EPIDEMIOLOGY

Thursday, November 12, 2009

• It is difficult to estimate the real prevalence of HCV accurately in the world, as it is mainly asymptomatic [80]
• On the basis of published reports, it is estimated that HCV prevalence is approximately 3% equating 170 million patients all over the world [80].
• Prevalence ranges from 0.08% to >10% in different regions of the world. It has also been reported that approximately 21% community acquired viral hepatitis is due to HCV.[81]
• Asia and Pacific region in recent years. Hepatitis C is a rapidly emerging health problem in Pakistan as in other Asian countries. Several published reports from different regions of Pakistan have indicated that approximately 10 million (6%) people with HCV are living in the country.[82,83]
• Recent studies showed seroprevalence rate from 0.1% to 15.9% in different regions of India and 1.5% in Saudi Arabia [84, 85, 86]
• The HCV distribution in China, Japan and Taiwan is 1 to 2%, 2% and 3.2% respectively.[87, 88]
• It was estimated that the seroprevalence rate in Malaysian blood donors was between 1.5 to 3%.[89]
• The estimated distribution of HCV infection in the United States ranges from 1.4% to 1.8%, affecting 4 million people.[90]
• In Europe, HCV infection prevalence is from 0.08% to 0.72% and 8.4% to 12.6% in UK and Italy respectively. [91]
• Between 20-30% patients with chronic HCV infection succumb to cirrhosis, further developing hepatocellular carcinoma (HCC).
• Prevalence of anti-HCV positivity in HCC patients was 3.2 %, 13.5%, and 7% in Italy, Pakistan and US respectively.[92, 93, 94]
• In Pakistan, anti-HCV has been present in nearly 80% of the patients, with alpha fetoprotein elevation in 75%, in patients with HCC.[95]


TRANSMISSION [79]
• Unsafe blood supply
• Current or past IVDU
• Reuse of glass syringes and needle
• Unsterilised medical equipments
• Organ transplant
• Ear piercing
• Tattooing
• Reuse of blades at barber’s community shop
• Unsafe sexual practices
• Vertical transmission
• Sharing tooth brush with HCV patients
• Occupational needle stick injury

CLINICAL FEATURES
Acute hepatitis
• Hepatitis C virus infection is rarely diagnosed during the acute phase of illness due to its asymptomatic nature. It is not astonishing that HCV infection has largely been ignored in the world.
• Average incubation period ranges from 3 to 12 weeks although HCV RNA can be detected in patients’ serum within 1 to 2 weeks.

• The serum level of HCV viremia rises rapidly during the first few weeks then slows down to maintaining levels between 105 to 107 IU/ml; followed by an increase in the serum level of ALT.

• A recent study has described that acute symptomatic resolution has been confirmed in 50% cases, whereas the absolute recovery from primary HCV infection does not appear in more than 15% cases.

• However, non-alcoholic groups had tremendous chances to clear virus.
Common symptoms includes

• Jaundice – appears in 25% of patients
• Fever
• Myalgia
• Fatigue
• Lethargy
• Increased ALT
• Anorexia
• Fulminant hepatic failure


Chronic hepatitis
HCV infection becomes chronic in most cases and there are usually no symptoms, however possible features include


• Fatigue
• Steatosis
• Cirrhosis - 20-30% patients with HCV develop cirrhosis in 20-30 years.
• 15-20% patients with HCV infection have only mild to moderate chronic hepatitis infection and may not develop cirrhosis
• HCC
• Varicael bleeding
• Ascites
• Hepatic encephalopathy


Extrahepatic features:
• Non-Hodgkin’s lymphoma
• Membranoproliferative glomerulonephritis
• Arthritis
• Sjogren’s syndrome
• Lichen planus
• Porphyria cutanea tarda
• Vasculitis
• Cryoglobulinaemia
Cryoglobulins (IgM, IgG or both) can be found in more than 50% HCV infected patients that can lead to severe vasculitis and renal failure
• Peripheral neuropathy
• Patients with HCV had a higher prevalence of DM as compared to general population and advance HCV infection was linked with higher prevalence of impaired fasting glucose in DM

INVESTIGATIONS
Who should be tested for HCV [79]:

● Persons who have injected illicit drugs in the recent and remote past, including those who injected only once and do not consider themselves to be drug users
● Persons with conditions associated with a high prevalence of HCV infection, including:
– Persons with HIV infection
– Persons with hemophilia who received clotting factor concentrates before
1987
– Persons who were ever on hemodialysis
– Persons with unexplained abnormal aminotransferase levels
● Prior recipients of transfusions or organ transplants, including:
– Persons who were notified that they had received blood from a donor who later tested positive for HCV infection
– Persons who received a transfusion of blood or blood products before July
1992
- Person who had a tattoo or acupuncture with unsterlized needle
– Persons who received an organ transplant before July 1992
● Children born to HCV-infected mothers
● Health care, emergency medical and public safety workers after a needle stick injury or mucosal exposure to HCV-positive blood
● Current sexual partners of HCV-infected persons*
Tests for HCV patients [79]:
• All patients suspected of having infection with HCV should be tested for antibody to HCV (anti-HCV) using an EIA (enzyme immunoassay) screening test.
• In low-risk patients with a positive EIA test, confirmatory testing with the recombinant immunoblot assay (RIBA) should be performed.
• For patients at low risk with a positive EIA and RIBA, confirmatory testing with a qualitative PCR test for detection of HCV RNA should be performed.
• For patients at moderate or high risk and/or unexplained elevated serum alanine aminotransferase (ALT) value, a positive EIA should be followed by a qualitative test for HCV RNA in the blood.
• For immunocompromised patients at high risk with unexplained elevated ALT value and a negative screening EIA, a qualitative test for detection of HCV RNA should be performed to diagnose HCV infection.

• Antibodies can be detected only after 4 to 6 months from exposure, and after 2 to 4 months from the onset of symptoms. This test will be positive in 97% of patients by 6 months after infection, and probably will persist for life.
• HCV RNA is usually positive from at symptom onset.
• HCV RNA testing should be performed in
(a) Patients with a positive anti-HCV test
(b) Patients for whom antiviral treatment is being considered, using a quantitative assay
(c) Patients with unexplained liver disease whose anti-HCV test is negative and who are immunocompromised or suspected of having acute HCV infection
• Patients with low-level viraemia may require HCV-RNA levels testing on two or more occasions to confirm infection
• HCV genotype should be determined in all HCV-infected persons prior to treatment in order to determine the duration of therapy and likelihood of response
• Regardless of the level of ALT, a liver biopsy should be done when the results will influence whether treatment is recommended, but a biopsy is not mandatory in order to initiate therapy.
• A liver biopsy may be obtained to provide information on prognosis
• Patients with HCV infections should be tested for HIV, Hepatitis A Virus (HAV) and HBV infections due to similar risk factors.
• If a patient is hepatitis C positive other tests which should be done include [80]:

1. ALT
2. Bilirubin
3. Albumin
4. Prothrombin time
• Prior to treatment, patients should have a baseline complete blood count (CBC), chemistry evaluations, serum creatinine, thyroid function tests and pregnancy tests in women

TREATMENT

• Early clearance of HCV, to prevent the risk of developing cirrhosis and HCC and to decrease mortality has been the aim of antiviral treatment in patients with HCV infection [96].
• Treatment should be considered for all patients with detectable HCV RNA and an abnormal liver biopsy, regardless of the presence or absence of liver enzyme elevation [96].
• Prior to making a decision regarding treatment, patients should be evaluated with HCV RNA, HCV genotype, liver enzymes (ALT), and liver biopsy, unless contraindicated.
• The decision to initiate antiviral therapy should be made based upon the willingness of the patient to undergo therapy, ability to regularly attend appointments, and agreement to use contraception to prevent pregnancy.
• The decision to initiate antiviral therapy should be made on an individualized basis that considers severity of liver disease, co-morbid conditions, the potential for serious side effects and the likelihood of response [96].
• Patients with HCV infection on methadone maintenance therapy should not be considered ineligible for treatment.
• The treatment of the actively using injection drug user is not contraindicated and may be appropriate under some circumstances.
• Patients with a history of well-controlled psychiatric disorders may be excellent candidates for antiviral therapy and should be under the care of a qualified mental health professional [96].


NON PHARMACOLOGICAL TREATMENT
• Alcohol and drug abuse should be treated before the initiation of antiviral therapy for HCV infection, as these may worsen the course of disease and outcome
• Persons found to be HCV-infected need to be counseled regarding prevention of spread of the virus to others.
• Environmental support is an important part of patient assessment because treatment may be given for up to one year, and the adverse effects of treatment may incapacitate patients [96]
• Family meetings can be helpful to prepare family members for side effects of treatment. Neuro-psychiatric side effects such as irritability and hostility can strain relationships if unexpected. These issues can be assessed with the collaboration of social services [96].
• Counsel those who are overweight (defined by a raised body mass index of >25 kg/m2) to attempt to lose weight.


PHARMACOLOGICAL TREATMENT
• If acetaminophen is to be given, the dose should not exceed 2 g per 24 hours [97].
• If patient has Hepatitis C, should be vaccinated against hepatitis A if they lack hepatitis A antibody [98].
• If patients lack antibodies to hepatitis B virus should be vaccinated against hepatitis B [98].
• If patient has Hepatitis C, pneumococcal vaccine and yearly influenza vaccination should be considered in patients who have developed cirrhosis

Characteristics of Persons for Whom Therapy Is Widely Accepted [79]
• Abnormal ALT values
• Liver biopsy showing chronic hepatitis with significant fibrosis (more-than-portal fibrosis: Metavir score >= 2; Ishak score >= 3)
• Compensated liver disease (total serum bilirubin < 1.5 g/dL; INR < 1.5; albumin > 3.4 g/dL; platelet count > 75,000 k/mm3; and no evidence of hepatic encephalopathy or ascites)
• Acceptable hematological and biochemical indices (hemoglobin > 13 g/dL for men and >12 g/dL for women; neutrophil count > 1.5 k/mm3; creatinine > 1.5 mg/dL)
• Treated previously for HCV infection
• History of depression but the condition is well controlled
• Willing to be treated and to conform to treatment requirements
• The presence of symptomatic cryoglobulinemia is an indication for HCV antiviral therapy, regardless of the stage of liver disease.

Characteristics of Persons for Whom Therapy Is Currently Contraindicated [79]
• Major, uncontrolled depressive illness
• Renal, heart, or lung transplantation recipient
• Autoimmune hepatitis or other condition known to be exacerbated by interferon and ribavirin
• Untreated hyperthyroidism
• Pregnant or unwilling/unable to comply with adequate contraception
• Severe concurrent disease such as severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes, obstructive pulmonary disease
• Under 3 years of age
• Known hypersensitivity to drugs used to treat HCV


Characteristics of persons for whom therapy should be individualized

• Persistently normal ALT values
• Failed prior treatment (nonresponders and relapsers) consisting of either interferon given alone or in combination with ribavirin, or consisting of peginterferon given alone
• Current users of illicit drugs or alcohol, but willing to participate in a substance abuse program (such as a methadone program) or alcohol support program
• Liver biopsy evidence of either no or only mild fibrosis (portal fibrosis: Metavir score <2; Ishak score <3)
• Acute hepatitis C
• Coinfected with HIV
• Under 18 years of age
• Chronic renal disease (on or not on hemodialysis)
• Decompensated cirrhosis
• Liver transplantation recipient

Treatment objectives and outcomes
The goal of treatment is to prevent complications of HCV infection; this is principally achieved by eradication of infection. Accordingly, treatment responses are frequently characterized by the results of HCV RNA testing.

• Infection is considered eradicated when there is a sustained virologic response (SVR), defined as the absence of HCV RNA in serum by a sensitive test at the end of treatment and 6 months later.
• Persons who achieve an SVR almost always have a dramatic earlier reduction in the HCV RNA level defined in some studies as a 2-log drop or loss of HCV RNA 12 weeks into therapy, referred to as an early virologic response (EVR).
• Continued absence of detectable virus at termination of treatment is referred to as end of treatment response (ETR).
• A patient is considered to have relapsed when HCV RNA becomes undetectable on treatment but is detected again after discontinuation of treatment.
• Persons in whom HCV RNA levels remain stable on treatment are considered nonresponders.
• Those whose HCV RNA levels decline (eg, by >2 logs), but never become undetectable, are referred to as partial responders.






Initiating Treatment [96]
• Prior to treatment, patients should have a baseline complete blood count (CBC), chemistry evaluations, serum creatinine, thyroid function tests, pregnancy tests in women, HIV testing, contraceptive counseling for men and women, and screening for depression.
• Prior to initiating treatment, patients should be informed of the possible side effects of therapy to allow them to anticipate and manage with these side effects.
• The treatment of choice for patients with chronic hepatitis C infection is combination pegylated interferon and ribavirin.
• Patients infected with genotype 1 or 4 should be treated for 48 weeks with combination pegylated interferon and ribavirin. The ribavirin dose should be 1000 mg a day in patients < 75 kg and 1200 mg a day in patients > 75 kg.
• Patients infected with genotype 2 or 3 should be treated for 24 weeks with combination pegylated interferon and ribavirin. The ribavirin dose should be 800 mg a day.

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