Hepatitis C (HCV)

Small enveloped RNA virus that causes the most common chronic blood borne infection in the U.S.

A positive-strand RNA virus encoding a polyprotein that undergoes proteolytic cleavage to 10 polypeptides, each with distinct functions.

Nonstructural proteins form a complex with viral RNA to initiate viral replication in a cytoplasmic membranous structure.

HCV interacts with lipid droplets and lipoprotein metabolism and the mature virus is released from cells as lipoviral particles.

Infects predominately hepatocytes.

Affects more than 2 million adults and is the leading cause of liver related mortality.

U.S. population-more than 2,400,000 people are infected.

As many as 350,000 die worldwide annually.

More than 15,000 residents die of hepatitis see every year unnecessarily.

80% of hepatitis C patients are viremic.

A hepatotropic virus.

About 5 million worldwide are co-infected with HIV.

In the US co- infection occurs in approximately one-third of all patients with HIV infection, with incidence 75-90% among intravenous drug users.

Co-infection with HIV associated with higher rates of end stage liver disease, liver cancer and mortality.

Affects 71 million individuals worldwide.

An estimated 6.1 million people who inject drugs have chronic hepatitis C and these individuals are responsible for most new infections in many countries.

Prevalence highest in African Americans, 6.1%.

Hepatitis C virus is recognized as the virus most often associated with extra hepatic manifestations.
Up to 2/3 of patients I have extra hepatic manifestations.
Extrahepatic manifestations include: cryoglobulinemic vasculitis, lymphoma, cardiovascular diseases,  insulin resistance, and type two diabetes, all associated with mobility, mortality, and quality-of-life impairment.

Sustained viral clearance is associated with a low risk of extra hepatic manifestations of HCV infection.: Decreases the risk of acute coronary syndrome, cardiovascular disease, insulin resistance, and type two diabetes.

Prevalence of antibodies to HCV 1.6% with peak prevalence 4.3% among individuals 40-49 years of age.

Most common cause of chronic liver disease in the US, and the leading cause of cirrhosis and hepatocellular carcinoma globally.

Almost half of individuals with antibodies to HCV age 20-59 years have a history of injection drug use.

Hepatitis C now leading Infectious disease killer in U.S.

The number of hepatitis C-linked deaths in the United States reached a record high in 2014, and the virus now kills more Americans than any other infectious disease.

There were 19,659 hepatitis C-related deaths in 2014, according to Centers for Disease Control and Prevention.

The number of hepatitis C-related deaths in 2013 exceeded the combined number of deaths from 60 other infectious diseases, including HIV and tuberculosis.

Untreated chronic HCV can progress with increasing fibrosis and reaches cirrhotic levels in 20 to 30% of patients and a related liver complication, including premature death in a smaller subset of patients.

Most cases are among baby boomers — those born between 1945 and 1965.

About 3.5 million Americans have hepatitis C and about half are unaware of their infection.

The CDC estimates 16- 41% of US inmates have serologic evidence of prior HCV exposure and 12-35% have chronic infection.

Patients released from the criminal justice system may account for up to 29-43% of the 2.7 million-3.9 million persons infected with hepatitis C in the US.

Most patients in the United States have now been infected with 10-30 years, making them at risk for hepatoma.

Classified into six major types.

Genotypes one, two, and three are found worldwide, while subtype 1a predominates in the US and subtype 1b predominates in Europe, Japan and China.

Hepatitis C infection increases the risk of death by 37%.

The leading indication for liver transplant.

Genotype 1 highly correlated with disease progression.

High BMI, Hispanic ethnicity is associated with disease progression, while African-Americans have a lower rate of disease progression than white patients.

Genotype 1 represent more than 70% of all cases of chronic HCV infection in the US.

Only 25-35% of individuals infected with HCV are aware of their condition.

The risk for hepatocellular carcinoma is 15-20 times higher in persons infected with hepatitis C, then in persons noninfected with this virus.

HCV directly oncogenic by interacting with host factors involved in signaling, transcription, proliferation, and apoptosis.

Hepatic carcinoma is uncommon in HCV patients without cirrhosis.

About 0.3% of children and teens aged 6-19 are infected with Hepatitis C

Most children acquire the infection through maternal neonatal transmission.

About 240,000 children in the US are living with Hepatitis C.

Acute disease represents approximately 20-30% of all the newly acquired infections.

Symptoms associated with a HCV infection occurs approximately nine weeks after exposure.

There is low level of viremia in the first two months after infection, followed by a brisk and exponential increase in viremia over a period of 8 to 10 days.

Symptoms of acute infection include fatigue, abdominal pain, jaundice, muscle and joint aches, disturbances, and diarrhea.

All persons who use or have used illicit injection drugs in the present or past, even if only once, as well as intranasal drug users who share paraphenalia, should be tested for HCV infection.

Individuals with unexplained LFT elevations, those ever on hemodialysis, children born to HCV infected mothers, or with HIV infection should be tested for the presence of HCV infection.

Potential sources of HCV include sexual partners, exposure of healthcare workers to HVC contaminated blood and blood productsand tatooing.

Prevalence of HCV infection is definitely higher among individuals with multiple sexual partners.

The risk of sexual transmission of the virus between monogamous partners is uncommon, and barrier protection among anonymous couples is not required.

Between one and 5% of monogamous sexual partners of the index HCV cases do test positive for anti-HCV.

HCV infected persons do not need to limit ordinary household activities except for those that might lead to blood exposure, such as sharing a razor or toothbrush.

HCV virus is not transmitted by kissing or sharing utensils, or breast feeding.

The incidence of acute HCV has declined substantially over the last 25 years, but despite declines injection drug use is the most common risk factor for new infections ( Williams IT et al).

Acute infection of HCV implies a 6 month period of exposure with a 20-50% chance of spontaneous resolution of infection.

Treatment of acute infection can be delayed until spontaneous clearance of infection, at which time treatment is not recommended.

The initiation of her treatment for acute infection after 6 months of monitoring may be appropriate.

Therapy that eradicates HCV may prevent progression to cirrhosis, liver decompensation, hepatocellular carcinoma, need for liver transplant, and death.

Chronic infections 3-5 times more common than HIV/AIDS infections in the U.S.

High seroprevalence rates from 15 to 50% occur in specific populations such as homeless, incarcerated persons, injection drug users and persons with hemophilia treated with clotting factors before 1992.

The high rate of chronic HCV infection observed in patients on hemodialysis is likely iatrogenic.

Majority of individuals infected with Hepatitis C have an ineffective immune response resulting in a persistent infection that may lead to chronic liver disease.

Up to 10% of patients have no known risk factors for the infection.

Since the availability of tests to detect HCV the rate of new cases has fallen by more than 80%.

Most common forms of transmission injection drug abuse, blood transfusion, prior to screening, and sexual exposure.

14-40% of infected people spontaneous clear the HCV and have no detectable virus in plasma.

Most patients remain asymptomatic throughout their lifetime.

One time hepatitis C virus screening is recommended for all individuals age 18 years or older.

Screening recommended for all adults at risk for infection, and one time, anti-HCV antibody test, followed by polymerase chain reaction testing for viremia, to screen all adults born between 1945 and 1965.

The USPSTF recommends all asymptomatic adults age 18-79 years, regardless of risk, to screen for hepatitis C virus.

People with continued risk for HCV infection such as drug injection users should be screened regularly.

Annual HCV testing is recommended for all individuals who inject drugs and for men who are infected with HIV, have sex with men without condom use, or have sex with men and I taking pre-exposure prophylaxis for HIV.
Interval repeat HCV testing is recommended for individuals with activities, exposures, and conditions or circumstances associated with increased risk of HCV infection.
One time HCV  screening is recommended for all individuals younger than 18 years with the increased risk of HCV exposure.

Prenatal HCV testing is recommended with each pregnancy.

Screening for individuals performed between 1945 and 1965, thosewithout ongoing risk factors for HCV need to be screened only once, and this recommendation applies to all asymptomatic adults without known liver disease or functional abnormalities.

People in this age group are considered at risk since they may have received a blood transfusion before universal blood screening in 1992, or may have had other related risk factors for HCV.

Individuals born between 1945 and 1965 account for as many as three fourths of the cases of HCV in the US.

Presently, injection drug use is the primary mode of HCV transmission in the U.S.

All individuals who use or have used illicit injection drugs, even if only once, as well as intranasal drug abusers who share paraphernalia, should be tested for, HCV infection.

Patients that have received the blood transfusion or a blood component transfusion before 1992, should be tested for HCV infection.

Hemophilia patients who have received blood products prior to 1987, after which viral inactivation procedures or implemented, should be tested for HCV infection.

Patients with unexplained elevations ALT, AST, on hemodialysis, children born to HCV infected mothers, should be tested for HCV infection.

HCV infection associated with glomerulonephritis and may be membranoproliferative, membranous or fibrillary (Johnson RL et al).

HCV-associated glomerulonephritis presentation includes proteinuria, microscopic hematuria, hypertension and renal insufficiency.

HCV-associated membranoproliferative glomerulonephritis associated with mixed cryoglobulinemia with monoclonal IgM and rheumatoid factor forming immune complexes depositied in blood vessels, including glomerular capillaries and causing an inflammatory response.

Polyneuropathy is the most common neurological manifestations of HCV infection, present in 45 – 60% of patients with symptomatic HCV- related cryoglobulinemia.

Such patients have symmetric distal axonal neuropathy with predominantly sensory features.

1/3 – 1/2 of patients with HCV infection have detectable levels of cryoglobulins.

Only about 5% of patients with hepatitis C develop symptomatic cryoglobulinemic vasculitis.

Palpable purpura and arthralgia are the most common features of cryoglobulinemia, occurring in about 90% of patients with symptoms.

HCV-associated glomerulonephritis urinary sediment contains red blood cells, red cell casts and protenuria.

HCV-associated glomerulonephritis can lead to renal failure (Tarantino A et al).

Prevalence of HCV infection higher among patients with multiple sexual partners, but sexual transmission of the virus between the monarch of its partners, is uncommon.

The risk of sexual transmission is sufficiently low that it is not advised to use barrier protection among monogamous couples.

Between one and 5% of monogamous sexual partners of index cases test positive for HCV.

A HCV infected person need not limit household activities, except for sharing our razor or toothbrush.

HCV is not transmitted by hugging, kissing, breast-feeding or sharing of utensils.

Only one third of patients with acute infection develop jaundice and most patients with chronic disease have few if any clinical manifestations, until cirrhosis appears.

Higher spontaneous clearance of HCV occurs with single exposure to the virus, younger age at exposure, female sex, and certain major histocompatiblity complex genes.

Of HCV antibody positive patients with hemophilia spontaneous clearance of HCV RNA reported in about 25% of those not co-infected with HIV compared to 10% or less clearance of those with HIC co-infection.

African-Americans less likely than Hispanics or whites clear the HCV spontaneously.

Coinfection with HIV is associated with decreased spontaneous clearance rates, white infection with HBV is associated with higher clearance rates.

The most common indication for orthotopic liver transplantation.

Most common cause of death from liver disease in the U.S.

Incidence is on decline, but rates of HCV related cirrhosis and hepatocellular carcinoma expected to peak in 2020.

Each year, 10,000 liver translants or deaths are attributable to HCV.

The rate of reinfection after liver transplant is virtually 100%.

IV drug abuse and blood transfusions account for most cases.

Chronic infection in patients on hemodialysis that require renal transplant, have impaired graft and recipient survival.

Only 5% or fewer individuals have an apparent exposure leading to infection.

More than 70% affected develop a chronic infection characterized by inflammation and hepatic fibrosis.

Potassium efflux is a activator of the NLRP3 inflammasome.

HCV infection induces potassium efflux in macrophages, thus leading to the maturation of pro-IL-1β via the NLRP3 inflammasome.

About 20% of patients infected get progressive liver disease with cirrhosis, end-stage liver disease or hepatocellular cancer over 20-40 years.

In patients with cirrhosis complications of liver disease or liver decompensation develops in about 30% of patients over a period of approximately 4 years (Di Bisceglie AM).

Chronic hepatitis C is associated with insulin resistance causing impaired glucose tolerance, as a result of fat accumulation in liver cells, increased insulin resistance secondary to increased tumor necrosis factor-alpha and damage to beta cells by the virus (Antonelli A et al).

Can cause a nonarticular pain syndrome.

HCV is classified into 6 major genotypes that may be used to determine the duration and dosage of therapy.

Genotype I is the most predominant in North America.

Elevated levels of HCV RNA and ALT and genotype 1 are independent risk predictors for hepatocellular carcinoma 5 or more years before its diagnosis (Lee M-H et al).

The risk of hepatocellular carcinoma for anti-HCV seropositive patients with undetectable serum HCV RNA levels is much lower than for individuals with detectable levels: Implying that patients with chronic HCV may be benefited from lowering serum HCV RNA to undetectable levels by effective treatments.

Treatment of HCV is recommended for all patients with chronic disease, except for those with less than 12 months to live due to non-liver related comorbid conditions.

Treatment priority should be given to patients with advanced fibrosis, compensated cirrhosis, liver transplant recipients, patients with severe extrahepatic hepatitis C, and those at risk for complications related to these conditions.

Optimal time of treatment is unknown.

Untreated chronic HCV can progress with increasing fibrosis, reaching cirrhosis in 20-30% of patients and related liver complications including premature death in a smaller subset.

Evidence has been demonstrated the high efficacy of the interferon-free medications for all HCV genotypes, including treatment naIve and nonresponding patients those with cirrhosis and those with comorbid conditions, including HIV.

In patients with undetectable serum HCV RNA levels, the incidence of hepatocellular carcinoma is moderately high for those who have had elevated serum ALT levels, suggesting that the serum ALT level is an important serum marker.Liver biopsy studies indicate substantial number of patients with infection and normal serum aminotransferase levels have advanced fibrosis or even cirrhosis (Puoti).

Most patients remain asymptomatic throughout their lifetime.

Needle stick injury associated with infection, but the incidence is no higher than 8-10%.

Recurrence is nearly universal after liver transplant and may lead to progressive allografts injury and liver failure.

Caused by a single stranded RNA virus with 85% progressing to chronic liver disease with 10-20% of patients developing cirrhosis over 20 years.

Goal for initiation of treatment is to achieve enduring clearing of HCV clearance or sustained virologic response.

Sustain viral response to treatment associated with decreased liver related morbidity and mortality.

No clinical benefit in continued interferon treatment for those who do not attain sustained virologic response.

SVR is associated with a reduced occurrence of liver disease, liver related deaths in patients with advanced hepatic fibrosis.

In a study of 530 patients with advanced hepatic fibrosis and chronic HCV infection followed for a median of 8.4 years, a sustained virologic response to interferon-based therapy was associated with lower all cause mortality (van der Meer AJ et al).

In the above study the risk of all cause mortality was almost 4 times lower in patients with SVR compared with patients without SVR.

In the above study they were able to reduce risk of hepatoma, liver failure, liver related mortality and liver transplantation in patients with SVR.

In a Spanish study the five year mortality was 2% of patients with cirrhosis and hepatitis C infection and a SVR compared to 14% mortality rate for those without a sustained viral response ( Fernandez-Rodriquez LM ET AL).

Genotype 1 accounts for 70-75% of all HCV infections in the U.S. and is associated with a lower rate of response to treatment.

Single nucleotide polymorphisms near IL28B gene are among strongest predictors of response to peg interferon alfa and ribavirin.

Genotype 2 or 3 responds favorably to antiviral therapy in 80% of patients.

It is suggested that patients with genotype 2 or 3 infection may respond to shorter courses of therapy than are presently recommended.

Undetectable viral levels at 12 weeks after the initiation of antiviral therapy is predictive of a response after 48 weeks of treatment.

Initiation of interferon treatment may result in a rapid decline in viral load as it inhibits viral production and viral release.

Following the rapid decline of viral load after the initiation of interferon therapy there is a slower decline dependent on the rate of death of infected cells that varies from 1.7 to more than 70 days.

The decline of viral load is eight times faster in patients with genotypes 2 or 3 compared to genotype 1.

The incidence of HCV infections declined sharply in the late 1980’s with approximately 35,000 new cases each year.

5-10% of patients with hepatitis C are also infected by HIV.

Estimated 150,000 to 300,0000 people infected with both HIV and hepatitis C, representing 15-30% of all people living with HIV infection and 70-90% of injection drug users.

6% of patients will have liver decompensation and 4% will have hepatocellular carcinoma.

Patients with cirrhosis have a 1-4% risk of developing hepatocellular carcinoma per year.

As little as 15 gm/day of alcohol-one can of beer or one glass of wine a day can increase the risk of end-stage liver disease in persons infected with HVC.

Most common blood-borne liver disorder in clinical practice today.

Liver biopsy the best test to establish the severity, stage the amount of liver fibrosis and provide short-term prognosis to the patient.

Patients with mild disease on biopsy and no fibrosis have and excellent 15-year prognosis, with less than 15% progression to cirrhosis after 15 years-in the absence of alcohol use.

Patients with bridging fibrosis at the time of diagnosis have a 100% chance of progressing to cirrhosis over the next 10 years if left untreated.

Acute hepatitis usually lasts two to four weeks and a minority have jaundice.

Serological testing for hepatitis C 92-97% sensitivity.

Gold standard for detecting hepatitis C is PCR test for Hepatitis C virus RNA.

Causes approximately 20% of cases of acute hepatitis in the U.S.

Mean incubation period 7 weeks with a range of 3-20 weeks.

A sustained virologic response can prevent progression to cirrhosis and in those with established cirrhosis it can reduce the risk of hepatic decompensation and Hepatocellular carcinoma.

Associated with a sustained virologic response in less than 20% of patients in patients treated with alpha interferon.

The specimen obtained from liver biopsy should be at least 10 mm from a 16-gauge or 20 mm from an 18-gauge needle specimen for proper staging.

A sustained virologic response defined as undetectable HCV RNA level in the blood at the end of treatment and at 6 months after treatment ends.

Sustained virologic response in 38-43% of patients treated with alfa- interferon and ribavirin.

Virological response at 6 months after discontinuation of alfa-interferon and ribavirin is predictive of a 97% rate of long-term complete response.

Marked variation in outcome of persistent infection and end stage liver disease.

Chronic infections occur in 65%-90% of individuals.

100 times more infectious than HIV.

Of genotype 2 patients, 70% may achieve remission with interferon and ribavirin, whereas a smaller percentage of genotype 1 patients achieve viral clearance and normalization of their liver tests.

Predictors of nonresponse to interferon therapy include genotype 1, high pretreatment viral load, age over 40 years, advanced fibrosis, and African-American ethnicity.

Interferon plus Ribavirin causes a response rate between 30-40%.

African American men are least likely to clear the virus spontaneously.

Greater proportion of white patients have a sustained virological response to interferon and ribavirin than black patients.

Concurrent chronic hepatitis B increases the risk of progressive liver disease.

Accounts for an estimated one-third of hepatoma cases in the U.S.

Hepatoma complicates cirrhosis secondary to HCV at a rate of from 0 to 3 percent per year.

Hepatoma rare in patients without cirrhosis.

Estimated that 20% of cases are sexually transmitted.

Healthcare workers are at risk of infection via accidental needle sticks, or through eye or mucous membrane contact or via broken skin exposure to infected fluids.

Cryoglobulins detected in up to one-half of patients with chronic hepatitis C, but vasculitic sequelae seen in only about 2-3% of patients.

Cryoglobulin vasculitis consists of skin involvement with palpable purpura in 80% of cases, nerve involvement in 50%, and renal involvement with type I membranoproliferative glomerulonephritis in 30%.

Cryoglobulin vasculitis appears in 10 to 15% of patients and has a spectrum of disease ranging from mild to life-threatening.

Continuing ribavirin monotherapy after achieving a virologic response with Interferon-ribavirin combination therapy does not improve sustained virologic response.

Sustained of viral response may be associated with improved long-term clinical outcomes, including survival.

Peginterferon alfa-2b-ribavirin treatment associated with sustained virological response and approximate 40% of patients with genotype 1 infection and 75% of patients with type 2 and 30.

PROVE1 study proved that the addition of telaprevir(Incivek) to pegylated interferon/ribavirin in treatment naI’ve patients significantly improved sustained viral response over pegylated interferon/ alone(McHutchinson et al).

PROVE3 study added telaprevir (Incivek) to pegylated interferon/ribavirin in patients with genotype 1 HVC who’ve failed standard therapy and it demonstrated a significant improvement in sustained viral response compared to pegylated interferon/ribavirin alone(McHutchinson et al).

A hepatitis C virus (HCV) NS3/4A protease inhibitor Boceprevir (Victrelis) indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection, in combination with peginterferon alfa and ribavirin.

Pegalated interferon alpha and ribavirin results in a sustained virologic response of 40-50% of patients with genotype 1 disease treated for 48 weeks.

Ribavirin, pegylated interferon and serine protease inhibitors telaprevir and boceprevir have increased the rates of HCV eradication in treatment naive patients from 20% to approximately 65%.

When used with former standard of care peg interferon and ribavirin boceprevir or telaprevir increases cure rates by 20-30%, and an additional 40-60% of patients will be able to abbreviate treatment time.

Almost all patients with untreated hepatitis C and all patients with genotype one infection who previously failed treatment with Telaprevir or boceprevir were cured with oral combination of Daclatasvir plus sofosbuvir in 211 patients (Sulkowski MS et al).

Ledipasvir with Sofosbuvir demonstrates 91-100% SVR in Hepatitis C given for 8-12 weeks.

New regimens are oral, pegylated interferon free and even ribavirin free and result in SVR response in 92-100% of cases.

In co-infected HIV and hepatitis C patients Ledipasvir plus Sofosbuvir associated with SVR of 98% (Osinuri A et al).

Direct acting antiviral oral agents that target multiple mechanisms of the HCV lifecycle are presently used.

Direct acting antiviral drugs have substantially improved treatment and made HCV eradication possible for most patients, including patients with HIV infection, severe renal and hepatic impairment, and a history of an organ transplantation.

Testing for chronic HCV infection begins with a HCV antibody test.

Prior to antiviral therapy, patients with detect HCV RNA should undergo HCV genotype/subtype testing, HIV testing, vaccination for hepatitis A and B virus for individuals who are not immune, GFR measurement, pregnancy testing, assessment the liver fibrosis using noninvasive testing, and radiologic screening for hepatocellular carcinoma for patients with cirrhosis.

Current guidelines recommend treating a person infected with HCV unless life expectancy is less than one year due to non-HCV-related comorbidities.

HCV treatment is recommended for the duration of 8-12 weeks.

HCV infection is considered cured if HCV RNA is below the detectable limit 12 weeks after completion of direct anti-viral therapy, known as a sustained virologic response.

If detectable HCV RNA returns within 12 weeks of treatment discontinuation is considered relapse and treatment emergent resistance is likely.

Relapse after 12 weeks is rare and guidelines recommended confirming sustain viral response 24-48 weeks after therapy.

Negative predictors for interferon therapy: genotype 1, high baseline HCV viral load, older age, African American race, IL28B TT haplotype, advanced liver fibrosis, previous non-response to interferon and HIV coinfection.

African-American race an independent risk factor for lower HCV viral load and poor response to pegylated interferon/ribavirin therapy in HIV infected patients.

African-American race associated with higher rate of IL28B genotype.

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