Author: Dr Fabiola Martin, MD, MDRes, FRCP, FHEA
Sexual health, HIV and HTLV Physician
Senior Clinical Lecturer and Head of Admissions, University of Queensland
In July 2018 world experts in Human T Leukaemia Virus (HTLV) and members of the International Retrovirology Association (IRVA) met in Tokyo to discuss recent discoveries and identify knowledge gaps. The meeting was held in a workshop style focusing on epidemiology, virology, transmission prevention, pathophysiology, immunology, disease and treatment. Each session kickstarted with a short presentation summarising current knowledge followed by an in-depth discussion focusing on prioritisation of future activity of IRVA including research, advocacy and dissemination of consensus guidelines.
The workshop also addressed the intention to support the World Health Organisation (WHO) in their response to the HTLV-1 Open Letter published earlier this year (1, 2). The letter invited WHO to endorse HTLV-1 as a stand-alone Health Topic to support people living with HTLV as well as clinicians. It is beyond the scope of this report to do justice to the vast amount of information shared. Therefore, the report will mainly focus on epidemiology, prevention and clinical research updates.
Human T Leukemia Virus was discovered in 1980 (3). It is an oncovirus and human retrovirus (4) originating from non-human primates through interspecies transmission in Central Africa many thousand years ago (5). HTLV integrates itself into the human DNA and causing a life-long chronic viral infection (3). Phylogenetic analysis has shown the existence of four distinct HTLV subtypes: HTLV-1,2,3 and 4 (6). Worldwide most people living with HTLV are infected with type 1 which is divided into subgroups: A = Cosmopolitan, B = Central and West African, C = Australasian/Melanesian, D = Central African and F (5). In Australia HTLV- 1c has been described in Central Australian Aboriginal people (7) but other subtypes may be observed in people originating from other parts of the world. Systematic review of published data on HTLV-1 origin and prevalence shows that it is an ancient virus and that its prevalence is complex with high endemicity and disease burden in specific geographical regions (8, 9). Currently available surveillance data is not comprehensive, and in many regions, accounting for 6 billion persons, HTLV-1 prevalence remains unknown. In Australia a high prevalence of HTLV-1 in Aboriginal people was described for the first time in 1988 (10). However several recent hospital and community-based cohort studies in Central Australia reported world-wide the highest prevalence rates of HTLV-1 in certain communities: 635/1889 (33.6 %) people tested positive and a sharp increase in prevalence rates was observed with age: 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 (11, 12, 13, 14). Another HTLV-1 high prevalence country is Japan where an estimated 0.8 million people live with HTLV-1; especially in Southern regions 30–40% of adults older than 50 years of age and up to 5.8% of pregnant women live with HTLV-1.
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 (15, 16). The lifetime probability of developing ATL is 4-5 in 100 people infected with HTLV-1 (17, 18), but ATL predominantly occurs as a consequence of mother to child transmission (MTCT), which contributes to 20-24% of all HTLV-1 infections (19). Therefore the lifetime probability of developing ATL is 1 in 4 in HTLV-1-infected infants (19). Japanese colleagues reported that in Japan alone an estimated 1000 people succumb to ATL every year (HTLV-1 Symposium Tokyo, Japan, July 2018). A more hopeful update was provided by Prof Kannagi on the safety and efficacy of the Phase 1 trial of the treatment Tax peptide-pulsed dendritic cell vaccine designed to augment the HTLV-1 Tax-specific cytotoxic T lymphocyte response in ATL patients who had relapsed after chemotherapy. In all patients, the performance status improved after vaccination without severe adverse events, patients achieved partial and complete remission, maintaining their remission status without any additional chemotherapy long-term (20).
In addition, HTLV-1 causes chronic, progressing, disabling and painful conditions such as myelopathy and polymyositis as well as chronic inflammatory pulmonary disease (13, 14), uveitis (21, 22, 23, 24) and dermatitis (25, 26, 27, 28, 29, 30, 31, 32). The lifetime risk of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) approaches 4 in 100 infected people (33, 34, 35, 36, 37, 38), with an average of 8 years delay in diagnosis and treatment due to lack of awareness and testing (39). 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 (40). HAM/TSP affects both adults and children but mostly women. Recently the development of HAM/TSP was reported in 63% of Japanese HTLV-1 positive kidney recipients (41) (18th International Retrovirology Conference in Tokyo in Japan in March 2017: Yuzawa K. et al O-5-7).
At the workshop Prof Yamano provided an update on the Japanese HAM/TSP cohort study: HAM-net (42). HAM/TSP patients reported needing 1 walking aid within 8 years of disease onset, 2 walking aids within 12.5 years and were wheelchair bound by 18 years, reflecting chronic disease progression reported previously (39, 43). Investigating 205 HAM/TSP patients three clinical sub-type of HAM/TSP can be described: rapid, slow and non-progressors (44). The outcome of rapid progressors was very poor. These patients needed to use wheelchairs much earlier than slow progressors. As previously reported cerebro-spinal fluid concentrations of biomarkers neopterin and CXCL10 clearly distinguished between these three groups (45). These biomarkers have been used to monitor treatment response in addition to clinical outcome measures. Prof Yamano also reported on the success of Mogamulizumab (Anti-CCR4) in improving inflammatory marker levels and clinical outcome measures in HAM/TSP patients (46, 47). He recommended starting patients on corticosteroids as induction therapy to halt inflammation and to switch to Mogamulizumab (Anti-CCR4) as maintenance therapy.
All the aforementioned HTLV-1 diseases have been observed in people living with HTLV-1 in Australia (12, 14, 24, 32, 48, 49, 50, 51, 52, 53). At the workshop Dr Einsiedel reported on recent data collected in Central Australia. In a catchment area 1 million km2 and in 5 remote communities (n= 52-121): 30-50% of people lived with HTLV-1. Virus prevalence was associated with increasing age. Five per cent of the cohort suffered from ATL, in addition patients suffered from HAM/TSP (<4%), uveitis, Strongyloides stercoralis co-infection, infective dermatitis and crusted scabies; 9.6% of people living with HTLV-1 suffered from bronchiectasis, which was more common in male patients. People with a positive HTLV-1 serology and high pro-viral load were at 2.5 and 12.5 fold increased risk of suffering from bronchiectasis. A community-based spirometry study reported that the severity of airway obstruction was strongly associated with HTLV-1 seroprevalence. In Central Australia higher HTLV-1 pro-viral load was associated with a 4 fold increased risk of premature death especially in people who suffered from bronchiectasis (54). These results high-light the need for patients to be able to access treatment for HTLV-1 diseases as well as drugs which reduce HTLV-1 pro-viral load.
HTLV-1 is a blood borne and sexually transmitted virus and can be transmitted through infected body fluids, via condom-less sexual intercourse (55, 56, 57, 58), breastfeeding (59, 60, 61, 62), sharing of needles (63, 64, 65, 66) and the transfusion (67, 68) and transplantation of infected blood and organ donations (41, 69, 70, 71).
As with most blood borne and sexually transmitted viruses the majority of people living with HTLV-1 transmit the virus unknowingly and are unaware that they are at risk of developing HTLV-1 diseases. Data from Central Australia (11), Japan (72) and Brazil (73, 74) report the importance of the sexual transmission of HTLV-1. 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 (72) and at the 2017 Australasian HIV & AIDS and Sexual Health Conference in Canberra in Australia (75). Worldwide it is mostly women, who carry the burden of HTLV-1 infection and its associated diseases. They become infected through condom-less sex (72) and unknowingly transmit the infection to their babies through breastfeeding. Therefore HTLV-1 is highly concentrated in families [1:3 to 1:4 of family members carry the virus (76, 77)].
At the workshop Dr Einsiedel provided an update on previously published data (52), where in Central Australia only 3 out of 143 children were found to be HTLV-1 positive despite the fact that traditionally in these communities prolonged breastfeeding was common practice. It was considered that this could be due to recruitment bias however these results may indicate that HTLV-1 is commonly acquired later in life in this region.
Though currently there is no cure for the two major human retroviral infections, since the viral DNA is integrated in the human genome, treatment for HTLV-1 diseases and effective transmission prevention strategies are available. So far 17 different prevention strategies are known to effectively reduce the risk the transmission of blood borne and sexually transmittable viruses, such as Hepatitis B & C and HIV (1, 2). There is irrevocable evidence that the transmission of HTLV-1 could also be averted. For example, the implementation of universal antenatal care HTLV-1 screening and avoidance of breast feeding in Japan has reduced the HTLV-1 prevalence from 20% to 2.5% since 1987 (78, 79). In 2017 Dr Olindo reported a significant reduction in HAM/TSP incidence due to antenatal and blood donor screening in the French island of Martinique, in the West Indies (80). Blood and organ donor testing can reduce HTLV-1 prevalence (81) and HTLV-1 diseases (41), (18th International Retrovirology Conference in Tokyo in Japan in March 2017: Yuzawa K. et al O-5-7). The expert group agreed that many known strategies such as safe-sex, condom and clean needle distribution campaigns needed to endorse the prevention of HTLV-1 too especially in regions with high endemicity. Addressing the implementation of effective transmission prevention strategies will be an important collaboration between the WHO and IRVA members.
The expert group discussed that HTLV prevalence remains uncharted in many areas of the world. An expansion of epidemiological research into new geographical regions such as India, China, Russia, Australia and many African countries is therefore required. Surveillance and public health research needs to focus on prevalence, mode of transmission, disease incidence and risk of disease development. It was acknowledged that reliable disease incidence data can only be gathered if health care providers know how to diagnose HTLV diseases in the first instance. So improved access to diagnostics guidelines and educational material, such as WHO Health Topics, for health care providers especially in regions of high HTLV-1 endemicity should be a top priority of IRVA members and the WHO.
At the moment the most reliable epidemiological data on ATL is only available in Japan, where HTLV education of care providers and mandatory reporting of HTLV and its associated diseases have translated into better surveillance, partner notification and transmission prevention strategies. Surveillance data shows that each year more than 4000 new HTLV-1 cases are sexually transmitted in Japan (72). Choosing the correct denominator is important for correct epidemiolocal data analysis, for example the life time risk of developing ATL is 4-5% in the general population but the risk to develop ATL is as high as 25% in people living with HTLV-1 who acquired their virus from their mothers through breastfeeding (19). It was agreed that IRVA should proactively work with the WHO on the standardization of protocols which guide sampling and testing and analysis of surveillance data to improve quality of data and reporting.
Standardization of HTLV-1 testing was discussed extensively. Currently there is no international agreement on how to diagnose a patient with HTLV-1 infection, though national and evidence based testing guidelines exist (82). The expert group agreed on the importance of considering different testing guidelines in specific settings. For example, to minimize transmission risk the HTLV-1 screening of blood or organ donors, with a rapid turn-around time, may suffice accepting false positive results. However, for the diagnosis and management of ATL and HAM/TSP, it is advocated that blood samples need to undergo screening, confirmation and pro-viral load testing for HTLV-1 accepting a longer turn-around time of results.
The expert group agreed that HTLV-1infection creates a chronic and progressive pro-inflammatory state and recommend to revisit HTLV-1 inflammatory diseases to re-describe the pathogenesis using modern laboratory, imaging, histopathology and clinical diagnostics tools to update data on cytokine profiles, neuroimaging and immunohistochemistry. This would allow a correct categorization of disease sub-types which would guide a more tailored management of disease.
The expert group recommended focusing on HTLV-1 transmission prevention strategies increasing research input into vaccine and pre and post-exposure prophylaxis. Prof Franchini proposed to conduct a Phase 1 clinical trial in young women using an available preventative HTLV-1 vaccine (83). A similar vaccine profile was tested for the prevention of HIV-1 in Thailand (84). The HTLV vaccine trial proposed would need to be powered sufficiently with a long follow up time to measure seroconversion rates and is ideally conducted in a high prevalence country.
In some setting Truvada is being used as prost-exposure prophylaxis (personal communication) though it has been reported that some primary HTLV-1 isolates from patients living with HTLV-1 harbor tenofovir resistance (85). More research is currently being conducted in identifying other potential drugs as exposure prophylaxis.
The expert group discussed the need to conduct patient focused research. Drug development needs to focus on the eradication of the virus, reduction of pro-viral load as well as treatment of specific diseases. Drugs need to be accessible in resource poor countries and available in non-injectable forms to make drug administration safe and affordable. Many people living with HTLV-1 associated diseases have no access to zidovudine, interferon or Mogamulizumab. Funding remains a major obstacle to research. Clinical trials often resolve to test already licensed medication for HTLV-1 associated diseases instead of identifying HTLV-1 specific drugs. This is mainly due to lack of support from governmental funding bodies or pharmaceutical companies.
The expert group will continue to work on the ATL and HAM/TSP treatment guidelines with the aim to publish both by the end of this year. In addition, the group will start working on HTLV-1 testing guidelines including a list of diseases which should trigger HTLV testing especially in symptomatic patients.
The groups raised awareness about up-coming HTLV meetings: In 2018 the South American HTLV experts will meet in Belem in Brazil (August 27-29, 2018 www.simposiohtlv.com.br). We are all also looking forward to the 19th International Conference on Human Retrovirology, HTLV and Related Viruses held in Lima, Peru (April 24-26, 2019 www.htlvperu2019.com).
Finally, the expert group unanimously agreed to reach out to the WHO again in support of a future consultation meeting to increase awareness about this oncovirus and find better ways of implementing known strategies to prevent the transmission of HTLV.
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