Cost-effectiveness of human T-cell leukemia virus type 1 (HTLV-1) antenatal screening for prevention of mother-to-child transmission.

Human T-cell leukemia virus type 1 (HTLV-1) is a carcinogenic retrovirus that causes adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM/TSP), an unremitting and progressive neurological disorder that presents with spastic paraparesis, neurogenic bladder, sphincter dysfunction, and mild sensory disturbance in the lower extremities. These diseases develop after a long incubation period and have a poor prognosis [ 1 – 4 ]. An estimated 5 to 10 million people worldwide are infected with HTLV-1 although data are missing or sparse for up to 6/7th of the global population, based on published seroprevalence rates [ 5 , 6 ]. The regions of HTLV-1 high prevalence are limited to the Southwestern part of Japan, sub-Saharan Africa and South America, the Caribbean area, and foci in the Middle East and Australia-Melanesia [ 5 ]. HTLV-1 is transmitted vertically from mother to child through breastfeeding, horizontally through sexual intercourse, and through direct contact via blood [ 7 – 9 ]. HTLV-1 antibody screening for blood donors has been implemented in Australia, Canada, Brazil, Japan, the United Kingdom, Latin America, the Caribbean, and Europe to reduce the risk of HTLV-1 infection through blood product transfusions [ 10 – 14 ]. Japan is the highest-endemic country in the world, where at least 1 million people are estimated to be HTLV-1 carriers [ 5 , 8 , 9 ]. The HTLV-1 epidemic area used to be limited to the southern islands of Kyushu and Okinawa, but has recently spread to non-endemic metropolitan areas such as Tokyo and Osaka due to domestic migration [ 15 ]. More than 2,800 new cases of HTLV-1 infection are estimated annually in Japan [ 16 ]. The number of deaths due to ATL remains close to 1,000 per year [ 9 , 15 ]. Laboratory screening for HTLV-1 infection has been routine practice for blood donors since 1986. The ATL Prevention Program in Nagasaki from 1987 to 2004 revealed a marked reduction of HTLV-1 mother-to-child transmission by withholding breastfeeding for carrier mothers and has recommended avoiding breastfeeding as the most reliable method for mother-to-child transmission prevention [ 17 ]. Japan is the first and only country in the world that has implemented nationwide HTLV-1 antenatal screening since 2011 to prevent mother-to-child transmission of HTLV-1 infection [ 18 ]. Withholding breastfeeding for mothers with positive HTLV-1 antibody tests at HTLV-1 antenatal screening can reduce the rate of mother-to-child transmission of HTLV-1 from 20.3% for long-term breastfeeding (≧6 months) and 7.4% for short-term breastfeeding (<6 months) down to 2.5% [ 7 ]. The Japanese guidelines for obstetrical practice by the Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists recommend that all pregnant women from early to mid-term pregnancy, up to about 30 weeks gestation, receive a screening test for HTLV-1 antibodies by particle agglutination or chemiluminescence immunoassay (CLIA) and a confirmatory test by line-blot assay (LIA) or PCR qualitative test [ 19 ]. Recently the maternal HTLV-1 seropositivity rate has been gradually decreasing [ 8 , 20 ]. Cost-effectiveness regarding HTLV-1 antenatal screening warrants evaluation as a national infection control policy for HTLV-1. This study aimed to assess the cost-effectiveness and health impact of HTLV-1 antenatal screening compared with no screening.

HTLV-1 antenatal screening (US$76.85, 24.94766 QALYs, ICER; US$40,100 per QALY gained, 24.94813 LYs, ICER; US$1,245,303 per LY gained) was cost-effective compared to no screening (US$2.18, 24.94580 QALYs, 24.94807 LYs) ( Table 2 ). HTLV-1, human T cell leukemia virus 1; QALY, quality-adjusted life-year; LY, life expectancy life-year; ICER, incremental cost-effectiveness ratio ICER tornado diagram showed that HTLV-1 antenatal screening is cost-effective compared with no screening at a WTP threshold of US$50,000 per QALY gained when the maternal HTLV-1 seropositivity rate is greater than 0.0022, HTLV-1 transmission rate with long-term breastfeeding from HTLV-1 seropositive mothers to children is greater than 0.154, HTLV-1 transmission rate with short-term breastfeeding from HTLV-1 seropositive mothers to children is greater than 0.043, HTLV-1 transmission rate with bottle feeding from HTLV-1 seropositive mothers to children is lower than 0.044, the health utility value of HTLV-1 carriers is lower than 0.77, and the cost of HTLV-1 antibody test is lower than US$94.8 ( Fig 2 ). The two-way sensitivity analysis revealed that HTLV-1 antenatal screening is more cost-effective the higher the maternal HTLV-1 seropositivity rate and the higher the proportion of long-term breastfeeding ( Fig 3 ). In the probabilistic sensitivity analysis using a second-order Monte-Carlo simulation for 1000 trials, the acceptability curve showed that HTLV-1 antenatal screening is 81.1% cost-effective at a WTP threshold of US$50,000 per QALY gained ( Fig 4 ). The incremental cost-effectiveness scatterplot showed that HTLV-1 antenatal screening is dominant for 811 trials to no screening in 1000 trials at a WTP threshold of US$50,000 per QALY gained ( Fig 5 ). HTLV-1 antenatal screening is cost-effective compared with no screening at a WTP threshold of US$50,000 per QALY gained when the maternal HTLV-1 seropositivity rate is greater than 0.0022, HTLV-1 transmission rate with long-term breastfeeding from HTLV-1 seropositive mothers to children is greater than 0.154, HTLV-1 transmission rate with short-term breastfeeding from HTLV-1 seropositive mothers to children is greater than 0.043, HTLV-1 transmission rate with bottle feeding from HTLV-1 seropositive mothers to children is lower than 0.044, the health utility value of HTLV-1 carriers is lower than 0.77, and the cost of HTLV-1 antibody test is lower than US$94.8. ICER, incremental cost-effectiveness ratio; WTP, willingness-to-pay; QALY, quality-adjusted life-year; HTLV-1, human T cell leukemia virus 1; ATL, adult T-cell leukemia-lymphoma; HAM/TSP, HTLV-1-associated myelopathy-tropical spastic paraparesis. HTLV-1 antenatal screening is optimal in the blue region which includes the base-case result (x). No screening is optimal in the orchid region. This figure shows that HTLV-1 antenatal screening is more cost-effective the higher the maternal HTLV-1 seropositivity rate and the higher the proportion of long-term breastfeeding. WTP, willingness-to-pay; HTLV-1, human T cell leukemia virus 1. The probabilistic sensitivity analysis analyzes 1000 simulations of the model in which input parameters are randomly varied across pre-specified statistical distributions. The x-axis represents the WTP threshold. The acceptability curve showed that HTLV-1 antenatal screening is 81.1% cost-effective at a WTP threshold of US$50,000 per QALY gained. CE, cost-effectiveness; QALY, quality-adjusted life-year; WTP, willingness-to-pay; HTLV-1, human T cell leukemia virus 1. Each dot represents a single simulation for a total of 1000 simulations. The ICE scatterplot showed that HTLV-1 antenatal screening is dominant in 811 trials to no screening in 1000 trials. ICE, incremental cost-effectiveness; QALY, quality-adjusted life-year; WTP, willingness-to-pay; HTLV-1, human T cell leukemia virus 1. For 10,517,942 individuals born between 2011 and 2021, HTLV-1 antenatal screening costs US$785 million, increases 19,586 QALYs and 631 LYs, and prevents 125,421 HTLV-1 carriers, 4,405 ATL cases, 67 HAM/TSP cases, 3,035 ATL-associated deaths, and 60 HAM/TSP-associated deaths, compared with no screening over a lifetime ( Table 3 ). HTLV-1, human T cell leukemia virus 1; QALY, quality-adjusted life-year; LY, life expectancy life-year; ATL, Adult T-cell leukemia-lymphoma; HAM/TSP, HTLV-1-associated myelopathy-tropical spastic paraparesis *Between 2011 and 2021, 10,517,942 babies were born in Japan.

This study demonstrated that HTLV-1 antenatal screening is cost-effective and has the potential to reduce ATL and HAM/TSP morbidity and mortality in Japan. The findings strongly support the recommendation for HTLV-1 antenatal screening as a national infection control policy in HTLV-1 high-prevalence countries.

A state-transition model was developed for two intervention strategies: HTLV-1 antenatal screening and no screening. Decision branches were directly connected to one Markov node per intervention strategy and the first event was modeled in a Markov cycle tree. The cycle length was set to one year. A half-cycle correction was applied. Incremental cost-effectiveness ratios (ICERs) were calculated and compared to a willingness-to-pay (WTP) threshold of US$50,000 per quality-adjusted life-year (QALY) gained [ 21 , 22 ]. A hypothetical cohort of 30-year-old individuals born to mothers who had or had not received HTLV-1 antenatal screening was targeted from a healthcare payer perspective with a lifetime horizon. The main outcome measures were costs, QALYs, life expectancy life-years (LYs), ICERs, HTLV-1 carriers, ATL cases, HAM/TSP cases, ATL-associated deaths, and HAM/TSP-associated deaths. The model was constructed using TreeAge Pro 2022 (TreeAge Software Inc., Williamstown, Massachusetts). As this was a modeling study with all inputs and parameters derived from the published literature and Japanese statistics, ethics approval was not required. For individuals born to mothers with positive HTLV-1 antibody tests at HTLV-1 antenatal screening, withholding breastfeeding reduces the probability of mother-to-child transmission of HTLV-1 from 20.3% for long-term breastfeeding and 7.4% for short-term breastfeeding to 2.5% [ 7 ]. Individuals born to mothers with negative HTLV-1 antibody tests have no restrictions on breastfeeding. Children infected with HTLV-1 from their mothers become HTLV-1 carriers. HTLV-1 carriers develop ATL and HAM/TSP depending on the incidence of each disease [ 23 , 24 ]. There are five clinical subtypes of ATL: acute, lymphoma, unfavorable chronic, favorable chronic, and smoldering [ 1 ]. Treatment of ATL patients depends on the subtype of ATL. Patients with the aggressive ATL subtypes, acute, lymphoma, and unfavorable chronic types of ATL, receive standard treatment followed by the Japanese practical guidelines for hematological malignancies and the literature [ 2 , 25 ]. Treatment of aggressive ATL subtypes includes allogeneic stem cell transplantation, the only curative therapy available [ 25 ]. 44.6% of patients with favorable chronic-type ATL progress to acute-type ATL, and 60% of patients with smoldering-type ATL progress to acute-type ATL [ 26 , 27 ]. Patients with HAM/TSP receive standard treatment followed by the Japanese practical guidelines for HAM [ 24 ]. In individuals born to mothers with positive HTLV-1 antibody tests, the probability of being infected with HTLV-1 through breastfeeding is 20.3% for long-term breastfeeding, 7.4% for short-term breastfeeding, and 2.5% for bottle feeding, making them HTLV-1 carriers. Patients with ATL and HAM/TSP receive treatment according to the Japanese practical guidelines for each disease. Clinical probabilities were collected using MEDLINE from 2000 to December 2022 ( Table 1 ). To obtain maternal HTLV-1 seropositivity, I assumed the maternal age to be 30 years, which is the average age of first-time pregnant women in Japan [ 9 ]. I obtained the maternal HTLV-1 seropositivity rate, HTLV-1 mother-to-child transmission rates with long-term breastfeeding, short-term breastfeeding, and bottle feeding, the incidence of ATL and HAM/TSP in HTLV-1 carriers, the proportion of ATL subtypes in ATL patients, transformation rate from HAM/TSP to ATL, transformation rate from favorable chronic-type and smoldering-type ATL to acute-type ATL, the 4-year survival rates for acute-type and unfavorable chronic-type ATL patients, and the mortality of favorable chronic-type and smoldering-type ATL and HAM/TSP from the literature and Japanese cancer statistics [ 1 , 3 , 4 , 7 , 8 , 23 , 24 , 26 , 27 , 28 , 29 ]. The mortality from other causes was calculated by the adjusted risk of death due to any cause in people with HTLV-1 infection when compared with HTLV-1-negative counterparts [ 30 ] and the values obtained from vital statistics [ 31 ]. HTLV-1, human T cell leukemia virus 1; ATL, Adult T-cell leukemia-lymphoma; HAM/TSP, HTLV-1-associated myelopathy-tropical spastic paraparesis; N/A, not applicable * Breastfeeding includes a mixture of breastfeeding and bottle feeding. Costs were calculated based on the Japanese medical fee schedule [ 32 ] and adjusted to 2021 Japanese yen, using the medical care component of the Japanese consumer price index and converted to 2021 US dollars, using the Organisation for Economic Co-operation and Development (OECD) purchasing power parity rate (US$1 = ¥96.76) ( Table 1 ) [ 33 ]. All direct costs were based on a healthcare payer perspective. The cost of the HTLV-1 antibody test was calculated based on the Japanese national fee schedule and medical insurance reimbursement table. The cost consisted of the antibody test by chemiluminescence immunoassay (CLIA) method, the confirmation test by line-blot assay (LIA) method [ 34 ], and the immunological test decision fee. Treatment costs for ATL, HAM/TSP, and allogeneic stem cell transplantation were calculated according to the Japanese practical guidelines for hematological malignancies and HAM [ 2 , 24 , 25 , 32 ]. All costs were discounted by 3% [ 35 , 36 ]. Health status was included to represent nine possible clinical states: (i) HTLV-1 uninfected state, (ii) HTLV-1 carrier, (iii) acute-type ATL, (iv) lymphoma-type ATL, (v) unfavorable chronic-type ATL, (vi) favorable chronic-type ATL, (vii) smoldering-type ATL, (viii) HAM/TSP, and (ix) death ( Fig 1 ). Health state utilities were obtained from the literature [ 37 , 38 , 39 ] and were calculated using utility weights with values ranging from 1 (healthy) to 0 (death) ( Table 1 ). The annual discounting of health state utilities was set at a rate of 3% [ 35 , 36 ]. The health states in the model are shown to be oval. In a yearly model cycle, transition paths occur between the health states and other health states, as represented by the arrows. HTLV-1, human T-cell leukemia virus type 1; ATL, adult T-cell leukemia-lymphoma; HAM/TSP, HTLV-1-associated myelopathy-tropical spastic paraparesis. To determine which strategy would be more cost-effective if one variable was tested over the widest possible range, holding all other variables constant, one-way sensitivity analyses were conducted on variables such as the maternal HTLV-1 seropositivity rate, the incidence of ATL and HAM/TSP among HTLV-1 carriers, the mortality of ATL and HAM/TSP, the cost of HTLV-1 antibody test, treatment cost of ATL and HAM/TSP, and health utilities ( Table 1 ). A two-way sensitivity analysis was conducted on the maternal HTLV-1 seropositivity rate and the proportion of long-term breastfeeding. To assess the impact of model uncertainty on the base case estimates, the probabilistic sensitivity analysis using a second-order Monte-Carlo simulation over 1000 trials was also performed. The uncertainty had a beta distribution for probability and accuracy, and a gamma distribution for cost. The Markov cohort analyses determined the cumulative lifetime probability of ATL cases and deaths, HAM/TSP cases and deaths, and HTLV-1 carriers in HTLV-1 antenatal screening and no screening. The cumulative lifetime number of ATL cases and deaths, HAM/TSP cases and deaths, and HTLV-1 carriers were obtained by multiplying the cumulative lifetime probabilities of the two strategies by the total number of births from 2011 to 2021 (10,517,942) [ 31 ].