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Mechanisms of HBV Functional Cure During Tenofovir-based ART in HIV/HBV coinfection

Award Number: R01AI147727
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Mechanisms of HBV Functional Cure During Tenofovir-based ART in HIV/HBV coinfection - SUMMARY / ABSTRACT People living with HIV and hepatitis B virus coinfection (HBV/HIV) experience increased mortality compared to infection with either HIV or chronic HBV alone. Therefore, within the growing movement to cure HBV, people with HBV/HIV should be prioritized. However, at present, people with HBV/HIV are excluded from virtually all clinical trials of novel HBV cure therapies because of concerns for reduced efficacy and safety. Whether and to what degree immunological control of the intrahepatic HBV reservoir (i.e., the targets of cure therapies) is impaired in HBV/HIV needs to be defined to accelerate HBV cure in this high-risk group. Including people with coinfection in HBV cure research is also important because shortly after starting HBV-active antiretroviral therapy, they sometimes achieve rapid seroclearance of hepatitis B surface antigen (presumed to be a manifestation of immune reconstitution), which is referred to as HBV ‘functional cure’. This phenomenon presents a natural experiment to identify the immune correlates to be targeted with HBV cure therapies. In this project, we will investigate the effects of immune dysfunction and restoration in HBV/HIV on control of HBV intrahepatic profiles. During the past 5 years, we collected longitudinal liver fine needle aspirations (FNAs) within a unique cohort of adults with HBV/HIV and HBV alone in Zambia, and through single-cell analysis of FNAs, identified how HIV disrupts immunity in the liver. To further define the impacts of untreated HIV coinfection on HBV reservoirs and the mechanisms leading to cure during immune reconstitution, we will collect core needle biopsies, which capture orders of magnitude larger numbers of hepatocytes (the site of HBV infection) than FNAs. Core needle biopsies will be analyzed in a multidisciplinary approach via (a) ddPCR measurement of HBV covalently closed circular DNA, the ultimate barrier to cure, and HBV DNA integration into the host genome, which can also produce sAg and mask the status of cccDNA control, and (b) single-cell and single nucleus analysis of immune and parenchymal cells, including HBV-infected hepatocytes. In Aim 1, we will cross- sectionally compare pre-treatment HBV intrahepatic profiles and define impairments in mechanisms of HBV viral control. Then in Aim 2, we will investigate the dynamics of the intrahepatic profile during ART-induced immune reconstitution and in the context of HBV FC. By comparing people with and without control of HBV during tenofovir-based therapies, we will identify specific cells types and signatures that can be targeted with cure therapeutic strategies.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $701,089 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	6	4/24/2026	COMPETING CONTINUATION	$701,549
2026	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	12/15/2025	NON-COMPETING CONTINUATION	-$460
														Subtotal = $701,089

Issue Date FY: 2023 ( Subtotal = $575,680 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	5	8/21/2023	NON-COMPETING CONTINUATION	$575,680
														Subtotal = $575,680

Issue Date FY: 2022 ( Subtotal = $642,704 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	8/16/2022	NON-COMPETING CONTINUATION	$642,704
														Subtotal = $642,704

Issue Date FY: 2021 ( Subtotal = $638,647 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	3	8/5/2021	NON-COMPETING CONTINUATION	$638,647
														Subtotal = $638,647

Issue Date FY: 2020 ( Subtotal = $642,573 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	2	7/22/2020	NON-COMPETING CONTINUATION	$642,573
														Subtotal = $642,573

Issue Date FY: 2019 ( Subtotal = $656,636 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	8/27/2019	NEW	$656,636
														Subtotal = $656,636

Grand Total All Awards = $3,857,329

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Mechanisms of HBV Functional Cure During Tenofovir-based ART in HIV/HBV coinfection

Award Number: R01AI147727

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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