HTLV-I/II
MICROBIOLOGY
- Human T-cell leukemia virus I and II (HTLV I and II): members of human type C retroviruses.
- Dx by HTLV-I or HTLV-II ELISA; greater sensitivity than Western blot and PCR.
CLINICAL
- Most infections asymptomatic in general population. Not known if HIV+ pts more likely to develop disease.
- HTLV-I
- Endemic in Caribbean, southern Japan, parts of Africa, South America. Transmitted by breast feeding, contaminated blood products, IDU, sexual contact.
- Adult T cell leukemia (ATL): 5% lifetime risk. Presents with B Sx, lymphadenopathy. Skin involvement (plaques, nodules) common.
- HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP): 0.5-2.0% lifetime risk. Progressive disease with leg stiffness, weakness, low back pain, bladder dysfunction.
- HTLV-I/HIV coinfected pts have higher CD4 counts than HTLV-I-negative HIV+ pts. OIs occur at higher CD4 counts than seen in HTLV-I-negative pts.
- Can cause immunosuppression; associated with Strongyloides hyperinfection and decreased reactivity to PPD.
- Vast majority of infected individuals will not develop disease.
- HTLV-II
- Endemic among IDUs; seroprevalence approximately 20%.
- Not definitively shown to cause human disease, but some reports suggest that it can cause HAM/TSP-like syndrome.
- Effect of HTLV-I/II on HIV disease progression controversial, with different studies reaching opposite conclusions.
SITES OF INFECTION
- CD4 cells are main target of infection of HTLV-I.
- HTLV-I-infected CD4 cells found in CSF of pts with HAM/TSP.
- In ATL, circulation of monoclonal transformed cells bearing HTLV-I provirus.
- HTLV-II infects peripheral blood mononuclear cells.
TREATMENT
Asymptomatic Infection
- No evidence for benefit of antiviral therapy. HTLV genome integrated into host DNA; therefore, eradication probably not possible.
ATL
- Conventional chemotherapy (standard regimen of vincristine, cyclophosphamide, doxorubicin, prednisone ranimustine, vindesine etoposide, carboplatin)
- Small prospective phase II trial showed encouraging results with AZT 1 gm/d PO and alpha interferon (9 MU/d SQ).
- A humanized anti-CCR4 antibody (mogamulizumab) has been shown to be effective as monotherapy or in combination with chemotherapy
HAM/TSP
- Corticosteroids, cyclophosphamides, alpha interferon, IVIG, plasmapheresis, and danazol have been used with inconsistent results.
- NRTIs have been tried based on in vitro activity against HTLV-I. AZT (1-2 gm/d) or 3TC (150 mg twice-daily) alone or AZT (250 mg twice-daily) and 3TC (150 mg twice-daily) used in 3 small studies. While decreased proviral HTLV-I load seen, Sx did not improve in most pts. TDF recently shown to have good in vitro activityagainst HTLV-I. In recent small randomized study of HIV-negative pts, 6 mos of AZT (300 mg twice-daily) and 3TC (150 mg twice-daily) had no effect on HTLV proviral load or clinical Sx
- If ART to be initiated in coinfected pts, include AZT, TDF, and/or 3TC in pts with HAM/TSP or ATL if possible.
- If NRTIs to be started for coinfected pts with HAM/TSP, should be used as component of ART to prevent NRTI resistance.
Prevention
- CDC recommends that pts with asymptomatic infection not breast feed, donate blood, or share needles. Latex condoms should be used.
Basis for recommendation
- Guidelines for counseling persons infected with human T-lymphotropic virus type I (HTLV-I) and type II (HTLV-II). Centers for Disease Control and Prevention and the U.S.P.H.S. Working Group. Ann Intern Med. 1993;118(6):448-54. [PMID:8382459]
Comment: A practical set of guidelines from the CDC.
References
- Bangham CRM. Human T Cell Leukemia Virus Type 1: Persistence and Pathogenesis. Annu Rev Immunol. 2018;36:43-71. [PMID:29144838]
Comment: A comprehensive review of HTLV-I
- Sato T, Coler-Reilly ALG, Yagishita N, et al. Mogamulizumab (Anti-CCR4) in HTLV-1-Associated Myelopathy. N Engl J Med. 2018;378(6):529-538. [PMID:29414279]
Comment: Phase1-2a trial showed improved mobility and muscle tone and a a decrease in HTLV-1 proviral load and inflammatory markers in patients with steroid-refractory HAM
Rating: Important - Ishida T, Jo T, Takemoto S, et al. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol. 2015;169(5):672-82. [PMID:25733162]
Comment: The complete response rate in patients treated with combination therapy was higher (52%) than patients treated with mogamulizumab monotherapy (33%).
- Ogura M, Ishida T, Hatake K, et al. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014;32(11):1157-63. [PMID:24616310]
Comment: An objective response was seen in 35% of patients with relapsed disease who were treated with mogamulizumab.
- Croda MG, de Oliveira AC, Vergara MP, et al. Corticosteroid therapy in TSP/HAM patients: the results from a 10 years open cohort. J Neurol Sci. 2008;269(1-2):133-7. [PMID:18258264]
Comment: Open study of 39 patients with HAM/TSP treated with pulses of methylprednisolone (1 gm/d x 3 days) every 3-4 mos. After mean follow up of 2.2 yrs there was significant improvement of some Sx
- Kchour G, Makhoul NJ, Mahmoudi M, et al. Zidovudine and interferon-alpha treatment induces a high response rate and reduces HTLV-1 proviral load and VEGF plasma levels in patients with adult T-cell leukemia from North East Iran. Leuk Lymphoma. 2007;48(2):330-6. [PMID:17325893]
Comment: 9 pts with ATL treated with AZT (200-900 mg/d PO) and IFN alpha (3-5 million units daily SQ). 7 pts had either partial or complete response.
- Turci M, Pilotti E, Ronzi P, et al. Coinfection with HIV-1 and human T-Cell lymphotropic virus type II in intravenous drug users is associated with delayed progression to AIDS. J Acquir Immune Defic Syndr. 2006;41(1):100-6. [PMID:16340481]
Comment: More recent study showing protective effective of HTLV-II coinfection in HIV-1 positive IDUs. Interestingly, in 5 treated coinfected patients there was increase in HTLV-II proviral load, while HIV viral load dropped, suggesting that HAART does not treat HTLV-II.
Rating: Important - Beilke MA, Theall KP, O'Brien M, et al. Clinical outcomes and disease progression among patients coinfected with HIV and human T lymphotropic virus types 1 and 2. Clin Infect Dis. 2004;39(2):256-63. [PMID:15307036]
Comment: Study showed improved survival and decreased progression to AIDS in HTLV-II-coinfected patients. These pts more likely to have other clinical complications, however. Trend towards improved survival in HTLV-I-coinfected pts. While higher CD4 counts seen in coinfected pts, no difference in frequency of OIs.
- Araujo A, Hall WW. Human T-lymphotropic virus type II and neurological disease. Ann Neurol. 2004;56(1):10-9. [PMID:15236397]
Comment: Critical review of literature linking HTLV-II to neurological disease.
- Macchi B, Balestrieri E, Mastino A. Effects of nucleoside-based antiretroviral chemotherapy on human T cell leukaemia/lymphotropic virus type 1 (HTLV-1) infection in vitro. J Antimicrob Chemother. 2003;51(6):1327-30. [PMID:12716774]
Comment: Looks at the effects of NRTIs on HTLV-I replication in vitro.
- Scapellato PG, Bottaro E, Brieschke MT, et al. CD4 cell count among HIV-infected patients with an AIDS-defining disease: higher count in patients coinfected than in those not coinfected with human T-cell lymphotropic virus type I. J Acquir Immune Defic Syndr. 2003;33(2):279-80. [PMID:12794568]
Comment: Retrospective study found CD4 count of 160 in 6 treatment-naive HTLV-I/HIV coinfected pts vs. 62 in 42 HTLV-negative, HIV+ pts who presented with AIDS defining disease.
- Thorstensson R, Albert J, Andersson S. Strategies for diagnosis of HTLV-I and -II. Transfusion. 2002;42(6):780-91. [PMID:12147033]
Comment: Detailed study of methods used in the diagnosis of HTLV infection.
- Hermine O, Allard I, Lévy V, et al. A prospective phase II clinical trial with the use of zidovudine and interferon-alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Hematol J. 2002;3(6):276-82. [PMID:12522449]
Comment: 19 pts with ATL, 6 of whom had been treated with chemotherapy, received AZT 1 gm/d and alpha interferon 9 MU SQ once-daily for >2 mos. Of 17 who could be evaluated, 9 had complete response, 4 had partial response. 15 relapsed after a median of 7 mos.
- Brites C, Alencar R, Gusmão R, et al. Co-infection with HTLV-1 is associated with a shorter survival time for HIV-1-infected patients in Bahia, Brazil. AIDS. 2001;15(15):2053-5. [PMID:11600839]
Comment: This study from Brazil, where HTLV-I is endemic, showed shorter survival in HTLV-I/HIV-coinfected pts than in HTLV-I seronegative HIV-infected pts.
Rating: Important - Eskild A, Samdal HH, Heger B. Co-infection with HIV-1/HTLV-II and the risk of progression to AIDS and death. The Oslo HIV Cohort Study Group. APMIS. 1996;104(9):666-72. [PMID:8972691]
Comment: Relative risk of progression to AIDS was 2.1 in a cohort of 30 HTLV-II/HIV-coinfected pts when compared to HTLV-II seronegative HIV positive pts.
- Hershow RC, Galai N, Fukuda K, et al. An international collaborative study of the effects of coinfection with human T-lymphotropic virus type II on human immunodeficiency virus type 1 disease progression in injection drug users. J Infect Dis. 1996;174(2):309-17. [PMID:8699060]
Comment: Study compared 61 HTLV-II/HIV-I coinfected pts to 309 HTLV-II seronegative HIV+ pts. No difference in rate of CD4 count decline or progression to AIDS in the 2 cohorts.
- Gill PS, Harrington W, Kaplan MH, et al. Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med. 1995;332(26):1744-8. [PMID:7760890]
Comment: 19 pts with ATL, some of whom had failed chemotherapy, treated with AZT (1 gm/d) and alpha-interferon (5-10 MU SQ once-daily). 26% complete response and 32% partial response.
- Briggs NC, Battjes RJ, Cantor KP, et al. Seroprevalence of human T cell lymphotropic virus type II infection, with or without human immunodeficiency virus type 1 coinfection, among US intravenous drug users. J Infect Dis. 1995;172(1):51-8. [PMID:7797946]
Comment: 98% of all HTLV infections in U.S. IDUs attributable to HTLV-II. Seroprevalence higher in HIV-infected pts.
HTLV-I/IIis the Johns Hopkins Guides Word of the day!