Hepatitis B virus is a major global health concern, with prevalence rates as high as 10–15% in some regions of the world.1,2 Even in the United States, which overall is a low-prevalence region (less than 2%),2 certain immigrant populations have much higher rates, reflective of their countries of origin.2,3 Perinatal transmission is an important cause of chronic hepatitis B, accounting for 35–50% of the disease in endemic countries.4 Whereas adults infected with hepatitis B virus infections have less than a 5% chance of developing chronic infection, 90% of perinatally infected children become chronic carriers.5–9 Chronically infected individuals are at high risk for cirrhosis and hepatocellular carcinoma. Approximately 25% of chronic hepatitis B carriers die prematurely as a result of one or both of these complications,2 and this rate may be up to 40% for perinatally infected individuals.10
Currently recommended active-passive immunoprophylaxis for all newborns of women positive for hepatitis B surface antigen is 85–95% effective in preventing perinatal transmission.11 However, multiple studies have shown that women with high levels of viral replication remain at elevated risk. Perinatal transmission rates despite appropriate neonatal prophylaxis in these highest-risk women have been reported to be 13–62.5%,12–19 with most estimates between 15% and 30%. The transition point in maternal viral load at which transmission rates begin to rise dramatically is approximately 106–108 copies/mL.12,13,16
A significant proportion of perinatal transmission in women with high viral loads is now believed to be intrauterine.13,14,17,20–22 Therefore, studies have been conducted to evaluate the benefit of maternal administration of either lamivudine or hepatitis B immune globulin (HBIG) in the third trimester to decrease transmission rates. Most of these studies have been in Asia, and the results have been promising. In 2010, Shi et al published two meta-analyses on the use of third-trimester maternal lamivudine or HBIG in women with high viral loads.18,19 These meta-analyses found a 69% and 67% reduction in infant hepatitis B surface antigen positivity at age 9–12 months with the use of lamivudine and HBIG, respectively. Despite this evidence, use of these agents to reduce perinatal hepatitis B virus transmission is not standard of care in the United States. Our objective was to estimate the cost-effectiveness of maternal treatment with lamivudine or HBIG.
MATERIALS AND METHODS
We created a decision-tree model to estimate the cost-effectiveness of maternal administration of lamivudine or HBIG in the third trimester to prevent perinatal hepatitis B transmission compared with no maternal treatment (Fig. 1). The decision tree was created and run using Microsoft Excel 2008 12.2.3. This project was not submitted to our institutional review board, as all data used were extracted from published studies, and no institutional or individual patient information is included in this analysis. The Medical University of South Carolina Office of Research Integrity states that a study of this kind is not considered to be human subjects research and thus does not require University IRB approval.
Our baseline assumptions are outlined in Table 1. The overall perinatal hepatitis B transmission rate without maternal treatment (15.7%) was obtained by averaging the transmission rates in the control groups from two recent meta-analyses, one on lamivudine and the other on HBIG, both by Shi et al.18,19 Both meta-analyses included randomized controlled trials of maternal lamivudine or HBIG compared with no maternal treatment, in English language or Chinese peer-reviewed literature. Transmission rates without treatment stratified by maternal viral load were taken from a study by Yuan et al.12 The odds ratios for perinatal transmission with maternal treatment compared with no treatment (0.31 and 0.33 for lamivudine and HBIG, respectively) were taken from the meta-analyses18,19 and applied to the averaged transmission rate without maternal treatment to obtain transmission rates with treatment (4.9% and 5.2% for lamivudine and HBIG, respectively). These numbers were all based on infant hepatitis B surface antigen positivity at age 9–12 months. We also used the odds ratios for perinatal transmission from the two meta-analyses18,19 and applied those numbers to transmission rates without treatment by maternal viral load to estimate the cost-effectiveness of treatment stratified by maternal viral load.
We assumed that 90% of infants infected perinatally would become chronic carriers.5–9 Because perinatal transmission rates are very low in women with low viral loads16 and thus additional treatment with lamivudine or HBIG is most beneficial in patients with high viral activity, we made the assumption that maternal hepatitis B virus DNA viral load would be assessed before initiating third-trimester maternal treatment.
We assumed 100% compliance with current recommendations for active-passive immunoprophylaxis (HBIG and vaccination) for all newborns of women positive for hepatitis B surface antigen. Thus our model applies the current standard of immunoprophylaxis to both groups. We assumed maternal dosing regimens of lamivudine 100 mg orally once daily from 28 weeks of gestation through 4 weeks postdelivery and HBIG 200 international units administered intramuscularly once monthly starting at 28 weeks of gestation, as these have been the most commonly studied regimens. Costs for lamivudine and HBIG were taken from the 2010 Red Book.23 The model also assumes no maternal or fetal risk from third-trimester use of lamivudine or HBIG.
The model was designed to estimate the lifelong medical costs of chronic hepatitis B infection from a health systems perspective. Life expectancy in patients with chronic hepatitis B was taken from 2006–2007 Florida State hospital discharge data, and life expectancy in a general population was taken from 2007 National Vital Statistics data.24,25 The lifelong cost of chronic hepatitis B infection was calculated based on published yearly costs by different hepatitis B health states defined from a health systems perspective,26 using previous studies to determine the number of patients who would progress to compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, hepatic transplant, or a combination of these over a lifetime.27–34 We assumed that all hepatocellular carcinoma cases arose in the setting of cirrhosis. Because the lifelong natural history of perinatal hepatitis B virus infection is not well described, we derived most of these assumptions from the literature on chronic hepatitis B in general, rather than literature specific to perinatally transmitted chronic hepatitis B. Although serious childhood complications do occur, most perinatally infected children do not experience significant complications until adulthood.35,36 For the model, we made the conservative assumption that no medical complications and therefore no costs accrue until age 20. Cost calculations are outlined in Tables 2 and 3.
A sensitivity analysis was then performed by varying the estimates for degree of reduction in perinatal transmission with maternal treatment, medical severity of chronic hepatitis B infection, and lifelong cost of chronic hepatitis B. We also varied the percentage of women who would warrant treatment after viral load determination, to evaluate the cost of checking viral loads in all patients to determine need for treatment in some.
Because HBIG and lamivudine are hypothesized to have different mechanisms of action in reducing perinatal hepatitis B transmission, it has been suggested that additive benefit may be expected if both HBIG and lamivudine are administered in combination.20 To our knowledge, this hypothesis has not been evaluated in prospective studies. To evaluate whether this strategy would be cost-effective, we estimated a model using both HBIG and lamivudine in combination, assuming varying levels of additional benefit in reducing perinatal hepatitis B transmission.
Using our base-case estimates, use of either lamivudine or HBIG was not only cost-effective, but also cost-saving, for all situations except lamivudine at a maternal viral load of less than 108 copies/mL. For every 100 pregnant women positive for hepatitis B surface antigen treated with lamivudine, 9.7 cases of chronic hepatitis B virus infections are prevented, with a cost-savings of $5,184 and 1.3 life-years gained per patient treated. For HBIG, 9.5 cases of chronic hepatitis B virus infections are prevented for each 100 pregnant women treated, with a cost savings of $5,887 and 1.2 life-years gained per patient treated. The only instance in which no cost savings was achieved (lamivudine at a maternal viral load of less than 108 copies/mL) had a cost per patient of $390 to prevent two cases of chronic hepatitis B virus infections for each 100 patients treated, well within the limits of what is commonly considered to be cost-effective. For each of the other cases considered, use of lamivudine or HBIG provided a cost savings, in addition to preventing chronic hepatitis B and its sequelae. Detailed results for the base-case estimates are outlined in Table 4.
One-way and multi-way sensitivity analyses were performed by altering estimates for the percentage of women whose viral load would warrant treatment (ie, the cost of checking viral loads in all women to determine need for maternal treatment in some), the degree of reduction in perinatal transmission with maternal treatment, the medical severity and life expectancy in chronic hepatitis B infection, and lifelong cost of chronic hepatitis B. The results are summarized in Table 5.
Adjustment of parameters related to percentage of chronic hepatitis B patients developing cirrhosis, decompensated cirrhosis, or hepatocellular carcinoma had modest effects on lifetime cost of chronic hepatitis B infection. Altering these parameters yielded a lowest lifetime cost of $72,045 and highest lifetime cost of $74,600. If both life expectancy (ranging from 50 years to 64.9 years) and distribution of chronic hepatitis B health states were altered, the lowest lifetime cost was $64,295 and highest was $74,600.
Altering the proportion of women who would have a viral load drawn, but not warrant maternal treatment, was also evaluated in the sensitivity analysis. The base-case estimates assumed that all women having a third-trimester viral load would be treated with lamivudine or HBIG. Because most experts recommend reserving third-trimester maternal treatment for women at highest risk of perinatal transmission from high viral activity, all women would need to have a viral load drawn to determine need for treatment. The proportion of women with viral loads high enough to warrant treatment would vary by population. Even if only 10% of women qualified for third-trimester maternal treatment based on high viral loads, one-way sensitivity analysis demonstrates that this strategy remains cost-saving for both lamivudine and HBIG.
The parameter most sensitive to changes in baseline estimates was the degree of reduction in perinatal transmission with treatment. One-way sensitivity analysis for lamivudine showed that for a baseline transmission rate without treatment of 15.7%,18 if the risk reduction with treatment is at least 18.5% (ie, from 15.7% to 12.8%), this strategy remains cost-saving. For HBIG, using the baseline transmission rate without treatment of 15.7%, treatment remains cost-saving if the reduction in perinatal transmission is at least 9.6% (ie, from 15.7% to 14.2%). When two-way sensitivity analysis was performed, as long as the degree of risk reduction was at least 39.5% for lamivudine and at least 30.6% for HBIG, treatment remained cost-saving even if only 10% of women tested with a third-trimester viral load warrant treatment.
When combination therapy of HBIG and lamivudine was evaluated using baseline estimates, this strategy remained cost-saving even if the degree of reduction was only 1% more than with either lamivudine or HBIG alone. Assuming a baseline transmission rate without treatment of 15.7%, and a reduction in transmission of 70% (compared with 69% for lamivudine), the cost savings are $2,278 per patient treated. If only 10% of patients in whom a viral load is drawn warrant treatment, using lamivudine and HBIG in combination remains cost-saving with $1,225 saved per patient treated.
Despite evidence of benefit, use of lamivudine or HBIG to reduce perinatal transmission of hepatitis B virus is not common practice in the United States. Our analysis demonstrates that adoption of maternal third-trimester treatment with either agent in women with high viral loads would be not only cost-effective, but also cost-saving.
Perinatal transmission of hepatitis B is uncommon in women with low viral loads, with some series even reporting no cases of transmission in women with viral loads less than 105 copies/mL.12,16 However, the literature is consistent in revealing a dramatic rise in perinatal transmission, despite appropriate neonatal prophylaxis, beginning at maternal viral loads around 106–108 copies/mL.12,13,16 The transmission rates range from 5% to 13% between 106 and 107 copies/mL, and rise to the 40–50% range in women with viral loads of 108 copies/mL or higher.12,13
Our model does have limitations. The model assumes no significant maternal or fetal risk from lamivudine or HBIG. Based on currently available data, this is a reasonable assumption, but potential concerns remain. Studies in both pregnant and nonpregnant patients show that short courses of lamivudine (12–16 weeks) are well tolerated and safe.18,37 Because a strategy of lamivudine to prevent perinatal transmission would not be initiated until the third trimester, birth defects should not be a concern, although data regarding teratogenesis are also reassuring.38 One serious theoretical concern regarding use of lamivudine is development of resistance. Long-term lamivudine use is associated with high rates of resistance: 12.8% after 1 year and 76% with 5 or more years of use.39,40 Resistance has not been reported to be an issue after short-term use of lamivudine in pregnancy for perinatal transmission prevention, but it remains a theoretical concern.
Another potential concern is postpartum flare of disease activity in hepatitis B virus–positive women treated with lamivudine. In one Dutch study,41 against a historical background flare rate of 10–27% per year, 36% of women not treated with lamivudine experienced a flare (3-fold increase in alanine aminotransferase) in the 6 months after delivery. Among women treated with lamivudine, this incidence was 62%. This study was retrospective, and the women in the lamivudine group were at greater risk of postpartum flares by virtue of higher disease activity. Nonetheless, withdrawal flares are known to occur in 17–25% of nonpregnant individuals after cessation of lamivudine therapy,42,43 and this risk will likely need to be evaluated in a prospective fashion in women treated to prevent perinatal transmission. The women in the study described above41 stopped lamivudine immediately after delivery, and the now more common regimen of continuing therapy until 4 weeks postpartum may provide some protection from posttreatment flare.
With regard to HBIG, its safety profile is also good. There has been no reported increase in hepatitis B virus mutation among infected newborns of mothers treated with HBIG.19 However, because HBIG is made from human plasma, there is a small theoretical risk of infectious disease transmission, and anaphylactic reactions are also theoretically possible. Significant adverse effects have not been reported in studies administering HBIG to pregnant women.19
An additional limitation of our model is that the lifelong history of congenitally acquired chronic hepatitis B is not clearly defined in the literature. We therefore used studies of chronic hepatitis B in general to derive our assumptions for prognosis and life expectancy. Because it is believed that perinatal transmission may lead to earlier onset of severe hepatic sequelae, our use of the general literature on chronic hepatitis B would, if anything, lead to more conservative conclusions. Likewise, we also made the conservative assumption that congenitally infected children would not have serious sequelae, and thus not accrue cost, until age 20. In fact, children with chronic hepatitis B do require periodic monitoring of their disease,44 and there can be rare serious sequelae during childhood.35,36 The costs of this surveillance were not included in our analysis. Again, the omission of these costs from our model would only underestimate cost savings from prevention of perinatal hepatitis B virus transmission.
Although our results are subject to the above limitations as well as the inherent limitations of cost-effectiveness analyses, our analysis demonstrates impressive cost savings across a wide range of assumptions. Based on our findings and the current literature demonstrating a consistent rise in perinatal transmission beginning at maternal viral loads around 106 copies/mL despite appropriate neonatal immunoprophylaxis,12,13,16 we recommend screening women positive for hepatitis B surface antigen at 24–28 weeks of gestation and initiating prophylaxis with either lamivudine or HBIG if the viral load is at least 106 copies/mL. Maternal prophylaxis to prevent perinatal hepatitis B virus transmission is both medically beneficial and cost-saving, and this strategy should be strongly considered in the United States.
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