Modeling hepatitis C micro-elimination among people who inject drugs with direct-acting antivirals in metropolitan Chicago

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and mortality worldwide. Direct-acting antiviral (DAA) therapy leads to high cure rates. However, persons who inject drugs (PWID) are at risk for reinfection after cure and may require multiple DAA treatments to reach the World Health Organization’s (WHO) goal of HCV elimination by 2030. Using an agent-based model (ABM) that accounts for the complex interplay of demographic factors, risk behaviors, social networks, and geographic location for HCV transmission among PWID, we examined the combination(s) of DAA enrollment (2.5%, 5%, 7.5%, 10%), adherence (60%, 70%, 80%, 90%) and frequency of DAA treatment courses needed to achieve the WHO’s goal of reducing incident chronic infections by 90% by 2030 among a large population of PWID from Chicago, IL and surrounding suburbs. We also estimated the economic DAA costs associated with each scenario. Our results indicate that a DAA treatment rate of >7.5% per year with 90% adherence results in 75% of enrolled PWID requiring only a single DAA course; however 19% would require 2 courses, 5%, 3 courses and <2%, 4 courses, with an overall DAA cost of $325 million to achieve the WHO goal in metropolitan Chicago. We estimate a 28% increase in the overall DAA cost under low adherence (70%) compared to high adherence (90%). Our modeling results have important public health implications for HCV elimination among U.S. PWID. Using a range of feasible treatment enrollment and adherence rates, we report robust findings supporting the need to address re-exposure and reinfection among PWID to reduce HCV incidence

Towards elimination of Hepatitis C in Vietnam

Vietnam has a high burden of viral hepatitis. This thesis strives to advance its elimination, addressing important gaps in the literature that I hope will contribute to treatment guidelines and health policy, both in Vietnam and internationally. Firstly, to define the hepatitis epidemic in Vietnam, I assimilate all published seroprevalence data since 1990 to estimate pooled prevalence of HBV, HCV and HDV in high and low risk populations. I show that although blood safety has improved, and HDV is largely confined to high-risk populations, a renewed focus on birth dose HBV vaccination and targeted HCV screening and treatment of people who inject drugs, is urgently required to meet elimination targets. The next chapters address HCV therapy, namely predictive factors for selecting individuals who could be treated for shorter duration, treatment failure in relation to rare HCV subtypes, and the clinical importance of resistance mutations. I describe a prospective clinical trial evaluating the efficacy of shortened sofosbuvir and daclatasvir therapy, based on early virological response: firstly, in genotype 1 or 6-infected individuals with mild disease (chapter 3) and then in genotype 6-infected individuals with advanced liver fibrosis (chapter 4). I show that shortened therapy, with retreatment if needed, can reduce antiviral use while maintaining high cure rates, but that day 2 virologic response alone is not an adequate predictor of cure. I demonstrate that a high frequency of putative NS5A inhibitor resistance mutations in genotype 6 infection does not impact cure rates, negating the need for costly genotyping in Vietnam. In my final data chapter, I explore an innovative means of decentralising HCV care. In two independent study populations from Vietnam and the UK, I show that an increase in routinely taken alanine transaminase after HCV therapy is a reliable screen for treatment failure that could substantially reduce reliance on nucleic acid testing in remote and resource-limited settings.Open Acces

Hepatitis C elimination among people living with HIV

Background: Hepatitis C virus (HCV) is a major cause of liver-related morbidity and mortality among people living with HIV globally. Aims: The broad aim of this research was to evaluate progress towards HCV elimination among people living with HIV in Australia. Specific aims included evaluating incidence and factors associated with HCV reinfection and patterns of drug use and sexual risk behaviours after treatment and characterizing the HCV cascade of care and factors associated with engagement in HCV care among people living with HIV in Australia. Methods: In Chapter Two, the risk of HCV reinfection following successful therapy among people living with HIV was evaluated in a global systematic review and meta-analysis, with factors associated with reinfection assessed using meta-regression. In Chapter Three, patterns of drug use and sexual risk behaviours and HCV reinfection incidence were assessed before and after direct-acting antiviral (DAA) scale-up in Australia among people with HIV/HCV coinfection enrolled in CEASE. In Chapter Four, the HCV cascade of care, including HCV testing and treatment, among people living with HIV was characterized in the pre (2010–2015) and post (2016–2018) DAA era in a population-based linkage study including all people living with HIV in New South Wales, Australia with an HCV notification. Factors associated with HCV testing and DAA treatment were assessed using logistic regression. Key Findings: Globally, HCV reinfection incidence following treatment among people living with HIV was similar following interferon-based and DAA therapy, with the highest risk among men who have sex with men and those with recent HCV infection. Following unrestricted DAA access and broad treatment uptake among people living with xviii HIV in Australia, HCV reinfection incidence was low despite stable pattens of risk behaviours before and after DAA treatment. The HCV care cascade among people living with HIV demonstrated high HCV RNA testing coverage (91%) and treatment uptake following DAA availability (7% pre DAA, 73% post DAA). Younger age, female gender, and rural region of residence were negatively associated with testing; no factors were associated with DAA treatment. Conclusion: To maintain progress towards HCV elimination, ongoing HCV screening and treatment of (re)infection among people living with HIV will be required. Enabling access to and ensuring broad coverage of HCV testing, treatment and prevention will be essential

Hepatitis C Screening and Treatment of Prisoners: Analysis of Policy and Practice in Kentucky

INTRODUCTION The United States and the Commonwealth of Kentucky are currently overwhelmed by a triad of complex epidemics—incarceration, opioid overdose deaths secondary to substance use disorders, and hepatitis C. Research has suggested hepatitis C screening and treatment of prisoners may be a cost-effective strategy to address the hepatitis C epidemic. Since Kentucky has been particularly impacted by these interrelated health threats, further exploration of hepatitis C in Kentucky prison populations and their potential role in addressing these epidemics is warranted. Primary Objective The main goal of this research was to examine hepatitis C screening and treatment policy and practice within the Kentucky correctional system, specifically among prisoners, as a potential target for multidisciplinary interventions to combat the substance use disorder and hepatitis C epidemics and prevent HCV transmission. METHODS Scholarly and grey literature sources as well as publicly available data sources and resources about hepatitis C screening and treatment in Kentucky correctional populations were reviewed for initial analysis of pertinent policy and practice applicable to Kentucky prisoners. RESULTS Hepatitis C prevalence among Kentucky prisoners estimated overall mean (95% CI) was 25.8% (14.5%-37.1%), nearly 16 times that of Kentucky non-institutionalized adults, and estimates of the number of infected persons include: 5,598 (3,146-8,051 95% CI) infected Kentucky state and federal prisoners; 4,993 (2,806-7,181 95% CI) infected Kentucky prison admissions; and 4,776 (2,679-6,854 95% CI) infected Kentucky prison releases. There may be an estimated 3,967-4,568 undiagnosed hepatitis C infected prisoners in Kentucky. From 2010-2013, about one third (n=1,205, 32.4%) of the 3,724 Kentucky state prisoners screened for hepatitis C were confirmed positive, but only 175 (14.5%) started treatment, leaving 1,030 (85.5%) untreated. Kentucky prisoner screening and treatment cost estimates were from $2.20 million ($1.41-$2.99 million 95$200 million ($112-$287 million 95% CI) at 50% discount for releasees, respectively, to up to $4.89 million ($3.12-$6.65 million 95$887 million ($498 million –$1.28 billion 95% CI) for treatment of infected cases. If the entire Kentucky Department of Corrections medical services budget was used solely to purchase HCV treatment regimens based on per patient hepatitis C treatment cost estimates, it could cover the following mutually exclusive options: 681 treatment regimens at the $83,735 Kentucky Medicaid cost; 909 treatment regimens at a 25$62,801; or 1,363 treatment regimens at a 50% discounted cost of $41,868. If the 1,030 untreated prisoners from 2010-2013 infected 1,030 community members upon release, costs to screen and treat the new cases could be up to$89.2 million. If left untreated, the lifetime healthcare costs for hepatitis C in the 1,030 prisoners and 566-875 new community cases of chronic hepatitis C could be $160-$191 million. CONCLUSIONS For prisoners to become part of the solution of this triad of epidemics, Kentucky must strive for creative funding sources, and effective collaboration, integration of services, and multi-disciplinary interventions

Governing through Health: The Biomedical and Public Health Management of Drug Using Bodies

Focused on the intersection of health, drug use, and poverty, this dissertation closely examines the use of discursive registers in the conceptualization of health among low-income people who inject drugs in New York City. Using qualitative in-depth interviews with 40 people who inject drugs, 13 health care practitioners who provide care for drug-using patients, and 4 researchers of drug use, the governmentality of a public health risk population--people who inject drugs--is traced. To historicize this population a genealogy of the injection drug user is conducted through the examination of public health research publications from the 1980s and historical literature on the HIV/AIDS epidemic. This dissertation sought to answer such questions as: How did the emergence in the 1980s of the injection drug user function as an act of governmentality? How do health care practitioners understand drug use among their patients and what are the implications of these understandings for the management of their health and their selves? How have risk discourse and particularly harm reduction discourse produced concepts of health and governed the bodies of low-income people who inject drugs? And, what can be done about health concerns that fall outside of risk discourse? The findings of this dissertation interrogate discourses of risk, such as harm reduction, and the discourse of addiction as disease by pointing to the narratives of illness offered by people who inject drugs. These narratives reveal that these individuals prioritize chronic health conditions from which they currently suffer over concerns of risk for infectious disease or the disease of addiction. Despite this, people who inject drugs are entangled in a complicated web of power through bio-political discourses of risk and disease that renders them subjects of disciplinary and pastoral technologies of power

Optimal treatment allocations in space and time for on-line control of an emerging infectious disease

A key component in controlling the spread of an epidemic is deciding where, whenand to whom to apply an intervention.We develop a framework for using data to informthese decisionsin realtime.We formalize a treatment allocation strategy as a sequence of functions, oneper treatment period, that map up-to-date information on the spread of an infectious diseaseto a subset of locations where treatment should be allocated. An optimal allocation strategyoptimizes some cumulative outcome, e.g. the number of uninfected locations, the geographicfootprint of the disease or the cost of the epidemic. Estimation of an optimal allocation strategyfor an emerging infectious disease is challenging because spatial proximity induces interferencebetween locations, the number of possible allocations is exponential in the number oflocations, and because disease dynamics and intervention effectiveness are unknown at outbreak.We derive a Bayesian on-line estimator of the optimal allocation strategy that combinessimulation–optimization with Thompson sampling.The estimator proposed performs favourablyin simulation experiments. This work is motivated by and illustrated using data on the spread ofwhite nose syndrome, which is a highly fatal infectious disease devastating bat populations inNorth America

Diagnostic strategies to enhance testing for hepatitis C virus infection

Background: Simplified and affordable HCV diagnostic pathways that incorporate innovative collection and testing methods are required to globally scale up HCV elimination efforts. This is especially applicable among highly marginalised populations. Aims: The aim of this research was to evaluate the performance of emerging diagnostic technologies with novel sample types such as dried blood spots (DBS) and finger-stick samples in clinical and decentralised settings. The specific aims include 1) Assessing performance of the Aptima HCV Quant Dx real-time assay for HCV RNA detection using DBS (from a laboratory and cohort collected population), 2) Evaluating performance of HCV core antigen (HCVcAg) detection in plasma and DBS, and 3) Performing a systematic review of point-of-care and DBS HCV RNA testing. Methods: In Chapter Two, HCV RNA detection from retrospective paired plasma and laboratory spotted DBS was compared on the Aptima assay. The same evaluation was performed in Chapter Three, however paired finger-stick capillary DBS and venepuncture collected samples obtained through the LiveRlife study (observational cohort study) were tested. In Chapter Four, detection of HCVcAg from plasma and DBS samples (LiveRlife study) was evaluated on the ARCHITECT-i2000R analyser. For Chapters Two, Three and Four data were analysed for assay sensitivity, specificity, bias and agreement and participant characteristics (Chapters Three and Four only) using statistical methods including paired T-test, Deming correlation, Bland-Altman, data distribution and summary statistics. In Chapter Five, bibliographic databases and conference presentations were searched for eligible studies. Meta-analysis was used to pool estimates. Key Findings: Laboratory spotted and clinically collected DBS samples tested on the Aptima assay displayed good sensitivity, specificity, and correlation to plasma for the detection of HCV RNA. HCVcAg testing in plasma may be an affordable tool for determining active HCV infection with the potential to reflex test from a positive anti-HCV antibody result. HCVcAg DBS testing showed lower sensitivity but may be suitable for screening high-risk populations in countries with medium to high (1.5-3.5% and >3.5%) HCV prevalence. Results from our systematic review showed excellent diagnostic performance among assays that detect HCV RNA from finger-stick whole blood and DBS samples. However, the proportion of invalid results following Xpert HCV Viral Load Finger-stick testing highlights the importance of operator training and quality assurance programs. Conclusion: Novel collection and testing methods, including DBS and finger-stick point-of-care are suitable diagnostic alternatives to standard pathology testing. A targeted testing approach that considers the setting and population could facilitate enhanced HCV testing, linkage to care and treatment