Silva, Marcus T.T.a; Neves, Elizabeth S.a; Grinsztejn, Beatrizc; de Melo Espíndola, Otáviob; Schor, Dorisb; Araújo, Abelardoa
aLaboratório de Pesquisa Clínica em Neuroinfecção
bLaboratório de Pesquisa em Patogenia Viral
cLaboratório de Pesquisa Clínica em DST/AIDS, Instituto de Pesquisa Clínica Evandro Chagas (IPEC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil.
Correspondence to Marcus Tulius T. Silva, MD, PhD, IPEC/FIOCRUZ, Laboratório de Pesquisa Clínica em Neuroinfecção, Avenida Brasil, 4365 – Rio de Janeiro, CEP 21040-360, Brazil. Fax: +55 21 26102921.e-mail: email@example.com
Received 9 February, 2011
Revised 9 August, 2011
Accepted 24 August, 2011
This study was sponsored by the Programa Nacional DST/AIDS do Ministério da Saúde, Fundação Oswaldo Cruz (FIOCRUZ), and Conselho Nacional de Desenvolvimento Científico e Tecnológico – Programa Bolsa de Produtividade em Pesquisa (CNPq).
HIV/human T-lymphotropic virus (HTLV) coinfection is expected both in people from HTLV endemic areas and in intravenous drug users. Furthermore, both viruses affect nervous system [1,2]. Little is known about the impact of HAART on HIV/HTLV coinfection, as majority of studies were performed before or in the initial years of HAART [1,3–5]. We aimed to determine the prevalence of HIV/HTLV coinfection and related neurological diseases in a cohort of HIV patients on HAART.
From 2678 HIV individuals, 500 on HAART were randomized to HTLV antibody analysis (HIV/HTLV group or HIV-control group). Additionally, 92 out of 726 HTLV individuals were randomly selected (HTLV group). All participants were submitted to neurological examination, CD4 cell counts, HIV viral load, HCV antibody test, and HTLV proviral load. A specific diagnostic form was used to identify peripheral neuropathy and myelopathy [6,7].
A logistic regression was employed to clarify whether independent variables could predict neurological outcome. We employed two models of multiple binary logistic regression. Potential risk factors were sex, age, CD4 cell count, virological group, and HCV infection. In the first model, the variable virological group contained three categories (HIV/HTLV, HIV, and HTLV group); in the second model, it contained only HIV/HTLV and HIV group. Additionally, we used correlation coefficient to quantify the strength of a relationship between coinfection and neurological outcomes. As variables were dichotomous, ϕ coefficient was used [rϕ = √(X2/N)]. Correlations can range from −1 (negative) to 1 (positive relationship). A correlation of 0 indicates no relationship. To interpret the effect size, we used the effect size threshold . We calculated the strength of association (rϕ) using X2-test. The following score was used to categorize rϕ value and the effect size: rϕ = 0.1 or less, small; rϕ more than 0.1 and 0.3 or less, medium; and rϕ more than 0.3, large effect size.
Four hundred and twenty-eight out of 500 HIV-individuals underwent HTLV testing; 72 were not available to complete the study. HIV/HTLV coinfection was diagnosed in 47 (10.9%). Neurological disease was more prevalent in HIV/HTLV than in HIV group (24 out of 47 vs. 57 out of 381, respectively; rϕ = 0.3302, X2 = 51.8). In logistic regression, age and coinfection were the only variables to predict neurological outcome; odds ratio (OR) for any neurological outcome was 8.73 (confidence interval 4.1–18.4) considering coinfection. Myelopathy was diagnosed in 12 and isolated peripheral neuropathy in another 12 coinfected individuals. Because HCV infection is also associated with peripheral neuropathy, we excluded all HCV-patients. Despite this, peripheral neuropathy was more prevalent in coinfected patients (23 vs. 11.2%; rϕ = 0.0818, X2 = 2.7; see Table 1).
Baseline CD4 cell counts were higher in the HIV/HTLV than in the HIV group, but not after HAART had been initiated. HTLV proviral load was similar in the HIV/HTLV and HTLV groups. Prevalence of peripheral neuropathy was higher in coinfected compared with HTLV patients (rϕ = 0.2260, X2 = 7.1, P = 0.007). Otherwise, myelopathy was more prevalent in the HTLV than in the HIV/HTLV group (rϕ = 0.1838, X2 = 4.7, P = 0.02).
HIV/HTLV coinfection was diagnosed in 10.9% of HIV-individuals on HAART from an HTLV endemic area. Coinfected patients were more likely to have peripheral neuropathy, myelopathy, and HCV infection. Furthermore, neither HTLV proviral load nor CD4 cell counts were influenced by HAART. Perhaps, the higher CD4 cell counts in coinfected patients reflect HTLV-1-associated lymphocyte proliferation; CD4 cell count cutoff values should be reviewed in this setting .
HTLV-1 is the causative agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Additionally, other neurological conditions have been associated with HTLV-1, emphasizing its ability to affect the nervous system . Noteworthy, a high proviral load is associated with the development of neurological diseases .
Similarly, several HIV-neurological diseases have been described since the beginning of HIV epidemic. HIV has been associated with vacuolar myelopathy that is clinically similar to but histopathologically distinct from HAM/TSP. In pre-HAART era, about 10% of AIDS patients were affected by vacuolar myelopathy, but nowadays it is rarely diagnosed.
It is estimated that the lifetime risk of HAM/TSP in HTLV-1 individuals is around 2%, but there are evidences that the rates are higher in coinfected patients; this increased risk may result from upregulated HTLV-1 levels, as suggested by the finding that HTLV-1 tax/rex mRNA expression levels are higher in coinfected patients . In addition, HTLV-1 proviral load might increase during immune reconstitution with HAART owing to expansion of the reservoir of CD4 cells containing HTLV-1 provirus . It is unknown whether HAART effects play a role in the neuropathogenesis of HTLV diseases. However, as patients on HAART survive longer, long-term complications, such as myelopathy and peripheral neuropathy, might emerge.
Berger et al. were the first to report that HIV could increase susceptibility to the development of myelopathy in coinfected patients. They described four coinfected patients and all except one had a myelopathy similar to HAM/TSP. In another study in the pre-HAART era, myelopathy was more prevalent in coinfected patients (11 out of 15 coinfected patients, OR = 14, P < 0.00004) .
Beilke et al. described four cases of myelopathy among 41 HIV/HTLV-1 patients, wherein only two of those were taking antiretroviral drugs (zidovudine as monotherapy). In our cohort, all patients were using HAART and 12 (25.5%) had myelopathy. Whether HAART predisposes coinfected individuals to develop myelopathy is still a matter of speculation.
Isolated peripheral neuropathy has also been described in association with HTLV. Zehender et al. studied 30 HIV/HTLV-2 patients and reported a higher frequency of peripheral neuropathy (OR 3.3, P < 0.009). In our cohort, peripheral neuropathy was also more prevalent in coinfected individuals even when we excluded HCV patients. It is noteworthy that unlike the report of Zehender et al., majority of our coinfected patients were infected with HTLV-1, highlighting its role in the pathogenesis of peripheral neuropathy as suggested .
Summarizing, we found a 10.9% prevalence of HIV/HTLV coinfection in a cohort of HIV individuals from a HTLV endemic area. Coinfection was associated with an increased risk of neurological diseases. HAART did not appear to protect against neurological diseases and had no impact on HTLV proviral load and CD4 cell counts. It remains an open question whether higher prevalence of neurological diseases was due to longer survival of HIV-patients on HAART. If this idea proves to be true, we should expect an increasing number of neurological complications among coinfected individuals in the future.
M.T.T.S. is acknowledged with original idea, wrote the manuscript, and performed the neurological assessments, revision of data, and statistical analysis.
E.S.N. performed the clinical assessment, revision of laboratorial data, and revision of the manuscript.
B.G. performed the statistical analysis, revision of laboratorial data, and revision of the manuscript.
O.M.E. and D.S. performed the laboratorial analysis.
A.A. performed the neurological assessments, revision of data, and revision of the manuscript.
The authors are indebted to Dr Maria José de Andrada-Serpa, MD, PhD for her scientific support during all the stages of this research.
Conflicts of interest
There are no conflicts of interest.
1. Turci M, Pilotti E, Ronzi P, Magnani G, Boschini A, Parisi SG, 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; 41:100–106.
2. Tulius Silva M, de Melo Espindola O, Bezerra Leite AC, Araujo A. Neurological aspects of HIV/human T lymphotropic vírus coinfection. AIDS Rev 2009; 11:71–78.
3. Beilke MA, Japa S, Moeller-Hadi C, Martin-Schild S. Tropical spastic paraparesis/human T leukemia virus type 1-associated myelopathy in HIV type 1-coinfected patients. Clin Infect Dis 2005; 41:e57–e63.
4. Harrison LH, Schechter M. Human T cell lymphotropic virus type II and human immunodeficiency virus type 1 disease progression. J Infect Dis 1997; 176:308–309.
5. Schechter M, Harrison LH, Halsey NA, Trade G, Santino M, Moulton LH, et al. Coinfection with human T-cell lymphotropic virus type I and HIV in Brazil. Impact on markers of HIV disease progression. JAMA 1994; 271:353–357.
6. Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force.Neurology 1991; 41:778–785.
7. De Castro-Costa CM, Araujo AQ, Barreto MM, Takayanagui OM, Sohler MP, da Silva EL, et al. Proposal for diagnostic criteria of tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). AIDS Res Hum Retroviruses 2006; 22:931–935.
8. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed.Hillsdale, New Jersey:Lawrence Erlbaum; 1988.
9. Schechter M, Moulton LH, Harrison LH. HIV viral load and CD4R lymphocyte counts in subjects coinfected with HTLV-I and HIV-1. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 15:308–311.
10. Araujo AQ, Silva MT. The HTLV-1 neurological complex. Lancet Neurol 2006; 5:1068–1076.
11. Silva MT, Harab RC, Leite AC, Schor D, Araujo A, Andrada-Serpa MJ. Human T lymphotropic virus type 1 (HTLV-1) proviral load in asymptomatic carriers, HTLV-1-associated myelopathy/tropical spastic paraparesis, and other neurological abnormalities associated with HTLV-1 infection. Clin Infect Dis 2007; 44:689–692.
12. Beilke MA, Japa S, Vinson DG. HTLV-I and HTLV-II virus expression increase with HIV-1 coinfection. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17:391–397.
13. Murphy EL, Grant RM, Kropp J, Oliveira A, Lee TH, Busch MP. Increased human T-lymphotropic virus type II proviral load following highly active retroviral therapy in HIV-coinfected patients. J Acquir Immune Defic Syndr 2003; 33:655–656.
14. Berger JR, Raffanti S, Svenningsson A, McCarthy M, Snodgrass S, Resnick L. The role of HTLV in HIV-1 neurologic disease. Neurology 1991; 41 (2 Pt 1):197–202.
15. Harrison LH, Vaz B, Taveira DM, Quinn TC, Gibbs CJ, de Souza SH, et al. Myelopathy among Brazilians coinfected with human T-cell lymphotropic virus type I and HIV. Neurology 1997; 48:13–18.
16. Zehender G, De Maddalena C, Osio M, Cavalli B, Parravicini C, Moroni M, Galli M. High prevalence of human T cell lymphotropic virus type II infection in patients affected by human immunodeficiency virus type 1-associated predominantly sensory polyneuropathy. J Infect Dis 1995; 172:1595–1598.
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