Chronic kidney disease (CKD) and cardiovascular disease (CVD), conditions with overlapping pathophysiologies, have emerged as major comorbidities among HIV-infected persons in the era of combination antiretroviral therapy. Some observational data implicate hepatitis C virus (HCV) as an independent risk factor for these conditions (in both HIV-uninfected and -coinfected populations). However, other studies failed to find associations between HCV and CKD or CVD. Moreover, it is challenging to completely account for important socioeconomic and behavioral confounders in observational studies. In the previous funding cycle of R01 DA026770, we established a cohort of approximately 300 participants - including dual uninfected, HIV monoinfected, HCV monoinfected, and HIV/HCV dual infected participants - with repeated measures of kidney injury markers, glomerular filtration rate by iohexol clearance from plasma (iGFR), vascular stiffness, and carotid intima-media thickness (IMT). We identified associations between HCV infection and iGFR slope, vascular stiffness, and carotid IMT. During the follow-up period of this cohort, which immediately preceded the availability of highly potent direct acting agents (DAAs), none of the HCV-infected participants received treatment for HCV. In this competing renewal, we propose a novel focus on the role of HCV in CKD and CVD, by leveraging previously collected data with targeted enrollment of HCV-infected (mono and dual) participants initiating treatment with newly available DAAs. In the next funding period, we propose to enroll an HCV treatment cohort - subjects preparing to initiate DAA-based HCV therapy - which will include both new recruits and participants followed previously (who begin DAAs in the current period). HCV treatment cohort subjects will have a minimum of one visit prior to starting DAA therapy and will then be followed for 36 months, the same as participants in the prior funding cycle. This approach will allow us to both assess pre- to post-HCV treatment biomarker changes in individual subjects (thereby eliminating inter-subject variability) and compare disease marker trajectories in the HCV treatment cohort with those in HCV-infected (but untreated) subjects followed in the prior period.
Our aims are to 1) Determine the effect of HCV treatment with DAAs on kidney injury and function and on sensitive indicators of CVD in HCV mono and HIV/HCV dual- infected participants, and 2) Elucidate the effects of HCV treatment with DAAs on putative inflammatory and metabolic mediators of CKD and CVD. To accomplish these objectives, we have expanded our research team with expertise on HCV treatment and HCV immunology and immune activation. Determining whether HCV treatment with DAAs can abrogate kidney and cardiovascular pathogenesis can inform the evolution of HCV treatment guidelines.

Public Health Relevance

Some information suggests that hepatitis C virus (HCV) contributes to kidney and heart disease, in addition to causing liver disease. However, observational data of this type is subject to confounding and may be misleading. New treatments for HCV are capable of curing the infection in most people. Using data previously collected from participants with untreated HCV, we propose to study whether HCV treatment with new drugs leads to improvements in measures of kidney and heart disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA026770-07
Application #
9110224
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Khalsa, Jagjitsingh H
Project Start
2009-03-31
Project End
2020-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Sheets, Kerry M; Atta, Mohamed G; Fine, Derek M et al. (2017) Longitudinal Assessment of Proximal Tubular Dysfunction in HIV Seropositive and Seronegative Persons: Correlates and Implications. J Acquir Immune Defic Syndr 75:45-51
Drozd, Daniel R; Kitahata, Mari M; Althoff, Keri N et al. (2017) Increased Risk of Myocardial Infarction in HIV-Infected Individuals in North America Compared With the General Population. J Acquir Immune Defic Syndr 75:568-576
Achhra, Amit C; Mocroft, Amanda; Ross, Michael et al. (2017) Impact of early versus deferred antiretroviral therapy on estimated glomerular filtration rate in HIV-positive individuals in the START trial. Int J Antimicrob Agents 50:453-460
Muzaale, A D; Althoff, K N; Sperati, C J et al. (2017) Risk of End-Stage Renal Disease in HIV-Positive Potential Live Kidney Donors. Am J Transplant 17:1823-1832
Atta, Mohamed G; Estrella, Michelle M; Fine, Derek M et al. (2016) Correlates and Longitudinal Renal and Cardiovascular Implications of FGF23 Levels in HIV-Positive Individuals. PLoS One 11:e0155312
Atta, Mohamed G; Estrella, Michelle M; Skorecki, Karl L et al. (2016) Association of APOL1 Genotype with Renal Histology among Black HIV-Positive Patients Undergoing Kidney Biopsy. Clin J Am Soc Nephrol 11:262-70
Lucas, Gregory M; Atta, Mohamed G; Fine, Derek M et al. (2016) HIV, Cocaine Use, and Hepatitis C Virus: A Triad of Nontraditional Risk Factors for Subclinical Cardiovascular Disease. Arterioscler Thromb Vasc Biol 36:2100-7
Lucas, Gregory M; Atta, Mohamed G; Zook, Katie et al. (2016) Factors associated with iohexol-based glomerular filtration rate slope over 36 months in HIV-negative and HIV-positive individuals. AIDS 30:619-26
Waheed, Sana; Attia, Doaa; Estrella, Michelle M et al. (2015) Proximal tubular dysfunction and kidney injury associated with tenofovir in HIV patients: a case series. Clin Kidney J 8:420-5
Waheed, Sana; Sakr, Ahmad; Chheda, Neha D et al. (2015) Outcomes of Renal Transplantation in HIV-1 Associated Nephropathy. PLoS One 10:e0129702

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