Publications

BACKGROUND

Pre-exposure prophylaxis (PrEP) for prevention of HIV infection has demonstrated efficacy in randomized controlled trials and in demonstration projects. For PrEP implementation to result in significant reductions in HIV incidence for men who have sex with men in the United States, sufficient access to PrEP care and continued engagement outside of demonstration projects is required.

METHODS

We report the results of a follow-up survey of 173 former participants from the Miami and San Francisco sites of the US PrEP Demo Project, administered 4-6 months after study completion.

RESULTS

Survey respondents continued to frequently access medical care and had a high incidence of sexually transmitted infections after completion of the Demo Project, indicating ongoing sexual risk behavior. Interest in continuing PrEP was high with 70.8% indicating that they were "very interested" in continuing PrEP. Among respondents, 39.9% reported continuation of PrEP after completion of the Demo Project, largely through their primary care providers and frequently at low or no cost. Variability in access and engagement was seen, with participants from the San Francisco site, those with medical insurance, and those with a primary care provider at the end of the Demo Project more likely to successfully obtain PrEP medication. Two respondents reported HIV seroconversion in the period between study completion and the follow-up survey.

CONCLUSIONS

Additional effort to increase equitable access to PrEP outside of demonstration projects is needed to realize the potential impact of this evidence-based prevention intervention.

BACKGROUND

Urine biomarkers have helped identify persons at risk for progressing to kidney disease in the setting of HIV infection. We explored factors associated with changes in 3 urine biomarkers over 10 years among women living with HIV.

METHODS

Prospective cohort of 294 HIV-infected women from the multicenter Women's Interagency HIV Study. Predictors included HIV viral and immunological parameters, comorbid conditions, and health-related behaviors. Outcomes were patterns of changes of urine interleukin-18 (IL-18), albumin-to-creatinine ratio (ACR), and alpha-1-microglobulin (α1m) over 10 years. We used quantile regression to examine patterns of change in each urine biomarker during follow-up and multivariable analysis of variance regression to identify predictors of biomarker changes.

RESULTS

Over 10 years, the median concentrations of IL-18 declined from 120 to 64 pg/mL, α1m rose from 0.7 to 1.5 ng/mL, and ACR remained stable (9-8 mg/g). In multivariate analyses, the strongest predictors of increases in IL-18 were higher baseline body mass index, increase in waist circumference, higher follow-up HIV viral load, lower follow-up CD4 cell count, hepatitis C virus (HCV) coinfection, and higher follow-up high density lipoprotein cholesterol. Predictors of increasing concentration of α1m were lower CD4 cell counts, higher diastolic blood pressure, HCV coinfection, and smoking. Finally, determinants of ACR increases during follow-up were higher follow-up diastolic blood pressure, HCV coinfection, higher follow-up HIV viral load, and triglyceride concentration.

CONCLUSIONS

Over 10 years, HIV disease status had different associations with each urine biomarker under study. Overall, the associations with changes in each biomarker support research into their use for longitudinal monitoring of kidney health.

The plasma kynurenine/tryptophan (KT) ratio, a marker of adaptive immune defects, strongly predicts mortality during treated human immunodeficiency virus (HIV) disease in Ugandans as compared to US-based populations. Here, the KT ratio and T-cell and plasma biomarkers of immune activation were measured among 535 HIV-infected Ugandans prior to ART initiation and at month 6 of viral suppression. The month 6 KT ratio (adjusted hazard ratio [aHR], 2.74), soluble CD14 level (aHR, 2.32), interleukin 6 level (aHR, 2.34), and D-dimer level (aHR, 1.95) were associated with mortality occurring ≥6 months after ART initiation. The KT ratio remained significantly predictive of mortality even after adjustment for the additional biomarkers, suggesting an independent contribution to clinical outcomes in resource-limited settings.

The history of the biomedical recognition manganese-caused neurotoxicity mirrors changing technologies as much as it does the ontology of parkinsonism. The initial 1837 report of manganese-induced neurologic injury was made by John Couper, a university-based physician in Scotland. He made clear that the outbreak occurred among workers at the Charles Tennant bleach manufactory in the environs of Glasgow. The relatively new technology of chlorine generation using manganese accounted for the novel exposure involved. At the time, this factory was the largest hypochlorite bleaching powder producer in the world. As the 19th century progressed, technological change in steel fabrication requiring higher manganese content greatly increased demand for the metal. Nonetheless, more than six decades elapsed before the next reports of manganese neurotoxicity emerged. Two unrelated outbreaks (both on Continental Europe) were reported within weeks of each other in 1901, one by von Jaksch and the other by Embden. All the cases were heavily exposed to manganese-containing dust. By the eve of the First World War, a total of 9 patients with manganese-caused neurologic illness had been reported in five separate Continental European publications. Meanwhile, new technology led to another exposure source. Magnetic separation techniques allowed the extraction of zinc from mixed ore also containing iron and manganese, leading to exploitation of a unique source of high manganese-content ore found in New Jersey. Not long after that technology's introduction, in 1912 Casamajor reported the first U.S. cases of manganism, detailing classic findings. Additional cases from the same cohort were reported a few years later, with continued exposure driven by First World War-driven demand for manganese to be used in armaments. The nosology of chronic manganese neurotoxicity remained in flux, with considerable emphasis on shared attributes with Wilson's disease, a syndrome only then recently described. A landmark 1924 primate study by Mella showed manganese-induced basal ganglion damage; human autopsy study data in the years following further supported the view that manganese toxicity represented a parkinsonian syndrome. As the 1937 centenary of Couper's first report approached, newer technologies (electric arc welding and battery making) were being linked to manganese-caused disease, even as mineral extraction was expanding as a global source of exposure.

We explored the association between liver metastases, tumor CD8 T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non-small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) ≤ 0.0001, and confirmed in the validation cohort ( = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; < 0.0001). In a subset of biopsied patients ( = 62), liver metastasis was associated with reduced CD8 T-cell density at the invasive tumor margin (liver metastasis group, = 547 ± 164.8; liver metastasis group, = 1,441 ± 250.7; < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4-2.0], compared with those without liver metastasis ( = 119, median PFS, 4.0 months; 95% CI, 2.1-5.1), = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8 T-cell infiltration, providing a potential mechanism for this outcome. .