 |
|
Brief Reports Indian Pediatrics 2002; 39:462-467 |
|||||||||||||||||||||||
|
Recombinant Interferon Therapy in Indian Children with HBV Related Chronic Liver Disease |
|||||||||||||||||||||||
|
R.C. Guptan
Childhood chronic hepatitis B virus infection often remains subclinical and produces significant morbidity and mortality in later life(1,2). The risk of developing cirrhosis and cancer in these children is however high if the age of acquisition of the infection is early childhood(3). Recombinant interferon (IFN) is now the standard therapeutic modality for the treatment of chronic HBV infection in adults, with response rates between 25-40%(4). The success of IFN therapy in children however, has been variably reported with higher response in European children compared to the Asian Chinese(5-7). Asian Chinese children are known to respond poorly to IFN even with steroid priming. An early mother-to-infant vertical transmission and subsequent immunotolerance are considered to be the primary factors of poor response in Chinese children(8). India with the second largest pool of HBV infected population in the world, has a large population of children with chronic hepatitis B virus infection. A prospective therapeutic trial was initiated in Indian children with chronic hepatitis B to assess the safety and efficacy of IFN therapy. Subjects and Methods Patients Twenty five children consecutively seen between January 1995 to 2000 were included in the trial if they fulfilled the following inclusion criteria: HBsAg positive >6 months, HBeAg positive, liver biopsy proven chronic liver disease, Child’s A or B liver disease, age <12 years and HBV DNA positive. The exclusion criteria were: HBeAb positive, decompensated liver disease, presence of hepatocellular carcinoma, positive for HCV, HIV, HDV, history of variceal bleed in the past 3 months, antiviral or immuno-modulatory therapy within the last 6 months, TLC <4,000/cumm, platelet count <80,000/cumm, serum bilirubin >5 mg/dl, auto-immune hepatitis, Wilson’s disease, or evidence of any systemic disease or malignancy. The children were divided into two groups based on the mode of HBV acquisition: (i) Vertically acquired HBV: Children whose mother had serological evidence of HBsAg, HBeAg or anti-HBe positivity; and (ii) Horizontally acquired HBV: Children, in whom the mother had negative markers of HBV infection: HBsAg, HBeAg, anti-HBe, or anti-HBs (in a non-immunized subject), IgG anti-HBC. Methods Serology Sera were stored at –70º C and thawed only once before performing viral studies. Samples were tested at 4 wk, at the initiation of therapy (baseline), 8 wk, 16 wk, and 48 wk for HBsAg, HBeAg, anti-HBe, IgM anti-HBc (Organon Teknika, The Netherlands), anti-HDV (The Abbott Laboratories, North Chicago, IL) and anti-HCV (3rd generation EIA, UBI 4.0 USA). Histology Adequate interpretable biopsy sample was available in 19 children. The liver biopsy sample was studied by an experienced pathologist for confirmation of chronic liver disease. All the biopsy samples were assessed for histological activity index (HAI) as described earlier(9). In 3 children, though the tissue was small, it was sufficient to suggest the presence of cirrhosis. The decision to include these 3 patients for therapy was based on HBsAg/HBeAg HBV DNA +ve status with ALT raised more than 1.5 times normal. Additionaly, abdominal ultrasound and endoscopy was done to look for evidence of chronic liver disease. If consent was available, a repeat liver biopsy was done within 6 months of completion of therapy. Molecular techniques Hepatitis B viral DNA was detected by molecular hybridization technique as des-cribed earlier(10). The sensitivity of the hybri-dization technique was 16 pg/ml. HCV-RNA was detected by using standard reverse-trans-cription polymerase chain reaction (RT-PCR). Treatment Protocol An informed written consent was obtained from the parents before starting interferon therapy (Viraferon, Schering Plough, Kenilworth, USA). IFN was given in a dose of 50 to 75,000 IU/kg body weight, subcuta-neously, every alternate day for 4-6 months. Depending on the age and body weight, the mean dose ranged between 4.5 to 9 MIU/week. The children were monitored for any serious adverse experience. The treatment outcomes were determined based on the following criteria: (i) Response: Loss of HBV DNA and HBeAg from the serum at the end-of-treatment; (ii) Non-response: HBeAg and HBV DNA positive throughout the treatment; (iii) Relapse: After the initial loss, appearance of HBV DNA or HBeAg in the serum; and (iv) Cure: Loss of HBsAg during the follow-up period. Monitoring for Adverse Experiences The side-effects of IFN therapy were carefully monitored. Patients or their guardians were asked to report any adverse event such as fever, rash, seizures or abdominal pain. Total leukocyte counts and platelet counts were done at least once a week and if the leukocyte count reduced below 3,000/cumm and the platelet count below 70,000/cumm one or more doses of IFN were temporarily withheld. Any sleep disorder or possible psychiatric problem was asked to be reported to the investigators. Overall, all the study subjects underwent a weekly medical examination under the treating doctors to rule out any possible side-effects. Statistical Analysis The data are expressed as Mean ± SD. While the significance of the continuous variables was calculated by the Student’s t-test, the chi-square test or Fisher’s exact test was used to analyze the discontinuous variables. Results All the twenty-five patients successfully completed the study with no serious adverse experience (Table I). The patients included 18 boys and 7 girls. The age ranged between 9 to 12 years with a mean of 8.6 ± 2.4 years. Of the 25 consecutive subjects; 12 (48%) had acquired the HBV infection vertically (Group I) while 13 (52%) had acquired it horizontally (Group II) (Table I). The number of cirrhotics in both the groups was comparable. The mean HAI at baseline in these patients was 7.9 ± 3.6. Incidentally, since repeat biopsy could be done only in three children the post-therapy histological changes could not be interpreted adequately. Only 10 (40%) of the 25 patients were symptomatic and had presented with jaundice (40%), abdominal discomfort (30%), and fever (30%). Mild hepatomegaly was detected in 10 (40%) patients. Table I-Baseline Characterization of Patients
At the end of the treatment, there was a significant reduction in the mean ALT (114 ± 13 vs 73 ± 7.7, p <0.05) compared to the baseline. Eleven (44%) patients lost HBeAg and HBV DNA from the serum at the end- of-therapy. Of these 11 patients, 5 (45%) developed anti-HBe during the follow up period. Overall seroconversion rate in our group of children was seen in 5 of 25 (20%). Vertically versus Horizontally Acquired Infection The mean age of the children in vertical infection (VI) group was similar to that in horizontal infection (HI) group (6.2 ± 2.5 vs 7.7 ± 3.4 yr., p = 0.06). The mean baseline ALT levels were significantly higher in HI vs. VI group (p <0.05). There was no difference between the number of cirrhosis patients in each group. The frequency of loss of HBeAg was higher in HI group, but it was not significant compared to VI group (53.8% vs 33%, p = ns). Of the 7 patients who lost HBeAg in HI group, 4 (57%) developed anti-HBe, while of the 4 in the VI group, only 1 (25%) developed anti-HBe (p = ns) Responder vs Non-Responder There were 14 (56%) non-responders in the study. The baseline clinical profile of non-responders and responders (n = 11) was comparable. The mean age of responders was 8.2 ± 3.0 yr. which was not different from mean age for non-responders, 5.6 ± 2.7 yr. The number of cirrhotic children in the responder 3/11 (27%) and non-responder 3/14 (21%) was comparable. There were no differences in the mean ALT levels in the responders and non-responders (115 ± 24 vs 132 ± 25 IU/L; p = ns). Adverse Experiences Fever and ‘flu-like syndrome’ was the commonest (60%) adverse experience during the treatment period. Severe adverse experiences in the form of bone marrow suppression (12%) and spontaneous bacterial peritonitis (4%) were uncommonly seen. All the patients recovered with conservative management and temporary suspension of interferon for 1-2 weeks. No fatal adverse experience was noted in any patient. Follow up Only one patient (10%) relapsed with in six months of follow-up. In the mean follow-up of 16 ± 4.2 months no further relapses reported. One cirrhotic child who had not responded to treatment earlier and had acquired the HBV infection vertically developed hepatocellular carcinoma (HCC). This apparently normal child with almost normal transaminases on follow up, presented with feeling of an abdominal mass and severe lower abdominal pain about two and half years after the initial IFN therapy. Ultrasound abdomen revealed a muticenteric large tumor on a cirrhotic liver. The alfa-feto protein was high (850,000 ng/ml) and HBeAg and HBV DNA were positive. Due to deranged coagulation profile he could not be taken up for palliative intra-tumor alcohol injection and succumbed to his disease within 2 months of diagnosis. Two children who had not responded at the end of treatment, lost HBeAg and HBV DNA during the follow-up period. Thus overall, 13 (52%) children responded to IFN therapy. Discussion Results of this first prospective therapeutic trial of interferon in Indian children with chronic HBV infection clearly demonstrates the therapeutic efficacy and safety of the drug in this population. A dose of 50-75,000 IU/kg body weight on alternate days for 4-6 months could achieve a response by HBeAg and HBV DNA loss in 44% of the subjects. The response rate increased to 52% at 16 ± 4.2 months of follow up. These results are quite similar to our earlier observations in adult Indian patients(11). The response rate in Indian children was higher than that reported from China(8,12,13) and comparable to that reported in the European children(5-7,14). Studies on Chinese children have shown that HBV infection acquired at birth results in an immunotolerant infection(8,12). Such children present with near normal ALT and have limited success with IFN therapy, even after steroid priming. Even higher doses of 10 MIU thrice a week could achieve only 8% HBV DNA loss in this population. Another possible reason for a good response to IFN therapy in our patients could be the high baseline ALT levels even in the vertically acquired infection group (Table I). It is well documented that patients who have raised ALT respond better to IFN therapy, probably due to a better T-cell mediated immune response(15). Our results need further confirmation possibly by including a control group of untreated children with chronic hepatitis B with raised ALT. In a recent study by Sokal et al., while 35% of the treated patients responded, 10% of the controls also seroconverted(14). The patients who responded had elevated ALT levels. Possible factors which could influence response to interferon such as age, sex, ALT levels or the state of underlying liver disease did not seem to predict the outcome of therapy in our study. The common side-effects to IFN therapy in the present study were similar to those reported in the adult patients earlier(11). These included fever and ‘flu-like’ syndrome while a small proportion of children required dose modification due to bone marrow suppression. None of our children suffered from major personality changes as described from the West(14). In summary, we conclude that almost 52% of the Indian children with chronic hepatitis B respond to IFN therapy. There is a trend to better response in those who acquire the infection through horizontal transmission. Larger studies with higher daily dosing interferon or in combination with nucleoside analogues are recommended. Contributors: RCG conducted the clinical study and monitored the IFN side-effects. VT did the serology and the DNA studies. VM studied the histo-pathological specimens, SKS co-ordinated the study particularly the design and interpretation and will act as the guarantor of the paper. Funding: None. Competing interests: None stated.
| |||||||||||||||||||||||
| References | |||||||||||||||||||||||
|
