Hepatitis C overview

# Overview
Hepatitis C virus (HCV) is a single-stranded RNA virus that causes liver damage. Initially discovered in 1989, HCV was found to be a bloodborne infection that develops into a chronic state in most cases. Although the exact pathogenesis and life cycle of HCV are not well understood, it has been demonstrated that impaired innate and adaptive immunity to acute HCV may contribute to the development of chronic infection. While the transfusion of blood and blood products along with injectable therapy were considered the most common risk factors for HCV in the past, the use of illegal intravenous drugs is currently the most important risk factor. In the absence of treatment, chronic HCV leads to liver cirrhosis several years after the initial infection, a course complicated by decompensated liver failure or hepatocellular carcinoma. Other extra-hepatic manifestations are also common. Specific patient populations should be screened for HCV first using HCV serological testing or, rarely, directly by measuring HCV RNA in patients who have had previous HCV exposure, treatment-induced clearance, or immunosuppression. The diagnosis is made when tests for anti-HCV and HCV RNA both return positive results. Measures to slow the progression of liver disease, such as vaccines against other diseases and increased awareness of the risks associated with the use of alcohol or drugs that injure the liver should be taken following diagnosis. Classically, interferon (IFN) therapy was used to treat HCV, followed by the use of ribavirin. More recently, protease inhibitors emerged as effective drugs of choice for HCV infection.

# Historical Perspective
The discovery of the hepatitis C virus was made based on early findings of patients with signs and symptoms of viral hepatitis lacking positive serologies for hepatitis A or B. These patients were originally described in 1974-5 as having "non-A, non-B viral hepatitis" (NANBH). It was not until 1989 that hepatitis C virus (HCV) was truly discovered when Qui-Lim Choo and colleagues successfully isolated the first cDNA clone 5-1-1 derived from the NANBH genome. The first interferon-alpha (INF-a) to treat HCV was developed in 1986 and approved in 1991. Approximately 10-15 years later, global efforts to reduce the burden of HCV were launched; worldwide campaigns were led by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC).

# Pathophysiology
In cases of isolated acute HCV infection, the host immune system stimulates the secretion of interferon-alpha and the activation of natural killer cells, which is followed by the activation of the adaptive immune system. Chronic HCV is characterized by the impairment of these mechanisms. Eventually, chronic HCV infection leads to local inflammation and fibrogenesis, which causes hepatic injury and cirrhosis. Hepatocellular carcinoma, a known complication of chronic HCV infection, arises in cases of cirrhosis; the role of oncogenic proteins of HCV in the pathogenesis of hepatocellular carcinoma has yet to be elucidated.

# Causes
The hepatitis C virus (HCV) is the causative agent of hepatitis C. It is a member of the genus Hepacivirus that belongs to the Flaviviridae family. It is an enveloped, single-stranded RNA virus. The RNA genome acts as a template for viral replication and eventually, protein biosynthesis. Humans are considered the only natural hosts for HCV. The virus is primarily transmitted by exposure to contaminated blood.

# Classification
HCV can be classified based on the isolated genotype and subtype. Six major genotypes have been identified. Several new genotypes and subtypes were recently discovered.

# Epidemiology and Demographics
Hepatitis C is a major health problem that affects approximately 2 to 4 million people in the United States, 5 to 10 million people in Europe, and 12 million people in India. Approximately 150,000 new cases occur annually in the United States and in Western Europe, although incidence rates are difficult to estimate with accuracy given the asymptomatic nature of early stages of the disease. While the prevalence of the disease appears to be declining, hepatitis C is still highly prevalent in specific areas of the world. Egypt is the country with the highest prevalence of HCV, HCV-associated cirrhosis, and hepatocellular carcinoma, and the prevalence tends to increase with age, suggesting ongoing new cases of HCV. Approximately one-fourth of all cases of cirrhosis and hepatocellular carcinoma are attributed to HCV worldwide. Hepatitis C affects males and females equally.

# Risk Factors
Risk factors for hepatitis C include intravenous drug use (most important), multiple blood transfusions prior to 1992, therapeutic injections for hemophilia prior to 1987, and work in the healthcare field (given that exposure to contaminated blood products is the most important mode of transmission).
Other, less common risk factors include occupational exposure to blood, such as contaminated needle sticks, Hemodialysis, solid organ transplantation from infected donors, birth to infected mother (in cases of detectable maternal HCV PCR at delivery), sexual intercourse with an infected partner, sexual intercourse with multiple partners, HIV infection, and tattoos or piercings with infected needle sticks.

# Screening
People living in regions highly prevalent with HCV and who have engaged in high-risk behaviors should be screened. Screening by serological testing, confirmed by nucleic acid amplification (NAT) for HCV RNA, is required.  Additionally, screening for other bloodborne infections, such as HBV and HIV, is required once a diagnosis is made.  The ideal frequency of testing in these patients is unclear and should be personalized according to the frequency of a patient's exposure to risk.

# Differentiating Hepatitis C from other Diseases
Hepatitis C must be differentiated from other diseases that cause hepatic injury and abnormal liver function tests such as other viral hepatitides (Hepatitis A, Hepatitic B, and Hepatitis E), and non-viral etiologies (e.g., alcoholic liver disease, non-alcoholic steatohepatitis, drug-induced liver injury, autoimmune hepatitis, and hepatocellular carcinoma).

# Natural History and Prognosis
The majority of individuals infected with HCV will become chronic carriers. The most common complications of HCV are hepatic, including liver cirrhosis years after the onset of infection and the consequent development of hepatocellular carcinoma. Other classical extrahepatic manifestations, such as cryoglobulinemia, lichen planus, membranoproliferative glomerulonephritis, and porphyria cutanea tarda are also complications of chronic HCV infection. Treatment is necessary for patients with chronic stable HCV infection; otherwise, prognosis is poor and progression of the disease may be fatal.

# Treatment
The treatment of hepatitis C has changed dramatically over the past decade.  Whereas relatively new protease inhibitors telaprevir and boceprevir were added to the regular regimen of IFN and ribavirin in 2011 to treat patients with genotype 1 HCV, newer oral agents sofosbuvir and simeprevir have demonstrated greater efficacy in viral clearance along with a better safety profile.  New guidelines from the AASLD and the IDSA have endorsed the use of these oral agents (particularly sofosbuvir) as first-line agents in the treatment of chronic HCV in both relapsers and treatment-naive patients.