusters in the United States. METHODS: We analyzed 156,553 partial HIV-1 polymerase sequences reported to the National HIV Surveillance System and inferred transmission clusters using 2 genetic distance thresholds (0.5% and 1.5%) and 2 periods for diagnoses (all years and 2013-2015, ie, recent diagnoses). For rapidly growing clusters (with ≥5 diagnoses during 2015), molecular clock phylogenetic analysis estimated the time to most recent common ancestor for all divergence events within the cluster. Cluster transmission rates were estimated using these phylogenies. RESULTS: A distance threshold of 1.5% identified 103 rapidly growing clusters using all diagnoses and 73 using recent diagnoses; at 0.5%, 15 clusters were identified using all diagnoses and 13 using recent diagnoses. Molecular clock analysis estimated that the 13 clusters identified at 0.5% using recent diagnoses had been diversifying for a median of 4.7 years, compared with 6.5-13.2 years using other approaches. The 13 clusters at 0.5% had a transmission rate of 33/100 person-years, compared with previous national estimates of 4/100 person-years. CONCLUSIONS: Our approach identified clusters with transmission rates 8 times those of previous national estimates. This method can identify groups involved in rapid transmission and help programs effectively direct and prioritize limited public health resources.

Optimising diagnosis of viraemic hepatitis C infection: the development of a target product profile.

BACKGROUND: The current low access to virological testing to confirm chronic viraemic HCV infection in low- and middle-income countries (LMIC) is limiting the rollout of hepatitis C (HCV) care. Existing tests are complex, costly and require sophisticated laboratory infrastructure. Diagnostic manufacturers need guidance on the optimal characteristics a virological test needs to have to ensure the greatest impact on HCV diagnosis and treatment in LMIC. Our objective was to develop a target product profile (TPP) for diagnosis of HCV viraemia using a global stakeholder consensus-based approach. METHODS: Based on the standardised process established to develop consensus-based TPPs, we followed five key steps. (i) Identifying key potential global stakeholders for consultation and input into the TPP development process. (ii) Informal priority-setting exercise with key experts to identify the needs that should be the highest priority for the TPP development; (iii) Defining the key TPP domains (scope, performance and operational characteristics and price). (iv) Delphi-like process with larger group of key stakeholder to facilitate feedback on the key TPP criteria and consensus building based on pre-defined consensus criteria. (v) A final consensus-gathering meeting for discussions around disputed criteria. A complementary values and preferences survey helped to assess trade-offs between different key characteristics. RESULTS: The following key attributes for the TPP for a test to confirm HCV viraemic infection were identified: The scope defined is for both HCV detection as well as confirmation of cure. The timeline of development for tests envisioned in the TPP is 5 years. The test should be developed for use by health-care workers or laboratory technicians with limited training in countries with a medium to high prevalence of HCV (1.5-3.5% and >3.5%) and in high-risk populations in low prevalence settings (<1.5%). A clinical sensitivity at a minimum of 90% is considered sufficient (analytical sensitivity of the equivalent of 3000 IU/ml), particularly if the test increases access to testing through an affordable price, increase ease-of-use and feasibility on capillary blood. Polyvalency would be optimal (i.e. ability to test for HIV and others). The only characteristic that full agreement could not be achieved on was the price for a virological test. Discussants felt that to reach the optimal target price substantial trade-offs had to be made (e.g. in regards to sensitivity and integration). CONCLUSION: The TPP and V&P survey results define the need for an easy-to-use, low cost test to increase access to diagnosis and linkage to care in LMIC.

HIV and hepatitis C virus infection in the United States: whom and how to test.

In the United States, of the 1.1 million persons infected with human immunodeficiency virus (HIV) and the 2.7 million infected with hepatitis C virus (HCV), approximately 16% and 50%, respectively, are unaware of their infection. Highly effective treatments have turned both diseases into manageable conditions, and in the case of hepatitis C, a disease that can be cured. Early diagnosis is imperative so that infected persons can take measures to stay healthy, get into care, benefit from therapy, and reduce the risk of transmission. In this report, we review current recommendations provided by the Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force on whom to screen for HIV and HCV infections, and recommendations from the CDC, the Association of Public Health Laboratories, and the Clinical and Laboratory Standards Institute on how to test for these infections.