Hepatitis C Virus
GENERAL PRINCIPLES
HCV is an RNA virus with six genotypes. Genotype 1 accounts for about 75% and genotypes 2 and 3 account for about 20% of HCV infections in the US.
HCV is the most common chronic blood-borne infection and is a global health problem, with approximately 180 million carriers worldwide.
The most frequent mode of transmission is parenteral. Less common modes of transmission include high-risk sexual practices and perinatal transmission. Transmission by transfusion of blood products (and their derivatives) and organ transplantation has been reduced to near zero in developed countries due to screening.
DIAGNOSIS
Clinical Presentation
The incubation period varies from 15 to 150 days.
Acute HCV hepatitis is defined as presenting within 6 months of exposure to HCV. During this time, there is a 20%-50% chance of spontaneous resolution of infection.4 Symptoms can be nonspecific and include malaise, fatigue, pruritus, headache, abdominal pain, myalgias, arthralgias, nausea, vomiting, anorexia, and fever.
Chronic HCV hepatitis runs an indolent course, sometimes for decades, with fatigue often as the only symptom. It may only become clinically apparent late in the natural course, when symptoms associated with advanced liver disease develop.
Extrahepatic manifestations include mixed cryoglobulinemia (10%-25% of patients with HCV), glomerular diseases (mixed cryoglobulinemia syndrome, membranous nephropathy, polyarteritis nodosa), porphyria cutanea tarda, cutaneous necrotizing vasculitis, lichen planus, lymphoma, diabetes mellitus, and other autoimmune disorders.
Diagnostic Testing
Antibodies against HCV (anti-HCV) can be detectable within 2 weeks of infection with third- generation enzyme immunoassays, which have a sensitivity of 97% and specificity of 99%. Antibodies do not confer immunity.
Anti-HCV testing is now available as point-of-care assay with equivalent performance as laboratory-based testing. A false-positive test (anti-HCV positive with HCV RNA negative) may be detected in the setting of autoimmune hepatitis (AIH) or hypergammaglobulinemia. A false-negative test (anti-HCV negative with HCV RNA positive) may be seen in HIV immunosuppressed individuals and in dialysis patients. HCV RNA detected by PCR is the gold standard for confirming the diagnosis of HCV infection and monitoring treatment response with detection limits of 12-43 IU#8725;mL. HCV nucleic acid testing can detect infection in as early as 3-5 days and may be used as a confirmatory test.
๎ HCV genotypes and subtypes can be detected by commercially available serologic and molecular assays. With the development of pangenotypic DAA regimens, pretreatment genotyping is only recommended for patients with previous HCV therapy failure.
Liver biopsy is rarely used to guide HCV treatment because of the availability of highly effective DAAT.
TREATMENT
Treatment should be considered for all patients with chronic HCV infection.
Patients with limited life expectancy that cannot be remediated by HCV treatment, liver transplantation, or another directed therapy should not be treated.
The goal of treatment is eradication of HCV, as determined by sustained virologic response (SVR). SVR is defined as the absence of detectable HCV RNA 12 weeks after completion of therapy. SVR reduces morbidity and end-stage complications of HCV infection including cirrhosis, HCC, and death.
Medications
Current treatment regimens for chronic HCV are oral and IFN-free and may include the following:
Ribavirin is a guanosine analog antiviral agent (nucleoside inhibitor). It is generally not effective when used alone but plays an important role in combination treatment.
DAAs target specific nonstructural proteins of the virus, resulting in disruption of viral replication.
Current treatment regimens for HCV include the combination of more than one DAA with or without ribavirin.๎ Nonstructural protein 3/4A (NS3/4A) protease inhibitors (PIs) include glecaprevir, asunaprevir, grazoprevir, voxilaprevir, and paritaprevir.
o NS5A inhibitors include ledipasvir, daclatasvir, elbasvir, velpatasvir, pribrentasvir, and ombitasvir. o NS5B polymerase inhibitors include sofosbuvir and dasabuvir.
๎ Pangenotypic regimens
#9632; Sofosbuvir (NS5B inhibitor) + velpatasvir (NS5A inhibitor) ? 12 weeks. Ribavirin can be added for patients with decompensated cirrhosis or patients who have previously failed therapy.
#9632; Glecaprevir (NS3#8725;4A PI) + pibrentasvir (NS5A inhibitor)duration of therapy varies based on presence or absence of cirrhosis and history of therapy.
#9632; Sofosbuvir (NS5B inhibitor) + velpatasvir (NS5A inhibitor) + voxilaprevir (NS3#8725;4A PI) approved for patients who have previously received therapy with a standard DAA regimen.
The selection of a particular treatment regimen is based on several factors, most notably: ๎ Treatment-naive (never-treated) or treatment-experienced (previously failed treatment) ๎ HCV genotype and subtype
๎ Cirrhosis
๎ Decompensated cirrhosis
๎ Potential drug interactions, especially the use of acid-blocking medications
๎ Severe chronic renal disease or end-stage renal disease
๎ Comorbid conditions (e.g., posttransplant state and HIV coinfection)
For chronic infection, all treatment regimens have similar efficacy.
Prevention
No pre- or postexposure prophylaxis or vaccine exists. Prevention of high-risk behaviors and lifestyle modifications should be encouraged.
Outcome and Prognosis
HCC develops in approximately 2%-4% of patients with chronic hepatitis C-related cirrhosis per year.