10 November 2023
Re: Why not eliminate HTLV-1 while eliminating HIV-1? We need HTLV-1 PEP/PrEP
Human T Lymphotropic/Leukaemia Virus-1 (HTLV-1), a sexually transmitted infection (STI) closely related to HIV-1, causes chronic infection, is transmitted from mother to baby and associated with significant morbidity and mortality. Therefore, it is one of the 2030 elimination targets of the World Health Organization’s global STI elimination strategy. There is robust evidence that FDA approved HIV-1 antiretrovirals widely used as PEP/PrEP are effective in preventing HTLV-1 transmission in vitro. Here, we encourage including the HTLV-1 transmission incidence into HIV-1 PEP/PrEP trials, since these are conducted frequently in HTLV-1 endemic regions, and this inclusion is not only feasible and of top-priority, but unethical if left ignored.
Dear Dr Merdad Parsey (Gilead)/ Dr Harmony Garges (ViiV),
We are writing to you on behalf of our co-signatories to encourage you to proactively include Human T Lymphotropic/ Leukaemia Virus-1 (HTLV-1) into your PEP/PrEP clinical trial programs. We know that, just like HIV-1, preventing HTLV-1 transmission reduces stigma, saves lives, is cost-effective and could lead to its elimination. Similar to HIV, HTLV-1 is a sexually transmitted human retrovirus, which is also transmitted vertically to babies, as well as through injecting drug use and infected blood and organ donations (1) . HTLV-1 clusters in families, affecting predominantly mothers and babies, often of poor economic status, exposed to stigma and discrimination due to HTLV-1 (2) . In addition, HTLV-1 affects many disadvantaged populations, our First Nation Peoples across many continents (3-6) .
In addition to many debilitating inflammatory manifestations of HTLV-1 (7-9) , in at least 5-10% of infected people HTLV-1 causes life-threatening diseases such as the aggressive blood cancer, adult T-cell leukaemia/lymphoma (ATL) (10) , which is strongly associated with mother-to-child transmission (11) , and a progressive, painful walking disability, called HTLV-1 associated myelopathy (HAM) (12) . People living with HAM have reported that living with HAM is worse than death (13) . The life expectancy of patients with ATL is ~10 months despite intensive chemotherapy and supportive therapy. In those with HTLV-1 diseases, morbidity and premature mortality rates are high (7, 12, 14-16) . In addition, as highlighted by the WHO report: people living with HTLV-1 infection have a 57% increase in adjusted mortality rate not solely attributed to ATL and HAM (17) .
As a sexually and vertically transmitted infection (STI), HTLV-1’s elimination is targeted by the World Health Organization (WHO), through their Global Health Sector Strategies on HIV, Viral Hepatitis, and STIs ending AIDS, hepatitis B and C and STIs by 2030 (18) . The Pan American Health Organisation (PAHO) is planning the inclusion of HTLV-1 in the elimination protocol of mother-to-child HIV, Syphilis, hepatitis B and C, Chagas (EMTC-Plus) (19) . But how can this be achieved for a virus for which, just like HIV, there is no vaccine or cure yet? Here we provide eight excellent reasons why this is feasible:
1. HTLV-1 is easily screened for: through validated, approved, highly sensitive and specific, affordable tests.
2. HTLV-1 is easy to target: it is not a ubiquitous virus and is present in clusters of regional high endemicity (1) .
3. HIV post-/pre-exposure prophylaxis (PEP/PrEP) trials were and are conducted in populations a) with high HTLV-1 regional endemicity and b) considered to be at risk of STI transmission.
4. HIV-1 antiretrovirals (ARVs) can be re-purposed: several ARVs, developed by Gilead/ ViiV, that could potentially prevent the vertical or horizontal transmission of HTLV-1 are already FDA approved as either a therapeutic, pre- or post- exposure prophylactic ARV against HIV-1.
5. HTLV-1 is easily prevented: transmission between individuals requires an HTLV-1 infected CD4 positive T lymphocyte (not free virus) to transfer its virus to another T lymphocyte before the initiation of the intracellular replication cycle (20-22) .
6. Unlike HIV-1, HTLV-1 is unlikely to develop resistance against ARVs (23, 24) .
7. HTLV-1 transmission prevention saves lives and money (11, 25, 26) .
8. It is the right thing to do: therefore unethical not to try to eliminate HTLV-1 together with HIV-1 (27) .
These reasons perfectly pave the way for repurposing existing HIV anti-retrovirals for prevention strategies (not treatment strategies) to meet WHO’s HTLV-1 elimination strategy by 2030. Both first- and second-generation integrase strand transfer inhibitors (INSTIs), including raltegravir, bictegravir (28) , and dolutegravir (29) , as well as the long-acting INSTI, cabotegravir (30) , effectively block cell-to-cell transmission of HTLV-1 in-vitro. Furthermore, tenofovir alafenamide (TAF), is as effective as TDF (28) in blocking HTLV-1 transmission in-vitro (29) .
Indeed, a comprehensive review of published in-vitro and in-vivo data on the efficacy of HIV-1 PEP/PrEP ARVs also effectively preventing HTLV-1 transmission, identified zidovudine (31) , tenofovir disoproxil fumarate (TDF), and bictegravir as the most promising candidates to test in HTLV-1 PEP/PrEP clinical trials (32) .
As a matter of fact, despite the paucity of HTLV-1 PEP/PrEP trials, licenced HIV-1 ARVs are either recommended off-licence to prevent the transmission of HTLV-1 to organ donors (33) or in occupational exposure (34) or repurposed to prevent mother-to-child HTLV-1 transmission (35, 36) . Desperate times, desperate measures.
But this does not need to be the case. Since 1990s thousands of HIV-1 sero-negative people have been recruited into HIV-1 PEP/PrEP clinical trials, most in areas of high HTLV-1 endemicity. For example, HPTN 084 phase 3 randomised clinical trial tested cabotegravir and TDF with emtricitabine in over 3000 women of reproductive age in 70 sites in sub-Saharan Africa (37) . Two HPTN 084 trial sites were in Malawi, but although it is known that HTLV-1 seroprevalence is high (>2%) in mothers and babies (38) , HTLV-1 sero-conversion was not tested. In our opinion, it would have been feasible and necessary to include HTLV-1 testing as an outcome measure into this and many other PrEP trials. Knowing what we have known about HTLV-1’s transmission for many decades, makes its ongoing omission from these potentially life-saving trials unethical.
Considering that HTLV-1 was identified more than 40 years ago, two years before HIV-1, it is shocking to know that there have been to date only two small studies that have specifically studied HTLV-1 PrEP, albeit not even in target populations (39, 40) . It would have been easy, logical and the ethically responsible course of action, to add on HTLV-1 incidence as an outcome measure to all HIV-1 PEP/PrEP trials conducted in high HTLV-1 endemic areas to measure the HTLV-1 seroconversion rate alongside HIV-1.
We and our patients, therefore, call on Gilead/ViiV to incorporate HTLV-1 into their HIV-1 PEP/PrEP trials from now on and/or design HTLV-1 specific PEP/PrEP trials using your licenced ARVs. Think of all the mother-to-child HTLV-1 transmissions and all the lives, that could have potentially been already saved over the last two decades of HIV-1 PEP/PrEP research!
The signatories of this letter, HTLV experts, people living with HTLV-1 and community advocates are most willing to offer their support and expertise to set up these important and live saving trials as a matter of urgency.
We are looking forward to hearing from you urgently.
Dr. Fabiola Martin (sexual health specialist) Dr. Goedele N. Maertens (Imperial College London)
1. Gessain A, Cassar O. ECDC Technical Report: Geographical distribution of areas with a high prevalence of HTLV-1 infection. ECDC.europa.au; 2015 06/08/2015.
2. Alvarez C, Verdonck K, Tipismana M, Gotuzzo E. A Peruvian family with a high burden of HTLV-1-associated myelopathy/tropical spastic paraparesis. BMJ Case Rep. 2015;2015.
3. Sobol I, Palacios C, Osborne G, Hildes J, MacDonald W, Harty A, et al. Initial management of an outbreak of the HTLV-1 virus in Nunavut, Canada. Alaska Med.2007;49(2 Suppl):204-6.
4. Eirin ME, Berini CA, Jones LR, Dilernia DA, Puca AA, Biglione MM. Stable human T-cell lymphotropic virus type 1 (HTLV-1) subtype a/subgroup a endemicity in Amerindians from Northwest Argentina: a health problem to be resolved. J Med Virol. 2010;82(12):2116-22.
5. Alva IE, Orellana ER, Blas MM, Bernabe-Ortiz A, Cotrina A, Chiappe M, et al. HTLV-1 and -2 infections among 10 indigenous groups in the Peruvian Amazon. Am J Trop Med Hyg. 2012;87(5):954-6.
6. Einsiedel L, Woodman RJ, Flynn M, Wilson K, Cassar O, Gessain A. Human T-Lymphotropic Virus type 1 infection in an Indigenous Australian population: epidemiological insights from a hospital-based cohort study. BMC public health. 2016;16:787.
7. Schierhout G, McGregor S, Gessain A, Einsiedel L, Martinello M, Kaldor J. Association between HTLV-1 infection and adverse health outcomes: a systematic review and meta-analysis of epidemiological studies. Lancet Infect Dis. 2020;20(1):133-43.
8. Cook LBM, Taylor GP. HTLV-1: the silent impact revealed. Lancet Infect Dis. 2020;20(1):12-4.
9. Martin F, Taylor GP, Jacobson S. Inflammatory manifestations of HTLV-1 and their therapeutic options. Expert Rev Clin Immunol. 2014;10(11):1531-46.
10. Hinuma Y, Nagata K, Hanaoka M, Nakai M, Matsumoto T, Kinoshita KI, et al. Adult T-cell leukemia: antigen in an ATL cell line and detection of antibodies to the antigen in human sera. Proc Natl Acad Sci U S A. 1981;78(10):6476-80.
11. Malik B, Taylor GP. Can we reduce the incidence of adult T-cell leukaemia/lymphoma? Cost-effectiveness of human T-lymphotropic virus type 1 (HTLV-1) antenatal screening in the United Kingdom. Br J Haematol. 2018.
12. Martin F, Fedina A, Youshya S, Taylor GP. A 15-year prospective longitudinal study of disease progression in patients with HTLV-1 associated myelopathy in the UK. J Neurol Neurosurg Psychiatry. 2010;81(12):1336-40.
13. Rosadas C, Assone T, Yamashita M, Adonis A, Puccioni-Sohler M, Santos M, et al. Health state utility values in people living with HTLV-1 and in patients with HAM/TSP: The impact of a neglected disease on the quality of life. PLoS neglected tropical diseases. 2020;14(10):e0008761.
14. Bazarbachi A, Plumelle Y, Carlos RJ, Tortevoye P, Otrock Z, Taylor G, et al. Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. J Clin Oncol. 2010;28(27):4177-83. 15. Marcusso RMN, Van Weyenbergh J, de Moura JVL, Dahy FE, de Moura Brasil Matos A, Haziot MEJ, et al. Dichotomy in Fatal Outcomes in a Large Cohort of People Living with HTLV-1 in Sao Paulo, Brazil. Pathogens. 2019;9(1).
16. Nagasaka M, Yamagishi M, Yagishita N, Araya N, Kobayashi S, Makiyama J, et al. Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1-associated myelopathy/tropical spastic paraparesis. Proceedings of the National Academy of Sciences of the United States of America. 2020;117(21):11685-91.
17. World Health Organization. Human T-lymphotropic virus type 1: Technical Report. World Health Organisation; 2020 1/02/2020.
18. World Health Organization. Global health sector strategies on, respectively, HIV, viral hepatitis and sexually transmitted infections for the period 2022-2030.: WorldHealthOrganization; 2022 2022.
19. Pan American Health Organization. The Response to HTLV in the Framework of Maternal and Child Health. Meeting Report, 18 August 2022.: PAHO; 2022.
20. Nejmeddine M, Barnard AL, Tanaka Y, Taylor GP, Bangham CR. Human T-lymphotropic virus, type 1, tax protein triggers microtubule reorientation in the virological synapse. The Journal of biological chemistry. 2005;280(33):29653-60.
21. Laydon DJ, Sunkara V, Boelen L, Bangham CRM, Asquith B. The relative contributions of infectious and mitotic spread to HTLV-1 persistence. PLoS Comput Biol. 2020;16(9):e1007470.
22. Hirons A, Khoury G, Purcell DFJ. Human T-cell lymphotropic virus type-1: a lifelong persistent infection, yet never truly silent. Lancet Infect Dis. 2021;21(1):e2-e10.
23. Mansky LM. In vivo analysis of human T-cell leukemia virus type 1 reverse transcription accuracy. Journal of virology. 2000;74(20):9525-31.
24. Afonso PV, Cassar O, Gessain A. Molecular epidemiology, genetic variability and evolution of HTLV-1 with special emphasis on African genotypes. Retrovirology. 2019;16(1):39.
25. Kowada A. Cost-effectiveness of human T-cell leukemia virus type 1 (HTLV-1) antenatal screening for prevention of mother-to-child transmission. PLoS neglected tropical diseases. 2023;17(2):e0011129.
26. Rosadas C, Costa M, Senna K, Santos M, Taylor GP. Cost-utility analysis of HTLV-1 targeted antenatal screening in the UK. AIDS Rev. 2023; Supl27. 2023.
27. Martin F, Tagaya Y, Gallo R. Time to eradicate HTLV-1: an open letter to WHO. Lancet. 2018;391(10133):1893-4.
28. Barski MS, Minnell JJ, Maertens GN. Inhibition of HTLV-1 Infection by HIV-1 First-and Second-Generation Integrase Strand Transfer Inhibitors. Front Microbiol. 2019;10:1877.
29. Kalemera MD, Maertens GN. Cell Culture Evaluation Suggests Widely Available HIV Drugs Will Make Effective HTLV-1 Prophylactics. Preprints 2023, 2023110045. . Preprints. 2023.
30. Schneiderman BS, Barski MS, Maertens GN. Cabotegravir, the Long-Acting Integrase Strand Transfer Inhibitor, Potently Inhibits Human T-Cell Lymphotropic Virus Type 1 Transmission in vitro. Front Med (Lausanne). 2022;9:889621.
31. Afonso PV, Mekaouche M, Mortreux F, Toulza F, Moriceau A, Wattel E, et al. Highly active antiretroviral treatment against STLV-1 infection combining reverse transcriptase and HDAC inhibitors. Blood. 2010;116(19):3802-8.
32. Bradshaw D, Taylor GP. HTLV-1 Transmission and HIV Pre-exposure Prophylaxis: A Scoping Review. Front Med (Lausanne). 2022;9:881547.
33. Armstrong MJ, Corbett C, Rowe IA, Taylor GP, Neuberger JM. HTLV-1 in solid-organ transplantation: current challenges and future management strategies. Transplantation. 2012;94(11):1075-84.
34. GovUK. Guidance: Human T-cell lymphotropic virus (HTLV) types 1 and 2: UK Health Security Agency. . https://www.gov.uk/guidance/human-t-cell-lymphotropic-virus-htlv-types-1-and-2#PEP, GOV.UK; 2020.
35. Motedayen Aval L, Boullier M, Lyall H, Collins GP, Ayto R, Kelly DF, et al. Adult T cell leukaemia/lymphoma (ATL) in pregnancy: A UK case series. EJHaem. 2021;2(1):131-5.
36. Bohiltea RE, Turcan N, Berceanu C, Munteanu O, Georgescu TA, Ducu I, et al. Implications of human T-lymphotropic virus in pregnancy: A case report and a review of the diagnostic criteria and management proposal. Exp Ther Med. 2021;21(1):82.
37. Delany-Moretlwe S, Hughes JP, Bock P, Ouma SG, Hunidzarira P, Kalonji D, et al. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial. Lancet. 2022;399(10337):1779-89.
38. Fox JM, Mutalima N, Molyneux E, Carpenter LM, Taylor GP, Bland M, et al. Seroprevalence of HTLV-1 and HTLV-2 amongst mothers and children in Malawi within the context of a systematic review and meta-analysis of HTLV seroprevalence in Africa. Trop Med Int Health. 2016;21(3):312-24.
39. Bradshaw D, Khawar A, Patel P, Tosswill J, Brown C, Ogaz D, et al. HTLV seroprevalence in people using HIV pre-exposure prophylaxis in England. J Infect. 2023;86(3):245-7.
40. Best A, Rambarran N. The demographic features and outcome indicators of the Barbados HIV Pre-exposure Prophylaxis Program, 2018-2019. Rev Panam Salud Publica.2021;45:e51.