HIV, HCV and the Menopausal Transition: Effects on Steatosis and Fibrosis Progression

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 DESCRIPTION (provided by applicant): Liver disease is a leading cause of non‐AIDS‐ related death in HIV‐infected men and women. While coinfection with HCV is a common cause of liver disease, 25‐44% of all liver‐related deaths occurs in HIV‐ monoinfected persons and may be related to non‐alcoholic fatty liver disease (NAFLD) or hepatic steatosis. NAFLD is common in HIV‐infected persons, but the factors associated with its progression and its role in liver fibrosis progression remains elusive. Women now represent about 25% of all HIV‐infected persons in the US. HIV‐infected women are living longer and many are transitioning to menopause. Both HIV and HCV infection are associated with early menopause; HIV/HCV coinfection may be associated with even earlier onset of menopause. Cross‐sectional studies indicate that menopause is associated with a higher prevalence of steatosis, but there are no studies of progression. Visceral obesity and metabolic perturbations increase during the menopausal transition and are risk factors for steatosis. The hormonal changes that characterize menopause may induce inflammation through increased gut permeability. HIV infection is also associated with gut microbial translocation and inflammation, as well as changes in metabolic parameters. We hypothesize that the menopausal transition will accelerate steatosis and fibrosis progression especially in HIV/HCV‐coinfected women, who will have longer cumulative effects of visceral obesity and systemic inflammation from gut microbial translocation due to earlier onset of menopause. In order to test our hypothesis, we propose a prospective study that leverages the research platform provided by the Women's Interagency HIV Study. The first Aim will examine the effects of the menopausal transition and its onset on steatosis progression in women with HIV, HCV, and neither infection. The second Aim will investigate the effects of visceral obesity and gut‐associated microbial translocation o steatosis progression during the menopausal transition in women with HIV, HCV, and neither infection. The third Aim will determine the effects of the menopausal transition and its onset on fibrosis progression in women. In a prior cross‐sectional study in three WIHS sites, we established the use of transient elastography (TE) to measure fibrosis. With the addition of new Continuous Attenuation Parameter software to TE, we will be able to quantify steatosis and fibrosis simultaneously to address our aims in 1,650 women with HIV monoinfection, HIV/HCV coinfection, HCV monoinfection, and neither infection. We will also measure Anti‐Mullerian Hormone (AMH) levels which yield a better estimate of ovarian reserve and thus estrogen depletion than self‐report of menopause. This study will lead to: 1) new information about how menopause affects steatosis and fibrosis progression in the context of HIV, HCV and neither infection; 2) provide quantitative, longitudinal assessments of steatosis and fibrosis, in patients at risk for progression; and 3) inform the development and optimal timing of focused sex‐ and age‐specific approaches to steatosis and fibrosis in HIV and HCV‐infected women.