Inferring HIV transmission patterns from viral deep-sequence data via latent typed point processes.

Viral deep-sequencing data play a crucial role toward understanding disease transmission network flows, providing higher resolution compared to standard Sanger sequencing. To more fully utilize these rich data and account for the uncertainties in outcomes from phylogenetic analyses, we propose a spatial Poisson process model to uncover human immunodeficiency virus (HIV) transmission flow patterns at the population level. We represent pairings of individuals with viral sequence data as typed points, with coordinates representing covariates such as gender and age and point types representing the unobserved transmission statuses (linkage and direction). Points are associated with observed scores on the strength of evidence for each transmission status that are obtained through standard deep-sequence phylogenetic analysis. Our method is able to jointly infer the latent transmission statuses for all pairings and the transmission flow surface on the source-recipient covariate space. In contrast to existing methods, our framework does not require preclassification of the transmission statuses of data points, and instead learns them probabilistically through a fully Bayesian inference scheme. By directly modeling continuous spatial processes with smooth densities, our method enjoys significant computational advantages compared to previous methods that rely on discretization of the covariate space. We demonstrate that our framework can capture age structures in HIV transmission at high resolution, bringing valuable insights in a case study on viral deep-sequencing data from Southern Uganda.

Multiple Infection and Human Immunodeficiency Virus Superinfection Among Persons who Inject Drugs in Indonesia and Ukraine.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 074 study evaluated an integrated human immunodeficiency virus (HIV) treatment and prevention strategy among persons who inject drugs (PWID) in Indonesia, Ukraine, and Vietnam. We previously detected multiple HIV infection in 3 of 7 (43%) of seroconverters with 3-8 HIV strains per person. In this report, we analyzed multiple HIV infection and HIV superinfection (SI) in the HPTN 074 cohort. METHODS: We analyzed samples from 70 participants in Indonesia and Ukraine who had viral load >400 copies/mL at enrollment and the final study visit (median follow-up, 2.5 years). HIV was characterized with Sanger sequencing, next-generation sequencing, and phylogenetic analysis. Additional methods were used to characterize a rare case of triple-variant SI. RESULTS: At enrollment, multiple infection was detected in only 3 of 58 (5.2%) participants with env sequence data. SI was detected in only 1 of 70 participants over 172.3 person-years of follow-up (SI incidence, 0.58/100 person-years [95% confidence interval, .015-3.2]). The SI case involved acquisition of 3 HIV strains with rapid selection of a strain with a single pol region cluster. CONCLUSIONS: These data from a large cohort of PWID suggest that intrahost viral selection and other factors may lead to underestimation of the frequency of multiple HIV infection and SI events.

Incident HIV Infection Among Young Men Associated With Female Sexual Partner Types Identified Through Latent Class Analysis, Rakai, Uganda.

BACKGROUND: Sexual partner characteristics are important determinants of HIV acquisition, but little is known about partner types of young men in sub-Saharan Africa. METHODS: Sexually active men aged 15-24 years from 5 rounds (2005-2013) of the Rakai Community Cohort Study in Uganda reported characteristics of up to 4 past-year female partners. Partner types were identified using latent class analysis. HIV incidence rates (IRs) were calculated by partner-type combinations, and individual-level risk adjusted IR ratios (aIRRs) relative to the lowest incidence type were estimated using the Poisson regression with generalized estimating equations. RESULTS: Young men (N = 1771) reported 4539 past-year female sexual partners. Three partner types were identified: type A: noncohabiting, student, medium duration partnerships; type B: cohabiting, nonstudent, longer duration partnerships; and type C: noncohabiting, nonstudent shorter duration partnerships. Type C partners engaged in the most HIV-related risk behaviors. Many men (29%) had more than 1 partner type/round. IR overall was 9.8/1000 person-years [95% confidence interval (CI): 4.7 to 20.6]. IR was 4.0 (95% CI: 1.2 to 12.7) for men with type A partners alone (41% of men). Relative to them, IR for those with type B partners alone (25%) was not significantly different. Men with type C partners alone (5%) had higher risk (aIRR = 3.2; 95% CI: 1.0 to 9.9), as did men with >1 partner type, including men with both type A and type B partners (12%; aIRR = 6.3; 95% CI: 2.5 to 15.9) and men with type C and other partner types (17%; aIRR = 4.3; 95% CI: 1.7 to 10.8). CONCLUSIONS: Partner-type combination was strongly associated with HIV incidence; type C partners and having more than 1 partner type were the riskiest patterns.

Severe Acute Respiratory Syndrome Coronavirus-2 seroprevalence in South-Central Uganda, during 2019-2021.

BACKGROUND: Globally, key subpopulations such as healthcare workers (HCW) may have a higher risk of contracting SARS-CoV-2. In Uganda, limited access to Personal Protective Equipment and lack of clarity on the extent/pattern of community spread may exacerbate this situation. The country established infection prevention/control measures such as lockdowns and proper hand hygiene. However, due to resource limitations and fatigue, compliance is low, posing continued onward transmission risk. This study aimed to describe extent of SARS-CoV-2 seroprevalence in selected populations within the Rakai region of Uganda. METHODS: From 30th November 2020 to 8th January 2021, we collected venous blood from 753 HCW at twenty-six health facilities in South-Central Uganda and from 227 population-cohort participants who reported specific COVID-19 like symptoms (fever, cough, loss of taste and appetite) in a prior phone-based survey conducted (between May and August 2020) during the first national lockdown. 636 plasma specimens collected from individuals considered high risk for SARS-CoV-2 infection, prior to the first confirmed COVID-19 case in Uganda were also retrieved. Specimens were tested for antibodies to SARS-CoV-2 using the CoronaChek™ rapid COVID-19 IgM/IgG lateral flow test assay. IgM only positive samples were confirmed using a chemiluminescent microparticle immunoassay (CMIA) (Architect AdviseDx SARS-CoV-2 IgM) which targets the spike protein. SARS-CoV-2 exposure was defined as either confirmed IgM, both IgM and IgG or sole IgG positivity. Overall seroprevalence in each participant group was estimated, adjusting for test performance. RESULTS: The seroprevalence of antibodies to SARS-CoV-2 in HCW was 26.7% [95%CI: 23.5, 29.8] with no difference by sex, age, or cadre. We observed no association between PPE use and seropositivity among exposed healthcare workers. Of the phone-based survey participants, 15.6% [95%CI: 10.9, 20.3] had antibodies to SARS-CoV-2, with no difference by HIV status, sex, age, or occupation. Among 636 plasma specimens collected prior to the first confirmed COVID-19 case, 2.3% [95%CI: 1.2, 3.5] were reactive. CONCLUSIONS: Findings suggest high seroprevalence of antibodies to SARS-CoV-2 among HCW and substantial exposure in persons presenting with specific COVID-19 like symptoms in the general population of South-Central Uganda. Based on current limitations in serological test confirmation, it remains unclear whether seroprevalence among plasma specimens collected prior to confirmation of the first COVID-19 case implies prior SARS-CoV-2 exposure in Uganda.

HIV combination prevention and declining orphanhood among adolescents, Rakai, Uganda, 2001-18: an observational community cohort study.

BACKGROUND: Orphanhood increased markedly in the 1980s and 1990s in sub-Saharan Africa because of HIV-related mortality. Little is known about the contribution of HIV interventions, such as antiretroviral therapy (ART) and male medical circumcision, to more recent trends in orphanhood. In this study, we examined trends over time in maternal-only, paternal-only, and double orphanhood among adolescents before and after ART and male medical circumcision became widely available in the Rakai region of south-central Uganda. We sought to understand the association between adolescent orphanhood and HIV combination prevention (community-level ART use and prevalence of male medical circumcision). We hypothesised that increasing combination prevention, including greater use of ART and higher prevalence of male medical circumcision, would be associated with a lower probability of orphanhood. METHODS: We examined the prevalence of orphanhood among adolescents aged 15-19 years, before and after roll-out of ART in mid-2004 and male medical circumcision in 2007, using data from 28 continuously followed communities within the Rakai Community Cohort Study. We used multinomial logistic regression with clustered SEs to estimate adjusted relative risk ratios (RRs) for maternal-only, paternal-only, and double orphanhood compared with non-orphanhood over 11 survey rounds between 2001 and 2018. Controlling for community HIV prevalence, household socioeconomic status, and adolescent age, we examined the association between community prevalence of ART use among people living with HIV and prevalence of male circumcision, including traditional circumcision. The primary outcome was orphanhood among adolescents aged 15-19 years. FINDINGS: Orphanhood declined from 52% (920 of 1768 participants) in 2001-02 to 23% (592 of 2609 participants) by 2016-18 (p<0·0001), while double orphanhood declined from 20% (346 of 1768 participants) to 3% (86 of 2609 participants) (p<0·0001). Community prevalence of ART use among people living with HIV increased from 11% (105 of 945 participants) in 2005-06 to 78% (1163 of 1485 participants) in 2016-18. Male circumcision rates rose from 19% (147 of 790 participants) in 2005-06 to 65% (3535 of 5433 participants) in 2016-18. In the multinomial logistic regression model, a 10% increase in community prevalence of ART use was associated with a decrease in maternal orphanhood (adjusted relative RR 0·90, 95% CI 0·85-0·95) and double orphanhood (0·80, 0·75-0·85). In the post-ART era, a 10% increase in the community prevalence of male circumcision was associated with a decrease in paternal orphanhood (2005-18, adjusted relative RR 0·92, 0·87-0·97) and double orphanhood (0·91, 0·85-0·98). INTERPRETATION: Widespread availability and uptake of HIV combination prevention was associated with marked reductions in orphanhood among adolescents. Reductions in orphanhood promise improved health and social outcomes for young people. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, and the Division of Intramural Research of the National Institute for Allergy and Infectious Diseases.

Trends and Correlates of Age-Disparate Sexual Partnerships in the United States: The National Health and Nutrition Examination Surveys.

ABSTRACT: This national survey demonstrates age-disparate (≥5 years; AD-5) sexual partnerships remain common among males and females aged 20 to 29 years in the United States (2005-2016). Females reported more older AD-5 partners, and males reported more younger AD-5 partners. Having AD-5 partners was associated with greater lifetime and recent number of sexual partners.

Severe Acute Respiratory Syndrome Coronavirus-2 Seropositivity in South-Central Uganda, During 2019 - 2021.

Background: Globally, key subpopulations such as healthcare workers (HCWs) have a higher risk of contracting SARS-CoV-2. In Uganda, limited access to personal protective equipment amidst lack of clarity on the extent and pattern of the community disease burden may exacerbate this situation. We assessed SARS-CoV-2 antibody seroprevalence among high-risk sub-populations in South-central Uganda, including HCWs, persons within the general population previously reporting experiencing key COVID-19 like symptoms (fever, cough, loss of taste and smell) and archived plasma specimens collected between October 2019 â€" 18 th March 2020, prior to confirmation of COVID-19 in Uganda. Methods: From November 2020 - January 2021, we collected venous blood from HCWs at selected health facilities in South-Central Uganda and from population-cohort participants who reported specific COVID-19 like symptoms in a prior phone-based survey conducted (between May to August 2020) during the first national lockdown. Pre-lockdown plasma collected (between October 2019 and March 18 th , 2020) from individuals considered high risk for SARS-CoV-2 infection was retrieved. Specimens were tested for antibodies to SARS-CoV-2 using the CoronaChek TM rapid COVID-19 IgM/IgG lateral flow test assay. IgM only positive samples were confirmed using a chemiluminescent microparticle immunoassay (CMIA) (Architect AdviseDx SARS-CoV-2 IgM) which targets the spike protein. SARS-CoV-2 exposure was defined as either confirmed IgM, both IgM and IgG or sole IgG positivity. Results: The seroprevalence of antibodies to SARS-CoV-2 in HCWs was 21.1% [95%CI: 18.2-24.2]. Of the phone-based survey participants, 11.9% [95%CI: 8.0-16.8] had antibodies to SARS-CoV-2. Among 636 pre-lockdown plasma specimens, 1.7% [95%CI: 0.9-3.1] were reactive. Conclusions: Findings suggest a high seroprevalence of antibodies to SARS-CoV-2 among HCWs and substantial exposure in persons presenting with specific COVID-19 like symptoms in the general population of South-central Uganda. Based on current limitations in serological test confirmation, it remains unclear whether pre-lockdown seropositivity implies prior SARS-CoV-2 exposure in Uganda.

Transactional Sex, Alcohol Use and Intimate Partner Violence Against Women in the Rakai Region of Uganda.

Transactional sex (TS) is prevalent in sub-Saharan Africa. Women's engagement in TS is linked with HIV infection; little is known about the relationship between TS, intimate partner violence (IPV) and alcohol use-established HIV risk behaviors. Using modified Poisson regression, we assessed associations between TS and physical, verbal and sexual IPV among 8248 women (15-49 years) who participated in the Rakai Community Cohort Study across forty communities in Uganda. An interaction term assessed moderation between alcohol use and TS and no significant interaction effects were found. In adjusted analysis, alcohol use and TS were significantly associated with all forms of IPV. In stratified analysis, TS was only associated with IPV in agrarian communities; alcohol use was not associated with physical IPV in trade communities or sexual IPV in trade and fishing communities. Identifying differences in IPV risk factors by community type is critical for the development of tailored interventions.

RESUMEN: El sexo transaccional (ST) es frecuente en África subsahariana. La participación de las mujeres en el ST está relacionada con la infección por VIH; Se sabe poco sobre la relación entre el ST, la violencia de pareja íntima (VPI) y el consumo de alcohol: conductas de riesgo establecidas para el VIH. Utilizando la regresión de Poisson modificada, evaluamos las asociaciones entre el ST y la VPI física, verbal y sexual entre 8,248 mujeres (15-49 años) que participaron en el Estudio de cohorte de la comunidad Rakai en cuarenta comunidades de Uganda. Un término de interacción evaluó la moderación entre el consumo de alcohol y el ST y no se encontraron efectos de interacción significativos. En el análisis ajustado, el consumo de alcohol y el ST se asociaron significativamente con todas las formas de VPI. En el análisis estratificado, el ST solo se asoció con la VPI en las comunidades agrarias; El consumo de alcohol no se asoció con la VPI física en las comunidades comerciales ni con la VPI sexual en las comunidades comerciales y pesqueras. Identificar las diferencias en los factores de riesgo de la violencia de género por tipo de comunidad es fundamental para el desarrollo de intervenciones personalizadas.

Recombination Analysis of Near Full-Length HIV-1 Sequences and the Identification of a Potential New Circulating Recombinant Form from Rakai, Uganda.

The Phylogenetics And Networks for Generalized HIV Epidemics in Africa (PANGEA-HIV) consortium has been vital in the generation and examination of near full-length HIV-1 sequences generated from Sub-Saharan Africa. In this study, we examined a subset (n = 275) of sequences from Rakai, Uganda, collected between August 2011 and January 2015. Sequences were initially screened with COMET for subtyping and then evaluated using bootscanning and phylogenetic inference. Among 275 sequences, 38.6% were subtype D, 19.3% were subtype A, 2.9% were subtype C, and 39.3% were recombinant. The recombinants were structurally diverse in the number of breakpoints observed, the location of recombinant segments, and represented subtypes, with AD recombinants accounting for the majority of all recombinants (29.8%). Within the AD subpopulation, we identified a potential new circulating recombinant form in five individuals where the polymerase gene was subtype D and most of env was subtype A (D-A junctures at HXB2 6760 and 8709). While the breakpoints were identical for the viruses from these individuals, the viral fragments did not cluster together. These results suggest selection for a viral strain where properties of the subtype A and subtype D portions of the virus confer a survival advantage. The continued study of recombinants will increase our breadth of knowledge for the genetic diversity and evolution of HIV-1, which can further contribute to our understanding toward a universal HIV-1 vaccine.

Prevalence, Magnitude, and Genotype Distribution of Urinary Cytomegalovirus (CMV) Shedding Among CMV-Seropositive Children and Adolescents in the United States.

BACKGROUND: There are limited nationally representative data on correlates of cytomegalovirus (CMV) shedding among children and adolescents. In addition, the genotype distribution of CMV infections has not been well characterized among general populations in the United States. METHODS: This study characterized urinary CMV shedding among CMV immunoglobulin G-positive 6- to 19-year-olds in the US household population using data from the 1999-2004 National Health and Nutrition Examination Survey (NHANES). Multivariable Poisson regression was used to estimate adjusted prevalence ratios (aPR) and corresponding 95% confidence intervals (CIs). Analyses were weighted and multiple imputation was performed to handle missing data (with the exception of CMV genotypes). RESULTS: Prevalence of urinary CMV shedding was significantly lower among 9- to 11-year-olds (20.6%; aPR = 0.61; 95% CI, 0.44-0.83) and 12- to 19-year-olds (7.0%; aPR = 0.21; 95% CI, 0.14-0.30) compared with 6- to 8-year-olds (34.4%). Among CMV shedders, the youngest age group also had the highest urinary CMV viral loads. The prevalence of urinary CMV shedding among obese individuals was significantly lower compared with lean individuals (aPR = 0.68; 95% CI, 0.47-0.99). Among CMV shedders, glycoprotein B (gB)1 (51%) was the most prevalent gB variant, followed by gB2 (29%), gB3 (21%), and gB4 (13%); glycoprotein H (gH)2 (60%) was more prevalent than gH1 (48%). Multiple (≥2) gB (14%) and multiple gH (7%) infections were detected among CMV shedders. CONCLUSIONS: This study underscores the importance of young children even above the age of 5 years as a potential source of CMV transmission. The detection of multiple CMV strains among CMV shedders may have implications for the transmission of viral diversity as well as vaccine development.

Genetic Cluster Analysis for HIV Prevention.

PURPOSE OF REVIEW: This review summarizes the use of genetic similarity clusters to understand HIV transmission and inform prevention efforts. RECENT FINDINGS: Recent emphases include the development of real-time cluster identification in order to interrupt transmission chains, the use of clusters to estimate rates of transmission along the HIV care cascade, and the extension of cluster analyses to understand transmission in the generalized epidemics of sub-Saharan Africa. Importantly, this recent empirical work has been accompanied by theoretical work that elucidates the processes that underlie HIV genetic similarity clusters; multiple studies suggest that clusters are not necessarily enriched with individuals with high transmission rates, but rather can reflect variation in sampling times within a population, with individuals sampled early in infection more likely to cluster. Analyses of genetic similarity clusters have great promise to inform HIV epidemiology and prevention. Future emphases should include the collection of additional sequence data from underrepresented populations, such as those in sub-Saharan Africa, and further development and evaluation of clustering methods.

Enhanced use of phylogenetic data to inform public health approaches to HIV among men who have sex with men.

The multidimensional nature and continued evolution of HIV epidemics among men who have sex with men (MSM) requires innovative intervention approaches. Strategies are needed that recognise the individual, social and structural factors driving HIV transmission; that can pinpoint networks with heightened transmission risk; and that can help target intervention in real time. HIV phylogenetics is a rapidly evolving field with strong promise for informing innovative responses to the HIV epidemic among MSM. Currently, HIV phylogenetic insights are providing new understandings of characteristics of HIV epidemics involving MSM, social networks influencing transmission, characteristics of HIV transmission clusters involving MSM, targets for antiretroviral and other prevention strategies and dynamics of emergent epidemics. Maximising the potential of HIV phylogenetics for HIV responses among MSM will require attention to key methodological challenges and ethical considerations, as well as resolving key implementation and scientific questions. Enhanced and integrated use of HIV surveillance, sociobehavioural and phylogenetic data resources are becoming increasingly critical for informing public health approaches to HIV among MSM.

Penile Immune Activation and Risk of HIV Shedding: A Prospective Cohort Study.

Background: Genital immune activation is suspected to modulate local human immunodeficiency virus (HIV) RNA levels and the risk of sexual HIV transmission. Methods: A prospective, observational cohort study of 221 HIV-infected men undergoing male circumcision (MC) was conducted in Rakai, Uganda. Penile lavage samples collected from the coronal sulcus at baseline and 4 weekly visits after MC were assayed for pro-inflammatory cytokines and HIV RNA. The main analysis was limited to 175 men with detectable HIV plasma viral load (VL > 400 copies/mL; n = 808 visits). The primary exposures of interest were individual and total cytokine detection at the previous postoperative visit. Adjusted prevalence risk ratios (adjPRR) of detectable HIV shedding (VL > 40 copies/mL) were estimated by Poisson regression models with generalized estimating equations and robust variance estimators and included adjustment for plasma HIV VL. Findings: Among men with a detectable plasma VL, penile HIV shedding was detected at 136 visits (16.8%). Detectable interleukin (IL)-1ß (adjPRR = 2.14; 95% confidence interval (CI) = 1.02-4.48), IL-6 (adjPRR = 2.24; 95% CI = 1.28-3.90), IL-8 (adjPRR = 2.42; 95% CI = 1.15-5.08), IL-10 (adjPRR = 2.51; 95% CI = 1.67-3.80), and IL-13 (adjPRR = 1.87; 95% CI = 1.15-3.03) were associated with penile HIV shedding at the subsequent visit. Men with 2-4 (adjPRR = 2.36; 95% CI = 1.08-5.14) and 5-7 (adjPRR = 3.00; 95% CI = 1.28-7.01) detectable cytokines had a greater likelihood of detectable penile HIV shedding at the subsequent visit, compared to men with ≤ 1 detectable cytokine. The total number of detectable cytokines was also associated with a higher penile log10 HIV VL at the subsequent visit among HIV shedders. Interpretation: Pro-inflammatory cytokine production had a dose-dependent and temporal association with penile HIV shedding, suggesting that genital immune activation may increase the risk of sexual HIV transmission by driving local HIV replication.

A transmission-virulence evolutionary trade-off explains attenuation of HIV-1 in Uganda.

Evolutionary theory hypothesizes that intermediate virulence maximizes pathogen fitness as a result of a trade-off between virulence and transmission, but empirical evidence remains scarce. We bridge this gap using data from a large and long-standing HIV-1 prospective cohort, in Uganda. We use an epidemiological-evolutionary model parameterised with this data to derive evolutionary predictions based on analysis and detailed individual-based simulations. We robustly predict stabilising selection towards a low level of virulence, and rapid attenuation of the virus. Accordingly, set-point viral load, the most common measure of virulence, has declined in the last 20 years. Our model also predicts that subtype A is slowly outcompeting subtype D, with both subtypes becoming less virulent, as observed in the data. Reduction of set-point viral loads should have resulted in a 20% reduction in incidence, and a three years extension of untreated asymptomatic infection, increasing opportunities for timely treatment of infected individuals.