JAIDS Journal of Acquired Immune Deficiency Syndromes:
Epidemiology and Social Science
Increased Prevalence of HTLV-1 in Patients With Pulmonary Tuberculosis Coinfected With HIV, but Not in HIV-Negative Patients With Tuberculosis
Norrgren, Hans R MD, PhD*†; Bamba, Sana MD‡; Larsen, Olav MD, PhD§; Silva, Zacarias Da MD†; Aaby, Peter PhD§; Koivula, Tuija PhD‖; Andersson, Sören MD, PhD‖
From the *Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden; †National Public Health Laboratory, Bissau, Guinea-Bissau; ‡Raoul Follereau Hospital, Bissau, Guinea-Bissau; §Projecto de Saude de Bandim, Indepth Network, Bissau, Guinea-Bissau; and ‖National Institute for Infectious Disease Control, Stockholm, Sweden.
Received for publication March 5, 2008; accepted May 6, 2008.
Supported by the Swedish International Development Cooperation Agency (SIDA), Department of Research Cooperation (SAREC), the Danish Medical Research Council, the Danish Research Academy, and the Science and Technology for Development Programme of the European Community.
The data have not been presented at any meeting.
Correspondence to: Hans Norrgren, MD, PhD, Department of Infectious Diseases, University Hospital of Lund, S-221 85 Lund, Sweden (e-mail: firstname.lastname@example.org).
Background: Few and inconclusive results have been presented regarding the influence of human T-lymphotropic virus 1 (HTLV-1) infection on the risk of acquiring tuberculosis (TB).
Methods: In 1994-1997, we performed a prospective study on hospitalized adult patients with pulmonary TB in Guinea-Bissau and compared the clinical outcome in HIV-2 and HIV-negative patients. We determined the prevalence of HTLV-1 in all patients screened and diagnosed with TB in that study and compared the infection rate with a serosurvey of HTLV-1 in a population sample from a community-based study conducted at the same time and in the same city.
Results: In the TB group, a total of 32 (11.4%) of 280 patients were positive for HTLV-1. This was significantly higher compared with the population-based group in which 74 (3.5%) of 2117 were HTLV-1 positive [crude odds ratio (OR) = 3.6; 95% confidence interval (CI) 2.2 to 5.6, P < 0.001]. However, in a logistic regression analysis controlling for age, gender, and HIV result, the difference was no longer significant (OR = 1.61; 95% CI 0.95 to 2.70, P = 0.074). In HIV-negative patients, no association was found between HTLV-1 and TB (OR = 1.18; 95% CI 0.48 to 2.89, P = 0.71), whereas a significant association was found in HIV-positive patients (OR = 2.41; 95% CI 1.26 to 4.61, P = 0.008).
Conclusions: The immunosuppressive effect of HTLV-1 alone was not enough to increase the risk of TB in a highly endemic country, but HTLV-1 increased the risk of TB among HIV-infected individuals.
The first human retrovirus, human T-lymphotropic virus 1 (HTLV-1), was discovered in 1980,1 and 3 years later, the HIV was identified.2 The heavy immunosuppressive effect of HIV especially on the cell-mediated part of the immune system and the rapidly growing epidemic of HIV in countries endemic of tuberculosis (TB) have made HIV a strong cofactor for both acquiring and worsening the outcome of TB.3 HTLV-1 infection is associated with adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis, and a growing body of evidence is showing that the virus also can cause immunosuppression in a multitude of complex pathways.4 The association between HTLV-1 and TB is, however, not that clear. In 2 studies, a history of TB was significantly more frequent in HTLV-1-positive patients compared with HTLV-1-negative controls,5,6 and in a case-control study from Brazil, a significant association between HTLV-1 and TB was reported.7 However, in a study from Senegal, no association was found.8
Guinea-Bissau is highly endemic of both HTLV-1 and TB, with an HTLV-1 prevalence of 3.6% in the adult urban population and 4.0% in an occupational cohort of police officers.9,10 In the latter study, the prevalence of HTLV-2 was found to be 0.4%.10 Both studies documented a significant correlation between HIV and HTLV-1/HTLV-2, a fact that has been described in other studies also and that is presumably explained by the common transmission routes for these viruses.11 The incidence of pulmonary TB in adults was very high in a community study in the capital Bissau, 471 per 100,000 person-years.12 Guinea-Bissau has the highest prevalence of HIV-2 in the world, although the prevalence over the last years has decreased markedly to around 2.5% among pregnant women in Bissau, whereas the prevalence of HIV-1 has increased to approximately 5%.13
Between 1994 and 1997, we conducted a prospective study on consecutive patients hospitalized at the TB hospital in Bissau with a diagnosis of pulmonary TB.14 Among patients with a positive culture of TB and a complete follow-up during the treatment period (N = 127), the prevalence of HIV-1, HIV-2, and HIV-1 + HIV-2 was 8.7%, 23.6%, and 9.4%, respectively.14 At the same time, a population-based study was performed in Bissau in which the overall prevalence of HTLV-1 was 3.6%.9
In the present study, we have analyzed frozen sera for HTLV-1 seroreactivity of all patients screened and diagnosed with TB in the above-mentioned study, and compared the results with the findings from the population-based study of HTLV-1 prevalence conducted at the same time and in the same city, the capital of Guinea-Bissau.
The TB study was conducted between October 1994 and December 1997 at the Raoul Follereau Hospital in Bissau. All patients who were initially hospitalized with a diagnosis of pulmonary TB were consecutively screened; only adults (15 years and older) living in Bissau with no history of TB were enrolled. In the previously presented report,14 only patients with a culture-confirmed TB were included (N = 127), but in the present analysis, we have added the patients with a TB diagnosis based on a smear-positive sputum sample or on clinical/radiological criteria (infiltrative, nodular, or cavitary lesions) (N = 106). In the original study, 47 consecutive patients originally enrolled were not included in the analysis because follow-up was interrupted due to the substitution of a study nurse. However, because the present analysis does not necessitate any follow-up data, we have included these 47 patients in the study. Hence, a total of 280 TB cases were included in the analysis.
The control group used was a population-based study based on 2127 adult individuals (15 years and older) from 304 randomly selected houses in Bissau.9 The serosurvey was conducted between March 1995 and March 1996. An HIV result was missing for 10 of these individuals.
Detection of antibodies to HTLV-1/HTLV-2 was achieved using the Organon Vironostika HTLV-1 (Organon Teknika B.V., Boxtel, The Netherlands) or the Murex HTLV-1/HTLV-2 GE80/81 (Murex Diagnostics Limited, Dartford, United Kingdom). Positive reactions were confirmed by Western blot, the Diagnostic Biotechnology HTLV-blot 2.3 (Genelabs Diagnostics, Singapore). The criteria for HTLV seropositivity were reactivity with at least 1 core band and at least 2 envelope bands. The recombinant gp46-I and gp46-II bands were used to differentiate between HTLV-1 and HTLV-2.
All sera from the TB study were screened by the Enzygnost HIV-1 + HIV-2 enzyme-linked immunosorbent assay (Behring, Marburg, Germany). Confirmation was carried out according to an alternative confirmatory strategy including 2 separate HIV-1 and HIV-2 enzyme-linked immunosorbent assays, Enzygnost anti-HIV-1 and Enzygnost anti-HIV-2, and a rapid simple assay, Recombigen HIV-1/HIV-2 RTD (Cambridge Biotech Limited, Galway, Ireland).15 Sera dually reactive for HIV-1 and HIV-2 were further tested by Peptilav 1-2 (Sanofi Diagnostics Pasteur, Marnes-la-Coquette, France). In the population-based study, screening for HIV was done using the Murex HIV 1 + HIV 2 enzyme-linked immunosorbent assay (Murex Diagnostics Limited), and confirmation and differentiation of positive samples were performed with Peptilav 1-2.
Sputum microscopy and TB culture were performed according to standard protocols at the National Public Health Laboratory in Bissau as previously described.16
Odds ratios with 95% confidence interval, P of χ2, Fisher exact test, and 1-way analysis of variance were calculated with Epi Info (Centers for Disease Control, Atlanta, USA, and WHO, Geneva, Switzerland). Multivariate logistic regression analyses were performed using STATA (Stata Corporation, College Station, TX). In the regression analyses, age was treated as a continuous variable.
The study was approved by the Research Ethics Committee at the Karolinska Institute, Stockholm, the Danish Central Scientific Ethical Committee, and the Ministry of Health in Guinea-Bissau.
In the TB group, a total of 32 (11.4%) of 280 patients were positive for HTLV-1, which was significantly higher compared with the population-based group in which 74 (3.5%) of 2117 were HTLV-1 positive (crude OR = 3.6; 95% confidence interval 2.2 to 5.6; Table 1). No patient in the TB group was HTLV-2 positive, but 1 sample in the population-based group was considered HTLV-2 positive (<0.1%). In the following, this HTLV-2-positive individual has been included in the HTLV-1-negative group. Mean age and the proportion of men were significantly higher in the TB study. Not surprisingly, the HIV prevalence was much higher in the TB group than in the population-based study. There were no significant differences in HTLV-1 or HIV prevalence among patients with or without culture-confirmed TB (data not shown).
The prevalence of HTLV-1 was significantly higher in HIV-2-positive and HIV-1 + HIV-2-positive patients than in HIV-negative patients in both studies. The prevalence of HTLV-1 increased with age and female gender in both the TB and the population-based study (Table 2). We, therefore, conducted a logistic regression analysis comparing the HTLV-1 prevalence in patients with TB and the population-based study according to HIV status, controlling for age and gender (Table 2). Interestingly, the HTLV-1 prevalence was not higher among patients with TB than among community controls when analyzing only HIV-negative patients. Likewise, no significant differences of HTLV-1 prevalence could be detected in any of the separate HIV-positive groups between patients with TB and the population-based group. However, among all HIV-positive patients, the OR for HTLV-1 positivity was 2.41 (95% confidence interval 1.26 to 4.61, P = 0.008) among patients with TB compared with the population-based group.
In the present study, we compared the prevalence of HTLV-1 among hospitalized patients with pulmonary TB and a population-based control group, with or without HIV. We could not find any significant difference of the HTLV-1 prevalence among HIV-negative patients in the 2 study groups, but when the analysis was restricted to only HIV-positive patients, the prevalence of HTLV-1 was significantly higher in patients with TB (22.0%) compared with the population-based group (12.3%). When analyzing HIV-1-, HIV-2-, and HIV-1 + HIV-2-positive patients separately, we found a trend of higher HTLV-1 prevalence in patients with TB, but the number of patients was rather limited, especially in patients infected with HIV-1 and HIV-1 + HIV-2, which obviously could affect the result. These findings suggest that the immunosuppressive effect of HTLV-1 alone is not enough to increase the risk for TB in a highly endemic country, but together with HIV, it works as an independent cofactor for increasing the risk of TB.
Conflicting results have previously been reported regarding the association between HTLV-1 and TB. Two studies have demonstrated a higher reported history of TB among HTLV-1-positive patients compared with HTLV-1-negative controls, but in none of the studies, the HTLV-1 status at the time of the TB infection was known.5,6 Furthermore, no information concerning HIV status was available in one of the studies,5 and in the other study, only 23 of 1305 subjects were tested for HIV.6 In 2 other studies, 1 from Brazil and 1 from Peru, they found higher frequencies of HTLV-1 than those expected among patients with TB, but in none of the studies, a statistical comparison was done with a control group without TB.17,18 Finally, in a case-control study from Brazil, a significant association was found between exclusively HIV-negative patients with lung or lymph node TB and HTLV-1,7 but in a similar study from Senegal, no association was observed.8 However, in the latter study, the number of HTLV-1-positive patients was rather limited (3 among cases and 2 among controls) so it would have required a much bigger population size to detect any significant difference.
Thus, our results are in agreement with another study group from West Africa but maybe in contrast to other findings from Japan and South America. One may speculate if different clades of HTLV-1 may have different effects on the immune system?
Biologically it is well documented that HTLV-1 interferes with the immune system, predominantly by infecting CD4+ cells eliciting a Th1-type response.4 This may explain the association with parasitic infections like strongyloidiasis and schistosomiasis because the expected Th2-type immune response is impaired by the HTLV-1 infection.19,20 The impaired T-cell function reduces also the response to tuberculin (purified protein derivate), which may imply a weaker immune defense against M. Tuberculosis.21
The selection of control group is of vital importance in the present study. The collection of blood samples was carried out over the same period in the 2 studies. Moreover, all the patients with TB were living in the capital Bissau, and subjects in the population-based group were living in 3 of the districts of Bissau. Although, we cannot rule ou the possibility that there might be differences in HTLV-1 prevalence in different districts of the capital, it seems less likely because the virus has been prevalent in the country for many years. In a group of pregnant women from Bissau taking part in a sentinel surveillance of HIV in 1988, the prevalence of HTLV-1 was found to be 3.3%,22 and in a 1996 survey of pregnant women in the 7 major regions of Guinea-Bissau (Bissau excluded), relatively small variations in the HTLV-1 prevalence were observed (1.7%-3.6%), except in one of the northern areas in which the prevalence was only 0.8%.23 We did not have information about ethnic origin of the participants, but the small variations in HTLV-1 prevalence found in the study of pregnant women from all the major regions in Guinea-Bissau (despite marked differences of ethnicity in different parts of the country) indicate that this factor has limited influence on the HTLV-1 prevalence. We also missed information regarding other possible risk factors like injecting drug use or socioeconomic factors, but as for injecting drug use, this was barely known in Guinea-Bissau at the time of the study.
In conclusion, our findings suggest that HTLV-1 alone is not a risk factor for pulmonary TB, but together with HIV, it increases the risk of developing TB. This may be of importance in countries highly endemic of HIV, HTLV-1, and TB.
We thank Mamadu Cande and José Bandanhi for their excellent fieldwork and the staff at the Raoul Follereau Hospital and the National Public Health Laboratory in Bissau. We also thank Helen Linder and Elisabeth Ericson-Ståhle at the Swedish Institute for Infectious Disease Control, Stockholm.
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