Chronic hepatitis B virus (HBV) infection is a serious public health problem in China that affects ∼93 million people (7.18% of the population), representing a quarter of all HBV-infected people worldwide (
The predominant mode of HBV infection involves perinatal transmission from chronically infected mothers to their infants (
Despite these encouraging results, a proportion of infants still test positive for the HBsAg (
Decision analysis software (TreeAge Pro 2012: TreeAge Software Inc., Williamstown, MA, USA) was used to estimate the clinical and economic outcomes for a hypothetical cohort of 10,000 pregnant Chinese women chronically infected with HBV. All women were considered positive for HBeAg with serum levels of HBV-DNA >6 log10 copies/mL. The following four strategies were compared: (1) postnatal IP for the infants only; (2) perinatal LAM and postnatal IP (LAM + IP); (3) perinatal LdT and postnatal IP (LdT + IP); and (4) perinatal TDF and postnatal IP (TDF + IP) (
HBIG, hepatitis B immunoglobulin; IP, immunoprophylaxis; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir.
If infants were infected by HBV, their lifetime clinical and economic outcomes were simulated using a Markov model based on a previous study (
A systematic review and network meta-analysis were performed to calculate odds ratios (ORs) for perinatal transmission of HBV; see
Variable | Base case | Range | Ref. |
---|---|---|---|
Probability of perinatal hepatitis B transmission with IP | 11.7% | 2.8–42.3% | |
Relative risk of perinatal hepatitis B transmission | |||
Vaccination |
1.85 | 1.37–2.44 | |
LAM + IP |
0.23 | 0.13–0.41 | |
LdT + IP |
0.56 | 0.25–1 |
|
TDF + IP |
1 | 0.5–1 | |
Compliance rate of IP | 44.0% | 37.6–86.0% | |
Adherence to antiviral treatment during pregnancy | 98.4% | 80.0–100% | |
Natural history parameters | |||
Normal ALT to elevated ALT | 0.2% | 0.1–0.2% | |
Normal ALT to HCC | 0.3% | 0.2–0.5% | |
Chronic HBV with elevated ALT to compensated cirrhosis | 3.8% | 0.5–12.3% | |
Chronic HBV with elevated ALT to HCC | 1.5% | 0.5–9.5% | |
Durable virologic response while on treatment | 15.0% | 5.0–30.0% | |
Receiving treatment with durable response | 50.0% | 0.0–100% | |
Durable response relapse to elevated ALT | 7.0% | 2.0–15.0% | |
Durable response relapse to HCC | 0.3% | 0.2–0.5% | |
Compensated to decompensated cirrhosis | 7.0% | 3.0–10.0% | |
Mortality from compensated cirrhosis | 4.8% | 2.0–13.1% | |
Mortality from decompensated cirrhosis | 17.3% | 5.8–22.1% | |
Cirrhosis to HCC | 3.3% | 1.0–11.3% | |
Liver transplantation for decompensated cirrhosis | 1.5% | 0.0–40.0% | |
Mortality from HCC | 40.0% | 32.0–47.3% | |
Liver transplantation for HCC | 0.1% | 0.0–40.0% | |
Mortality first year after liver transplantation | 15.0% | 7.5–30.0% | |
Mortality second and subsequent years after liver transplantation | 1.5% | 0.8–3.0% | |
Health-state utility weights for quality of life adjustments | |||
Normal ALT | 1.00 | 0.95–1.00 | |
Elevated ALT | 0.99 | 0.90–1.00 | |
Durable response | 1.00 | 0.90–1.00 | |
Compensated cirrhosis | 0.80 | 0.70–0.93 | |
Decompensated cirrhosis | 0.60 | 0.50–0.70 | |
HCC | 0.73 | 0.50–0.80 | |
Liver transplantation | 0.86 | 0.70–0.90 |
alanine aminotransferase hepatitis B virus hepatocellular carcinoma immunoprophylaxis lamivudine telbivudine tenofovir
Prevention efficacy of LAM was assumed to not be superior to LdT.
The reported ORs of HBV transmission were 0.21 (95% CI [0.12–0.38]) for LAM + IP versus IP, and 0.55 (95% CI [0.24–1.29]) for LdT + IP versus LAM + IP. The corresponding relative risks (RRs) of HBV transmission were then calculated using the formula:
Although IP is the current recommendation in China to interrupt perinatal hepatitis B transmission, (
The high reported adherence to antiviral treatment in pregnant mothers (
Under the National Immunization Program, free HBV vaccinations are available to all Chinese infants, covering 97.6% of infants born from HBsAg-positive mothers in 2009 (
We obtained from a published study the natural history estimates of chronic HBV infection and health-state utility weights for calculating quality-adjusted life years (QALYs) (
For cost analyses, the costs of HBV-marker tests (inclusive of HBeAg and HBsAg tests), HBV-DNA quantification, antiviral drugs, vaccination, and HBIG were included. The actual cost of HBV-DNA quantification for one mother who is going to receive antiviral treatment was calculated as
The costs of vaccination and HBIG were obtained from published studies, (
All cost estimates were converted to US Dollars according to the 2013 conversion rate (1 US Dollar = 6.13 Chinese Yuan) using the medical care component of the Consumer Price Index and discounting costs and QALYs to 2013 amounts at a rate of 3% per year (
Variable | Base case (USD) | Range (USD) | Ref. |
---|---|---|---|
Hepatitis B vaccination, three times | $3.0 | $1.5–6.0 | |
Hepatitis B immunoglobulin administration | $40.0 | $20.0–80.0 | |
LAM, daily |
$2.5 | $1.3–5.0 | |
LdT, daily |
$3.6 | $1.8–7.2 | |
TDF, daily |
$8.7 | $4.4–17.4 | |
Ratio of proportion of mothers with <6 to>6 log10 copies/mL HBV-DNA | 0.136 | 0.068–0.273 | |
HBV-DNA quantification | $16.3 | $8.2–32.6 | |
HBV-marker test | $3.3 | $1.6–6.6 | |
Chronic hepatitis B, annual |
$1,780 | $890–3,560 | |
Compensated cirrhosis, annual | $2,759 | $1,380–5,518 | |
Decompensated cirrhosis, annual | $5,130 | $2,565–10,260 | |
Hepatocellular carcinoma, annual | $7,302 | $3,651–14,604 | |
Liver transplantation, first year | $37,458 | $18,729–74,916 | |
Liver transplantation, second and subsequent years, annual | $3,276 | $1,638–6,552 | |
Discount rate, annual | 3% | 0–5% | – |
hepatitis B virus lamivudine telbivudine tenofovir US Dollar
Administered from week 28 of gestation to 4 weeks after delivery.
50% of patients with durable response were assumed to continue receiving treatment.
Short-term outcomes evaluated clinical and economic outcomes during the period from the initiation of the strategies to 6 months after birth, including the number of infections, incremental infections averted, prophylaxis costs, incremental costs, and the corresponding incremental cost-effectiveness ratio (ICER). Long-term outcomes evaluated lifetime clinical and economic outcomes under four strategies, including HBV-related death, QALYs, incremental QALYs, lifetime costs, incremental lifetime costs, and the corresponding ICER. The ICER was used to compare alternative strategies after eliminating those that were dominated (more costly and less effective). It was calculated as the incremental cost divided by the incremental health benefit (e.g., infections averted and QALYs gained) for one strategy compared to the next less-costly strategy. The cost-effectiveness analyses were conducted from a societal perspective in accordance with the World Health Organization recommendations, and cost-effectiveness thresholds were based on the gross domestic product (GDP) per capita: highly cost-effective (ICER < GDP per capita); cost-effective (GDP per capita < ICER < 3 × GDP per capita); and not cost-effective (ICER > 3 × GDP per capita) (
One- and two-way sensitivity analyses were performed to identify influential clinical and cost-related variables. In addition, a probabilistic sensitivity analysis was conducted based on a second-order Monte Carlo simulation (
Antiviral strategies prevented more perinatal hepatitis B transmissions than IP alone. The fewest number of infections occurred with LdT + IP and TDF + IP (
The area of each rectangle represents the proportion of pregnant women, and the density of dots represents the probability of perinatal transmission of HBV. The unit of HBV-DNA is copies/mL. HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IP, immunoprophylaxis; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir.
Strategy | Infections ( |
Incremental infections averted ( |
Cost (USD) | Incremental cost (USD) | ICER |
---|---|---|---|---|---|
IP | 1,727 | – | $239,000 | – | – |
LAM + IP | 284 | 1,443 | $3,078,568 | $2,839,568 | 1,967 |
LdT + IP | 167 | 117 | $4,147,944 | $1,069,376 | 9,178 |
TDF + IP | 167 | 0 | $9,105,960 | $4,958,016 | – |
incremental cost-effectiveness ratio (US dollars per incremental infection averted) immunoprophylaxis lamivudine telbivudine tenofovir US Dollar
In the long-term, the more effective strategies resulted in fewer instances of hepatocellular carcinoma and HBV-related death, and increased the QALYs (
Strategy | HCC ( |
HBV-related deaths ( |
QALYs | Incremental QALYs | Cost (USD) | Incremental cost (USD) | ICER (95% CI) |
---|---|---|---|---|---|---|---|
IP | 385 | 304 | 292,167 | – | $4,897,077 | – | Dominated |
TDF + IP | 37 | 29 | 295,664 | – | $9,556,428 | – | Dominated |
LAM + IP | 63 | 50 | 295,403 | – | $3,843,301 | – | – |
LdT + IP | 37 | 29 | 295,664 | 261 | $4,598,412 | $755,111 | $2,891 (−$932∼$20,372) |
confidence interval hepatitis B virus hepatocellular carcinoma incremental cost-effectiveness ratio (US Dollar per quality-adjusted life year gained) immunoprophylaxis lamivudine telbivudine quality-adjusted life year tenofovir US Dollar
One-way sensitivity analyses were performed across the ranges of all clinical and cost-related variables. The cost-effectiveness of LdT + IP was only sensitive to one of them, the RR of HBV transmission in comparison to LAM + IP. If the RR is above 0.92, LdT + IP would be not cost-effective.
A two-way sensitivity analysis showed that LdT + IP remains cost-effective even when its cost is doubled and that of LAM halved. When TDF + IP protects more infants than LdT + IP and simultaneously the cost of TDF goes down, TDF + IP may become cost-effective (
Acceptability curves constructed from probabilistic sensitivity analyses showed that LdT + IP was highly cost-effective in 89.8% of the trials under a willingness-to-pay threshold of $6,800, and cost-effective in 83.7% under a threshold of $20,400 (
Chinese gross domestic product per capita was approximately $6,800 in 2013. IP, immunoprophylaxis; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir; USD, US Dollar; QALY, quality-adjusted life year.
Antiviral treatment as prophylaxis for perinatal hepatitis B transmission is recommended in updated guidelines from the European Association for the Study of the Liver, Asian Pacific Association for the Study of the Liver, and the National Institute for Health and Care Excellence (
Implementation of the National Immunization Program that provides HBV vaccinations to all neonates and extends HBIG administration to those whose mothers are infected with HBV has greatly reduced the prevalence of HBV (
From a cost-effectiveness perspective, China will benefit from the use of LAM or LdT antiviral strategies to prevent HBV transmission. Indeed, Chinese hepatologists in tertiary hospitals have been prescribing these agents to pregnant women with chronic HBV infection for several years (
Sensitivity analyses indicate that the tradeoff between the use of LdT and LAM is influenced by the RR of HBV transmission. However, LdT remains more cost-effective than LAM when transmission risk is reduced by >8%. The sensitivity analyses also indicate that more information is needed concerning the efficacy and cost of TDF. It is difficult to determine an added benefit of TDF when studies with large sample sizes show a 100% efficacy with LdT (
There are several important strengths of the current study. This study is the first decision analysis that compares all currently available antiviral agents for the prevention of perinatal transmission of HBV. In the model used for the analyses, the only variables that differed among each antiviral strategy were the prevention efficacy and the cost. Consistent with previous studies, (
There are some limitations of this study that should be mentioned. First, the risk of side effects when using antiviral agents during pregnancy was not considered. However, controlled studies demonstrate that LAM, LdT, or TDF do not increase the number of birth defects or complications (
In conclusion, this cost-effectiveness analysis focusing on pregnant women positive for HBeAg with HBV-DNA > 6 log10 copies/mL suggests that supplemental use of LdT during late pregnancy combined with IP for their infants is cost-effective in China.
Each infant is immune to or chronically infected with hepatitis B virus (HBV). Infected infants reside in of the following states each year: normal alanine aminotransferase (ALT), elevated ALT, durable response, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, or dead (not shown).
The nodes are weighted by sample size and the edges are weighted by the number of studies.
HBV, hepatitis B virus; IP, immunoprophylaxis; LdT, telbivudine; TDF, tenofovir; USD, US Dollar.
TDF cost: $8, $7, $6, $5, $4, and $3.6. Chinese gross domestic product per capita was approximately $6,800 in 2013. IP, immunoprophylaxis; LAM, lamivudine; LdT, telbivudine; TDF, tenofovir; USD, US Dollar; QALY; quality-adjusted life year.
alanine aminotransferase
confidence interval
hepatitis B e antigen
hepatitis B immunoglobulin
hepatitis B surface antigen
hepatitis B virus
incremental cost-effectiveness ratio
immunoprophylaxis
lamivudine
telbivudine
odds ratio
quality-adjusted life year
relative risk
tenofovir
The authors declare there are no competing interests.
The following information was supplied regarding data availability:
The research in this article did not generate any raw data.