Colleen F. Kelley

Understanding Racial HIV/STI Disparities in Black and White Men Who Have Sex with Men: A Multilevel Approach

Background The reasons for black/white disparities in HIV epidemics among men who have sex with men have puzzled researchers for decades. Understanding reasons for these disparities requires looking beyond individual-level behavioral risk to a more comprehensive framework. Methods and Findings From July 2010-Decemeber 2012, 803 men (454 black, 349 white) were recruited through venue-based and online sampling; consenting men were provided HIV and STI testing, completed a behavioral survey and a sex partner inventory, and provided place of residence for geocoding. HIV prevalence was higher among black (43%) versus white (13% MSM (prevalence ratio (PR) 3.3, 95% confidence interval (CI): 2.5–4.4). Among HIV-positive men, the median CD4 count was significantly lower for black (490 cells/µL) than white (577 cells/µL) MSM; there was no difference in the HIV RNA viral load by race. Black men were younger, more likely to be bisexual and unemployed, had less educational attainment, and reported fewer male sex partners, fewer unprotected anal sex partners, and less non-injection drug use. Black MSM were significantly more likely than white MSM to have rectal chlamydia and gonorrhea, were more likely to have racially concordant partnerships, more likely to have casual (one-time) partners, and less likely to discuss serostatus with partners. The census tracts where black MSM lived had higher rates of poverty and unemployment, and lower median income. They also had lower proportions of male-male households, lower male to female sex ratios, and lower HIV diagnosis rates. Conclusions Among black and white MSM in Atlanta, disparities in HIV and STI prevalence by race are comparable to those observed nationally. We identified differences between black and white MSM at the individual, dyadic/sexual network, and community levels. The reasons for black/white disparities in HIV prevalence in Atlanta are complex, and will likely require a multilevel framework to understand comprehensively.

The relation between symptoms, viral load, and viral load set point in primary HIV infection.

Objectives:To examine the relation between symptoms, initial viral load, and viral load set point in primary HIV infection (PHI). Design:Prospective cohort of patients with preseroconversion or recent seroconversion HIV infection (typically <60 days) in San Francisco. Methods:Subjects were questioned about 21 potential PHI symptoms at enrollment and were subsequently followed with viral load measures. Results:The analysis included 57 subjects with preseroconversion HIV infection and 120 with recent seroconversion. In univariate analysis, most symptoms and the total number of symptoms were each associated with a significantly higher initial viral load. In stepwise multiple linear regression, however, only the number of symptoms was independently associated with a higher initial viral load, with an increase in the initial viral load of 0.08 log10 per additional symptom (P < 0.001). In univariate analysis, more PHI symptoms were associated with a higher viral load set point, but in a multivariable mixed-effects model, this association was accounted for by the initial viral load, which was strongly correlated with viral load set point (R = 0.44, P < 0.001). Conclusions:A high initial viral load was associated with more symptoms during PHI. The strong correlation between initial HIV-1 RNA viral load levels and viral load set point suggests that early interactions between the HIV-1 virus and a new host, even before fully developed adaptive immune responses, are important in establishing viral load set point.

Applying a PrEP Continuum of Care for Men Who Have Sex With Men in Atlanta, Georgia

Reductions in human immunodeficiency virus (HIV) incidence with pre-exposure prophylaxis (PrEP) for men who have sex with men (MSM) will require significant coverage of those at risk. We propose a simplified framework, similar to the HIV care continuum, to achieve protection with PrEP as follows: 1. At-risk MSM; 2. Awareness of and willingness to take PrEP; 3. Access to healthcare; 4. Receiving a prescription; and 5. Adhering to effective PrEP. We evaluated the PrEP care continuum on an Atlanta cohort of MSM and projected how many MSM might achieve protection from HIV. Even with optimistic estimates, few Atlanta MSM (15%) are projected to achieve protection from HIV with PrEP given the significant barriers described. Each continuum step represents an important point for intervention that could substantially increase the overall effectiveness of PrEP. In addition, novel strategies for PrEP delivery are needed to achieve the necessary effectiveness for Atlanta MSM at risk of HIV.

Evidence of persistent low-level viremia in long-term HAART-suppressed, HIV-infected individuals.

Background:HAART can effectively reduce plasma HIV RNA levels to below the level of detection in most HIV-infected patients. The degree to which residual low-level viremia persists during HAART remains unclear. Methods:We identified 180 individuals (median duration of HIV infection 12 years) who had at least two consecutive plasma HIV-1 RNA levels below the level of detection (<50–75 copies/ml) while taking antiretroviral drugs; 36 of 180 had been virologically suppressed for more than 5 years. Longitudinal plasma samples that were taken from these individuals during periods of viral load suppression were selected and analyzed. The isothermal transcription-mediated amplification (TMA) (limit of detection <3.5 copies RNA/ml) assay was used to measure persistent viremia. A ‘detuned’ EIA assay was used to obtain quantitative HIV antibody levels. Results:A total of 1606 TMA assays were performed on 438 specimens in 180 HAART-suppressed individuals (median 3 replicates per specimen). In the first year of viral suppression, plasma RNA levels declined significantly (P = 0.001), but after month 12 there was no evidence for a continued decline (P = 0.383). In the first year of viral suppression, HIV antibody levels also declined (P = 0.054), but after month 12 there was no evidence for a continued decline (P = 0.988). Conclusion:Viremia continued to decline during the first 12 months after viremia became undetectable using conventional methods, and then remained stable. HIV antibody levels also decreased in the first year of viral suppression and then remained stable. Viremia and the HIV-associated host response appear to achieve a steady-state ‘set-point’ during long-term combination therapy.

Trends in Hospitalizations for AIDS-Associated Pneumocystis jirovecii Pneumonia in the United States (1986 to 2005)

BACKGROUND Although hospitalizations for AIDS-associated Pneumocystis jirovecii pneumonia (PCP) in the United States have decreased since the introduction of chemoprophylaxis and potent combination antiretroviral therapy (ART), PCP remains an important cause of illness and death among AIDS patients. METHODS We analyzed trends in AIDS-associated PCP hospital discharges using the National Hospital Discharge Surveys between 1986 and 2005. RESULTS An estimated 539 million patients were discharged from hospitals between 1986 and 2005, of whom an estimated 312,411 had AIDS-associated PCP. The proportion of patients discharged from the hospital with AIDS-associated PCP decreased from 31% before the introduction of chemoprophylaxis (1986 to 1989) to 17% with chemoprophylaxis (1990 to 1995) and subsequently to 9% after the introduction of ART in 1996 (p < 0.001). Mortality from AIDS-associated PCP decreased from 21 to 16% and subsequently to 7% between these three time periods (p < 0.001). Among those who received mechanical ventilation, mortality decreased from 79% in the prechemoprophylaxis era to 31% in the ART era (p < 0.001) alongside an increase (from 5 to 11%) in the use of mechanical ventilation. We also observed a shift in the population at-risk for PCP over time: a greater proportion of black people, women, and people from Southern states were affected (all p < 0.001). CONCLUSIONS While there have been significant reductions in hospitalizations and hospital mortality for AIDS-associated PCP over the last 20 years, these reductions have not been homogenous across demographic subpopulations and geographic regions and point to new at-risk populations. Furthermore, mortality in severe cases of PCP that require mechanical ventilation has improved substantially.

The Comparability of Men Who Have Sex With Men Recruited From Venue-Time-Space Sampling and Facebook: A Cohort Study

Background Recruiting valid samples of men who have sex with men (MSM) is a key component of the US human immunodeficiency virus (HIV) surveillance and of research studies seeking to improve HIV prevention for MSM. Social media, such as Facebook, may present an opportunity to reach broad samples of MSM, but the extent to which those samples are comparable with men recruited from venue-based, time-space sampling (VBTS) is unknown. Objective The objective of this study was to assess the comparability of MSM recruited via VBTS and Facebook. Methods HIV-negative and HIV-positive black and white MSM were recruited from June 2010 to December 2012 using VBTS and Facebook in Atlanta, GA. We compared the self-reported venue attendance, demographic characteristics, sexual and risk behaviors, history of HIV-testing, and HIV and sexually transmitted infection (STI) prevalence between Facebook- and VTBS-recruited MSM overall and by race. Multivariate logistic and negative binomial models estimated age/race adjusted ratios. The Kaplan-Meier method was used to assess 24-month retention. Results We recruited 803 MSM, of whom 110 (34/110, 30.9% black MSM, 76/110, 69.1% white MSM) were recruited via Facebook and 693 (420/693, 60.6% black MSM, 273/693, 39.4% white MSM) were recruited through VTBS. Facebook recruits had high rates of venue attendance in the previous month (26/34, 77% among black and 71/76, 93% among white MSM; between-race P=.01). MSM recruited on Facebook were generally older, with significant age differences among black MSM (P=.02), but not white MSM (P=.14). In adjusted multivariate models, VBTS-recruited MSM had fewer total partners (risk ratio [RR]=0.78, 95% CI 0.64-0.95; P=.01) and unprotected anal intercourse (UAI) partners (RR=0.54, 95% CI 0.40-0.72; P<.001) in the previous 12 months. No significant differences were observed in HIV testing or HIV/STI prevalence. Retention to the 24-month visit varied from 81% for black and 70% for white MSM recruited via Facebook, to 77% for black and 78% for white MSM recruited at venues. There was no statistically significant differences in retention between the four groups (log-rank P=.64). Conclusions VBTS and Facebook recruitment methods yielded similar samples of MSM in terms of HIV-testing patterns, and prevalence of HIV/STI, with no differences in study retention. Most Facebook-recruited men also attended venues where VTBS recruitment was conducted. Surveillance and research studies may recruit via Facebook with little evidence of bias, relative to VBTS.

Measuring Population Transmission Risk for HIV: An Alternative Metric of Exposure Risk in Men Who Have Sex with Men (MSM) in the US

Background Various metrics for HIV burden and treatment success [e.g. HIV prevalence, community viral load (CVL), population viral load (PVL), percent of HIV-positive persons with undetectable viral load] have important public health limitations for understanding disparities. Methods and Findings Using data from an ongoing HIV incidence cohort of black and white men who have sex with men (MSM), we propose a new metric to measure the prevalence of those at risk of transmitting HIV and illustrate its value. MSM with plasma VL>400 copies/mL were defined as having ‘transmission risk’. We calculated HIV prevalence, CVL, PVL, percent of HIV-positive with undetectable viral loads, and prevalence of plasma VL>400 copies/ml (%VL400) for black and white MSM. We used Monte Carlo simulation incorporating data on sexual mixing by race to estimate exposure of black and white HIV-negative MSM to a partner with transmission risk via unprotected anal intercourse (UAI). Of 709 MSM recruited, 42% (168/399) black and 14% (44/310) white MSM tested HIV-positive (p<.0001). No significant differences were seen in CVL, PVL, or percent of HIV positive with undetectable viral loads. The %VL400 was 25% (98/393) for black vs. 8% (25/310) for white MSM (p<.0001). Black MSM with 2 UAI partners were estimated to have 40% probability (95% CI: 35%, 45%) of having ≥1 UAI partner with transmission risk vs. 20% for white MSM (CI: 15%, 24%). Discussion Despite similarities in other metrics, black MSM in our cohort are three times as likely as white MSM to have HIV transmission risk. With comparable risk behaviors, HIV-negative black MSM have a substantially higher likelihood of encountering a UAI partner at risk of transmitting HIV. Our results support increasing HIV testing, linkage to care, and antiretroviral treatment of HIV-positive MSM to reduce prevalence of those with transmission risk, particularly for black MSM.

The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial

BACKGROUND Microneedle patches provide an alternative to conventional needle-and-syringe immunisation, and potentially offer improved immunogenicity, simplicity, cost-effectiveness, acceptability, and safety. We describe safety, immunogenicity, and acceptability of the first-in-man study on single, dissolvable microneedle patch vaccination against influenza. METHODS The TIV-MNP 2015 study was a randomised, partly blinded, placebo-controlled, phase 1, clinical trial at Emory University that enrolled non-pregnant, immunocompetent adults from Atlanta, GA, USA, who were aged 18-49 years, naive to the 2014-15 influenza vaccine, and did not have any significant dermatological disorders. Participants were randomly assigned (1:1:1:1) to four groups and received a single dose of inactivated influenza vaccine (fluvirin: 18 μg of haemagglutinin per H1N1 vaccine strain, 17 μg of haemagglutinin per H3N2 vaccine strain, and 15 μg of haemagglutinin per B vaccine strain) (1) by microneedle patch or (2) by intramuscular injection, or received (3) placebo by microneedle patch, all administered by an unmasked health-care worker; or received a single dose of (4) inactivated influenza vaccine by microneedle patch self-administered by study participants. A research pharmacist prepared the randomisation code using a computer-generated randomisation schedule with a block size of 4. Because of the nature of the study, participants were not masked to the type of vaccination method (ie, microneedle patch vs intramuscular injection). Primary safety outcome measures are the incidence of study product-related serious adverse events within 180 days, grade 3 solicited or unsolicited adverse events within 28 days, and solicited injection site and systemic reactogenicity on the day of study product administration through 7 days after administration, and secondary safety outcomes are new-onset chronic illnesses within 180 days and unsolicited adverse events within 28 days, all analysed by intention to treat. Secondary immunogenicity outcomes are antibody titres at day 28 and percentages of seroconversion and seroprotection, all determined by haemagglutination inhibition antibody assay. The trial is completed and registered with ClinicalTrials.gov, number NCT02438423. FINDINGS Between June 23, 2015, and Sept 25, 2015, 100 participants were enrolled and randomly assigned to a group. There were no treatment-related serious adverse events, no treatment-related unsolicited grade 3 or higher adverse events, and no new-onset chronic illnesses. Among vaccinated groups (vaccine via health-care worker administered microneedle patch or intramuscular injection, or self-administered microneedle patch), overall incidence of solicited adverse events (n=89 vs n=73 vs n=73) and unsolicited adverse events (n=18 vs n=12 vs n=14) were similar. Reactogenicity was mild, transient, and most commonly reported as tenderness (15 [60%] of 25 participants [95% CI 39-79]) and pain (11 [44%] of 25 [24-65]) after intramuscular injection; and as tenderness (33 [66%] of 50 [51-79]), erythema (20 [40%] of 50 [26-55]), and pruritus (41 [82%] of 50 [69-91]) after vaccination by microneedle patch application. The geometric mean titres were similar at day 28 between the microneedle patch administered by a health-care worker versus the intramuscular route for the H1N1 strain (1197 [95% CI 855-1675] vs 997 [703-1415]; p=0·5), the H3N2 strain (287 [192-430] vs 223 [160-312]; p=0·4), and the B strain (126 [86-184] vs 94 [73-122]; p=0·06). Similar geometric mean titres were reported in participants who self-administered the microneedle patch (all p>0·05). The seroconversion percentages were significantly higher at day 28 after microneedle patch vaccination compared with placebo (all p<0·0001) and were similar to intramuscular injection (all p>0·01). INTERPRETATION Use of dissolvable microneedle patches for influenza vaccination was well tolerated and generated robust antibody responses. FUNDING National Institutes of Health.

Asthma Phenotypes, Risk Factors, and Measures of Severity in a National Sample of US Children

Objective. To examine a nationally representative sample of US children aged 6 to 16 years old and determine whether there are differences in risk factors and measures of severity between children with different asthma phenotypes. Methods. We analyzed data from the Third National Health and Nutrition Examination Survey. We used questionnaire and skin-prick testing data to separate children into the following mutually exclusive categories: atopic asthma, nonatopic asthma, resolved asthma, frequent respiratory symptoms with no asthma diagnosis, and normal. We used multivariate regression to determine whether demographic or potential risk factors varied between phenotypes and whether measures of severity varied by phenotype. Results. We found that 4.8% of children had atopic asthma, 1.9% had nonatopic asthma, 3.4% had resolved asthma, and 4.3% had frequent respiratory symptoms. Risk factors varied by phenotype, for example, the mean BMI was higher among children with nonatopic asthma, prenatal maternal smoking was a risk factor for resolved asthma, and child care attendance was a risk factor for frequent respiratory symptoms with no asthma diagnosis. Patients with atopic and nonatopic asthma were similar for most measures of asthma severity (medication use, health status, and lung function impairment). In contrast, patients with resolved asthma had fewer symptoms but a similar level of lung function impairment to that seen in patients with current asthma, whereas children with frequent respiratory symptoms but no asthma diagnosis had normal lung function. Conclusions. Asthma risk factors and measures of severity vary between children with different asthma phenotypes.

Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials

Summary Background The Zika virus epidemic and associated congenital infections have prompted rapid vaccine development. We assessed two new DNA vaccines expressing premembrane and envelope Zika virus structural proteins. Methods We did two phase 1, randomised, open-label trials involving healthy adult volunteers. The VRC 319 trial, done in three centres, assessed plasmid VRC5288 (Zika virus and Japanese encephalitis virus chimera), and the VRC 320, done in one centre, assessed plasmid VRC5283 (wild-type Zika virus). Eligible participants were aged 18–35 years in VRC19 and 18–50 years in VRC 320. Participants were randomly assigned 1:1 by a computer-generated randomisation schedule prepared by the study statistician. All participants received intramuscular injection of 4 mg vaccine. In VRC 319 participants were assigned to receive vaccinations via needle and syringe at 0 and 8 weeks, 0 and 12 weeks, 0, 4, and 8 weeks, or 0, 4, and 20 weeks. In VRC 320 participants were assigned to receive vaccinations at 0, 4, and 8 weeks via single-dose needle and syringe injection in one deltoid or split-dose needle and syringe or needle-free injection with the Stratis device (Pharmajet, Golden, CO, USA) in each deltoid. Both trials followed up volunteers for 24 months for the primary endpoint of safety, assessed as local and systemic reactogenicity in the 7 days after each vaccination and all adverse events in the 28 days after each vaccination. The secondary endpoint in both trials was immunogenicity 4 weeks after last vaccination. These trials are registered with ClinicalTrials.gov, numbers NCT02840487 and NCT02996461. Findings VRC 319 enrolled 80 participants (20 in each group), and VRC 320 enrolled 45 participants (15 in each group). One participant in VRC 319 and two in VRC 320 withdrew after one dose of vaccine, but were included in the safety analyses. Both vaccines were safe and well tolerated. All local and systemic symptoms were mild to moderate. In both studies, pain and tenderness at the injection site was the most frequent local symptoms (37 [46%] of 80 participants in VRC 319 and 36 [80%] of 45 in VRC 320) and malaise and headache were the most frequent systemic symptoms (22 [27%] and 18 [22%], respectively, in VRC 319 and 17 [38%] and 15 [33%], respectively, in VRC 320). For VRC5283, 14 of 14 (100%) participants who received split-dose vaccinations by needle-free injection had detectable positive antibody responses, and the geometric mean titre of 304 was the highest across all groups in both trials. Interpretation VRC5283 was well tolerated and has advanced to phase 2 efficacy testing. Funding Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.