Changes in weight and weight distribution across the lifespan among HIV-infected and -uninfected men and women.

Examine body composition changes across the lifespan of HIV-infected compared to uninfected adults. Longitudinal study of antiretroviral therapy (ART)-treated HIV-infected and uninfected participants from the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. Body mass index (BMI), waist (WC), hip circumference (HC), and waist-to-height ratio (WHtR) measured at semiannual visits from 1999 to 2014. The age effect on outcomes over time was investigated using multivariate, piecewise, linear mixed-effect regression models adjusted for demographics, substance use, and comorbidities. Person-visits from 2363 men (1059 HIV-infected/1304 HIV-uninfected) and 2200 women (1455 HIV-infected/745 HIV-uninfected), median ages 45 [IQR 39,51] and 40 [32,46], respectively, were included. BMI gains were slower among HIV-infected participants of 40 years or less (P < 0.001), similar between HIV-infected and uninfected persons 40 to 60 years of age, and plateaued after age 60 in both groups. WC and WHtR increased across the age spectrum (P < 0.001) regardless of HIV serostatus, with significantly greater gains in HIV-infected men more than 60. Black race and Hispanic ethnicity were associated with greater BMI and WC. Lower BMI, WC, hip circumference, and WHtR were associated with hepatitis C infection among women only, and with substance use among all participants, and with lower CD4 cell count and shorter ART duration among HIV-infected participants. Slower BMI gain among younger HIV-infected adults may be partly explained by substance use and hepatitis C infection, and suggests that lower BMI does not represent improved health. Further analysis of muscle and fat abundance and quality will advance understanding of metabolic risk over the lifespan, a key to reducing morbidity in an aging population.

Prevalence, correlates, and outcomes of cryptococcal antigen positivity among patients with AIDS, United States, 1986-2012.

BACKGROUND: Cryptococcal meningitis (CM) is one of the most common causes of AIDS-related mortality worldwide, accounting for 33%-63% of all cases of adult meningitis in sub-Saharan Africa and >500 000 deaths annually. In sub-Saharan Africa, the World Health Organization recommends routinely screening AIDS patients with a CD4 count ≤100 cells/µL for cryptococcal infection. In the United States, there are no recommendations for routine screening. We aimed to determine the prevalence of cryptococcal infection and outcomes of those infected among people living with advanced AIDS in the United States, to inform updates in the prevention and management of CM. METHODS: Using stored sera from participants in the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study from 1986 to 2012, we screened 1872 specimens with CD4 T-cell counts ≤100 cells/µL for cryptococcal antigen (CrAg) using the CrAg lateral flow assay. RESULTS: The overall prevalence of CrAg positivity within the study population was 2.9% (95% confidence interval, .2%-3.8%). Results from multivariable analysis revealed that a previous diagnosis with CM and a CD4 count ≤50 cells/µL were significantly associated with CrAg positivity. Participants who were CrAg positive had significantly shorter survival (2.8 years) than those who were CrAg negative (3.8 years; P = .03). CONCLUSIONS: The prevalence of cryptococcal infection among advanced AIDS patients in the United States was high and above the published cost-effectiveness threshold for routine screening. We recommend routine CrAg screening among human immunodeficiency virus-infected patients with a CD4 count ≤100 cells/µL to detect and treat early infection.

Value of a quality assessment program in optimizing cryopreservation of peripheral blood mononuclear cells in a multicenter study.

Cryopreservation of peripheral blood mononuclear cells (PBMC) allows assays of cellular function and phenotype to be performed in batches at a later time on PBMC at a central laboratory to minimize assay variability. The Multicenter AIDS Cohort Study (MACS) is an ongoing prospective study of the natural and treated history of human immunodeficiency virus (HIV) infection that stores cryopreserved PBMC from participants two times a year at four study sites. In order to ensure consistent recovery of viable PBMC after cryopreservation, a quality assessment program was implemented and conducted in the MACS over a 6-year period. Every 4 months, recently cryopreserved PBMC from HIV-1-infected and HIV-1-uninfected participants at each MACS site were thawed and evaluated. The median recoveries of viable PBMC for HIV-1-infected and -uninfected participants were 80% and 83%, respectively. Thawed PBMC from both HIV-1-infected and -uninfected participants mounted a strong proliferative response to phytohemagglutinin, with median stimulation indices of 84 and 120, respectively. Expression of the lymphocyte surface markers CD3, CD4, and CD8 by thawed PBMC was virtually identical to what was observed on cells measured in real time using whole blood from the same participants. Furthermore, despite overall excellent performance of the four participating laboratories, problems were identified that intermittently compromised the quality of cryopreserved PBMC, which could be corrected and monitored for improvement over time. Ongoing quality assessment helps laboratories improve protocols and performance on a real-time basis to ensure optimal cryopreservation of PBMC for future studies.

A comparison of ad hoc methods to account for non-cancer AIDS and deaths as competing risks when estimating the effect of HAART on incident cancer AIDS among HIV-infected men.

OBJECTIVE: To compare three ad hoc methods to estimate the marginal hazard of incident cancer acquired immune deficiency syndrome (AIDS) in a highly active antiretroviral therapy (1996-2006) relative to a monotherapy/combination therapy (1990-1996) calendar period, accounting for other AIDS events and deaths as competing risks. STUDY DESIGN AND SETTING: Among 1,911 human immunodeficiency virus (HIV)-positive men from the Multicenter AIDS Cohort Study, 228 developed cancer AIDS and 745 developed competing risks in 14,202 person-years from 1990 to 2006. Method 1 censored competing risks at the time they occurred, method 2 excluded competing risks, and method 3 censored competing risks at the date of analysis. RESULTS: The age, race, and infection duration adjusted hazard ratios (HRs) for cancer AIDS were similar for all methods (HR approximately 0.15). We estimated bias and confidence interval coverage of each method with Monte Carlo simulation. On average, across 24 scenarios, method 1 produced less-biased estimates than methods 2 or 3. CONCLUSIONS: When competing risks are independent of the event of interest, only method 1 produced unbiased estimates of the marginal HR, although independence cannot be verified from the data. When competing risks are dependent, method 1 generally produced the least-biased estimates of the marginal HR for the scenarios explored; however, alternative methods may be preferred.

Longitudinal assessment of de novo T cell production in relation to HIV-associated T cell homeostasis failure.

Loss of circulating CD4+ T cells in HIV-1 disease is balanced by CD8+ lymphocytosis to maintain normal CD3+ T cell counts [blind T cell homeostasis (TCH)]. However, for unknown reasons TCH generally fails 1.5-2.5 years before clinically defined AIDS. We investigated whether TCH failure was associated with changes in thymic production of T cells. Using specimens stored prospectively in the Multicenter AIDS Cohort Study (MACS), we measured expression of signal-joint T cell receptor excision circles (sjTRECs), a marker for thymic T cell production, and the fraction of proliferating naive and memory T cells during a 6-8 year period bracketing TCH failure. Segmented regression modeling assessed (1) rates of change in TREC levels before and after TCH failure, and (2) whether these were affected by cellular proliferation, which may dilute sjTREC levels. TCH failure was associated with a large decline in sjTREC (median 1109-fold, p = 0.028); the rate of this decline was only slightly affected when increased proliferation of naive T cells or other peripheral lymphocytes was taken into account. Preferential loss of naive CD4+ T cells was also noted before TCH failure, as has been seen in other studies. These results suggest that deficits in de novo T cell production, either through the decline of thymic function or the destruction of naive T cells, are likely to play an important role in TCH failure and progression of HIV-1 disease.

Evaluation of a low-cost method, the Guava EasyCD4 assay, to enumerate CD4-positive lymphocyte counts in HIV-infected patients in the United States and Uganda.

OBJECTIVE: To evaluate the EasyCD4 assay, a less expensive method to enumerate CD4+ lymphocytes, in resource-limited settings. DESIGN: Cross-sectional study conducted in the United States and Uganda. METHODS: We compared CD4+ cell counts obtained on replicate samples from HIV-infected patients by the EasyCD4 assay, a microcapillary flow-based system, and by standard flow cytometry or FACSCount with linear regression and the Bland-Altman method. RESULTS: Two hundred eighteen samples were analyzed (77 in the United States and 141 in Uganda). In the United States, mean +/- SD CD4 was 697 +/- 438 cells/microL by standard flow cytometry and 688 +/- 451 cells/microL by EasyCD4. In Uganda, the mean +/- SD CD4 was 335 +/- 331 cells/microL by FACSCount and 340 +/- 327 cells/microL by EasyCD4. The 2 methods were highly correlated (US cohort, r2 = 0.97, slope = 1.0, intercept = -18; Ugandan cohort, r2 = 0.92; slope = 0.95; intercept = 23). The mean differences in CD4 cell counts were 9.0 and -4.6 cells/microL for the US and Ugandan cohorts, respectively, and they were not significant in either cohort. In the Ugandan cohort, sensitivity and specificity of the EasyCD4 for CD4 below 200 cells/microL were 90% and 98%, respectively. Positive predictive value was 96%; negative predictive value was 93%. CONCLUSIONS: Our results suggest that EasyCD4 may be used with high positive and negative predictive value in resource-limited settings.