Proinflammatory oscillations over the menstrual cycle drives bystander CD4 T cell recruitment and SHIV susceptibility from vaginal challenge.

BACKGROUND: The menstrual cycle influences HIV infection-risk in women, although the timing and underlying mechanism are unclear. Here we investigated the contribution of the menstrual cycle to HIV susceptibility through evaluating immune behavior with infection-risk over time. METHODS: Blood and vaginal lavage samples were collected from 18 pig-tailed macaques to evaluate immune changes over reproductive cycles, and from 5 additional animals undergoing repeated vaginal exposures to simian HIV (SHIV). Peripheral blood mononuclear cell (PBMC) samples from healthy women (n = 10) were prospectively collected over the course of a menstrual cycle to profile T cell populations. Immune properties from PBMC and vaginal lavage samples were measured by flow cytometry. Plasma progesterone was measured by enzyme immunoassay. The oscillation frequency of progesterone concentration and CCR5 expression on CD4 T cells was calculated using the Lomb-Scargle periodogram. SHIV infection was monitored in plasma by RT-PCR. Immune measures were compared using generalized estimating equations (GEE). FINDINGS: Macaques cycle-phases were associated with fluctuations in systemic immune properties and a type-1 inflammatory T cell response with corresponding CCR5+ memory CD4 T cell (HIV target cell) infiltration into the vaginal lumen at the late luteal phase. Power spectral analysis identified CCR5 oscillation frequencies synchronized with reproductive cycles. In a repetitive low-dose vaginal challenge model, productive SHIV163P3 infection only occurred during intervals of mounting type-1 T cell responses (n = 5/5). Finally, we identify similar type-1 inflammatory T cell responses over the menstrual cycle are occurring in healthy women. INTERPRETATION: These data demonstrate that periodic shifts in the immune landscape under menstrual cycle regulation drives bystander CCR5+ CD4 T cell recruitment and HIV susceptibility in the female reproductive tract. FUNDING: This study was supported by the U.S. Centers for Disease Control and Prevention, Atlanta, GA 30329 and NIH grants to Emory University (K23AI114407 to A.N.S., the Emory University Center for AIDS research [P30AI050409], and Atlanta Clinical and Translational Sciences Institute [KLR2TR000455, UL1TR000454]). DISCLAIMER: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. Centers for Disease Control and Prevention or the Department of Health and Human Services.

Evaluation of Sexual Risk Behavior Among Study Participants in the TDF2 PrEP Study Among Heterosexual Adults in Botswana.

OBJECTIVE: Among participants of a clinical trial to test the efficacy of tenofovir/emtricitabine in protecting heterosexual men and women living in Botswana from HIV infection, the aim was to determine (1) if sexual risk behavior, specifically condomless sex acts and number of sex partners, changed over time, (2) factors associated with condomless sex acts and number of sex partners, and (3) the effect of participant treatment arm perception on risk behavior to address the possibility of risk compensation. METHODS: A longitudinal modeling of rates of risk behaviors was used to determine if the rate of condomless sex acts (#acts/person) and rate of sex partners (#partners/person) changed over time and which factors were associated with behavior change. RESULTS: One thousand two hundred participants were analyzed over 1 year. There was a 25% decrease in the rate of sex partners among participants sexually active in the last 30 days. The rate of reported condomless sex acts was greater for males [rate ratio (RR) = 1.34; confidence interval (CI): 1.07 to 1.67] and participants whose sexual debut in years was ≤15 years of age (RR = 1.65; CI: 1.14 to 2.38) and 16-17 (RR = 1.68; CI: 1.22 to 2.31) compared with those ≥20 years. Rate of reported sex partners was greater for males (RR = 3.67; CI: 2.86 to 4.71) and participants whose age at sexual debut in years was ≤15 (RR = 2.92; CI: 2.01 to 4.22) and 16-17 (RR = 2.34; CI: 1.69 to 3.24) compared with those ≥20. There was no effect of participant treatment arm perception on risk behavior. CONCLUSIONS: Our study of preexposure prophylaxis to prevent HIV infection found no evidence of risk compensation which may have been due to participants' motivations to reduce their risk behaviors and risk-reduction counseling.

Measuring the potential role of frailty in apparent declining efficacy of HIV interventions.

OBJECTIVE: In recent HIV intervention trials, intervention efficacies appear to decline over time. Researchers have attributed this to "waning," or a loss of intervention efficacy. Another possible reason is heterogeneity in infection risk or "frailty." We propose an approach to assessing the impact of frailty and waning on measures of intervention efficacy and statistical power in randomized-controlled trials. METHODS: Using multiplicative risk reduction, we developed a mathematical formulation for computing disease incidence and the incidence rate ratio (IRR) as a function of frailty and waning. We designed study scenarios, which held study-related factors constant, varied waning and frailty parameters and measured the change in disease incidence, IRR, and statistical power. RESULTS: We found that frailty alone can impact disease incidence over time. However, frailty has minimal impact on the IRR. The factor that has the greatest influence on the IRR is intervention efficacy and the degree to which it is projected to wane. We also found that even moderate waning can cause an unacceptable decrease in statistical power while the impact of frailty on statistical power is minimal. DISCUSSION: We conclude that frailty has minimal impact on trial results relative to intervention efficacy. Study resources would, therefore, be better spent on efforts to keep the intervention efficacy constant throughout the trial (e.g., enhancing the vaccine schedule or promoting treatment adherence).

Patterns of condom use among students at historically Black colleges and universities: implications for HIV prevention efforts among college-age young adults.

Over 1.1 million Americans are living with human immunodeficiency virus (HIV), and African-American youth and young adults are disproportionately affected. Condoms are the most effective prevention tool, yet data regarding condom use patterns for African-American college youth are lacking. To inform and strengthen HIV prevention strategies with African-American college-age youth, we surveyed students attending 24 historically Black colleges and universities regarding condom use patterns. Students were administered anonymous questionnaires online to explore knowledge, attitudes, and practices related to condom use during last sexual intercourse (LSI). Among 824 sexually active respondents (51.8% female, median age 20 years, 90.6% heterosexuals), 526 (63.8%) reported condom use during LSI. Students who used condoms for disease prevention, whose mothers completed high school or had some college education or completed college were more likely to have used a condom during LSI. Spontaneity of sexual encounters, not feeling at risk of HIV, and partner-related perceptions were associated with condom non-use during LSI (p<0.05). Over a third of our college youth sample did not use a condom during LSI and may benefit from increased condom education efforts. These efforts should highlight condoms' effectiveness in protection from HIV. Future HIV education and prevention strategies with similar groups of young adults should explore the implications of maternal education, clarify perceptions of HIV risk, and consider strategies that increase consistent condom use to interrupt sexual transmission of HIV.

HIV/AIDS knowledge scores and perceptions of risk among African American students attending historically black colleges and universities.

OBJECTIVE: African American young adults are disproportionately affected by the HIV/AIDS epidemic and often unaware of their personal risk for HIV. Historically black colleges and universities (HBCUs) enroll 25% of college-educated African American young adults and can play an important role in HIV prevention. We examined HIV/AIDS knowledge of students at HBCUs to inform and strengthen our HIV prevention efforts at HBCUs. METHODS: African American undergraduate HBCU students completed online surveys assessing HIV/AIDS knowledge and behaviors, and we analyzed data to assess their knowledge and behaviors. RESULTS: A total of 1,051 of 1,230 surveys completed (85.4%) were analyzable. Eighty-two percent of students had average/high HIV knowledge scores. Seventy-nine percent of students surveyed perceived themselves to be at low risk for HIV infection; 64% of those who had at least two or more sex partners had not used a condom at last sex encounter. In the final model, significant independent effects were identified for average/high knowledge of HIV risk, including agreeing with assessing a potential partner's HIV risk by all of the five actions listed (adjusted odds ratio [AOR] = 2.7, 95% confidence interval [CI] 1.7, 4.3) and never using a needle to inject drugs (AOR=5.6, 95% CI 3.2, 9.7). CONCLUSIONS: Educating students about effectively assessing sex partner risk will improve HIV knowledge and prevention efforts at HBCUs.

Epidemiology of HIV among Asians and Pacific Islanders in the United States, 2001-2008.

BACKGROUND: Recent analyses have shown increases in combined annual HIV diagnosis rates for Asians and Pacific Islanders (API). METHODS: Using surveillance data from 33 states and 4 dependent areas we investigated the epidemiology of HIV among API during 2001-2008. RESULTS: HIV diagnoses for API during 2001-2008 were predominantly among persons age 30-39 years (40%) and males (78%). The primary risk factor for males was sexual contact with males (78%) and for females, heterosexual contact (86%). API were the only racial/ethnic groups with a statistically significant estimated annual percentage increase (4.4%) in HIV diagnoses over the time period. Thirty-seven percent of HIV diagnoses among API progressed to AIDS in <12 months, with significantly greater likelihood among those 30 years and older. Survival was lower among API with AIDS diagnosis after 49 years of age, and was higher among persons with AIDS whose primary risk factor for infection was heterosexual contact. CONCLUSIONS: In contrast to other racial/ethnic groups, API were the only groups to show a significant increase in HIV diagnoses. A clearer understanding of the reasons for this trend is needed, so that appropriate interventions can be selected and adapted to prevent increased HIV prevalence among API in the U.S.

Provision of HIV counseling and testing services at five community-based organizations among young men of color who have sex with men.

In the context of monitoring and improving CDC-funded HIV prevention programs, we describe HIV tests and infections, provision of results, previous HIV tests, and risk behaviors for young (aged 13-29) men of color who have sex with men who received HIV tests at five community-based organizations. Of 1,723 tests provided, 2.1% were positive and 75.7% of positives were previously unaware of their infection. The highest positivity rate was among men aged 25-29 (4.7%). Thirty-four percent of tests were provided to men who were tested for the first time. Over half the tests (53.2%) were provided to men who reported sex with a person of unknown HIV status, and 34% to men who reported sex with an anonymous partner. Continued and more focused prevention efforts are needed to reach and test young men of color who have sex with men and to identify previously undiagnosed HIV infections among this target population.

Assessing mediation in HIV intervention studies.

OBJECTIVES: A mediator is a psychosocial construct that is targeted by an intervention to bring about behavior change. Recent literature suggests that a widely used approach for assessing mediation, namely the causal steps method, can be severely statistically underpowered. This article describes three standard methods for assessing mediation: causal steps, difference in coefficients, and product of coefficients. We also demonstrate the use of asymmetric confidence limits (ACLs) in testing mediation. METHODS: We compared the results obtained by ACL construction with results obtained based on the causal steps and product of coefficients approaches to analyze data from the Seropositive Urban Men's Intervention Trial. RESULTS: ACL construction uncovered previously unidentified mediating factors. We also identified a marginally significant suppressor, which means that, with regard to this factor, the intervention had effects that were opposite from the desired direction. CONCLUSIONS: ACLs are preferred for this type of analysis because of their statistical power and because they are informative regardless of whether the intervention has a significant effect on the outcome. Furthermore, ACLs present the size of the mediating effect rather than just a binary decision regarding significance.

Epidemiologic issues in study design and data analysis related to FoodNet activities.

The Foodborne Disease Active Surveillance Network (FoodNet) seeks to determine and to monitor the burden of foodborne diseases in the United States more precisely and to attribute these diseases to specific food vehicles or other exposures. These objectives present statistical and epidemiologic challenges. Estimates of the burden of foodborne diseases should include an estimate of the uncertainty in such calculations. Monitoring the burden of foodborne diseases should account for the expansion of the FoodNet population over time. Attributing foodborne diseases to specific vehicles is facilitated by FoodNet case-control studies of sporadic illness. This article discusses the strengths and limitations of the various studies aimed at addressing these objectives in this supplement. Furthermore, because the FoodNet surveillance areas were not chosen specifically to reflect the demographic composition of the US population, this article also discusses the generalizability of FoodNet results to the US population.

Trends in population-based active surveillance for shigellosis and demographic variability in FoodNet sites, 1996-1999.

Shigella is a common cause of diarrhea in the United States, and accurate surveillance is needed to determine the burden of illness that they cause. Active surveillance for culture-confirmed Shigella infection was done as part of the Foodborne Diseases Active Surveillance Network (FoodNet). A total of 4317 cases of shigellosis were reported during 1996-1999 in the original FoodNet surveillance areas. The average annual incidence was 7.4 cases/100,000 population. The incidence was similar during 1996-1998, but it declined in 1999 to 5.0 cases/100,000 population. State-to-state variability was seen in the incidence of shigellosis. Higher incidence was observed in California and Georgia. Shigella sonnei accounted for 70% of the infections, followed by Shigella flexneri (24%). Compared with other age groups, the incidence was highest among children aged 1-4 years of (36.3 cases/100,000 population). Marked demographic differences were observed between infections with S. sonnei and S. flexneri.

Chicken consumption is a newly identified risk factor for sporadic Salmonella enterica serotype Enteritidis infections in the United States: a case-control study in FoodNet sites.

The sources of sporadic Salmonella enterica serotype Enteritidis (SE) infections in the United States are unclear. To determine risk factors for sporadic SE infection, we conducted a population-based case-control study in 5 Foodborne Disease Active Surveillance Network surveillance areas. During the 12-month study, 396 cases of SE infection were ascertained. Among the 182 case patients and 345 controls, SE infection was univariately associated with international travel (matched odds ratio [MOR], 61; 95% confidence interval [CI], 8-447), eating undercooked eggs (MOR, 2.2; 95%CI, 1-5), and eating chicken prepared outside of the home (MOR, 2.2; 95% CI, 1.3-3.4). Multivariate analysis revealed that eating chicken outside of the home remained the only significant risk factor for illness (MOR, 2.0; 95% CI, 1.1-3.6). Chicken consumption has not previously been identified in the United States as a risk factor for SE infection. Measures to prevent SE infections include educating consumers and food handlers about food safety and interventions to decrease contamination of eggs and poultry.

Breast-feeding decreases the risk of sporadic salmonellosis among infants in FoodNet sites.

Among the population of the Foodborne Diseases Active Surveillance Network (FoodNet) surveillance areas ("FoodNet sites") in 1996, children under 12 months of age had the highest incidence of sporadic salmonellosis. We conducted a case-control study in 5 FoodNet sites to identify risk factors for sporadic infant salmonellosis. A case patient was a child under 12 months of age with a laboratory-confirmed, nontyphoidal serogroup B or D Salmonella infection. Twenty-two case patients were matched with 39 control subjects by age and either telephone exchange or vital record birth list. In a multivariate analysis, case patients were more likely to have a liquid diet containing no breast milk than a liquid diet containing only breast milk (matched odds ratio, 44.5; P=.04). Case-patients were more likely to reside in a household where a member had diarrhea (matched odds ratio, 13.2; P=.01). To decrease their infants' risk of salmonellosis, mothers should be encouraged to breast-feed their infants. Caretakers of infants should learn about salmonellosis, hand washing, and safe preparation of formula and solid food.