Risk Factors for Active Tuberculosis after Antiretroviral Treatment Initiation in Abidjan
http://www.100md.com
美国呼吸和危急护理医学 2005年第7期
Programme PAC-CI Centre de Diagnostic et de Recherches sur le SIDA (CeDReS), Centre Hospitalier Universitaire de Treichville, Abidjan, Cte d'Ivoire
INSERM U.593, Universitee Victor Segalen Bordeaux 2, Bordeaux, France
ABSTRACT
Rationale: In sub-Saharan Africa: (1) tuberculosis is the first cause of HIV-related mortality; (2) the incidence of tuberculosis in adults receiving highly active antiretroviral therapy (HAART) is lower than in untreated HIV-infected adults but higher than in HIV-negative adults; and (3) factors associated with the occurrence of tuberculosis in patients receiving HAART have never been described. Objective: To look for the risk factors for active tuberculosis in HIV-infected adults receiving HAART in Abidjan. Methods: Seven-year prospective cohort of HIV-infected adults, with standardized procedures for documenting morbidity. We analyzed the incidence of active tuberculosis in patients who started HAART and the association between the occurrence of tuberculosis and the characteristics of these patients at HAART initiation. Main Results: A total of 129 adults (median baseline CD4 count 125/mm3) started HAART and were then followed for 270 person-years (P-Y). At HAART initiation, 31 had a history of tuberculosis and none had current active tuberculosis. During follow-up, the incidence of active tuberculosis was 4.8/100 P-Y (95% confidence interval [CI], 2.5eC8.3) overall, 3.0/100 P-Y (95% CI, 1.1eC6.6) in patients with no tuberculosis history, and 11.3/100 P-Y (95% CI, 4.1eC24.5) in patients with a history of tuberculosis (adjusted hazard ratio, 4.64; 95% CI, 1.29eC16.62, p = 0.02). Conclusion: The risk of tuberculosis after HAART initiation was significantly higher in patients with a history of tuberculosis than in those with no tuberculosis history. If confirmed by others, this finding could lead to assessment of new patterns of time-limited tuberculosis secondary chemoprophylaxis during the period of initiation of HAART in sub-Saharan African adults.
Key Words: Africa south of the Sahara HAART HIV risk factors tuberculosis
In nonindustrialized countries, the incidence of opportunistic diseases in HIV-infected adults is likely to decrease with the increasing access to antiretroviral drugs, as previously reported in industrialized countries (1eC3). In sub-Saharan Africa, where tuberculosis (TB) has long been identified as the first cause of HIV-related mortality in adults (4), one study has already shown a dramatic decrease in the TB incidence in adults receiving highly active antiretroviral therapy (HAART) compared with those not receiving it (5). However, though reduced by HAART, the incidence of active TB continues to be higher in HIV-infected adults receiving HAART than in HIV-negative patients (5), and TB has been reported to remain the most common cause of intermediate-term severe morbidity in adults receiving HAART (6). In the HAART era, TB will thus continue to be an everyday problem for the sub-Saharan African teams in charge of HIV-infected patients.
The aim of this study was to look for the factors associated with the occurrence of active TB in a cohort of HIV-infected adults receiving HAART in Cte d'Ivoire.
METHODS
Patients
Between March 1996 and July 2003, 723 HIV-infected adults have been followed in Abidjan in the Cotrame ANRS 1203 cohort, the procedures of which have been described previously (6). Additional detail is provided in the online supplement. All patients described here are those from the Cotrame cohort who have started HAART. Baseline was the day of HAART initiation. The protocol of the Cotrame study has been approved by the ethics committee of the Ivoirian Ministry of Health.
Diagnosis and Treatment of TB
On admission to the Cotrame cohort, patients reporting a history of TB were asked to return the national program registration card. On admission and during follow-up in the cohort, including before HAART and after HAART was started, patients with symptoms consistent with TB were investigated with at least three sputum direct examinations and cultures and one chest X-ray. Other procedures for investigating signs and symptoms in the Cotrame cohort center have been described previously (7). When an episode of active TB was diagnosed, the treatment was given according to the national TB program recommendations. Additional detail is provided in the online supplement.
Definition of TB
The following criteria were required for the diagnosis of active TB.
"Definitive" TB: (1) consistent clinical picture and (2) positive culture for Mycobacterium tuberculosis of sputum sample or bronchoalveolar lavage ("pulmonary" TB) or from normally sterile body fluid or tissue from a site other than lungs ("extrapulmonary" TB). "Presumptive" pulmonary TB: (1) consistent clinical picture > 30 days, (2) positive smear for acid-fast bacilli in sputum or bronchoalveolar lavage sample or absence of microbiological evidence of pneumonia from any other known pathogen, (3) unsuccessful response to standard antibiotic therapy, and (4) successful response to standard antituberculous therapy. "Presumptive" extrapulmonary TB: (1) Consistent clinical picture > 30 days, (2) positive smear for acid-fast bacilli in normally sterile body fluid or tissue from a site other than lungs or no other microbiologic explanation, and (3) successful response to standard antituberculous therapy.
Definition of Prior TB
Patients were considered to have: (1) a history of active TB at HAART initiation if they reported a history of TB on admission to the Cotrame cohort or if they had an episode of active TB that was considered to be cured between their admission to the Cotrame cohort and HAART initiation; (2) a prevalent episode of active TB if they had an episode of active TB that was under treatment on HAART initiation, or if an episode of active TB was documented after HAART initiation and the date of the first symptoms recorded in the Cotrame center medical record preceded the date of HAART initiation; or (3) an incident episode of active TB if TB was documented after HAART initiation and the date of the first symptoms was posterior to HAART initiation.
Statistical Analyses
The incidence rate of TB was defined as the number of patients with incident active TB per 100 patient-years (/100 P-Y) of at-risk follow-up. Univariate Cox proportional hazard regression models for first events were used to study the association between incident TB and baseline characteristics (8). A multivariate model was then used to study the association between incident TB and all characteristics associated with TB with a p < 0.25 in a univariate analysis. We decided a priori that the baseline CD4 count and the history of TB would be included in the multivariate model, even if not associated with TB with a p < 0.25 in a univariate analysis. Additional detail is provided in the online supplement.
RESULTS
Patients
During the study period, 129 of the 723 patients participating in the Cotrame cohort started HAART. Baseline characteristics, initial treatment regimens, and follow-up characteristics are reported in Table 1.
History of TB
At HAART initiation, no patient had current, active TB and 31 patients had a history of active TB, including 27 with one previous episode and 4 with two episodes. The last episode was pulmonary in 21 (68%), extrapulmonary in 5 (16%), and both pulmonary and extrapulmonary in 5 (16%). The median period between diagnosis of the last episode and HAART initiation was 2.8 years (interquartile range 1.4eC4.7). Of the 31 previous episodes, 12 were diagnosed and treated in one of the national TB program centers before the patients were included in the Cotrame cohort, and 19 were diagnosed and treated in the Cotrame cohort center while patients were already participating in the Cotrame cohort, but not yet receiving HAART. All of the 31 previous episodes were considered as cured after a standard 6-month rifampin-based regimen, according to national program criteria.
Incident TB Episodes
During follow-up under HAART, 12 patients had 14 episodes of TB, an overall incidence of 4.8/100 P-Y (95% CI, 2.5eC8.3). Among the first 12 episodes, the first symptoms appeared before the sixth month after HAART initiation in three, between 6 and 12 months in two, between 12 and 24 months in four, and after 24 months in three. In the two patients who had two episodes, the symptoms of the second episode appeared 14 and 15 months after the first episode, respectively. Of the first 12 episodes, 6 occurred in patients with no history of TB (incidence rate 3.0/100 P-Y; 95% CI, 1.1eC6.6) and 6 in patients with a history of TB (incidence rate 11.3/100 P-Y; 95% CI, 4.1eC24.5). The probability of remaining free from active TB was 0.98 (95% CI, 0.95eC0.99) at 12 months and 0.95 (0.90eC0.99) at 24 months in patients with no TB history versus 0.90 (0.78eC1.00) at 12 months and 0.80 (0.63eC0.96) at 24 months in patients with a history of TB.
Of the 14 episodes, 8 were diagnosed as definitive (pulmonary: 7; pulmonary and renal: 1) and 6 as presumptive (miliary: 1; pleural and pulmonary: 1; pulmonary only: 4), including 2 with positive sputum smear and culture not performed. An antibiogram was performed in seven of the eight episodes of definitive TB. The strain was isoniazide sensitive in six of the seven strains, and rifampicin and ethambutol sensitive in all strains. Table 2 shows, for the 12 first episodes: the date of HAART initiation, the presence of a history of TB together with the interval since the last episode, the interval from HAART initiation to the first symptoms of the incident episode, the most recent CD4 count, the pulmonary or extrapulmonary localization, and the diagnosis certainty. Eleven episodes were considered to be cured after a standard 6-month regimen, and one patient died before the end of the antituberculous treatment.
In univariate analysis, age, sex, schooling, professional activity, number of people at home, electricity at home, World Health Organization clinical stage, absolute neutrophil count, platelet count, and marital status were not associated with the risk of TB with a p 0.25. These variables were thus not included in the multivariate analysis. The following baseline variables were associated with the risk of TB with a p < 0.25 and were therefore included in the multivariate analysis (Table 3): hemoglobin count (p = 0.24), body mass index (p = 0.16), baseline HAART regimen (p = 0.17), history of TB (p = 0.03), and running water at home (p = 0.05). Finally, the baseline CD4 count was not associated with the risk of TB in univariate analysis (p = 0.91). However, it was one of the variables considered a priori to be included in the multivariate model, as defined in METHODS. In multivariate analysis, the only variable which remained associated with the occurrence of TB was a history of TB. The adjusted hazard ratio of TB was 4.64 in patients with a history of TB compared with those with no TB history (95% CI, 1.29eC16.62, p = 0.02) (Table 3). Additional detail on analysis is provided in the online supplement.
DISCUSSION
This study is the first to look for factors associated with active TB in adults receiving HAART in sub-Saharan Africa. We followed a cohort of 129 HIV-infected adults receiving HAART for a median of 26 months in Abidjan. Our main finding was that the risk of active TB after HAART initiation was significantly higher in patients with a previous history of TB than in those with no TB history.
There are several points to be made about this finding. First, all patients with a history of TB had previously been considered to be cured after a standard 6-month regimen, according to national program criteria that include microbiologic and radiologic control. An active search for TB before initiating HAART was done in all symptomatic patients, according to the procedures of the study center. However, such an active search was not done in asymptomatic patients, and one cannot totally exclude that some cases of incident TB were, in fact, preexisting cases. Only 3 of the 12 TB episodes began within the 6 months after HAART initiation, including 2 in patients with no TB history. If these three episodes would have been preexisting cases, this would have tended to minimize the association between newly active TB and history of TB.
Second, 33% of our TB cases were smear-negative and culture-negative TB, and one cannot exclude that some of these were not true TB cases. However, acid-fast smear has long been reported to be more frequently negative in HIV-infected patients than in HIV-negative subjects (9), and this rate of presumptive cases is in the range of those usually reported in studies of HIV-associated TB in sub-Saharan African adults (5, 10).
Third, the cohort study was not designed to collect information on all HIV disease risk factors. Some important TB risk factors, such as the exposition/exposure to TB at home or at work, have not been documented. When finding an association between the new active TB and a TB history, there could be a confounding effect.
Together with these limitations, this study has several strong points. The Cotrame cohort was designed to study in the long term the causes of morbidity in HIV-infected adults. At inclusion, the history of TB before the inclusion in the cohort was carefully documented through the forms of the national TB program. Patients were followed a median of 41 months before HAART was started. Standardized procedures of investigations and diagnostic criteria were applied. An event documentation committee approved all diagnoses (6, 7). As a result of all these points, the diagnosis of active TB under HAART and the history of TB before starting HAART could be documented over a long period and under favorable conditions, which is uncommon in most HIV care centers in sub-Saharan Africa. The association between TB incidence and history of TB we observed is thus unlikely to be due to misdiagnoses or misclassifications. We believe that this association should be considered as a serious hypothesis to be borne out by more specific studies.
If confirmed, this could have implications in terms of TB secondary prophylaxis. Though with proven medium-term benefits (11eC13), TB secondary prophylaxis is not routinely applied in sub-Saharan Africa, partly because of the fear of potential long-term risks associated with a lifelong treatment with one or various antituberculous drugs, both for the individual and for the population. The increasing access to HAART could either end the need for TB secondary prophylaxis or document the need for it. On the one hand, HAART leads to a dramatic increase in the CD4 count and to a consecutive, noticeable decrease in the incidence of TB. Thus, treating HIV-positive patients with TB with HAART could now be considered as the most appropriate intervention to decrease the risk of TB recurrence (14), and prophylaxis for TB in HIV-infected patients might be seen as outdated. On the other hand, if the risk of TB recurrence remains high in patients who start HAART, before an increased CD4 count (13), TB secondary prophylaxis could be restricted to the period during which patients are at higher risk of TB, and prophylaxis could be stopped as soon as the CD4 rise over a given threshold. To explore the latter hypothesis, further therapeutic trials should assess whether: (1) HIV-infected, immunocompromised adults with active TB could benefit from post-treatment isoniazid prophylaxis until CD4 count is increased and (2) HIV-infected adults who present for the first time with criteria for starting HAART and a history of successfully treated active TB could benefit from receiving isoniazid 300 mg/day in combination with HAART until CD4 count is increased. In these trials, the best CD4 threshold to stop TB prophylaxis should be studied by comparing various arms (e.g., stopping isoniazid when the CD4 count went higher than 200, 350, or 500 CD4/mm3).
Reporting a higher incidence of TB in patients with a history of TB inevitably leads to question if the TB episodes would were more frequent relapses from persistent bacilli rather than reinfection with new bacilli occurring since the previous episode. Studies including restriction fragment length polymorphism fingerprinting have now clearly shown that both mechanisms may be equally involved in TB recurrence in sub-Saharan HIV-infected adults (15eC17). One can also imagine that reinfection with new TB bacilli could be more frequent in HIV-infected patients through the same mechanisms, as nontuberculous mycobacteriosis has been shown to be more frequent in patients with a history of TB (18). However, our study did not include fingerprinting and therefore does not contribute to this debate.
Finally, it is important to highlight that this study did not address the association between HAART and active TB, and that our findings do not imply that HAART is associated with an increase in the overall TB incidence. Before the HAART era in the Cotrame Cohort, the incidence of active TB was estimated at 10.1/100 P-Y (19). Important studies have now shown a decrease in the incidence of opportunistic infections in patients receiving HAART (1eC3), including studies performed in sub-Saharan African and focusing on the incidence of TB (5). Though it is difficult to compare incidences reported in studies from different settings, the global incidence of TB that we observed in our cohort is consistent with that reported in South Africa in HIV-infected adults receiving HAART (5) and lower than the incidence reported in HIV-infected adults not receiving HAART in Cte d'Ivoire (19) and in other sub-Saharan African countries (20). The incidence of TB in our group of patients with history of TB is in the upper limit of the range of incidence of TB recurrence that has been reported in HIV-infected adults who do not receive HAART in sub-Saharan Africa (21). In our cohort of adults receiving HAART, it is thus just as if the incidence of TB would have been reduced more in patients with no TB history than in those with TB history.
In conclusion, in this cohort of adults starting HAART, active TB was more frequent in patients with a previous history of TB than in patients with no TB history. Globally, the TB incidence appeared to be reduced compared with the incidence observed in the same setting and the same population before the HAART era. Cohorts of adults receiving HAART in sub-Saharan Africa should carefully record data on TB history at baseline, and further studies should explore the causal mechanisms and other risk factors. If confirmed, this could be a first step toward new patterns of time-limited TB secondary chemoprophylaxis in Africa.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
REFERENCES
Girardi E, Antonucci G, Vanacore P, Libanore M, Errante I, Matteelli A, Ippolito G. Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection. AIDS 2000;14:1985eC1991.
Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med 1998;338:853eC860.
Kirk O, Gatell JM, Mocroft A, Pedersen C, Proenca R, Brettle RP, Barton SE, Sudre P, Phillips AN. Infections with Mycobacterium tuberculosis and Mycobacterium avium among HIV-infected patients after the introduction of highly active antiretroviral therapy: EuroSIDA Study Group JD. Am J Respir Crit Care Med 2000;162:865eC872.
Lucas SB, Hounnou A, Peacock C, Beaumel A, Djomand G, N'Gbichi J-M, Yeboue K, Hondee M, Diomande M, Giordano C, et al. The mortality and pathology of HIV infection in a West African city. AIDS 1993;7:1569eC1579.
Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002;359:2059eC2064.
Seyler C, Anglaret X, Dakoury-Dogbo N, Messou E, Toure S, Danel C, Diakire N, Dandle A, Inwoley A, Maurice C, et al. Medium-term survival, morbidity and immunovirological evolution in HIV-infected adults receiving antiretroviral therapy, Abidjan, Cote d'Ivoire. Antivir Ther 2003;8:385eC393.
Anglaret X, Dakoury-Dogbo N, Bonard D, Toure S, Combe P, Ouassa T, Menan H, N'Dri-Yoman T, Dabis F, Salamon R. Causes and empirical treatment of fever in HIV-infected adult outpatients, Abidjan, Cote d'Ivoire. AIDS 2002;16:909eC918.
Cox D. Regression models and life-tables. J R Statist Soc B 1972;34:187eC220.
Klein NC, Duncanson FP, Lenox TH III, Pitta A, Cohen SC, Wormser GP. Use of mycobacterial smears in the diagnosis of pulmonary tuberculosis in AIDS/ARC patients. Chest 1989;95:1190eC1192.
Siddiqi K, Lambert ML, Walley J. Clinical diagnosis of smear-negative pulmonary tuberculosis in low-income countries: the current evidence. Lancet Infect Dis 2003;3:288eC296.
Perrins JH, St Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, Portnels F, Willame J-C, Mandala JK, Kaboto M, et al. Pulmonary tuberculosis in HIV-infected patients in Zare: a controlled trial of treatment for either 6 or 12 months. N Engl J Med 1995;332:779eC784.
Fitzgerald DW, Desvarieux M, Severe P, Joseph P, Johnson WD Jr, Pape JW. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial. Lancet 2000;356:1470eC1474.
Churchyard GJ, Fielding K, Charalambous S, Day JH, Corbett EL, Hayes RJ, Chaisson RE, DeCock KM, Samb B, Grant AD. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy AIDS 2003;17:2063eC2070.
Harries AD, Chimzizi RB, Nyirenda TE, van Gorkom J, Salaniponi FM. Preventing recurrent tuberculosis in high HIV-prevalent areas in sub-Saharan Africa: what are the options for tuberculosis control programmes Int J Tuberc Lung Dis 2003;7:616eC622.
Gilks CF, Godfrey-Faussett P, Batchelor BI, Ojoo JC, Ojoo SJ, Brindle RJ, Paul J, Klimari J, Bruce MC, Bwayo J, et al. Recent transmission of tuberculosis in a cohort of HIV-1-infected female sex workers in Nairobi, Kenya. AIDS 1997;11:911eC918.
Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, Godfrey-Faussett P. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001;358:1687eC1693.
Glynn JR, Yates MD, Crampin AC, Ngwira BM, Mwaungulu FD, Black GF, Chaguluka SD, Mwafulirwa DT, Floyd S, Murphy C, et al. DNA fingerprint changes in tuberculosis: reinfection, evolution, or laboratory error J Infect Dis 2004;190:1158eC1166.
Corbett EL, Churchyard GJ, Clayton T, Herselman P, Williams B, Hayes R, Mulder D, DeCock KM. Risk factors for pulmonary mycobacterial disease in South African gold miners: a case-control study. Am J Respir Crit Care Med 1999;159:94eC99.
Attia A, Huet C, Anglaret X, Toure S, Ouassa T, Gourvellec G, Menan H, Dakoury Dogbo M, Combe P, Chene G, et al. HIV-1-related morbidity in adults, Abidjan, Cote d'Ivoire: a nidus for bacterial diseases. J Acquir Immune Defic Syndr 2001;28:478eC486.
van der Sande MA, Schim van der Loeff MF, Bennett RC, Dowling M, Aveika AA, Togun TO, Sabally S, Jeffries D, Adegbola RA, Sarge Njie R, et al. Incidence of tuberculosis and survival after its diagnosis in patients infected with HIV-1 and HIV-2. AIDS 2004;18:1933eC1941.
Korenromp EL, Scano F, Williams BG, Dye C, Nunn P. Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect Dis 2003;37:101eC112.(Catherine Seyler, Siaka T)
INSERM U.593, Universitee Victor Segalen Bordeaux 2, Bordeaux, France
ABSTRACT
Rationale: In sub-Saharan Africa: (1) tuberculosis is the first cause of HIV-related mortality; (2) the incidence of tuberculosis in adults receiving highly active antiretroviral therapy (HAART) is lower than in untreated HIV-infected adults but higher than in HIV-negative adults; and (3) factors associated with the occurrence of tuberculosis in patients receiving HAART have never been described. Objective: To look for the risk factors for active tuberculosis in HIV-infected adults receiving HAART in Abidjan. Methods: Seven-year prospective cohort of HIV-infected adults, with standardized procedures for documenting morbidity. We analyzed the incidence of active tuberculosis in patients who started HAART and the association between the occurrence of tuberculosis and the characteristics of these patients at HAART initiation. Main Results: A total of 129 adults (median baseline CD4 count 125/mm3) started HAART and were then followed for 270 person-years (P-Y). At HAART initiation, 31 had a history of tuberculosis and none had current active tuberculosis. During follow-up, the incidence of active tuberculosis was 4.8/100 P-Y (95% confidence interval [CI], 2.5eC8.3) overall, 3.0/100 P-Y (95% CI, 1.1eC6.6) in patients with no tuberculosis history, and 11.3/100 P-Y (95% CI, 4.1eC24.5) in patients with a history of tuberculosis (adjusted hazard ratio, 4.64; 95% CI, 1.29eC16.62, p = 0.02). Conclusion: The risk of tuberculosis after HAART initiation was significantly higher in patients with a history of tuberculosis than in those with no tuberculosis history. If confirmed by others, this finding could lead to assessment of new patterns of time-limited tuberculosis secondary chemoprophylaxis during the period of initiation of HAART in sub-Saharan African adults.
Key Words: Africa south of the Sahara HAART HIV risk factors tuberculosis
In nonindustrialized countries, the incidence of opportunistic diseases in HIV-infected adults is likely to decrease with the increasing access to antiretroviral drugs, as previously reported in industrialized countries (1eC3). In sub-Saharan Africa, where tuberculosis (TB) has long been identified as the first cause of HIV-related mortality in adults (4), one study has already shown a dramatic decrease in the TB incidence in adults receiving highly active antiretroviral therapy (HAART) compared with those not receiving it (5). However, though reduced by HAART, the incidence of active TB continues to be higher in HIV-infected adults receiving HAART than in HIV-negative patients (5), and TB has been reported to remain the most common cause of intermediate-term severe morbidity in adults receiving HAART (6). In the HAART era, TB will thus continue to be an everyday problem for the sub-Saharan African teams in charge of HIV-infected patients.
The aim of this study was to look for the factors associated with the occurrence of active TB in a cohort of HIV-infected adults receiving HAART in Cte d'Ivoire.
METHODS
Patients
Between March 1996 and July 2003, 723 HIV-infected adults have been followed in Abidjan in the Cotrame ANRS 1203 cohort, the procedures of which have been described previously (6). Additional detail is provided in the online supplement. All patients described here are those from the Cotrame cohort who have started HAART. Baseline was the day of HAART initiation. The protocol of the Cotrame study has been approved by the ethics committee of the Ivoirian Ministry of Health.
Diagnosis and Treatment of TB
On admission to the Cotrame cohort, patients reporting a history of TB were asked to return the national program registration card. On admission and during follow-up in the cohort, including before HAART and after HAART was started, patients with symptoms consistent with TB were investigated with at least three sputum direct examinations and cultures and one chest X-ray. Other procedures for investigating signs and symptoms in the Cotrame cohort center have been described previously (7). When an episode of active TB was diagnosed, the treatment was given according to the national TB program recommendations. Additional detail is provided in the online supplement.
Definition of TB
The following criteria were required for the diagnosis of active TB.
"Definitive" TB: (1) consistent clinical picture and (2) positive culture for Mycobacterium tuberculosis of sputum sample or bronchoalveolar lavage ("pulmonary" TB) or from normally sterile body fluid or tissue from a site other than lungs ("extrapulmonary" TB). "Presumptive" pulmonary TB: (1) consistent clinical picture > 30 days, (2) positive smear for acid-fast bacilli in sputum or bronchoalveolar lavage sample or absence of microbiological evidence of pneumonia from any other known pathogen, (3) unsuccessful response to standard antibiotic therapy, and (4) successful response to standard antituberculous therapy. "Presumptive" extrapulmonary TB: (1) Consistent clinical picture > 30 days, (2) positive smear for acid-fast bacilli in normally sterile body fluid or tissue from a site other than lungs or no other microbiologic explanation, and (3) successful response to standard antituberculous therapy.
Definition of Prior TB
Patients were considered to have: (1) a history of active TB at HAART initiation if they reported a history of TB on admission to the Cotrame cohort or if they had an episode of active TB that was considered to be cured between their admission to the Cotrame cohort and HAART initiation; (2) a prevalent episode of active TB if they had an episode of active TB that was under treatment on HAART initiation, or if an episode of active TB was documented after HAART initiation and the date of the first symptoms recorded in the Cotrame center medical record preceded the date of HAART initiation; or (3) an incident episode of active TB if TB was documented after HAART initiation and the date of the first symptoms was posterior to HAART initiation.
Statistical Analyses
The incidence rate of TB was defined as the number of patients with incident active TB per 100 patient-years (/100 P-Y) of at-risk follow-up. Univariate Cox proportional hazard regression models for first events were used to study the association between incident TB and baseline characteristics (8). A multivariate model was then used to study the association between incident TB and all characteristics associated with TB with a p < 0.25 in a univariate analysis. We decided a priori that the baseline CD4 count and the history of TB would be included in the multivariate model, even if not associated with TB with a p < 0.25 in a univariate analysis. Additional detail is provided in the online supplement.
RESULTS
Patients
During the study period, 129 of the 723 patients participating in the Cotrame cohort started HAART. Baseline characteristics, initial treatment regimens, and follow-up characteristics are reported in Table 1.
History of TB
At HAART initiation, no patient had current, active TB and 31 patients had a history of active TB, including 27 with one previous episode and 4 with two episodes. The last episode was pulmonary in 21 (68%), extrapulmonary in 5 (16%), and both pulmonary and extrapulmonary in 5 (16%). The median period between diagnosis of the last episode and HAART initiation was 2.8 years (interquartile range 1.4eC4.7). Of the 31 previous episodes, 12 were diagnosed and treated in one of the national TB program centers before the patients were included in the Cotrame cohort, and 19 were diagnosed and treated in the Cotrame cohort center while patients were already participating in the Cotrame cohort, but not yet receiving HAART. All of the 31 previous episodes were considered as cured after a standard 6-month rifampin-based regimen, according to national program criteria.
Incident TB Episodes
During follow-up under HAART, 12 patients had 14 episodes of TB, an overall incidence of 4.8/100 P-Y (95% CI, 2.5eC8.3). Among the first 12 episodes, the first symptoms appeared before the sixth month after HAART initiation in three, between 6 and 12 months in two, between 12 and 24 months in four, and after 24 months in three. In the two patients who had two episodes, the symptoms of the second episode appeared 14 and 15 months after the first episode, respectively. Of the first 12 episodes, 6 occurred in patients with no history of TB (incidence rate 3.0/100 P-Y; 95% CI, 1.1eC6.6) and 6 in patients with a history of TB (incidence rate 11.3/100 P-Y; 95% CI, 4.1eC24.5). The probability of remaining free from active TB was 0.98 (95% CI, 0.95eC0.99) at 12 months and 0.95 (0.90eC0.99) at 24 months in patients with no TB history versus 0.90 (0.78eC1.00) at 12 months and 0.80 (0.63eC0.96) at 24 months in patients with a history of TB.
Of the 14 episodes, 8 were diagnosed as definitive (pulmonary: 7; pulmonary and renal: 1) and 6 as presumptive (miliary: 1; pleural and pulmonary: 1; pulmonary only: 4), including 2 with positive sputum smear and culture not performed. An antibiogram was performed in seven of the eight episodes of definitive TB. The strain was isoniazide sensitive in six of the seven strains, and rifampicin and ethambutol sensitive in all strains. Table 2 shows, for the 12 first episodes: the date of HAART initiation, the presence of a history of TB together with the interval since the last episode, the interval from HAART initiation to the first symptoms of the incident episode, the most recent CD4 count, the pulmonary or extrapulmonary localization, and the diagnosis certainty. Eleven episodes were considered to be cured after a standard 6-month regimen, and one patient died before the end of the antituberculous treatment.
In univariate analysis, age, sex, schooling, professional activity, number of people at home, electricity at home, World Health Organization clinical stage, absolute neutrophil count, platelet count, and marital status were not associated with the risk of TB with a p 0.25. These variables were thus not included in the multivariate analysis. The following baseline variables were associated with the risk of TB with a p < 0.25 and were therefore included in the multivariate analysis (Table 3): hemoglobin count (p = 0.24), body mass index (p = 0.16), baseline HAART regimen (p = 0.17), history of TB (p = 0.03), and running water at home (p = 0.05). Finally, the baseline CD4 count was not associated with the risk of TB in univariate analysis (p = 0.91). However, it was one of the variables considered a priori to be included in the multivariate model, as defined in METHODS. In multivariate analysis, the only variable which remained associated with the occurrence of TB was a history of TB. The adjusted hazard ratio of TB was 4.64 in patients with a history of TB compared with those with no TB history (95% CI, 1.29eC16.62, p = 0.02) (Table 3). Additional detail on analysis is provided in the online supplement.
DISCUSSION
This study is the first to look for factors associated with active TB in adults receiving HAART in sub-Saharan Africa. We followed a cohort of 129 HIV-infected adults receiving HAART for a median of 26 months in Abidjan. Our main finding was that the risk of active TB after HAART initiation was significantly higher in patients with a previous history of TB than in those with no TB history.
There are several points to be made about this finding. First, all patients with a history of TB had previously been considered to be cured after a standard 6-month regimen, according to national program criteria that include microbiologic and radiologic control. An active search for TB before initiating HAART was done in all symptomatic patients, according to the procedures of the study center. However, such an active search was not done in asymptomatic patients, and one cannot totally exclude that some cases of incident TB were, in fact, preexisting cases. Only 3 of the 12 TB episodes began within the 6 months after HAART initiation, including 2 in patients with no TB history. If these three episodes would have been preexisting cases, this would have tended to minimize the association between newly active TB and history of TB.
Second, 33% of our TB cases were smear-negative and culture-negative TB, and one cannot exclude that some of these were not true TB cases. However, acid-fast smear has long been reported to be more frequently negative in HIV-infected patients than in HIV-negative subjects (9), and this rate of presumptive cases is in the range of those usually reported in studies of HIV-associated TB in sub-Saharan African adults (5, 10).
Third, the cohort study was not designed to collect information on all HIV disease risk factors. Some important TB risk factors, such as the exposition/exposure to TB at home or at work, have not been documented. When finding an association between the new active TB and a TB history, there could be a confounding effect.
Together with these limitations, this study has several strong points. The Cotrame cohort was designed to study in the long term the causes of morbidity in HIV-infected adults. At inclusion, the history of TB before the inclusion in the cohort was carefully documented through the forms of the national TB program. Patients were followed a median of 41 months before HAART was started. Standardized procedures of investigations and diagnostic criteria were applied. An event documentation committee approved all diagnoses (6, 7). As a result of all these points, the diagnosis of active TB under HAART and the history of TB before starting HAART could be documented over a long period and under favorable conditions, which is uncommon in most HIV care centers in sub-Saharan Africa. The association between TB incidence and history of TB we observed is thus unlikely to be due to misdiagnoses or misclassifications. We believe that this association should be considered as a serious hypothesis to be borne out by more specific studies.
If confirmed, this could have implications in terms of TB secondary prophylaxis. Though with proven medium-term benefits (11eC13), TB secondary prophylaxis is not routinely applied in sub-Saharan Africa, partly because of the fear of potential long-term risks associated with a lifelong treatment with one or various antituberculous drugs, both for the individual and for the population. The increasing access to HAART could either end the need for TB secondary prophylaxis or document the need for it. On the one hand, HAART leads to a dramatic increase in the CD4 count and to a consecutive, noticeable decrease in the incidence of TB. Thus, treating HIV-positive patients with TB with HAART could now be considered as the most appropriate intervention to decrease the risk of TB recurrence (14), and prophylaxis for TB in HIV-infected patients might be seen as outdated. On the other hand, if the risk of TB recurrence remains high in patients who start HAART, before an increased CD4 count (13), TB secondary prophylaxis could be restricted to the period during which patients are at higher risk of TB, and prophylaxis could be stopped as soon as the CD4 rise over a given threshold. To explore the latter hypothesis, further therapeutic trials should assess whether: (1) HIV-infected, immunocompromised adults with active TB could benefit from post-treatment isoniazid prophylaxis until CD4 count is increased and (2) HIV-infected adults who present for the first time with criteria for starting HAART and a history of successfully treated active TB could benefit from receiving isoniazid 300 mg/day in combination with HAART until CD4 count is increased. In these trials, the best CD4 threshold to stop TB prophylaxis should be studied by comparing various arms (e.g., stopping isoniazid when the CD4 count went higher than 200, 350, or 500 CD4/mm3).
Reporting a higher incidence of TB in patients with a history of TB inevitably leads to question if the TB episodes would were more frequent relapses from persistent bacilli rather than reinfection with new bacilli occurring since the previous episode. Studies including restriction fragment length polymorphism fingerprinting have now clearly shown that both mechanisms may be equally involved in TB recurrence in sub-Saharan HIV-infected adults (15eC17). One can also imagine that reinfection with new TB bacilli could be more frequent in HIV-infected patients through the same mechanisms, as nontuberculous mycobacteriosis has been shown to be more frequent in patients with a history of TB (18). However, our study did not include fingerprinting and therefore does not contribute to this debate.
Finally, it is important to highlight that this study did not address the association between HAART and active TB, and that our findings do not imply that HAART is associated with an increase in the overall TB incidence. Before the HAART era in the Cotrame Cohort, the incidence of active TB was estimated at 10.1/100 P-Y (19). Important studies have now shown a decrease in the incidence of opportunistic infections in patients receiving HAART (1eC3), including studies performed in sub-Saharan African and focusing on the incidence of TB (5). Though it is difficult to compare incidences reported in studies from different settings, the global incidence of TB that we observed in our cohort is consistent with that reported in South Africa in HIV-infected adults receiving HAART (5) and lower than the incidence reported in HIV-infected adults not receiving HAART in Cte d'Ivoire (19) and in other sub-Saharan African countries (20). The incidence of TB in our group of patients with history of TB is in the upper limit of the range of incidence of TB recurrence that has been reported in HIV-infected adults who do not receive HAART in sub-Saharan Africa (21). In our cohort of adults receiving HAART, it is thus just as if the incidence of TB would have been reduced more in patients with no TB history than in those with TB history.
In conclusion, in this cohort of adults starting HAART, active TB was more frequent in patients with a previous history of TB than in patients with no TB history. Globally, the TB incidence appeared to be reduced compared with the incidence observed in the same setting and the same population before the HAART era. Cohorts of adults receiving HAART in sub-Saharan Africa should carefully record data on TB history at baseline, and further studies should explore the causal mechanisms and other risk factors. If confirmed, this could be a first step toward new patterns of time-limited TB secondary chemoprophylaxis in Africa.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
REFERENCES
Girardi E, Antonucci G, Vanacore P, Libanore M, Errante I, Matteelli A, Ippolito G. Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection. AIDS 2000;14:1985eC1991.
Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med 1998;338:853eC860.
Kirk O, Gatell JM, Mocroft A, Pedersen C, Proenca R, Brettle RP, Barton SE, Sudre P, Phillips AN. Infections with Mycobacterium tuberculosis and Mycobacterium avium among HIV-infected patients after the introduction of highly active antiretroviral therapy: EuroSIDA Study Group JD. Am J Respir Crit Care Med 2000;162:865eC872.
Lucas SB, Hounnou A, Peacock C, Beaumel A, Djomand G, N'Gbichi J-M, Yeboue K, Hondee M, Diomande M, Giordano C, et al. The mortality and pathology of HIV infection in a West African city. AIDS 1993;7:1569eC1579.
Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet 2002;359:2059eC2064.
Seyler C, Anglaret X, Dakoury-Dogbo N, Messou E, Toure S, Danel C, Diakire N, Dandle A, Inwoley A, Maurice C, et al. Medium-term survival, morbidity and immunovirological evolution in HIV-infected adults receiving antiretroviral therapy, Abidjan, Cote d'Ivoire. Antivir Ther 2003;8:385eC393.
Anglaret X, Dakoury-Dogbo N, Bonard D, Toure S, Combe P, Ouassa T, Menan H, N'Dri-Yoman T, Dabis F, Salamon R. Causes and empirical treatment of fever in HIV-infected adult outpatients, Abidjan, Cote d'Ivoire. AIDS 2002;16:909eC918.
Cox D. Regression models and life-tables. J R Statist Soc B 1972;34:187eC220.
Klein NC, Duncanson FP, Lenox TH III, Pitta A, Cohen SC, Wormser GP. Use of mycobacterial smears in the diagnosis of pulmonary tuberculosis in AIDS/ARC patients. Chest 1989;95:1190eC1192.
Siddiqi K, Lambert ML, Walley J. Clinical diagnosis of smear-negative pulmonary tuberculosis in low-income countries: the current evidence. Lancet Infect Dis 2003;3:288eC296.
Perrins JH, St Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, Portnels F, Willame J-C, Mandala JK, Kaboto M, et al. Pulmonary tuberculosis in HIV-infected patients in Zare: a controlled trial of treatment for either 6 or 12 months. N Engl J Med 1995;332:779eC784.
Fitzgerald DW, Desvarieux M, Severe P, Joseph P, Johnson WD Jr, Pape JW. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial. Lancet 2000;356:1470eC1474.
Churchyard GJ, Fielding K, Charalambous S, Day JH, Corbett EL, Hayes RJ, Chaisson RE, DeCock KM, Samb B, Grant AD. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy AIDS 2003;17:2063eC2070.
Harries AD, Chimzizi RB, Nyirenda TE, van Gorkom J, Salaniponi FM. Preventing recurrent tuberculosis in high HIV-prevalent areas in sub-Saharan Africa: what are the options for tuberculosis control programmes Int J Tuberc Lung Dis 2003;7:616eC622.
Gilks CF, Godfrey-Faussett P, Batchelor BI, Ojoo JC, Ojoo SJ, Brindle RJ, Paul J, Klimari J, Bruce MC, Bwayo J, et al. Recent transmission of tuberculosis in a cohort of HIV-1-infected female sex workers in Nairobi, Kenya. AIDS 1997;11:911eC918.
Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, Godfrey-Faussett P. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001;358:1687eC1693.
Glynn JR, Yates MD, Crampin AC, Ngwira BM, Mwaungulu FD, Black GF, Chaguluka SD, Mwafulirwa DT, Floyd S, Murphy C, et al. DNA fingerprint changes in tuberculosis: reinfection, evolution, or laboratory error J Infect Dis 2004;190:1158eC1166.
Corbett EL, Churchyard GJ, Clayton T, Herselman P, Williams B, Hayes R, Mulder D, DeCock KM. Risk factors for pulmonary mycobacterial disease in South African gold miners: a case-control study. Am J Respir Crit Care Med 1999;159:94eC99.
Attia A, Huet C, Anglaret X, Toure S, Ouassa T, Gourvellec G, Menan H, Dakoury Dogbo M, Combe P, Chene G, et al. HIV-1-related morbidity in adults, Abidjan, Cote d'Ivoire: a nidus for bacterial diseases. J Acquir Immune Defic Syndr 2001;28:478eC486.
van der Sande MA, Schim van der Loeff MF, Bennett RC, Dowling M, Aveika AA, Togun TO, Sabally S, Jeffries D, Adegbola RA, Sarge Njie R, et al. Incidence of tuberculosis and survival after its diagnosis in patients infected with HIV-1 and HIV-2. AIDS 2004;18:1933eC1941.
Korenromp EL, Scano F, Williams BG, Dye C, Nunn P. Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect Dis 2003;37:101eC112.(Catherine Seyler, Siaka T)