Time to eradicate HTLV-1: an open letter to WHO
10, May 2018
**Summary version of this letter published Lancet here.
On behalf of Human T Cell Leukemia Virus-1 (HTLV-1) positive patients, expert clinicians and scientists working in the field of HTLV-1 clinical and laboratory research.
Dear Dr. Tedros Ghebreyesus,
We are writing to you today to ask you to support the promotion of proven effective transmission prevention strategies against one of the most potent human carcinogens, Human T Leukemia Virus subtype 1 (HTLV-1).
With this letter, we hope to raise your awareness about several current shortcomings and potential solutions in this field.
Our global community has been slow to respond to the HTLV-1 predicament, a virus transmitted through body fluids, causing significant morbidity and mortality. This is almost certainly due to having to address many other pressing health priorities. However today we are encouraged by the WHO’s mandate to value a healthy sexual life and the availability of many WHO fact sheets on other blood borne and sexually transmitted viruses such as Hepatitis B and C and HIV.
HTLV-1 is transmitted through the same routes as HIV-1 through infected body fluids, via condom-less sexual intercourse (1-4), breastfeeding (5-7), sharing of needles (8-11) and the transfusion (12, 13) and transplantation of infected blood and organ donations (14-17).
Recently published prevalence data from Central Australia (where in some communities 45% of adults live with HTLV-1)(18), Japan (19) and Brazil (20, 21) report the importance of HTLV-1’s sexual transmission. The sexual transmission of HTLV-1 was also highlighted in several presentations at the 18th International Retrovirology Conference in Tokyo in Japan in March 2017 (Satake, M. et al O-1-5, Morita, M. et al P-A-6, Fuchi, N. et al P-A-12) and at the 2017 Australasian HIV & AIDS and Sexual Health Conference in Canberra in Australia (22).
In 2012 Antoine Gessain and Olivier Cassar (23) published a systematic review of available data on HTLV-1 origin and prevalence, which we are drawing upon to provide you with an overview of the word distribution of HTLV-1. It is well understood that HTLV-1 originated from non-human primates. It is an ancient virus and its prevalence is complex, in that it is highly endemic in some parts of the world, but regrettably available surveillance data is not comprehensive, and in many regions, accounting for 6 billion persons, HTLV-1 prevalence remains unknown.
HTLV-1 has been detected in most parts of Africa. In Gabon, a HTLV-1 sero-prevalence of 5–10% has been observed in adults, 1-5% in pregnant women and in some villages up to 25% of older women are HTLV-1 positive. In Nigeria, an estimated 850,000 to 1.7 million people are infected with this virus. In Central African Republic, HTLV-1 infection has been reported in 7% of older, female Pygmies of Southern region.
In Japan, an estimated 0.8 million people are HTLV-1 positive and in Southern regions 30–40% of adults > 50 years of age and up to 5.8% of pregnant women carry this virus.
In Jamaica, the estimated mean HTLV-1 sero-prevalence is 6.1% (1.7- 17.4%) in the general population (including older persons) and is as high as 2–3.8% among pregnant women and blood donors. Other Caribbean islands that have been studied have similar prevalence rates.
In areas of Brazil, especially in people of African ancestry, HTLV-1 prevalence has been reported in 1.3% in blood donors, 1.8% in the general population and 1.05% in pregnant women with 33% of their family members including children found to be positive.
In Iran, up to 3% of adults are infected in the Mashad area but HTLV-1 is found across the country.
In Romania, the HTLV-1 prevalence has been reported to be 5.3/10,000 among first-time blood donors, and 3-25% in poly-transfused patients.
In non-endemic areas, due to the migration of people and the sexual transmission of the virus, HTLV-1 and 2 have also been detected. In the UK 20,000 – 30,000 people live with the virus, whilst in metropolitan France an estimated 10,000 – 25,000 people are HTLV-1 infected. In the USA, it is estimates that approximately 266,000 individuals are infected with HTLV-1 or -2, and that 3,600 people with HAM/TSP remain undiagnosed.
In a recent hospital-based cohort study in Central Australia, 635/1889 (33.6 %) tested Indigenous people were HTLV-1 positive. Only one of 77 (1.3 %) children tested positive but with age a sharp increase in prevalence rates were observed (15-29 years, 17.3 %; 30-49 years, 36.2 %; 50-64 years, 41.7 %), reaching 48.5 % in men older than 50 years of age (18).
As with most blood borne and sexually transmitted viruses the majority of HTLV-1 positive people transmit the virus unknowingly and are unaware that they are at risk of developing diseases caused by HTLV-1.
HTLV-1 was the 1st infectious agent discovered to be the direct cause of human cancer and is the most carcinogenic of all oncoviruses (24). HTLV-1 causes Adult T Cell Leukemia/Lymphoma (ATL) which depending on subtype, timing of diagnosis and access to treatment, has a median survival of 8 to 10 months despite all the advances in chemotherapy and supportive therapy (25, 26). The lifetime probability of developing ATL is 4-5 in 100 people infected with HTLV-1 (27, 28), and ATL is attributed to the acquisition of the infection in infancy, through breastfeeding. Thus, it is a preventable malignancy and, in our opinion public health efforts to prevent its transmission should be comparable to other preventable cancers. For instance, the WHO’s promotion and prevention strategies to reduce smoking related lung cancers are exemplary (WHO Health Topic: Tobacco), though the lifetime risk of developing lung cancer through smoking cigarettes is only 14: 1000 (29).
In addition, HTLV-1 causes chronic, progressing, disabling and painful conditions such as myelopathy and polymyositis as well as chronic inflammatory pulmonary disease, uveitis and dermatitis (30).
The lifetime risk of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) approaches 4 in 100 infected people (31-36), with an average of 8 years delay in diagnosis and treatment due to lack of awareness and testing (37). Patients with HAM/TSP suffer from decades of progressive walking disability, chronic severe back and leg pain, incontinence and urinary retention, severe constipation and sexual dysfunction, all of which lead to social isolation. HAM/TSP affects both adults and children but mostly women, and has been associated with the acquisition of HTLV-1 through organ donation (17) (18th International Retrovirology Conference in Tokyo in Japan in March 2017: Yuzawa K. et al O-5-7).
Despite its distinct etiology and distinctive pattern there is no International Classification of Disease Code (ICD code) for HAM/TSP, an extraordinary state of affairs for a disease described for the first time by Eric Cruickshank in 1956 (38), linked to HTLV-1 in 1985 and for which WHO has had diagnostic criteria since 1989 (39). Patients living with HTLV-1 and/or suffering from HAM/TSP find this omission incredulous. We truly hope that you can help us rectify this serious oversight in order to reduce the under-diagnosis and under-reporting of this disease.
HTLV-1 was discovered 37 years ago (40), just before the AIDS epidemic. It is acknowledged that HTLV-1 research led to the idea that AIDS might be caused by a new retrovirus and therefore greatly abetted the identification of HIV-1. It is disappointing that despite the significance of HTLV-1 research in the fight against AIDS, in comparison to HIV-1, people who are infected with HTLV-1 have received very little attention in form of publicity, development of international clinical guidelines or financial investment into drug development and clinical trials (41).
Worldwide it is mostly women, who carry the burden of HTLV-1 infection and its associated diseases: Women, who become infected through condom-less sex, and their babies, who are infected through breastfeeding. Therefore HTLV-1 is highly concentrated in families [1:3 to 1:4 of family members carry the virus (42, 43)].
In your speech on 3 July 2017 you fearlessly stated that the WHO is fully committed to ‘Every Woman Every Child’. You asked for quality, equity and dignity in services for sexual and reproductive health, equal rights and the empowerment of women, girls and communities. Today we are asking you to include families at risk of HTLV-1 in your list of goals to improve global health.
We would like to support the WHO by using published evidence on HTLV-1’s prevalence and mode of transmission together with the established understanding of effective transmission prevention strategies against blood borne and sexually transmitted viruses, to produce a clear and evidence-based WHO HTLV-1 Fact Sheet, which would inform WHO web-users world-wide.
A recent review of WHO’s website revealed that the information on HTLV-1 could benefit from an evidence-based update, supported by HTLV-1 experts and patient representatives living with this virus. We need to visibly share the information that about 80% of HTLV-1 infection is transmitted sexually [4000 cases/annum of sexual transmission in Japan alone (19)] with most of the remaining 20% of transmission being attributed to mother to child transmission, predominantly through breastfeeding [up to 32% risk to the infant depending on the duration of breastfeeding (44)]. We would like to see an emphasis on the fact that HTLV-1 is highly transmissible through infected blood and that the risk through organ transplantation may be 100% with 2 out of 3 organ recipients thus infected developing HAM/TSP within 4 years (18th International Retrovirology Conference in Tokyo in Japan in March 2017: Yuzawa K. et al O-5-7).
So far, an astounding 17 different prevention strategies have been identified to reduce the risk the transmission of other blood borne and sexually transmittable viruses, such as Hepatitis B & C and HIV (Table 1) but not for HTLV-1.