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Research Article| Volume 86, ISSUE 3, P245-247, March 2023

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HTLV seroprevalence in people using HIV pre-exposure prophylaxis in England

Open AccessPublished:February 09, 2023DOI:https://doi.org/10.1016/j.jinf.2023.01.033
HTLV seroprevalence in people using HIV pre-exposure prophylaxis in England
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      Highlights

      • •
        First study to evaluate the potential risk of HTLV transmission amongst people who use HIV-PrEP.
      • •
        No (0/2015) HTLV-1/HTLV-2 cases found in people who use HIV-PrEP in England.
      • •
        Similar studies are needed amongst HIV-PrEP uses elsewhere, particularly in HTLV-1 endemic settings.

      Summary

      Objectives

      HTLV-1 is predominantly a sexually-transmitted infection but testing is not mentioned in HIV-PrEP guidelines. We ascertained HTLV-1/HTLV-2 seroprevalence amongst HIV-PrEP users in England.

      Methods

      An unlinked anonymous seroprevalence study.

      Results

      Amongst 2015 HIV-PrEP users, 95% were men, 76% of white ethnicity and 83% had been born in Europe. There were no HTLV-1/HTLV-2 seropositive cases (95% confidence interval 0% – 0.18%).

      Conclusions

      There were no HTLV positive cases, likely reflecting the demographic of mostly white and European-born individuals. Similar studies are needed worldwide to inform public health recommendations for HIV-PrEP using populations, particularly in HTLV-endemic settings.

      Keywords

      Introduction

      HIV pre-exposure prophylaxis (HIV-PrEP) is highly effective in reducing the likelihood of HIV acquisition in HIV-negative people at risk of exposure.
      • McCormack S.
      • Dunn D.T.
      • Desai M.
      • et al.
      Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial.
      Lancet. 2016; 387: 53-60
      Guidelines recommend testing for sexually transmitted infections (STIs) both before starting, and periodically while on HIV-PrEP, including bacterial infections, HIV, hepatitis C virus, and, for those who are non-immune, hepatitis B virus.

      Preexposure prophylaxis for the prevention of HIV infection. IN The United States –2021 update: a clinical practice guideline. Available at: https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf.

      Diagnosed infections can be treated promptly to reduce onward transmission. HTLV-1 is not mentioned in HIV-PrEP guidelines; however, it is predominantly sexually transmitted, causes adult T-cell leukaemia/lymphoma or myelopathy in 10% of those infected, and is associated with an increased risk of death (Relative Risk 1.57, 95% CI 1.37-1.80) in those without a classically HTLV-associated condition.
      • 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: 133-143
      The 2021 WHO Technical Report on HTLV-1 called for strengthening of global public health measures against its spread. We therefore evaluated the potential risk of HTLV to HIV-PrEP users in England, 96% of whom are gay and bisexual men who have sex with men (GBMSM),
      • Sullivan AK.
      The HIV pre-exposure prophylaxis (PrEP) IMPACT trial: baseline demographics, coverage and first regimen choice.
      in: Proceedings of the Fifth Joint Conference of the British HIV Association (BHIVA) and the British Association for Sexual Health and HIV (BASHH). 2021
      through a seroprevalence study.

      Materials and methods

      Specimen ascertainment

      We conducted an irreversibly-unlinked, anonymous seroprevalence surveillance study in eight HIV-PrEP clinics in England, including five in London. We used serum or EDTA plasma samples where at least 500ul remained after testing for HIV, syphilis or viral hepatitis as part of standard care HIV-PrEP follow-up. Samples were identified (1) at clinic visit (prospective ascertainment) or (2) retrospectively from local laboratory archives by ascertaining current PrEP-user status from the national STI surveillance system, Genitourinary Medicine Clinic Activity Dataset (GUMCAD). Samples were available from September 2019 to November 2021. All specimens were labelled only with a unique Study Number and no patient identifiable information.
      Limited demographic and clinical information for each individual were extracted from GUMCAD: date of sample collection, sex, age range, country of birth, ethnicity, any history of syphilis, and history of bacterial STI (chlamydia, gonorrhoea, or syphilis) within the previous 12 months. Countries of birth were grouped into HTLV-endemic and non-endemic categories according to criteria of the European Centres of Disease Control.

      Geographical distribution of areas with a high prevalence of HTLV-1 infection. Available at: https://www.ecdc.europa.eu/sites/default/files/media/en/publications/Publications/geographical-distribution-areas-high-prevalence-HTLV1.pdf.

      After data extraction and de-duplication, all identifiers were irreversibly deleted except for Study Numbers. Samples were transferred to the HTLV reference laboratory.

      Testing

      All testing was performed with the Abbott Architect rHTLV-I/II assay (Abbott Laboratories Weisbaden, Germany), a Chemiluminescent Microparticle Immunoassay (CMIA), according to the manufacturer's instructions.
      To determine the pooling size for testing, a set of positive samples were serially diluted (2 fold) in normal human plasma (NHS Blood and Transplant) from neat to 1/128, with final volumes of 400uL. We included four anti-HTLV-1 reactive, three anti-HTLV-2 reactive, two dual reactive and three non-typeable reactive samples, with specimen Sample/Cut-off ratios at neat encompassing a range from 8.0 to 96.8. The lowest positive sample (anti-HTLV-2 reactive at 8.0 neat) remained positive (Sample/cut-off >1) at 1/8 but not at 1/16. Therefore, to ensure detection in pooled samples to at least the level of this lowest positive sample, pools of 5 were used.
      The individual samples in any reactive pool were further tested by Abbott Architect rHTLV-I/II CMIA and reactivity was confirmed and typed by Western blot MP Diagnostics 2.2 according to the manufacturer's instructions.

      Sample size

      We estimated the sample size according to the ability to detect a change in HTLV-1 seroprevalence amongst HIV-PrEP users in serial surveys. Approximately 7% of HIV-PrEP users in England were born in an HTLV-1 endemic country (internal communication, PrEP Impact Trial investigators). If the observed HTLV-1 prevalence were 0% in individuals born in low prevalence countries, a sample size of 1,500 would give a 95% Confidence Interval (CI) of 0-0.27% around this prevalence. If the prevalence were 0.2%, then the 95% CI would be 0.04-0.61%. For assessing changes in prevalence in a subsequent survey of the same size, with 80% power and 5% significance level, for those born in low prevalence countries, 1,368 in each survey would allow a change from 0% to 0.7% to be detected, or from 0.2% to 1.2%. For those born in high prevalence countries, changes from 1% to 9% or 2% to 11% can be detected. Allowing for a proportion of stored samples being of poor quality for testing, we therefore aimed to test a minimum of 1500 specimens.

      Statistical methods

      The number of samples tested by age, sex, country of birth, ethnicity and bacterial STI history are described, and the overall prevalence as well as prevalence with those from an HTLV-endemic country given with a 95% exact confidence interval.

      Ethics

      This study was classified as surveillance permitting the collection of data without patient consent under section 251 of the UK National Health Service Act 2006 and Regulation 3 of the associated Health Service (Control of Patient Information) Regulations 2002. Ethical approval was provided by the UK Health Security Agency Research Ethics and Governance Group (Reference Number: NR0154).

      Results

      There were 2015 specimens from unique individuals matched via GUMCAD as HIV-PrEP users and with sufficient volume for testing. Demographic characteristics are shown in Table 1. Most individuals (95%) were male; 76% were of white ethnicity; 55% were aged 30-49 years and 82% were born in the UK or European Union. Overall, n = 144/1732 (8%) individuals were born in an HTLV-1 endemic country, with the five most frequent country of births being Brazil (n = 41, 2%), Nigeria (n = 14, 0.8%), Romania (n = 11, 0.6%), South Africa (n = 10, 0.6%) and Colombia (n = 9, 0.5%) . A bacterial STI, chlamydia, gonorrhoea or syphilis, had been diagnosed in the previous year in 39% of participants.
      Table 1Demographic characteristics of HIV-PrEP users.
      Number%
      Total2015
      Gender2007
      Male190495
      Female1035
      Ethnicity1655
      White126576
      Mixed/other17711
      Black1087
      Asian1056
      Age (years)1994
      <3069735
      30-49109154
      >/=5022611
      Country/region of birth1732
      UK109763
      European Union33319
      South America664
      Sub Saharan Africa543
      North Africa / Middle East402
      Australasia352
      North America332
      South Asia262
      East Asia251
      South East Asia231
      Other Europe141
      Caribbean7<1
      Central America5<1
      HTLV-1 endemic country1448
      STI history2015
      Any history of syphilis19310
      Any bacterial STI in previous year
      Chlamydia trachomatis, Neisseria gonorrhoeae or Treponema pallidum.
      		79139
      low asterisk Chlamydia trachomatis, Neisseria gonorrhoeae or Treponema pallidum.
      No specimen (0/2,015) was positive for HTLV antibodies by Abbott Architect CMIA. This gave a seroprevalence of 0%, 95% CI 0% – 0.18%. In relation to PrEP users born in HTLV-1-endemic countries, the 95% CI for 0/144 is 0% – 2.5%.

      Conclusions

      We found no cases of HTLV-1 or HTLV-2 in this HIV-PrEP-using population at high risk of a bacterial STI. This likely reflects the demographic, with 76% being of white ethnicity and 92% born in a non-HTLV endemic country. These data are reassuring that HTLV is not circulating widely amongst current HIV-PrEP-users in England and are consistent with the low HTLV prevalence in the UK general population, estimated at 0.04% in pregnant women.

      Geographical distribution of areas with a high prevalence of HTLV-1 infection. Available at: https://www.ecdc.europa.eu/sites/default/files/media/en/publications/Publications/geographical-distribution-areas-high-prevalence-HTLV1.pdf.

      HTLV-1 seroprevalence was greater amongst UK HIV-positive individuals attending a South London hospital at 0.6% (5/777), likely reflecting the higher proportion of individuals of Afro-Caribbean heritage (50% versus 7%).
      • Cooke F.J.
      • Geretti A.M.
      • Zuckerman M.
      Human T-cell lymphotropic virus antibody prevalence in HIV-1-infected individuals attending a sexual health clinic in South-East London.
      J Med Virol. 2005; 76: 143-145
      To our knowledge, only one other study has described HTLV prevalence in HIV-PrEP-users. In Barbados, one HTLV-1 positive case was diagnosed amongst 134 (0.7%) people enrolled in a national PrEP program, 67% of whom were GBMSM.
      • 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
      This is consistent with the high HTLV-1 prevalence in the Barbados general population, at 4.3% (43/1,007) in pregnant women.

      Geographical distribution of areas with a high prevalence of HTLV-1 infection. Available at: https://www.ecdc.europa.eu/sites/default/files/media/en/publications/Publications/geographical-distribution-areas-high-prevalence-HTLV1.pdf.

      Other studies in HTLV-endemic and non-endemic settings have shown that HTLV-1 seroprevalence amongst GBMSM may be increased compared to the general population.
      • Bradshaw D.
      • Taylor GP.
      HTLV-1 transmission and HIV pre-exposure prophylaxis: a scoping review.
      Front Med. 2022; 9 (Lausanne)881547
      HTLV-1 risk factors in GBMSM include HIV-coinfection, multiple partners, condomless receptive anal intercourse, syphilis, and HSV-2, a profile that overlaps with that of HIV-PrEP-users.
      • Bradshaw D.
      • Taylor GP.
      HTLV-1 transmission and HIV pre-exposure prophylaxis: a scoping review.
      Front Med. 2022; 9 (Lausanne)881547
      Non-GBMSM HIV-PrEP-users may also be at increased risk for HTLV-1. In Kenya, Lesotho, and Tanzania, 50% of 47,352 PrEP-users were female sex workers (FSW), a group at high risk of HTLV-1 acquisition in much of Africa.
      • Reed J.B.
      • Shrestha P.
      • Were D.
      • et al.
      HIV PrEP is more than ART-lite: Longitudinal study of real-world PrEP services data identifies missing measures meaningful to HIV prevention programming.
      J Int AIDS Soc. 2021; 24: e25827
      ,
      • Fox J.M.
      • Mutalima N.
      • Molyneux E.
      • 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 (TM & IH): 312-324
      People who inject drugs (PWID) at high HIV risk are also recommended to take HIV-PrEP and are at risk of HTLV-1 particularly in endemic settings such as Brazil.
      • de Araujo A.C.
      • Casseb J.S.
      • Neitzert E.
      • et al.
      HTLV-I and HTLV-II infections among HIV-1 seropositive patients in Sao Paulo, Brazil.
      Eur J Epidemiol. 1994; 10: 165-171
      HTLV-1 seroprevalence data are therefore needed for HIV-PrEP cohorts internationally, including GBMSM, FSW and PWID. This will permit ascertainment of the risk of HTLV-1 transmission to HIV-PrEP users, and inform country-specific public health interventions, such as an offer of HTLV testing at baseline and counselling on use of condoms for those infected. HTLV-1 incidence should also be measured in HIV-PrEP programs, together with the potential activity of tenofovir disoproxil-emtricitabine or tenofovir alafenamide-emtricitabine as HTLV-PrEP.
      • Bradshaw D.
      • Taylor GP.
      HTLV-1 transmission and HIV pre-exposure prophylaxis: a scoping review.
      Front Med. 2022; 9 (Lausanne)881547
      Evaluation of the injectable integrase strand transfer inhibitor cabotegravir as HTLV-PrEP should also be explored given its potent in vitro activity.
      • Schneiderman B.S.
      • Barski M.S.
      • Maertens GN.
      Cabotegravir, the Long-acting integrase strand transfer inhibitor, potently inhibits human T-cell lymphotropic virus Type 1 transmission in vitro.
      Front Med. 2022; 9 (Lausanne)889621
      Unlike HIV, antiviral therapy to treat established HTLV is lacking, placing greater emphasis on transmission prevention.
      Our finding of 8% of individuals within this high risk sexually active cohort having been born in an HTLV endemic country also supports the need for expanded HTLV testing in sexual health settings. In a previous UK report, most HTLV diagnoses (84%, 75/89) were made in secondary care, with almost no testing performed in sexual health, antenatal clinics or general practice.
      • Ireland G.
      • Croxford S.
      • Tosswill J.
      • et al.
      Human T-lymphotropic viruses (HTLV) in England and Wales, 2004 to 2013: testing and diagnoses.
      Eurosurveillance. 2017; 22 (: bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin)
      Similarly, a recent report from Spain described a disproportionately high number of HTLV cases (22%, 96/428) diagnosed following symptomatic presentation and highlighted that late presentation of HTLV-1 in Europe could result from poor clinical suspicion, especially in individuals born in certain HTLV endemic regions such as Sub Saharan Africa, or with sex partners from these regions.
      • de Mendoza C.
      • Perez L.
      • Fernandez-Ruiz M.
      • et al.
      Late presentation of human T-lymphotropic virus type 1 infection in Spain reflects suboptimal testing strategies.
      Int J Infect Dis. 2022; 122 (IJID: official publication of the International Society for Infectious Diseases): 970-975
      The authors called for expanded HTLV testing in sexual health and antenatal settings to identify asymptomatic carriers and thereby enable implementation of transmission prevention interventions.
      Other notable findings include the lack of any sample with non-specific reactivity, which likely reflects the use of pooled testing. It has previously been shown that non-specific reactivity on the Abbott Architect rHTLV-I/II CMIA is usually at a level of OD/CO ≤ 4; therefore, any low level reactivity would become negative on pooling in a 1:5 ratio.
      • Tosswill J.H.C.
      • Taylor G.P.
      Interpretation of low reactivity in the Abbott Architect rHTLV I/II assay.
      Transfus Med. 2018; 28: 326-330
      An important limitation of the study was the lack of information on history of injection drug use (IDU), which is a well-recognised route of HTLV transmission, particularly HTLV-2. Therefore, we were unable to assess the risk of HTLV transmission through IDU in this PrEP-using cohort.
      In conclusion, we found no cases of HTLV amongst 2,015 HIV-PrEP-users at high bacterial STI risk in England. Our survey should be repeated in 3-5 years to assess for the early introduction of HTLV-1 in the PrEP-using population, and in the HIV-PrEP programs of other countries, particularly where HTLV-1 is endemic in the general population.

      Declaration of Competing Interest

      None

      Acknowledgments

      The authors wish to acknowledge the patients who contributed to this study. This work was supported by a grant from Gilead Sciences. The funder had no role in study design or conduct or in the analysis or presentation of study findings. All authors confirm that they do not have an association that might pose a conflict of interest.

      Appendix. Supplementary materials

      References

        • McCormack S.
        • Dunn D.T.
        • Desai M.
        • et al.
        Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial.
        Lancet. 2016; 387: 53-60
        View in Article

      2. Preexposure prophylaxis for the prevention of HIV infection. IN The United States –2021 update: a clinical practice guideline. Available at: https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf.

        View in Article
        • 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: 133-143
        View in Article
        • Sullivan AK.
        The HIV pre-exposure prophylaxis (PrEP) IMPACT trial: baseline demographics, coverage and first regimen choice.
        in: Proceedings of the Fifth Joint Conference of the British HIV Association (BHIVA) and the British Association for Sexual Health and HIV (BASHH). 2021
        View in Article

      5. Geographical distribution of areas with a high prevalence of HTLV-1 infection. Available at: https://www.ecdc.europa.eu/sites/default/files/media/en/publications/Publications/geographical-distribution-areas-high-prevalence-HTLV1.pdf.

        View in Article
        • Cooke F.J.
        • Geretti A.M.
        • Zuckerman M.
        Human T-cell lymphotropic virus antibody prevalence in HIV-1-infected individuals attending a sexual health clinic in South-East London.
        J Med Virol. 2005; 76: 143-145
        View in Article
        • 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
        View in Article
        • Bradshaw D.
        • Taylor GP.
        HTLV-1 transmission and HIV pre-exposure prophylaxis: a scoping review.
        Front Med. 2022; 9 (Lausanne)881547
        View in Article
        • Reed J.B.
        • Shrestha P.
        • Were D.
        • et al.
        HIV PrEP is more than ART-lite: Longitudinal study of real-world PrEP services data identifies missing measures meaningful to HIV prevention programming.
        J Int AIDS Soc. 2021; 24: e25827
        View in Article
        • Fox J.M.
        • Mutalima N.
        • Molyneux E.
        • 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 (TM & IH): 312-324
        View in Article
        • de Araujo A.C.
        • Casseb J.S.
        • Neitzert E.
        • et al.
        HTLV-I and HTLV-II infections among HIV-1 seropositive patients in Sao Paulo, Brazil.
        Eur J Epidemiol. 1994; 10: 165-171
        View in Article
        • Schneiderman B.S.
        • Barski M.S.
        • Maertens GN.
        Cabotegravir, the Long-acting integrase strand transfer inhibitor, potently inhibits human T-cell lymphotropic virus Type 1 transmission in vitro.
        Front Med. 2022; 9 (Lausanne)889621
        View in Article
        • Ireland G.
        • Croxford S.
        • Tosswill J.
        • et al.
        Human T-lymphotropic viruses (HTLV) in England and Wales, 2004 to 2013: testing and diagnoses.
        Eurosurveillance. 2017; 22 (: bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin)
        View in Article
        • de Mendoza C.
        • Perez L.
        • Fernandez-Ruiz M.
        • et al.
        Late presentation of human T-lymphotropic virus type 1 infection in Spain reflects suboptimal testing strategies.
        Int J Infect Dis. 2022; 122 (IJID: official publication of the International Society for Infectious Diseases): 970-975
        View in Article
        • Tosswill J.H.C.
        • Taylor G.P.
        Interpretation of low reactivity in the Abbott Architect rHTLV I/II assay.
        Transfus Med. 2018; 28: 326-330
        View in Article

      Article info

      Publication history

      Published online: February 09, 2023
      Accepted: January 20, 2023

      Identification

      DOI: https://doi.org/10.1016/j.jinf.2023.01.033

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