Impact and economic analysis of human T-cell lymphotropic virus type 1 (HTLV-1)-targeted antenatal screening, England and Wales, 2021.

BackgroundHuman T-cell lymphotropic virus type 1 (HTLV-1) is a neglected virus that can cause severe disease and be transmitted from mother to child through breastfeeding. Avoidance of breastfeeding prevents 80% of vertical transmission. The United Kingdom (UK) is currently assessing whether HTLV-1-targeted antenatal screening should be implemented.AimWe aimed to assess the impact and cost-effectiveness of a targeted programme to prevent HTLV-1 vertical transmission in England and Wales.MethodsWe estimated the number of pregnant women who have high risk of HTLV-1 infection based on their or their partner's country of birth. With data from 2021, we used a mathematical model to assess cost-effectiveness of HTLV-1 antenatal screening. We also estimated the annual number of infant infections and the number that could be prevented with screening and intervention.ResultsWe estimate that ca 99,000 pregnant women in England and Wales have high risk of HTLV-1 infection. In the absence of screening, 74 (range: 25-211) HTLV-1 infections in infants would be expected to occur every year in England and Wales. Implementation of targeted screening would prevent 58 (range: 19-164) infant infections annually. The intervention is effective (incremental 0.00333 quality-adjusted life years (QALY)) and cost-saving (GBP -57.56 (EUR -66.85)).ConclusionOur findings support implementation of HTLV-1 targeted antenatal screening to reduce vertical transmission from mothers to infants in the UK.

Detecção pré-natal de infecção pelo vírus T-linfotrópico humano (HTLV) 1/2 em gestantes / Prenatal detection of human T-lymphotropic virus (HTLV) 1/2 infection in pregnant women

INTRODUÇÃO: O vírus T-linfotrópico humano HTLV-1 e HTLV-2 são retrovírus com potencial oncogênico, sendo particularmente associados à gênese da leucemia de células T do adulto (ATL). Além disso, estes se relacionam a diversas doenças não-neoplásicas de natureza inflamatória, sendo a mielopatia associada ao HTLV/paraparesia espástica tropical (HAM/TSP) e uveíte pelo HTLV-1 (HU) as mais conhecidas. A infecção pelo HTLV-1/2 tem distribuição mundial, com uma estimativa de até 15 a 20 milhões de pessoas afetadas e, uma vez estabelecida, permanece por toda a vida do indivíduo e na maioria dos casos permanece assintomática, tornando estes indivíduos reservatórios virais. Cerca de 4% dos portadores de HTLV-1 desenvolverão ATL, uma malignidade de células T CD4+ altamente agressiva. Por sua vez, a incapacitante HAM, afeta 2 a 3% das pessoas infectadas. As principais formas de transmissão do HTLV-1e 2 são a relação sexual desprotegida, a transmissão vertical, a amamentação e a exposição direta a sangue ou tecidos infectados. Independentemente da região do mundo, a soroprevalência aumenta com a idade, particularmente nas mulheres, tendo em vista a facilidade da transmissão sexual

Assessment of HTLV-1 proviral load, LAT, BIM, c-FOS and RAD51 gene expression in adult T cell leukemia/lymphoma.

Adult T cell leukemia/lymphoma (ATLL) is a life-threatening malignancy of HTLV-1 infected Th lymphocytes. In the present study host-virus interactions were investigated by assessment of HTLV-1 proviral load (PVL) and host gene expression. A cross-sectional study was carried out on 18 ATLL, 10 HAM/TSP patients and 18 HTLV-1 asymptomatic carriers (ACs). DNA and mRNA of the peripheral blood mononuclear cells were extracted for PVL and LAT, BIM, c-FOS and RAD51 gene expression measurement using qRT-PCR. The mean PVL in ATLL patients was 11,430 ± 3770 copies/104 which was statistically higher than ACs, 530 ± 119 copies/104, (p < 0.001). The expression of BIM, and c-FOS in ATLL patients were higher than HTLV-1 ACs; however, there were no statistically significant differences. The expression of RAD51 as an essential player on DNA repair showed around 160 times increase in ATLL group (166 ± 95) compared to ACs (1.04 ± 0.34) which is statistically significant (p < 0.001). Interestingly, there was a positive correlation between RAD51 expression and HTLV-PVL. The expression of LAT as a central adaptor in TCR signaling interestingly was around 36 times higher in ATLL group than ACs (ATLL; 41.33 ± 19.91 vs. ACs; 1.15 ± 0.22, p < 0.001). This finding showed that TCR signaling pathway mainly provides the growth factors for transformed cells. Furthermore, the overexpression of RAD51 which has been induced in HTLV-1 infected cells as a consequence of virus replication is not able to overcome the DNA damage toward cell transformation.

Reducing the global burden of HTLV-1 infection: An agenda for research and action.

Even though an estimated 10-20 million people worldwide are infected with the oncogenic retrovirus, human T-lymphotropic virus type 1 (HTLV-1), its epidemiology is poorly understood, and little effort has been made to reduce its prevalence. In response to this situation, the Global Virus Network launched a taskforce in 2014 to develop new methods of prevention and treatment of HTLV-1 infection and promote basic research. HTLV-1 is the etiological agent of two life-threatening diseases, adult T-cell leukemia and HTLV-associated myelopathy/tropical spastic paraparesis, for which no effective therapy is currently available. Although the modes of transmission of HTLV-1 resemble those of the more familiar HIV-1, routine diagnostic methods are generally unavailable to support the prevention of new infections. In the present article, the Taskforce proposes a series of actions to expand epidemiological studies; increase research on mechanisms of HTLV-1 persistence, replication and pathogenesis; discover effective treatments; and develop prophylactic and therapeutic vaccines.

Infection with human T-lymphotropic virus types-1 and -2 (HTLV-1 and -2): Implications for blood transfusion safety.

Many countries currently perform antibody screening for HTLV-1 infection in blood donors, and this intervention is likely cost-effective in preventing HTLV-1 related diseases in high prevalence countries. However, a number of high-income countries with low prevalence of HTLV-1 infection also perform universal HTLV-1 screening and debate has arisen regarding the cost-effectiveness of these strategies. Filter-based leukoreduction is likely to substantially reduce HTLV-1 transmission by removing infected lymphocytes, but actual laboratory data on its efficacy is currently lacking. Similarly, cost-effectiveness research on HTLV-1 prevention strategies is limited by poor data on prevalence, transmission efficacy and the cost of treating HTLV1 diseases.

Human T-lymphotropic virus and transfusion safety: does one size fit all?

Human T-cell leukemia viruses (HTLV-1 and HTLV-2) are associated with a variety of human diseases, including some severe ones. Transfusion transmission of HTLV through cellular blood components is undeniable. HTLV screening of blood donations became mandatory in different countries to improve the safety of blood supplies. In Japan and Europe, most HTLV-infected donors are HTLV-1 positive, whereas in the United States a higher prevalence of HTLV-2 is reported. Many industrialized countries have also introduced universal leukoreduction of blood components, and pathogen inactivation technologies might be another effective preventive strategy, especially if and when generalized to all blood cellular products. Considering all measures available to minimize HTLV blood transmission, the question is what would be the most suitable and cost-effective strategy to ensure a high level of blood safety regarding these viruses, considering that there is no solution that can be deemed optimal for all countries.

[HTLV and "donating" milk]. / HTLV-1 et don de lait maternel.

In France, the screening for human T-cell leukemia/ lymphoma virus type 1 and 2 (HTLV-1 and HTLV-2) during the donation of human milk has been carried out from 1992 with the application of the circular DGS 24 November 1992. The screening for antibodies against these viruses is regulated and done systematically during every donation of milk. Breast feeding being the main mode of transmission of the HTLV-1, the last ministerial decree of 25 August 2010 has made the screening test compulsory for the anonymous donation and for the personalized donation (of a mother for her own child) from all women including those affected by the infection. The milk delivered by milk banks is pasteurized (62.5 °C for 30 minutes) before freezing at -18 °C, which inactivates the pathogens. This double means of prevention of the transmission of the HTLV-1 paradoxically seems disproportionate in the absence of any precautionary measure in the case of direct breast-feeding and the use of mother's raw milk. Indeed, in most neonatal intensive care units in maternity hospitals, unpasteurized milk is administered to the neonates without any systematic preliminary testing of the serological HTLV-1 status of the mother. An increased sensitization of the community of the obstetricians, midwives and neonatologists by the Association of the Milk Banks of France (ADLF) and the Société de pathologie exotique could address the issue of screening for HTLV-1 in "donated" milk and breast-feeding.

Strategies for diagnosis of HTLV-I and -II.

BACKGROUND: No gold standard exists for diagnosis of HTLV infection. The aim of thus study was to compare the accuracy of a combination of two sensitive ELISAs with Western blot (WB), a line immunoassay, and PCR for diagnosis of HTLV infection. STUDY DESIGN AND METHODS: Nine hundred eighty-five specimens were tested for the presence of HTLV antibodies by HTLV-I and/or HTLV-II EIAs (Murex and Ortho), WB (Diagnostic Biotechnology), line immunoassay (INNO-LIA, Innogenetics), and/or presence of HTLV DNA by PCR. The results were compared with the probable HTLV infection status of each subject, as determined by detailed review of all available laboratory, clinical, and epidemiologic data. RESULTS: The sensitivity for diagnosis of HTLV-I infection was high for all assays evaluated, but both PCR and WB had a lower sensitivity rate (approx., 80%) for confirmation of HTLV-II. INNO-LIA detected 94 percent of the HTLV-II-positive samples. However, Murex EIA in combination with Ortho EIA was 100-percent sensitive for the detection of both HTLV-I and HTLV-II antibodies. Furthermore, the number of samples giving indeterminate results in the ELISA combination was much lower as compared with WB (2.5% vs. 50%). CONCLUSION: Based on these findings, a new, more sensitive and specific test strategy for HTLV diagnosis than the current algorithm, which includes WB, is proposed. Thereby, both the direct and indirect costs can be substantially reduced.

Quantitative assessment of subclinical spasticity in human T-cell lymphotropic virus type I infection.

OBJECTIVE: To compare human T-cell lymphotrophic virus type I (HTLV-I) seropositive and seronegative women for symptoms and signs of spasticity. BACKGROUND: Infection with HTLV-I causes tropical spastic paraparesis/ HTLV-I-associated myelopathy (TSP/HAM). Certain populations, including female commercial sex workers (FSW), are at increased risk of developing this infection. Fewer than 5% of HTLV-I-seropositive persons develop TSP/HAM, which is typically associated with spasticity. METHODS: Cross-sectional study of 255 registered FSW in Callao, Perú, involving a questionnaire detailing demographics and neurologic symptoms, standard neurologic examination, quantitative assessment of spasticity (QSA) of muscle tone, and serologic testing for HTLV-I. Participants and examiners were blinded to serology results. RESULTS: On the questionnaire and neurologic examination, none of the 32 HTLV-I-seropositive or 223 seronegative women had signs or symptoms of spasticity. However, mean values on QSA were significantly higher among seropositive women (27.1 Newton-meters/radian [N-m/r]) than among seronegative women (21.6 N-m/r, p = 0.01), indicating a subclinical increase in lower extremity tone. With values of QSA divided into tertiles, and the first tertile serving as the comparison group, the odds ratio for seropositivity was 1.4 (95% confidence interval [CI] 1.0 to 2.0) in the second and 3.1 (95% CI 2.2 to 4.3) in the third tertile, after adjusting for age and place of birth. CONCLUSIONS: Although a standard neurologic evaluation could not distinguish between women with and without HTLV-I infection, QSA indicated significantly increased lower extremity tone in those with infection. Long-term follow-up will determine whether these subclinical findings in asymptomatic women progress to overt TSP/HAM.

[Cost-effective approach to the screening of HIV, HBV, HCV, HTLV in blood donors in France]. / Approche coût-efficacité du dépistage des virus VIH, VHB, VHC, HTLV chez les donneurs de sang en France.

In order to provide greater safety in blood transfusions, public health authorities have imposed the use of screening tests. The purpose of this paper is to estimate the cost-effectiveness ratios of the screening test used in France. Four risks were studied: HIV, HBV, HCV and HTLV. Two efficiency measures were used: cost per positive blood donation detected and cost per case of prevented infection transmission. Moreover, for HTLV alone, the efficiency was estimated by the cost per prevented pathology. Data concerning the costs were provided by the French Blood Agency; those concerning the results of the screening campaigns were provided by the official health authorities, the other data used in the calculations were drawn either from the French Blood Agency data or from a review of international literature. Results gave information about the expenditure devoted to the screening of virologic risks associated with blood transfusion in France (250 million francs per year for the four viruses studied). They stressed the differences in screening efficiency according to the test studied (the cost by prevented seroconversion varied from 31,795 francs for HBV, 72,180 francs for HCV, 676,596 francs for HIV to 6,137,346 francs for HTLV screening test in the base case) and especially the very low efficiency of the systematic screening of the HTLV virus (from 34 to 307 million francs per prevented leukemia).

International forum: Saudi Arabia. Donor screening for HTLV-I in Saudi Arabia: is it cost effective?

After screening over 100,000 blood donations for the presence of anti-HTLV-I antibodies, a final prevalence of 0.0038% was established in a multinational donor population. Among 38,201 donations by Saudi Arabian donors, the prevalence was found to be 0.0052%. Fifty-eight donors were found to be repeat reactive in the EIA screen test, but only 6.9% of these (n = 4) were truly infected with HTLV-I as judged by the Western blot result. These results indicate that Saudi Arabia is non-endemic for HTLV-I as well as HTLV-II. The cost effectiveness of screening for HTLV-I in healthy blood donors from this area is highly questionable. Calculations point to a final risk of a case of post-transfusion HTLV-I associated disease of approximately one per 100 years at the current level of activity.

[Vertical transmission human T-cell lymphotropic virus type-I (HTLV-I)--genetic diagnosis and assessment of the probable routes of HTLV-I infection].

Human T-cell lymphotropic virus type-I (HTLV-I) provirus DNA from peripheral lymphocyte of 39 infants delivered by 26 pregnant carriers was detected by the nested double polymerase chain reaction (PCR) method to identify vertical transmission (VT) of HTLV-I. The 39 infants included 12 breast-fed and 27 bottle-fed infants. Particle agglutination (PA) assay and indirect immunofluorescence (IF) test with 467 cells were performed to detect anti-HTLV-I antibody. In breast-fed infants, two (16.7%) cases were both seropositive and PCR-positive and others were both negative, so there was perfect agreement between seropositivity and PCR-positivity. In bottle-fed infants, two (7.4%) cases were seropositive but PCR-negative. This seropositivity was supposed to be due to the transplacental maternal anti-HTLV-I antibody. In 25 seronegative bottle-fed infants, 4 (14.8%) cases were PCR-positive. No significant difference was found in the PCR-positivity rate between the breast-fed and bottle-fed groups. Our study showed the usefulness of the PCR method in identifying VT, the existence of silent carriers especially in bottle-fed infants and the possibility of transplacental or birth canal routes of HTLV-I infection.

Seroepidemiology of HTLV-I/II in universal screening of blood donations in France.

OBJECTIVE: To evaluate the serological and epidemiological characteristics of HTLV-I/II-positive blood donors in continental France during the first 6 months of universal screening of blood donations (n = 1,816,927). METHOD: A collaborative investigation of all confirmed anti-HTLV-I/II-positive samples reported by blood transfusion centres was performed. Seventy-three out of 77 reported samples were retested at two reference laboratories. Epidemiological data on risk factors were compiled. RESULTS: Of the 73 retested samples, 66 were confirmed to be HTLV-I-positive and one to be HTLV-II-positive; six samples were designated false-positive, mainly because of non-specific reactivity to recombinant gp21 in Western blot. The overall prevalence of HTLV-I/II in continental France is 0.039 per thousand. The main risk factor identified for HTLV-I infection was directly (origin) or indirectly (heterosexual contact) linked to endemicity in the Caribbean. The cost per case of avoided contamination in the 6-month period of this study was 1.36 million French francs. CONCLUSIONS: Sixty-two per cent of HTLV-I/II-infected blood donations would not have been discarded through the previous targeted HTLV screening or through other mandatory tests, including anti-hepatitis B core. To avoid false-positive results, we propose a new algorithm of diagnosis.

Detection of human T-cell lymphotropic virus type 1 infection by the polymerase chain reaction using dried blood specimens on filter papers.

A simple method for detection of proviral DNA sequences of human T-cell lymphotropic virus type 1 (HTLV-1) was developed using dried blood specimens on filter papers. The whole blood was blotted onto the Guthrie paper. After the blood has dried, the blotted paper was punched out into small discs. The discs were then boiled to prepare the template for PCR (filter paper-PCR method). The filter paper-PCR method detected even a single HTLV-1-infected cell in three discs. The sensitivity of the filter paper-PCR method was equivalent to that of the method in which DNA was extracted with phenol and used as the template for PCR (DNA extraction-PCR method). In addition, DNA in the blotted filter paper was still utilizable as the template after the storage at 25 degrees C for at least 7 wk. A total of 53 clinical specimens from 30 seropositive and 23 seronegative individuals who were screened by particle agglutination (PA) test were analysed for HTLV-1 DNA by both PCR methods. Of 30 PA-positive specimens, 28 were also positive for HTLV-1 antibody by Western blot (WB) analysis, but two were indeterminate. The twenty eight WB-positive and one of the two indeterminate specimens were positive for HTLV-1 proviral DNA by both PCR methods. Of 23 PA-negative specimens, 22 were negative for HTLV-1 proviral DNA by both PCR methods. However, one PA-negative specimen was positive by both PCR methods. This patient was a 16-mth-old infant who was born to an HTLV-1 carrier mother and fed thereafter without her breast milk. In comparison to DNA extraction-PCR method, the sensitivity and specificity of the filter paper-PCR method was 100%, respectively.

Screening blood products for HTLV-I: what is the best approach?

A recent concern for disease transmission by blood transfusion is T-lymphotropic virus type I (HTLV-I). This virus is endemic in Japan, the Caribbean basin, subsaharan Africa, and, to a lesser extent, the southeastern United States and parts of Central and South America. HTLV-I, which has been shown to be transmitted via transfusion, is associated with adult T-cell leukemia (ATL) and certain degenerative neurological disorders. Antibodies to HTLV-I, an indicator of exposure to the virus, have been demonstrated in 0.025% of healthy U.S. donors. This study, using the Decision Tree Model, presents an approach to a donor screening policy which should be cost-effective and yet ensure a safe blood supply.