At present, there are no clear guidelines as to when antiretroviral (ARV) therapy for human immunodeficiency virus (HIV) should be stopped in the setting of elevated liver enzymes. In large part, this is due to a limited understanding of the natural history of ARV-related hepatotoxicity. We have undertaken a pilot study (Caryn Morse is PI) to estimate the prevalence of hepatic fibrosis in a cohort of HIV-infected patients who have chronically elevated transaminases while on ARV therapy in the absence of Hepatitis B (HBV) or C (HCV) coinfection. Liver biopsy specimens are being evaluated for fibrosis by microscopic examination, the current gold standard for assessing the nature and severity of liver disease. Fibrosis, as well as other histopathology, is being measured using a validated scoring system. Sixty-two patients have enrolled in the study and undergone liver biopsy. Significant liver abnormalities, primarily steatohepatitis, but also fibrosis, have been seen in the 40 patients. A paper describing the histopathologic abnormalities and clinical correlates of these patients was recently published. We plan to continue to follow these patients long-term to better understand the natural history of these liver abnormalities. We have also examined the predictive value of Fibroscans, which were performed in parallel with other evaluations, for identifying fibrosis in patients with elevated transaminases but without HBV or HCV co-infection. This study will provide clinically relevant information on the significance of elevated transaminases in HIV-infected patients without co-infection with HCV or HBV, and facilitate management of such patients. Progressive liver disease has become an important non-opportunistic complication of HIV infection in the HAART era. Liver fibrosis is a significant problem in HIV-infected patients, including those with HCV co-infection, as well as, based on the study summarized above, in patients without HCV infection. Agents that can prevent progression of fibrosis, and potentially even reverse fibrosis, may thus provide clinical benefit, but to date no effective drug has been identified that can consistently prevent progression of fibrosis. Recently a monoclonal antibody that targets LOXL2, an enzyme involved in collagen synthesis, has been found in animal models to be effective in preventing as well as reversing fibrosis. A humanized form of this antibody has been developed and has entered phase 1 clinical trials. We have completed a phase 1 clinical trial with this antibody (Caryn Morse is PI) in 3 groups of patients with biopsy-documented liver fibrosis: HIV mono-infected patients, HCV mono-infected patients, and HIV-HCV co-infected patients. The primary endpoint of this study was safety, and secondary endpoints included effect on liver fibrosis based on pre- and post-treatment liver biopsies, as well as other non-invasive markers of fibrosis. A total of 18 patients completed this study, the results of which were recently published. The drug was overall well-tolerated; however, no anti-fibrosis activity was identified in this 6-month study. This study provided important preliminary information about the safety and potential efficacy of this monoclonal antibody in patients with liver fibrosis. Biomarkers including D-dimer and IL-6 have been shown to predict mortality in HIV-infected patients independent of CD4 and viral load. To better understand the mechanism leading to D-dimer elevation, we have undertaken a cross-sectional study to examine markers of coagulation, platelet function, endothelial activation and inflammation, and to identify correlates of elevated D-dimer levels. Our hope is that this analysis will provide insights into which of these pathways is leading to D-dimer elevation. To date we have enrolled approximately 230 HIV+ patients and HIV-volunteers. Preliminary analysis suggests that TNF-alpha, sVCAM, and von Willebrand Factor correlate with levels of D-Dimer. These data suggest that ongoing monocyte activation plays a role in D-dimer elevation. We plan to enroll an additional 60 patients to study the correlates of immunologic non-response in patients receiving HAART, to include 30 subjects and 30 controls. We plan to examine immunophenotypic characteristics of the patients, as well as look for evidence of infection with a variety of viral pathogens, including unknown viruses. We also plan to look at T-cell receptor repertoire diversity. To date, 42 patients have enrolled in this phase of the study. The goal is to better understand the mechanisms leading to poor immunologic response in HIV-infected patients.

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIACL008075-12
Application #
9352010
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Clinical Center
Department
Type
DUNS #
City
State
Country
Zip Code
Chwiki, Sarah; Campos, Maria Mercedes; McLaughlin, Mary E et al. (2017) Adverse effects of antiretroviral therapy on liver hepatocytes and endothelium in HIV patients: An ultrastructural perspective. Ultrastruct Pathol 41:186-195
Mattingly, Aviva S; Unsal, Aylin B; Purdy, Julia B et al. (2017) T-cell Activation and E-selectin Are Associated With Coronary Plaque in HIV-infected Young Adults. Pediatr Infect Dis J 36:63-65
Gharib, Ahmed M; Han, Ma Ai Thanda; Meissner, Eric G et al. (2017) Magnetic Resonance Elastography Shear Wave Velocity Correlates with Liver Fibrosis and Hepatic Venous Pressure Gradient in Adults with Advanced Liver Disease. Biomed Res Int 2017:2067479
Meissner, Eric G; McLaughlin, Mary; Matthews, Lindsay et al. (2016) Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial. Liver Int 36:1783-1792
Matthews, Lindsay; Kleiner, David E; Chairez, Cheryl et al. (2015) Pioglitazone for Hepatic Steatosis in HIV/Hepatitis C Virus Coinfection. AIDS Res Hum Retroviruses 31:961-6
Morse, Caryn G; McLaughlin, Mary; Proschan, Michael et al. (2015) Transient elastography for the detection of hepatic fibrosis in HIV-monoinfected adults with elevated aminotransferases on antiretroviral therapy. AIDS 29:2297-302
Morse, Caryn G; McLaughlin, Mary; Matthews, Lindsay et al. (2015) Nonalcoholic Steatohepatitis and Hepatic Fibrosis in HIV-1-Monoinfected Adults With Elevated Aminotransferase Levels on Antiretroviral Therapy. Clin Infect Dis 60:1569-78
Calderón, Mónica M; Chairez, Cheryl L; Gordon, Lori A et al. (2014) Influence of Panax ginseng on the steady state pharmacokinetic profile of lopinavir-ritonavir in healthy volunteers. Pharmacotherapy 34:1151-8
Burbelo, Peter D; Bayat, Ahmad; Rhodes, Craig S et al. (2014) HIV antibody characterization as a method to quantify reservoir size during curative interventions. J Infect Dis 209:1613-7
Buckner, Clarisa M; Moir, Susan; Kardava, Lela et al. (2014) CXCR4/IgG-expressing plasma cells are associated with human gastrointestinal tissue inflammation. J Allergy Clin Immunol 133:1676-85.e5

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