What is HTLV-1?
HTLV-1 is the short name of the Human T-Lymphotropic Virus type 1. It is called this because it infects a type of white blood cell called a T-lymphocyte. HTLV-1 is a virus. A virus is a minute organism that usually can only be seen when magnified many thousands of times by an electron microscope. Viruses do not have their own metabolism (life-support system) and can only make all their components parts (i.e. genetic code, enzymes, sugars and proteins) by infecting living cells. Once formed viruses are released from the infected cell. To replicate again they must find a new cell to infect. The discovery of HTLV-1 was first reported in 1980.
Who is likely to be infected by HTLV-1?
HTLV-1 is a very old virus, which appears to have infected and moved with mankind for thousands of years. The origin of HTLV-1 is from monkeys, in which it is known as STLV-1 (S for simian), in central Africa. HTLV-1 is thought to have migrated during ancient times with Native American Indians in North and South America, with Australian aborigines, the Melanesian people of the South West Pacific, and to Japan. During the last few centuries it has migrated from West, Central and Southern Africa to the Caribbean, the Middle East, and again to North and South America. In some regions more than 1% of the population are infected. In most of Europe HTLV-I has been mainly found among people who originated from these endemic areas. However, in recent years it has become apparent that HTLV-1 is relatively common in native Romanians and that in Western Europe HTLV-1 is increasingly found in persons born in the region. In the UK this now accounts for about 4 in 10 of all newly diagnosed infections.
How would I know if I am infected?
Most people who are infected with HTLV-1 are completely unaware of the infection because they are perfectly well. As they have no symptoms or signs of the infection this is known as asymptomatic carriage. We have estimated that in the U.K 22,000 people are infected with HTLV-1, most are asymptomatic carriers and less than 2000 have ever been diagnosed over the last 20 years. Thus 90% are unaware of their infection.
Does routine testing for HTLV occur in the UK?
Since 2002, all blood donors have routinely been tested for HTLV by the NHS Blood and Transplant Services. A look back exercise was carried out to trace and screen anyone previously having received a blood donation from any newly diagnosed infected blood donors.
Routine testing does not occur in sexual health clinics or in antenatal clinics.
Like blood donations all organ donors are tested from HTLV infections.
Some infertility clinics offer routine testing to those referred to them for investigation.
Where can I get tested in the UK?
At the National Centre for Human Retrovirology, by appointment.
Your GP may be able to test for HTLV in their surgery. If you are resident in the UK we are happy to liaise with your GP regarding this.
Why should I consider testing for HTLV?
The main reasons for being tested are:
• A family member or partner is known to be infected with HTLV.
• The development of symptoms which resemble those that the virus can cause.
• The diagnosis of another viral infection with similar routes of transmission e.g. Hepatitis B, C or HIV.
Testing is important for the prevention of transmission of HTLV-1 and HTLV-2, for the assessment of risk of related disease and for the detection and treatment of HTLV-associated diseases.
What does the test detect?
The presence of HTLV antibodies can be detected by a blood test.
Soon after becoming infected with HTLV, the body responds by producing antibodies to fight the infection. HTLV antibodies, which are produced only in response to HTLV and not to any other infection, can easily be detected in the laboratory but only if the correct test is done.
HTLV infection does not show up in routine blood tests such as those requested by your family doctor or routine hospital tests.
Because HTLV causes a lifelong infection, the presence of specific HTLV antibodies is proof of infection.
Do I need to repeat the test?
The absence of HTLV antibodies excludes HTLV infection unless exposure has only just recently occurred and the test was done before the body has had time to respond to the infection. The best data indicate that if infection has occurred antibodies are always present by three months after the exposure. Therefore if a recent infection is suspected and the antibody test is negative the test should be repeated three months later. Further testing thereafter is not required. For more details see ‘What is the window period after infection before antibody tests for HTLV-1 infection are always positive’.
What is the window period after infection before antibody tests for HTLV-1 infection are always positive?
1. The best published data are from Angela Manns and co-authors in a 1991 paper published in the journal ‘Blood’. They repeatedly tested blood transfusion recipients who had been transfused with HTLV-1 infected blood with an enzyme linked Immunosorbent assay (EIA) which used HTLV proteins obtained by breaking up the whole virus. In 9 definite infections the EIA had become positive at a median of 55 days (1) (i.e. half of all the recipients who were shown to be infected with HTLV had a positive EIA at 55 days).
2. In follow-up paper including 24 seroconversions the median was 51 days (IQR 36-72 days) (2).
3. Using the screening assay 2/3 of infected recipients had antibodies to HTLV-1 detected by day 64 following exposure and all infected recipients had antibodies to HTLV-1 detected by day 110 following exposure.
4. However in the confirmatory assay, (a ‘western blot’ in which different virus proteins are separated on a test strip allowing antibodies to the different proteins to be distinguished – this shows as a band on the strip), all infected transfusion recipients had at least one detectable band at 55 days (8 weeks) with a band first detected in half the recipients as early as 40 days (6 weeks).
5. These data were used to estimate the seroconversion window period by Schrieber and colleagues in their 1996 New England Journal of Medicine paper estimating the risk of transmission of HTLV-1 by a blood donor infected with HTLV-1 donating blood during the window period(3). They cite the window period to be 51 days (range 36 – 72 days) although this is the IQR not the full range.
6. In Manns' 1991 paper all recipients were positive on the screening assay by 110 days with the last documented negative results (screening assay) at 83 days. Therefore a conservative figure would be out to the mid point between the last negative and first positive result from the 1991 Manns' paper i.e. (96 days).
7. The screening tests used to check for antibodies to HTLV are better today than they were 20 years ago, using recombinant proteins to make them both very sensitive and very specific. (This means they are very good at detecting antibodies when they are present and have a very low rate of false positive results).
8. In a study of three resipients of infected organs antibodies were detected no later than 39 days post exposure (4).
How does HTLV-1 infection occur?
HTLV-1 can be transmitted from person-to-person in four ways:
From an infected mother to her baby.
• Up to 1 in 4 children born to mothers with HTLV-1 will be infected. However most infections occur through breast-feeding and if this is avoided less than 1 in 20 babies will become infected. The risk of infection through breast feeding increases with the duration of breast feeding and may be low during the first three months.
• Antenatal screening has been introduced in Japan. In the UK the National Screening Committee last reviewed whether HTLV infection should be added to the screening programme in England in 2013 and advised that it was not indicated. This decision was due for review in 2016. http://legacy.screening.nhs.uk/htlv
• Consequently HTLV-1 infection is not routinely tested for in the UK antenatal clinics so if you are pregnant and think you may be carrier, you need to speak to your doctor or midwife and specifically discuss this test.
• In the UK umbilical cord blood donors are screened for HTLV infection at the time of donation. As testing and confirmation can take several days this means that some mothers are first informed that they are HTLV-1 infected after they have already started breast-feeding. If you are planning to store cord blood we recommend that you are tested prior to delivery.
Between sexual partners through unprotected (no condom) intercourse.
• The risk of transmission from an infected man is greater than from an infected woman. The best information indicates that in an existing relationship lasting 5 years there is a 7% chance of transmission. The rate of infection through unprotected intercourse is likely to be much higher in other settings as in this study all the uninfected partners in the relationship had already been exposed to HTLV-1 infection without becoming infected and it is therefore possible that there is an unintended bias for couples at lower risk of transmission to have been included in the study.
• Since the use of condoms protects against many other more infectious infections, we recommend the use of condoms, unless a couple are trying to have a baby.
• Transmission risk is related to HTLV-1 viral burden.
Through transfusion of blood or tissue transplantation from a HTLV-I infected donor.
• The risk from an infected unit of blood may be as high as 85% but depends on how the blood is handled and stored.
• A recent study in the UK found the risk of transmission from unscreened, unfiltered blood to be 30%. The same study demonstrated that a process known as leucodepletion was highly effective at reducing transmission. Most but not all blood products can be treated this way.
• The risk of infection due to transplantation of an organ from an infected donor is not known but several cases of HAM following HTLV-1 infection acquired in this manner have been documented. A small study from Japan, reported in 2017, found that all recipients transplanted with a kidney from a HTLV-1 infected donor became infected. Furthermore 2/3 of the recipients developed HAM.
• Persons with HTLV-I infection should not donate blood, organs or sperm and should not carry an organ donor card.
• All blood donations in the UK and many other countries are screened for HTLV-1 infection.
• Not all countries, including many in Europe, have HTLV donor screening programmes.
• On the basis of these latest data, HTLV experts at a workshop during the 18th International Conference on Human Retrovirology in Japan, March 2017 agreed that all solid organ donations should be screened for HTLV infections regardless of the country of transplantation.
Through the sharing or reuse of needles and syringes to inject drugs.
• The use of disposable equipment for injections prevents transmission. In Europe and North America HTLV-2 infection has been associated with injecting drug use either directly, by the infected subject, or indirectly.
• To date there have been no proven HTLV-1 infections between medical staff and patients in either direction.
What disease does HTLV-1 cause?
The majority of persons infected with HTLV-1 do not develop any disease due to HTLV-1. The virus remains in the body throughout life without causing obvious harm. A minority will develop disease due to HTLV-1, usually after several decades of infection. There are two main types of disease directly caused by HTLV-1: the white blood cell cancer, adult T-cell leukaemia/lymphoma (ATL) and diseases characterised by inflammation of which the best know is HTLV-1-associated myelopathy (HAM) where inflammation most notably occurs in the spinal cord.
Adult T-cell Leukaemia/Lymphoma (ATL): This rare form of cancer of the blood occurs in less than 20 patients per year in the UK. The risk of ATL in an HTLV-1 carrier is approximately 4% but depends on gender, route of infection and HTLV-1 viral burden.
HTLV-1 associated myelopathy (HAM): This is an inflammation of nerves in the spinal cord that causes stiffness and weakness of the legs, backache, a ‘weak’ bladder and constipation. Not all of these symptoms may be present, especially at the beginning. The disease often starts very slowly and the symptoms may be attributed to arthritis or getting old. In the UK fewer than 10 persons are diagnosed with HAM each year.
Other HTLV-1 associated inflammatory diseases: HTLV-I can also cause inflammation of the eye (uveitis), joints (arthritis), muscles (myositis), lung (alveolitis and bronchiectasis), thyroid (thyroiditis) and skin (dermatitis). These conditions are less common than ATL and HAM and the skin condition is usually only seen in tropical climates.
HTLV-1 and co-infections
HTLV-1 infection can coexist with other infections with variable effects.
Strongyloidiasis: An infection acquired in the tropics can, after lying dormant for years, cause a serious illness in HTLV-1 carriers. Although rare in the UK, all HTLV-1 carriers who have lived in the regions where strongyloides is present should be screened for Strongyloidiasis.
Schistosomiasis: Although there are few studies there is evidence that HTLV-1 infection also impacts on the infection with Schistosoma mansoni with less response to treatment.
Tuberculosis: In some regions tuberculosis infection has been found to be more common in carriers of HTLV-1 infection than in the general population. An impact on testing for Tuberculosis has also been reported with the skin test found to be negative in HTLV carriers in Japan. We have observed that a ‘modern’ test for tuberculosis infection – the TB T-spot often gives an indeterminate response in patients with HTLV-1 infection.
Hepatitis C virus: Co-infection with hepatitis C and HTLV-1 has been reported to be associated with lower levels of HCV virus but a higher rate of liver cell cancer than seen with hepatitis C virus alone.
HIV: Patients who have HIV and HTLV may be at a slightly higher risk of developing HAM due to the underlying inflammation that HTLV is associated with. Patients with both infections may also develop rare infections, called opportunistic infections at a high CD4 count.
Can HTLV-I infection be treated?
At present there is no treatment to cure (eradicate) the infection. Since 90% of all infected persons go through life without developing any HTLV-1 associated diseases any such treatment would have not only to be effective but also very safe.
Is everyone infected with HTLV-I at equal risk of developing an HTLV-I associated disease?
ATL is unlikely to develop following infection acquired in adult-life. This means that avoiding infection of babies is very important for the prevention of ATL in the next generation. The greatest risk of mother-to-child transmission of HTLV-1 is through breastfeeding. 80% of all such infections can be avoided by choosing formula feeding.
Japanese data show the life time risk of ATL to be higher for males (6%) than females (2%). This most likely reflects the greater risk to females of infection in adult life. The lifetime risk of ATL following infection during the first 1-2 years of life is therefore higher than these figures suggest.
A Japanese study showed that HTLV-1 carriers who smoked were at higher risk of developing ATL, with a hazard ratio of 2.03 for every 20 cigarettes smoked per day, althoug this has not been investigated in other population (5).
HTLV-1 asymptomatic carriers with low viral load (fewer viruses in the blood) are less likely to develop ATL. Data from UK and Japan suggest that ATL develops in carriers with viral loads greater than 4% (see section on HTLV viral load).
A subpopulation of carriers both infected with HTLV-1 as babies and with a viral load greater than 4% are at high risk of ATL and should be offered specific routine monitoring.
HAM seems to be less common among the Japanese with HTLV-1 infection than among other populations and evidence is emerging that the immune system is important in controlling infection. Recent data from Brazil suggest higher rates of HAM than previously reported suggesting additional co-factors may be important.
HTLV-1 asymptomatic carriers with low viral load (fewer viruses in the blood) are unlikely to develop HAM. A cut-off of 1% has been suggested between low and high risk with the risk of HAM increasing with exponentially with viral loads above 1%
HAM is more common in females than males.
HAM can occur within months of HTLV-1 infection. Introduction of HTLV-1 blood donor screening reduced the number of new cases of HAM by 20% after 2 years. HAM occurring within 3 years of transplantation acquired infection has been documented on several occasions.
The risks relating to other HTLV-1-associated inflammations are less well studied but two observations can be made:
• HTLV-1 associated inflammatory disease is associated with high HTLV-1 viral load.
• HTLV-1 associated inflammatory disease is more commonly observed in patients already diagnosed with another HTLV-1 associated condition.
1. Manns A, Murphy E, Wilks RJ, Haynes G, Figueroa JP, Hanchard B, et al. Detection of early human T-cell lymphotropic virus type I antibody patterns during seroconversion among transfusion recipients. Blood. 1991;77(4):896-905.
2. Manns A, Wilks RJ, Murphy E, Haynes G, Figueroa JP, Barnett M, et al. A prospective study of transmission by transfusion of HTLV-I and risk factors associated with seroconversion. Int J Cancer. 1992;51:886-91.
3. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The Risk of Transfusion-Transmitted Viral Infections. New England Journal of Medicine. 1996;334(26):1685-90.
4. Cook LB, Melamed A, Demontis MA, Laydon DJ, Fox JM, Tosswill JH, et al. Rapid dissemination of human T-lymphotropic virus type 1 during primary infection in transplant recipients. Retrovirology. 2016;13(1):3.
5. Kondo H, Soda M, Sawada N, Inoue M, Imaizumi Y, Miyazaki Y, Iwanaga M, Tanaka Y, Mizokami M, Tsugane S. Smoking is a risk factor for development of adult T-cell leukemia/lymphoma in Japanese human T-cell leukemia vuris type-1 carriers. Cancer Causes Control. 2016;27(9):1059-1066.
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