Another important consequence of identifying HCV was that researchers were now able to analyze the molecular components of the virus and determine which ones could be ideal targets for drugs.
While scientists were working towards characterizing HCV, they were also making strides in its treatment. A huge step toward drug design occurred in , when three different groups of investigators, including NIDDK intramural researchers, were able to grow the virus in cells in the laboratory. This allowed for the study of the HCV life cycle and the identification of essential viral components.
These studies then led to the development of the fi therapies that were specifically designed to block HCV replication by directly targeting parts of the virus. While broadly antiviral therapies like interferon and ribavirin were somewhat effective, the side effects made the treatments difficult to tolerate. These drugs—telaprevir and boceprevir, along with several similar drugs approved later—targeted the HCV protease that is critical for viral replication. When used in conjunction with peginterferon and ribavirin, protease inhibitors yielded SVR rates of up to 75 percent.
However, this triple therapy was accompanied by additional side effects to those already present with peginterferon and ribavirin. Nevertheless, the success of HCV-specific protease inhibitors showed that the virus had vulnerabilities that could be exploited by a well-designed and properly administered drug.
More new anti-HCV drugs were developed and tested over the next several years. These new drugs included sofosbuvir and dasabuvir, which interfered with the activity of the HCV polymerase, an enzyme that is responsible for the viral replication. Members of a second class of drugs, ledipasvir and daclatasvir, targeted the NS5A region of the virus, which makes a structural protein critical for viral replication.
Many of these drugs were initially tested in conjunction with peginterferon and ribavirin, or in combination with a protease inhibitor. Generally, the results were SVR rates of at least 80 percent.
With the success of DAA therapies, it soon became apparent that when several of them were used in combination, interferon was no longer necessary. This was a crucial step in the progress of hepatitis C therapy, because eliminating the need for peginterferon avoided the many distressing side effects that accompanied interferon-based therapy.
These all-oral regimens also opened up the possibility of treatment in individuals in whom peginterferon could not be safely administered. Perhaps the most successful DAA combination was that of sofosbuvir and ledipasvir; with these two drugs, the SVR rates soared to 99 to percent. Furthermore, this combination was successful with just 8 to 12 weeks of treatment. After years of painstaking research, there was a bona fide cure for hepatitis C that worked for nearly everyone.
With such high rates of success with current treatments, it may seem like the hepatitis C story is in its final chapters, but it is not over yet. A vaccine against hepatitis C would cause the prevalence of the disease to plummet, but efforts to produce a vaccine, while still under way, have not yet been successful.
While hepatitis A and B have vaccines, the hepatitis C virus is more variable than either of these viruses, which, along with other factors, complicates vaccine development efforts.
Additionally, the current drugs show great promise, but the costs of the more successful FDA-approved DAA treatments are extremely high, which present a significant obstacle to many with the disease. But the research has come a long way. This enzyme catalyzes the positive RNA strand into its negative-strand intermediate, which in turn serves as the template for new positive-strand synthesis. These are then packaged with core and envelop glycoprotein into mature virions, which then exit the cell via exocytosis.
HCV cannot integrate into the host's genome. Over the years, many genotypes of HCV have been identified. The dominant genotype globally is genotype 1, which is also associated with more severe liver disease and a much greater risk of developing liver cancer. The virus is detectable in plasma within days of exposure, often 1 to 4 weeks. When a chronic infection is established, HCV does not appear to be cytopathic; it is the local inflammatory response that triggers fibrogenesis.
The severity of liver fibrosis tightly correlates with the increased risk of hepatocellular carcinoma via facilitating genetic aberrations and promoting neoplastic clones. Although usually not associated with symptoms, acute HCV infection may cause malaise, nausea, and right upper quadrant pain, followed by dark urine and jaundice. This is clinically indistinguishable from any other acute viral hepatitis. Persistently infected individuals tend to be asymptomatic for the most part.
Symptoms are nonspecific and include fatigue or malaise, intermittent right upper quadrant pain, and joint pain as well as a general feeling of being unwell with overall reduced quality of life. It is challenging to relate these symptoms to HCV alone, as there could be a potential psychological basis due to the knowledge of having an underlying chronic disease.
At this stage, they could have physical signs indicating stigmata of chronic liver disease with caput-medusae, spider angiomas, palmar erythema, asterixis, anasarca, and fluid thrill.
Moreover, they may have signs and symptoms of other extrahepatic manifestations like mixed cryoglobulinemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, lichen planus, neurocognitive changes, insulin resistance, and B cell lymphoproliferative disorders.
These cannot differentiate between past or current HCV infection. HCV Rapid Antibody Test with rapid turnover can be an essential public health tool in nontraditional settings. There are three scenarios in which the HCV RNA test should be considered upfront: 1 exposure within the past six months, 2 an immunocompromised host, and 3 suspicion for reinfection. Further evaluation consists of checking the viral genotype, which is still important in choosing the most optimal regimen and also for predicting the response to therapy.
Other baseline evaluations include testing for HIV, hepatitis B surface antigen, susceptibility to hepatitis A and hepatitis B virus infections, and screening for other underlying causes of liver disease such as autoimmune liver disease, hemochromatosis, and Wilson disease. Before determining the HCV treatment strategy, the next step is to stage the disease, utilizing liver biopsy gold standard or approved imaging modalities with or without noninvasive biomarkers. Lastly, all of these patients should also undergo variceal screening and screening for hepatocellular carcinoma.
A liver biopsy is not routine, but it may help determine the severity of the disease. Other indications for a liver biopsy include 1 uncertain diagnosis, 2 presence of another liver disorder, and 3 immunocompromised patient. Treatment can permanently eradicate HCV infection such that HCV RNA is no longer detectable in blood or liver with a decline in antibody titers and improved liver pathology. Before the development of the all-oral DAAs, the mainstay of therapy was injectable pegylated interferon and ribavirin.
These three classes are used in different combinations to make a robust treatment regimen against the various genotypes of hepatitis C. The standard regimens are anywhere from 12 weeks to 24 weeks with or without ribavirin based on the genotype, treatment experience, and presence or absence of cirrhosis. With the current DAAs, it is the Genotype 3 infection, which is the least responsive that is associated with rapid accelerated fibrosis progression and a higher incidence of hepatocellular carcinoma.
For example, the combination of sofosbuvir and ledipasvir in a single pill and the combination of grazoprevir and elbasvir as a single pill. There are many more drugs in phase III and IV clinical trials that appear to have a pan-genotypic potential such that it will eliminate the need to check the hepatitis C genotype. Defining each regimen for the various genotypes is beyond the scope of this chapter.
The progression of the disease is more common in alcoholic, cirrhotics, and those with a coexisting HBV infection. Individuals who have an undetectable viral load generally have a decreased risk of developing cirrhosis and death. Several other crucial issues are related to treating hepatitis C in special populations, for example, individuals who are co-infected with HIV and Hepatitis C.
Many drug-drug interactions are encountered between the patient's antiretroviral therapy and the oral DAAs for Hepatitis C. With co-infected individuals with Hepatitis B, there have been case reports of Hepatitis B reactivation due to the phenomenon of viral interference. Treating Hepatitis C in patients with end-stage renal disease poses another challenge in itself, although progress has been made, and there are regimens for them.
Numerous drug-drug interactions between Hepatitis C drugs and their immunosuppressive medications have been encountered in patients who are organ transplant recipients, requiring frequent blood level monitoring.
Antiviral resistance is a new adverse event brought about by the use of DAA agents; it needs to be keyed in when selecting a regimen in previously treated individuals, and with some drugs e. The other challenging groups include the decompensated cirrhotics CTP stage B or C and the recurrent hepatitis C seen after liver transplantation.
Details are beyond the scope of this summary. Hepatitis C is a serious infection that has high morbidity and mortality. The management of HCV is prohibitively expensive, and newer antivirals offer a potential cure for the disorder.
The infection is best managed by an interprofessional team that also includes nurses and pharmacists. All clinicians who see patients with HCV should educate them and advise them against the use of alcohol, which is known to accelerate the progression of the infection.
Also, the infectious disease nurse should provide basic sex education and inform these patients that they may transmit the virus to their partners during sexual intercourse. Additionally, these patients should avoid sharing personal care products with others. The patients should be told not to donate blood or any organs as the risk of transmission is high. Hepatitis C is a liver disease caused by the hepatitis C virus.
When someone is first infected with the hepatitis C virus, they can have a very mild illness with few or no symptoms or a serious condition requiring hospitalization. For reasons that are not known, less than half of people who get hepatitis C are able to clear, or get rid of, the virus without treatment in the first 6 months after infection. Most people who get infected will develop a chronic, or lifelong, infection. Left untreated, chronic hepatitis C can cause serious health problems including liver disease, liver failure, liver cancer, and even death.
The hepatitis C virus is usually spread when someone comes into contact with blood from an infected person. This can happen through:. Many people with hepatitis C do not have symptoms and do not know they are infected. If symptoms occur, they can include: yellow skin or eyes, not wanting to eat, upset stomach, throwing up, stomach pain, fever, dark urine, light-colored stool, joint pain, and feeling tired.
If symptoms occur with a new infection, they usually appear within 2 to 12 weeks, but can take up to 6 months to develop. People with chronic hepatitis C can live for years without symptoms or feeling sick.
When symptoms appear with chronic hepatitis C, they often are a sign of advanced liver disease. A blood test called a hepatitis C antibody test can tell if you have been infected with the hepatitis C virus—either recently or in the past.
If you have a positive antibody test, another blood test is needed to tell if you are still infected or if you were infected in the past and cleared the virus on your own. Getting tested for hepatitis C is important to find out if you are infected and get lifesaving treatment. Treatments are available that can cure most people with hepatitis C in 8 to 12 weeks.
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