J Acquir Immune Defic Syndr
BACKGROUND: Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine has proven highly effective in preventing HIV acquisition and is therefore offered to all participants in the control group as part of the standard of care package in many new HIV prevention studies. We propose a methodology for predicting HIV incidence in a hypothetical "placebo arm" for open-label studies or clinical trials with active control among African women. We apply the method to an open-label PrEP study, HIV Prevention Trials Network 082, which tested strategies to improve PrEP adherence in young African women all of whom were offered PrEP. METHODS: Our model predicted HIV infection risk for female study cohorts in sub-Saharan Africa using baseline behavioral risk factors and contemporary HIV prevalence and viral suppression in the local male population. The model was calibrated to HIV incidence in the Vaginal and Oral Interventions to Control the Epidemic study. RESULTS: Our model reproduced the annual HIV incidence of 3.2%-4.8% observed over 1 year of follow-up in the placebo groups of 4 completed clinical studies. We predicted an annual HIV incidence of 3.7% (95% confidence interval: 3.2 to 4.2) among HIV Prevention Trials Network 082 participants in the absence of PrEP and other risk reduction interventions. CONCLUSIONS: We demonstrated the potential of the proposed methodology to provide HIV incidence predictions based on assessment of individual risk behaviors and community and time-specific HIV exposure risk using HIV treatment and viral suppression data. These estimates may serve as comparators in HIV prevention trials without a placebo group.
J Acquir Immune Defic Syndr
BACKGROUND: In the 2019 State of the Union Address, President Trump announced a plan for "Ending the HIV Epidemic" in the United States, with a goal to reduce new HIV infections by 90% by 2030. Phase I of the plan set an intermediate goal of a 75% reduction within 5 years, focusing on select states and counties. METHODS: We assessed the feasibility of the first phase of the plan by estimating the fraction of HIV diagnoses that occur within the targeted region, using a statistical model to predict new HIV cases in each county. We suggested new areas that should be added to the current plan, prioritizing by both a "Density Metric" of new HIV cases and a "Gap Metric" quantifying shortcomings in antiretroviral therapy and pre-exposure prophylaxis uptake. RESULTS: We found the current plan targets less than 60% of new diagnoses. The plan should be expanded to Puerto Rico, Florida, Georgia, Louisiana, and Maryland as well as parts of New York, North Carolina, Texas, and Virginia, areas which were prioritized by both metrics. CONCLUSION: Many of the highest priority areas, both by density of HIV cases and by lack of viral suppression and pre-exposure prophylaxis use, were not covered by the original plan, particularly in the South. The current plan to end the HIV epidemic must be expanded to these areas to feasibly allow for a 75% reduction in new HIV cases within 5 years.
Pediatr Clin North Am
As treatment evolves and the population who survive childhood cancer ages and increases in number, researchers must use novel approaches to prevent, identify and mitigate adverse effects of treatment. Future priorities include collaborative efforts to pool large cohort data to improve detection of late effects, identify late effects of novel therapies, and determine the contribution of genetic factors along with physiologic and accelerated aging among survivors. This knowledge should translate to individual risk prediction and prevention strategies. Finally, we must utilize health services research and implementation science to improve adoption of survivorship care recommendations outside of specialized pediatric oncology centers.
J Oncol Pharm Pract
INTRODUCTION: Although consistent use of tyrosine kinase inhibitors (TKIs) confers significant improvements in long-term survival for individuals with chronic myeloid leukemia (CML), only 70% of CML patients are adherent to TKIs. Understanding the factors that contribute to non-adherence and establishing dynamic adherence patterns in this population are essential aspects of targeted drug monitoring and intervention strategies. METHODS: Newly diagnosed CML patients were identified in the MarketScan database and relevant covariate values extracted. Proportion of days covered (PDC) per 30-day interval was used to calculate adherence over a 12-month follow-up period. We conducted a latent profile analysis (LPA) on these PDC estimates to identify distinct, dynamic patterns of TKI adherence. Identified trajectories were grouped into four clinically relevant categories and predictors of membership in these categories were determined via multinomial logistic regression. RESULTS: Four broad adherence categories were identified from the LPA: never adherent, initially non-adherent becoming adherent, initially adherent becoming non-adherent, and stable adherent. Results from the subsequent multinomial logistic regression indicated that younger age, female sex, greater monthly financial burden, fewer comorbidities, fewer concomitant medications, year of diagnosis, higher starting dose, TKI type, and a longer duration from diagnosis to treatment were significantly associated with membership in at least one of the three non-stable adherent groups. CONCLUSION: Select sociodemographic and clinical characteristics were found to predict membership in clinically meaningful groups of longitudinal TKI adherence. These findings could have major implications for informing personalized monitoring and intervention strategies for individuals who are likely to be non-adherent.
Cancer Epidemiol Biomarkers Prev
The cancer early detection biomarker field was, compared to the therapeutic arena, in its infancy when the Early Detection Research Network (EDRN) was initiated in 2000. The EDRN has played a crucial role in changing the culture and the ways people do biomarker studies.The EDRN proposed biomarker developmental guidelines and biomarker pivotal trial study design standards, created biomarker reference sets and functioned as a unbiased broker for the field, implemented the most rigorous blinding policy in biomarker field, developed an array of statistical and computational tools for early detection biomarker evaluations, and developed a multi-disciplinary team-science approach. We reviewed these contributions made by the EDRN and their impacts in bringing the field to more maturity. Challenges and opportunities on the future of cancer early detection biomarker translational research are discussed, particularly in strengthening biomarker discovery pipeline and conducting more efficient biomarker validation studies. EDRN's approach and success changed how the biomarker field does biomarker studies.
Background: Premature menopause is an independent risk factor for cardiovascular disease in women, but mechanisms underlying this association remain unclear. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic cells with leukemogenic mutations without detectable malignancy, is associated with accelerated atherosclerosis. Whether premature menopause is associated with CHIP is unknown. Methods: We included postmenopausal women from the UK Biobank (N=11,495) aged 40-70 years with whole exome sequences and from the Women's Health Initiative (WHI, N=8,111) aged 50-79 years with whole genome sequences. Premature menopause was defined as natural or surgical menopause occurring before age 40 years. Co-primary outcomes were the presence of (1) any CHIP and (2) CHIP with variant allele frequency (VAF) >0.1. Logistic regression tested the association of premature menopause with CHIP, adjusted for age, race, the first 10 principal components of ancestry, smoking, diabetes mellitus, and hormone therapy use. Secondary analyses considered natural vs. surgical premature menopause and gene-specific CHIP subtypes. Multivariable-adjusted Cox models tested the association between CHIP and incident coronary artery disease (CAD). Results: The sample included 19,606 women, including 418 (2.1%) with natural premature menopause and 887 (4.5%) with surgical premature menopause. Across cohorts, CHIP prevalence in postmenopausal women with vs. without a history of premature menopause was 8.8% vs. 5.5% (P<0.001), respectively. After multivariable adjustment, premature menopause was independently associated with CHIP (all CHIP: OR 1.36, 95% 1.10-1.68, P=0.004; CHIP with VAF >0.1: OR 1.40, 95% CI 1.10-1.79, P=0.007). Associations were larger for natural premature menopause (all CHIP: OR 1.73, 95% CI 1.23-2.44, P=0.001; CHIP with VAF >0.1: OR 1.91, 95% CI 1.30-2.80, P<0.001) but smaller and non-significant for surgical premature menopause. In gene-specific analyses, only DNMT3A CHIP was significantly associated with premature menopause. Among postmenopausal middle-aged women, CHIP was independently associated with incident coronary artery disease (HR associated with all CHIP: 1.36, 95% CI 1.07-1.73, P=0.012; HR associated with CHIP with VAF >0.1: 1.48, 95% CI 1.13-1.94, P=0.005). Conclusions: Premature menopause, especially natural premature menopause, is independently associated with CHIP among postmenopausal women. Natural premature menopause may serve as a risk signal for predilection to develop CHIP and CHIP-associated cardiovascular disease.
J Infect Dis
We performed a multivariable analysis of potential risk factors (including CMV reactivation) for clinical outcomes by day 28 (death or continued hospitalization, ventilator-free days [VFD], ICU-free days [ICUFD], hospital free days [HFD]) from pooled cohorts of two previous prospective studies of CMV seropositive adults with sepsis. CMV reactivation at any level, >100, >1,000 IU/mL, peak viral load, and area under the curve were independently associated with the clinical outcomes. We identified the potential effect size of CMV on outcomes that could be used as endpoints for future interventional trials of CMV prevention using antiviral prophylaxis in ICU patients with sepsis.
BACKGROUND: 47 is a gut-homing integrin heterodimer that can act as a non-essential binding molecule for HIV. A previous study in heterosexual African women found that individuals with higher proportions of 47 expressing CD4+ T cells were more likely to become infected with HIV, as well as present with faster disease progression. It is unknown if this phenomenon is also observed in men who have sex with men (MSM) or people who inject drugs (PWID). METHODS: MSM and transgender women who seroconverted as part of the HVTN 505 HIV vaccine trial and PWID who seroconverted during the ALIVE cohort study were selected as cases and matched to HIV-uninfected controls from the same studies (1:1 and 1:3, respectively). Pre-seroconversion PBMC samples from cases and controls in both studies were examined by flow cytometry to measure levels of 47 expression on CD4+ T cells. Multivariable conditional logistic regression was used to compare 47 expression levels between cases and controls. A Kaplan-Meier curve was used to examine the association of 47 expression pre-seroconversion with HIV disease progression. FINDINGS: In MSM and transgender women (n=103 cases, 103 controls), there was no statistically significant difference in the levels of 47 expression on CD4+ T cells between cases and controls (adjusted odds ratio [adjOR] =1.10, 95% confidence interval [CI]=0.94,1.29; p=0.246). Interestingly, in PWID (n=49 cases, 143 controls), cases had significantly lower levels of 47 expression compared to their matched controls (adjOR=0.80, 95% CI=0.68, 0.93; p=0.004). Among HIV-positive PWID (n=47), there was no significant association in HIV disease progression in individuals above or below the median level of 47 expression (log-rank p=0.84). INTERPRETATION: In contrast to findings in heterosexual women, higher 47 expression does not predict HIV acquisition or disease progression in PWID or MSM. FUNDING: This study was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. The study was also supported by extramural grants from NIAID T32AI102623 (E.U.P.), and UM1AI069470.