Evidence-Based Pharmacology Paper on HCV Patients

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Evidence-based pharmacology
20.09.2021
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Viral hepatitis C (HCV) constitutes the primary reason of advanced liver disease with the highest mortality, liver transplantation, and puts people at risk of severe comorbidities. The diversity of virus and its resistance pose the challenges to an effective and short duration treatment. Several decades of continuous research of pathogenesis, genomics, and antiviral therapy have contributed to the development of the cure for HCV in comparison with HIV/AIDS. The new era of direct-acting antiviral agents opens advanced possibilities of timely and the least harmful therapy. Consequently, the paper is aimed at discovering how pathophysiology, genomic issues, and individual features of the HCV patients are managed with the latest acknowledged findings in virology and clinical guidelines for HCV management.

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Pathophysiology

HCV is referred to the blood-transmitted infectious disease associated with the unsafe healthcare-associated injections, contaminated drug injections, mother-to-child and sexual transmissions (World Health Organization [WHO], 2016). The non-cytopathic kind of virus affects liver cells in the process of simultaneous replication. As a result, the liver cells are exposed to necrosis together with hepatic steatosis. The latter follows metabolic derangements caused by the virus replication. Depending on individual immune response and virus genotype, the exposure may result in minimal changes, but also may lead to persistent infection. The continuous functioning of HCV in liver cells leads to chronic hepatitis, severe fibrosis, cirrhosis, and liver cancer (European Association for the Study of the Liver [EASL], 2014). The acute type of response with jaundice occurs in 20% of the infected patients (Lingala & Ghany, 2015). The majority of infections are noticed after the 6-month exposure period leading to the chronic type of HCV. Lingala and Ghany (2015) point to the development of cirrhosis in a 25-30-year time span in 20-30% of cases.

The RNA virus is rather variable contributing to the existence of 7 genotypes diverging up to 35 % and 120 subtypes diverging up to 20 % (Irshad, Mankotia, & Irshad, 2013; Scheel & Rice, 2013). Genotype 1 and 2 are the most frequently detected worldwide. Genotype 1 is prevalent in Americas. The disease development is rather similar in all the genotypes. In particular, the prognosis of comorbidities like liver cancer and cirrhosis does not differ across the genotypes. However, the highest severity of liver disease and steatosis are typical for genotype 3 (Scheel & Rice, 2013). Irshad et al. (2013) consider HCV 1b a more aggressive form that is prevalent in the patients with liver cirrhosis. Still, the course of the disease is rather variable due to the diversity of the factors’ combinations.

The severity and progress of disease depend on the set of individual, viral, and outer factors that undergo little modifications. Age continuum constitutes one of the determinant backgrounds for the illness development. The fibrosis progress is referred to as the most apparent indicator of the age influence. In particular, older patients are noticed for the faster development of expanded fibrosis (Lingala & Ghany, 2015). The age of 40 is a critical point for the appearance of positive preconditions for the disorder. The reasons for such transformation are connected with the immunological and physiological changes with the age. The latter may concern decreased liver volume and blood flow in liver (Lingala & Ghany, 2015). The factor can be facilitated with such aspects as male gender, obesity, and alcohol abuse. Together with other co-factors, the age issue is responsible for the sustained response to the interferon therapy (EASL, 2014). The host aspects shape the genome functioning of HCV and the character of interactions in the host liver cells.

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Genomic Issues

Hepacivirus is the positive-stranded RNA that belongs to the Flaviviridae family (Irshad et al., 2013). HCV is represented by the 9.6-kb genome with a long open reading frame consisting of over 9000 nucleotides and the 5’ and 3’ untranslated regions at the flanks (Irshad et al., 2013). The genome is organized in the form of polyprotein generated by 10 proteins: structural (E1, E2, and core) and non-structural (NS 1-5) ones (Scheel & Rice, 2013). Within the polyprotein, envelope sections and NS1 and NS5B are the most variable parts.

The peculiarities of the virus targeting are also connected with the limited proofreading capability of HCV RNA that affects resistance to the interferon therapy and modify pathogenesis (Irshad et al., 2013). The feature is responsible for multiple errors in replication. The quasispecies model of circulation contributes to viral clearance. Accordingly, the exemplars with low genetic diversity can experience spontaneous eradication (Lingala & Ghany, 2015).

Still, the variability and mutagenesis of non-structural proteins determine unpredictable complexity of the virus life cycle. The introduction and replication occur in hepatocytes. The receptor-mediated endocytosis enables the penetration and release of HCV genome in cytoplasm that is later translated into the HCV polyprotein with functional proteins (Ramage et al., 2015). Structural proteins, on the one hand, are responsible for the virus release. On the other hand, non-structural proteins such as NS2, NS3, NS4A, NS4B, NS5A, NS5B enable virus replication. The function of p-7 protein that interacts with mitochondrial proteins is insufficiently understood (Ramage et al., 2015). Moreover, 139 HCV host protein-protein combinations are found in the life cycle of HCV that complicates the full understanding of all the disease pathways. These interactions are manifested in the diversity of the genotypes and subtypes with the specific nucleotide sequence. The peptides combination has a profound impact on the disease course. The literature review enables one to reveal the evolution of scientific knowledge on the problem and find the evidence for clinical practice.

Literature Review

HCV was discovered in 1989, and since then it has been considered the first cause of post-transfusion hepatitis (Scheel & Rice, 2013). The studies on the problem were complicated by the presence of virus in the chimpanzee species only. Such specifics made the evolution of knowledge about the pathogenesis, methods of detection, and processes related to the cell culture take a long time. The systematic review by Irshad et al. (2013) discusses the peculiarities that provide the healthcare professional with the highest level of evidence. The accumulated data on immune response, genotype diversity, and clinical conditions related to the HCV pathogenesis during the last two decades are also presented in the article (Irshad et al., 2013). Another review by Lingala and Ghany (2015) provides a deep insight into the natural history of HCV taking into account the factors influencing the HCV outcomes. The explanation and comprehensive understanding of the disease follow the advances in the genomics witnessing of the significance of the numerous HCV proteins’ interactions (Ramage et al., 2015).

The appearance of the first generation of direct-acting agents (DAA) in 2011 is reflected in a number of recent studies in the field. In particular, the review by Scheel and Rice (2013) includes the comparison of two treatment approaches approved since the HCV detection. According to the findings, the therapy based on direct-antiviral agents (DAA) remains acknowledged worldwide and is a progressive standard for HCV treatment (Scheel & Rice, 2013; WHO, 2016). Alongside, the report by Hunt and Pockros (2013) indicates the constant progress in the different combinations and treatment schedules of DAAs, pegylated interferon, and ribavirin. Accordingly, the application of the second-generation antiviral agents is considered in the clinical guidelines of authoritative healthcare organizations.

Clinical guidelines serve another major document to find the high-quality evidence for the HCV management. The clinical decision-making in the HCV management for European countries is addressed in “EASL Clinical Practice Guidelines: Management of Hepatitis C Virus Infection” (EASL, 2014) and its updated version (European Association for the Study of the Liver [EASL], 2017). The document includes the up-to-date DAA treatment regimens approved in Europe and the US. The recommendations are designated to guide healthcare providers in finding an optimal treatment for chronic and acute HCV types of disease. The comparison of two versions shows significant improvements in the treatment of HCV due to the combination of DDAs during the last two years. The World Health Organization also continues joint efforts in generating the universal evidence-based report on the HCV management. The updated version of “Guidelines for the Screening, Care and Treatment of Persons with Hepatitis C Infection” appeared in 2016, and it involves the newest approved DAA acknowledged by the regulatory authorities (WHO, 2016). It offers the framework for policy makers as well as healthcare professionals in provision of the least harmful, cost-, time-, and cure-efficient therapy for HCV. The promising alternative for HCV eradication concerns the development of the HCV vaccine. This process has been actively discussed and manifested in a number of clinical trials in the recent years (Kumar et al., 2016).

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While collecting the evidence base for the HCV pathophysiology and treatment, the information and data from the peer-reviewed sources published during the last 7 years were accumulated. Systematic reviews, clinical trials, and guidelines as the evidence with the highest level of confidence constituted the objects of search in EMBASE, Cochrane Library, and MEDLINE networks. The guidelines of the world leading health organizations like the European Association for the Study of the Liver (EASL) and the World Health Organization (WHO) assist in generating comprehensive vision of the problem. Systematic reviews and randomized controlled trials suggest the primary sources of search in PubMed database to sort out clinical evidence for treatment approaches to HCV. Accordingly, HCV, pathophysiology, treatment, clinical guidelines and antiviral agents were the keywords used in the literature search to get the comprehensive vision of the disease management. The literature collection on the topic contributed to distinguishing treatment approaches, which are constantly improved according to the newest clinical trials.

Treatment Approaches

The aim of treatment is to pull through liver disease while eradicating the virus activity. In the case of HCV cirrhosis, albeit the cure from HCV and decompensation, the life-threating conditions may remain present. According to EASL (2014), the therapy endpoint is undetectable HCV virus after a 24-week follow-up period determined with sustained virologic response (SVR) with the accuracy of detection lower than 15 IU/ml. WHO strongly recommends all the patients with the chronic condition and injecting drugs to undergo the pre-assessment for treatment (2016). Scheduled treatment is recommended for people suffering from expanded fibrosis. The individualized treatment plan is suggested for patients with less severe HCV.

The antiviral treatment is based on the inhibition of membrane-associated replication and maturation of non-structural proteins. Permanent advances in the HCV biology contribute to the development of a broad set of antiviral compounds (Scheel & Rice, 2013). Taking into account the genotype diversity, the efficiency of treatment is highly dependent on the selection of the medicines suitable to the virus genotype. Though 46% of the HCV cases refer to genotype 1, and 30% to genotype 3, the genotypes vary across the world and in Southeast Asia in particular (WHO, 2016). The healthcare professionals of the World Health Organization (2016) tend to come with the pan-genotypic treatment in the nearest future facilitating the comprehensive disease management.

The first achieved treatment approach relied on non-specific antivirals with insufficiently understood mechanisms of action. The pegylated interferon-? (PEG) therapy together with ribavirin (RBV) lasted for 48 weeks (Scheel & Rice, 2013). Interferon- ? IFN is argued to suppress virus development whereas ribavirin supports an IFN-induction, activates T-helper 1 and diminishes mutagenesis of newly generated viral RNA (Scheel & Rice, 2013). However, the treatment caused severe adverse events (AE) that led to the therapy termination. PEG may provoke influenza-like illnesses, depression, fatigue symptoms, autoimmune disorders, and anemia. Sustained virologic response (SVR) that serves an indicator of cure from 12 to 24 weeks was present in only 50% of patients (Au & Pockros, 2014). Besides, the PEG+RBV combination is found to be more efficient for curing of genotypes 2 and 3 than for hepatitis C 1 (Au & Pockros, 2014). The therapy is included in EASL Clinical Practice Guidelines for the treatment of HCV genotypes 2, 3, 4, and 5. The combination of the therapy with NS3/4 protease inhibitors contributed to better results (EASL, 2014). These were the first-generation DAAs added to the clinical evidence-based practice in 2011.

The invention of multiple DAAs has contributed to the newly amended standard of HCV treatment. DAA medicines modify virus cycle targeting HCV NSs that results in disruption of replication (Au & Pockros, 2014). The direct-antiviral therapy is advantageous, as it provides the oral administration of drugs, results in fewer side effects, is less durable (8-12 weeks) and is efficient in 90% of cases. The US Food and Drug Administration primarily approved telaprevir and boceprevir as first-generation HCV NS3/4A serine protease inhibitors (PI) to apply with PEG+RBV to treat HCV patients with genotype 1 (Au & Pockros, 2014). These first-generation agents increased SVR to 67-75%, but still caused significant anemia and skin disorders. The EASL Clinical Practice Guidelines consider using the approved combination PEG+RBV and telaprevir or boceprevir for the treatment of HCV genotype 1 (EASL, 2014). Still, in the World Health Organization guidelines the latter therapy is conditionally recommended with the medium level of evidence (WHO, 2016).

The second-generation drugs suggest other advances in the field targeting specific sections of viruses and their life cycles. Consequently, besides PI, nucleoside and non-nucleoside inhibitors, NS5A inhibitors, and host-targeting antiviral agents (HTAs) were added to perspective recommendations (EASL, 2014). The most recent approval of the second-generation DAAs is reflected in the updated guidelines of WHO. In particular, the triple sofosbusvir and PEG+RBV or dual sofosbusvir and ribavirin therapies are strongly recommended to eradicate genotypes 1, 2, 3, and 4. The high level of evidence is achieved in the studies comparing this therapy with the PEG+RBV one (WHO, 2016). Similarly, the combination PEG+RBV with simeprevir was found beneficial for treating HCV 1a and 1b. Moreover, DAAs were combined in one pill like Harvoni including ledipasvir and sofosbuvir, and approved by the US Food and Drug Administration in 2014 (US Food and Drug Administration [FDA], 2014). The innovations have enabled healthcare professionals to simplify treatment regimen and shorten treatment duration to 12 weeks, while SVR during this period was obtained in 94% of patients (FDA, 2014). Altogether, the permanent progress in the antiviral therapy determines the appropriateness of the multiple set of DAAs of the second-generation to treat the disease orally, in the shortest time and with the least AEs. Moreover, the clinical trials argue that such combinations are effective enough to pull through several genotypes at once (WHO, 2016). The updated recommendations of EASL rely on the IFN-free regimes as the most efficient in treating HCV patients that are na?ve or experienced in therapy, have compensated or decompensated dysfunctions (EASL, 2017). Over 11 HCV DAAs in the tablet forms and dual combinations were in Europe and the US for the 12 weeks’ therapy so far (WHO, 2016). Alongside, the unrestricted access to the efficient treatment options constitutes the primary challenge for the public health. Consequently, the efforts should be directed to the generation of cost-efficient and easy to monitor DAA therapies (Scheel & Rice, 2013).

The latest findings by Indian researchers Kumar et al. (2016) contribute to the development of a vaccine for prevention of HCV that may become the appropriate strategy for developing countries. The vaccine considers application of virus-like particles (HCV-LPs) based on adenovirus while combining them with different genotype immunogens (Kumar et al., 2016). The trials showed the reduction of the viruses’ bindings in the case of hepatocellular carcinoma that is in evidence of neutralizing antibodies of the vaccine (Kumar et al., 2016). Consequently, further progress in vaccine development will contribute to the alternative option in treatment efforts. Another problem of the holistic care of the HCV patients concerns the follow-up monitoring which is still rather discursive due to the virus evolution and the variety of co-factors.

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Follow-up Treatment

Follow-up treatment and monitoring highly depend on the genotype of HCV, the combination of antiviral drugs, and the progress of liver dysfunction at the moment the treatment starts. Sustained virologic response serves the primary indicator to evaluate the success of therapy. The first treatment approach involving dual IFN-therapy requires 24-48 follow-up weeks depending on the baseline tests of 4, 12 and 24 weeks to confirm the virus eradication (Simmons, Saleem, Heath, Cooke, & Hill, 2015). While the cure rate, in this case, is only 50%, secondary therapy may be recommended (EASL, 2014). These flaws in the previously acknowledged approaches are addressed in the updated version of EASL Recommendations. In particular, the treatment-experienced HCV patients are included in the groups for whom the advanced IFN-free therapy is recommended. The cure rate in the retreatment group undergoing the dual combination of the second-generation DDA reaches 96-100% with SVR12 (EASL, 2017).

The IFN-free DAA therapy that has been chosen as a final treatment approach requires similar follow-up recommendations. The critical post-treatment period is 48 weeks when HCV RNA retest determines the efficiency of the treatment. The recommendations concern non-cirrhotic patients who achieve SVR. Cirrhotic patients with SVR should undergo ultrasound screening for hepatocellular carcinoma every 6 months. Additionally, the history of environmental factors like alcohol abuse or risky sexual behavior may be the reason for additional monitoring. Furthermore, the peer-reviewed studies represented in EOSL recommendations argue that this type of patient has 1-8% risk of reinfection in a year (EASL, 2017). Consequently, such group requires behavioral modifications as one of the follow-up healthcare options. In the case of non-sustained virologic response after IFN-free regimen, the retreatment using the DAAs with “a high barrier to resistance” like sofosbuvir (EASL, 2017). Still, retreatment recommendations are still under consideration and need further approval with direct evidence.

Conclusion

The analysis of recent studies in healthcare-related to screening, pathophysiology, and treatment of HCV indicates a new era in the understanding and managing of an infectious and life-threatening disorder. HCV liver dysfunction is caused by the positive-stranded RNA virus with a high rate of variability, host and environmental factors. The rapid progress in genomics contributed to the detection of 10 structural and non-structural proteins that determine the replication of HCV virus. The variability of host-pathogen protein interaction remains an insufficiently studied problem. Alongside, the approval of the second-generation IFN-free DAAs point to the therapy advancements toward the shortened, the least harmful and more efficient oral therapy that results in the cure of HCV in 99% of cases. The DAA treatment is also promising in diminishing the severity of HCV-associated cirrhosis course and prevention of liver cancer. The invention of the HCV vaccine is the main aim of the HCV management for the nearest future.

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