Hepatitis C

Epidemiology

Chronic hepatitis C occurs only infrequently in childhood. Based on our own research, the estimated rate is about 1/2000 children in Germany [13]. Many of these patients were found to have received blood or blood prod-

Table 2. Advantages and disadvantages of antiviral medications for chronic hepatitis B

Advantages

Disadvantages

IFN-a

Anti-HBs seroconversion ~5%

Significant side effects

Anti-HBe seroconversion 26-38%

Expensive

Lamivudine

Few if any complications In most patients HBV-DNA and GPT decrease during therapy Available in juice form Resistance development

No anti-HBs seroconversion Anti-HBe seroconversion only 10-15%

Higher than spontaneous development Less long-term experience

Adefovir

Like lamivudine but fewer resistances

More expensive and little experience with children

ucts, in other words a treatment via parenteral injection in countries where inadequate measures of sterilization were practiced. While this method of infection is becoming increasingly less important, the vertical route of infection for HCV is steadily increasing.

Serological diagnosis

Screening tests to determine the levels of anti-HCV antibodies are conducted using commercial tests, whereas HCV-RNA is detected via PCR. Usually a PCR is conducted to quantify the "viral-load", which provides the number of circulating HCV genomes. A positive finding is followed by HCV geno-typing. Characteristically, the transaminases progress in an often unsteady and fluctuating manner, and the discovery of normal levels is not unusual. A liver biopsy is usually not necessary and should only be performed if there is any reason to suspect significant liver damage or as a means of ruling out other liver diseases.

Transmission

The risk of vertical infection is 3-8%. The method of birth does not influence the risk of transmission. Transmission via blood or blood products still occurs, and remains an important consideration. Blood transmissions took place either before the introduction of screening tests for HCV in the early 1990s, or the child originated from a country without adequate screening methods. Although transmission is possible during sexual intercourse, it seldom occurs. With monogamous partners, the transfer of HCV is so rare that a concern about such transmission does not even justify condom use [14].

What Anti Hcv Means
Figure 4. Continuing response to therapy (%) (HCV-RNA negative 6 months after end of treatment). Black, genotype 1; gray, genotype 2 or 3. Columns from left to right: (1)+(2): [15], review (n = 366); (3)+(4) [16] (n = 41); (5)+(6) [17] (n = 61); (7)+(8) [18] (n = 118).

Therapy

In comparison to hepatitis B, at least 50% of patients with chronic hepatitis C can be cured. IFN-a-2b (Intron A®) plus ribavirin (Rebetol®) is the approved treatment for children. Ribavirin can be obtained in capsule form as well as in juice form for smaller children. Based on numerous studies conducted in pediatric patients, successful treatment is assured with these two drugs.

With the combination therapy of IFN-a and ribavirin, approximately 45% of patients infected with genotype 1 and 4 and about 90% of those with genotypes 2 and 3, can be cured (Fig. 4). The rate of successfully treated pediatric patients therefore corresponds to those of adults [19].

To avoid late complications and to reduce the chances of contagion, and to maintain the high rates of success, treatment for all chronically infected children should be considered. Treatment with IFN-a is much better tolerated in childhood than in adulthood and, therefore, it is best to think about treatment before puberty, as long as there are no contraindications.

Children also experience the typical side effects of interferon, (see above), but usually they are significantly milder than in adults. Side effects are particularly present in the early phase of treatment, and can be treated with paracetamol given as a prophylaxis before each injection. After the first weeks many children get used to the side effects of interferon, which is a further argument for the treatment during childhood. In about 10% of children, specific thyroid antibodies are produced, which may cause hypo-thyroidism and in some instances must be treated (yet unpublished).

Therapy regimen

IFN-a is given over 12 weeks, 3 MU/m2 3 x/week s.c. plus ribavirin 15 mg/kg per day. In the eventuality that HCV-RNA decreases by more than 99% after 3 months, treatment should either be continued for the total of 48 weeks or ceased. Treatment must be terminated if HCV-RNA continues to rise in spite of treatment.

PegIntron® is given over 12 weeks 1.5 ^g/kg 1 x/week s.c. plus ribavirin 15 mg/kg per day. In case that HCV-RNA decreases by more than 99% after 3 months treatment should either be continued for the total of 48 weeks or ceased. Treatment must be terminated if HCV-RNA continues to rise in spite of treatment.

Due to good response to therapy, patients with genotypes 2 and 3 need only be treated for 6 months as a whole.

Contraindications and side effects

The most common side effects are flu-like symptoms, which often subside after a few weeks. For the most part they arise after an injection with IFN-a and can be mitigated by paracetamol given as a prophylaxis (for details see Tab. 3). Side effects are definitively less pronounced before puberty. The induction of autoimmune thyroiditis is possible. Ribavirin may induce an anemia, which has little clinical relevance in most cases.

Second line treatment

Basically, unsuccessful treatment can be re-attempted at a later time with another interferon (for example, Multiferon® or consensus interferon). However, no experience has been documented on repetition of treatment in children. We are currently conducting a study in previously treated children who are now receiving Multiferon® plus ribavirin. It is expected that patients who were free of the virus for a short time and became positive again during or after treatment, could profit from re-treatment. For patients who did not become HCV RNA negative during the first treatment period, re-treatment will most likely have less benefit. In any case, the rate of recovery with re-treatment is expected not to exceed 20% for patients infected with genotype 1.

Table 3. Side effects of interferon-alpha therapy plus ribavirin [19]

Patrick Gerner

Side effect

%

Serious %

Headaches

69

3

Fever

61

Abdominal pain

39

Vomiting

42

Myalgia

32

2

Diarrhea

25

< 1

Pharyngitis

27

Weight loss

25

Alopecia

23

Inflammation at place of injection

19

< 1

Emotional instability

16

Depression

13

< 1

Pruritis

12

Arthralgia

15

High hopes for the treatment of chronic hepatitis C are being pinned on two new groups of substances: protease inhibitors and polymerase inhibitors that suppress HCV replication. These have been around for a number of years. Some are presently being tested in Phase II studies on patients. The most promising drugs are SCH 503034, VX 950 and valopicitabine (NM 283). It is expected that at least one of these substances will be employed for the treatment of chronic hepatitis C in adults, at least in drug trials. Presumably, these new drugs will be used in combination with other antiviral substances.

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