Publications

OBJECTIVES

HIV/hepatitis C virus (HCV) coinfection is associated with insulin resistance, but the mechanism is unclear. We hypothesized that intestinal epithelial damage and the consequent monocyte/macrophage activation and inflammation explain this perturbation.

DESIGN

Cross-sectional study of 519 adults (220 HIV+/HCV-; 64 HIV-/HCV+; 89 HIV+/HCV+; 146 HIV-/HCV-).

METHODS

We used multivariable linear regression to evaluate associations of HIV and HCV with the homeostasis model assessment of insulin resistance (HOMA-IR) and if intestinal fatty (FA) acid binding protein (I-FABP, a marker of gut epithelial integrity), soluble CD14 (sCD14) and soluble CD163 (sCD163) (markers of monocyte/macrophage activation), and IL-6 (an inflammatory cytokine) mediated this association.

RESULTS

HIV+/HCV+ and HIV-/HCV+ had greater demographic-adjusted HOMA-IR [mean (95% confidence interval (CI)): 1.96 (1.51, 2.54) and 1.65 (1.22, 2.24)] than HIV+/HCV- and HIV-/HCV-[1.41 (1.18, 1.67) and 1.44 (1.17, 1.75), respectively]. After additional adjustment for lifestyle and metabolic factors, HIV+/HCV+ remained associated with 36% (95% CI: 4, 80%) greater HOMA-IR relative to HIV-/HCV-, whereas HIV-/HCV+ and HIV+/HCV- had smaller differences. Adjustment for sCD163 substantially attenuated the difference between HIV+/HCV+ and HIV-/HCV-; adjustment for I-FABP, sCD14, and IL-6 had little effect. Higher sCD163 was independently associated with 19% (95% CI: 7, 33%), 26% (95% CI: 15, 39%), 25% (95% CI: 14, 37%), and 23% (95% CI: 11, 36%) greater HOMA-IR in HIV+/HCV+, HIV-/HCV+, HIV+/HCV-, and HIV-/HCV- (all estimates per doubling of sCD163). I-FABP, sCD14, and IL-6 were not associated with HOMA-IR.

CONCLUSION

HIV/HCV coinfection is associated with greater HOMA-IR, even after controlling for demographic, lifestyle, and metabolic factors. sCD163, which appears independent of intestinal epithelial damage and inflammation, partly explains this association. Our findings that the association of sCD163 with HOMA-IR occurred even in the absence of HIV and HCV, indicate that viral and nonviral factors affect sCD163 levels. Its role in insulin resistance needs elucidation.

Ongoing controversy over the optimal approach to breast cancer screening has led to discordant professional society recommendations, particularly in women age 40 to 49 years. One potential solution is risk-based screening, where decisions around the starting age, stopping age, frequency, and modality of screening are based on individual risk to maximize the early detection of aggressive cancers and minimize the harms of screening through optimal resource utilization. We present a novel approach to risk-based screening that integrates clinical risk factors, breast density, a polygenic risk score representing the cumulative effects of genetic variants, and sequencing for moderate- and high-penetrance germline mutations. We demonstrate how thresholds of absolute risk estimates generated by our prediction tools can be used to stratify women into different screening strategies (biennial mammography, annual mammography, annual mammography with adjunctive magnetic resonance imaging, defer screening at this time) while informing the starting age of screening for women age 40 to 49 years. Our risk thresholds and corresponding screening strategies are based on current evidence but need to be tested in clinical trials. The Women Informed to Screen Depending On Measures of risk (WISDOM) Study, a pragmatic, preference-tolerant randomized controlled trial of annual vs personalized screening, will study our proposed approach. WISDOM will evaluate the efficacy, safety, and acceptability of risk-based screening beginning in the fall of 2016. The adaptive design of this trial allows continued refinement of our risk thresholds as the trial progresses, and we discuss areas where we anticipate emerging evidence will impact our approach.