Global Alert and Response (GAR)

Hepatitis C


Prevention and Treatment

- Guidelines for epidemic measures
- Future considerations

Prevention
There are no vaccine or immune globulin (IG) products available to prevent HCV infection.52

Blood banks should discard donor units with elevated liver enzyme levels (ALT and/or AST) even after the test for anti-HCV has been established.52

The value of prophylactic IG is not clear.41, 74

Post-exposure prophylaxis with IG is not effective in preventing infection.

A small fraction of potentially infectious donors who escape detection because they lack detectable antibodies still exists. For the prevention of posttransfusion hepatitis it is therefore important that blood transfusions should be given only when absolutely necessary.41

Needle-exchange programs for injecting drug users may help to limit the spread of HCV infection as well as of HIV and HBV.5, 41

For couples in a stable relationship, the risk posed to sexual partners of HCV-infected patients is not sufficiently high to support recommendations against specific sexual practices.41

HCV carriers should be strongly discouraged from drinking alcohol because there is evidence that HCV acts as a cofactor in developing more severe liver injury in alcoholics.24, 39, 41, 94, 97

As there is no vaccine against hepatitis C available, the only means of protection are the implementation universal precautions and safe injection practices. Screening and treatment of blood products is the only way to prevent transfusion-associated cases.95, 96

Comprehensive strategy to prevent and control hepatitis C virus (HCV) infection and HCV-related disease94, 103:

• Primary prevention activities include
 - screening and testing of blood, plasma, organ, tissue, and semen donors
 - virus inactivation of plasma-derived products
 - adequate sterilization of reusable material such as surgical or dental instruments
 - risk-reduction counseling and services
 - implementation and maintenance of infection-control practices
 - needle and syringe exchange programs

• Secondary prevention activities include
 - identification, counseling, and testing of persons at risk
 - medical management of infected persons

• Professional and public education

• Surveillance and research to monitor disease trends and the effectiveness of prevention activities and to develop improved prevention methods.

Prevention of spread of infection should be the main goal at the current time until cost effective therapies become available.3

Treatment
The rationales for treatment of chronic hepatitis are to reduce inflammation, to prevent progression to fibrosis, cirrhosis, and HCC through the eradication of the virus in chronically infected patients, and to decrease infectivity and control the spread of the disease.103

Combination therapy results in better treatment responses than monotherapy; the highest response rates have been achieved with pegylated interferon in combination with ribavirin. Genotype determinations influence treatment decisions. Currently the best indicator of effective treatment is a sustained viral response, defined by the absence of detectable HCV RNA in the serum as shown by a qualitative HCV RNA assay with lower limit of detection of 50 IU/mL or less at 24 weeks after the end of treatment.3, 5, 94

Interferon has been shown to normalize liver tests, improve hepatic inflammation and reduce viral replication in chronic hepatitis C and is considered the standard therapy for chronic hepatitis C. Currently, it is recommended for patients with compensated chronic hepatitis C (anti-HCV positivity, HCV RNA detection, abnormal ALT levels over at least 6 months, fibrosis shown by liver biopsy).3, 5, 94, 103 Interferon-a is given subcutaneously at doses of 3 million units 3 times a week for 24 months. Patients with a reduced ALT activity or HCV RNA level within the first month of treatment are more likely to have a sustained response than patients in whom these changes do not occur. About 50% of patients respond to interferon-a by normalizing ALT at the end of therapy, but half of these relapse within the 6 months of follow-up after IFN withdrawal. The long-term biochemical response falls then to 20-25%. Only a minority of these have a persistent disappearance of HCV RNA from serum. 3, 31, 39, 41, 94, 101

The duration of therapy depends on the genotype and level of viremia. In patients with genotype 2 or 3, the duration is 24 weeks, while patients with genotype 1 need 48 weeks of treatment. 4, 65, 69

Combination therapy, approved in many countries, increases the proportion of patients who have a sustained viral response (SVR), reaching 40%-50%, compared with response rates of 15%-25% with interferon alone.17, 31, 56, 94, 101

Infections with genotype 1 strains of HCV are less responsive to interferon than infections with other genotypes of HCV.3, 4, 41, 52, 65 The genotype should not be used as a reason to deny treatment.5 In 2003, combination therapy with pegylated interferon and ribavirin is the therapy of choice for naïve patients. SVRs of 42 to 46 percent were achieved for genotype 1 using pegylated interferon and ribavirin for 48 weeks. Patients with genotypes 2 and 3 achieved SVRs of 76 to 82 percent after 24 weeks of treatment.4, 65

Combination therapy with pegylated interferon and ribavirin for 24 or 48 weeks should be the treatment of choice for patients who relapse after interferon treatment. A relapse rate of less than 20% occurs in relapse patients treated with combination therapy for a year. 16 Nonresponders are sometimes refractory to retreatment and do not necessarily benefit from escalating the dose.3, 4, 17, 31, 39, 41, 52, 65, 101

The sooner in the evolution of the infection the treatment is started, the better the chances of responding to interferon-a therapy.9, 34, 60, 72 A few studies suggest that treatment of acute hepatitis C with interferon-a results in a reduction in the proportion of patients who progressed to chronic disease, but this approach requires further studies.31, 39, 52

Persistent viremia at week 4 of therapy provides an accurate identification of nonresponders to interferon treatment. In these patients, interruption of treatment or other therapeutic options should be considered.20

Transplantation is an option for patients with cirrhosis who manifest clinically evident end-stage liver disease. After transplantation, however, the donor liver almost always becomes infected, and the risk of progression to cirrhosis reappears.41, 79

If chronic hepatitis inflammation is an important factor in the development of HCC, then a therapeutic approach to lessen the extent of chronic hepatic inflammation should have important implications for the management of patients with chronic hepatitis C.52

There are no licensed treatments or guidelines for the treatment of infants or children infected with HCV.77, 94

Patients with chronic hepatitis C and concurrent HIV infection may have an accelerated course of HCV disease. Therefore, although there are no HCV therapies specifically approved for patients co-infected with HIV, these patients should be considered for treatment.65

Corticosteroids, ursodiol, thymosin, acyclovir, amantadine, and rimantadine are not effective.44

To protect their liver, people with HCV infection should avoid alcohol consumption, not start any new medicine (not even herbal) without a physician’s knowledge, and get vaccinated against hepatitis A and B .24, 94

The absence of cirrhosis, young age, and a short, known duration of serum transaminase elevations are associated with a better response to interferon therapy.31

Response to interferon-a therapy is also influenced by the iron content of the liver.31 However, iron depletion improves ALT levels, but is ineffective in achieving viral eradication in patients retreated with interferon-a.36

Response to therapy is influenced by duration of therapy, dosage, infecting viral load and disease stage. The strain of the infecting virus may also affect the clinical response.

The treatment strategy to be adopted depends on availability of drugs and cost.3

Patient adherence is critical to the success of HCV treatment.

Currently, there is no rationale to treat patients with chronic hepatitis C and normal ALT levels, since they are usually asymptomatic and rarely develop cirrhosis, although the definition of a “normal” ALT varies from center to center.90

Click here for: Monitoring guidelines
Click here for: Types of response
Click here for: Management of treatment failures
Click here for: Contraindications to interferon therapy for chronic hepatitis C
Click here for: Side effects of interferon therapy
Click here for: Contraindications to ribavirin
Click here for: Side effects of ribavirin
Click here for: Liver transplantation

Guidelines for epidemic measures
1) When two or more cases occur in association with some common exposure, a search for additional cases should be conducted.

2) Introduction of strict aseptic techniques. If a plasma derivative like antihemophilic factor, fibrinogen, pooled plasma or thrombin is implicated, the lot should be withdrawn from use.

3) Tracing of all recipients of the same lot in search for additional cases.

4) Relaxation of sterilization precautions and emergency use of unscreened blood for transfusions may result in increased number of cases.

Future considerations
A better understanding of the host and viral mechanisms that are involved in promoting the development of a persistently infected state will provide insights into the mechanisms of viral evasion of host defences.41

Improvement in assessing disease severity and stage, predicting progression, predicting response before, and likelihood of relapse during treatment should be encouraged.38

The strengthening of regional and national centers of expertise for diagnosis, screening and therapy is to be encouraged.94, 103

Existing WHO guidelines for the safety and preparation of plasma products should be implemented.103

The additive value of amantadine to interferon or to interferon-ribavirin combination in inducing sustained viral clearance should be explored.82

Drugs that can normalize serum ALT, and thus reduce the progression of liver disease, such as interferon, ursodeoxycholic acid, ribavirin and glycyrrhizin should be evaluated in the purpose of reaching persistent ALT normalization in patients who are incapable of otherwise clearing the virus.82

More effective and better tolerated therapies are central clinical research challenges.38

 


Monitoring5, 103
It is recommended that progression of liver disease be monitored every 6 months by checking blood counts and liver enzymes. In patients with more advanced liver disease, level of ?-fetoprotein and ultrasonography should be added.4

Patients with chronic hepatitis C should be examined, questioned about side effects, and have blood tested for ALT/ AST every 1 to 4 weeks while on therapy. Evaluation should continue for at least 6 months after stopping therapy to assess whether the response to therapy is sustained.31

Early response is assessed at 3 months by evaluating the patient’s ALT and/or HCV RNA response.

End-of-treatment response is assessed by ALT and/or HCV RNA estimation when therapy is completed.

Sustained response is assessed by ALT and/or HCV RNA estimation 6-12 months after completion of treatment.

Types of response103
Sustained response: clearance of HCV RNA from the blood and persistent normalization of serum ALT levels observed 6-12 months after therapy has ended (virological and biochemical response).

Patients with a sustained virological response will remain HCV RNA negative for at least 5 years after stopping therapy and experience a long-term biochemical and histological outcome with a decrease in total inflammatory activity and a decrease in the reversible components of fibrosis. These parameters may yet not mean that patients are cured from HCV since they may not reflect definitive viral clearance.: HCV RNA may still be detectable in the liver of serum HCV RNA negative patients showing ongoing inflammatory change. Nevertheless, sustained virological responders have a highly reduced risk of disease progression.13

Transient (relapsing) response: Complete virological and biochemical response at end of treatment followed by the re-emergence of virus and /or elevation of ALT levels during follow-up.

Breakthrough response: Temporary virological and biochemical response occurring during therapy followed by reappearance of HCV RNA and/or an abnormal ALT level before the end of treatment.

Nonresponse: HCV RNA remains detectable and/or ALT fails to normalize throughout the treatment phase. When a discordant virological and biochemical response occurs, the virological response should take precedence when interpreting the response to therapy.

Interferon treatment and more so combination therapy significantly reduces viral load, serum ALT activity, improves histological activity and blocks progression of fibrosis in patients who have not cleared HCV compared to the natural history of the disease. Patients who still have a positive HCV PCR after treatment should therefore no longer be called nonresponders to interferon. interferon might even reduce the incidence of HCC and mortality.71

Management of treatment failures
Transient (relapsing) responders, who were treated initially for 6 months, can be considered for re-treatment with combined pegylated interferon-a and ribavirin for 6-12 months. Transient responders already treated for 12 months have a low probability of achieving a sustained response.

Treatment should be discontinued when a breakthrough response occurs. Patients’ inclusion in trials of new treatment regimens should be considered.103

Treatment should be considered for discontinuation in patients who are not responding after 3 months of therapy (detectable HCV RNA and abnormal ALT). Inclusion into controlled clinical trials looking for alternative new treatment regimens should be considered. Patients who fail to achieve a virologic and/or biochemical response following 6-12 months of therapy are unlikely to respond to additional treatment regimens.94, 103

Contraindications to interferon therapy for chronic hepatitis C
Hepatic decompensation
  albumin <3.0 g/l
   bilirubin >51.3 µ mol/l (30 mg/l)
  prolonged prothrombin time >3.0 s
Portal hypertension
  variceal bleed
  ascites
  encephalopathy
Hypersplenism
  leukopenia (<2 x 109/l)
   thrombocytopenia (<7 x 107/l)
Psychiatric depression
  severe, suicide attempt
Autoimmune disease
  polyarteritis nodosa, rheumatoid arthritis
Major system impairment
  cardiac failure
  obstructive airways disease
  uncontrolled diabetes
Pregnancy
Current intravenous drug abuse
Organ transplantation except liver

Side effects of interferon therapy
Constitutional
  flu-like illness
  fever
   rigors
   arthralgia
   myalgia
  fatigue
Hematologic
   leukopenia
   thrombocytopenia
Alopecia
Neuropsiachiatric
  depression
  insomnia
  irritability
Weight loss
Ocular
Autoimmune
   hypothyroidism
  diabetes

In the currently recommended doses for the treatment of chronic hepatitis C, interferon causes side effects that are generally mild and well tolerated. With prolonged therapy, the occurrence of late and severe side effects should lead to the discontinuation of interferon.31

Contraindications to ribavirin
end-stage renal failure
anemia
hemoglobinopathies
ischemic heart disease
severe heart disease
pregnancy
no reliable method of contraception
uncontrolled arterial hypertension

Side effects of ribavirin
Ribavirin can induce hemolytic anemia and can cause problems to patients with preexisting anemia, bone marrow suppression, or renal failure. In these patients, if combination therapy cannot be avoided, attempts should be made to correct the anemia.94

Hemolytic anemia caused by ribavirin can be life-threatening for patients with ischemic heart disease or cerebral vascular disease.94

Ribavirin is teratogenic, and there are contraindications to consumption during pregnancy.94

Liver transplantation
Liver transplantation is indicated in patients with life-threatening cirrhosis or HCC.5

Patients with cirrhosis who have a life expectancy of 1-2 years without transplantation because of recurrent or refractory ascites, Child-Pugh C cirrhosis, uncontrolled gastrointestinal bleeding, severe encephalopathy, or bacterial peritonitis, should be considered for liver transplantation, where this is possible.5, 79

Patients with HCC can be considered for transplantation if there are less than 3 nodules of 3-5 cm and if there is no extrahepatic spread.5, 22, 27, 32, 61, 75

After liver transplantation, HCV reinfection is almost constant,5, 79 and at 4 months:
     - 75% of patients have acute hepatitis
2 years:
     - 50% of patients have chronic hepatitis
3 years:
     - 50% of patients have normal graft or mild lesions
     - 5% have develop severe lesions
4 years:
     - 70% of patients have chronic hepatitis
5 years:
     - 10% of patients have HCV-related cirrhosis on the graft
     - 70% of patients have survived (in Europe)
10 years:
     - 60% of patients have survived (in Europe)

These survival rates compare to the rates obtained after transplantation for other non-malignant liver diseases.5, 22, 27, 32, 61, 75

Liver grafts are rapidly infected since HCV viremia increases as early as 3 days post-transplant. HCV RNA levels increase progressively, and at 1 month, the HCV RNA level may be dramatically increased compared to pretransplant values.79

Recurrent HCV infection after liver transplantation is currently treated with interferon and ribavirin.50

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