William G. Cumberland

CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency.

The CD8+ T-cell response is central to control and eventual elimination of persistent viral infections. Although it might be expected that CD8+ T-cell activation would be associated with a better clinical outcome during viral infections, in long-term HIV-1 infection, high levels of CD8+ T-cell activation are instead associated with faster disease progression. In this study, cell surface expression of CD38, a flow cytometric marker of T-cell activation of CD8+ T cells, had predictive value for HIV-1 disease progression that was in part independent of the predictive value of plasma viral burden and CD4+ T-cell number. Measurements of CD38 antigen expression on CD8+ T cells in HIV-1-infected patients may be of value for assessing prognosis and the impact of therapeutic interventions. The pathogenetic reason why CD8+ T-cell activation is associated with poor outcome in HIV-1 disease remains unknown. Possibly CD8+ T-cell activation contributes to immunologic exhaustion, hyporesponsiveness of T cells to their cognate antigens, or perturbations in the T-cell receptor repertoire.

An Empirical Study of the Ratio Estimator and Estimators of its Variance

Abstract This paper reports results from an empirical study of the ratio estimator for a finite population total. From each of six real populations, 1,000 simple random samples, 1,000 restricted random samples, and three nonrandom samples of size 32 are drawn. Performance of the ratio estimator and of five estimators of its variance is compared with theoretical results generated using (a) prediction (superpopulation) models and (b) probability sampling distributions. The results, presented graphically, show that theory based on prediction models can reveal relationships that are essential in making inferences, but that are concealed in probability sampling analyses.

Elevated relative fluorescence intensity of CD38 antigen expression on CD8+ T cells is a marker of poor prognosis in HIV infection: Results of 6 years of follow‐up

Relative fluorescence intensity measurements from a flow cytometer were used to evaluate expression of CD38 and HLA-DR antigens. These molecules are associated with cellular activation and are present at increased levels on the CD8+ lymphocytes of HIV-infected subjects. In the current study, the prognostic value of mean fluorescence intensity measurements of CD38 and HLA-DR on CD8+ cells was compared to results from our previous study in which we reported prognostic value for an elevated percentage of CD8+ cells that were positive for expression of the CD38 antigen (Giorgi et al.: JAIDS 6:904-912, 1993). Using the proportional hazards model, elevated mean fluorescence intensity of CD38 expression on CD8+ cells had prognostic value for development of AIDS that was almost identical to the prognostic value of the percentage of CD8+ cells that were positive for expression of CD38. This prognostic value was in addition to that provided by the patients CD4+ cell measurement. To our knowledge, this is the first report that a measurement of fluorescence intensity can be used as a prognostic marker in an immunodeficiency disease. Efforts are needed to establish methods that will allow widespread application of this observation in the clinical management of HIV-infected subjects.

Effects of a behavioral intervention to reduce risk of transmission among people living with HIV: The Healthy Living Project randomized controlled study

Context:The US Centers for Disease Control and Prevention (CDC) strongly recommend comprehensive risk counceling and services for people living with HIV (PLH); yet, there are no evidence-based counseling protocols. Objective:To examine the effect of a 15-session, individually delivered, cognitive behavioral intervention on a diverse sample of PLH at risk of transmitting to others. Design:This was a multisite, 2-group, randomized, controlled trial. Participants:Nine hundred thirty-six HIV-infected participants considered to be at risk of transmitting HIV of 3818 persons screened were randomized into the trial. Participants were recruited in Los Angeles, Milwaukee, New York, and San Francisco. Intervention:Fifteen 90-minute individually delivered intervention sessions were divided into 3 modules: stress, coping, and adjustment; safer behaviors; and health behaviors. The control group received no intervention until the trial was completed. Both groups completed follow-up assessments at 5, 10, 15, 20, and 25 months after randomization. Main Outcome Measure:Transmission risk, as measured by the number of unprotected sexual risk acts with persons of HIV-negative or unknown status, was the main outcome measure. Results:Overall, a significance difference in mean transmission risk acts was shown between the intervention and control arms over 5 to 25 months (χ2 = 16.0, degrees of freedom = 5; P = 0.007). The greatest reduction occurred at the 20-month follow-up, with a 36% reduction in the intervention group compared with the control group. Conclusion:Cognitive behavioral intervention programs can effectively reduce the potential of HIV transmission to others among PLH who report significant transmission risk behavior.

Variance Estimation in Finite Population Sampling

Abstract Under a linear regression model, the best linear unbiased estimator (BLUE) for a finite population total can be obtained. The problem studied here is that of estimating the variance for setting large-sample confidence intervals about the BLUE when the model generating this estimate is inaccurate. A robust variance estimator is derived, and its asymptotic properties are shown to compare favorably with those of the weighted least-squares variance estimator. The robust variance estimator is shown to be asymptotically equivalent to the jackknife variance estimator under rather general conditions. These are extensions of results previously established for the ratio estimator by Royall and Eberhardt (1975).

Social Networking Technologies as an Emerging Tool for HIV Prevention: A Cluster Randomized Trial

BACKGROUND Social networking technologies are an emerging tool for HIV prevention. OBJECTIVE To determine whether social networking communities can increase HIV testing among African American and Latino men who have sex with men (MSM). DESIGN Randomized, controlled trial with concealed allocation. (ClinicalTrials.gov: NCT01701206). SETTING Online. PATIENTS 112 MSM based in Los Angeles, more than 85% of whom were African American or Latino. INTERVENTION Sixteen peer leaders were randomly assigned to deliver information about HIV or general health to participants via Facebook groups over 12 weeks. After participants accepted a request to join the group, participation was voluntary. Group participation and engagement were monitored. Participants could request a free, home-based HIV testing kit and completed questionnaires at baseline and 12-week follow-up. MEASUREMENTS Participant acceptance of and engagement in the intervention and social network participation, rates of home-based HIV testing, and sexual risk behaviors. RESULTS Almost 95% of intervention participants and 73% of control participants voluntarily communicated using the social platform. Twenty-five of 57 intervention participants (44%) requested home-based HIV testing kits compared with 11 of 55 control participants (20%) (difference, 24 percentage points [95% CI, 8 to 41 percentage points]). Nine of the 25 intervention participants (36%) who requested the test took it and mailed it back compared with 2 of the 11 control participants (18%) who requested the test. Retention at study follow-up was more than 93%. LIMITATION Only 2 Facebook communities were included for each group. CONCLUSION Social networking communities are acceptable and effective tools to increase home-based HIV testing among at-risk populations. PRIMARY FUNDING SOURCE National Institute of Mental Health.

Serum beta 2-microglobulin level increases in HIV infection: relation to seroconversion, CD4 T-cell fall and prognosis.

Beta2-microglobulin (β2-M), a marker that is increased in serum during immune activation, was investigated during the course of HIV infection. β2-M rose promptly in the first phase of HIV infection in people who were participating in a longitudinal study where serum samples and lymphocyte subset data were obtained at 6-monthly intervals. A rise in β2-M level in the first seropositive sample was seen in 93% of 50 HIV seroconverters, and those with high (or low) levels of β2-M at the end of year 1 tend to remain high (or low) in the ensuing years. Eighty-three per cent of seroconverters experienced a fall in CD4 T cells in the first year. The magnitude of the CD4 T-cell decline, however, did not correlate with the rise in β2-M in specific individuals in the first year. Nevertheless, 2–3 years after seroconversion, the initially increased β2-M levels did correlate inversely with the (reduced) level of CD4 T cells (P < 0.001). Thus, the pattern of disease reflected by β2-M level is established in the first year of infection and persists through the following 2 years. β2-M levels were found to correlate with rate of CD4 T-cell fall in individuals with established HIV infection. Three groups of HIV-seropositive people with similar CD4 T-cell numbers at the first measurements (about 600–800 × 106/l) but different rates of CD4 T-cell fall over the following 2 years were evaluated by β2-M levels. The group with stable CD4 T-cell numbers showed a significantly lower level of β2-M than the groups with moderately or rapidly declining CD4 T-cell numbers. Increases in β2-M levels during the 2 years of observation were found in people exhibiting a rapid decline in CD4 T cells (about 200 cells/year). The level of β2-M appears to be an indicator of HIV activity and of the rate of CD4 T-cell fall. Serum β2-M level was also found to be a good indicator of AIDS occurrence within 3 years. In a study of 399 men who were seropositive and without AIDS at entry, β2-M and CD4 T cells had about equal predictive power, but the combination of CD4 T cell and β2-M levels provided a more powerful prognostic ability than either alone.

A school salad bar increases frequency of fruit and vegetable consumption among children living in low-income households

OBJECTIVE To measure change in fruit and vegetable (F&V) consumption among elementary-school children after the introduction of a salad bar programme as a lunch menu option in the US Department of Agricultures (USDA) reimbursable lunch programme in Los Angeles Unified School District (LAUSD). DESIGN A cross-sectional sample of children was interviewed before and after a salad bar intervention (1998 and 2000, respectively) utilising a 24-hour food recall questionnaire. Frequencies of F&V consumption were calculated. SETTING The evaluation took place in three LAUSD elementary schools participating in the salad bar programme and the USDA reimbursable lunch programme. SUBJECTS Three hundred and thirty-seven children in 2nd-5th grade (7-11 years old). RESULTS After the salad bar was introduced, there was a significant increase in frequency (2.97 to 4.09, P < 0.001) of F&V consumed among the children studied. The increase in frequency of F&V consumed was almost all due to an increase during lunch (84%). Mean energy, cholesterol, saturated fat and total fat intakes were significantly lower in the children after the salad bar was introduced in the schools compared with the intakes in the children before the salad bar was introduced. CONCLUSION A salad bar as a lunch menu option in the USDA reimbursable lunch programme can significantly increase the frequency of F&V consumption by elementary-school children living in low-income households.

Social networking technologies as emerging tools for HIV prevention: A Cluster Randomized Trial

BACKGROUND Social networking technologies are an emerging tool for HIV prevention. OBJECTIVE To determine whether social networking communities can increase HIV testing among African American and Latino men who have sex with men (MSM). DESIGN Randomized, controlled trial with concealed allocation. (ClinicalTrials.gov: NCT01701206). SETTING Online. PATIENTS 112 MSM based in Los Angeles, more than 85% of whom were African American or Latino. INTERVENTION Sixteen peer leaders were randomly assigned to deliver information about HIV or general health to participants via Facebook groups over 12 weeks. After participants accepted a request to join the group, participation was voluntary. Group participation and engagement were monitored. Participants could request a free, home-based HIV testing kit and completed questionnaires at baseline and 12-week follow-up. MEASUREMENTS Participant acceptance of and engagement in the intervention and social network participation, rates of home-based HIV testing, and sexual risk behaviors. RESULTS Almost 95% of intervention participants and 73% of control participants voluntarily communicated using the social platform. Twenty-five of 57 intervention participants (44%) requested home-based HIV testing kits compared with 11 of 55 control participants (20%) (difference, 24 percentage points [95% CI, 8 to 41 percentage points]). Nine of the 25 intervention participants (36%) who requested the test took it and mailed it back compared with 2 of the 11 control participants (18%) who requested the test. Retention at study follow-up was more than 93%. LIMITATION Only 2 Facebook communities were included for each group. CONCLUSION Social networking communities are acceptable and effective tools to increase home-based HIV testing among at-risk populations. PRIMARY FUNDING SOURCE National Institute of Mental Health.

First Phase 1 Double-Blind, Placebo-Controlled, Randomized Rectal Microbicide Trial Using UC781 Gel with a Novel Index of Ex Vivo Efficacy

Objectives Successful control of the HIV/AIDS pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. We report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo. Methods HIV-1 seronegative, sexually-abstinent men and women (N = 36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1∶1∶1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint. Results All 36 subjects enrolled completed the 7–14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1BaL showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration. Conclusions Single and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant AEs, high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538)