A study of the safety, immunology, virology, and microbiology of adjunctive etanercept in HIV-1-associated tuberculosis
Wallis, Robert Sa,b; Kyambadde, Peterc; Johnson, John La; Horter, Libbya; Kittle, Rodneya,d; Pohle, Monikaa; Ducar, Constancee; Millard, Monicaa; Mayanja-Kizza, Harrietc; Whalen, Christophera; Okwera, Alphonsec
From the aDepartment of Medicine, Case Western Reserve University, Cleveland, OH, USA; bDepartment of Medicine, University of Medicine and Dentistry – New Jersey Medical School, Newark, NJ, USA; cDepartments of Medicine and Microbiology, Makerere University, Kampala, Uganda; dJoint Clinical Research Center, Kampala, Uganda; eDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Correspondence to Robert S. Wallis, Department of Medicine, UMDNJ-NJMS, 185 South Orange Avenue, MSB I-503, Newark, NJ 07103, USA.
Tel: +1 973 972 8778; fax: +1 973 972 8878; e-mail: firstname.lastname@example.org
Received: 6 February 2003; revised: 2 June 2003; accepted: 25 June 2003.
Objective: Tumor necrosis factor (TNF), an important inflammatory mediator in tuberculosis, has been implicated in causing accelerated HIV disease progression in HIV-associated tuberculosis. However, TNF blockade, particularly by monoclonal antibody, has been associated with the reactivation of latent Mycobacterium tuberculosis infection by the impairment of mycobacterial immunity. This phase 1 study examined the safety, microbiology, immunology, and virology of TNF blockade using etanercept (soluble TNF receptor, Enbrel) during the initial treatment of HIV-associated tuberculosis.
Design: A single-arm trial, with key endpoints compared with historical controls, conducted in Mulago Hospital, Kampala, Uganda.
Subjects: Sixteen HIV-1-infected patients and 42 CD4-frequency-matched controls with sputum smear-positive tuberculosis and CD4 cell counts > 200 cells/μl.
Intervention: Etanercept 25 mg, eight doses administered subcutaneously twice weekly beginning on day 4 of tuberculosis therapy.
Main outcome measures: Serial examination, radiography, sputum culture, CD4 T-cell counts, plasma log10 HIV-RNA copy numbers.
Results: Trends towards superior responses to tuberculosis treatment were evident in etanercept-treated subjects in body mass, performance score, number of involved lung zones, cavitary closure, and time to sputum culture conversion. Etanercept treatment resulted in a 25% increase in CD4 cells by week 4 (P = 0.1 compared with controls). The change in CD4 cell count was inversely related to the change in serum neopterin, a marker of macrophage activation. There was no effect on plasma HIV RNA.
Conclusion: Etanercept can be safely administered during the initial treatment of pulmonary tuberculosis. Further studies are warranted to examine the effects of etanercept on T-cell numbers, activation and apoptosis in AIDS and tuberculosis.
Tuberculosis is the most common presenting illness for AIDS patients worldwide. Despite appropriate tuberculosis treatment, such patients show an accelerated loss of CD4 T cells, and are at a greater risk of subsequent opportunistic infection and death than matched controls without tuberculosis [1,2]. These adverse clinical outcomes are accompanied by sustained cellular immune activation and increased rates of spontaneous and antigen-induced T-cell apoptosis [3–7]. Tumor necrosis factor (TNF), a cytokine abundantly produced by Mycobacterium tuberculosis-infected macrophages, has been implicated as a key mediator in this process, given its ability to promote both HIV expression and apoptosis [8,9]. TNF is also an important mediator of the local and systemic inflammatory response in tuberculosis, causing many of the clinical manifestations of the illness. However, clinical trials to examine the role of TNF in HIV-associated tuberculosis have to date been limited by the lack of potency and specificity of the possible interventions, which have included pentoxifylline, prednisolone, and thalidomide, drugs with diverse immunological and anti-inflammatory effects.
The present study examined the safety, microbiology, virology, and immunology of eight doses etanercept (Enbrel) given twice a week during the initial 4 weeks of treatment of HIV-1-infected patients with pulmonary tuberculosis. Etanercept is a recombinant protein consisting of the human type II (p75) TNF receptor coupled to the Fc portion of immunoglobulin G. Its binding of TNF and lymphotoxin (also known as TNF-β) has potent effects in rheumatoid arthritis and other chronic inflammatory conditions . In this study, etanercept permitted the specific inhibition of TNF without otherwise disturbing a complex network of immune mediators.
TNF is essential for host defences against tuberculosis . Patients treated with TNF inhibitors, particularly anti-TNF monoclonal antibody, are at increased risk of the reactivation of latent tuberculosis and other intracellular infections . As the safety of etanercept in patients with active tuberculosis had not been established, this study was undertaken as a single-arm phase 1 trial with safety as its main objective. Its secondary objectives included immunological, virological, and microbiological endpoints, recognizing that the power of these observations would be limited by the small sample size. These endpoints were compared with CD4-matched control subjects selected from the placebo arm of a randomized trial of adjunctive prednisolone in HIV-1-associated tuberculosis, conducted at the same site during the preceding 2 years.
Written informed consent and Institutional Review Board approval was obtained in accordance with US Department of Health and Human Services guidelines. Inclusion criteria required that subjects be HIV-1 seropositive with CD4 cell counts greater than 200 cells/μl, between 18 and 50 years of age, with an initial episode of pulmonary tuberculosis (based on a positive sputum acid-fast smear, chest radiography compatible with tuberculosis, and subsequent confirmation of at least one sputum specimen with growth of at least 10 colonies of M. tuberculosis).
Individuals were excluded if they had a previous history of treatment for tuberculosis; jaundice or abnormal liver enzymes [serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) > 100 IU/l]; hemoglobin less than 8 g/dl; white blood cell count less than 3.0 × 103/mm3; serum creatinine greater than 177 μM/l (2 mg/dl); Karnofsky performance scale score less than 50%; respiratory rate greater than 35/min; known active intravenous drug or alcohol abuse; treatment with any investigational agents, immunomodulators, chemotherapy or radiation therapy within 60 days; neoplasms other than basal cell carcinoma or in-situ carcinoma of the cervix; pregnancy or breast feeding; individuals requiring or likely to require corticosteroids; asthma; known infection with drug-resistant M tuberculosis; treatment with protease inhibitors during the preceding 6 weeks; change in antiretroviral therapy anticipated during the next 8 weeks; evidence of acute myocardial infarction, high-grade ventricular ectopy or other serious arrhythmias or conduction disturbance on screening electrocardiogram; history of multiple sclerosis; allergy or intolerance of trimethoprim or sulfonamides; or suspected meningeal or miliary tuberculosis. Individuals were not excluded for concurrent antiretroviral therapy other than protease inhibitors; however, no such treated subjects were screened.
Enrolled subjects were admitted to the National TB Treatment Centre of Mulago Hospital, Kampala, Uganda. Subjects began standard short-course tuberculosis chemotherapy, consisting of 2 months of daily isoniazid, rifampin, ethambutol, and pyrazinamide, followed by 4 months of daily isoniazid and rifampin. The milligram daily doses of these four drugs were determined according to body weight: less than 50 kg, 300, 450, 800, 1500 mg; 50–70 kg, 300, 600, 1000, 2000 mg; greater than 70 kg, 300, 600, 1200, 2000 mg, respectively. Pyridoxine 50 mg was administered daily for 6 months. Etanercept 25 mg was administered subcutaneously twice a week for eight doses, starting on day 4 of tuberculosis therapy. Co-trimoxazole (160/800 mg) was administered daily for one year, because of concerns about possible opportunistic infections as a result of etanercept, and because some studies found that this intervention improves survival in HIV- associated tuberculosis in Africa [12–14].
Week 2 safety evaluation
All subjects underwent a safety evaluation after the 4th dose of etanercept, in which changes from baseline to week 2 in plasma HIV RNA and quantitative sputum acid-fast microscopy were determined. These values, along with clinical data regarding signs and symptoms of HIV and tuberculosis, were reviewed by an external safety monitoring board. The discontinuation of etanercept treatment was recommended by the study protocol for subjects whose plasma HIV RNA increased by 1 log or more, or whose sputum acid-fast bacillus (AFB) counts increased by 0.2 logs or greater.
Outpatient tuberculosis treatment
Subjects were discharged to home after the completion of etanercept treatment at the end of week 4. The remainder of the tuberculosis therapy was self-administered. Adherence was monitored by attendance at scheduled monthly clinic appointments, dispensing records, and testing for urinary isonicotinic acid (MycoDyn Uritec; Symcon, Solana Beach, CA, USA) at monthly intervals. At each monthly clinic visit during tuberculosis treatment, a focused history and physical examination was conducted to identify signs and symptoms of tuberculosis and other potential HIV-related adverse events. The final examination was conducted 6 months after the completion of tuberculosis therapy.
Transaminase levels, creatinine, and complete blood counts were measured on weeks 4 and 8, and at the conclusion of tuberculosis treatment. Two sputum specimens were subjected to microscopic examinations and culture for mycobacteria each month during tuberculosis treatment, and 6 months after the completion of treatment. Sputum processing for quantitative microscopy, culture and drug susceptibility testing was performed as previously described [15,16]. Sputum culture conversion was defined as the first negative sputum culture without subsequent positive cultures. Plasma HIV RNA was measured by the HIV Amplicor Monitor test v1.5 manual method (Roche Molecular Systems, Indianapolis, IN, USA). Serum neopterin was measured by enzyme-linked immunosorbent assay (ICN, Costa Mesa, CA, USA).
Forty-two control subjects were randomly selected from among those recruited to the placebo arm of a randomized trial of adjunctive prednisolone in HIV-associated tuberculosis, conducted at the same clinical site from November 1998 to July 2000. A manuscript describing that study is currently in preparation. Its enrollment criteria and tuberculosis treatment were identical to those of the present study. CD4 T-cell counts and plasma HIV-RNA copy numbers of the control subjects were measured in the same laboratory as in the present study. The two protocols differed in that subjects enrolled in the prednisolone trial: (i) were not hospitalized for the first month of treatment; (ii) did not undergo a safety evaluation at week 2; and (iii) were not treated with co-trimoxazole for one year. Controls were randomly selected from three ranges of CD4 cell values so that the frequency distribution of their CD4 cell counts matched that of etanercept-treated subjects.
Differences were examined by a two-tailed t-test, using SigmaStat (SPSS, Chicago, IL, USA), unless otherwise indicated. Paired t-tests were used to examine the change from baseline within subjects. The time to sputum culture conversion was analysed by survival analysis, using a log rank test.
Subjects and controls
From August 2001 to April 2002, 16 subjects were enrolled from among 233 who were screened. A total of 196 were excluded because of negative HIV-1 serology, normal chest radiographs, negative sputum acid-fast microscopy, or the inability to produce sputum. Fifty-eight were excluded because of laboratory or clinical disease severity indicators outside the limits of the study. Three later withdrew consent or did not return for enrollment. Two subjects were eligible but were not enrolled because of a regulatory hold. Four subjects were excluded for other reasons. Some subjects had multiple reasons for exclusion. No subjects were excluded because of protease inhibitor use at the time of tuberculosis diagnosis; none initiated antiretroviral therapy during the period of tuberculosis treatment. The baseline characteristics of the subjects and 42 CD4-frequency-matched controls are shown in Table 1.
Treatment with etanercept was initiated on day 4 of tuberculosis chemotherapy. All subjects underwent a safety evaluation on day 14, at which time changes from baseline in quantitative sputum acid-fast smear and plasma HIV-RNA copy numbers were reviewed by an external monitoring board. The mean log10 sputum AFB count was 6.65 ± 0.81/ml on entry, and 5.92 ± 0.75/ml on day 14 (P = 0.009). Two subjects showed more than a 0.2 log increase in sputum AFB counts during this interval; both were discontinued from etanercept treatment. In both instances, sputum AFB counts had been unusually low at baseline (4.35 and 5.28 log10 AFB/ml), indicating that these specimens may have been inadequate. Sputum cultures of both subjects converted appropriately to negative by week 8, and remained so subsequently.
The mean log10 plasma HIV-RNA copy number was 5.00 ± 0.7/ml on entry and 5.19 ± 0.9/ml on day 14 (P = 0.3). One subject had a greater than 1 log increase in copy numbers, and was discontinued from etanercept treatment. The clinical course of this subject is described in detail below.
At the time of diagnosis, from 58 to 93% of subjects reported cough, dyspnea, inability to carry out usual daily activities, loss of appetite, fever, and episodes of sweating. Except for cough, these proportions declined progressively during treatment, being present in 20–60% of subjects by the end of week 2, and in less than 25% by the end of week 8. The weight at baseline was 53.2 ± 8.8 kg (mean ± SD). The weight gained by week 4 was 1.81 ± 1.8 kg in all subjects, and 2.18 ± 1.5 kg in those subjects who received all eight scheduled etanercept doses. The mean weight gain was greater than that observed in control subjects (1.73 ± 2.0 kg), although the difference was not statistically significant (P = 0.40). The mean increase in performance score in individuals whose baseline score was less than 90 was 8.6 ± 5.3 in all subjects, and 9.1 ± 5.4 in those subjects who received all eight scheduled doses. This value was greater than that observed in controls (5.1 ± 8.9), although the difference was not statistically significant (P = 0.20).
Sputum cultures were positive for M. tuberculosis in four out of 14 (28.6%) at week 8; cultures of two subjects could not be evaluated because of contamination. The corresponding proportion in CD4-matched controls was also 28.6%. Overall, sputum culture conversion occurred slightly more rapidly in etanercept-treated subjects (P = 0.05), as indicated in Fig. 1. Seventy-seven tests for urinary isonicotinic acid were performed during the ambulatory phase of treatment (months 2–6); of these, only three were negative, indicating high compliance with treatment. All surviving subjects completed the final evaluation 6 months after the completion of tuberculosis therapy without relapse. Two of the 16 subjects had isoniazid-resistant isolates. Both showed satisfactory responses to treatment according to quantitative sputum microscopy on week 2, converted to negative sputum acid-fast culture by week 8, and remained so through their final evaluation.
As indicated in Table 2, log HIV-RNA copy numbers increased by +0.26 ± 0.4 copies/ml during etanercept treatment (P = 0.043). A corresponding increase of +0.05 ± 0.7 log10 copies/ml was observed during this interval in CD4-matched controls; the difference between etanercept-treated subjects and controls in changes from baseline was not significant (P = 0.31). At 6 months, HIV-RNA values in etanercept-treated subjects had returned to baseline (mean change −0.10, P = 0.58). Similarly, no change in HIV-RNA copy numbers was apparent in controls at month 4, the last evaluation in that study.
The CD4 T-cell count on entry was 394 ± 128 cells/μl. Counts tended to increase by week 4 of etanercept treatment: the increase was 62 ± 195 cells/μl in all subjects (P = 0.22), and 96 ± 186 cells/μl in subjects receiving all eight scheduled etanercept doses (P = 0.088). Total lymphocyte counts tended to decrease during this interval (2770 ± 1500 cells/μl at baseline versus 2380 ± 700 cells/μl at week 4, P = 0.3). CD4 cell counts in matched controls increased by 24 ± 120 cells/μl (P = 0.1 compared with etanercept-treated subjects). The serum neopterin level at baseline was 10.5 ± 7.0 ng/ml. The change from baseline to week 4 was −0.4 ± 3.6 ng/ml in all subjects, and −0.7 ± 3.8 ng/ml in subjects receiving all eight etanercept doses. The corresponding change from baseline in controls was −0.1 ± 4.6 ng/ml (P = 0.7). An inverse relationship was observed between the change in neopterin and the change in the log CD4 cell count from baseline to week 4 using the Spearman rank test (r = −0.37, P = 0.004 in all subjects; r = −0.50, P = 0.058 in etanercept-treated subjects).
Radiographs obtained during treatment were scored according to the number of lung zones involved. The change from baseline to month 6 tended to be superior in treated subjects compared with controls (−2.5 ± 1.1 versus −1.9 ± 1.5 lung zones, respectively), although this did not reach statistical significance (P = 0.2). Fifty-five per cent of etanercept recipients with cavitary disease at baseline had a closure of all cavities by month 6, versus 34% in CD4-matched control subjects (P = 0.3 by Fisher's exact test).
One subject, who entered the study with a CD4 cell count of 612 cells/μl, a log10 plasma HIV-RNA copy number of 4.18 copies/ml. and a serum neopterin level of 14.7 ng/ml, noted increased cough and dyspnea at week 2. The log10 plasma HIV-RNA copy number at that time had increased to 6.60 copies/ml. Levofloxacin and high-dose co-trimoxazole were added; etanercept was discontinued. Blood cultures and smears for malaria were negative. Bronchoscopy with bronchoalveolar lavage was non-diagnostic. The plasma HIV-RNA log copy number decreased to 5.17 on week 3, but increased again to 6.49 on week 4, at which time the CD4 cell count was 405 cells/μl. The subject developed unilateral leg edema during month 3 of treatment. Deep venous thrombosis, severe pulmonary hypertension, and presumed chronic pulmonary embolism were diagnosed at that time by Doppler ultrasound venography and echocardiography. The subject died despite anticoagulation. Autopsy was not performed. Sputum cultures obtained after 2 and 3 months of anti-tuberculosis treatment were negative. A review of laboratory data and serial chest radiographs by an outside reviewer indicated a satisfactory response to tuberculosis therapy. The primary cause of death was thought to be pulmonary embolism.
Two subjects developed transient asymptomatic transaminase elevations after 1 and 2 months of treatment, thought to be caused by isoniazid. In both cases, isoniazid was re-instituted uneventfully once transaminase values had normalized. Two subjects developed dermatomal herpes zoster after 1 and 2 months of treatment, thought to be possibly related to etanercept. For comparison, one case of zoster occurred in the control subjects during the first 6 months of observation. Finally, one etanercept recipient was found to have intestinal perforation and peritonitis 11 months after study entry, thought to be caused by adhesions from previous abdominal surgery.
Many questions remain regarding the mechanisms leading to T-cell loss in AIDS. Recent studies have implicated activation-induced apoptosis of uninfected ‘bystander’ T cells as a major factor, rather than direct viral cytopathicity or CD8-mediated cytotoxicity [17,18]. TNF provides an important signal for the apoptosis of activated lymphocytes . The observation that TNF blockade in HIV-associated tuberculosis results in increased numbers of circulating CD4 cells supports the potential role of this cytokine in HIV–tuberculosis co-pathogenesis. The inverse relationship between the CD4 cell count and serum neopterin, a marker of macrophage activation, is consistent with this observation . Similar increases in CD4 cell counts, attributed to the inhibition of apoptosis, have been reported in two studies in which HIV-infected individuals were treated with prednisone [20,21]. Further studies will be required to determine whether the increases observed in this study are caused by the inhibition of apoptosis, whether they are accompanied by other immunological or clinical benefits, and whether they occur in subjects with lower baseline CD4 cell counts.
The inhibition of TNF as a therapeutic modality is not without potential hazard. Animals lacking the gene for TNF or its receptors, or treated with neutralizing antibody or soluble TNF receptor, show increased susceptibility to Mycobacterium bovis bacillus Calmette–Guerin, M. tuberculosis, Listeria, Cryptococcus, and other intracellular pathogens [8,22–24]. Patients with rheumatoid arthritis or inflammatory bowel disease treated with neutralizing monoclonal antibody to TNF are at increased risk of the reactivation of latent M. tuberculosis infection . Nonetheless, the current study demonstrates that treatment with the TNF inhibitor etanercept does not interfere with the response to treatment for pulmonary tuberculosis, as assessed by serial clinical examination, chest radiography, sputum microscopy and culture. Indeed, several treatment-related parameters in the present study (weight gain, performance score, sputum culture conversion, radiographic extent of disease and cavity closure) showed trends towards superiority in the etanercept group. Sputum culture status after 8 weeks of treatment is an indicator of the risk of relapse [26,27]. The lack of a deleterious effect on this parameter is therefore significant. In this respect, etanercept is similar to corticosteroids and pentoxifylline, which modulate the inflammatory response in tuberculosis but do not interfere with tuberculosis treatment [28–31]. Larger, randomized placebo- controlled trials will be required to determine whether etanercept improves the response to tuberculosis therapy by accelerating sputum culture conversion.
Within the limits imposed by the small sample size and short treatment interval, etanercept treatment also appeared to be safe with respect to other potential HIV-related adverse events. The single fatality occurred in a subject whose elevated serum neopterin at baseline placed him at a greater than fourfold increased risk of death . Although deep venous thrombosis and pulmonary embolism have been reported in controlled clinical trials of etanercept in patients with rheumatoid or psoriatic arthritis, the incidence of these adverse events has not been related to the administered dose, nor has it differed significantly from that in control subjects. The incidence of deep venous thrombosis in tuberculosis has been estimated to be 3–10%, apparently reflecting hemostatic changes induced by the acute inflammatory response [32–34]. Further studies of the impact of HIV-1 infection on venous thrombosis in tuberculosis are warranted.
Etanercept treatment did not result in a reduction of plasma HIV RNA, despite the recognized importance of TNF as a signal for HIV expression via nuclear factor B, and the apparent role of the inflammatory response in tuberculosis driving local HIV expression [35–38]. This negative finding may indicate that factors other than TNF regulate HIV expression in tuberculosis.
In summary, adjunctive treatment with the TNF inhibitor etanercept did not interfere with the response to treatment for pulmonary tuberculosis in 16 HIV-1-infected individuals, in whom CD4 T-cell counts increased by 25%. Further studies are warranted to examine the effects of etanercept on T-cell activation and apoptosis, and to determine whether its addition to standard tuberculosis therapy confers any clinical benefits.
The authors would like to thank the members of the external safety review board, Allison Elliott, Jeurgen Freers, Moses Kamya, Peter Katahaa, Peter Mugyenyi, and Pontiano Kaleebu, as well as Margaret Wyza, Roy Mugerwa, David Hom, and Thomas Daniel for their timely assistance with this study. They would also like to thank Sr Clare Drajoru and the nursing staff of the National TB Treatment Centre, Wards 5 and 6, Mulago Hospital, for providing outstanding nursing care during the inpatient phase of the study.
Sponsorship: Financial support was provided by a grant from Immunex Corporation (Seattle, WA, USA), and by National Institutes of Health contract NO1-AI45244/AI95383.
1. Whalen C, Horsburgh CR, Hom D, Lahart C, Simberkoff M, Ellner J. Accelerated course of human immunodeficiency virus infection after tuberculosis. Am J Respir Crit Care Med
2. Whalen CC, Nsubuga P, Okwera A, Johnson JL, Hom DL, Michael NL, et al
. Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda. AIDS
3. Hirsch CS, Toossi Z, Othieno C, Johnson JL, Schwander SK, Robertson S, et al
. Depressed T-cell interferon-gamma responses in pulmonary tuberculosis: analysis of underlying mechanisms and modulation with therapy. J Infect Dis
4. Wallis RS, Vjecha M, Amir Tahmasseb M, Okwera A, Byekwaso F, Nyole S, et al
. Influence of tuberculosis on human immunodeficiency virus (HIV-1): enhanced cytokine expression and elevated beta 2-microglobulin in HIV-1-associated tuberculosis. J Infect Dis
5. Wallis RS, Helfand MS, Whalen C, Johnson JL, Mugerwa RD, Vjecha M, et al
. Immune activation, allergic drug toxicity, and mortality in HIV-positive tuberculosis. Tubercl Lung Dis
6. Hirsch CS, Toossi Z, Vanham G, Johnson JL, Peters P, Okwera A, et al
. Apoptosis and T cell hyporesponsiveness in pulmonary tuberculosis. J Infect Dis
7. Mayanja-Kizza H, Johnson JL, Hirsch CS, Peters P, Surewicz K, Wu M, et al
. Macrophage-activating cytokines in human immununodeficiency virus type 1-infected and -uninfected patients with pulmonary tuberculosis. J Infect Dis
8. Kindler V, Sappino AP, Grau GE, Piguet PF, Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell
9. Oliveira Pinto LM, Garcia S, Lecoeur H, Rapp C, Gougeon ML. Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3. Blood
10. Husni ME, Maier AL, Mease PJ, Overman SS, Fraser P, Gravallese EM, et al
. Etanercept in the treatment of adult patients with Still's disease. Arthritis Rheum
11. Gardam MA, Keystone EC, Menzies R, Manners S, Skamene E, Long R, et al
. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis
12. Badri M, Ehrlich R, Wood R, Maartens G. Initiating co-trimoxazole prophylaxis in HIV-infected patients in Africa: an evaluation of the provisional WHO/UNAIDS recommendations. AIDS
13. Maynart M, Lievre L, Sow PS, Kony S, Gueye NF, Bassene E, et al
. Primary prevention with cotrimoxazole for HIV-1-infected adults: results of the pilot study in Dakar, Senegal. J Acquired Immune Defic Syndr
14. Anglaret X, Chene G, Attia A, Toure S, Lafont S, Combe P, et al
. Early chemoprophylaxis with trimethoprim–sulphamethoxazole for HIV-1-infected adults in Abidjan, Cote d'Ivoire: a randomised trial. Cotrimo-CI Study Group. Lancet
15. Wallis RS, Perkins M, Phillips M, Joloba M, Demchuk B, Namale A, et al
. Induction of the antigen 85 complex of M. tuberculosis in sputum: a determinant of outcome in pulmonary tuberculosis. J Infect Dis
16. Siddiqi SH, Hwangbo CC, Silcox V, Good RC, Snider DEJ, Middlebrook G. Rapid radiometric methods to detect and differentiate Mycobacterium tuberculosis/M. bovis from other mycobacterial species. Am Rev Respir Dis
17. Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino RM, Paul WE. CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med
18. Kovacs JA, Lempicki RA, Sidorov IA, Adelsberger JW, Herpin B, Metcalf JA, et al
. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med
19. Schoedon G, Troppmair J, Fontana A, Huber C, Curtius HC, Niederwieser A. Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukemia lines of man and mouse. Eur J Biochem
20. Andrieu JM, Lu W, Levy R. Sustained increases in CD4 cell counts in asymptomatic human immunodeficiency virus type 1-seropositive patients treated with prednisolone for 1 year. J Infect Dis
21. Wallis RS, Kalayjian R, Jacobson JM, Fox L, Purdue L, Shikuma CM, et al
. A study of the immunology, virology, and safety of prednisone in HIV-1-infected subjects with CD4 cell counts of 200–700/mm. J Acquired Immune Defic Syndr
22. Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol
23. Yamada K, Yoshino K, Sekikawa K, Madarame H, Yagita H, Nakane A. Effect of a matrix metalloproteinase inhibitor on host resistance against Listeria monocytogenes infection. FEMS Immunol Med Microbiol
24. Kaneko H, Yamada H, Mizuno S, Udagawa T, Kazumi Y, Sekikawa K, et al
. Role of tumor necrosis factor-alpha in Mycobacterium-induced granuloma formation in tumor necrosis factor-alpha-deficient mice. Lab Invest
26. Mitchison DA. Assessment of new sterilizing drugs for treating pulmonary tuberculosis by culture at 2 months [Letter]. Am Rev Respir Dis
27. Benator D, Bhattacharya M, Bozeman L, Burman W, Cantazaro A, Chaisson R, et al
. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet
28. Nemir RL, Cardona J, Vaziri F, Toledo R. Prednisone as an adjunct in the chemotherapy of lymph node-bronchial tuberculosis in childhood: a double-blind study. II. Further term observation. Am Rev Respir Dis
29. Tripathy SP, Ramakrishnan CV, Nazareth O, Parthasarathy R, Santha Devi T, Arumainayagam DC, et al
. Study of chemotherapy regimens of 5 and 7 months’ duration and the role of corticosteroids in the treatment of sputum-positive patients with pulmonary tuberculosis in South India. Tubercle
30. Wallis RS, Nsubuga P, Okwera A, Whalen C, Mugerwa RD, Oette D, et al
. Pentoxifylline in human immunodeficiency virus-seropositive tuberculosis: a randomized, controlled trial. J Infect Dis
31. Wallis RS, Johnson JL, Okwera A, Nsubuga P, Whalen CC, Mugerwa RD, et al
. Pentoxifylline in human immunodeficiency virus-positive tuberculosis: safety at 4 years [Letter]. J Infect Dis
32. White NW. Venous thrombosis and rifampicin. Lancet
33. Robson SC, White NW, Aronson I, Woollgar R, Goodman H, Jacobs P. Acute-phase response and the hypercoagulable state in pulmonary tuberculosis. Br J Haematol
34. Turken O, Kunter E, Sezer M, Solmazgul E, Cerrahoglu K, Bozkanat E, et al
. Hemostatic changes in active pulmonary tuberculosis. Int J Tubercl Lung Dis
35. Osborn L, Kunkel S, Nabel GJ. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A
36. Toossi Z, Mayanja-Kizza H, Hirsch CS, Edmonds KL, Spahlinger T, Hom DL, et al
. Impact of tuberculosis (TB) on HIV-1 activity in dually infected patients. Clin Exp Immunol
37. Mayanja-Kizza H, Wajja A, Wu M, Peters P, Nalugwa G, Mubiru F, et al
. Activation of beta-chemokines and CCR5 in persons infected with human immunodeficiency virus type 1 and tuberculosis. J Infect Dis
38. Collins KR, Quinones-Mateu ME, Wu M, Luzze H, Johnson JL, Hirsch C, et al
. Human immunodeficiency virus type 1 (HIV-1) quasispecies at the sites of Mycobacterium tuberculosis infection contribute to systemic HIV-1 heterogeneity. J Virol
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Treatment of opportunistic infections in adolescent and adult patients infected by the human immunodeficiency virus during the era of highly active antiretroviral therapy - AIDS Study Group (GESIDA) and National AIDS Plan Expert Committe
Enfermedades Infecciosas Y Microbiologia Clinica, 26(6):
British Journal of DermatologyThe impact of treatment with tumour necrosis factor-alpha antagonists on the course of chronic viral infections: a review of the literatureBritish Journal of Dermatology
International Journal of Dermatology
Use of etanercept in human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) patients
International Journal of Dermatology, 45(6):
GutSafe and effective application of anti-TNF-alpha in a patient infected with HIV and concomitant Crohn's diseaseGut
Infectious Disease Clinics of North AmericaImpact of biologic agents on infectious diseasesInfectious Disease Clinics of North America
Zeitschrift Fur RheumatologieRisk of infection by biologicsZeitschrift Fur Rheumatologie
Annals of the Rheumatic DiseasesUpdated consensus statement on biological agents for the treatment of rheumatic diseases, 2009Annals of the Rheumatic Diseases
Best Practice & Research in Clinical RheumatologyProblems encountered during anti-tumour necrosis factor therapyBest Practice & Research in Clinical Rheumatology
Clinical Infectious DiseasesAdalimumab Treatment of Life-Threatening TuberculosisClinical Infectious Diseases
Rheumatology InternationalThe use of etanercept in a patient with disseminated tuberculosisRheumatology International
Clinical Infectious DiseasesTreatment of HIV-Related Inflammatory Cerebral Cryptococcoma with AdalimumabClinical Infectious Diseases
Annals of the Rheumatic DiseasesUpdate on tuberculosis and other opportunistic infections associated with drugs blocking tumour necrosis factor alphaAnnals of the Rheumatic Diseases
Gastroenterology Clinics of North AmericaSafety Profile of IBD Therapeutics: Infectious RisksGastroenterology Clinics of North America
RespirologyThe immunology of tuberculosis: From bench to bedsideRespirology
Clinical Infectious Diseases
Reconsidering adjuvant immunotherapy for tuberculosis
Clinical Infectious Diseases, 41(2):
Clinical Infectious Diseases
Reactivation of latent granulomatous infections by infliximab
Clinical Infectious Diseases, 41():
Annals of the Rheumatic DiseasesUpdated consensus statement on biological agents for the treatment of rheumatic diseases, 2007Annals of the Rheumatic Diseases
International Journal of Tuberculosis and Lung Disease
A Phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis
International Journal of Tuberculosis and Lung Disease, 12(2):
Joint Bone SpineUse of infliximab to treat psoriatic arthritis in HIV-positive patientsJoint Bone Spine
Archives of Dermatology
Successful treatment with etanercept of von Zumbusch pustular psoriasis in a patient with human immunodeficiency virus
Archives of Dermatology, 144(4):
Journal of Crohns & ColitisEuropean evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel diseaseJournal of Crohns & Colitis
Autoimmune Diseases and Treatment: Organ-Specific and Systemic Disorders
Anticytokine therapy, especially anti-interferon-gamma, as a pathogenetic treatment in Th-1 autoimmune diseases
Autoimmune Diseases and Treatment: Organ-Specific and Systemic Disorders, 1051():
Medical Science MonitorSerum neopterin concentrations in healthy healthcare workers compared with healthy controls and patients with pulmonary tuberculosisMedical Science Monitor
Expert Review of Anti-Infective TherapyImmunological options for the treatment of tuberculosis: evaluation of novel therapeutic approachesExpert Review of Anti-Infective Therapy
Journal of Rheumatology
Differences between anti-tumor necrosis factor-alpha monoclonal antibodies and soluble TNF receptors in host defense impairment
Journal of Rheumatology, 32():
RheumatologyTNF-blocking agents and tuberculosis: new drugs illuminate an old topicRheumatology
Journal of Infectious Diseases
Viral gene expression in HIV Transgenic mice is activated by Mycobacterium tuberculosis and suppressed after antimycobacterial chemotherapy
Journal of Infectious Diseases, 195(2):
IBD 2007 - Achievements in Research and Clinical Practice
Inflammatory bowel disease coexistent with viral hepatitis and HIV
IBD 2007 - Achievements in Research and Clinical Practice, 159():
Arthritis & Rheumatism-Arthritis Care & ResearchReintroduction of Etanercept During Treatment of Cutaneous Mycobacterium marinum Infection in a Patient With Ankylosing SpondylitisArthritis & Rheumatism-Arthritis Care & Research
Cellular MicrobiologyPenitentiary or penthouse condo: the tuberculous granuloma from the microbe's point of viewCellular Microbiology
Clinical Infectious DiseasesTherapeutic Use of Infliximab in Tuberculosis to Control Severe Paradoxical Reaction of the Brain and Lymph NodesClinical Infectious Diseases
Annals of the Rheumatic DiseasesSafety of antitumour necrosis factor (anti-TNF) therapy in patients with chronic viral infections: hepatitis C, hepatitis B, and HIV infectionAnnals of the Rheumatic Diseases
Indian Journal of Medical Research
HIV-TB co-infection: Epidemiology, diagnosis & management
Indian Journal of Medical Research, 121(4):
Current Molecular Medicine
Current strategies in TB immunotherapy
Current Molecular Medicine, 7(4):
Alimentary Pharmacology & TherapeuticsReview article: chronic viral infection in the anti-tumour necrosis factor therapy era in inflammatory bowel diseaseAlimentary Pharmacology & Therapeutics
Current Drug Targets
How to Manage the Infectious Risk under Anti-TNF in Inflammatory Bowel Disease
Current Drug Targets, 11(2):
Nature Reviews RheumatologyTumor necrosis factor blockade and the risk of viral infectionNature Reviews Rheumatology
Medical Clinics of North AmericaSafety Profile of IBD Therapeutics: Infectious Risks (Reprinted from Gastroenterology Clinics of North America, vol 38)Medical Clinics of North America
Clinical Infectious DiseasesThe Absence of CD4(+) T Cell Count Recovery Despite Receipt of Virologically Suppressive Highly Active Antiretroviral Therapy: Clinical Risk, Immunological Gaps, and Therapeutic OptionsClinical Infectious Diseases
Autoimmunity ReviewsIncidence and nature of infectious disease in patients treated with anti-TNF agentsAutoimmunity Reviews
Nature Clinical Practice RheumatologyDrug Insight: different mechanisms of action of tumor necrosis factor antagonists - passive-aggressive behavior?Nature Clinical Practice Rheumatology
Clinical Infectious DiseasesMycobacterial and other serious infections in patients receiving anti-tumor necrosis factor and other newly approved biologic therapies: Case finding through the emerging infections networkClinical Infectious Diseases
Expert Review of Anti-Infective TherapyTreatment of tuberculosis in childrenExpert Review of Anti-Infective Therapy
British Journal of DermatologyBritish Association of Dermatologists' guidelines for biologic interventions for psoriasis 2009British Journal of Dermatology
Failure to reconstitute CD4+T-cells despite suppression of HIV replication under HAART
AIDS Reviews, 8(2):
Expert Review of Anti-Infective TherapySurrogate markers to assess new therapies for drug-resistant tuberculosisExpert Review of Anti-Infective Therapy
British Medical BulletinThe implications of anti-tumour necrosis factor therapy for viral infection in patients with inflammatory bowel diseaseBritish Medical Bulletin
European Journal of ImmunologyExpression of apoptosis-related genes in an Ethiopian cohort study correlates with tuberculosis clinical statusEuropean Journal of Immunology
Dermatologica SinicaUse of etanercept to treat toxic epidermal necrolysis in a human immunodeficiency virus-positive patientDermatologica Sinica
Journal of Infectious DiseasesReduced Inflammation and Lymphoid Tissue Immunopathology in Rhesus Macaques Receiving Anti-Tumor Necrosis Factor Treatment During Primary Simian Immunodeficiency Virus InfectionJournal of Infectious Diseases
Trends in MicrobiologyRising to the challenge: new therapies for tuberculosisTrends in Microbiology
Journal of Internal MedicineShortening the 'short-course' therapy-insights into host immunity may contribute to new treatment strategies for tuberculosisJournal of Internal Medicine
Nature Reviews RheumatologyBedfellows: mycobacteria and rheumatoid arthritis in the era of biologic therapyNature Reviews Rheumatology
Current Opinion in Infectious DiseasesInfectious complications of tumor necrosis factor blockadeCurrent Opinion in Infectious Diseases
AIDS; clinical trial; etanercept; safety; soluble TNF receptor; tuberculosis; tumor necrosis factor
© 2004 Lippincott Williams & Wilkins, Inc.
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