Anna B. Cope

Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies

The quantitative viral outgrowth assay (QVOA) provides a precise minimal estimate of the reservoir of resting CD4(+) T-cell infection (resting cell infection [RCI]). However, the variability of RCI over time during antiretroviral therapy (ART), relevant to assess potential effects of latency-reversing agents or other interventions, has not been fully described. We performed QVOA on resting CD4(+) T cells obtained via leukapheresis from 37 human immunodeficiency virus (HIV)-infected patients receiving stable suppressive ART for a period of 6 years. Patients who started ART during acute (n = 17) or chronic (n = 20) HIV infection were studied once HIV RNA levels were <50 copies/mL for ≥ 6 months. Using random effects analysis of 160 RCI measurements, we found that RCI declined significantly over time (P < .001), with an estimated mean half-life of 3.6 years (95% confidence interval, 2.3-8.1 years), remarkably consistent with findings of prior studies. There was no evidence of more rapid decay in acute versus chronic HIV infection (P = .99) for patients suppressed ≥ 6 months. RCI was reliably estimated with longitudinal measurements generally showing < 2-fold variation from the previous measure. When QVOA is performed in this format, RCI decreases of >6-fold were rare. We suggest that a 6-fold decline is a relevant threshold to reliably identify effects of antilatency interventions on RCI.

Antiretroviral therapy initiated during acute HIV infection fails to prevent persistent T-cell activation.

Abstract:Initiation of antiretroviral therapy during acute HIV-1 infection may prevent persistent immune activation. We analyzed longitudinal CD38+HLA-DR+ CD8+ T-cell percentages in 31 acutely infected individuals who started early (median 43 days since infection) and successful antiretroviral therapy, and maintained viral suppression through 96 weeks. Pretherapy a median of 72.6% CD8+ T cells were CD38+HLA-DR+, and although this decreased to 15.6% by 96 weeks, it remained substantially higher than seronegative controls (median 8.9%, P = 0.008). Shorter time to suppression predicted lower activation at 96 weeks. These results support the hypothesis that very early events in HIV-1 pathogenesis may result in prolonged immune dysfunction.

Ocular Syphilis — Eight Jurisdictions, United States, 2014–2015

Ocular syphilis, a manifestation of Treponema pallidum infection, can cause a variety of ocular signs and symptoms, including eye redness, blurry vision, and vision loss. Although syphilis is nationally notifiable, ocular manifestations are not reportable to CDC. Syphilis rates have increased in the United States since 2000. After ocular syphilis clusters were reported in early 2015, CDC issued a clinical advisory (1) in April 2015 and published a description of the cases in October 2015 (2). Because of concerns about an increase in ocular syphilis, eight jurisdictions (California, excluding Los Angeles and San Francisco, Florida, Indiana, Maryland, New York City, North Carolina, Texas, and Washington) reviewed syphilis surveillance and case investigation data from 2014, 2015, or both to ascertain syphilis cases with ocular manifestations. A total of 388 suspected ocular syphilis cases were identified, 157 in 2014 and 231 in 2015. Overall, among total syphilis surveillance cases in the jurisdictions evaluated, 0.53% in 2014 and 0.65% in 2015 indicated ocular symptoms. Five jurisdictions described an increase in suspected ocular syphilis cases in 2014 and 2015. The predominance of cases in men (93%), proportion of those who are men who have sex with men (MSM), and percentage who are HIV-positive (51%) are consistent with the epidemiology of syphilis in the United States. It is important for clinicians to be aware of potential visual complications related to syphilis infections. Prompt identification of potential ocular syphilis, ophthalmologic evaluation, and appropriate treatment are critical to prevent or manage visual symptoms and sequelae of ocular syphilis.

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.

Incident sexually transmitted infection as a biomarker for high-risk sexual behavior after diagnosis of acute HIV.

Background Sexually transmitted infection (STI) diagnosis after diagnosis of acute HIV infection (AHI) indicates ongoing high-risk sexual behavior and possible risk of HIV transmission. We assessed predictors of STI acquisition and the effect of time since care entry on STI incidence in patients with AHI in care and receiving consistent risk-reduction messaging. Methods Data on incident gonorrhea, chlamydia, trichomoniasis, primary/secondary syphilis, demographic, and clinical risk factors were abstracted from medical charts for patients diagnosed as having AHI and engaged in care. Poisson regression models using generalized estimating equations were fit to estimate incidence rates (IRs), IR ratios, and robust 95% confidence intervals. Results Among 185 patients with AHI, 26 (14%) were diagnosed as having at least 1 incident STI over 709.4 person-years; 46 STIs were diagnosed during follow-up (IR, 6.8/100 person-years). The median time from HIV care entry to first STI diagnosis was 609 days (range, 168–1681 days). Men who have sex with men (P = 0.03), a shorter time between presentation to medical care and AHI diagnosis (P = 0.06), and STI diagnosis before AHI diagnosis (P = 0.0003) were predictors of incident STI. Sexually transmitted infection IR greater than 1 year after entering care was double that of patients in care 1 year or less (IR ratio, 2.0; 95% confidence interval, 0.8–4.9). HIV viral load was above the limits of detection within 1 month of 11 STI diagnoses in 6 patients (23.1%) (median, 15,898 copies/mL; range, 244–152,000 copies/mL). Conclusions Despite regular HIV care, STI incidence was high among this primarily young, men who have sex with men AHI cohort. Early antiretroviral initiation may decrease HIV transmission given ongoing risk behaviors despite risk-reduction messaging.

Measuring Concurrency Attitudes: Development and Validation of a Vignette-Based Scale.

Background Concurrent sexual partnerships (partnerships that overlap in time) may contribute to higher rates of HIV transmission in African Americans. Attitudes toward a behavior constitute an important component of most models of health-related behavior and behavioral change. We have developed a scale, employing realistic vignettes that appear to reliably measure attitudes about concurrency in young African American adults. Methods Vignette-based items to assess attitudes about concurrency were developed following focus groups and cognitive testing of items adapted from existing scales assessing psychosocial constructs surrounding related sexual behaviors. The new items were included in a telephone survey of African American adults (18–34 years old) in Eastern North Carolina immediately before and after a radio campaign designed to discourage concurrency. We performed an exploratory factor analysis on each sample (pre- and post-campaign) to cross-validate results. We retained factors with a primary loading of ≥0.50 and no secondary loading >0.30. Cronbach’s coefficient alpha was used to evaluate internal reliability. Associations in the predicted direction between the mean responses to items on the final factor and known correlates of concurrency validated the scale. Results Factor analysis in a random pre-campaign subsample yielded a one-factor 6-item scale with acceptable internal consistency (Cronbach’s α = 0.79). As expected, the attitude factor was positively associated with participation in concurrent partnerships, whether assessed by self-report (r = 0.298, p<0.0001) or deduced from dates of recent sexual partnerships (r = 0.298, p<0.0001). The factor was also positively associated with alcohol (r = 0.216, p<0.0001) and drug use (r = 0.225, p<0.0001) and negatively associated with increasing age (r = -0.088, p- = 0.02) and female gender (r = -0.232, p<0.0001). Factor analyses repeated in the second random pre-campaign subsample and post-campaign sample confirmed these results. Conclusion A vignette-based scale may be an effective measure of key attitudes related to concurrency and potentially a useful tool to evaluate interventions addressing this network pattern.

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

ABSTRACT 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.

Fixed-dose combination emtricitabine/tenofovir/efavirenz initiated during acute HIV infection; 96-week efficacy and durability

Background:Updated guidelines recommend immediate antiretroviral treatment (ART) during acute HIV infection (AHI), but efficacy data on regimens during AHI are limited. Methods:We provide final data on a prospective, single-arm 96-week open-label study of once-daily emtricitabine/tenofovir/efavirenz initiated during AHI. The primary endpoint was the proportion of responders with HIV RNA less than 200 copies/ml by week 24. We examined time to viral suppression, retention, and CD8+ cell activation through week 96 in relation to baseline characteristics. Results:Between January 2005 and December 2011, 92 AHI participants enrolled. Most participants (78%) were men who have sex with men (MSM), and 42% were young MSM (18–25 years of age). Two participants withdrew leaving 90 patients for analysis. Eighty-one (90%) remained on therapy and achieved viral suppression to less than 200 copies/ml by week 24, and 71 (79%) to less than 50 copies/ml at week 48. The median time from ART initiation to suppression less than 200 copies/ml was 65 days (range 7–523) and to less than 50 copies/ml was 105 days (range 14–523). The frequency of immune activation declined from a median of 67% to 16% through week 96. Retention on study was maintained in 92% of participants at week 48 and in 83% through week 96. Among 75 participants retained through week 96, 92% were suppressed to less than 50 copies/ml. Among 39 young MSM, 79% completed a week 96 visit and 67% were suppressed at week 96. Conclusion:ART during AHI resulted in rapid and sustained viral suppression with high rates of retention in care and on ART in this cohort including a large proportion of young MSM.

The Number of Interviews Needed to Yield New Syphilis and Human Immunodeficiency Virus Cases Among Partners of People Diagnosed With Syphilis, North Carolina, 2015

Compare syphilis investigation yield among patient groups using number needed to interview. Goal To increase investigation efficiency. Study Design Retrospective review of North Carolina 2015 syphilis investigations, using the number of cases needed to interview (NNTI) and the total number of cases and contacts needed to interview (TNTI) to compare yield of new syphilis and human immunodeficiency virus diagnoses between patient groups. Results We reviewed 1646 early syphilis cases and 2181 contacts; these yielded 241 new syphilis cases (NNTI, 6.9; TNTI, 16.4) and 38 new human immunodeficiency virus cases (NNTI, 43). Interviews of women (prevalence difference [PD] = 6%, 95% confidence interval [CI], 12–16), patients <30 years old (PD = 5%, 95% CI, 1–8), and patients with titer >1:16 (PD = 5%, 95% CI, 1–9) yielded more new syphilis cases in our adjusted model; no other patient factors increased investigation yield. Conclusions The NNTI and TNTI are useful measures of efficiency. Prioritizing early syphilis investigation by gender, rapid plasmin reagin titer, and age provides small increases in efficiency; no other factors increased efficiency.

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.