Chronic hepatitis B is a significant cause of morbidity and mortality and can lead to cirrhosis, hepatocellular carcinoma (HCC), and death. Chronic hepatitis B affects ≈5% of the world's population (1). Evidence of previous infection with hepatitis B is found in 4.8% of the United States population (2). It is estimated that 200,000-300,000 new cases of hepatitis B virus (HBV) infections occur annually in the United States (3,4) with an annual incidence of 11.5 per 100,000 population (4,5).
Although acute hepatitis B is primarily a disease of adults, children are at higher risk of developing chronic infection (6). In 1989, children <10 years old represented only 8% of cases of acute hepatitis B infections (5) but accounted for one-third of chronic infections (3).
Several studies have shown that α-interferon (IFN) is effective in decreasing viral replication in patients with chronic hepatitis B (7-11). IFN significantly increases conversion from hepatitis B e antigen (HBeAg) positive to HBeAg negative, clearance of HBV DNA from serum. normalization of serum aminotransferase levels, and improvement in hepatic histopathology (12). A metaanalysis of 16 studies in which IFN was used to treat adult patients with chronic hepatitis B who were HBeAg positive showed that 33% converted to hepatitis B negative versus 12% in controls (9). In that study, it was further shown that 7.8% of patients treated with 7 million U per week to 30 million U/m2/week of IFN for 3-6 months lost their surface antigen compared with 1.8% in controls.
Several trials of IFN in children with chronic hepatitis B infection have been completed. Response to IFN, measured as net increase in seroconversion from HBeAg positive to HBeAg negative or in clearance of HBV DNA from serum has varied from 0 to 8% in studies from China (13,14) to 7.5-63.5% in studies from Europe (15-21). In the European studies, conversion rates ranged from 21 to 78% for treatment groups and from 8 to 25% in the control population, with the increase in conversion rate attributed to IFN ranging from a low of 7.5% to a maximum of 63.5% (Table 1).
The use of IFN for treatment of chronic hepatitis B is well accepted in adults, and two recent studies have suggested that it is cost effective (22,23). Its use in children remains limited for several reason: (a) the smaller number of reports of treated children, (b) the widespread impression that children infected perinatally will invariably respond poorly to therapy, (c) the pain associated with the repeated injections, (d) the high cost of the medication, (e) the prolonged duration of the treatment, and (f) the fact that IFN has not yet been approved in the United States for children with chronic hepatitis B.
The purpose of this study was to determine the economic and clinical consequences of treating children and adolescents with evidence of chronic active hepatitis (CAH) due to HBV with IFN. We compared the cost effectiveness of IFN treatment in children, adolescents, and adults with CAHB.
Source of Data
A Medline search was made of English-language studies of the natural history of CAH due to HBV and the effect of IFN on the course of CAH in adults and children.
We considered for this analysis therapy of patients with a histologic diagnosis of CAH, and no evidence of cirrhosis, with active viral replication, confirmed by a positive HBeAg, positive HBV DNA, and increased transaminases (at least 1.5 times upper limit of normal) for 6 months or longer. These patients would also be positive for hepatitis B surface antigen (HBsAg) but negative for anti-delta antibody. We estimated the number of years of life that would be saved by treating cohorts of 10,000 patients with CAH due to hepatitis B with IFN at different ages (2, 12, and 25 years of age). We estimated the average cost for treatment of patients at each age, and then calculated the cost per year of life saved. The assumptions used for this cost-benefit analysis are detailed in the next section.
We assumed that all patients would enter the study at a similar stage in their disease. To compare the patients receiving IFN with a control population, we assumed that the patients who did not respond to IFN would have the same clinical course and complications as untreated controls.
Natural History of Chronic Hepatitis B in Adults
Complications of chronic hepatitis B have been noted to appear from 15 months to 32 years after initial exposure (24). We chose a disease-free latency period from initial presentation to onset of the first cases of cirrhosis of 10 years. Adults with CAH have an estimated 50% lifetime risk of developing decompensated cirrhosis or HCC (25,26). In our model, we used an annual incidence of cirrhosis of 3%; this led to 5,363 of the initial 10,000 patients developing decompensated cirrhosis or HCC over a lifetime. After the development of cirrhosis, the risk of decompensation is reported to be between 2.3 and 10% per year (27-30). In our model, we used an annual risk of decompensation of cirrhosis of 5%. The risk of death after decompensation has been estimated to be 13% per year by Fattovich et al. (27), 17.2% per year by De Jongh et al. (28), and 23% per year by D'Amico et al. (29). We assumed for our analysis that 17% of patients who have decompensated cirrhosis and who do not get liver transplantation would die each year.
Patients with cirrhosis caused by HBV are at increased risk of HCC, estimated between 1.5 and 2.8% per year (27,30-32). We used an annual incidence of HCC of 2% among patients with cirrhosis. Mortality from HCC is estimated at 95% over 5 years (33), yielding an annual mortality rate of 40%, which we used in our model.
Natural History of Chronic Hepatitis B in Children
Because the vast majority of children infected with hepatitis B are asymptomatic (15), it is difficult to determine the latency between initial infection and the onset of chronic liver disease. HBsAg-associated cirrhosis has been reported in infants as young as 10 months (34) and in a series of 292 children with chronic HBV infection ages 1-13 years followed prospectively (35), 10 children (3.4%, mean age 4.0 ± 3.3 years) had cirrhosis at initial presentation. In our baseline analysis, we used the same latency period as for adults (10 years). The risk of cirrhosis and HCC is related to the length of time that a person has chronic infection (36), and it is estimated that infants who become chronically infected with HBV have a higher lifetime risk of cirrhosis and HCC than adults do (26). Therefore, we used the same annual risk of cirrhosis (3%) as for adults. The survival of patients with complications of CAH caused by HBV does not vary with the age of initial infection (28,31,37,38); therefore, we used the same rate of decompensation and mortality from decompensated cirrhosis as for adults. Several reports have shown that HCC in childhood is etiologically related to chronic HBV infection (39-41). Although the risk of developing HCC during childhood appears to be smaller than in adults with chronic hepatitis B (42), there have been few prospective studies of large numbers of children with chronic hepatitis B to help define that risk with precision. In a brief letter, a group from Italy (43) reported on the follow-up, during a mean period of 6.1 years, of 103 children with biopsy-proven chronic hepatitis B, 5 of whom had cirrhosis. One child, initially found to be HBsAg positive at 15 months of age, was diagnosed with HCC at age 11. From a group of 415 children from Taiwan followed prospectively for an average of 7.1 years, 30 had liver biopsies; 2 had cirrhosis and 1 developed HCC at 11 years of age (44). Epidemiologic studies have supported the assumption that the lifetime risk of HCC related to HBV is greater when chronic infection is acquired early in life (45). We used a risk of HCC of 1% per year for children with cirrhosis in our model.
Effect of Treatment with IFN
We assumed for this analysis that successful treatment with IFN would eliminate the risk of cirrhosis and HCC. A major determinant of the cost per year of life saved by IFN treatment is the proportion of treated patients protected from disease; for that reason, we used a high and a low estimate of the protection rate by IFN. We chose as our high protection rate 30%, which approximates reported net seroconversion rates of HBeAg in adults and European children treated with IFN (7,18,19,21). We chose as our conservative estimate of the benefit from treatment with IFN a value of 6%, which is the mean net rate of HBsAg seroconversion reported in the meta-analysis performed by Wong et al. (9), and is close to the reported net rates of seroconversion of HBsAg in European children treated with IFN (Table 1).
Life expectancy for our patient population was estimated at 75.5 years (46). Duration of follow-up has been examined for 35 years after the latency period. We limited our analysis to the outcome of a single treatment course with IFN.
An estimate of the cost of evaluation, treatment with IFN, and follow-up of 10,000 patients with CAH B was made. For this estimate, we used (a) a cost of $100 per 10 million U of IFN and (b) a treatment regimen consisting of 10 million U/m2 (with a maximum of 10 million U) taken three times a week for a total of 16 weeks. Based on these assumptions, the cost of treatment per person treated was $4,800 for adults and adolescents and $2,640 for an average 2-year-old boy (using a body surface area of 0.55 m2). Medical costs for treated patients included those incurred for an initial liver biopsy, repeated office visits (seven annual visits the 1st year), and routine laboratory tests at each clinic visit, with a total cost of $1.250 per patient. After the 1st year, responders would be seen on average once a year. From the time of initial evaluation, nonresponders and control patients without cirrhosis or HCC would be seen on average three times a year for a cost of $100 per visit for physician fees and laboratory tests. These costs are summarized in Table 2. We used published estimates of lifetime medical costs incurred by patients with cirrhosis and HCC (25,47); these costs are listed in Table 3. Because not all patients with HCC have cirrhosis (48), we applied the costs for cirrhosis in addition to those for HCC to half the patients with HCC.
We assumed that all patients who develop decompensated cirrhosis would be considered for liver transplantation. Liver transplantation for chronic hepatitis B is controversial; patients often become reinfected with HBV after transplantation, leading to decreased survival (49). Although long-term use of hepatitis B immune globulin seems to result in improved graft and patient survival (50,51), this remains an unsettled issue (52). Consequently, we have estimated the costs per year of life saved with and without including the cost of liver transplant. When calculating the cost of liver transplantation, we used data obtained at our institution: we estimated that half of patients with cirrhosis and end-stage liver disease would qualify for liver transplantation, and 85% of those would actually receive a liver transplant. We estimated the costs of follow-up of transplant recipients, using our current survival rates for patients with chronic hepatitis B of 60% at 1 year, 45% at 5 years, and 35% at 10 years. The estimated cost of liver transplantation ($120,000) and the follow-up and medication costs per year of $15,000 were also obtained from our institution. Based on current practices, liver transplantation was not considered as a treatment option for patients with HCC.
Recommendations for screening for HCC vary (32,53). The high number of false-positive and false-negative results from screening tests for HCC have raised concerns about its cost effectiveness (54). In addition, a study in which α-fetoprotein and ultrasonography were used to monitor patients with cirrhosis failed to show an increase in survival in the patients in whom a cancer was detected (55). Therefore, we did not include costs of screening tests for HCC in our calculations. All costs and years of life saved were discounted at a rate of 5% per year.
We examined the effect of varying the response rate to IFN therapy on the costs per patient treated. We also estimated the impact of a longer latency period for children on the cost per year of life saved.
Cost of Treatment With and Without IFN
Discounted costs incurred for medical care of CAH B are compared in Table 4 and 5 for children, adolescents, and adulsts receiving either standard care or treatment with IFN. If costs of liver transplantation are included, in the case of a 30% response rate, the use of IFN leads to savings in the children's group and to a small cost of ≈$1,000 for adolescents and adults. If a more conservative response rate to IFN of 6% is used, the use of IFN is associated with a modest increase in expense in comparison to standard care of ≈$2,900 (children) to ≈$5,000 (adolescents and adults) per patient treated. If the costs of liver transplantation are not included in the calculations, the results vary only little. With a 30% response, treating children with IFN saves money over standard care. The costs for treating adolescents and adults with IFN exceed those of standard care by $1,857 and $1,543 per patient, respectively. In the case of a 6% response, total costs per person treated with IFN therapy over standard care are estimated at ≈$3,100 for children and $5,200 for adolescents and adults.
Years of Life Saved by IFN
Based on the assumptions already detailed, after discounting 5% per year and including liver transplantation, the use of IFN would lead to an average increase in life expectancy ranging from 0.2 years in adults to 0.5 years in children in the case of a 6% response and from 1.1 years in adults to 2.6 years in children in the case of a 30% response. Without transplant, a 6% response rate would result in an average increase in life expectancy of 0.1 (adults) to 0.2 (children) year; a 30% response rate would lead to an increase in life expectancy of 0.5 (adults) to 1.0 year (children), on average (Table 6). The figures for adolescents are intermediate between those of children and adults.
Cost per Year of Life Saved
As shown in Table 6, if costs of liver transplantation are included, treatment with IFN leads to savings in comparison with standard care in the toddlers' groups and is associated with a minimal cost for adolescents ($510) and adults ($934) in the case of a 30% response. If a 6% response rate is used, the cost per year of life saved for children remains reasonable at $5,700; this cost per year of life saved is approximately ¼ that for adults ($22,100). The cost per year of life saved for adolescents is intermediate at $12,900. Even if the cost of liver transplantation are not included, treatment of children with IFN is less expensive than standard care, in the case of a 30% response rate to IFN. With a 6% response, the cost per year of life saved for children ($16,000) is less than one-third the cost per year of life saved for adults ($51,200), with adolescents having an intermediate cost ($33,500).
Total costs per patient treated calculated as a function of the response rate for the three age groups considered are plotted in Fig. 1. The three curves run roughly parallel to each other, with the one for children shifted to the left in relation to the ones for adults and adolescents. The cost of IFN therapy is recouped with a response rate of 29% or better for children and with a response rate of 40% or better for adults. When we examine the effect of a longer latency period of 15 or 20 years for children on the cost of treatment, we find that the cost per year of life saved for children remains lower than that of adults, with a latency period of 10 years (Table 7).
Our results support the use of IFN to treat patients with CAH even with the assumption of a relatively low seroconversion rate of 6-30%. At present, our conclusion must be based on multiple assumptions that will require long term follow-up of large numbers of patients treated with IFN for confirmation. Our analysis is particularly sensitive to the assumption that response to IFN by conversion of HBeAg prevents the onset of cirrhosis and HCC. At present, the reported improvement in the histological appearance after seroconversion suggests that treatment will be effective in preventing fibrosis, but a long-term follow-up of patients will be required to confirm this assumption.
Two recent cost-effectiveness studies of IFN therapy in adults with chronic hepatitis B have had similar conclusions to ours. Garcia de Ancos et al. (23) reported that the cost of IFN therapy was recouped if social costs and an assigned value for lives saved by IFN therapy was included in their calculations. In a more recent report, Wong et al. (22) concluded that treatment of chronic hepatitis B with IFN-α2b was a dominant strategy, and that it saved both lives and money. In both studies, the authors used undiscounted figures for the estimation of life expectancy; neither one included the cost of liver transplantation (22,23).
There is, to our knowledge, no previous study of the cost effectiveness of treatment of chronic hepatitis B with IFN in children. Before the institution of immunization of neonates against HBV, children <10 years represented only 8% of reported cases of acute hepatitis B in the United States but accounted for one-third of chronic infections (3). In addition, this group represents an important reservoir for transmission of the virus, to house-hold contacts during their childhood (56-58) then, as adults, through sexual, parenteral, and vertical transmission. Therefore, this represents an important public health concern, and prevention of the consequences of chronic infection in children is an important goal.
We have found that treating children and adolescents with HBV is even more cost effective than treating adults and results in a greater increase in life expectancy. The reasons for the lower costs per year of life saved are the smaller dose of medication used in toddlers and because treatment at an earlier age results in a greater increase in life expectancy for those who respond. This finding does not include any estimate of the savings resulting from the prevention of secondary cases of hepatitis B. Such an estimate would be difficult, and we have not included it in our model. These savings would be greater for children and adolescents than for adults. We have considered only medical costs and have not included indirect costs such as those incurred for traveling for clinic appointments or loss of income secondary to hospitalizations. The inclusion of these costs would make treatment with IFN a more attractive option.
A key factor in the cost effectiveness of IFN therapy is the net conversion rate after treatment with IFN. Recent studies have reported net HBeAg conversion rates of up to 60% in adults (59) and >60% in young children (16). We have intentionally chosen a conservative estimate of the response to IFN in our model. Even with this bias against IFN, we have found that, with a response rate of 30%, IFN therapy leads to a slight cost savings in toddlers. In view of the higher response rates reported in recent studies in toddlers, IFN therapy seems to be a more attractive option in this age group. As indicated in our sensitivity analysis, these higher response rates, if they are confirmed, would result in substantial savings.
Some patients do not respond to IFN therapy during the 1st year but will undergo spontaneous seroconversion of HBeAg after the end of the treatment with IFN. This suggests that some patients who undergo seroconversion during treatment would have done so even without therapy and that the net effect of IFN may be overestimated from controlled studies with short follow-up periods. We have designed our model to reflect the reported lifetime risk of complications of cirrhosis and HCC at different ages; this figure takes into account patients who seroconvert spontaneously and whose liver disease does not progress. Indeed, the incidence of cirrhosis we used for adults is lower than that reported in studies of shorter duration (6-17%) (31,37,60-62).
As can be seen in Table 1, the studies published differ in the dose of IFN used and the duration of treatment. We chose a treatment period of 16 weeks, which is the duration of treatment in most studies of adult patients and a dose of 10 million U/m2, which is the highest dose used in the studies conducted in children. In recent trials in children, lower dosages of IFN have been used for a longer time (6 million U/m2 for up to 24 weeks) (63). The costs of this regimen, $3,626 for children and $6,434 for adolescents, are similar to those used in our baseline assumptions of $3,890 and $6,050 for children and adolescents, respectively.
It might be argued that children have lower response rates to IFN than adults do. This impression stems mostly from reports in Chinese children, the majority of whom seem to have a state of immune tolerance, as evidenced by low serum aminotransferase levels in the face of ongoing viral replication (64,65). However, Chinese children with chronic hepatitis B who have elevated transaminase levels have response rates similar to those reported in European children and in adults (65). In their study of 90 Chinese children positive for HBeAg, Lai et al. (14) found that 8.3% of patients who received IFN with or without priming with prednisone converted from HBeAg to antibody to hepatitis B e antigen (anti-HBe), compared with none of the control patients. However, of 5 children with elevated alanine aminotransferase at entry who received IFN, 3 (60%) became negative for HBeAg, whereas only 2 of 55 (4%) children with normal pretreatment transaminases converted to anti-HBe (14). Our inclusion criteria stipulate that patients would have elevated transaminases. Studies in European children have yielded response rates similar to those reported for adults. The mean seroconversion rate of HBeAg from the European studies listed in Table 1 (25.8%) is close to that reported in the meta-analysis of 16 studies of IFN for adult patients with chronic hepatitis B (21%) (9). In their cost-effectiveness study of IFN, Wong et al. (22) restricted their analysis to nine reports in which recombinant IFN-α2b had been used and found an average conversion rate for HBeAg of 37%. Only four of the pediatric groups listed in Table 1 were treated with IFN-α2b; their average conversion rate for HBeAg is 39.8%. Thus, we have used the same response rate for the different age groups in our model. In addition, as shown in the sensitivity analysis, the cost per patient treated remains smaller for children even if adults have a response rate to IFN that is up to 11% higher than the response rate of children.
The cost per year of life saved for children in our most conservative estimates ($16,017) compares favorably with published estimates of costs per year of life saved by such widely accepted health interventions as treatment of end-stage renal disease with center dialysis ($24,800) (66) or treatment of hypercholesterolemia with cholestyramine ($117,400) (67).
A striking correlation has been noted between age distribution of HBV infections and that of HCC, the peak age of HCC being younger in areas with a high incidence of HBV infections (68). In Western countries, where mostly adults are affected by acute HBV infections (36), the average age of patients with HCC is 61 years (69). In countries with a high incidence of HBV, where the rates of perinatal and horizontal transmission to children are much higher (3), the average age of patients with HCC is 37 years (68). Several cases of perinatal transmission of HBsAg with development of HCC in the first decade have been documented (70,71). This suggests that the risk of HCC is in part related to the duration of chronic HBV infection (36). In other words, the latency period between acute infection and HCC is probably independent of the age of initial exposure. We used in our model the same latency for the different age groups. The sensitivity analysis shows that, even with a latency period of 20 years used for children, their cost per year of life saved would be less than that of adults, with a latency of 10 years.
The availability of a treatment that can limit the progression of chronic hepatitis B to cirrhosis and HCC when given early and our finding that this therapy is cost effective underscore the fact that early detection of chronic hepatitis caused by HBV may be critical. Our data suggest that this would lead to additional savings in health expenditures. Formal evaluation of the cost effectiveness of such a “screening” program should be considered.
In conclusion, IFN is cost effective if current assumptions of protection from the complications of CAH B are confirmed. It is more cost effective to treat toddlers because of the lower dose of IFN required, the greater number of years of life saved, and the added prevention of secondary infection by conversion of HBsAg carriers.
Acknowledgment: We thank Ms. Kelli Thompson for her patience and her help in preparing the manuscript.
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Keywords:© Lippincott-Raven Publishers
α-Interferon; Chronic active hepatitis B; Cost-benefit analysis; Children