Person:

Lo, Janet

Hepatosteatosis is highly prevalent among patients living with human immunodeficiency virus. In a 1-year, randomized, double-blind trial of atorvastatin or placebo, atorvastatin increased liver/spleen ratio among patients with nonalcoholic fatty liver disease, indicating a reduction in hepatosteatosis. This reduction in hepatosteatosis is associated with reduction in low-density lipoprotein cholesterol with statin therapy.

Objective: Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH, NCT01762046) is a novel resource of genetic and biochemical data following glipizide and metformin administration. We describe recruitment, enrollment, and phenotyping procedures and preliminary results for the first 668 of our planned 1,000 participants enriched for individuals at risk of requiring anti-diabetic therapy in the future. Methods: All individuals are challenged with 5 mg glipizide × 1; twice daily 500 mg metformin × 2 days; and 75-g oral glucose tolerance test following metformin. Genetic variants associated with glycemic traits and blood glucose, insulin, and other hormones at baseline and following each intervention are measured. Results: Approximately 50% of the cohort is female and 30% belong to an ethnic minority group. Following glipizide administration, peak insulin occurred at 60 minutes and trough glucose at 120 minutes. Thirty percent of participants experienced non-severe symptomatic hypoglycemia and required rescue with oral glucose. Following metformin administration, fasting glucose and insulin were reduced. Common genetic variants were associated with fasting glucose levels. Conclusions: SUGAR-MGH represents a viable pharmacogenetic resource which, when completed, will serve to characterize genetic influences on pharmacological perturbations, and help establish the functional relevance of newly discovered genetic loci to therapy of type 2 diabetes. Trial Registration ClinicalTrials.gov NCT01762046

Background. Human immunodeficiency virus (HIV)-1 elite controllers (ECs) represent an ideal population to study the effects of HIV persistence on chronic inflammation in the absence of antiretroviral therapy (ART). Methods. Twenty inflammatory markers measured in cohorts of ECs, HIV suppressed noncontrollers, and HIV-uninfected controls were compared using rank-based tests and partial least squares discriminant analysis (PLSDA). Spearman correlations were determined among the inflammatory markers, residual viremia by the single-copy assay, and CD4+ T cell slope. Results. Significant differences were seen between cohorts in 15 of the soluble inflammatory markers. Human immunodeficiency virus-1 ECs were found to have the highest levels for all of the markers with the exception of RANTES. In particular, median levels of 7 inflammatory markers (soluble CD14 [sCD14], interferon [IFN]-γ, IFN-γ-inducible protein [IP]-10, interleukin [IL]-4, IL-10, sCD40L, and granulocyte-macrophage colony-stimulating factor) were twice as high in the HIV-1 ECs compared with either of the HIV-suppressed or uninfected groups. Multivariate PLSDA analysis of inflammatory markers improved differentiation between the patient cohorts, discerning gender differences in inflammatory profile amongst individuals on suppressive ART. Soluble markers of inflammation in ECs were not associated with either levels of residual HIV-1 viremia or CD4+ T cell decline. Conclusions. Despite maintaining relatively low levels of viremia, HIV-1 ECs had elevated levels of a set of key inflammatory markers. Additional studies are needed to determine whether ECs may benefit from ART and to further evaluate the observed gender differences.

Abstract HIV‐infected patients commonly experience changes in central and peripheral fat content as well as ectopic fat accumulation. However, whether hepatic and epicardial fat stores relate differentially to body composition or how these associations are modified by HIV status has not been well explored. A previously recruited sample of 124 HIV‐infected patients and 58 healthy controls had undergone dual energy X‐ray absorptiometry (DEXA) and computed tomography (CT) from which body composition measures, liver–spleen ratio, and epicardial fat volume were obtained. Unique to the HIV‐infected group, there was a parabolic association between abdominal subcutaneous adipose tissue (SAT) area and liver–spleen ratio (P = 0.03, inflection point 324 cm2) such that hepatic fat content was greatest at the extremes of low and high SAT. A quadratic model also closely described the relationship between mean leg fat and liver–spleen ratio among patients with HIV (P = 0.02, inflection point 4.7 kg), again suggesting greater liver fat content with both low and high leg fat. Notably, an analogous relationship of epicardial fat with SAT was not evident among HIV‐infected individuals or healthy controls. In contrast, visceral adipose tissue (VAT) linearly related to both liver–spleen ratio in HIV and epicardial fat volume irrespective of HIV status in multivariable models. In conclusion, our analyses implicate both low and high SAT as risk factors for hepatic fat accumulation in HIV. These findings add to growing evidence of SAT dysfunction in the setting of HIV infection, and highlight key physiologic differences between hepatic and epicardial fat depots.

Abstract Background: Proprotein convertase subtilisin/kexin 9 (PCSK9) is known to mediate homeostasis of low-density lipoprotein cholesterol (LDL-c), but it may also participate in immune reactivity and atherogenesis. Methods: We compared circulating PCSK9 levels among asymptomatic individuals with and without HIV. Further, within each group, we assessed the relationship between PCSK9 levels, traditional cardiovascular disease risk factors, immune activation, and subclinical coronary atherosclerotic plaque. Results: PCSK9 levels were higher among HIV-infected (n = 149) vs matched non-HIV-infected subjects (n = 69; 332 [272, 412] ng/mL vs 304 [257, 375] ng/mL; P = .047). Among HIV-infected subjects, significant albeit modest positive associations were noted between PCSK9 levels and markers of systemic monocyte activation including sCD14 (rho = 0.22; P = .009) and sCD163 (rho = 0.23; P = .006). In this group, PCSK9 levels related weakly to LDL-c (rho = 0.16; P = .05) and also to Framingham Point Score but did not relate to subclinical coronary atherosclerotic plaque parameters. Conclusions: Among HIV-infected individuals, circulating PCSK9 levels are elevated and related to systemic markers of monocyte activation but not to coronary plaque parameters. Additional studies are needed to determine the effects of PCSK9 on immune activation and atherogenesis in HIV and to assess whether PCSK9 inhibition reduces immune activation and coronary atherosclerotic plaque burden. Clinical Trial Registration NCT00455793.