Treatment considerations for hepatitis C are based on the presentation of the disease acute vs chronic , genotype, laboratory values, presence of co-infection HIV, hepatitis B and co-morbidities. Hence, every patient should be carefully evaluated with respect to treatment indications, associated co-morbidities, adherence to treatment and reliability of follow-up.
Treatment of chronic hepatitis C in adults is recommended for those who have detectable HCV RNA levels, elevated aminotransferase ALT levels, liver biopsy findings suggestive of progressive liver disease and the absence of any serious co-morbid conditions or contraindications as listed in Table 1 Strader et al , ; Dienstag and McHutchison, ALT levels however, do not always correlate with disease severity and hence, treatment should not be denied in those with normal ALT levels Bacon, The therapy of hepatitis C has improved substantially over the years Figure 1.
The current recommended treatment of chronic HCV is the combination of peginterferon and ribavirin. The overall response rates were substantially increased by the addition of the oral nucleoside analog ribavirin.
The mechanism of action of ribavirin is not well understood. Progress in therapy of hepatitis C. Another significant advance in HCV therapy came with the development of long-acting pegylated interferon peginterferon. The combination of peginterferon and ribavirin has been shown to yield the highest response rates in three pivotal trials Manns et al , ; Fried et al , ; Hadziyannis et al , These results were significantly better than those achieved with standard combination therapy or peginterferon monotherapy.
The current recommended regimen is summarized in Table 2. There is no current established treatment for patients with genotype 4, 5 or 6. These patients are usually treated with the same regimen used for genotype 1 patients El-Zayadi et al , An optimal treatment regimen for acute hepatitis C has not yet been established.
Hence, a delay of treatment for 8—12 weeks after the onset of acute hepatitis C has been suggested. Both IFN and peginterferon with or without the combination of ribavirin have been used in various studies with promising results. There are three types of response to therapy: SVR, relapse or breakthrough, and non-response. ALT levels return to normal and liver histology shows improvement. Various factors have been associated with lower response rates in patients undergoing treatment with peginterferon and ribavirin.
Hence, these factors should be reviewed when considering therapy. Treatment with peginterferon and ribavirin is associated with numerous adverse effects Table 3. Most patients undergoing treatment experience side effects ranging from mild to severe.
As a result, patient education of potential side effects as well as monthly visits for monitoring blood counts and symptoms should be emphasized before the initiation of therapy. The most common side effects of peginterferon are fatigue, muscle aches and psychological side effects such as depression, anxiety, irritability and sleep disturbance.
The most common side effect of ribavirin is hemolytic anemia, which usually warrants dose reduction. Many new approaches to therapy of chronic hepatitis C are being studied in clinical trials. Some of the recent advances have been made in the modification of the dose and duration of current recommended combination therapy. Ribavirin in high doses — mg has been shown to achieve higher SVR rates in a small trial at the expense of a higher toxicity profile Lindahl et al , New forms of IFN are being tested clinically.
A new generation of small molecule inhibitors targeting the viral-encoded enzymes, such as the proteases and polymerases is being developed. Many of them are in late phase clinical trials Pawlotsky, Although some of them are quite promising in suppressing HCV levels in HCV-infected people, drug resistant mutants emerge rapidly after the initiation of therapy. Therefore they would have to be used in combination with IFN-based therapy. Treatment of hepatitis C has improved substantially in response rates across all genotypes.
However, progress remains to be made to improve the SVR rates for genotype 1 patients as well as relapsers and non-responders. Until the above-discussed new agents pass rigorous scrutiny in clinical trials, the current combination therapy of peginterferon and ribavirin will remain the mainstay treatment of hepatitis C for the next 3—5 years.
National Center for Biotechnology Information , U. Oral Dis. Author manuscript; available in PMC Jan 8. Author information Copyright and License information Disclaimer. Copyright notice. The publisher's final edited version of this article is available at Oral Dis. Tupaia Treeshrew, Anathana ellioti is potentially a good model to study the HCV infection, but the instability of the infection and its low level limit the use of these animals. The immunotolerized rat model supports the HCV replication.
Histological and biochemical evidence of infection were present, but viremia was relatively low as compared with viral load in humans[ ]. Mouse models compared with other animal models, have some advantages, such as producing animals in a short time short gestation period , lower breeding cost and their small size making them easy to manipulate[ , - ].
Heterotopic liver graft mouse model seemed to be suitable to evaluate the putative effect of anti-HCV drugs, but the short and low viremia and loss of the liver graft were limiting factors. The main limitation of the model is the absence of a normal immune system, which may be overcome by combining the model with a human hemato-lymphoid system, the value and reproducibility of which has yet to be established[ ]. The main limitations of these models are the low number of animals that can be generated and the high cost[ - ].
Recent study demonstrated that hepatocyte-like cells differentiated from human embryonic stem cells and patient-derived induced pluripotent stem cells could be engrafted in the liver parenchyma of immune-deficient transgenic mice carrying the urokinase-type plasminogen activator gene driven by the major urinary protein promoter.
This efficient engraftment and in vivo HCV infection of human stem cell-derived hepatocytes provide a model to study chronic HCV infection in patient-derived hepatocytes, action of antiviral therapies, and the biology of HCV infection[ - ]. Established human hepatocarcinoma cell line Huh-7 and its derivatives support the HCV replication.
However, as every transformed cell line, they resemble the primary cells only partially. Thus, results of experiments performed on these cells might not be always appropriated[ ].
The primary human hepatocytes and human fetal hepatocytes are more clinically and physiologically relevant. Thus, they are used to test the susceptibility of HCV to drugs and drug-metabolizing enzymes. Another in vitro model, the micropatterned co-cultures of primary human hepatocytes surrounded by a supportive stroma that expressed all known HCV entry factors. Using this method in combination with the highly sensitive luminescence-based and fluorescence reporter systems, the efficiency of anti-HCV therapeutics has been evaluated[ ].
Recent studies show that both embryonic[ ] and induced pluripotent[ , ] stem cells can be differentiated into hepatocytes, that are phenotypically similar to human fetal liver.
Study of genetic defects that impact the HCV infection could be performed in a human iPS-derived hepatocyte-like cell-based model[ ]. Induced human liver-like cells supported the entire life cycle of HCV genotype 2a reporter virus.
Produced infectious particles were able to infect HuH Thus, the evaluation of antiviral drugs using these cells was possible[ ]. Analysis of precision-cutting adult human liver slices from infected or non-infected individuals represents another promising model. In fact, this model allowes to maintain the tridimensional structure of liver and analyse gene and protein expression.
Thus, this approach allowed to validate the efficiency of the new antiviral drugs[ , ]. The HCV causes damage to the liver cells, but the exact mechanism of this phenomenon is unknown. It is believed, that the damage is largely mediated by the host immune response. In immunocompetent and immunocompromised patients with little, or no intrahepatic damage, including inflammation, high levels of the HCV replication have been reported[ , , ].
However, high levels of an intrahepatic HCV replication are usually tolerated by the host immune system. However, why in most patients the immune response cannot resolve the infection remains obscure. The liver fibrosis is caused by inflammatory cells of the intrahepatic infiltrate secreting cytokines and chemokines to activate hepatic stellate cells HSC to secrete collagen[ ]. HSCs may exist as several different phenotypes with distinct molecular and cellular functions and features, each of which contributes significantly to the liver homeostasis and the disease.
The quiescent stellate cells are critical to the normal metabolic functioning of the liver. The liver injury provokes the transdifferentiation of quiescent stellate cells to their activated phenotype, leading to a metabolic reprogramming.
Through these changes, the activated stellate cells drive the fibrotic response to injury and the development of cirrhosis. As liver injury subsides, the activated stellate cells can be eliminated by one of three pathways: Apoptosis, senescence or reversion to an inactivated phenotype. Reduction in the number of activated stellate cells contributes to the regression of fibrosis or cirrhosis and the liver repair in most, but not all patients.
The relative inputs of these three pathways on the fibrosis regression are not clearly defined[ ]. In response to HCV antigens, the PD-1 blockade enhanced an interleukin-2 IL-2 —dependent proliferation of intrahepatic Tregs and enhanced the overall ability of Tregs to inhibit T-effector cells.
An increase in Treg proliferation with PD-1 blockade was linked to this effect[ ]. A typical model of the wound-healing response to a persistent liver injury is the hepatic fibrosis occurring in the chronic hepatitis C[ ]. Cytokines and chemokines capable of activating hepatic stellate cells to secrete collagen are secreted by the inflammatory cells of the intrahepatic infiltrate[ , ]. Thus, the fibrogenesis seems to be linked to the HCV expression through indirect mechanisms, mediated by a virally driven inflammation, but the direct role of viral factors in the disease progression should be investigated in more details.
The cell injury, such as an oxidative stress and a steatosis, may be induced specifically by several viral proteins alone which could directly activate the hepatic stellate cells[ , ]. Moreover, a reduced portal pressure and a decreased all-cause mortality are improved when the reversal occurs[ ].
The stellate cells can respond to cytokines and growth factors after priming stimuli. Then the proliferation, contractility, fibrogenesis, matrix degradation and proinflammatory signaling are enhanced.
Now, it is clear that there are disease-specific pathways of fibrosis, without all activated cytokine pathways[ , ]. This is especially relevant to NAFLD, where there are many convergent pathogenic routes[ - ].
Importantly, different families of inflammatory cell types and their subsets may either promote or inhibit fibrosis[ - ]. Lipids are required for the HCV replication and particles assembly. As mentioned above, HCV can modify the host serum lipid profile and this ese modification s can provoke the steatosis[ ]. On one hand, in HCV-infected patients, the steatosis can be considered as a marker of the liver disease progression[ ] and, on the other hand, as an indication of the reduced response to therapy[ ].
However, if it is not metabolic or alcoholic steatosis, an efficient antiviral therapy is capable to reduce it[ , ]. Using sensitive PCR assays, the HCV was revealed in leukocytes and there are evidences that these cells may represent a reservoir of the virus after treatment[ , ].
Interestingly, the pool of the HCV quasi-species differs between the plasma and peripheral blood monocytes, suggesting an independent spread of HCV within different cell types[ , ]. A cell line established from transformed lymphocytes supported the HCV replication and also enable production of infectious viral particles capable to infect peripheral blood B cells[ ]. The significance of these extrahepatic HCV reservoirs is not well understood, although one could speculate that the leukocyte compartments might represent an additional route by which HCV can directly manipulate the immune system and also another means by which the virus avoids the eradication.
The most frequent associated pathology is a mixed cryoglobulinemia. They are produced by HCV activated B cells. The cryoglobulins deposed in small and medium vessels are the cause of systemic vasculitis which can manifest in level joint, skin, renal or peripheral nerves[ ].
Other observed extrahepatic manifestations are the following: lymphoma, thyroid disorders, diabetes, xerostomia and xerophthalmia[ - ].
The HCV infection cure leads to a gradual decrease of the cryoglobulin level in serum, followed by the remission of cryoglobulin-related symptoms and pathologic lesions[ ]. Interestingly, as a result of treatment the incidence of type 2 diabetes is also reduced by approximately two thirds[ , ].
In some cases, asthenia, fever and muscle, and joint pain can appear. While, signs of jaundice are not frequent. Acute hepatitis C is characterized by a transient increase in the rate of serum transaminases. The first detectable virus marker is viral RNA that appears one to two weeks after exposure.
The viral RNA becomes undetectable within three to four months after infection. Various factors could promote the viral clearance. Similarly, hepatitis acute symptoms would reflect a significant immune response of the host. The gene polymorphism of interleukin IL 28B also influences the host immune response[ , ]. The fulminant hepatitis C is exceptional[ ]. When the viral replication persists for more than six months after acute infection, the hepatitis is considered chronic.
At the stage of chronic hepatitis, most patients are asymptomatic and may have no non-specific symptoms such as fatigue, arthralgia or myalgia. The transaminase levels may be moderately increased or even normal[ ]. The long-term evolution of chronic infection is variable. The factors that accelerate the disease progression are the following: acquisition of more than 40 years, male gender, co-infection by HIV, higher body mass index, fatty liver and alcohol consumption[ ].
The cirrhosis may be associated with a liver failure, as a decompensation following a portal hypertension ascites, gastrointestinal bleeding, etc. Thirty-three percent of patients with HCC die within one year after diagnosis[ , ]. Natural history of hepatitis C virus infection and start to treat. The Child—Pugh score employs five clinical measures of liver disease: Total bilirubin, Serum albumin, Prothrombin time, Ascites, Hepatic encephalopathy. The letter F refers to the scars of the liver caused by the aggression.
It is classified from F0 to F4: F1, F2 are minimal to moderate fibrosis, F3 corresponds to a pre-cirrhotic stage and F4 corresponds to cirrhosis. Red arrows indicated the time to start treatment[ ].
For HCV diagnosis both serologic and nucleic acid-based tests were developed[ , ]. When an acute hepatitis C is considered, a serologic screening alone is insufficient, because mature anti-HCV antibodies are developed late after transmission of the virus.
Morphological methods like immunohistochemistry, in situ hybridization or PCR from liver specimens play no relevant role in the diagnosis of hepatitis C because of their low sensitivity, poor specificity and low efficacy compared to serologic and nucleic acid-based approaches. This assay comprises 5 different antibodies targeted the HCV core. The test is highly specific However, HCV core antigen correlated well, but not fully linearly, with HCV RNA serum levels, and false-negative results might be obtained in patients with an impaired immunity[ - ].
Another study has shown that the HCV core antigen quantification could be an alternative to the HCV RNA quantification for on-treatment antiviral response monitoring[ ]. Here, a HCV core antigen below the limit of quantification at treatment 1 wk was strongly predictive of RVR, whereas patients with a less than 1 log10 decline in HCV core antigen at treatment 12 wk had a high probability of achieving nonresponse. The new HCV core antigen assay could be a cheaper, though somewhat less sensitive, alternative for nucleic acid testing.
Since the HCV RNA is detectable within a few days of infection; the nucleic acid-based tests are efficient in an early diagnostic of acute hepatitis C and should be considered as mandatory. The HCV RNA measurement is furthermore important in determination of the HCV genotype, selection of treatment strategy, therapy duration and evaluation of the treatment success[ ].
For a number of antiviral combination therapies, the HCV RNA follow-up studies are essential to define the outcome of the treatment and further therapeutic strategies, if necessary. Traditionally, the tests should be repeated 24 wk after treatment completion to assess whether a sustained virologic response SVR has been achieved. However, as the probability of a virologic relapse is similar after 12 and 24 wk, the new time point for assessment of final virological treatment outcome is 12 wk after the end-of-treatment[ , ].
Both qualitative and quantitative PCR-based detection assays are available. The measurements are essential in the treatment monitoring when the virus load is gradually reducing. HCV genotyping is mandatory for every patient who considers antiviral therapy[ ]. For DAA-based therapies, the determination of HCV genotypes and even subtypes is important because of significantly distinct barriers to resistance on the HCV subtype level. However, the importance for the HCV genotyping may decline with the availability of highly and broadly effective all oral combination therapies in the future.
Both direct sequence analysis and reverse hybridization technology allow the HCV genotyping. Current assays were improved by additionally analyzing the coding regions, in particular the genes encoding core protein and the NS5B, both of which provide non-overlapping sequence differences between the genotypes and subtypes[ , ].
All people with confirmed chronic HCV infection should be offered a high-quality care as soon as possible. Simultaneously, the screening and management of alcohol use is essential to prevent the progression to cirrhosis[ , ].
The modelling suggests that the treatment early in the course of HCV disease for all or specific populations could prevent the disease progression and onward transmission[ - ]. In fact, not all people with chronic HCV infection will progress to fibrosis[ ]. So, medical authorities of a country to should decide when to start anti-HCV treatment.
It should be emphasized that the transmission has been documented among people recently cured who lacked access to prevention services[ ]. More research is needed to determine cost-effective eligibility criteria for both key and other populations that maximize reductions in the HCV-related morbidity, mortality, and transmission in different epidemiological contexts.
The WHO guidelines recommend the prioritizing treatment among people with an advanced fibrosis or cirrhosis in order to prevent a liver cancer[ ].
However, the liver biopsy test is expensive and can lead to complications such as infections, excessive bleeding, pain, or accidental injury to other organs. The use of liver function tests and platelet counts to determine the degree of liver fibrosis, such as the aminotransferase-to-platelet ratio index and the Fibrosis-4 score could be a non-invasive alternative and a more useful approach for gauging treatment eligibility across different tiers of health systems[ , ].
Monitoring systems should be put in place for people who do not initiate treatment immediately. In the course of the last two decades, treatment of the HCV infection has significantly improved. For nearly 15 years, the combination of pegylated interferon alfa and ribavirin PR allowed a moderate sustain virologic response SVR. It revolutionized the treatment of chronic hepatitis C[ , ].
In , telaprevir and boceprevir obtained a market approval. From the standard of care is a combination of DAAs. These medicines are much more effective, safer and better-tolerated than the older therapies. The estimation of a putative virus resistance profile prior to an antiviral therapy can help to select the optimal treatment regimen for individual patients[ , ]. Selected directly acting antiviral agents and host targeting agents in the pipeline[ 63 ].
Selected directly acting antiviral agents and host targeting agents whose development has been stopped or temporarily halted[ 63 ]. A prominent genetic diversity of HCV in combination with non-trivial replication cycle poses serious problems in virus research and therapy of virus-associated diseases. However, during the last several years a significant progress in understanding of the HCV molecular biology and pathogenesis has been achieved.
In many aspects that allows to making a great step forward towards antivirals design, that result in DAA therapy. However, even with the new drugs the HCV-associated problems, of both fundamental and applied origin, are not solved. In fact, the resolution of these problems is going hand in hand. First, in the absence of direct cytopathic effect, the mechanism of lipid deregulation, that results in liver pathologies, is not completely understood. Second, the system of the HCV control during latency and putative triggers of virus active replication were poorly investigated.
Third, design of prophylactic vaccine is still in its infancy. Finally, the access to drugs and therapies for the people leaving in the third world is very restricted. Indeed, an easy access to diagnosis and treatment is still missing to drug users, people in difficult socio-economic situations, migrants, prisoners, because of themselves or health policy. Therefore, fundamental studies on virus-cell interactions and studies directing towards development of the prophylactic vaccine should be intensified.
Conflict-of-interest statement: The authors have no conflict of interest to declare. Manuscript source: Invited manuscript. Peer-review started: December 5, First decision: December 11, Article in press: February 7, Specialty type: Gastroenterology and hepatology. Country of origin: France. Peer-review report classification. Grade A Excellent : A. Grade B Very good : B. National Center for Biotechnology Information , U. Journal List World J Hepatol v.
World J Hepatol. Published online Feb Vladimir Alexei Morozov and Sylvie Lagaye. Author information Article notes Copyright and License information Disclaimer.
Published by Baishideng Publishing Group Inc. All rights reserved. This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. This article has been cited by other articles in PMC. Abstract Hepatitis C virus HCV is a major cause of liver diseases including liver cirrhosis and hepatocellular carcinoma. Open in a separate window. Figure 1. Figure 2. Figure 3.
Table 1 Overview of the size of hepatitis C virus proteins. Protein No. Core protein p22 The core protein of HCV is translated as an immature protein of 22 kDa, that it is composed of amino acids aa. Figure 4. Post-entry events It was shown by a traffic monitoring that after binding to the cells surface, the virus particles enter into the cells using clathrin dependent endocytic pathway[ , ]. Figure 5. Viral assembly and release A assembly of the virion is another multi-step process and certain steps of it remains obscure.
Virus release and extracellular particles The detail mechanism of the HCV release requires more comprehensive investigation. Math 1. Figure 6. Figure 7. HCV replicon systems The HCV genome was identified in by cloning it from infected chimpanzee, while in humans the amounts were too low for detection[ ].
Animal models Chimpanzee could be a good model to study the HCV infection[ , ]. In vitro models Established human hepatocarcinoma cell line Huh-7 and its derivatives support the HCV replication. Ex vivo model Analysis of precision-cutting adult human liver slices from infected or non-infected individuals represents another promising model. Alterations of lipid metabolism Lipids are required for the HCV replication and particles assembly.
Figure 8. Nucleic acid testing for HCV Since the HCV RNA is detectable within a few days of infection; the nucleic acid-based tests are efficient in an early diagnostic of acute hepatitis C and should be considered as mandatory.
Table 3 Selected directly acting antiviral agents and host targeting agents in the pipeline[ 63 ]. Table 4 Selected directly acting antiviral agents and host targeting agents whose development has been stopped or temporarily halted[ 63 ].
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Nat Med. Elicitation of strong immune responses by a DNA vaccine expressing a secreted form of hepatitis C virus envelope protein E2 in murine and porcine animal models. Download references. You can also search for this author in PubMed Google Scholar. PH and MA evaluated and screened the data. MHY and TH contributed to data curation. SHM conceptualized and supervised the study. SA and SHM revised the manuscript critically for important intellectual content.
All authors read and approved the final manuscript. Correspondence to Sayed-Hamidreza Mozhgani. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Reprints and Permissions. Shayeghpour, A. Hepatitis C virus DNA vaccines: a systematic review. Virol J 18, Download citation. Received : 16 August Accepted : 26 November Published : 13 December Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Abstract Background Vaccination against HCV is an effective measure in reduction of virus-related public health burden and mortality.
Results Twenty-seven articles were included.
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