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).
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.
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