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In recent years, phylogenetic analysis of HIV sequence data has been used in research studies to investigate transmission patterns between individuals and groups, including analysis of data from HIV prevention clinical trials, in molecular epidemiology, and in public health surveillance programs. Phylogenetic analysis can provide valuable information to inform HIV prevention efforts, but it also has risks, including stigma and marginalization of groups, or potential identification of HIV transmission between individuals. In response to these concerns, an interdisciplinary working group was assembled to address ethical challenges in US-based HIV phylogenetic research. The working group developed recommendations regarding (1) study design; (2) data security, access, and sharing; (3) legal issues; (4) community engagement; and (5) communication and dissemination. The working group also identified areas for future research and scholarship to promote ethical conduct of HIV phylogenetic research. [ABSTRACT FROM AUTHOR]

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. Here, the authors use a molecular epidemiological approach to investigate the frequency and intensity of clustering of HIV with different set-point viral loads and find that frequently transmitted strains in genetic transmission clusters have significantly higher viral loads than nonclustered viruses. [ABSTRACT FROM AUTHOR]

Effective population screening of HIV and prevention of HIV transmission are only part of the global fight against AIDS. Community-level effects, for example those aimed at thwarting future transmission, are potential outcomes of treatment and may be important in stemming the epidemic. However, current clinical trial designs are incapable of detecting a reduction in future transmission due to treatment. We took advantage of the fact that HIV is an evolving pathogen whose transmission network can be reconstructed using genetic sequence information to address this shortcoming. Here, we use an HIV transmission network inferred from recently infected men who have sex with men (MSM) in San Diego, California. We developed and tested a network-based statistic for measuring treatment effects using simulated clinical trials on our inferred transmission network. We explored the statistical power of this network-based statistic against conventional efficacy measures and find that when future transmission is reduced, the potential for increased statistical power can be realized. Furthermore, our simulations demonstrate that the network statistic is able to detect community-level effects (e.g., reduction in onward transmission) of HIV treatment in a clinical trial setting. This study demonstrates the potential utility of a network-based statistical metric when investigating HIV treatment options as a method to reduce onward transmission in a clinical trial setting. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the analysis was to explore HIV-1 subtype diversity in the United States and understand differences in prevalence of non-B subtypes and circulating recombinant forms (CRFs) between demographic/risk groups and over time.Methods: We included HIV-1 polymerase sequences reported to the National HIV Surveillance System for HIV infections diagnosed during 2006-2013 in seven states. We assigned subtype or CRF using the automated subtyping tool COMET, assessed subtype/CRF prevalence by demographic characteristics and country of birth, and determined changes in subtype/CRF by HIV diagnosis year.Results: Of 32,968 sequences, 30,757 (93.3%) were subtype B. The most common non-B subtypes and CRFs were C (1.6%), CRF02_AG (1.4%), A (0.6%), CRF01_AE (0.5%), and G (0.3%). Elevated percentages of non-B infections occurred among persons aged <13 years at diagnosis (40.9%), Asians (32.1%), persons born outside the United States (22.6%), and persons with infection attributable to heterosexual contact (12.0%-15.0%). Prevalence of non-B infections increased from 5.9% in 2006 to 8.5% in 2013.Conclusions: Subtype B continues to predominate in the United States. However, the percentage of non-B infections has grown in recent years, and numerous demographic subgroups have much higher prevalence. Subgroups and areas with high prevalence of non-B infections might represent sub-epidemics meriting further investigation. [ABSTRACT FROM AUTHOR]

Background: HIV intervention activities directed toward both those most likely to transmit and their HIV-negative partners have the potential to substantially disrupt HIV transmission. Using HIV sequence data to construct molecular transmission clusters can reveal individuals whose viruses are connected. The utility of various cluster prioritization schemes measuring cluster growth have been demonstrated using surveillance data in New York City and across the United States, by the Centers for Disease Control and Prevention (CDC)., Methods: We examined clustering and cluster growth prioritization schemes using Illinois HIV sequence data that include cases from Chicago, a large urban center with high HIV prevalence, to compare their ability to predict future cluster growth., Results: We found that past cluster growth was a far better predictor of future cluster growth than cluster membership alone but found no substantive difference between the schemes used by CDC and the relative cluster growth scheme previously used in New York City (NYC). Focusing on individuals selected simultaneously by both the CDC and the NYC schemes did not provide additional improvements., Conclusion: Growth-based prioritization schemes can easily be automated in HIV surveillance tools and can be used by health departments to identify and respond to clusters where HIV transmission may be actively occurring., Competing Interests: J.O.W. received funding from Gilead Sciences, LLC, as a grant paid to his institution. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

An important component underlying the disparity in HIV risk between race/ethnic groups is the preferential transmission between individuals in the same group. We sought to quantify transmission between different race/ethnicity groups and measure racial assortativity in HIV transmission networks in major metropolitan areas in the United States. We reconstructed HIV molecular transmission networks from viral sequences collected as part of HIV surveillance in New York City, Los Angeles County, and Cook County, Illinois. We calculated assortativity (the tendency for individuals to link to others with similar characteristics) across the network for three candidate characteristics: transmission risk, age at diagnosis, and race/ethnicity. We then compared assortativity between race/ethnicity groups. Finally, for each race/ethnicity pair, we performed network permutations to test whether the number of links observed differed from that expected if individuals were sorting at random. Transmission networks in all three jurisdictions were more assortative by race/ethnicity than by transmission risk or age at diagnosis. Despite the different race/ethnicity proportions in each metropolitan area and lower proportions of clustering among African Americans than other race/ethnicities, African Americans were the group most likely to have transmission partners of the same race/ethnicity. This high level of assortativity should be considered in the design of HIV intervention and prevention strategies.

Molecular epidemiology (ME) is one tool used to end the HIV epidemic in the United States. We combined clinical and behavioral data with HIV sequence data to identify any overlap in clusters generated from different sequence datasets; to characterize HIV transmission clusters; and to identify correlates of clustering among people living with HIV (PLWH) in Washington, District of Columbia (DC). First, Sanger sequences from DC Cohort participants, a longitudinal HIV study, were combined with next-generation sequences (NGS) from participants in a ME substudy to identify clusters. Next, demographic and self-reported behavioral data from ME substudy participants were used to identify risks of secondary transmission. Finally, we combined NGS from ME substudy participants with Sanger sequences in the DC Molecular HIV Surveillance database to identify clusters. Cluster analyses used HIV-Transmission Cluster Engine to identify linked pairs of sequences (defined as distance ≤1.5%). Twenty-eight clusters of ≥3 sequences (size range: 3-12) representing 108 (3%) participants were identified. None of the five largest clusters (size range: 5-12) included newly diagnosed PLWH. Thirty-four percent of ME substudy participants ( n  = 213) reported condomless sex during their last sexual encounter and 14% reported a Syphilis diagnosis in the past year. Seven transmission clusters (size range: 2-19) were identified in the final analysis, each containing at least one ME substudy participant. Substudy participants in clusters from the third analysis were present in clusters from the first analysis. Combining HIV sequence, clinical and behavioral data provided insights into HIV transmission that may not be identified using traditional epidemiological methods alone. Specifically, the sexual risk behaviors and STI diagnoses reported in the substudy survey may not have been disclosed during Partner Services activities and the survey data complemented clinical data to fully characterize transmission clusters. These findings can be used to enhance local efforts to interrupt transmission and avert new infections.

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.

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.

Transgender people continue to be at high-risk for HIV acquisition, but little is known about the characteristics of their sexual partners. To address this gap, we examined sociodemographic and sexual characteristics of cisgender men who have sex with men (MSM) on pre-exposure prophylaxis (PrEP) reporting transgender sexual partners.A cohort of 392 MSM in southern California in a randomized clinical trial for PrEP adherence were followed from 2013 to 2016. Multivariable generalized estimating equation and logistic models identified characteristics of MSM reporting transgender sexual partners and PrEP adherence.Only 14 (4%) MSM reported having transgender sexual partners. MSM were more likely to report transgender partners if they were African American, had incident chlamydia, reported injection drug-using sexual partners, or received items for sex. Most associations remained significant in the multivariable model: African American (adjusted odds ratio [AOR] 11.20, P = .01), incident chlamydia (AOR 3.71, P = .04), and receiving items for sex (AOR 5.29, P = .04). There were no significant differences in PrEP adherence between MSM reporting transgender partners and their counterpart.MSM who report transgender sexual partners share characteristics associated with individuals with high HIV prevalence. Identifying this group distinct from larger cohorts of MSM could offer new HIV prevention opportunities for this group of MSM and the transgender community.

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.

Background: Studying HIV transmission networks provides insight into the spread of HIV and opportunities for intervention. We identified transmission dynamics among risk groups and racial/ethnic groups in the United States., Methods: For HIV-1 pol sequences reported to the US National HIV Surveillance System during 2001-2012, we calculated pairwise genetic distance, identified linked pairs of sequences (those with distance ≤1.5%), and examined transmission category and race/ethnicity of these potential transmission partners., Results: Of 40,950 sequences, 12,910 (32%) were linked to ≥1 other sequence. Of men who have sex with men (MSM) who were linked to ≥1 sequence, 88% were linked to other MSM and only 4% were linked to heterosexual women. Of heterosexual women for whom we identified potential transmission partners, 29% were linked to MSM, 21% to heterosexual men, and 12% to persons who inject drugs. Older and black MSM were more likely to be linked to heterosexual women. Assortative mixing was present for all racial/ethnic groups; 81% of blacks/African Americans linked to other blacks., Conclusions: This analysis is the first use of US surveillance data to infer an HIV transmission network. Our data suggest that HIV infections among heterosexual women predominantly originate from MSM, followed by heterosexual men. Although few MSM were linked to women, suggesting that a minority of MSM are involved in transmission with heterosexual women, these transmissions represent a substantial proportion of HIV acquisitions by heterosexual women. Interventions that reduce transmissions involving MSM are likely to also reduce HIV acquisition among other risk groups.

Objective: The objective of this study is to understand the spread of HIV among and between age and racial/ethnic groups of men who engage in male-to-male sexual contact (MSM) in the United States., Design: An analysis of HIV-1 pol sequences for MSM collected through the US National HIV Surveillance System (NHSS) during 2001-2012., Methods: Pairwise genetic distance was calculated to determine potential transmission partners (those with very closely related nucleotide sequences, i.e. distance ≤1.5%). We described race/ethnicity and age of potential transmission partners of MSM., Results: Of 23 048 MSM with HIV sequences submitted to NHSS during 2000-2012, we identified potential transmission partners for 8880 (39%). Most potential transmission partners were of the same race/ethnicity (78% for blacks/African-Americans, 64% for whites and 49% for Hispanics/Latinos). This assortative mixing was even more pronounced in the youngest age groups. Significantly fewer young black/African-American and Hispanic/Latino MSM had older potential transmission partners than young white MSM., Conclusion: Black/African-American MSM, who are more profoundly affected by HIV, were more likely to have potential HIV transmission partners who were of the same race/ethnicity and similar in age, suggesting that disparities in HIV infections are in large part not due to age-disassortative relationships. Concerted efforts to increase access to preexposure prophylaxis, quality HIV care and effective treatment are needed to interrupt transmission chains among young, black/African-American MSM.