Friday, 17 May 2013

Hepatitis C : The silent epidemic

About 180 million people are infected with hepatitis C worldwide, yet little information is known about this insidious disease. Hepatitis C is the principal indication for liver transplant as well as the leading cause of death from liver disease. Although there are vaccines available for hepatitis A and B, there is currently no approved vaccine for HCV (Hepatitis C virus) prevention. 

There are six major types of HCV, which is classified as genotype 1 to 6. Different genotypes response differently to specific therapies; therefore, genetic testing aids in the prediction of individual's therapy response.

How is Hepatitis C transmitted?

Exposure to infected blood through sexual contact, from mother to child, from transfusion of infected blood, or sharing of infected needles among drug users is the main source of acute infection. Other risky behaviours such as tattooing, snorting drugs, body piercing which involves sharing of infected equipment have been associated with Hepatitis C as well.

How does the disease progress?

After exposure to infectious blood, acute infection will develop. Up to 80% of acute infection cases will lead to chronic infection, which will further progress to HCV- related cirrhosis during a 25- to 30- year period. About 3% of this population will develop hepatocellular carcinoma, a serious type of liver cancer, eventually.

Not all cases of acute infection is severe since the virus may be cleared spontaneously by a person's cellular immune response. There are patients who carry the virus, yet do not exhibit any evidence of liver disease. The majority of the infected population will unfortunately develop progressive immune response, causing damage to the liver architecture over time. Prolonged liver failure will lead to liver cirrhosis, namely, the hardening of the liver, which will require liver transplantation.

How do you feel after an acute infection?

Unfortunately, most patients will not exhibit any symptoms. If symptoms do appear, they tend to be generally non specific. Abdominal pain, fever, malaise, nausea, loss of appetite; typically appear within 4 - 12 hours after exposure. 

Those who carry the virus may remain asymptomatic for years. Only in the fifth to the sixth decades of life, when the immune system is more vulnerable, these chronic carriers will present with more severe symptoms associated with hepatocellular carcinoma and liver cirrhosis.

How does the doctor test for Hepatitis C?


To screen for exposure to hepatitis C, antibody to HCV (anti-HCV) is tested. This test has high sensitivity, yet it is unable to differentiate between acute, chronic or resolved infection.


If a person is tested anti- HCV-positive, he will be further tested for the HCV RNA which will detect the viral nucleic acid present in the body. This second test will confirmed that  person is having active HCV infection.

As different genotypes of HCV require different types of drug treatment, HCV genotype assays are conducted to provide further information on the type of therapies the patients will respond to.

For patients who have a specific nucleotide sequence (CC, CT or TT) near the IL28B gene and who are treated with Pegylated Interferon alfa and ribavirin, there is a higher success rate, indicated by sustained virologic response (SVR) up to 69%. Thus, testing of IL28B genotype was recommended by the  AASLD (American Association for the Study of Liver Disease  2011 guidelines for patients who want to know the probability of treatment response.

Interpretation of HCV Laboratory Data
Anti-HCVHCV RNAInterpretation
++Clinical assessment is required to differentiate acute and chronic disease
+-Resolution of acute infection
-+Early acute infection
--Absence of infection

What is a liver biopsy and when is it necessary?

Liver tissue is examined to determine the degree of liver damage and detect signs of hepatocellular carcinoma. Low stage indicates minimal or no fibrosis (hardening of tissue). Typically, in these cases, treatment is not initiated. 

It is an invasive procedure which is the gold standard to classify the degree of liver fibrosis in to stages

How is chronic infection treated?

According to the latest 2011 AASLD guideline, for genotype 1, triple thepary with Pegylated Interferon alfa, ribavirin and a protease inhibitor such as boceprevir or telaprevir is the first line therapy.

For genotype 2-6, combination therapy with Peginterferon alfa and ribavirin remains the recommended first line therapy as mentioned in the 2009 guideline.

Therapies are only indicated or patients who older than 18 years,  with detectable HCV RNA,  and high fibrosis as seen in biopsy. These patients must have compensated liver disease, without anemia (as defined by hemoglobin at least 13g/dL in men and 12 g/dL in women). No kidney disease (serum creatinine less than 1.5mg/dL) nor active infection( neutrophil count 1500) should be present.

What is Pegylated Interferon alfa?

There are two available agents ,namely Pegylated Interferon alfa-2a (Pegasys) and Pegylated Interferon alfa-2b (PEG-Intron). These are subcutaneous weekly injections which are administered over a specific period of time depending on the patients' response.

Comparison of Pegylated Interferon Alfas
Differences
Pegylated Interferon Alfa-2a (Pegasys)
Pegylated Interferon Alfa-2b (PEG-Intron
Dosing
180mcg mcg/week
1.5 mcg/kg/week
Adverse event profile
Fatigue, fever, headache, nausea, myalgia, anxiety
Anorexia, arthralgia, musculoskeletal pain, insomnia, depression, rigors, hair fall

What is Ribavirin?

It belongs to the class nucleoside analog which inhibits viral replication which is available in tablet, capsule and oral solution. Dosing depends on the HCV genotype and the patient's weight.

Ribavirin Weight-based dosing
HCV Genotype
Ribavirin
Weight(kg)
Dose (mg/day) in 2 divided doses
1 or 4
Copegus 200mg tablet with Pegasys or Rebetol 200mg capsule with PEG-Intron
less than 75
1000

The most serious adverse events is hemolytic anemia which occurs in 10% to 13% cases. Dose reduction or discontinuation of the therapy is warranted. Ribavarin is teratogenic, which means it can cause deformity in fetus. Patients on ribavirin should avoid pregnancy during treatment and for 6 months after treatment; thus, female patients and female partners of male patients need to have adequate contraception.

What are protease inhibitors (PI) telaprevir and boceprevir?

PI interferes with HCV life cycle by inhibiting protease enzyme. It is especially potent against HCV genotype 1 replication.  Before starting treatment, there are many drug interaction associated with PI and thus co administration with CYP3A4  and P-glycoprotein substrates or inducers are contraindicated. 


Boceprevir 200mg tablet (Victrelis) : 
FDA indicated for Chronic HCV genotype 1 treatment (in combination with Pegylated Interferon alfa and ribavirin) in adults patients with compensated liver disease. Before starting boceprevir, there is a lead-in phase during which dual therapy of Pegylated Interferon alfa and ribavirin is administered for 4 weeks first. At week 5, boceprevir will be added. Recommended dose is 800 mg by mouth three times a day. Dose should be taken with food. Adverse events include anemia, neutropenia and dysgeunia.

Telaprevir 375 mg tablet  (Incivek) :
FDA indicated for Chronic HCV genotype 1 treatment (in combination with Pegylated interferon alfa and ribavirin) in adults patients with compensated liver disease. Recommended dose is 750 mg by mouth three times a day for 12 weeks. The dose should be taken with non low-fat meal ( meals contain more than 20 g of fat. Adverse events include rash, pruritus, fatigue, hyperuricemia, nausea, vomiting.

What are the goals of treatment?
If the treatment goes well, HCV RNA will be undetectable at week 4, which is defined as the rapid virologic response (RVR). The treatment is considered successful if no HCV RNA is detectable at 24 weeks after treatment is completed, which is called sustained virologic reponse (SVR)

Where can I learn more about hepatitis C?
Please refer to www.cdc.gov/hepatitis/hcv/patienteduhcv.htm for more information

* A note for Singaporean patients:
Protease inhibitors must be especially ordered for patients in restructured hospitals and it will take time (usually up to 4 weeks) before the delivery of medicine. The cost of drug can be more than $10,000 per course of treatment. However, in some hospital, ribavarin and pegylatedinterferon alfa fees may be waived for patients on boceprevir. 

For patients on dual therapy of Pegylated Interferon alfa and ribavarin, Pegylated Interferon alfa, the cost of ribavarin may be waived. Check with your hepatologists for more information