Progression of a large syphilis outbreak in rural North Carolina through space and time: Application of a Bayesian Maximum Entropy graphical user interface.

In 2001, the primary and secondary syphilis incidence rate in rural Columbus County, North Carolina was the highest in the nation. To understand the development of syphilis outbreaks in rural areas, we developed and used the Bayesian Maximum Entropy Graphical User Interface (BMEGUI) to map syphilis incidence rates from 1999-2004 in seven adjacent counties in North Carolina. Using BMEGUI, incidence rate maps were constructed for two aggregation scales (ZIP code and census tract) with two approaches (Poisson and simple kriging). The BME maps revealed the outbreak was initially localized in Robeson County and possibly connected to more urban endemic cases in adjacent Cumberland County. The outbreak spread to rural Columbus County in a leapfrog pattern with the subsequent development of a visible low incidence spatial corridor linking Roberson County with the rural areas of Columbus County. Though the data are from the early 2000s, they remain pertinent, as the combination of spatial data with the extensive sexual network analyses, particularly in rural areas gives thorough insights which have not been replicated in the past two decades. These observations support an important role for the connection of micropolitan areas with neighboring rural areas in the spread of syphilis. Public health interventions focusing on urban and micropolitan areas may effectively limit syphilis indirectly in nearby rural areas.

Sustained Virologic Suppression With Dolutegravir/Lamivudine in a Test-and-Treat Setting Through 48 Weeks.

Background: We assessed the efficacy and safety of dolutegravir/lamivudine (DTG/3TC) in a US test-and-treat setting at a secondary 48-week time point of the multicenter, single-arm, phase IIIb STAT study. Methods: Participants were eligible adults newly diagnosed with human immunodeficiency virus (HIV)-1 and had started once-daily DTG/3TC within 14 days of diagnosis, before laboratory results were available. Antiretroviral therapy (ART) was modified if baseline testing indicated DTG or 3TC resistance, hepatitis B virus (HBV) coinfection, or creatinine clearance <30 mL/min per 1.73 m2, and these participants remained in the study. A proportion with HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48 was calculated among all participants (intention-to-treat-exposed [ITT-E] missing = failure analysis) and those with available data (observed analysis). Results: At Week 48, 82% of all participants regardless of ART (107 of 131; ITT-E missing = failure) and 97% with available data (107 of 110; observed analysis) achieved HIV-1 RNA <50 copies/mL. High proportions of virologic response were seen overall, including in participants with high viral load (≥500 000 copies/mL; 89%) or low CD4+ cell count (<200 cells/mm3; 78%) at baseline. Ten participants had treatment modification (baseline HBV coinfection, n = 5; participant/proxy decision, n = 2; baseline M184V resistance mutation, adverse event [AE; rash], and pregnancy, n = 1 each) before Week 48. Two participants met confirmed virologic failure criteria. No treatment-emergent resistance was observed. Ten participants reported drug-related AEs (all grade 1-2); no serious drug-related AEs occurred. Conclusions: Results demonstrated high proportions of participants with sustained virologic suppression, no treatment-emergent resistance, and good safety over 48 weeks, supporting first-line use of DTG/3TC in a test-and-treat setting.

Dolutegravir/lamivudine as a first-line regimen in a test-and-treat setting for newly diagnosed people living with HIV.

OBJECTIVES: Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting. DESIGN: The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting. METHODS: Eligible adults initiated DTG/3TC 14 days or less after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance less than 30 ml/min per 1.73 m2, participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA less than 50 copies/ml at Week 24, regardless of antiretroviral regimen, among all participants (intention-to-treat exposed) and those with available HIV-1 RNA data (observed). RESULTS: Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in eight participants [five with HBV co-infection, one with baseline M184V, one for adverse event (rash), one participant decision]. At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA less than 50 copies/ml. Incidence of drug-related adverse events was low (7%); no drug-related serious adverse events occurred. CONCLUSION: These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed [ClinicalTrials.gov, NCT03945981; see Supplemental Digital Content 1, video abstract (Video abstract summarizing the STAT study design and results), http://links.lww.com/QAD/C189].

Lost and found: applying network analysis to public health contact tracing for HIV.

Infectious disease surveillance is often case-based, focused on people diagnosed and their contacts in a predefined time window, and treated as independent across infections. Network analysis of partners and contacts joining multiple investigations and infections can reveal social or temporal trends, providing opportunities for epidemic control within broader networks. We constructed a sociosexual network of all HIV and early syphilis cases and contacts investigated among residents of 11 contiguous counties in North Carolina over a two-year period (2012-2013). We anchored the analysis on new HIV diagnoses ("indexes"), but also included nodes and edges from syphilis investigations that were within the same network component as any new HIV index. After adding syphilis investigations and deduplicating people included in multiple investigations (entity resolution), the final network comprised 1470 people: 569 HIV indexes, 700 contacts to HIV indexes who were not also new cases themselves, and 201 people who were either indexes or contacts in eligible syphilis investigations. Among HIV indexes, nearly half (48%; n = 273) had no located contacts during single-investigation contact tracing, though 25 (9%) of these were identified by other network members and thus not isolated in the final multiple investigation network. Constructing a sociosexual network from cases and contacts across multiple investigations mitigated some effects of unobserved partnerships underlying the HIV epidemic and demonstrated the HIV and syphilis overlap in these networks.

Factors Associated With Human Immunodeficiency Virus Infections Linked in Genetic Clusters But Disconnected in Partner Tracing.

BACKGROUND: Successful partner notification can improve community-level outcomes by increasing the proportion of persons living with human immunodeficiency virus (HIV) who are linked to HIV care and virally suppressed, but it is resource intensive. Understanding where HIV transmission pathways may be undetected by routine partner notification may help improve case finding strategies. METHODS: We combined partner notification interview and HIV sequence data for persons diagnosed with HIV in Wake County, NC in 2012 to 2013 to evaluate partner contact networks among persons with HIV pol gene sequences 2% or less pairwise genetic distance. We applied a set of multivariable generalized estimating equations to identify correlates of disparate membership in genetic versus partner contact networks. RESULTS: In the multivariable model, being in a male-male pair (adjusted odds ratio [AOR], 16.7; P = 0.01), chronic HIV infection status (AOR, 4.5; P < 0.01), and increasing percent genetic distance between each dyad member's HIV pol gene sequence (AOR, 8.3 per each 1% increase, P < 0.01) were all associated with persons with HIV clustering but not being identified in the partner notification network component. Having anonymous partners or other factors typically associated with risk behavior were not associated. CONCLUSIONS: Based on genetic networks, partnerships which may be stigmatized, may have occurred farther back in time or may have an intervening partner were more likely to be unobserved in the partner contact network. The HIV genetic cluster information contributes to public health understanding of HIV transmission networks in these settings where partner identifying information is not available.

Effects of Different Doses of GEN-003, a Therapeutic Vaccine for Genital Herpes Simplex Virus-2, on Viral Shedding and Lesions: Results of a Randomized Placebo-Controlled Trial.

Background: GEN-003 is a candidate therapeutic vaccine for genital herpes simplex virus type 2 (HSV-2). We compared virologic and clinical impact of varying GEN-003 doses. Methods: Adults with symptomatic HSV-2 received placebo or GEN-003 (30 or 60 µg antigen with 25, 50, or 75 µg adjuvant). Viral shedding and lesion rates before vaccination were compared with those measured immediately after vaccination, then at weeks 29-33 and 53-57 after last dose. Results: Compared with baseline shedding rates, the rate ratios for viral shedding immediately after treatment were as follows: 0.82 (95% confidence interval [CI], 0.49-1.36), 30 µg antigen/25 µg adjuvant (30/25) dose; 0.64 (95% CI, 0.45-0.92), 30/50 dose; 0.63 (95% CI, 0.37-1.10), 30/75 dose; 0.56 (95% CI, 0.36-0.88), 60/25 dose; 0.58 (95% CI, 0.38-0.89), 60/50 dose; 0.45 (95% CI, 0.16-0.79), 60/75 dose; and 0.98 (95% CI, 0.76-1.26), placebo. Lesion rate reductions by GEN-003 ranged from 31% to 69%, but lesion rates also decreased among placebo recipients (62%). Reductions in shedding and lesion rate were durable for 12 months for the 60 µg antigen plus 50 or 75 µg adjuvant groups. No serious adverse events occurred with vaccination. Conclusions: The most efficacious vaccine combinations for GEN-003 were the 60 µg/50 µg and 60 µg/75 µg doses.

Leveraging Phylogenetics to Understand HIV Transmission and Partner Notification Networks.

BACKGROUND: Partner notification is an important component of public health test and treat interventions. To enhance this essential function, we assessed the potential for molecular methods to supplement routine partner notification and corroborate HIV networks. METHODS: All persons diagnosed with HIV infection in Wake County, NC, during 2012-2013 and their disclosed sexual partners were included in a sexual network. A data set containing HIV-1 pol sequences collected in NC during 1997-2014 from 15,246 persons was matched to HIV-positive persons in the network and used to identify putative transmission clusters. Both networks were compared. RESULTS: The partner notification network comprised 280 index cases and 383 sexual partners and high-risk social contacts (n = 131 HIV-positive). Of the 411 HIV-positive persons in the partner notification network, 181 (44%) did not match to a HIV sequence, 61 (15%) had sequences but were not identified in a transmission cluster, and 169 (41%) were identified in a transmission cluster. More than half (59%) of transmission clusters bridged sexual network partnerships that were not recognized in the partner notification; most of these clusters were dominated by men who have sex with men. CONCLUSIONS: Partner notification and HIV sequence analysis provide complementary representations of the existent partnerships underlying the HIV transmission network. The partner notification network components were bridged by transmission clusters, particularly among components dominated by men who have sex with men. Supplementing the partner notification network with phylogenetic data highlighted avenues for intervention.

Integration of Contact Tracing and Phylogenetics in an Investigation of Acute HIV Infection.

BACKGROUND: The integration of traditional contact tracing with HIV sequence analyses offers opportunities to mitigate some of the barriers to effective network construction. We used combined analyses during an outbreak investigation of spatiotemporally clustered acute HIV infections to evaluate if the observed clustering was the product of a single outbreak. METHODS: We investigated acute and recent HIV index cases reported in North Carolina from 2013 to 2014 and their reported contacts. Contact tracing networks were constructed with surveillance data and compared with phylogenetic transmission clusters involving an index case using available HIV-1 pol sequences including 1672 references. Clusters were defined as clades of 2 or more sequences with a less than 1.5% genetic distance and a bootstrap of at least 98% on maximum-likelihood phylogenies. RESULTS: In total, 68 index cases and 210 contacts (71 HIV infected) were reported. The contact tracing network involved 58 components with low overall density (1.2% statewide); 33% of first-degree contacts could not be located. Among 38 (56%) of 68 index cases and 34 (48%) of 71 contacts with sequences, 13 phylogenetic clusters were identified (size 2-4 members). Four clusters connected network components that were not linked in contact tracing. The largest component (n = 28 cases) included 2 distinct phylogenetic clusters and spanned 2 regions. CONCLUSIONS: We identified the concurrent expansion of multiple small transmission clusters rather than a single outbreak in a largely disconnected contact tracing network. Integration of phylogenetic analyses provided timely information on transmission networks during the investigation. Our findings highlight the potential of combined methods to better identify high-risk networks for intervention.

Brief Report: Longitudinal Opioid Use Among HIV-Infected Patients, 2000 to 2014.

Longitudinal opioid prescription use is unknown among HIV-infected patients. Group-based trajectory modeling followed by multinomial logistic regression was used to identify distinct trajectories and their association with baseline characteristics among 1239 HIV-infected UNC CFAR HIV Clinical Cohort participants, 2000-2014. Three trajectories were identified: (1) 72% never/sporadic opioid use (referent group), (2) 11% episodic use (associated with female sex, depression, drug-related diagnoses, antiretroviral therapy use, and undetectable HIV RNA), and (3) 16% chronic use (associated with older age, female sex, and mental health diagnoses). Overall, opioid prescription decreased substantially with longer time in HIV care among both episodic and chronic users.

Longitudinal HIV Care Trajectories in North Carolina.

BACKGROUND: Long-term HIV care and treatment engagement is required for maximal clinical and prevention benefits, but longitudinal care patterns are poorly understood. We used the last 10 years' worth of HIV surveillance data from North Carolina to describe longitudinal HIV care trajectories from diagnosis. METHODS: We conducted a retrospective, population-based cohort study of all persons newly diagnosed with HIV in North Carolina between March 31, 2006 and March 31, 2015 (N = 16,207). We defined HIV care attendance in each 3-month and 6-month interval after diagnosis as the presence of viral load and/or CD4 records (care visit proxies) in the interval. We used group-based trajectory modeling to identify common care trajectories and baseline predictors thereof. RESULTS: A predicted 26% of newly HIV-diagnosed persons showed consistently high care attendance over time; ∼16% exhibited steadily declining attendance; ∼26% showed consistently low attendance; ∼17% had initially weak attendance with an increase starting ∼1.5 year later; and ∼15% showed initially weak attendance with an increase starting ∼3 years later. Older age at diagnosis was protective against all suboptimal trajectories (with the "consistently high" pattern as referent), and being a man who has sex with men was protective against 3 of the 4 suboptimal patterns. CONCLUSIONS: As measured by surveillance-based laboratory proxies, most newly HIV-diagnosed persons exhibited suboptimal care trajectories, but there was wide variation in the particular pathways followed. The insights provided by this analytical approach can help to inform the design of epidemic models and tailored interventions, with the ultimate goal of improving HIV care engagement and transmission prevention.

Variations in Clinical Presentation of Ocular Syphilis: Case Series Reported From a Growing Epidemic in the United States.

Ocular syphilis, a form of neurosyphilis, has been increasingly diagnosed in the United States. This case series summarizes the course of 6 patients recently diagnosed with ocular syphilis, emphasizing the varied sociodemographic factors and the wide range of symptoms and outcomes that are seen in patients with this disease.

Distance to testing sites and its association with timing of HIV diagnosis.

Early HIV diagnosis enables prompt treatment initiation, thereby contributing to decreased morbidity, mortality, and transmission. We aimed to describe the association between distance from residence to testing sites and HIV disease stage at diagnosis. Using HIV surveillance data, we identified all new HIV diagnoses made at publicly funded testing sites in central North Carolina during 2005-2013. Early-stage HIV was defined as acute HIV (antibody-negative test with a positive HIV RNA) or recent HIV (normalized optical density <0.8 on the BED assay for non-AIDS cases); remaining diagnoses were considered post-early-stage HIV. Street distance between residence at diagnosis and (1) the closest testing site and (2) the diagnosis site was dichotomized at 5 miles. We fit log-binomial models using generalized estimating equations to estimate prevalence ratios (PR) and robust 95% confidence intervals (CI) for post-early-stage diagnoses by distance. Models were adjusted for race/ethnicity and testing period. Most of the 3028 new diagnoses were black (N = 2144; 70.8%), men who have sex with men (N = 1685; 55.7%), and post-early-stage HIV diagnoses (N = 2010; 66.4%). Overall, 1145 (37.8%) cases traveled <5 miles for a diagnosis. Among cases traveling ≥5 miles for a diagnosis, 1273 (67.6%) lived <5 miles from a different site. Residing ≥5 miles from a testing site was not associated with post-early-stage HIV (adjusted PR, 95% CI: 0.98, 0.92-1.04), but traveling ≥5 miles for a diagnosis was associated with higher post-early HIV prevalence (1.07, 1.02-1.13). Most of the elevated prevalence observed in cases traveling ≥5 miles for a diagnosis occurred among those living <5 miles from a different site (1.09, 1.03-1.16). Modest increases in post-early-stage HIV diagnosis were apparent among persons living near a site, but choosing to travel longer distances to test. Understanding reasons for increased travel distances could improve accessibility and acceptability of HIV services and increase early diagnosis rates.

Can Young Adults Accurately Report Sexual Partnership Dates? Factors Associated With Interpartner and Dyad Agreement.

BACKGROUND: Sexual partnership dates are critical to sexually transmitted infection/HIV research and control programs, although validity is limited by inaccurate recall and reporting. METHODS: We examined data from 302 heterosexual adults (151 index-partner dyads) to assess reliability of reporting. Dates of first sex and last sex were collected through individual interviews and joint dyad questionnaires, which were completed together with their partners. We compared index- and partner-reported dates to estimate interpartner agreement. We used log-linear regression to model associations between interpartner differences and partnership characteristics. To assess validity, we compared individually reported dates with those from joint dyad questionnaires. RESULTS: Most partnerships (66.2%) were 2 years or less in duration, and many (36.2%) were nonmonogamous. Interpartner agreement to within 1, 30, and 365 days was, respectively, 5.6%, 43.1%, and 81.3% for first sex, and 32.9%, 94.5%, and 100.0% for last sex. In adjusted models, longer relationship duration was associated with disagreement on first sex dates; partnership nonmonogamy was associated with disagreement on dates of first sex and last sex. Within dyads, several participant characteristics were associated with reporting dates closer to joint dyad responses (e.g., for first sex date, female sex [54.7%], having fewer sex partners [58.5%], and greater relationship commitment [57.3%]). However, percent agreement to within 30, 60, and 90 days was similar for all groups for both first and last sex dates. CONCLUSIONS: Agreement was high on date of last sex but only moderate on date of first sex. Methods to increase accuracy of reporting of dates of sex may improve STI research.

Influence of Detection Method and Study Area Scale on Syphilis Cluster Identification in North Carolina.

BACKGROUND: Identifying geographical clusters of sexually transmitted infections can aid in targeting prevention and control efforts. However, detectable clusters can vary between detection methods because of different underlying assumptions. Furthermore, because disease burden is not geographically homogenous, the reference population is sensitive to the study area scale, affecting cluster outcomes. We investigated the influence of cluster detection method and geographical scale on syphilis cluster detection in Mecklenburg County, North Carolina. METHODS: We analyzed primary and secondary syphilis cases reported in North Carolina (2003-2010). Primary and secondary syphilis incidence rates were estimated using census tract-level population estimates. We used 2 cluster detection methods: local Moran's I using an areal adjacency matrix and Kulldorff's spatial scan statistic using a variable size moving circular window. We evaluated 3 study area scales: North Carolina, Piedmont region, and Mecklenburg County. We focused our investigation on Mecklenburg, an urban county with historically high syphilis rates. RESULTS: Syphilis clusters detected using local Moran's I and Kulldorff's scan statistic overlapped but varied in size and composition. Because we reduced the scale to a high-incidence urban area, the reference syphilis rate increased, leading to the identification of smaller clusters with higher incidence. Cluster demographic characteristics differed when the study area was reduced to a high-incidence urban county. CONCLUSIONS: Our results underscore the importance of selecting the correct scale for analysis to more precisely identify areas with high disease burden. A more complete understanding of high-burden cluster location can inform resource allocation for geographically targeted sexually transmitted infection interventions.

Ten Years of Screening and Testing for Acute HIV Infection in North Carolina.

OBJECTIVE: To describe demographic and behavioral characteristics of persons with acute HIV infection (AHI) over time. METHODS: We conducted a retrospective assessment of AHI identified through the Screening and Tracing Active Transmission (STAT) program from 2003 to 2012 in North Carolina (NC). AHI was identified using pooled nucleic acid amplification for antibody negative samples and individual HIV-1 RNA for antibody indeterminate samples. The STAT program provides rapid notification and evaluation. We compared STAT-collected demographic and risk characteristics with all persons requesting tests and all non-AHI diagnoses from the NC State Laboratory of Public Health. RESULTS: The STAT Program identified 236 AHI cases representing 3.4% (95% confidence interval: 3.0% to 3.9%) of all HIV diagnoses. AHI cases were similar to those diagnosed during established HIV. On pretest risk-assessments, AHI cases were predominately black (69.1%), male (80.1%), young (46.8% < 25 years), and men who have sex with men (MSM) (51.7%). Per postdiagnosis interviews, the median age decreased from 35 (interquartile range 25-42) to 27 (interquartile range 22-37) years, and the proportion <25 years increased from 23.8% to 45.2% (trend P = 0.04) between 2003 and 2012. AHI men were more likely to report MSM risk post-diagnosis than on pretest risk-assessments (64%-82.9%; P < 0.0001). Post-diagnosis report of MSM risk in men with AHI increased from 71.4% to 96.2%. CONCLUSIONS: In NC, 3.4% of individuals diagnosed with HIV infection have AHI. AHI screening provides a real-time source of incidence trends, improves the diagnostic yield of HIV testing, and offers an opportunity to limit onward transmission.

Association of perceived partner non-monogamy with prevalent and incident sexual concurrency.

OBJECTIVES: Concurrency is suggested as an important factor in sexually transmitted infection transmission and acquisition, though little is known regarding factors that may predict concurrency initiation. We examined the association between perception of a partner's non-monogamy (PPNM) and simultaneous or subsequent concurrency among at-risk heterosexual young adults in the Los Angeles area. METHODS: We used Poisson regression models to estimate the relationship between PPNM and incident concurrency among 536 participants participating in a cohort study, interviewed at 4-month periods during 1 year. Concurrency was defined as an overlap in reported sexual partnership dates; PPNM was defined as believing a partner was also having sex with someone else. RESULTS: Participants (51% female; 30% non-Hispanic white, 28% non-Hispanic black, 27% Hispanic/Latino) had a mean age of 23 years and lifetime median of nine sex partners. At each interview (baseline, 4-month, 8-month and 12-month), 4-month concurrency prevalence was, respectively, 38.8%, 27.4%, 23.1% and 24.5%. Four-month concurrency incidence at 4, 8 and 12 months was 8.5%, 10.6% and 17.8%, respectively. Participants with recent PPNM were more likely to initiate concurrency (crude 4-month RR=4.6; 95% CI 3.0, 7.0; adjusted 4-month RR=4.0, 95% CI 2.6 to 6.1). CONCLUSIONS: Recent PPNM was associated with incident concurrency. Among young adults, onset of concurrency may be stimulated, relatively quickly, by the PPNM. Programmes which promote relationship communication skills and explicit monogamy expectations may help reduce concurrency.

Measuring the HIV Care Continuum Using Public Health Surveillance Data in the United States.

The HIV care continuum is a critical framework for situational awareness of the HIV epidemic; yet challenges to accurate enumeration of continuum components hamper continuum estimation in practice. We describe local surveillance-based estimation of the HIV continuum in the United States, reviewing common practices as recommended by the Centers for Disease Control and Prevention. Furthermore, we review some challenges and biases likely to threaten existing continuum estimates. Current estimates rely heavily on the use of CD4 cell count and HIV viral load laboratory results reported to surveillance programs as a proxy for receipt of HIV-related outpatient care. As such, continuum estimates are susceptible to bias because of incomplete laboratory reporting and imperfect sensitivity and specificity of laboratory tests as a proxy for routine HIV care. Migration of HIV-infected persons between jurisdictions also threatens the validity of continuum estimates. Data triangulation may improve but not fully alleviate biases.