Ann M. Dennis

Late entry to HIV care among Latinos compared with non-Latinos in a southeastern US cohort.

BACKGROUND Late diagnosis of human immunodeficiency virus (HIV) infection remains common despite advances in therapy and prognosis. The southeastern United States is a rapidly growing Latino settlement area where ethnic disparities may contribute to late presentation to care. METHODS We assessed demographic and clinical factors between racial/ethnic groups at the time of HIV care initiation in the University of North Carolina Center for AIDS Research Clinical Cohort. We identified independent predictors of late presentation, defined as a CD4(+) T lymphocyte (CD4) count <350 cells/mm(3) or an AIDS-defining event (ADE), using log-linear binomial regression. RESULTS During the period 1999-2009, 853 patients initiated HIV care, of whom 11% were Latino, 28% were white, and 61% were black. Median initial CD4 counts were lower for Latino patients (186 cells/mm(3)) than white patients (292 cells/mm(3); P = .006) and black patients (302 cells/mm(3); P = .02). Latino persons were more likely to be late presenters than white or black persons (76% vs 58%; P < .001) and accounted for 86%, 75%, and 50% of all presenting cases of active tuberculosis, histoplasmosis, and toxoplasmosis, respectively. Latino ethnicity, older age, male sex, and earlier entry year were independently associated with late presentation (P < .05 for all). In multivariable analyses, Latino persons were 1.29 times more likely to present to care late than white or black persons (95% confidence interval, 1.15-1.45). CONCLUSIONS Latinos are more likely to initiate HIV care later in the course of illness than are black and white persons and account for a majority of several ADEs. Strategies to improve earlier HIV testing among Latinos in new settlement areas are needed.

Prevalence of transmitted antiretroviral drug resistance differs between acutely and chronically HIV-infected patients.

Abstract:The associations of acute HIV infection (AHI) and other predictors with transmitted drug resistance (TDR) prevalence were assessed in a cohort of HIV-infected, antiretroviral-naïve patients. AHI was defined as being seronegative with detectable HIV RNA. Binomial regression was used to estimate prevalence ratios and 95% confidence intervals for associations with TDR. Among 43 AHI patients, TDR prevalence was 20.9%, whereas prevalence was 8.6% among 677 chronically infected patients. AHI was associated with 1.9 times the prevalence of TDR (95% confidence intervals: 1.0 to 3.6) in multivariable analysis. AHI patients may represent a vanguard group that portends increasing TDR in the future.

Phylogenetic insights into regional HIV transmission.

Objectives:Despite prevention efforts, new HIV diagnoses continue in the southern United States, where the epidemic is characterized by significant racial/ethnic disparities. We integrated phylogenetic analyses with clinical data to reveal trends in local HIV transmission. Design:Cross-sectional analysis of 1671 HIV-infected individuals each with one B-subtype pol sequence obtained during chronic (82%; UNC Center for AIDS Research Clinical Cohort) or acute/recent (18%; Duke/UNC Acute HIV Consortium) infection. Methods:Phylogenies were inferred using neighbor joining to select related sequences then confirmed with Bayesian methods. We characterized transmission clusters (clades n ≥ 3 sequences supported by posterior probabilities = 1) by factors including race/ethnicity and transmission risk. Factors associated with cluster membership were evaluated for newly diagnosed patients. Results:Overall, 72% were men, 59% black and 39% men who have sex with men (MSM). A total of 557 (33%) sequences grouped in either 108 pairs (n = 216) or 67 clusters (n = 341). Clusters ranged from three to 36 (median 4) members. Composition was delineated primarily by race, with 28% exclusively black, and to a lesser extent by risk group. Both MSM and heterosexuals formed discrete clusters, although substantial mixing was observed. In multivariable analysis, patients with age 30 years or less (P = 0.009), acute infection (P = 0.02), local residence (P = 0.002) and transmitted drug resistance (P = 0.02) were more likely to be cluster members, whereas Latinos were less likely (P < 0.001). Conclusion:Integration of molecular, clinical and demographic data offers a unique view into the structure of local transmission networks. Clustering by black race, youth and transmitted drug resistance and inability to identify Latino clusters will inform prevention, testing and linkage to care strategies.

Phylogenetic studies of transmission dynamics in generalized HIV epidemics: an essential tool where the burden is greatest?

Abstract:Efficient and effective HIV prevention measures for generalized epidemics in sub-Saharan Africa have not yet been validated at the population level. Design and impact evaluation of such measures requires fine-scale understanding of local HIV transmission dynamics. The novel tools of HIV phylogenetics and molecular epidemiology may elucidate these transmission dynamics. Such methods have been incorporated into studies of concentrated HIV epidemics to identify proximate and determinant traits associated with ongoing transmission. However, applying similar phylogenetic analyses to generalized epidemics, including the design and evaluation of prevention trials, presents additional challenges. Here we review the scope of these methods and present examples of their use in concentrated epidemics in the context of prevention. Next, we describe the current uses for phylogenetics in generalized epidemics and discuss their promise for elucidating transmission patterns and informing prevention trials. Finally, we review logistic and technical challenges inherent to large-scale molecular epidemiological studies of generalized epidemics and suggest potential solutions.

Social network based recruitment successfully reveals HIV-1 transmission networks among high risk individuals in El Salvador

Objective:HIV in Central America is concentrated among certain groups such as men who have sex with men (MSM) and female sex workers (FSWs). We compared social recruitment chains and HIV transmission clusters from 699 MSM and 787 FSWs to better understand factors contributing to ongoing HIV transmission in El Salvador. Methods:Phylogenies were reconstructed using pol sequences from 119 HIV-positive individuals recruited by respondent-driven sampling (RDS) and compared with RDS chains in 3 cities in El Salvador. Transmission clusters with a mean pairwise genetic distance ⩽0.015 and Bayesian posterior probabilities =1 were identified. Factors associated with cluster membership were evaluated among MSM. Results:Sequences from 34 (43%) MSM and 4 (10%) FSW grouped in 14 transmission clusters. Clusters were defined by risk group (12 MSM clusters) and geographic residence (only 1 spanned separate cities). In 4 MSM clusters (all n = 2), individuals were also members of the same RDS chain, but only 2 had members directly linked through recruitment. All large clusters (n ≥ 3) spanned >1 RDS chain. Among MSM, factors independently associated with cluster membership included recent infection by BED assay (P = 0.02), sex with stable male partners (P = 0.02), and sex with ≥3 male partners in the past year (P = 0.04). Conclusions:We found few HIV transmissions corresponding directly with the social recruitment. However, we identified clustering in nearly one-half of MSM suggesting that RDS recruitment was indirectly but successfully uncovering transmission networks, particularly among recent infections. Interrogating RDS chains with phylogenetic analyses may help refine methods for identifying transmission clusters.

HIV risk behaviors and sociodemographic features of HIV-infected Latinos residing in a new Latino settlement area in the Southeastern United States

The Southeastern United States (US) has a rapidly growing Latino population, yet little is known about HIV-infected Latinos in the region. To help inform future prevention studies, we compared sociodemographic, clinical, and behavioral characteristics between immigrant and US-born HIV-infected Latinos using face-to-face interviews conducted at three clinics in North Carolina. Questions encompassed HIV testing, acculturation, sexual- and substance-related behaviors, and migration history. Behavioral data were compared with 451 black and white clinic patients. Differences were tested using Pearsons and Kruskal–Wallis tests. Participants (n=127) were primarily male (74%) and immigrants (82%). Most immigrants were Mexican (67%), had low acculturation scores (92%), and were diagnosed a median of 8 years (IQR 0–12) following immigration. Compared with US-born Latinos, immigrants had lower CD4 counts at clinic entry (median 187 vs. 371 cells/mm3) and were less likely to have graduated high school (49% vs. 78%) or have insurance (9% vs. 52%; all P <0.05). Most immigrants identified as heterosexual (60%) and reported fewer lifetime partners than US-born Latinos (median 6 vs. 20; P=0.001). Immigrant men were less likely to report sex with men than US-born men (43% vs. 81%; P=0.005). Immigrant men also had similar risk behaviors to black men, and US-born Latino men exhibited behaviors that were more similar to white men in our clinic. At the time of survey, >90% of participants were receiving antiretroviral therapy (ART) and most had achieved HIV RNA <50 copies/mL (62% immigrants vs. 76% US-born; P=0.32). In conclusion, Latino immigrants were more likely to present with advanced disease, identify as heterosexual, and report different risk behaviors than US-born Latinos, yet receipt and response to ART were similar between the two groups. Prevention strategies should prioritize finding innovative methods to reach Latino immigrants for routine early testing regardless of risk stratification and include programs targeted toward the different needs of immigrant and US-born Latinos.

Using nearly full-genome HIV sequence data improves phylogeny reconstruction in a simulated epidemic

HIV molecular epidemiology studies analyse viral pol gene sequences due to their availability, but whole genome sequencing allows to use other genes. We aimed to determine what gene(s) provide(s) the best approximation to the real phylogeny by analysing a simulated epidemic (created as part of the PANGEA_HIV project) with a known transmission tree. We sub-sampled a simulated dataset of 4662 sequences into different combinations of genes (gag-pol-env, gag-pol, gag, pol, env and partial pol) and sampling depths (100%, 60%, 20% and 5%), generating 100 replicates for each case. We built maximum-likelihood trees for each combination using RAxML (GTR + Γ), and compared their topologies to the corresponding true tree’s using CompareTree. The accuracy of the trees was significantly proportional to the length of the sequences used, with the gag-pol-env datasets showing the best performance and gag and partial pol sequences showing the worst. The lowest sampling depths (20% and 5%) greatly reduced the accuracy of tree reconstruction and showed high variability among replicates, especially when using the shortest gene datasets. In conclusion, using longer sequences derived from nearly whole genomes will improve the reliability of phylogenetic reconstruction. With low sample coverage, results can be highly variable, particularly when based on short sequences.

Putting it all together: Lessons from the Jackson HIV outbreak investigation

One need only glance at a map of HIV prevalence in the United States to realize that the Southeast is disproportionately impacted (Figure). Though this region contains a little over one third of the national population, more than half of all newly diagnosed cases of HIV came from the South in 2010.1 Inequity in the social determinants of health has served to concentrate a variety of communicable and non-communicable diseases among the South’s poor and disadvantaged, of whom Blacks make up a outsized proportion.2, 3 Recent estimates suggest that 1 in every 5 Southern Black men who have sex with men (MSM) are living with HIV infection, a number nearly 5 times that of Southern White MSM.4 In the past several years, the epidemic has begun to affect young MSM more greatly. In 2011, the Centers for Disease Control and Prevention (CDC) reported that young, Black MSM aged 13–29 experienced a 48% increase in HIV incidence from 2006–2009.5 Unfortunately, such statistics are no longer surprising for those of us living in the South and providing care for the scores of young, Black MSM being diagnosed with HIV each year. The real challenge for the future lies in identifying and addressing the root causes of this disparity, in order to effect meaningful reductions in HIV incidence among those at greatest risk. Figure 1 Prevalence of HIV infection in the United States, 2009 The two-year investigation of an HIV outbreak among young, Black MSM in and around Jackson, Mississippi yields significant insights into this challenge. The study, coordinated by the CDC and the Mississippi State Department of Health (MSDH), was modeled on a 2004 investigation of multiple HIV diagnoses among Black MSM attending colleges and universities in central North Carolina.6, 7 In five previous papers8–12 and their article in this issue of Sexually Transmitted Diseases,13 Oster and her colleagues from the CDC and MSDH provide us with a nuanced picture of the state of the HIV epidemic among Black MSM in the Deep South and a glimpse of how similar outbreak investigations could take place in the future. In their work, Oster et al. present a portrait of the epidemic that is heavily influenced by stigma surrounding homosexuality and HIV in the Black community.14–16 Young, Black MSM, ostracized by their families and support systems,12 migrate to a handful of “safe” venues located in the more urban area of Jackson to socialize and meet new sex partners.11–13 HIV-infected and uninfected men are both drawn to (or forced toward) the same few venues, characterized in the current paper11 using an “affiliation” network.17 This co-localization creates an overlapping social and sexual network with an enriched HIV prevalence – a phenomenon similar to recent observations in North Carolina, as well.18 Black MSM in the resulting tight-knit system find safety in numbers, but may also have the mistaken impression that HIV prevalence is low among people with demographics like their own.19 Evidence for this comes from two sources: over half of HIV-infected men thought they were “unlikely” or “very unlikely” to ever acquire HIV,8 and participants reported less consistent condom usage with casual partners, compared to main partners.13 Among Black MSM, intense stigmatization of persons living with HIV12 further complicates efforts to have open, honest discussion about serostatus with sexual partners. When young men with less education about HIV and STI prevention10 enter the sexual network and have sex with older partners, among whom the prevalence of HIV is greater, their odds of HIV infection are markedly increased.9, 10, 20 Taken together, it becomes clearer why HIV infections are more frequent among young, Black MSM, despite no demonstrable differences in their risk behavior, compared to MSM of other racial/ethnic groups.21 In a sexual network with high HIV prevalence, even a single lapse in preventive behavior has a much higher probability of resulting in a transmission event.18 In-depth investigations like the one conducted by CDC and MSDH are relatively rare in the HIV literature, given the enormous commitment of time and resources needed to successfully bring the data from field notes to published manuscripts. Perhaps the most unique aspect of the Jackson investigation was its use of molecular epidemiological methods in order to corroborate and extend the findings from “traditional” case-control,9, 10 qualitative,12 and network analyses (social and affiliation).13 The study team analyzed genotypic sequence data from nearly 800 individuals diagnosed with HIV in Mississippi between 2005–2008, collected from CDC’s Variant, Atypical, and Resistant HIV Surveillance (VARHS) system and local surveillance specimens from Black MSM aged 16–25 diagnosed in early 2008.11 Using sophisticated computational methods, they reconstructed phylogenetic trees depicting the genetic relatedness of the viruses, and then analyzed the characteristics of individuals whose viruses appeared in groups or “clusters” of highly similar sequences. Such clusters represent groups of individuals who likely share transmission of the same virus. It is important to note that only nucleotide sequences are included in phylogenetic analyses; tree structure is “solved” without considering the demographic or behavioral characteristics of individuals who supplied the viral specimens. Therefore, this method provides an additional way to understand transmission, independent of participant-reported history. Additional information can be gleaned by looking for patterns of shared characteristics among individuals identified in these clusters. Sequences from young Black MSM in Mississippi appeared in 21 out of 82 clusters, though these men contributed only 16% of the overall viruses studied. The members of these 21 clusters were all remarkably homogenous; of the 69 individuals in these clusters, all were men, 96% were Black, 88% were MSM, and 70% were under age 25. When examining the geographic locations from which the individuals came, most clusters involving young, Black MSM contained residents from two or more regions of Mississippi. Together, these findings strongly and independently support the conceptual framework of the epidemic among Southern Black MSM, as outlined above. Phylogenetic analyses can complement traditional methods in other ways, as well. In the present paper,13 Oster and colleagues were only able to obtain very limited identifying information concerning sex partners, such that the resulting sexual network was fractured into 20 separate components. Given the findings of the phylogenetic study, it seems likely this network would coalesce into fewer, larger groupings if the genetic relatedness of the participants’ viruses could be evaluated. Phylogenetic data can also shed light on broader patterns of HIV transmission, if large numbers of sequences are analyzed in conjunction with clinical and demographic data. Two recent studies, one from North Carolina22 and another from sites around the United States23 both found homogeneity among Blacks within clusters of related sequences, suggesting the same assortative mixing or homophily seen among Black MSM in the Jackson investigation is true across the country. Phylogenetic analyses are not without their limitations, however. Individuals with closely related sequences could have directly transmitted HIV to one another – or they could have a common shared partner or multiple intermediaries. Neither the directionality nor exact date of transmission can be determined using sequences alone, but phylogenetic data can be used to support or refute information collected from putative partners.24–26 Molecular epidemiology’s role in assisting public health efforts and improving our understanding of HIV transmission in the United States undoubtedly will increase over time. HIV nucleotide sequence data from “baseline” or pre-treatment resistance testing are widely available, since such testing is recommended for all individuals entering care.27 Phylogenetic analytical methods and computational speed have advanced markedly in the past decade, allowing large datasets to be analyzed more rapidly than ever before. As elegantly shown in the Jackson investigation, integrating these new methods with traditional, time-tested epidemiological approaches can deepen our understanding of the complex transmission dynamics of HIV in the United States. Though the Jackson outbreak investigation has revealed much about HIV’s spread in young, Black MSM, we still must parlay these findings into more effective strategies for both primary and secondary prevention. Testing campaigns and sexual health messages ought to be directed at the “virtual” and physical venues frequented by these men, but we also need to address stigmatizing forces in their home communities through direct engagement and education. HIV treatment resources need to be available in rural and urban communities, to ensure access to the treatment we know will sustain individual health and reduce infectiousness to others. We must better understand why Black MSM living with HIV are shunned by their peers, and empower men to make discussions of serostatus more common. This will require bringing together an unlikely group of stakeholders for frank discussions about HIV and what can be done to prevent it. Urban and rural community and religious leaders, business and website owners, at-risk uninfected MSM, and men living with HIV all need to be a part of the effort. The stakes are as high, as are the barriers to success – but we really have no choice at this point but to rise to the challenge.

HIV Transmission Patterns Among Immigrant Latinos Illuminated by the Integration of Phylogenetic and Migration Data.

Latinos represent a growing proportion of HIV cases in North Carolina (NC). Understanding how immigrants are involved in local HIV transmission is important to guide interventions. We used phylogenetics to characterize Latino involvement in local HIV transmission chains. Transmission clusters were identified from maximum-likelihood phylogenies constructed with HIV pol sequences from 177 Latinos and 1,496 non-Latinos receiving care in NC. Highly supported clusters involving one or more Latinos were characterized. Migration data were obtained from interviews and chart review. Factors associated with cluster membership were identified using log-binomial regression. Most Latinos were male (76%), immigrants (83%), and had HIV-1B (99%). Immigrants were more likely to report heterosexual risk (67% vs. 23%) than U.S.-born Latinos (p < 0.01). We identified 32 clusters that included one or more Latinos; these involved 53 Latinos (30%) and 41 non-Latinos. Immigrant and U.S.-born Latinos were equally likely to be in clusters, but immigrants were more likely to be in clusters with another Latino (78% vs. 29%; p = 0.02). Cluster composition by ethnicity and risk behavior varied by cluster size; larger clusters contained fewer immigrants and more men who have sex with men (MSM). Factors associated with immigrant membership in local transmission clusters included age <30 years [RR 2.34 (95% CI 1.47-3.73)], Mexican origin [RR 2.55 (95% CI 1.29-6.88)], and residing in the United States longer before diagnosis [RR 1.53 (95% CI 1.09-2.15), per 10 years]. While some Latinos immigrate with HIV infection, many immigrants are involved in transmission networks after arrival, particularly MSM. HIV testing and prevention interventions must consider this heterogeneity and may be better targeted by integrating phylogenetic analyses.

Rising prevalence of non-B HIV-1 subtypes in North Carolina and evidence for local onward transmission.

Abstract HIV-1 diversity is increasing in North American and European cohorts which may have public health implications. However, little is known about non-B subtype diversity in the southern United States, despite the region being the epicenter of the nation’s epidemic. We characterized HIV-1 diversity and transmission clusters to identify the extent to which non-B strains are transmitted locally. We conducted cross-sectional analyses of HIV-1 partial pol sequences collected from 1997 to 2014 from adults accessing routine clinical care in North Carolina (NC). Subtypes were evaluated using COMET and phylogenetic analysis. Putative transmission clusters were identified using maximum-likelihood trees. Clusters involving non-B strains were confirmed and their dates of origin were estimated using Bayesian phylogenetics. Data were combined with demographic information collected at the time of sample collection and country of origin for a subset of patients. Among 24,972 sequences from 15,246 persons, the non-B subtype prevalence increased from 0% to 3.46% over the study period. Of 325 persons with non-B subtypes, diversity was high with over 15 pure subtypes and recombinants; subtype C (28.9%) and CRF02_AG (24.0%) were most common. While identification of transmission clusters was lower for persons with non-B versus B subtypes, several local transmission clusters (≥3 persons) involving non-B subtypes were identified and all were presumably due to heterosexual transmission. Prevalence of non-B subtype diversity remains low in NC but a statistically significant rise was identified over time which likely reflects multiple importation. However, the combined phylogenetic clustering analysis reveals evidence for local onward transmission. Detection of these non-B clusters suggests heterosexual transmission and may guide diagnostic and prevention interventions.