Time to eradicate HTLV-1: an open letter to WHO

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), but ATL only occurs as a consequence of mother to child transmission (MTCT), which contributes to 20-24% of all HTLV-1 infections (28). Therefore the lifetime probability of developing ATL is 1 in 4 HTLV-1-infected infants (28). 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 increased risk of developing lung cancer through smoking cigarettes is about 160/1000 (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 .

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 with most of the remaining 20% of transmission being attributed to mother to child transmission, predominantly through breastfeeding . 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.

  HBV HTLV HIV HCV
Discovered 1965 1980 1983 1989
Vaccine ✓ NA NA NA
Test ✓ ✓ ✓ ✓
Routine blood product screening ✓ ✓ ✓ ✓
Routine organ transplant screening ✓ (✓) ✓ ✓
Routine antenatal screening ✓ (✓) ✓ ✓
Routine sexual health screening ✓ (✓) ✓ (✓)
Treatment or Cure ✓  (✓) ✓ ✓
Mother to child transmission prevention ✓ (✓) ✓ (✓)
Partner notification ✓ (✓) ✓ ✓
Needle exchange programs ✓ (✓) ✓ ✓
Condoms ✓ ✓ ✓ ✓
Strategies for condom-less anal sex()  (✓) ? ✓ (✓)
Post-exposure prophylaxis (✓) ? ✓ ?
Pre-exposure prophylaxis (✓) ? ✓ ?
Voluntary medical male circumcision NA ? ✓ NA
Testing and treating sexually transmitted infections ✓ ✓ ✓ ✓
Education of medics, patients, population ✓ (✓) ✓ ✓
Total number of widely available interventions 12/16 4/12 16/17 10/13
Legend: Not available = NA; The intervention is available =✓ ; The intervention could be available = (✓); Could be effective but not researched =?

Without a doubt, the availability and level of access to these strategies varies significantly from region to region, but there is a very clear directive from the WHO that they work and should be implemented. Especially in combination, they are so effective that many nations are now planning the eradication of three of these viruses.

There is irrevocable evidence that the transmission of HTLV-1 would be averted by

  • using condoms when having sex,
  • avoiding the transfusion and transplantation of infected blood and organs,
  • advising HTLV-1 antibody positive mothers not to breast-feed their babies (if deemed safe) or reducing duration to 3 – 6 months,
  • using sterile needles, and
  • by educating healthcare professionals and the population about preventions strategies.

For HTLV-1, some of the aforementioned strategies are implemented inconsistently most probably due to a lack of an international consensus and directive. For example, universal antenatal care (ANC) screening is implemented only in Japan. In Brazil, HTLV-1 ANC screening is recommended in some regions but not necessarily implemented. In the UK, ANC screening is not recommended at all, despite recent evidence that it would be cost effective to identify positive mothers and council against breastfeeding and therefore prevent HTLV-1 transmission and ATL disease in their children long-term (18th International Retrovirology Conference in Tokyo in Japan in March 2017: Malik B. et al O-3-2, submitted for publication). If we add to this the prevention of other HTLV-1 diseases the cost effectiveness would be still greater.

In Japan, it is permitted to transplant HTLV-1 positive organs despite recent evidence showing that 63% of recipients of HTLV-1 positive kidneys developed HAM/TSP .

Nowhere that we know of is HTLV-1 part of routine sexually transmitted infection screening or needle exchange programs despite indisputable knowledge of its mode of transmission.

Here we propose the universal HTLV-1 testing of blood and organ donors, and the prevention of HTLV-1 positive blood transfusion and organ transplantations. We offer to support the WHO to develop a HTLV-1 Fact Sheet which provides clear advice that HTLV-1 is an oncovirus and can cause severe inflammation. We wish to inform HTLV-1 infected people that they need lifelong clinical and laboratory monitoring (HTLV-1 pro-viral load, lymphocyte count etc.), so that they are diagnosed early when they develop HTLV-1 diseases, so they can access treatment and clinical trials in a timely fashion. We encourage the WHO to support the recommendation that all people living with HTLV-1 are informed, that HTLV-1 is sexually transmitted and that their partners need to be notified and tested. HTLV-1 positive patients need to be informed that HTLV-1 can be transmitted through breastmilk and we need to advise to have their children tested for HTLV-1.

We are pleased to report that even the variable usage of some of these intervention strategies against HTLV-1 have led to a measurable change in the HTLV-1 prevalence profile. In Japan since the introduction of HTLV-1 ANC in 1987 in the Nagasaki region the HTLV-1 prevalence in mothers has reduced from 7.2% to 1% (http://www.med.nagasaki-u.ac.jp/gyneclgy/now/now_htlv-1.html). Following the national roll out of ANC screening the mother to child transmission has reduced form 20% to 2.5% in Japan (45). In 2017 Dr Lezin reported a significant reduction in HAM/TSP incidence due to ANC and blood donor screening in the French island of Martinique, in the West Indies (46).

Therefore, we propose a WHO HTLV-1 Vision for the prevention of HTLV-1 transmission: ‘Let’s eradicate HTLV-1 together!’ and a WHO HTLV-1 Mission:

‘Intervention strategies to achieve the eradication of HTLV-1’.

This may be achieved with the implementation of 5 strategies:

Strategy #1 protects the sexually active population:

Routine HTLV-1 testing in sexual health clinics should be available to all attendees. All people diagnosed with HTLV-1 need to be followed up medically and monitored clinically, immunologically and virologically to be able to access treatment promptly. We need to promote CMPC:  Counsel & Monitor HTLV-1 positive patients, notify Partners and promote Condom usage. This strategy also supports HTLV-1 positive parents to test their children for HTLV-1.

Strategy #2 protects blood and organ donors and recipients:

We need to test donors and not use products potentially infected with HTLV and make medical follow up and CMPC available to those infected.

Strategy #3 protects mothers, babies and fathers:

We need routine antenatal care testing and advise against breastfeeding by mothers who are HTLV-1 positive where safe, alternative methods of infant feeding are available. Alongside we need to promote CMPC.

Strategy #4 protects people who inject drugs:

We need to promote HTLV-1 testing and provide free safe needles through needle exchange programmes together with CMPC promotion.

 Strategy #5 supports the population and health care providers:

Access to up-to-date and evidence-based WHO HTLV-1 Fact Sheet and its diseases will allow health care providers to diagnose HTLV-1 and its diseases more often and in a timely fashion. Informed people are more likely to protect themselves and ask for a HTLV-1 test.

Words are important. We need to change the way we talk about HTLV-1 to increase its visibility and are guided by the beautiful language used for the USA National HIV/AIDS Strategy:

Vision: International HTLV Strategy

“Our world will become a place where new HTLV infections are very rare and when they do occur, every person, regardless of age, gender, race/ethnicity, sexual orientation, gender identity or socio-economic circumstance, will have unfettered access to high quality, life-extending care, free from stigma and discrimination.”

Thank you for considering our point of view and we are looking forward to hearing from you and to support your efforts to increase the visibility of people living with HTLV-1.

Yours sincerely,

Fabiola Martin, MD, MDRes, FRCP, FHEA              
Sexual Health, HIV, HTLV Physician
Head of MD Program Admissions
Faculty of Medicine
The University of Queensland, Brisbane, Australia
Honorary Senior Lecturer in HIV Medicine
University of York, York, United Kingdom

Robert Gallo, MD
Co-Founder & International Scientific Advisor
Global Virus Network
The Homer & Martha Gudelsky
Distinguished Professor in Medicine
Co-Founder & Director
Institute of Human Virology at the
University of Maryland School of Medicine

*This paragraph has been updated in light of a recent publication from a GVN HTLV-1 Task Force member (Dr. Graham Taylor).

Signatories:

  1. Fabiola Martin, The University of Queensland, Australia and Global Virus Network HTLV-1 Task Force, [email protected]
  2. Kristy Blackeborough-Wesson, HTLV-1 Patient representative, UK
  3. Sandra Do Valle, HTLV-1 Patient representative, Brazil
  4. Shane Schincke, HTLV-1 Patient representative, Australia, [email protected]
  5. Scott McGill, Acting CEO, Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine, Australia, [email protected]
  6. Stuart Aitken, Sexual Health Society of Queensland, Australia, [email protected]
  7. Graham Neilsen, Sexual Health and HIV Physician, The University of Queensland, Australia, [email protected]
  8. Caroline Harvey, Sexual Health and Reproductive Health Physician, Australia, [email protected]
  9. Yutaka Tagaya, Institute of Human Virology at the University of Maryland School of Medicine, USA, and Global Virus Network HTLV-1 Task Force, [email protected]
  10. Christian Bréchot, Global Virus Network, USA, [email protected]
  11. Edward McSweegan, Global Virus Network, USA, [email protected]
  12. Viviana Simon, Icahn School of Medicine at Mount Sinai, USA, and Global Virus Network HTLV-1 Task Force, [email protected]
  13. Claudine Pique, Institute Cochin, France, [email protected]
  14. Charles Bangham, Imperial College London, UK and Global Virus Network HTLV-1 Task Force, [email protected]
  15. Sören Andersson, Örebro University, Sweden, [email protected]
  16. Olivier Hermine, Hôpital Necker-Enfants Malades, France and Global Virus Network HTLV-1 Task Force, [email protected]
  17. Ali Bazarbachi, American University of Beirut-Medical Center, Lebanon and Global Virus Network HTLV-1 Task Force, [email protected]
  18. Anne Van Den Broeke, University of Liège, Belgium, [email protected]
  19. Carol Hlela,University of Cape Town and Red Cross Children’s Hospital, South Africa, [email protected]
  20. Marina Martins, Fundação Hemominas, Brazil, [email protected]
  21. Anna Bárbara Proietti, Fundação Hemominas, Brazil, [email protected]
  22. Umberto Bertazzoni, University of Verona, Italy and Global Virus Network HTLV-1 Task Force, [email protected]
  23. Roberto Accolla, Università degli Studi dell’Insubria, Italy, and Global Virus Network HTLV-1 Task Force, [email protected]
  24. Renaud Mahieux, Ecole Normale Supérieure de Lyon, France and Global Virus Network HTLV-1 Task Force, [email protected]
  25. Madeleine Duc Dodon, Ecole Normale Supérieure de Lyon, France, [email protected]
  26. Jean-Marie Peloponese, University of Montpellier, France and Global Virus Network HTLV-1 Task Force, [email protected]
  27. Houshang Rafatpanah, Mashhad University of Medical Sciences, Iran, [email protected]
  28. Beatrice Macchi, University of Rome Tor Vergata, Italy and Global Virus Network HTLV-1 Task Force, [email protected]
  29. Maria Fernanda Rios Grassi, Fundação Oswaldo Cruz, Brazil, [email protected] Top of FormBottom of Form
  30. Jean-Claude Twizere, University of Liège, Belgium, [email protected]
  31. Jordana Grazziela Alves Coelho dos Reis, FIOCRUZ, Brazil, [email protected]
  32. Noreen Sheehy, University College Dublin, Ireland and Global Virus Network, [email protected]
  33. Lucy Cook, CNWL NHS Foundation Trust, UK, [email protected]
  34. Hideki Hasegawa, Hokkaido University, Japan and Global Virus Network HTLV-1 Task Force, [email protected]
  35. Paul Fields, Guy’s and St Thomas’ NHS Foundation Trust, UK, [email protected]
  36. Toshi Watanabe, University of Tokyo, Japan and Global Virus Network HTLV-1 Task Force, [email protected]
  37. Vincenzo Ciminale, University of Padova, Italy and Global Virus Network HTLV-1 Task Force, [email protected]
  38. Stephane Olindo, Centre Hospitalier Universitaire de Bordeaux, France, [email protected]
  39. Raymond Cesaire, The University Hospital of Martinique, France, [email protected]
  40. Agnes Lezin, The University Hospital of Martinique, France, [email protected]
  41. Eduardo Gotuzzo, Universidad Peruana Cayetano Heredia, Peru and Global Virus Network HTLV-1 Task Force, [email protected]
  42. Mitsuaki Yoshida, Japanese Foundation for Cancer Research, Japan, [email protected]
  43. Masao Matsuoka, Kyoto University, Japan and Global Virus Network HTLV-1 Task Force, [email protected]
  44. Yamano Yoshihisa, Marianna University School of Medicine, Japan and Global Virus Network HTLV-1 Task Force, [email protected]
  45. Genoveffa Franchini, National Institutes of Health, USA, [email protected]
  46. Bernardo Galvao-Castro, Bahiana School of Medicine and Public Health, Salvador, [email protected]
  47. Johan Van Weyenbergh, The Katholieke Universiteit Leuven, Belgium and Global Virus Network, [email protected]
  48. Abelardo Araujo, Universidade Federal do Rio de Janeiro, Brazil, [email protected]
  49. Damian Purcell, The Peter Doherty Institute for Infection and Immunity at The University of Melbourne, Australia and Global Virus Network HTLV-1 Task Force, [email protected]
  50. Luc Willems, University of Liège, Belgium and Global Virus Network HTLV-1 Task Force, [email protected]
  51. Steve Jacobson, National Institutes of Health, USA, and Global Virus Network HTLV-1 Task Force, [email protected]
  52. Shaan Shiva Bassi, BSc., patient advocate (htlvaware.com)
  53. Ed Murphy, University of California, San Francisco, USA and Global Virus Network HTLV-1 Task Force, [email protected]
  54. John Kaldor, The University of New South Wales, Australia and Global Virus Network HTLV-1 Task Force, [email protected]
  55. Masao Matsuoka, Kyoto University, Japan and Global Virus Network HTLV-1 Task Force, [email protected]
  56. Antoine Gessain, Institut Pasteur, France and Global Virus Network HTLV-1 Task Force, antoine.[email protected]
  57. Lloyd Einsiedel, Baker Institute, Australia and Global Virus Network HTLV-1 Task Force, [email protected]
  58. Graham P Taylor, Imperial College London, UK, and Global Virus Network HTLV-1 Task Force, [email protected]
  59. William Hall, University College Dublin and Global Virus Network HTLV-1 Task Force, [email protected]
  60. Robert C. Gallo, Institute of Human Virology at the University of Maryland School of Medicine and Global Virus Network HTLV-1 Task Force, [email protected]

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