ABSTRACT


Viral hepatitis is a persisting concern.
Outbreaks of hepatitis A occur in developing countries, where only 10 to 20% of the population is seroprotected.
The disease may cause fulminant liver failure and death. Targeted vaccination include IV drug users, homosexuals, and chronic hepatitis patients, but does not allow to reduce the incidence significantly. Secondary prophylaxis of household contacts is efficient to prevent secondary cases, and should be proposed. Universal vaccination is now progressing for hepatitis B. Vaccination failure may occur in low birth weight infants, or in infants contaminated in utero.

Chronic carriers progress to cirrhosis and hepatocarcinoma, the latter risk being most important for men infected at birth. Alcohol intake should be avoided in carrier adolescents. Interferon is able to triple the rate of HBe ag loss and decuple the rate of HBs ag loss after one year , shortening disease evolution, and hopefully decreasing the risk of unfavourable outcome. Similarly, Lamivudine increases by four times the rate of HBe ag loss in adults. However, precore mutants may be selected by the immune pressure after seroconversion in children, and YMDD mutants appear in 15 % of Lamivudine treated patients after one year, more frequently in patients with high initial viral load. Hepatitis C is mainly acquired in childhood true vertical transmission.

The risk is related to presence and amount of maternal HCV RNA at the time of birth. Infection rate is higher in children form HIV positive mothers, and higher if they are themselves co-infected with HIV. Breast milk feeding is not a risk factor, and there is so far no argument to propose cesarean delivery to HCV positive mothers. Treatment with interferon alone is poorly efficient, although pediatric studies remain scarce. Combination treatment using Ribavirin plus interferon yield a higher success in eradicating viral infection in adults.

HEPATITIS A


A has now become a preventable disease, although universal vaccination is so far not yet recommended.
Because of the low natural seroprotection of the population in developed countries, western populations become increasingly susceptible to hepatitis A outbreaks.

Beside person to person direct transmission, this resistant virus persists for long periods in the environment.
Contaminated material or food can therefore be the source of large , long lasting, foodborne outbreaks, sometimes even disseminated by industrial frozen food 1**. IV drug users or homosexuals have also been recognised now as high risk groups for outbreaks. Hepatitis A is also a potential risk for patients with underlying chronic liver disease. In particular, hepatitis C patients are at risk of developing fulminant course, as observed in 7 of 17 hepatitis C patients prospectively followed 2*.

Hence, vaccination of patients with chronic liver disease is advocated, and trials have shown a 73% response rate after a single dose of hepatitis A vaccine in hepatitis C patients, and 83% in other chronic liver disease patients 3.
The disease is often considered as benign, and paediatricians are insufficiently aware of the risk of fulminant liver failure, or death 4,5.
Among symptomatic patients from a US sentinel study, hospitalisation was required in 13% while 0.2% died 5. In addition to its high efficiency in primary prophylaxis, the hepatitis A vaccine has also been shown efficient in secondary prophylaxis: The vaccine given to household contacts of sporadic cases, within 8 days of first symptoms, was able to reduce the incidence of secondary infection from 13.3% to 2.8 %.

For such secondary prophylaxis, vaccination of 18 household contacts was required to prevent one case of secondary hepatitis A 6**.

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HEPATITIS B


Chronic hepatitis B remains a subject of deep concern.
Universal early childhood vaccination has been adopted in the United states in 1991, and immunization rate has increased up to 86% in 1996 in the US. However, one fifth of the physicians are not yet convinced about its importance 7.

In high endemicity area, universal vaccination has been shown able to decrease the carriage rate in the population, including amongst non vaccinated children true reduction of horizontal transmission8,9. In addition, this is the first vaccine able to decrease the incidence of childhood cancer 8,9.
In full term babies, vaccination administred in the immediate newborn period allows to reach a 95% seroprotection rate, but in low weight premature babies, response rate is poorer, and vaccination in low risk groups should be delayed until they reach 2 kg, or two months of life.
Response rate of premature newborn after three dosis of vaccine reached 84% in babies weighing > 1500 g, versus 68% or less in babies < 1500g. Ninety six percent of children who did not achieve seroprotection weighed < 1700 g at birth 10.

Failure of vaccination in babies from HBs ag positive mothers is related to positive HBs antigenemia at birth, suggestive of intrauterine infection, as observed in 2.4% of 665 newborns form carrier mothers.
All of them became chronic carrier 11. However, despite availability of vaccination, prevalence of hepatitis B has not decreased in the United states between 1980 & 1994, with an estimated 330000 new cases per year, among which 16000 to 18000 were reported to CDC as acute hepatitis 12.

Furthermore, the increased incidence of hepatocellular carcinoma in the United States is thought to be due to the increasing number of HBV and HCV patients, with patients infected in the 1960s &1970s reaching now two to three decades of evolution 13,14**. Amongst 610 chronic hepatitis B adult patients, the cumulative progression rate to cirrhosis reached 21% after 10years and 37% after 15 years, while the amount of alcohol intake was shown to be an independent factor of progression to cirrhosis 15*.

Adolescent carriers should therefore be advised not to start alcohol consumption, as this may lead to the more aggressive pattern of evolution seen in adults as compared to children. In the same study, progression rate to hepatocellular carcinoma was 5% at ten years and 19% at fifteen years 15*. Hepatocarcinoma may develop in these patients before onset of cirrhosis 16.

Among patients infected at birth , the lifetime risk of hepatocarcinoma reaches 50% for men and 20% for women 14**. Natural evolution studies are scarce, and contaminated by treatment received. Over 185 mediterranean children followed for an average of 13 years, some of them treated, 84% cleared HBe ag on follow up but only 6 % lost HBs ag. Hepatitis relapse was observed after HBe ag loss in 9 patients, some of them being infected with HBe minus precore mutants.
Two patients developed hepatocellular carcinoma 17*.

A minority of these children were born from HBs ag positive mothers, and similar studies in children contaminated at birth are lacking. Precore stop codom mutant viruses coexists with the wild type virus in 10 to 25% of chronic hepatitis B children, and this percentage rises to 39% after HBe seroconversion 18.
The mutant may be selected by host immune pressure, which may explain the higher percentage of mutants found in late infected children (65%) as compared to children contaminated at birth (37.5%), who have a higher immune tolerance towards the virus 18. Beside vaccination, any treatment likely to eradicate HBV infection is likely to reduce the risk of cirrhosis and hepatocarcinoma 16. Early treatment may be more beneficial, if started before integration of viral DNA in the majority of host hepatocytes nuclear DNA 13,19. A large multicenter, multinational study involving 144 children was undertaken to evaluate the efficacy of interferon alfa 2 B to promote HBe ag loss in chronic carriers with elevated transaminases. Patients received Interferon alfa 2b, 6MU/m˛, 3 times weekly for six months 20**.

Twenty six percent of treated children, as compared to 11% of untreated, cleared HBe ag at one year, and 33 % at 18 months. HBe ag loss was also more rapidly observed in inteferon treated patients than in natural seroconverters. Ten percent of treated patients lost also HBs antigen, versus 1% of controls.
Transaminases normalised and liver histology improved in responders 20. According to these data, and provided that analysis performed in young adults can be applied to children, interferon treatment would be able to increase life expectancy , decrease disease related costs and perhaps complication of hepatocarcinoma 14,16.

Beside interferon, Lamivudine has emerged as a new treatment alternative in chronic hepatitis B infected individuals 21**. Given in adults at a dosis of 100 mg once daily, the drug is able to inhibit rapidly viral replication, and promote HBe ag loss in 16% versus 4% of controls at one year. Seventy two percent of the patients normalised transaminases as compared with 24% in the placebo group. Liver necroinflammatory score improved in 56% of treated patients versus 25% of placebo treated patients. However, genotypic mutations (YMDD) were demonstrated in 14% of treated patients, but not in placebo patients 21,22.
YMDD mutants are resistant to Lamivudine, and should be suspected in case of recurrent viral replication under treatment. The drug is currently mainly used to prevent recurrent hepatitis B after liver transplantation, and emergence of genetic mutants is most likely to occur in patients with high viral load prior to treatment 8. These patients probably have preexisitng resistant virus as a minority species prior to exposure to lamivudine 8*.

A pediatric pharmacokinetic study has determined that clearance of lamivudine was higher in young children, and reached adult profile from twelve years old. In young children, the recommended dosis is 3mg/kg, once daily 23. Currently, long term lamivudine treatment is being investigated for chronic hepatitis B in children.

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L'HEPATITIS C

Hepatitis C virus (HCV) infection is relatively infrequent in childhood, even in endemic areas, due to the lower exposure of children to efficient routes of transmission such as transfusions (in the past years), drug abuse and other percutaneous routes 24.

For this reason some aspects of infection and associated liver disease, such as the natural history and the efficacy of therapy, are largely undefined. In fact most attention in recent years has been devoted to the epidemiological aspects of infection, with particular respect to vertical transmission.
Large series of mother infant pairs have been now analysed to establish the rate and predictors of transmission. Resti et al 25 ** found that the transmission rate from 403 infected mothers without HIV coinfection to their offspring was 3%, including 5% of viremic and none of HCV RNA negative mothers.

The risk of transmission was unrelated to breast feeding and to caesarean delivery. The safety of breast feeding from asymptomatic mothers with HCV infection is also reported by Kumar et al. 26. The authors, however, describe putative transmission by breast milk in three children delivered by cesarean section who become viremic at 3 months of age, when their mothers developed symptomatic hepatitis.
They suggest to avoid breast feeding by symptomatic mothers with high viral charge 26. Maternal virus load is though to influence the rate of vertical transmission and HCV RNA levels were shown to increase late in pregnancy and return to baseline levels one year after delivery in women with chronic hepatitis C 27*.
The highest rate of transmission from mothers who are HCV and HIV coinfected is confirmed by Mazza et al. 28 and by Papaevangelou et al. 29. The rate of infection is significantly higher (40%) in HIV coinfected children as compared to babies infected with HCV alone (7.5%). The significance of HIV and HCV cotransmission remains unexplained 28,29.

Independently of its low efficiency, vertical transmission has become the main route for pediatric HCV infection after the introduction of blood screening. Bortolotti at al. 30* investigated the routes of transmission in 106 consecutive, anti-HCV positive Italian children without underlying diseases and found that 93% of those born after 1990 had an anti-HCV positive mother, while 54% of older children had been transfused.; 45% of infected mothers had a history of covert percutaneous exposure, while one third reported drug abuse. The authors suggest that, following the adoption of general preventive measures, maternal drug abuse is likely to remain the most important source of infection for children in the Western world 30*.

The American Academy of Pediatric thus recommends screening infants born to HCV-infected mothers and persons with risk factors for HCV such as injection drug use, transfusions received before 1992 or hemodyalisis 31.
One peculiar epidemiological aspect of HCV infection is its role in the development of chronic hepatitis after liver transplantation. Davison et al. 32 studied the prevalence of HCV infection in 80 children with a median follow-up of 4.4 years after liver transplantation and found that only three children transplanted prior to donor screening were infected, but only one was associated with chronic hepatitis.

A similar prevalence (4%) has been reported by McDiarmid et al 33** in 321 children surviving more than one year. However the authors showed that all infected patients had histological features of chronic hepatitis with cirrhosis in one case; all but one patient were treated with interferon and 23% died for liver failure. The epidemiological aspects of HCV infection in childhood are revised by Thomas et al 34, Ebeling 35 and Bernard 36. Chronic hepatitis C is a mild disease in children, but it has a poor propensity for spontaneous remission over the years and thus can proceed to a more severe liver disease in adulthood. For this reason attempts have been made to treat children with hepatitis C with interferon. Jonas et al. 37 used recombinant interferon alpha 2a to treat 21 children (2 with thalassemia major) for 6 months at a dose of 3MU/m2 thrice weekly.
The response rate at this time, including normalisation of alanine aminotransferase and clearance of HCV RNA, was obtained in 19% of cases.

Further management of patients was not homogeneous because the authors either protracted treatment or retreated some patients, thus introducing several biases which prevent an accurate evaluation of sustained response and of predictors of response. Vegnente et al 38 treated 25 otherwise healthy children with recombinant alpha 2b interferon at the dose of 5MU/m2 for 12 months and obtained a complete response in only 12% at the end of treatment and of 8% at the end of a further 12 months follow-up.
The data of these recent papers contrast with the results of previous pilot studies which provided greater response rates: a selection bias linked to the small sample size and the improvement of techniques for the detection of HCV RNA could explain the differences. Sawada et al. 39 investigated 24 children with chronic hepatitis C, most with haemato-oncologic diseases, treated with human lymphoblastoid interferon At the dose of 0.1 MU/kg body weight daily for 2 weeks and then thrice weekly for 24 weeks. The response rate was 50% at 6 months and 42% at 18 months. Patients with primary malignant disease responded less well to interferon.
The effects of IFN treatment of children with chronic hepatitis C has been reviewed by Al- Tawil 40. A high proportion of children, as well as adults with hepatitis C do not benefit of interferon therapy.

For this reason a combination therapy with a standard dose of interferon associated with ribavirin administered orally has been experimented in adult patients. McHutchison et al 41** used a combination of interferon and ribavirin, administered at the dose of 1000-1200 mg per day, for 24 or 48 weeks. The rate of sustained response, defined as an undetectable serum HCV RNA 24 weeks after treatment was completed, was 31 and 30% respectively, versus 13% in patients who received interferon alone for 48 weeks.

These encouraging results are confirmed by the effect of combination therapy in patients who relapsed after a course of interferon. Davis et al. 42** could obtain a sustained response in 48% of patients versus 8% of patients retreated with interferon alone. There is so far no experiences of combination therapy in children with hepatitis C. The prevention of HCV transmission, in the absence of vaccine, relies on general preventive measures. A further improvement of blood screening by introducing polymerase chain reaction screening of blood donations for HCV RNA has been recently proposed 43. Suggestions regarding the opportunity of cesarean section for children of infected mothers are not currently supported by sufficient data.

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CONCLUSION

In conclusion, any prophylactic measure to reduce the risk of acquiring viral hepatitis should be taken. Wide - universal ? - vaccination should be promoted, as targeted vaccination have shown their limit.
Hepatitis A outbreaks may threaten the increasing number of unprotected individuals, and the risk of the disease should not be ignored. Twenty years after vaccine availability, disease eradication is far from achieved for hepatitis B. Such slowly evolving disease does not impress sufficiently the physicians.

However, cirrhosis and hepatocarcinoma are a reality for young adults, and vaccination has been shown to reduce this risk. Treatment with interferon or lamivudine yield an insufficient success rate, and very long term studies and new therapeutic tools are needed to convince paediatricians that children in the early stage of the disease may benefit from treatment .
Unfortunately, no prevention can be proposed for hepatitis C acquired vertically from HCV positive mothers, and treatment success is even poorer than for hepatitis B.
Additional studies are needed to determine risk factors of transmission, but there is no evidence that breast feeding should be avoided or cesarean section proposed. Amniotic punction may be another so far non investigated risk factor of transmission. hg

LINK

For more information, visit http://www.pedihepa.org
- Service de pédiatrie générale , Université Catholique de Louvain, cliniques St Luc -

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References

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