Hepatitis C Virus-Host Interactions and Therapeutics: Current Insights and Future Perspectives

Hepatitis C virus (HCV) interaction with host cells is pivotal for natural disease course starting from asymptomatic acute infection to progress into persistent chronic infection and subsequent extrahepatic manifestations, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The HCV infection biology in infected host cells via virus attachment, virus genome replication, mRNA translation, new virion formation, and egress from infected cells involves highly coordinated participation of the virus- and host-specific proteins, a plethora of genes, and cell signaling cascade. The progression of persistent chronic hepatitis C (CHC) infection to hepatic fibrosis, cirrhosis, and HCC involves viral invasion strategies against host immune system defense mechanisms as well as impeding healthy metabolic and signaling networks of the liver cells. Thereby, HCV-induced liver injury via chronic inflammatory processes that fail to resolve is responsible for decompensated cirrhosis and on occasion, hepatocarcinogenesis in infected individuals. With the latest advancement and rapid expansion of our knowledge in hepatology, the human liver is deciphered as an immunologically distinct organ with its specialized physiological niche. The relationship between human hepatocytes and different components of the immune system is quite complex and dynamic. The immunopathogenesis of various viral infections demonstrates that the immune system plays an essential role to determine the progression of many hepatic diseases through immune cell communication and cell signaling networks. In this book chapter, we overview HCVhost interactions and their intricate interplay with complex crosstalk to propagate less fetal acute HCV infection to CHC and subsequent hepatocarcinogenesis (i.e. HCC) in infected individuals.

The progression of acute HCV infection to chronic disease and subsequent extrahepatic comorbidities involve both viruses and host cellular proteins interactions as well as insurrection or subjection of cell signaling and metabolic pathways in infected cells. This interaction between host-specific factors and the hepatitis C genome also weakens or impairs other physiological or metabolic regulatory roles of the hepatocytes. Several host cell proteins promote hepatitis C infection through binding to HCV nonstructural proteins (e.g., PPP2R5D). Some studies also found cytokine (e.g., IL-10, IL-6, TNF-α, and TGF-β1) gene polymorphisms to be highly associated with chronic hepatitis C (CHC) infection progression, whereas, polymorphism in some host genes (e.g., PNPLA3, ADAR-1, and IFIH1) are found to be actively involved in the induction of advanced liver fibrosis in patients co-infected with HIV-1/HCV. Host lipid metabolism reprogramming through host lipid regulators (e.g., ANGPTL-3 and 4) is also considered essential for CHC progression to severe liver disease (e.g., cirrhosis and HCC). Several microRNAs (e.g., miR-122, miR135a) are supposed to be key mediators of HCV infection progression and development of HCC in infected individuals and associated hepatic comorbidities. In chapter 1, we have illustrated the potential roles of virus-specific proteins in HCV molecular pathogenesis. Herein, we will elucidate the host-specific culprits that subvert, impede or disrupt host cells' communications, cell signaling, and metabolic pathways to propagate HCV infection. We will also elaborate that how the subversion of infected host-cell signaling and metabolic pathways disrupt cellular networks to evolve advanced fibrosis and hepatocarcinogenesis in HCV-infected individuals.

An ample understanding of the HCV life cycle and infection biology has also significantly increased our knowledge of hepatitis C immune responses against acute infection to the progression of chronic hepatitis C and associated comorbidities. As expected in chimpanzees (the best in vivo model so far to study hepatitis C infection kinetics, molecular pathogenesis, and immunopathology) and humans, several arms of the immune responses are activated following HCV infection. Some of the underlying mechanisms both for innate immune responses and adaptive immune responses to viral clearance and persistent HCV infection are fully understood, however; some fundamental questions in hepatitis C immunopathology remain to be answered and some immune responses hypothesis demands further studies to validate. Some mechanistic issues of viral evasion strategies during infection progression and the future development of prophylactic and protective anti-HCV vaccines will be largely dependent on the full understanding of the kinetics of adaptive immune responses against HCV infection. As generally presumed the inefficient role of innate immunity in self-resolving HCV infection, the potent immune responses of CD8+ T and CD4+ T cells are critically important after the acute phase of the infection. In particular, the plausible understanding of CD4+ T cells responses against persistent infection will certainly be central to the development of future HCV vaccines. In this chapter, we overview the host immune responses against hepatitis C acute infection and subsequent CHC infection, their regulation by viral and cellular proteins, and the virus purging strategies while impairing host defense system mechanisms.

Hepatitis C screening and diagnosis are both pre-requisite to predicting infection endemicity, transmission risks and identifying vulnerable hepatitis C infected populations in highly endemic areas of the infection prevalence. It is also pivotal to select optimal treatment choices and their impact, including cost and access to care, especially in resource-constrained areas in an era of all oral interferon-free direct-acting antivirals. Furthermore, hepatitis C screening is also very crucial to “find the missing millions” to achieve the hepatitis C elimination goal by 2030. It seems only possible by implementing new screening and diagnostic approaches like RNA point-of-care (RNAPOC) testing, rapid diagnostic tests (RDTs), and dried blood spot (DBS) sample testing, especially in remote communities having poor health infrastructure and where phlebotomies are a major concern for samples collection from patients who inject drugs (PWIDs). In addition to that, it is also very much required to bring HCV diagnostic facilities to decentralized healthcare centers which provide care for people at high risk or opportunistic infection of hepatitis C transmission by sexual contacts (e.g., men who have sex with men (MSM), sex workers, current or former IDUs, people who are incarcerated, and people in drug harm reduction centers). In this book chapter, we will discuss consensus-based recommendations and approaches for hepatitis C screening and diagnosis in general and vulnerable populations with their potential significance for the identification and diagnosis of high-risk individuals of hepatitis C transmission. We will also emphasize the importance of initial HCV screening before the start of HCV treatment.

Considering advances in hepatitis C therapy, global management of HCV infection becomes practicable, but some influential factors, like the capacity of countries to identify and proper diagnosis of infected individuals with immense HCV genotypic variations among different global regions and at-risk populations, cannot be passed over. Approximately, 71 million people are infected with chronic HCV infection and about 80% of them remain undiagnosed. Standard protocol for HCV diagnosis includes a preliminary serological (HCV antibody) test accompanied by an expensive confirmatory test for HCV RNA detection in serum samples of patients. However, gaps remain in the accessibility, affordability, and availability of goldstandard HCV diagnostic strategies. In pursuance of achieving the goals of the World Health Organization (WHO) for HCV elimination as a public health threat by 2030, efficient, reliable, and simplified diagnostic pathways are needed to unveil. As such, simplified sensitive strategies that can enhance the single-test diagnostic approach might assist linkage to care and direct-acting antivirals (DAAs) treatment uptake. Herein, we will discuss a few advanced diagnostic approaches to subdue some of these constraints. HCV self-testing and digital devices for the detection of HCV infection would be of prime importance in the near future. Furthermore, the availability of smart, robust, and mobile diagnostic platforms to find the missing millions in harder-to-reach populations and vulnerable individuals would also be required to link every diagnosed one with cascades of care. We will briefly cover all aspects of HCV screening and diagnostic algorithms in this book chapter along with potential advantages and disadvantages.

During the last decade, the advent and approval of almost a dozen all-oral interferon-free direct-acting antivirals (IFN-free DAAs) to cure hepatitis C-infected general and harder-to-treat populations have entirely changed the treatment paradigms against this “silent epidemic”. The clinical trials of generic IFN-free DAAs, while achieving 95% to 100% sustained virologic response rates (SVRs) in treated individuals, have proven their worth as “magic pills” in hepatitis C therapeutics. Following their real-world clinical usage data with SVR rates, more than 95% have raised the hopes to treat everyone infected with hepatitis C in near future, albeit certain barriers still need to be broken. These regimens, in combination or as a fixed-dose combination (FDC) of a single pill, are highly efficacious against all major hepatitis C genotypes and sub-genotypes. Furthermore, the regimens are well tolerable, with fewer adverse events, and with lesser chances of post-treatment viral relapse or breakthrough in treated patients. The dose algorithms are well-defined for all adult patient groups and in different pathological states of the infection and their recommendations are according to extrahepatic manifestations of hepatitis C in infected individuals. Furthermore, the clinical trials of some DAAs are underway to approve their recommendations in HCV-infected infants, children, and pregnant female patients. In this chapter, we will illustrate the most attractive pharmaco-characteristics of these novel therapeutic regimens to be considered while treating hepatitis C-infected populations. We will also elaborate on the infected subpopulations for which such regimens are not recommended and further research is extensively needed. 

Unlike other infectious diseases and viral infections, the long-term chronicity of hepatitis C infection could worsen or propagate to irreversible extrahepatic manifestations like decompensated cirrhosis or the development of hepatocellular carcinoma. The recent real-world clinical data of hepatitis C patients treated with IFN-free DAAs are still fewer to conclude or decide the best treatment protocols and guidelines for those who are still awaiting the treatment. However; based on the clinical data retrieved from the diverse patient cohorts, multicenter and multinational clinical studies, and pre- and post-therapeutic monitoring of hepatitis Ctreated patients enable the clinicians, physicians, and health care providers to sketch consensus treatment guidelines and recommendations for the safe administration of DAAs in general and vulnerable hepatitis C infected populations. Interestingly and luckily, the treatment guidelines and recommendations approved by the FDA and CDC are following and working well in real-world clinical, hospital, and primary health care centers to manage hepatitis C, infected individuals. Albeit; for certain special populations like pediatric and pregnant hepatitis C females, we do not have clear guidelines for DAAs usage and their therapeutic monitoring. Furthermore, certain DAAs are not recommended in decompensated cirrhotics, in HCV rebound patients, and in previous treatment failure with a DAAs regimen. In this book chapter, we enlist updated treatment guidelines and recommendations to treat general as well as special hepatitis C-infected populations with DAAs and will briefly portray an overview of the pros and cons of these recommendations in real-world clinical settings.

Certain hepatitis C-infected populations are still challenging to treat in the era of all-oral interferon-free direct-acting antivirals (IFN-free DAAs), which are highly efficacious, well-tolerable, and relatively safe in treated individuals. Such difficult-to-treat patients were also challenging even to manage with pegylated interferon (PEG-IFN) plus a nucleoside analog ribavirin (RBV) once known as the “gold standard of hepatitis C care”. People infected with hepatitis C genotype 3, decompensated cirrhosis, individuals with co-infection status (e.g., HCV/HBV, HCV/HIV, HCV/CKD), hepatitis C patients with induction of hepatocellular carcinoma (HCC), previous treatment failure with PEG-IFN plus RBV or DAAs failures, and viral relapse patients with the use of one or more DAA combinations are even compromised to achieve higher SVR rates with IFN-free DAAs. Similarly, some DAAs have suboptimal clinical efficacies in harder-to-cure populations and some are contraindicated and can worsen hepatitis C-associated hepatic pathological states if administered without drug monitoring. Interestingly, DAAs in clinical trials conducted for their administration approvals demonstrated to achieve satisfactory SVRs in hepatitis Cinfected special populations. Recently, limited data from real-world cohorts depict the excellent efficacy and safety of IFN-free DAAs in real-life clinical situations, similar to clinical trials. It is still uncertain whether either viral or host factors are responsible for the trivial effectiveness of DAAs in such populations. In this chapter, we will discuss the management of harder-to-treat special populations with DAAs by exploring some real-world cohort data as well as the treatment algorithms, guidelines, and recommendations for those patients in real-world clinical settings.

Oral interferon-free DAAs (IFN-free DAAs) have proven their clinical and therapeutic worth in real-life situations by achieving higher sustained virologic response rates (SVRs >90%) in treated individuals. After their recommendations to be administered to hepatitis C-infected populations in 2017 more than 5 million hepatitis C-infected individuals have been treated across the world and the overall health care burden of active hepatitis C comorbidities and mortalities have been declined from 130 million hepatitis C patients to approximately 71 million. Despite these great achievements in hepatitis C therapeutics, certain patient-oriented, clinical, and societal challenges are still prevailing to accept IFN-free DAAs on the large scale clinical, hospital, and primary health care settings in low and middle-income countries as well as even in developed nations. High therapy costs, treatment access and monitoring, coinfection status of certain vulnerable hepatitis C infected populations, racial disparity, pre-, and post-therapeutic monitoring, and long-term follow-ups are potential barriers to consensually implementing uniform treatment algorithms and accessibility to DAAs regimens worldwide. Furthermore, recurrence of hepatitis C infection, reactivation risks of co-infections (e.g., HCV/HIV, HCV/HBV or HCV/CKD), minefield risks of hepatocellular carcinoma (HCC) rebound, and surveillance of hepatitis C liver transplant recipients which are on treatment with IFN-free DAAs also limit the administration of these regimens to every hepatitis C infected individual. In this book chapter, we will explore all these real-world challenges and will discuss/suggest the strategies to coup them in clinical, hospital, and community settings to improve the cascades of care and scale-up HCV cure.

The ongoing COVID-19 pandemic with its devastating impacts in terms of huge disease burden and patient management on the world’s leading healthcare systems and jolting the world’s biggest economies, has leveraged the lesson that to prevent the transmission and elimination of a viral pandemic, endemic, or epidemic in future, a prophylactic or protective vaccine would be indispensable. In this scenario, DAAs regimens alone would not be sufficient to eliminate the HCV epidemic by 2030 or beyond and there would always be the demand for a prophylactic or protective vaccine to prevent the transmission of this epidemic again from vulnerable populations. The anti-mRNA-based treatment strategies (e.g., anti-HCV protein-specific oligonucleotides, RNA interference (RNAi), and micro RNA (miRNA)), and some potential anti-hepatitis C vaccine models have been widely and extensively studied as an alternative or adjuvant therapeutic approaches for hepatitis C in the recent past and some of those models are still in the pipeline. The approval of the first RNAi therapy against a hereditary protein deposition disorder has urged investigators to refocus this approach against hepatitis C because it represents the most thoroughly studied treatment strategy against hepatitis C in the last two decades. Furthermore, some emerging approaches like host targeting agents (HTA), nanoparticles-containing immunogens, and nanomedicine-based therapeutic agents are also in their full investigative form. In this book chapter, we will discuss and highlight emerging hepatitis C treatment approaches that could be the game-changer to vanquishing HCV by 2030 while used as an adjuvant or compensatory regimen with DAAs.

The worldwide prevalence of the hepatitis C virus takes a heavy toll on lives, communities, and health systems. Every year more than 4 million peoples die from hepatitis C-related liver cancers and cirrhosis- a mortality tool comparable to that of HIV and tuberculosis. It needs for a global health sector strategy stems from the scale and complexity of the hepatitis C epidemic, along with growing recognition of its massive public health burden, and the huge opportunities for action. It is a golden time now to establish a coherent public health hepatitis C response that prioritizes effective interventions, promotes service delivery approaches that ensure quality and equity to test and treat every hepatitis C infected individual, takes programs to achieve the sustained impact of hepatitis C diagnostics and therapeutics at the population level, and establishes clear stakeholder responsibility and accountability. There are unprecedented opportunities to act while ending the hepatitis C epidemic and are feasible with the tools and approaches currently available and in the pipeline. For the greatest impact, these opportunities should be combined and tailored for specific populations, locations, and settings. New opportunities and health sector policies provide a ray of hope for the elimination of hepatitis C as a public health threat. In this book chapter, we will highlight the goals, aims, opportunities, and barriers to a coherent public health policy for hepatitis C effective interventions at screening, diagnostic, and therapeutic scale in general and vulnerable hepatitis C infected populations and their consensus implementations to healthcare systems.

To put an end to hepatitis C from the world, the quality and equity of hepatitis C screening, diagnosis, and treatment must be accessible to everyone infected with the virus, regardless of age, sex, racism, nationalism, and religious differences. If several key strategies are successfully implemented, countries could collectively meet the WHO target of reducing new HCV infections by around 80% by 2030, compared with 2015. But even with successful implementation, the target of reducing HCV mortality by 65% would take until 2032, according to recent data. To evaluate the power of several interventions those help to reach these goals, several transmission models with data from affected countries that comprise hepatitis C patients demographics, virus prevalence in vulnerable populations, current dynamics of prevention programs, the natural history of hepatitis C and its prevalence, and percentages of deaths caused by hepatitis C must be considered. In addition to that, the models to project what it would take to reach the targets would need to change and improve blood safety and infection control, vertical transmission of hepatitis C infection, extending harm reduction services for PWIDs, expanded testing, and increased treatment with DAAs, with intensive improvements in public health care sectors and strong political will in third-world countries where hepatitis C is almost endemic would be required. In this book chapter, we are focusing on the achievements of the GHSS 2016-2021 plan for hepatitis C with their probable implementations in WHO member states as well as cross-cutting priority actions for the next decade.