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

Akiko Kowada

doi:10.1371/journal.pntd.0011129

. 2023 Feb 21;17(2):e0011129. doi: 10.1371/journal.pntd.0011129

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

Akiko Kowada ^1,^*

Editor: Graham P Taylor²

PMCID: PMC9983854 PMID: 36809372

Abstract

Background

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy-tropical spastic paraparesis (HAM/TSP) with a poor prognosis. This study aimed to evaluate the cost-effectiveness and health impact of HTLV-1 antenatal screening.

Methodology/Principal findings

A state-transition model was developed for HTLV-1 antenatal screening and no screening over a lifetime horizon from a healthcare payer perspective. A hypothetical cohort of 30-year-old individuals was targeted. The main outcomes were costs, quality-adjusted life-years (QALYs), life expectancy life-years (LYs), incremental cost-effectiveness ratios (ICERs), HTLV-1 carriers, ATL cases, HAM/TSP cases, ATL-associated deaths, and HAM/TSP-associated deaths. The willingness-to-pay (WTP) threshold was set at US$50,000 per QALY gained. In the base-case analysis, HTLV-1 antenatal screening (US$76.85, 24.94766 QALYs, 24.94813 LYs, ICER; US$40,100 per QALY gained) was cost-effective compared with no screening (US$2.18, 24.94580 QALYs, 24.94807 LYs). Cost-effectiveness was sensitive to the maternal HTLV-1 seropositivity rate, HTLV-1 transmission rate with long-term breastfeeding from HTLV-1 seropositive mothers to children, and the cost of the HTLV-1 antibody test. HTLV-1 antenatal screening was cost-effective when the maternal HTLV-1 seropositivity rate was greater than 0.0022 and the cost of the HTLV-1 antibody test was lower than US$94.8. Probabilistic sensitivity analysis using a second-order Monte-Carlo simulation showed that HTLV-1 antenatal screening was 81.1% cost-effective at a WTP threshold of US$50,000 per QALY gained. For 10,517,942 individuals born between 2011 and 2021, HTLV-1 antenatal screening costs US$785 million, increases19,586 QALYs and 631 LYs, and prevents 125,421 HTLV-1 carriers, 4,405 ATL cases, 3,035 ATL-associated deaths, 67 HAM/TSP cases, and 60 HAM/TSP-associated deaths, compared with no screening over a lifetime.

Conclusion/Significance

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.

Author summary

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. HTLV-1 is endemic in the Southwestern part of Japan, sub-Saharan Africa, South America, the Caribbean area, foci in the Middle East, and Australia-Melanesia. Based on published seroprevalence rates, which are missing or sparse for up to 6/7th of the global population, an estimated 5 to 10 million people worldwide are infected with HTLV-1. Treatment of ATL and HAM/TSP is very difficult and no vaccine is available. HTLV-1 transmission patterns include mother-to-child transmission through breastfeeding, horizontal transmission through sexual intercourse, and direct contact transmission through blood. HTLV-1 antenatal screening is effective to prevent mother-to-child transmission of HTLV-1. The probability of mother-to-child transmission of HTLV-1 through long-term and short-term breastfeeding can be reduced from 20.3% and 7.4% to 2.5% by withholding breastfeeding. However, Japan is the only country in the world that has implemented HTLV-1 antenatal screening. This study demonstrates that HTLV-1 antenatal screening is cost-effective and has the potential to reduce the number of cases and deaths from ATL and HAM/TSP in HTLV-1 high prevalence countries.

Introduction

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.

Materials and methods

Study design

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.

Model structure

HTLV-1 antenatal screening

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].

No screening

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.

Model inputs

Clinical probability

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].

Table 1. Input parameters of selected variables.

Variable	Baseline value	Sensitivity analysis range	Reference
Probability
Maternal HTLV-1 seropositivity rate	0.0027	0.001–0.004	8
HTLV-1 transmission rate with long-term breastfeeding (≧6 months) from HTLV-1 seropositive mothers to children	0.203	0.1–0.3	7
HTLV-1 transmission rate with short-term breastfeeding (<6 months) from HTLV-1 seropositive mothers to children	0.074	0.02–0.1	7
HTLV-1 transmission rate with bottle feeding from HTLV-1 seropositive mothers to children	0.025	0.001–0.06	7
Proportion of long-term breastfeeding^* (≧6 months)	0.374	0.3–0.5	28,29
Proportion of short-term breastfeeding^* (<6 months)	0.591	0.5–0.7	28,29
Proportion of bottle feeding	0.035	0–0.1	28,29
Annual ATL rate in HTLV-1 carriers	0.000976	0.0005–0.0015	23
Proportion of acute-type ATL in ATL patients	0.508	0.477–0.539	1
Proportion of lymphoma-type ATL in ATL patients	0.249	0.222–0.276	1
Proportion of unfavorable chronic-type ATL in ATL patients	0.094	0.076–0.112	1
Proportion of favorable chronic-type ATL in ATL patients	0.044	0.031–0.057	1
Proportion of smoldering-type ATL in ATL patients	0.105	0.086–0.124	1
Transformation rate from favorable chronic-type ATL to acute-type ATL	0.446	0.4–0.8	26,27
Transformation rate from smoldering-type ATL to acute-type ATL	0.6	0.4–0.8	26,27
HAM/TSP rate in HTLV-1 carriers	0.000033	0.000022–0.000044	24
Transformation rate from HAM/TSP to ATL	0.00381	0.00343–0.00419	3
4-year acute-type ATL survival rate (%)	16.8	6.7–26.9	1
4-year lymphoma-type ATL survival rate (%)	19.6	9.7–29.5	1
4-year unfavorable chronic-type ATL survival rate (%)	26.6	16.8–36.0	1
Mortality of favorable chronic-type and smoldering-type ATL	0.079	0.06–0.12	26,27
Mortality of HAM/TSP	0.024	0.015–0.033	4
Adjusted risk of death due to any cause in people with HTLV-1 when compared with HTLV-1-negative counterparts	1.57	1.37–1.80	30
Cost, US$ (US$1 = ¥ 96.76)
HTLV-1 antibody initial and confirmation test	76.4	57.3–95.5	32,34
Treatment for ATL	108,581	81,436–135,725	2,25,32
Treatment for HAM/TSP	6,700	5,025–8,375	24,32
Utility
HTLV-1 uninfected state	1	0.7–1	37,38,39
HTLV-1 carrier	0.712	0.684–1
Acute-type ATL	0.67	0.58–0.76
Lymphoma-type ATL	0.67	0.58–0.76
Unfavorable chronic-type ATL	0.67	0.58–0.76
Favorable chronic-type ATL	0.69	0.60–0.78
Smoldering-type ATL	0.7	0.61–0.79
HAM/TSP	0.299	0.271–0.327
Death	0	N/A

Open in a new tab

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.

Cost

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 utility

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].

Fig 1 — 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.

Sensitivity analysis

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.

Markov cohort analysis

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].

Results

Base-case analysis

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).

Table 2. Base-case analysis.

Strategy	Cost, US$	Incremental cost, US$	Effectiveness, QALYs	Incremental QALYs	ICER, US$/QALY gained	Effectiveness, LYs	Incremental LYs	ICER, US$/LY gained
No screening	2.18	-	24.94580	-	-	24.94807	-	-
HTLV-1 antenatal screening	76.85	74.67	24.94766	0.00186	40,100	24.94813	0.00006	1,245,303

Open in a new tab

HTLV-1, human T cell leukemia virus 1; QALY, quality-adjusted life-year; LY, life expectancy life-year; ICER, incremental cost-effectiveness ratio

Sensitivity analyses

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).

Fig 2 — 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.

Fig 3 — 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.

Fig 4 — 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.

Fig 5 — 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.

Cumulative lifetime economic and health outcomes

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).

Table 3. Economic and health outcomes of HTLV-1 antenatal screening vs no screening.

Outcome	HTLV-1 antenatal screening		No screening		Difference, HTLV-1 antenatal screening vs no screening
Outcome	Per person	Per 10,517,942 persons^*	Per person	Per 10,517,942 persons^*	Per person	Per 10,517,942 persons^*
Cumulative lifetime cost, US$	76.85	808,322,795	2.18	22,910,660	74.67	785,412,136
Cumulative lifetime QALYs	24.94766	262,398,045	24.94580	262,378,459	0.00186	19,586
Cumulative lifetime LYs	24.94813	262,403,006	24.94807	262,402,375	0.00006	631
Cumulative lifetime HTLV-1 carriers	0.0031206	32,822	0.0150451	158,244	-0.0119245	-125,421
Cumulative lifetime ATL cases	0.0001096	1,153	0.0005284	5,558	-0.0004188	-4,405
Cumulative lifetime ATL-associated deaths	0.0000755	794	0.0003641	3,830	-0.0002886	-3,035
Cumulative lifetime HAM/TSP cases	0.0000017	18	0.0000081	86	-0.0000064	-67
Cumulative lifetime HAM/TSP-associated deaths	0.0000015	16	0.0000072	75	-0.0000057	-60

Open in a new tab

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.

Discussion

This study demonstrated that HTLV-1 antenatal screening is cost-effective compared with no screening in Japan. The main reason for the superior cost-effectiveness of HTLV-1 antenatal screening is that withholding breastfeeding for HTLV-1 seropositive mothers significantly reduces the mother-to-child transmission rate of HTLV-1 infection, resulting in fewer HTLV-1 carriers and subsequently fewer ATL and HAM/TSP cases and deaths.

The study showed that the lifetime per person cost of HTLV-1 antenatal screening was US$74.67 higher than that of no screening. However, further cost savings may be expected in the future by promoting low-cost HTLV-1 antenatal screening through high-volume screening worldwide.

To the best of my knowledge, this is the first modelling study in HTLV-1 high-prevalence countries to evaluate the cost-effectiveness and health impact of HTLV-1 antenatal screening. Malik et al suggested, based on a modelling study, that HTLV-1 antenatal screening meets the cost-efficacy standards in the UK, one of the HTLV-1 low-prevalence countries [40]. This study demonstrated that HTLV-1 antenatal screening is cost-effective in Japan, one of the HTLV-1 high-prevalence countries.

The main HTLV-1 highly endemic regions are localized in the world: the Southwestern part of Japan, sub-Saharan Africa and South America, the Caribbean area, and foci in the Middle East and Australia-Melanesia [5]. Djuicy et al demonstrated that rural adult populations in Gabon are highly endemic to HTLV-1, with an overall prevalence of 8.7% [41]. Paiva et al reported that high maternal HTLV-1 proviral load and breastfeeding beyond 12 months were independently associated with mother-to-child transmission of HTLV-1 infection, highlighting the need for both antenatal HTLV-1 screening and advising mothers on breastfeeding in Brazil [42]. Ngoma et al found that the pooled HTLV-1 seroprevalence was 3.19% (95% CI 2.36–4.12%) in sub-Saharan Africa, indicating the need to implement effective prevention programs and interventions in sub-Saharan Africa [43]. In these HTLV-1 high-prevalence countries, HTLV-1 antenatal screening may be more cost-effective the higher the maternal HTLV-1 seropositivity rate and the higher the proportion of long-term breastfeeding, based on the findings. Policy makers in high-endemic countries could consider implementing HTLV-1 antenatal screening to prevent mother-to-child transmission as a cost-effective strategy for national HTLV-1 infection control.

Recently, horizontal transmission of HTLV-1 through sexual intercourse has also become an important route of HTLV-1 infection [44]. A large-scale educational campaign that includes condom use and avoidance of high-risk sexual behaviors would be effective in preventing sexual transmission of HTLV-1 just as an HIV campaign has been effective [45,46]. It is important to raise awareness about HTLV-1 infection and prevention not only in endemic areas but also in all regions of the country.

Unfortunately, no vaccine is currently available, likely due to the low interest of pharmaceutical companies associated with the restricted markets in industrialized countries [47]. However, HTLV-1 causes serious diseases, ATL and HAM/TSP, and thus places in the same category of viruses for which efficient vaccines are made and used. Furthermore, there are factors favoring the feasibility of the vaccine against HTLV-1: HTLV-1 has a relatively low antigenic variability, natural immunity occurs in humans, and experimental vaccination with the envelope antigen is successful in animal models. Vaccines against HTLV-1 would have important public health value in oncology, neurology, and AIDS, and are expected to play a pioneering role in the field of oncology, neurology, and AIDS [48]. In the future, vaccines against HTLV-1 should be developed and widely served to prevent transmission of HTLV-1 from mother to child and between sexual partners.

There are negative impacts of not breastfeeding. For mothers, it increases the long-term risk of cancer (breast, ovarian, endometrium), endometriosis, diabetes, osteoporosis, hypertension, cardiovascular diseases, metabolic syndrome, rheumatoid arthritis, Alzheimer disease, and multiple sclerosis. For infants, it increases the risk of otitis media, upper and lower respiratory tract infection, asthma, RSV bronchiolitis, atopic dermatitis, gastroenteritis, inflammatory bowel disease, diabetes, leukemia, and sudden infant death syndrome [49,50].

This study has several limitations. First, the cost of health supervision and counseling for pregnant women with confirmed HTLV-1 infection at HTLV-1 antenatal screening was not taken into account. Second, the costs of hospitalization, rehabilitation, and complications from treatment of ATL and HAM/TSP were not included. Third, HTLV-1 horizontal transmission rate was not taken into account in the model. The HTLV-1 horizontal transmission rate from males to females is greater than the HTLV-1 horizontal transmission rate from females to males [16]. Fourth, nonmedical indirect costs, such as lost productivity, work absenteeism, and income loss, were not calculated in this study. Fifth, the model did not consider the disadvantages such as depression and anxiety felt by HTLV-1-positive mothers and their families, and the influence on their children of withholding breastfeeding. Sixth, the adverse health effects on mothers and infants of withholding breastfeeding were not considered in the model. Seventh, twins were not taken into account in the analysis. Eighth, the model didn’t account for other HTLV-1-associated diseases such as HTLV-1-associated uveitis, infective dermatitis, bronchiectasis, bronchitis, bronchiolitis, seborrheic dermatitis, Sjögren’s syndrome, rheumatoid arthritis, fibromyalgia, and ulcerative colitis. Finally, there are different costs and medical systems in each country. Further cost-effectiveness studies by the variance of each country are needed.

Conclusion

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.

Data Availability

All relevant data are within the manuscript.

Funding Statement

The author received no specific funding for this work.

References

1.Imaizumi Y, Iwanaga M, Nosaka K, Ishitsuka K, Ishizawa K, Ito S, Amano M, et al. Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study. Cancer Sci. 2020;111:4567–4580. doi: 10.1111/cas.14658 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, et al. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 2007;25:5458–5464. doi: 10.1200/JCO.2007.11.9958 [DOI] [PubMed] [Google Scholar]
3.Nagasaka M, Yamagishi M, Yagishita N, Araya N, Kobayashi S, Makiyama J, et al. Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis. Proc Natl Acad Sci. U S A. 2020;117:11685–11691. doi: 10.1073/pnas.1920346117 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Martin F, Fedina A, Youshya S, Taylor GP. A 15-year prospective longitudinal study of disease progression in patients with HTLV-1 associated myelopathy in the UK. J Neurol Neurosurg Psychiatry. 2010;8:1336–1340. doi: 10.1136/jnnp.2009.191239 [DOI] [PubMed] [Google Scholar]
5.Gessain A, Cassar O. Epidemiological Aspects and World Distribution of HTLV-1 Infection. Front Microbiol. 2012;3:388. doi: 10.3389/fmicb.2012.00388 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.World Health Organization. Human T-lymphotropic virus type 1 https://www.who.int/news-room/fact-sheets/detail/human-t-lymphotropic-virus-type-1 Accessed 14 December, 2022.
7.Hino S. Establishment of the milk-borne transmission as a key factor for the peculiar endemicity of human T-lymphotropic virus type 1 (HTLV-1): the ATL Prevention Program Nagasaki. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87:152–166. doi: 10.2183/pjab.87.152 [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Satake M, Yamaguchi K, Tadokoro K. Current prevalence of HTLV-1 in Japan as determined by screening of blood donors. J Med Virol. 2012;84:327–335. doi: 10.1002/jmv.23181 [DOI] [PubMed] [Google Scholar]
9.Iwanaga M. Epidemiology of HTLV-1 Infection and ATL in Japan: An Update. Front Microbiol. 2020;11:1124. doi: 10.3389/fmicb.2020.01124 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Tynell E, Andersson S, Lithander E. Arneborn M. Blomberg J. Hansson H. B, et al. Screening for human T cell leukaemia/lymphoma virus among blood donors in Sweden: cost effectiveness analysis. BMJ. 1998;316:1417–1422. doi: 10.1136/bmj.316.7142.1417 [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Soares BC, Proietti AB, Proietti FA ; Interdisciplinary HTLV-I/II Research Group. HTLV-I/II and blood donors: determinants associated with seropositivity in a low risk population. Rev Saude Publica. 2003;37:470–476. doi: 10.1590/s0034-89102003000400012 [DOI] [PubMed] [Google Scholar]
12.Eusebio-Ponce E, Candel FJ, Paulino-Ramirez R, Serrano-García I, Anguita E. Seroprevalence and Trends of HTLV-1/2 among Blood Donors of Santo Domingo, Dominican Republic, 2012–2017. Rev Esp Quimioter. 2021;34:44–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Tosswill JH, Taylor GP, Tedder RS, Mortimer PP. HTLV-I/II associated disease in England and Wales, 1993–7: retrospective review of serology requests. BMJ. 2000;320:611–612. doi: 10.1136/bmj.320.7235.611 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Gotuzzo E. Risk of transfusion-transmitted human T-cell lymphotropic virus-type I in Latin America. Int J Infect Dis. 2000;4:59–61. doi: 10.1016/s1201-9712(00)90094-8 [DOI] [PubMed] [Google Scholar]
15.Ito S, Iwanaga M, Nosaka K, Imaizumi Y, Ishitsuka K, Amano M, et al. Epidemiology of adult T-cell leukemia-lymphoma in Japan: An updated analysis, 2012–2013. Cancer Sci. 2021;112:4346–4354. doi: 10.1111/cas.15097 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Sagara Y, Nakamura H, Satake M, Watanabe T, Hamaguchi I. Increasing horizontal transmission of human T-cell leukemia virus type 1 in adolescents and young adults in Japan. J Clin Virol. 2022;157:105324. doi: 10.1016/j.jcv.2022.105324 [DOI] [PubMed] [Google Scholar]
17.Itabashi K, Miyazawa T, Sekizawa A, et al. A Nationwide Antenatal Human T-Cell Leukemia Virus Type-1 Antibody Screening in Japan. Front Microbiol. 2020;11:595. doi: 10.3389/fmicb.2020.00595 [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Yonemoto N, Suzuki S, Sekizawa A, Hoshi S, Sagara Y, Itabashi K. Implementation of nationwide screening of pregnant women for HTLV-1 infection in Japan: analysis of a repeated cross-sectional study. BMC Public Health. 2020;20:1150. doi: 10.1186/s12889-020-09258-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Minakami H, Maeda T, Fujii T, Hamada H, Iitsuka Y, Itakura A, et al. Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2014 edition. J Obstet Gynaecol Res. 2014;40:1469–1499. doi: 10.1111/jog.12419 [DOI] [PubMed] [Google Scholar]
20.Suzuki S, Hoshi SI, Sekizawa A, Sagara Y, Kinoshita K, Kitamura T. Recent Prevalence of Human T-cell Leukemia Virus Type 1 Carrier Associated with Horizontal Transmission in Pregnant Japanese Women. Jpn J Infect Dis. 2021;74:576–578. doi: 10.7883/yoken.JJID.2021.097 [DOI] [PubMed] [Google Scholar]
21.Iino H, Hashiguchi M, Hori S. Estimating the range of incremental cost-effectiveness thresholds for healthcare based on willingness to pay and GDP per capita: A systematic review. PLoS One. 2022;17:e0266934. doi: 10.1371/journal.pone.0266934 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Ministry of Health, Labor and Welfare. Establishment of reference values for cost-effectiveness evaluation. 2018. https://www.mhlw.go.jp/file/05-Shingikai-12404000-Hokenkyoku-Iryouka/0000211609.pdf (Japanese) Accessed 14 December, 2022. [Google Scholar]
23.Arisawa K, Soda M, Endo S, Kurokawa K, Katamine S, Shimokawa I, et al. Evaluation of adult T-cell leukemia/lymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan. Int J Cancer. 2000;85:319–324. doi: [DOI] [PubMed] [Google Scholar]
24.Japanese Society of Neurology. JSN Practical guidelines for HTLV-1-associated myelopathy (HAM), 2019. [Japanese] https://www.neurology-jp.org/guidelinem/ham/ham_2019.pdf Accessed 14 December, 2022. [Google Scholar]
25.Tsukasaki K, Fukushima T. JSH Practical Guidelines for Hematological Malignancies, 2018: II. Lymphoma-8. Adult T-cell leukemia-lymphoma. Int J Hematol. 2019;109:249–259. doi: 10.1007/s12185-018-02588-5 [DOI] [PubMed] [Google Scholar]
26.Takasaki Y, Iwanaga M, Imaizumi Y, Tawara M, Joh T, Kohno T, et al. Long-term study of indolent adult T-cell leukemia-lymphoma. Blood. 2010;115:4337–4343. doi: 10.1182/blood-2009-09-242347 [DOI] [PubMed] [Google Scholar]
27.Taniguchi H, Imaizumi Y, Takasaki Y, Nakashima J, Kato T, Itonaga H, et al. Clinical features at transformation in adult T-cell leukemia-lymphoma with smoldering and chronic types. Int J Hematol. 2019;109:402–408. doi: 10.1007/s12185-019-02602-4 [DOI] [PubMed] [Google Scholar]
28.Ministry of Health, Labor and Welfare. Infant and Young Child Nutrition Survey. 2015.https://www.mhlw.go.jp/file/06-Seisakujouhou-11900000-Koyoukintoujidoukateikyoku/0000134207.pdf. (Japanese) Accessed 14 December, 2022. [Google Scholar]
29.Inano H, Kameya M, Sasano K, Matsumura K, Tsuchida A, Hamazaki K, et al. Factors influencing exclusive breastfeeding rates until 6 months postpartum: the Japan Environment and Children’s Study. Sci Rep. 2021;11:6841. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Schierhout G, McGregor S, Gessain A, Einsiedel L, Martinello M, Kaldor J. Association between HTLV-1 infection and adverse health outcomes: a systematic review and meta-analysis of epidemiological studies. Lancet Infect Dis. 2020;20:133–143. doi: 10.1016/S1473-3099(19)30402-5 [DOI] [PubMed] [Google Scholar]
31.Ministry of Health, Labour and Welfare. Vital Statistics. [Japanese] https://www.mhlw.go.jp/toukei/list/81-1a.html Accessed 14 December, 2022.
32.Igakutsushin-sya. National fee schedule and Medical insurance reimbursement table in Japan [Japanese]. Tokyo: Igakutsushin-sya, Japan; 2021. [Google Scholar]
33.PPPs (Purchasing Power Parities) and exchange rates [Organisation for Economic Co-operation and Development (OECD) Website]. https://stats.oecd.org/Index.aspx?DataSetCode=SNA_TABLE4. Accessed 14 December, 2022.
34.The Japanese Society of HTLV-1 and Associated Diseases. Diagnostic Guidelines for HTLV-1 Infection, 2nd Edition (November 2019). https://www.jpeds.or.jp/uploads/files/20191223_HTLV-1_ver.2.pdf (Japanese) Accessed 14 December, 2022.
35.Sanders GD, Neumann PJ, Basu A, Brock DW, Feeny D, Krahn M, et al. Recommendations for Conduct, Methodological Practices, and Reporting of Cost-effectiveness Analyses: Second Panel on Cost-Effectiveness in Health and Medicine. JAMA. 2016; 316:1093–1103. doi: 10.1001/jama.2016.12195 [DOI] [PubMed] [Google Scholar]
36.Edejer TT-T, Baltussen R, Adam T, World Health Organization. Making choices in health: who guide to cost-effectiveness analysis. Geneva, Switzerland:2003:67–71. https://apps.who.int/iris/handle/10665/42699 Accessed 14 December, 2022. [Google Scholar]
37.Ikeda S, Shiroiwa T, Igarashi A, Noto S, Fukuda T, Saito S, et al. Developing a Japanese version of the EQ-5D-5L value set. J. Natl. Inst. Public Health. 2015;64:47–55. [Japanese] [Google Scholar]
38.Rosadas C, Assone T, Yamashita M, Adonis A, Puccioni-Sohler M, Santos M, et al. Health state utility values in people living with HTLV-1 and in patients with HAM/TSP: The impact of a neglected disease on the quality of life. PLoS Negl Trop Dis. 2020;14:e0008761. doi: 10.1371/journal.pntd.0008761 [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Patel KK, Zeidan AM, Shallis RM, Prebet T, Podoltsev N, Huntington SF. Cost-effectiveness of azacitidine and venetoclax in unfit patients with previously untreated acute myeloid leukemia. Blood Adv. 2021;5:994–1002. doi: 10.1182/bloodadvances.2020003902 [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Malik B, Taylor GP. Can we reduce the incidence of adult T-cell leukaemia/lymphoma? Cost-effectiveness of human T-lymphotropic virus type 1 (HTLV-1) antenatal screening in the United Kingdom. Br J Haematol. 2019;184:1040–1043. doi: 10.1111/bjh.15234 [DOI] [PubMed] [Google Scholar]
41.Djuicy DD, Mouinga-Ondémé A, Cassar O, Ramassamy J-L, Idam Mamimandjiami A, Bikangui R, et al. Risk factors for HTLV-1 infection in Central Africa: A rural population-based survey in Gabon. PLoS Negl Trop Dis. 2018;12:e0006832. doi: 10.1371/journal.pntd.0006832 [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Paiva AM, Assone T, Haziot MEJ, Smid J, Fonseca LAM, Luiz ODC, et al. Risk factors associated with HTLV-1 vertical transmission in Brazil: longer breastfeeding, higher maternal proviral load and previous HTLV-1-infected offspring. Sci Rep. 2018;8:7742. doi: 10.1038/s41598-018-25939-y [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Ngoma AM, Omokoko MD, Mutombo PB, Mvika ES, Muwonga JM, Nollet KE, et al. Population-based prevalence of human T-lymphotropic virus type 1 in sub-Saharan Africa: a systematic review and meta-analysis. Trop Med Int Health. 2019;24:1277–1290. doi: 10.1111/tmi.13305 [DOI] [PubMed] [Google Scholar]
44.Paiva A, Casseb J. Sexual transmission of human T-cell lymphotropic virus type 1. Rev Soc Bras Med Trop. 2014;47:265–274. doi: 10.1590/0037-8682-0232-2013 [DOI] [PubMed] [Google Scholar]
45.Frey K, Lociciro S, Blank P, Schwenkglenks M, Dubois-Arber F, Rosenbrock R, et al. ’Break the Chains 2015’ community-based HIV prevention campaign for men who have sex with men in Switzerland: non-randomised evaluation and cost analysis. BMJ Open. 2020;10:e032459. doi: 10.1136/bmjopen-2019-032459 [DOI] [PMC free article] [PubMed] [Google Scholar]
46.Onoya D, Mohlabane N, Maduna V, van Zyl J, Sewpaul R, Naidoo Y. Testing in the HIV Counselling and Testing (HCT) campaign, HIV risk behaviours and ART enrolment in South Africa. Public Health. 2016;136:152–160. doi: 10.1016/j.puhe.2016.03.029 [DOI] [PubMed] [Google Scholar]
47.Willems L, Hasegawa H, Accolla R, Bangham C, Bazarbachi A, Bertazzoni U, et al. Reducing the global burden of HTLV-1 infection: An agenda for research and action. Antiviral Res. 2017;137:41–48. doi: 10.1016/j.antiviral.2016.10.015 [DOI] [PubMed] [Google Scholar]
48.de Thé G, Bomford R. An HTLV-I vaccine: why, how, for whom?. AIDS Res Hum Retroviruses. 1993;9:381–386. doi: 10.1089/aid.1993.9.381 [DOI] [PubMed] [Google Scholar]
49.Del Ciampo LA, Del Ciampo IRL. Breastfeeding and the Benefits of Lactation for Women’s Health. Aleitamento materno e seus benefícios para a saúde da mulher. Rev Bras Ginecol Obstet. 2018;40:354–359. [DOI] [PMC free article] [PubMed] [Google Scholar]
50.American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2012;129:e827–e841. doi: 10.1542/peds.2011-3552 [DOI] [PubMed] [Google Scholar]

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011129.r001

Decision Letter 0

Eugenia Corrales-Aguilar

10 Oct 2022

Dear Dr. Kowada,

Thank you very much for submitting your manuscript "Cost-effectiveness and health impact of HTLV-1 antenatal screening for prevention of mother-to-child transmission" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Eugenia Corrales-Aguilar

Section Editor

PLOS Neglected Tropical Diseases

Eugenia Corrales-Aguilar

Section Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Methods need clarification as per comments on the Summary and General Comments session.

Reviewer #2: (No Response)

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Please see comments on Summary and General Comments session.

Reviewer #2: (No Response)

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Please see comments on Summary and General Comments session.

Reviewer #2: (No Response)

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Minor Comments.

1. The estimate of 20 million people infected with HTLV-1 worldwide is from de The & Bomford(3), not Gessain & Cassar(4)– who estimated 5 – 10 million based on published seroprevalence but acknowledged that data pertinent to 6/7th of the global population were missing or sparse.

2. Regions of high prevalence include Iran and Central Australia – this is mentioned in the discussion but omitted from the introduction.

3. In the author summary an explanation of the type of disease would be helpful for HAM/TSP (as is given for ATL).

4. Line 123 countries which screen – please provide a reference.

5. Line 365 – How do you know that the proposed large scale education campaign will be effective in preventing sexual transmission? Perhaps compare to HIV campaign and reference.

6. The term “we” is used in the manuscript but there is only one author. In which case either use I or write in the third person.

Reviewer #2: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The addition of a cost effectiveness study from Japan on antenatal screening for prevention of mother-to-child HTLV-1 transmission is welcome. Indeed, it is interesting that no such study has previously been published either leading up to the decision to extend HTLV antenatal screening nationally circa 2011 or since. The only previous study, from the UK– a low prevalence country – concluding that even in the UK screening could be cost effective(1). The paper by A. Kowada concludes that antenatal screening in Japan meets the cost criteria for screening based on provider willingness to pay values of US$ 50,000 or 100,000 per QALY. These are higher than in the UK

Major Comments.

1. The life-time risk of HAM/TSP cited in the introduction is 0.18 – 1.8% (although higher rates have been reported. Which rate was used for this study?

2. The life-time risk of ATL is cited in the introduction to be 5%. Was the association of ATL risk with acquisition of HTLV-1 in early life considered in the analysis?

3. Why were the thresholds $50 and $100,000 chosen? What is the accepted cost per QALY in Japan?

4. In the methods it is not clear what “other causes” of mortality were considered in the model. In the results on HAM/TSP and ATL cases are presented. Please clarify. Also, what impact does the adj Mortality Rate of 1.57 as reported by Schierhout(2) have on the cost effectiveness? Noting that this cannot be attributed to deaths from ATL or HAM

5. In the model structure the assumption is that all mothers breast-feed. Is this the case in Japan and if so for how long?

6. What is the negative impact (QALY cost) of not breast-feeding?

7. The effectiveness of the intervention is given as reducing transmission from 20% to 3% but the rate of transmission is determined by the duration of breast feeding. This should be taken into account in the model.

8. The cost of the antibody screening is given as US$ 76.4 per person inclusive of confirmatory test. How was this calculated? It is taken from a table of medical fees but high-volume screening is likely to be cheaper in terms of the reagents and in personnel as it is added to other screening assays. Has this been considered?

9. The impact of sexual transmission was considered. What was estimate of life-time risk that a person infected through in early life would transmit HTLV-1 through sexual intercourse? How was it calculated? Was this different for males and females?

10. In the section on cumulative lifetime health effects the number of cases of ATL and HAM prevented seem small for ATL with an expected ATL rate of 2.8% only and very small for HAM with a lifetime risk of just 0.15%. A detailed explanation of these rates is required for the reader to understand the findings.

11. In the analysis how are twins accounted for?

12. In Figure 2C the pivot point for effectiveness seems to be at about $25,000 per QALY). Why consider $100,000 per QALY?

13. Table 3 is confusing with cumulative life-time cost of HTLV-1 antenatal screening given as US$ 866 million and various sums presented as reduction regardless of whether these are losses or gains.

14. Furthermore the reduction in cases in Table 3 requires explanation. Why is the reduction in disease not at the same as the reduction in cases of infection?

15. In the discussion reference is made to the implementation of a national antenatal screening programme in 2011 and that recently maternal seroprevalence has been decreasing. Clearly an antenatal screening programme from 2011 cannot have impacted maternal seroprevalence already especially as the average age of mothers in Japan is 30 years. Comment should be made on the extent of screening in Japan in the preceding years noting the introduction of HTLV antenatal screening in Nagasaki was early as the late 1980s?

16. In the comment on depression and anxiety whilst acknowledging that all diagnostic tests and screening programmes are inevitably associated with a degree of anxiety the current statement implies that this would be particularly a feature of HTLV screening and does not take into account the depression and anxiety that occurs when parents discover that they were not offered testing and interventions for a preventable infection causing cancer and neurological disease (as HTLV-1) and see these occurring in the children (even as adults). It is important to discuss both elements since the psychological aspects are not included – not just the potential negative aspects.

1. Malik B, Taylor GP. Can we reduce the incidence of adult T-cell leukaemia/lymphoma? Cost-effectiveness of human T-lymphotropic virus type 1 (HTLV-1) antenatal screening in the United Kingdom. Br J Haematol. 2018;184:1040-3.

2. Schierhout GM, S; Gessain, A; Einsiedel, L; Martinello, M, Kaldor, J. The association between HTLV-1 infection and adverse health outcomes:a systematic review and meta-analysis of epidemiologic studies. Lancet Infect Dis. 2019.

3. de The G, Bomford R. An HTLV-I vaccine: why, how, for whom? AIDS Res Hum Retrovirol. 1993;9(5):381-6.

4. Gessain A, Cassar O. Epidemiological Aspects and World Distribution of HTLV-1 Infection. Front Microbiol. 2012;3:388.

Reviewer #2: 1. As this paper is written, it appears to have an overwhelmingly major flaw: It seems to assume that prevention of an HTLV-1 infection increases the utility of the person in question in by far most cases from 0.712 to 1. The author appears to assume that a person who is not an HTLV-1 carrier, is in perfect health and has a utility of 1. That assumption is incorrect because there are many other factors and conditions than HTLV-1 that can cause less than perfect health. Correction would greatly reduce the number of QALYs gained by screening, possibly by a factor greater than 10, so that cost-effectiveness of screening would change from well within what is generally considered cost-effective, to well outside of that. Correction would therefore reverse the main conclusion of the paper and require a major revision of the text and tables.

Some comments of less importance than the above:

2. The author mentions several times “more cost-effective” while the paper only compares screening with not-screening, therefore there is only one cost-effectiveness ratio at play, so that there is no comparison (“more”) of cost-effectiveness ratios possible.

3. The text seems often unclear about whether a number mentioned concerns incidence or prevalence. E.g. line 78 seems to describe prevalence, while line 111 seems to quote the same number but describes it as incidence.

4. At line 155: are those individuals all pregnant women? If so, please say so.

5. At line 171: as I read the paper, compliance rate does not affect the estimated cost-effectiveness ratio

6. At line 191 under the heading ‘no screening’: is the probability of sexual transmission not considered in the screening arm?

7. It is generally left unclear how sexual transmission affects the cost-effectiveness of screening. Does it have any influence on the presented estimates?

8. Does direct transmission play any role in this model?

9. The one-way sensitivity analysis does not seem to just involve changing one parameter at the time (with results usually presented in a tornado diagram), but to involve only one parameter altogether.

10. At line 207: Reference 20 does not describe test specificity as 100%. Furthermore, the false positivity rates mentioned there, would cause that around half of test positives are false positives.

11. At line 336: This paper does not demonstrate that screening reduces morbidity and mortality but rather, makes literature based quantitative assumptions concerning effects on morbidity and mortality in order to estimate cost-effectiveness.

12. At line 379: The paper leaves unclear how a gender difference in horizontal transmission affects the cost-effectiveness of screening.

13. At lines 386-389: As mentioned under 1., the paper seems to assume that HTLV-1 carriers have a much lower utility than non-carriers therefore it seems incorrect to state that other diseases than ATL and HAM/TSP were not taken into account, on the contrary, it seems that their effects are gravely overestimated.

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

PLoS Negl Trop Dis. 2023 Feb 21;17(2):e0011129. doi: 10.1371/journal.pntd.0011129.r002

Author response to Decision Letter 0

25 Oct 2022

Attachment

Submitted filename: Response to Reviewers comments.docx

Click here for additional data file.^{(45.1KB, docx)}

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011129.r003

Decision Letter 1

Graham P Taylor, Eugenia Corrales-Aguilar

6 Dec 2022

Dear Dr. Kowada,

Thank you very much for submitting your manuscript "Cost-effectiveness and health impact of HTLV-1 antenatal screening for prevention of mother-to-child transmission" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Thank you for addressing point by point the reviewers' comments. This has been most helpful. Further clarification of how onward sexual transmission was incorporated into the model is required as well as how the contribution of sexually acquired transmission to the total number of cases of HTLV-1 in Japan has been factored into the incidence data. See the points below and the further comments from Reviewer 1.

Line 131 – are 4000 infections in adults and adolescents diagnosed each year or is this the estimated number of new infections per year?

Line 217 and Table 1– the horizontal infection rate is 0.000046 on the 2016 paper of HTLV-1 incidence in Japanese blood donors. This is the infection rate but not the transmission rate. A carrier infected in early life will have potentially more opportunity to transmit than a carrier who does not become infected until they become sexually active. Please also confirm that the transmission rate when incorporated into the model describes the life-time risk of transmission following early life infection and not the risk per 100,000 person years. This is not clear at the moment. I note too that the work of Satake et al has recently been updated in J Clin Virol 2022.

(The incidence density was significantly higher in women (6·88 per 100 000 person-years; 95% CI 6·17-7·66) than in men (2·29 per 100 000 person-years; 95% CI 1·99-2·62; p<0·0001).

The number of seroconversions per 100,000 person-years was 1.54 for men and 4.21 for women – satake et al J Clin Virol . 2022 Dec;157:105324. doi: 0.1016/j.jcv.2022.105324.

Although the seroconversions per 100,000 person years is lower than in the 2016 report the sero-conversion rate amongst adolescents and Young adults had increased.

Line 307 – “The sexual transmission rate didn’t affect the cost-effectiveness of screening”. Do you mean that the number of transmissions attributed to early life infection was so low that if did not increase the cost-effectiveness of screening. How many sexual transmissions would have been prevented by the avoidance of mother-to-child transmission. This should be added to the section on cumulative lifetime health effects.

In this section the estimate on ATL-associated deaths is 64% of the total of ATL cases whereas the data input was that the 4 year survival of 16%. Why is the mortality rate in the model so low. On the other hand 71 HAM associated deaths were prevented out of 177 cases – a 40% mortality. The suggestion in the text is that these numbers may be wrong. What is their contribution to the cost-effectiveness?

In the response to Reviewer one you state Yes, the association of ATL risk with acquisition of HTLV-1 in early life was considered in the analysis. In the model, HTLV-1 is transmitted mainly through mother-to-child transmission (MTCT), even if horizontal transmission through sexual intercourse is being considered. However, the data used for ATL risk was the published incidence rate – which would include all persons infected with HTLV-1 regardless of the age of infection. Whilst ATL has been reported following infection in adult life a strong association with infection in early life remains. The relative contribution of infection in early v adult life is therefore likely to impact significantly in the model. What proportion of all HTLV-1 infection in adults in Japan did you consider to be related to mother-to-child transmission? The increasing rates of infection with increasing age, especially among females, indicate a considerable infection after early life.

In your response to point 16 Reviewer 1 you have stated that anxiety related to screening would be a particular feature of HTLV-1 screening. It is not clear that this was your intention. If not, please amend. If so, why for example would HTLV-1 screening cause more anxiety than other antenatal screening tests – eg for Down’s syndrome or HIV?

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Graham P Taylor, MB, DSc

Academic Editor

PLOS Neglected Tropical Diseases

Eugenia Corrales-Aguilar

Section Editor

PLOS Neglected Tropical Diseases

***********************

Line 131 – are 4000 infections in adults and adolescents diagnosed each year or is this the estimated number of new infections per year?

(The incidence density was significantly higher in women (6·88 per 100 000 person-years; 95% CI 6·17-7·66) than in men (2·29 per 100 000 person-years; 95% CI 1·99-2·62; p<0·0001).

The number of seroconversions per 100,000 person-years was 1.54 for men and 4.21 for women – satake et al J Clin Virol . 2022 Dec;157:105324. doi: 0.1016/j.jcv.2022.105324.

Although the seroconversions per 100,000 person years is lower than in the 2016 report the sero-conversion rate amongst adolescents and Young adults had increased.

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Methods are adequate.

Authors need to clarify if they have included secondary vertical transmissions, or horizontal transmission only (Page 13, line 217)

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Figure 1 A needs editing as it is not clear. Consider changing scale.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: Authors should keep both thresholds (50,000 and 100,000) in the discussion.

--------------------

Editorial and Data Presentation Modifications?

Reviewer #1: The study is well designed, clear and important. I would strongly advise to keep both thresholds in the discussion 50,000 and 100,000. This information is important as it shows that HTLV antenatal screening is not only cot-effective, but highly cost-effective, as authors have used a conservative threshold.

--------------------

Summary and General Comments

Reviewer #1: The paper is well written, timely and important. Only minor comments as above. The inclusion of short discussion adding both threshold is important in a broader context of cost-effectiveness of such intervention in other settings.

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Figure Files:

Data Requirements:

Reproducibility:

References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice.

PLoS Negl Trop Dis. 2023 Feb 21;17(2):e0011129. doi: 10.1371/journal.pntd.0011129.r004

Author response to Decision Letter 1

13 Dec 2022

Attachment

Submitted filename: Ver2 Response to Reviewers comments.docx

Click here for additional data file.^{(24.5KB, docx)}

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011129.r005

Decision Letter 2

Graham P Taylor, Eugenia Corrales-Aguilar

9 Jan 2023

Dear Dr. Kowada,

Thank you very much for submitting your manuscript "Cost-effectiveness and health impact of HTLV-1 antenatal screening for prevention of mother-to-child transmission" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you further modify the manuscript according to the review recommendations.

The focus of concern is mainly (but not only) on the impact of horizontal transmission of HTLV-1 in the two scenarios and how the reduced transmission from the screened pregnant lady after diagnosis of HTLV-1 infection has been calculated based on the expected behaviour change as well as the horizontal transmission that does not occur during their lifetime from the infants in whom HTLV-1 was prevented. If either or both of these have not been included in the analysis, and there is insufficient data to include in the revision, then this should be made clear as a limitation and an underestimate of the potential benefit of the antenatal screening.

Please also address the other, minor points.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Sincerely,

Graham P Taylor, MB, DSc

Academic Editor

PLOS Neglected Tropical Diseases

Eugenia Corrales-Aguilar

Section Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: Line 166-167 author say that a hypothetical cohort of 30-year individuals was targeted. Is the author referring to pregnant women? The model should focus on pregnant women, since they are the target population of the intervention. This needs to be clear

Line 191 “Patients with favorable and smoldering types of ATL continue to be followed up without treatment”. How long are they followed up for? What rate of transformation to the more aggressive forms of ATL were imputed in the model.

ine 194-195 Author states "The probability of HTLV-1 transmission through sexual intercourse is considered", does it refer to the sexual transmission in the 30-year-old cohort (from sexual partners to pregnant women or from pregnant women to their sexual partners?) or the sexual transmission that may occur during the lifetime of the babies born from those mothers? If it refers to the 30-year-old cohort, it is not expected that sexual transmission would affect or be affected by antenatal screening program and should not be considered. However, prevention of sexual transmission to a partner can also be prevented by safer sex (condom use), once the women is aware of their serostatus due to antenatal screening.

If it refers to secondary sexual transmission throughout the babies` life author should not use the incidence rate in blood donors. The horizontal transmission rate used is that of the incidence found among persons of reproductive age however all models of infection have shown the prevalence of infection to increase with age and that the rate of increase is higher in older age. Therefore the model should not use the same horizontal transmission rate throughout the person’s life as this under-estimates the number of infections prevented.

The transmission rate of HTLV through sex is expected to be much higher than incidence in blood donors at reproductive age, but would vary according to different variables, such as gender of the infected individual, number of partners, frequency of unprotected sex, co-infection with other STI, HTLV proviral load, etc. The rate of sexual transmission was estimated as 60% from male to female and 0.4% from female to male in a 10y period, but this is an estimation only and has a lot of uncertainties. In the Miyazaki cohort of sero-discordant couples the transmission rate over 5 years was 7% with a male-to-female rate 4-fold higher than females-to-males. Some references regarding sexual transmission rate

https://pubmed.ncbi.nlm.nih.gov/15809908/

https://pubmed.ncbi.nlm.nih.gov/8418183/

https://pubmed.ncbi.nlm.nih.gov/2877031/

In terms of those who are infected in early life – there is clearly a longer period of risk of horizontal transmission that those who are infected in later life, but we do not know whether this translates into a greater overall risk of horizontal transmission as behavioural factors may differ between the two risk groups.

If horizontal transmision is being considered the model should include the transmissions relating to the unscreened pregnant lady and transmissions relating to the infants who become infected as a result of the non-screening strategy. As there is only one row for horizontal transmission it seems that only the mother is considered but this is not completely clear.

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Line 304-305 "Cost effectiveness is not sensitive to the horizontal sexual transmission rate". See comment above.

Table 3. the cumulative lifetime HTLV-1 carriers with horizontal transmission is higher if antenatal screening is implemented, with a gain of 91 cases. This does not seem to be correct. Higher number of infected people is expected without antenatal screening, and therefore, more people would be able to transmit HTLV through sex. There is no reason that could explain higher number of sexual transmission if antenatal screening is implemented.

Table 3. ATL cases are primarily associated with vertical transmission. Therefore, the reduction of number of ATL cases should be proportional to the reduction of number of infections that would be prevented. In table 3 number of carriers with vertical transmission reduces from 158,244 to 32,822, while number of ATL reduces from 14,804 to 10,392. Even considering horizontal transmission, the number of ATL seem to be too high. Please explain the model for generating the number of cases of ATL. It would appear from the numbers that the model considered most cases of ATL to be consequence of horizontal trasmission.

Table 3 – the LY gain is 456 despite the 4412 fewer cases of ATL – this amounts about 1 month of life expectancy gain for each case of ATL prevented – again this seems difficult to explain.

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

--------------------

Editorial and Data Presentation Modifications?

Reviewer #1: (No Response)

--------------------

Summary and General Comments

Reviewer #1: The study addresses an important gap in the literature. It is not clear, however, how horizontal transmission was considered in the model. This is a major limitation and should be addressed.

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Figure Files:

Data Requirements:

Reproducibility:

References

PLoS Negl Trop Dis. 2023 Feb 21;17(2):e0011129. doi: 10.1371/journal.pntd.0011129.r006

Author response to Decision Letter 2

17 Jan 2023

Attachment

Submitted filename: Ver3 Response to Reviewers comments.docx

Click here for additional data file.^{(22.9KB, docx)}

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011129.r007

Decision Letter 3

Graham P Taylor, Eugenia Corrales-Aguilar

31 Jan 2023

Dear Dr. Kowada,

We are pleased to inform you that your manuscript 'Cost-effectiveness of HTLV-1 antenatal screening for prevention of mother-to-child transmission' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Graham P Taylor, MB, DSc

Academic Editor

PLOS Neglected Tropical Diseases

Eugenia Corrales-Aguilar

Section Editor

PLOS Neglected Tropical Diseases

***********************************************************

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0011129.r008

Acceptance letter

Graham P Taylor, Eugenia Corrales-Aguilar

13 Feb 2023

Dear Dr. Kowada,

We are delighted to inform you that your manuscript, "Cost-effectiveness of human T-cell leukemia virus type 1 (HTLV-1) antenatal screening for prevention of mother-to-child transmission," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.

Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Attachment

Submitted filename: Response to Reviewers comments.docx

Click here for additional data file.^{(45.1KB, docx)}

Attachment

Submitted filename: Ver2 Response to Reviewers comments.docx

Click here for additional data file.^{(24.5KB, docx)}

Attachment

Submitted filename: Ver3 Response to Reviewers comments.docx

Click here for additional data file.^{(22.9KB, docx)}

Data Availability Statement

All relevant data are within the manuscript.

[pntd.0011129.ref001] 1.Imaizumi Y, Iwanaga M, Nosaka K, Ishitsuka K, Ishizawa K, Ito S, Amano M, et al. Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study. Cancer Sci. 2020;111:4567–4580. doi: 10.1111/cas.14658 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref002] 2.Tsukasaki K, Utsunomiya A, Fukuda H, Shibata T, Fukushima T, Takatsuka Y, et al. VCAP-AMP-VECP compared with biweekly CHOP for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study JCOG9801. J Clin Oncol. 2007;25:5458–5464. doi: 10.1200/JCO.2007.11.9958 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref003] 3.Nagasaka M, Yamagishi M, Yagishita N, Araya N, Kobayashi S, Makiyama J, et al. Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis. Proc Natl Acad Sci. U S A. 2020;117:11685–11691. doi: 10.1073/pnas.1920346117 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref004] 4.Martin F, Fedina A, Youshya S, Taylor GP. A 15-year prospective longitudinal study of disease progression in patients with HTLV-1 associated myelopathy in the UK. J Neurol Neurosurg Psychiatry. 2010;8:1336–1340. doi: 10.1136/jnnp.2009.191239 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref005] 5.Gessain A, Cassar O. Epidemiological Aspects and World Distribution of HTLV-1 Infection. Front Microbiol. 2012;3:388. doi: 10.3389/fmicb.2012.00388 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref006] 6.World Health Organization. Human T-lymphotropic virus type 1 https://www.who.int/news-room/fact-sheets/detail/human-t-lymphotropic-virus-type-1 Accessed 14 December, 2022.

[pntd.0011129.ref007] 7.Hino S. Establishment of the milk-borne transmission as a key factor for the peculiar endemicity of human T-lymphotropic virus type 1 (HTLV-1): the ATL Prevention Program Nagasaki. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87:152–166. doi: 10.2183/pjab.87.152 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref008] 8.Satake M, Yamaguchi K, Tadokoro K. Current prevalence of HTLV-1 in Japan as determined by screening of blood donors. J Med Virol. 2012;84:327–335. doi: 10.1002/jmv.23181 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref009] 9.Iwanaga M. Epidemiology of HTLV-1 Infection and ATL in Japan: An Update. Front Microbiol. 2020;11:1124. doi: 10.3389/fmicb.2020.01124 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref010] 10.Tynell E, Andersson S, Lithander E. Arneborn M. Blomberg J. Hansson H. B, et al. Screening for human T cell leukaemia/lymphoma virus among blood donors in Sweden: cost effectiveness analysis. BMJ. 1998;316:1417–1422. doi: 10.1136/bmj.316.7142.1417 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref011] 11.Soares BC, Proietti AB, Proietti FA ; Interdisciplinary HTLV-I/II Research Group. HTLV-I/II and blood donors: determinants associated with seropositivity in a low risk population. Rev Saude Publica. 2003;37:470–476. doi: 10.1590/s0034-89102003000400012 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref012] 12.Eusebio-Ponce E, Candel FJ, Paulino-Ramirez R, Serrano-García I, Anguita E. Seroprevalence and Trends of HTLV-1/2 among Blood Donors of Santo Domingo, Dominican Republic, 2012–2017. Rev Esp Quimioter. 2021;34:44–50. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref013] 13.Tosswill JH, Taylor GP, Tedder RS, Mortimer PP. HTLV-I/II associated disease in England and Wales, 1993–7: retrospective review of serology requests. BMJ. 2000;320:611–612. doi: 10.1136/bmj.320.7235.611 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref014] 14.Gotuzzo E. Risk of transfusion-transmitted human T-cell lymphotropic virus-type I in Latin America. Int J Infect Dis. 2000;4:59–61. doi: 10.1016/s1201-9712(00)90094-8 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref015] 15.Ito S, Iwanaga M, Nosaka K, Imaizumi Y, Ishitsuka K, Amano M, et al. Epidemiology of adult T-cell leukemia-lymphoma in Japan: An updated analysis, 2012–2013. Cancer Sci. 2021;112:4346–4354. doi: 10.1111/cas.15097 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref016] 16.Sagara Y, Nakamura H, Satake M, Watanabe T, Hamaguchi I. Increasing horizontal transmission of human T-cell leukemia virus type 1 in adolescents and young adults in Japan. J Clin Virol. 2022;157:105324. doi: 10.1016/j.jcv.2022.105324 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref017] 17.Itabashi K, Miyazawa T, Sekizawa A, et al. A Nationwide Antenatal Human T-Cell Leukemia Virus Type-1 Antibody Screening in Japan. Front Microbiol. 2020;11:595. doi: 10.3389/fmicb.2020.00595 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref018] 18.Yonemoto N, Suzuki S, Sekizawa A, Hoshi S, Sagara Y, Itabashi K. Implementation of nationwide screening of pregnant women for HTLV-1 infection in Japan: analysis of a repeated cross-sectional study. BMC Public Health. 2020;20:1150. doi: 10.1186/s12889-020-09258-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref019] 19.Minakami H, Maeda T, Fujii T, Hamada H, Iitsuka Y, Itakura A, et al. Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2014 edition. J Obstet Gynaecol Res. 2014;40:1469–1499. doi: 10.1111/jog.12419 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref020] 20.Suzuki S, Hoshi SI, Sekizawa A, Sagara Y, Kinoshita K, Kitamura T. Recent Prevalence of Human T-cell Leukemia Virus Type 1 Carrier Associated with Horizontal Transmission in Pregnant Japanese Women. Jpn J Infect Dis. 2021;74:576–578. doi: 10.7883/yoken.JJID.2021.097 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref021] 21.Iino H, Hashiguchi M, Hori S. Estimating the range of incremental cost-effectiveness thresholds for healthcare based on willingness to pay and GDP per capita: A systematic review. PLoS One. 2022;17:e0266934. doi: 10.1371/journal.pone.0266934 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref022] 22.Ministry of Health, Labor and Welfare. Establishment of reference values for cost-effectiveness evaluation. 2018. https://www.mhlw.go.jp/file/05-Shingikai-12404000-Hokenkyoku-Iryouka/0000211609.pdf (Japanese) Accessed 14 December, 2022. [Google Scholar]

[pntd.0011129.ref023] 23.Arisawa K, Soda M, Endo S, Kurokawa K, Katamine S, Shimokawa I, et al. Evaluation of adult T-cell leukemia/lymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan. Int J Cancer. 2000;85:319–324. doi: [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref024] 24.Japanese Society of Neurology. JSN Practical guidelines for HTLV-1-associated myelopathy (HAM), 2019. [Japanese] https://www.neurology-jp.org/guidelinem/ham/ham_2019.pdf Accessed 14 December, 2022. [Google Scholar]

[pntd.0011129.ref025] 25.Tsukasaki K, Fukushima T. JSH Practical Guidelines for Hematological Malignancies, 2018: II. Lymphoma-8. Adult T-cell leukemia-lymphoma. Int J Hematol. 2019;109:249–259. doi: 10.1007/s12185-018-02588-5 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref026] 26.Takasaki Y, Iwanaga M, Imaizumi Y, Tawara M, Joh T, Kohno T, et al. Long-term study of indolent adult T-cell leukemia-lymphoma. Blood. 2010;115:4337–4343. doi: 10.1182/blood-2009-09-242347 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref027] 27.Taniguchi H, Imaizumi Y, Takasaki Y, Nakashima J, Kato T, Itonaga H, et al. Clinical features at transformation in adult T-cell leukemia-lymphoma with smoldering and chronic types. Int J Hematol. 2019;109:402–408. doi: 10.1007/s12185-019-02602-4 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref028] 28.Ministry of Health, Labor and Welfare. Infant and Young Child Nutrition Survey. 2015.https://www.mhlw.go.jp/file/06-Seisakujouhou-11900000-Koyoukintoujidoukateikyoku/0000134207.pdf. (Japanese) Accessed 14 December, 2022. [Google Scholar]

[pntd.0011129.ref029] 29.Inano H, Kameya M, Sasano K, Matsumura K, Tsuchida A, Hamazaki K, et al. Factors influencing exclusive breastfeeding rates until 6 months postpartum: the Japan Environment and Children’s Study. Sci Rep. 2021;11:6841. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref030] 30.Schierhout G, McGregor S, Gessain A, Einsiedel L, Martinello M, Kaldor J. Association between HTLV-1 infection and adverse health outcomes: a systematic review and meta-analysis of epidemiological studies. Lancet Infect Dis. 2020;20:133–143. doi: 10.1016/S1473-3099(19)30402-5 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref031] 31.Ministry of Health, Labour and Welfare. Vital Statistics. [Japanese] https://www.mhlw.go.jp/toukei/list/81-1a.html Accessed 14 December, 2022.

[pntd.0011129.ref032] 32.Igakutsushin-sya. National fee schedule and Medical insurance reimbursement table in Japan [Japanese]. Tokyo: Igakutsushin-sya, Japan; 2021. [Google Scholar]

[pntd.0011129.ref033] 33.PPPs (Purchasing Power Parities) and exchange rates [Organisation for Economic Co-operation and Development (OECD) Website]. https://stats.oecd.org/Index.aspx?DataSetCode=SNA_TABLE4. Accessed 14 December, 2022.

[pntd.0011129.ref034] 34.The Japanese Society of HTLV-1 and Associated Diseases. Diagnostic Guidelines for HTLV-1 Infection, 2nd Edition (November 2019). https://www.jpeds.or.jp/uploads/files/20191223_HTLV-1_ver.2.pdf (Japanese) Accessed 14 December, 2022.

[pntd.0011129.ref035] 35.Sanders GD, Neumann PJ, Basu A, Brock DW, Feeny D, Krahn M, et al. Recommendations for Conduct, Methodological Practices, and Reporting of Cost-effectiveness Analyses: Second Panel on Cost-Effectiveness in Health and Medicine. JAMA. 2016; 316:1093–1103. doi: 10.1001/jama.2016.12195 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref036] 36.Edejer TT-T, Baltussen R, Adam T, World Health Organization. Making choices in health: who guide to cost-effectiveness analysis. Geneva, Switzerland:2003:67–71. https://apps.who.int/iris/handle/10665/42699 Accessed 14 December, 2022. [Google Scholar]

[pntd.0011129.ref037] 37.Ikeda S, Shiroiwa T, Igarashi A, Noto S, Fukuda T, Saito S, et al. Developing a Japanese version of the EQ-5D-5L value set. J. Natl. Inst. Public Health. 2015;64:47–55. [Japanese] [Google Scholar]

[pntd.0011129.ref038] 38.Rosadas C, Assone T, Yamashita M, Adonis A, Puccioni-Sohler M, Santos M, et al. Health state utility values in people living with HTLV-1 and in patients with HAM/TSP: The impact of a neglected disease on the quality of life. PLoS Negl Trop Dis. 2020;14:e0008761. doi: 10.1371/journal.pntd.0008761 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref039] 39.Patel KK, Zeidan AM, Shallis RM, Prebet T, Podoltsev N, Huntington SF. Cost-effectiveness of azacitidine and venetoclax in unfit patients with previously untreated acute myeloid leukemia. Blood Adv. 2021;5:994–1002. doi: 10.1182/bloodadvances.2020003902 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref040] 40.Malik B, Taylor GP. Can we reduce the incidence of adult T-cell leukaemia/lymphoma? Cost-effectiveness of human T-lymphotropic virus type 1 (HTLV-1) antenatal screening in the United Kingdom. Br J Haematol. 2019;184:1040–1043. doi: 10.1111/bjh.15234 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref041] 41.Djuicy DD, Mouinga-Ondémé A, Cassar O, Ramassamy J-L, Idam Mamimandjiami A, Bikangui R, et al. Risk factors for HTLV-1 infection in Central Africa: A rural population-based survey in Gabon. PLoS Negl Trop Dis. 2018;12:e0006832. doi: 10.1371/journal.pntd.0006832 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref042] 42.Paiva AM, Assone T, Haziot MEJ, Smid J, Fonseca LAM, Luiz ODC, et al. Risk factors associated with HTLV-1 vertical transmission in Brazil: longer breastfeeding, higher maternal proviral load and previous HTLV-1-infected offspring. Sci Rep. 2018;8:7742. doi: 10.1038/s41598-018-25939-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref043] 43.Ngoma AM, Omokoko MD, Mutombo PB, Mvika ES, Muwonga JM, Nollet KE, et al. Population-based prevalence of human T-lymphotropic virus type 1 in sub-Saharan Africa: a systematic review and meta-analysis. Trop Med Int Health. 2019;24:1277–1290. doi: 10.1111/tmi.13305 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref044] 44.Paiva A, Casseb J. Sexual transmission of human T-cell lymphotropic virus type 1. Rev Soc Bras Med Trop. 2014;47:265–274. doi: 10.1590/0037-8682-0232-2013 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref045] 45.Frey K, Lociciro S, Blank P, Schwenkglenks M, Dubois-Arber F, Rosenbrock R, et al. ’Break the Chains 2015’ community-based HIV prevention campaign for men who have sex with men in Switzerland: non-randomised evaluation and cost analysis. BMJ Open. 2020;10:e032459. doi: 10.1136/bmjopen-2019-032459 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref046] 46.Onoya D, Mohlabane N, Maduna V, van Zyl J, Sewpaul R, Naidoo Y. Testing in the HIV Counselling and Testing (HCT) campaign, HIV risk behaviours and ART enrolment in South Africa. Public Health. 2016;136:152–160. doi: 10.1016/j.puhe.2016.03.029 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref047] 47.Willems L, Hasegawa H, Accolla R, Bangham C, Bazarbachi A, Bertazzoni U, et al. Reducing the global burden of HTLV-1 infection: An agenda for research and action. Antiviral Res. 2017;137:41–48. doi: 10.1016/j.antiviral.2016.10.015 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref048] 48.de Thé G, Bomford R. An HTLV-I vaccine: why, how, for whom?. AIDS Res Hum Retroviruses. 1993;9:381–386. doi: 10.1089/aid.1993.9.381 [DOI] [PubMed] [Google Scholar]

[pntd.0011129.ref049] 49.Del Ciampo LA, Del Ciampo IRL. Breastfeeding and the Benefits of Lactation for Women’s Health. Aleitamento materno e seus benefícios para a saúde da mulher. Rev Bras Ginecol Obstet. 2018;40:354–359. [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0011129.ref050] 50.American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2012;129:e827–e841. doi: 10.1542/peds.2011-3552 [DOI] [PubMed] [Google Scholar]

PERMALINK

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

Akiko Kowada

Roles

Abstract

Background

Methodology/Principal findings

Conclusion/Significance

Author summary

Introduction

Materials and methods

Study design

Model structure

HTLV-1 antenatal screening

No screening

Model inputs

Clinical probability

Table 1. Input parameters of selected variables.

Cost

Health utility

Fig 1. Simplified schematic depiction of a state transition diagram.

Sensitivity analysis

Markov cohort analysis

Results

Base-case analysis

Table 2. Base-case analysis.

Sensitivity analyses

Fig 2. ICER tornado diagram for HTLV-1 antenatal screening versus no screening.

Fig 3. Two-way sensitivity analysis for the maternal HTLV-1 seropositivity rate and the proportion of long-term breastfeeding.

Fig 4. Cost-effectiveness acceptability curve.

Fig 5. ICE scatterplot with a 95% confidence ellipse at a WTP threshold of US$50,000 per QALY gained.

Cumulative lifetime economic and health outcomes

Table 3. Economic and health outcomes of HTLV-1 antenatal screening vs no screening.

Discussion

Conclusion

Data Availability

Funding Statement

References

Decision Letter 0

Eugenia Corrales-Aguilar

Roles

Author response to Decision Letter 0

Decision Letter 1

Graham P Taylor

Eugenia Corrales-Aguilar

Roles

Author response to Decision Letter 1

Decision Letter 2

Graham P Taylor

Eugenia Corrales-Aguilar

Roles

Author response to Decision Letter 2

Decision Letter 3

Graham P Taylor

Eugenia Corrales-Aguilar

Roles

Acceptance letter

Graham P Taylor

Eugenia Corrales-Aguilar

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases