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Blocking HTLV-1/2 silent transmission in Brazil: Current public health policies and proposal for additional strategies

['Carolina Rosadas', 'Section Of Virology', 'Department Of Infectious Disease', 'Imperial College London', 'London', 'United Kingdom', 'Maria Luiza B. Menezes', 'Departamento Materno-Infantil', 'Faculdade De Ciências Médicas', 'Universidade De Pernambuco']

Date: 2021-09

HTLV-1 is already included in the Clinical Protocol and Therapeutic Guidelines for Sexually Transmitted Infections (PCDT IST) published by the Brazilian MoH [ 32 ]. Information about HTLV-1 is also available on the website of the Department of Chronic Diseases and Sexually Transmitted Infections of MoH. Additional strategies aiming to prevent HTLV-1/2 sexual transmission should include the following:

Screening for HTLV-1 is compulsory for both donors and recipients for assisted reproduction. HTLV-1 infection is considered an exclusion criterion for reproductive gamete donors since 2011 [ 33 ]. It is important to stress that HTLV-1 infection should not be an obstacle for HTLV-1 discordant couples wishing to procreate. Medical advice should be sought, and couples should be tested for other STI. If the woman is infected by HTLV-1, assisted reproduction (domestic insemination) should be offered. If the man is infected, sperm washing followed by artificial insemination could be considered based on biological principle. This process, current in use for HIV discordant couples, should be highly effective in preventing HTLV-1 transmission by separating the sperm from the seminal fluid and cells. This is recommended by the American Society for Reproductive Medicine [ 34 ]. However, the European Society of Human Reproduction and Embryology (ESHRE) concluded that there is not enough evidence to recommend the routine use of advanced processing of semen from HTLV-1/2 seropositive patients [ 35 ]. In the absence of sperm washing, the use of barrier contraception except following ovulation with support and education for the couple to identify the fertile period could be considered as a risk reduction strategy. It is worth noting that published transmission data are focused on discordant couples where HTLV transmission has not occurred despite prior unprotected sexual intercourse and that the risk of transmission in new relationships may be considerably higher. A case of HAM following a single sexual exposure to HTLV-1 has been reported [ 36 ].

Effective prevention of HTLV-1/2 sexual transmission is primarily linked to the use of barrier methods during sexual activity. However, public policies to prevent this route of infection should not rely solely on safer sex, but rather on an integrated strategy, requiring biomedical, behavioural, and structural interventions, as for other STI [ 32 ]. Perversely, strategies developed to prevent HIV transmission may result in increased exposure to HTLV if reliance on, for example, HIV-specific pre-exposure prophylaxis (PreP) displaces broader STI reduction approaches, unless antiretrovirals that inhibit both viruses (particularly integrase inhibitors) are used.

HTLV-1/2 infected cells are present in seminal and vaginal fluid and are transmitted by unprotected sexual intercourse [ 26 – 29 ]. High HTLV-1 DNA copy number (also known as proviral load, PVL) in circulating peripheral blood mononuclear cells (PBMCs) is a known risk factor for sexual transmission, and the efficiency of HTLV-1 transmission is higher from male to female than from female to male [ 26 ]. Some authors hypothesise that penile ulcers and lesions on vaginal mucosa, which may occur as a result of other sexually transmitted infections (STIs), may facilitate HTLV-1 sexual transmission. In fact, cervicitis increases HTLV-1 shedding, and the prevalence of HTLV-1 infection is higher in patients with STI, such as syphilis, chlamydia, and human papilloma virus [ 30 , 31 ].

Needle sharing among people who inject recreational drugs is another important route of HTLV-1/2 parenteral dissemination. High prevalence rates of HTLV-1/2 among this specific population have been frequently reported [ 2 , 49 – 51 ]. A comprehensive strategy focusing on this vulnerable population is of utmost importance. These are already undergoing as part of HIV-1 and other STI prevention programmes and comprise a range of activities including more simple strategies such as offering harm reduction initiatives, provision of sterile needles for people who inject drugs, and enabling the safe disposal of needles and syringes up to more complex interventions. Complex interventions comprise behavioural and structural changes aiming to reduce stigma, inequalities, and any barrier that may prevent access to universal health. HTLV-1/2 transmission by skin scarification and self-flagellation has been reported in indigenous people and during religious ceremonies [ 52 – 54 ].

The current Brazilian policies to prevent HTLV-1/2 parenteral transmission are important but still need improvement. A crucial point is to include complementary tests (confirmatory and discriminatory for HTLV-1 and HTLV-2) for those persons with seroreactive tests in the screening assay. Positive ELISA tests should be followed by western blot (WB) and/or PCR to avoid false-positive results and the uncertainty and discomfort that unconfirmed reactivity generates for the donors. Assays for confirmatory testing for HTLV-1/2 were made available to the public health system in 2016 but are limited to those persons who need laboratory confirmation of ATL [ 43 ]. The inclusion of line immunoassay (LIA) is recommended based on its superior performance compared to WB [ 44 – 46 ]. A screening test is insufficient to diagnose HTLV-1/2 infection, and confirmation is necessary for those who are willing to donate their blood and organs. Blood and organ donation is, above all, an act of kindness and selflessness. It is not unusual to come across individuals who have been informed of a reactive HTLV-1/2 ELISA test with no further testing, who are subsequently shown to be uninfected, sometimes years after being informed of the screening test result. The impact of a false-positive HTLV-1/2 diagnosis is profound, influencing key life decisions and should not be underestimated. Using the methodology previously described [ 47 ] and considering (1) 3.3 million of blood donors; (2) specificity of screening test [ 48 ]; and (3) prevalence of HTLV-1 infection in blood donors [ 2 ], we have estimated that HTLV-1/2 screening would result in 8,580 to 256,080 false-positive results annually. The lack of national reference centres for counselling and follow-up of PLHTLV or those with seroreactivity in screening test adds uncertainty for those newly diagnosed individuals.

HTLV-1/2 screening of blood donors was implemented in Brazil in 1993 and constitutes a key measure to control parenteral transmission of these viruses [ 37 ]. Donors and recipients of organs, tissues, cells, or body parts are also screened since 2009 [ 38 ]. HTLV-1/2 infection is a definitive exclusion criterion. ATL and HAM has been described in patients infected peri-transplantation. The risk of HTLV-1 infection following solid organ transplantation is 100%, and the risk of HAM following HTLV-1 infection acquired by this route is high (40%) and occurs after a relatively short interval (3.8 years) [ 39 – 41 ]. The risk acceptance of HTLV-1 infection as a consequence of solid organ transplantation was investigated in Canada and confirmed that patients would not be willing to forego HTLV-1 screening of solid organs donors [ 42 ].

HTLV-1/2 mother-to-child transmission.

HTLV-1/2 is transmitted from mother to child, mainly by breastfeeding. Residual transmission may occur in about 2.5% of those children that are exclusively fed by milk formula substitutes, indicating that transmission may occur during pregnancy or delivery [55]. In Brazil, in urban areas, mother-to-child transmission rate was reported to be 14.1% [56], with an estimated number of new infections reaching at least 16,500 new cases annually [57]. Low-income pregnant women with (i) high HTLV-1 PVL in blood and milk; (ii) breastfeeding for longer periods; (iii) HLA concordance between mother and child; (iv) Strongyloides sp. coinfection; and (v) patients with HAM have a higher risk of transmitting HTLV-1 to their children [55]. Vertical transmission of HTLV-1 is not only implicated with higher risk of adverse clinical outcome associated with HTLV-1 infection but also with maternal feelings of guilt [58,59]. Among highly vulnerable indigenous communities in the Amazon region of Brazil, mother-to-child transmission of HTLV-2 is common and reaches as high as 30% [54,60]. There are no clear consequences of the perpetuation of this virus among semi-closed and isolated communities nor policies towards the elimination of HTLV-2 among these population groups.

The Brazilian MoH recommends the interruption of breastfeeding, using pharmaceutical intervention of mothers to suppress lactation (Cabergolin), and provision of milk formula substitutes for those babies born of HTLV-1/2 seropositive women [32,61]. The first step should be to identify those pregnant women that are infected with HTLV-1/2. A national antenatal screening programme is of utmost importance and should be a priority in the country. Some Brazilian States, including Bahia, Minas Gerais, and Mato Grosso do Sul, have implemented HTLV-1/2 policies for antenatal screening, but the measure should be expanded and implemented nationally, as in Japan. In fact, Japan first implemented regional antenatal screening combined with other policies to avoid mother-to-child transmission in the late 1980s [62,63]. The national screening programme, established in 2010, is one of the main pillars to achieve their aim to eliminate HTLV-1/2 infection in Japan. It is worth mentioning that short-term breastfeeding and use of freeze and thaw maternal milk were reported to reduce the risk of transmission but not as effectively as the avoidance of breastfeeding. Although all the measures were initially recommended in Japan, this was revised in 2016 to recommend exclusive milk formula substitutes feeding for the babies of all mothers who are positive for HTLV-1 [63]. In situations where exclusive formula feeding is not acceptable, feasible, affordable, sustainable, and safe (AFASS), alternative methods to reduce the risk of transmission may still be considered. Limiting the duration of breastfeeding is not always practical or achieved, and, therefore, in such settings, innovative alternatives are needed.

A graphic summary for the proposed clinical management of HTLV-1/2 infection in pregnant women and prevention of mother-to-child transmission is shown in Fig 1. Antenatal screening is strongly recommended at the first trimester, which would allow proper confirmatory testing and counselling for those seropositive mothers prior to delivery. The diagnostic algorithm should be similar as to the general population, using an ELISA or CMIA as screening test, followed by confirmation using PCR, WB, or LIA [64]. Pregnancy does not adversely affect HTLV-1 diagnosis[65]. Counselling and detailed clinical evaluation should be offered to identify signs or symptoms of any HTLV-1/2–associated diseases, and it is important to reinforce the information about the risk of HTLV-1/2 transmission and importance of avoidance of breastfeeding. Stigma and prejudice may impair the adherence of new mothers to the recommendations [66,67]. A recent study commissioned by WHO identified that women infected by HTLV express concerns about social perceptions of not breastfeeding, as well as the artificial alternatives of breast milk[59,66]. Mothers commonly indicate that they are afraid of not bonding to the child if they do not breastfeed [59]. Misconceptions must be fully discussed during counselling. In addition, the limited knowledge of healthcare professionals about HTLV-1/2 should be addressed in order to avoid misleading recommendations [68].

HTLV-1/2 testing should be offered for relatives, including sexual partners and children of previous pregnancies. Antiretroviral drugs do not decrease HTLV-1/2 PVL in established infection and are not currently recommended for the prevention of mother-to-child transmission, although this has been offered in very high–risk cases of mothers with ATL in pregnancy [69]. Although some argue that cesarean section should be recommended to pregnant women with HTLV-1/2 infection [70], there is no consensus about the impact of the procedure in reducing the risk of HTLV-1/2 mother-to-child transmission. However, avoiding contact between maternal blood and the neonate during delivery was linked to the reduction of HTLV-1 transmission among exclusive formula-feed children in Japan [71]. In Brazil, when a woman living with HTLV-1/2 is submitted to cesarean section, immediate clamping of the umbilical cord is recommended [72].

Postnatal care should include early cessation of breastfeeding. Milk formula substitutes should be offered for women living with HTLV-1/2, which is already available in some Brazilian states, including Bahia and São Paulo. Screening of infants is necessary to rule out mother-to-child transmission of HTLV-1/2, and the aforementioned diagnostic algorithm can be used if the child is older than 18 months. If the child is tested earlier, maternal antibodies may be detected by serological assays. Seroconversion has been shown in long-term follow-up studies with incident infection in breastfed babies as late as 3 years of age [73,74]. No seroconversions were reported in a longitudinal study of breastfed children from age 2 to 12 years old [75]. Multidisciplinary lifelong follow-up is needed for PLHTLV. Specialised centres play an important role advising mothers-to-be who live with HTLV-1/2 infection. Studies showed that they are vital as the women tend to trust their advice even when faced with contradictory views from other health staff [66,68,76].

The Brazilian MoH has implemented one of the most successful antenatal programmes to prevent other STI, including HIV-1 and in three Brazilian cities (São Paulo, Curitiba e Umuarama), the elimination of vertical transmission of HIV-1 has been highly successful. The network and knowledge are already established in the country, and the prevention of HTLV-1/2 transmission should be considered as an extension of a successful existing programme. Recently, HTLV-1/2 infection has been addressed in the Clinical Protocol and Therapeutic Guidelines for Prevention of Vertical Transmission of HIV, Syphilis, and Viral Hepatitis, published by the Brazilian MoH [61].

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