David L. Thomas - US grants

Project Summary The goal of R01DA013324 renewal is to investigate the host genetic basis for hepatitis B virus (HBV) recovery in persons living with and without HIV. HBV Infection results in either a successful immune response and recovery or a chronic infection. Anti-viral drugs control HBV replication but cannot cure chronic hepatitis B (CHB). Moreover, lifelong therapy is unsustainable for many, which is a major threat to the calls to eliminate HBV by 2030. A cure for HBV is urgently needed. Understanding how HBV infection is naturally controlled in many infected persons may provide lessons for how to produce a ?functional? cure. There is overwhelming evidence that host genetic differences explain why some persons can recover from an HBV infection including family studies, candidate gene studies, and genome wide association studies (GWAS) in Asian populations. However, these prior GWAS excluded European- and African-ancestry populations despite high HBV endemicity in Africa (>6% of the population has CHB). We propose to renew R01013324 to fill in the missing knowledge on host genetic basis for HBV recovery and to extend that work by detailed studies of host and virus. To this end, Aim 1 focuses on discovering novel genetic variants in a panel of African ancestry individuals by comparing single nucleotide polymorphisms (SNP) from existing GWAS data in persons with HBV recovery (N=8667) and with CHB (N=1594). The inclusion of persons living with HIV (PLWH) allows comparisons of mechanisms of recovery based on HIV. Aim 2 follows by performing a trans-ethnic GWAS analysis using the African ancestry panel from Aim 1 along with European ancestry individuals from North America and the UK Biobank and with Chinese ancestry individuals. These GWAS data are available through collaborators and will also include PLWH. Aim 3 focuses on integrating the host genomic data from Aims 1 and 2 with viral genomics to understand the influence of the host immune response on the viral genome. Deep sequencing of HBV will be performed on 759 individuals to determine viral amino acid changes that are associated with host SNPs identified in Aims 1 and 2. A viral-host genomewide interaction analysis will also be performed, and HBV sequence differences will be compared by HIV status.Our group has made multiple important discoveries on the host genetic basis of hepatitis C virus spontaneous clearance. Using our developed expertise, we and our team of international collaborators will apply our methodological approaches to HBV recovery. Because CHB is the leading cause of liver disease and hepatocellular carcinoma and a leading cause of morbidity and mortality in PLWH, discovering a functional cure has important public health implications.

Hepatocellular carcinoma (HCC) is a very common and lethal cancer in Africa, and as patients with HIV live longer, the HCC burden may increase. In prior studies, our team identified chronic infection with hepatitis B and C viruses (HBV, HCV), HIV and Schistosomiasis mansoni (Sm) as independent risk factors for HCC. Compared to the US, HCC in sub-Saharan Africa occurs at younger age and more advanced stage with survival of only months. Proposed is an East and West African partnership between colleagues at Makerere University in Uganda, Fann University in Senegal and Johns Hopkins University focused on HIV and hepatocellular carcinoma (HCC) in Africa: The H2A Consortium. Building on long-standing collaborative research, mentoring and clinical activities in both countries, our overarching goal is to reduce the heavy burden of HCC in sub-Saharan Africa. We advocate investigating cancer interception strategies using appropriate medical treatments to interrupt or reverse the impact of HCC-causing infections. To understand our data demonstrating synergistic interaction between chronic HBV and Sm infections, we will examine HBV clinical and immunological responses in the periphery and the liver in response to Sm treatment with praziquantel. Over time, liver Sm-related inflammation transitions from a Th1 to Th2 bias, and we hypothesize this transition may promote HBV replication. We will evaluate the dynamics of plasma HBV DNA during Sm treatment and correlate these with contemporaneous changes in plasma cytokines to characterize Th1 shifted inflammation. We also concurrently examine HBV specific CD4+ and CD8+ T cell responses, and measures of Sm treatment efficacy. Through investigation of liver biopsies on patients before and after SM treatment as well as with HCC, we anticipate confirming in humans that Sm is pro-carcinogenic and that Sm treatment only partially diminishes expression of pro-carcinogenic genes. HIV will be evaluated as a modifier of each relationship. Given our strong record, the proposed research has a high likelihood for successful contribution to reducing the burden and improving understanding of chronic infections and HCC in Africa.

Summary/Abstract In the U.S., 2.7 million individuals are estimated to have chronic HCV infection which includes nearly 1.3 million individuals in correctional facilities. Injection drug use remains the most common route of HCV transmission and in a recent New Orleans, Louisiana sample, 77% of people who inject drugs (PWID) had acquired HCV in the past. Moreover, it is estimated that 89% of PWID have experienced incarceration. HCV coinfection with HIV is also particularly common with approximately 25% of people living with HIV (PLWH) also coinfected with HCV. Furthermore, about 80% of PLWH who inject drugs also have HCV. As HIV-related morbidity and mortality have declined among PLWH in the ART era, HCV, a leading cause of liver cancer and liver failure, has emerged as an important cause of morbidity and mortality especially among PWID. PWID and PLWH are disproportionately represented in incarcerated populations. The purpose of this research proposal is to investigate the impact of HCV treatment of HIV/HCV coinfected and HCV monoinfected incarcerated persons on HCV elimination. Of particular importance is understanding why safe, curative treatment has not reached most of the incarcerated HCV infected persons who largely are unaware of their infected status. The high cost of HCV treatment is a major reason for this knowledge gap. High treatment prices provide an enormous incentive for states to shroud the epidemiology and treatment of HCV. Subtle and even overt barriers to testing and treatment are sustained to diminish the net economic impact. Accordingly, relative to HIV, little HCV testing and treatment has occurred in correctional facilities in the U.S. Louisiana removed the cost of medications as a factor by establishing an alternative payment strategy with the goal of treating 80% of HCV infected persons by 2024 in their HCV Elimination Program. Under the program, Louisiana pays the same amount for HCV medications no matter how many persons are treated. Thus, now for the first time, we have the opportunity to investigate rigorously the burden of HCV in the correctional system in a U.S. state, the dynamics of incarceration, and the resulting prevalence of infection. We want to apply this new knowledge to estimating the potential impact of treatment on community HCV transmission and mortality. In the next cycle, we propose research to achieve these aims: (1) To characterize the dynamics of HCV infection in the correctional system among HIV/HCV coinfected and HCV monoinfected incarcerated persons; (2) To assess treatment impact as the trajectory of decline in HCV viremia among HCV antibody positive incarcerated persons and whether this trajectory differs between those with and without HIV; (3) To disentangle the impact of the correctional HCV treatment program on HCV viremic decline, and to assess the impact of scale-up of correctional treatment programs on HCV incidence and mortality in Louisiana and elsewhere.