Kogieleum Naidoo, MBChB; Nonhlanhla Yende-Zuma, MSc; Nesri Padayatchi, MBChB; Kasavan Naidoo, MSc; Niraksha Jithoo, MBChB; Gonasagrie Nair, MBChB; Sheila Bamber, MBChB; Santhana Gengiah, MA; Wafaa M. El-Sadr, MD, MPH; Gerald Friedland, MD; Salim Abdool Karim, PhD
Disclaimer: All authors had access to the data, commented on drafts, and approved the final report. Dr. Naidoo had final responsibility for the decision to submit the report for publication.
Acknowledgment: The authors thank the patients for their participation in this study; Ms. Natasha Samsunder for laboratory analysis; Mrs. Anneke Grobler for statistical support; Ms. Tanuja Gengiah and Ms. Anushka Naidoo for pharmacy support; Professor Y.M. Moosa, Dr. Aarthi Singh, and Dr. Munira Khan for additional clinical support; Mr. Faldie Burton for data management; and all other members of the SAPiT study team.
Grant Support: The Centre for the AIDS Programme of Research in South Africa was established as part of the Comprehensive International Program of Research on AIDS (CIPRA) (grant AI51794) from the National Institutes of Health. The U.S. President's Emergency Plan for AIDS Relief funded the care of all of the participants in the trial. The Global Fund to Fight AIDS, Tuberculosis and Malaria funded the cost of the drugs used in the trial. The research infrastructure to conduct the trial, including the data management, laboratory, and pharmacy cores, was established through the CIPRA grant. Drs. Naidoo and Padayatchi were supported by the Columbia University-Southern Africa Fogarty AIDS International Training and Research Program, which is funded by the Fogarty International Center of the National Institutes of Health (grant D43TW00231).
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0437.
Reproducible Research Statement:Study protocol: Available by contacting the authors. Statistical code and data set: Available from Ms. Yende-Zuma (e-mail, firstname.lastname@example.org). Access to all items will be restricted (based on prior ethical approval for data use and on completion of written agreements with the author or research sponsor).
Requests for Single Reprints: Kogieleum Naidoo, MBChB, Doris Duke Medical Research Institute, 2nd Floor, University of KwaZulu-Natal, 719 Umbilo Road, Private Bag X7, Congella, 4013, Durban, South Africa.
Current Author Addresses: Drs. Naidoo, Padayatchi, Nair, and Abdool Karim; Ms. Yende-Zuma; and Mr. Naidoo: Doris Duke Medical Research Institute, 2nd Floor, University of KwaZulu-Natal, 719 Umbilo Road, Private Bag X7, Congella, 4013, Durban, South Africa.
Dr. Jithoo: Postnet Suite 998, Private Bag X9, Benmore, 2010, Gauteng, South Africa.
Dr. Bamber and Ms. Gengiah: eThekwini Research Clinic, 3 Richards Road, Berea, 4000, Durban, South Africa.
Dr. El-Sadr: Mailman School of Public Health, Columbia University, 722 West 168th Street, Room 1312, New York, NY 10032.
Dr. Friedland: Yale University School of Medicine, 135 College Street, Suite 323, New Haven, CT 06510.
Author Contributions: Conception and design: Kogieleum Naidoo, N. Padayatchi, W.M. El-Sadr, G. Friedland, S. Abdool Karim.
Analysis and interpretation of the data: Kogieleum Naidoo, N. Yende-Zuma, N. Padayatchi, G. Friedland, S. Abdool Karim.
Drafting of the article: Kogieleum Naidoo, N. Yende-Zuma, Kasavan Naidoo, N. Jithoo, W.M. El-Sadr, S. Abdool Karim.
Critical revision of the article for important intellectual content: Kogieleum Naidoo, N. Yende-Zuma, N. Padayatchi, Kasavan Naidoo, N. Jithoo, S. Gengiah, W.M. El-Sadr, G. Friedland, S. Abdool Karim.
Final approval of the article: Kogieleum Naidoo, N. Padayatchi, W.M. El-Sadr, G. Friedland, S. Abdool Karim.
Provision of study materials or patients: Kogieleum Naidoo.
Statistical expertise: N. Yende-Zuma.
Obtaining of funding: S. Abdool Karim.
Administrative, technical, or logistic support: Kogieleum Naidoo, N. Padayatchi, N. Jithoo, S. Gengiah.
Collection and assembly of data: Kogieleum Naidoo, N. Yende-Zuma, Kasavan Naidoo, N. Jithoo, G. Nair, S. Bamber.
Concerns about the immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during antituberculosis treatment in co-infected patients.
To assess IRIS incidence, severity, and outcomes relative to the timing of ART initiation in patients with HIV-related tuberculosis.
Randomized, open-label clinical trial. (ClinicalTrials.gov registration number: NCT00398996)
An outpatient clinic in Durban, South Africa.
642 patients co-infected with HIV and tuberculosis.
In a secondary analysis of the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial, IRIS was assessed in patients randomly assigned to initiate ART within 4 weeks of tuberculosis treatment initiation (early integrated treatment group), within 4 weeks of completion of the intensive phase of tuberculosis treatment (late integrated treatment group), or within 4 weeks after tuberculosis therapy completion (sequential treatment group). The syndrome was defined as new-onset or worsening symptoms, signs, or radiographic manifestations temporally related to treatment initiation, accompanied by a treatment response. Severity of IRIS, hospitalization, and time to resolution were monitored.
Incidence of IRIS was 19.5 (n = 43), 7.5 (n = 18), and 8.1 (n = 19) per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Among patients with a baseline CD4+ count less than 0.050 × 109 cells/L, IRIS incidence was 45.5, 9.7, and 19.7 per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Incidence of IRIS was higher in the early integrated treatment group than in the late integrated (incidence rate ratio, 2.6 [95% CI, 1.5 to 4.8]; P < 0.001) or sequential (incidence rate ratio, 2.4 [CI, 1.4 to 4.4]; P < 0.001) treatment groups. More severe IRIS cases occurred in the early integrated treatment group than in the other 2 groups (35% vs. 19%; P = 0.179), and patients in the early integrated treatment group had significantly higher hospitalization rates (42% vs. 14%; P = 0.007) and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) than patients in the other 2 groups.
It was not possible to assess IRIS in more patients in the sequential treatment group (n = 74) than in the late integrated (n = 50) and early integrated (n = 32) treatment groups because of loss to follow-up, withdrawal, or death within 6 months of scheduled ART initiation. This study did not assess IRIS risk in nonambulatory patients or in those with extrapulmonary and smear-negative tuberculosis.
Initiation of ART in early stages of tuberculosis treatment resulted in significantly higher IRIS rates, longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings are particularly relevant to patients initiating ART with a CD4+ count less than 0.050 × 109 cells/L, given the increased survival benefit of early ART initiation in this group.
Comprehensive International Program of Research on AIDS.
In HIV-infected patients being treated for tuberculosis, initiation of antiretroviral therapy (ART) is associated with the immune reconstitution inflammatory syndrome (IRIS).
When ART was introduced within the first 4 weeks of tuberculosis treatment of HIV-infected patients, IRIS was more frequent, was more severe, and resolved more slowly.
In HIV-infected patients with CD4+ counts less than 0.050 × 109 cells/L who are receiving tuberculosis therapy, the greater risk for IRIS with early ART initiation must be balanced with a previously shown decreased mortality in this population with early ART initiation.
The timing of initiation of ART during tuberculosis therapy should be individualized.
SAPiT trial study schema.
ART = antiretroviral therapy; SAPiT = Starting Antiretroviral Therapy at Three Points in Tuberculosis; TB = tuberculosis.
Study flow diagram.
ART = antiretroviral therapy; ARV = antiretroviral drug; TB = tuberculosis.
Baseline Characteristics of Participants in the SAPiT Trial
Appendix Table 1.
Patterns of Patient Withdrawal, by Study Group
Appendix Table 2.
Baseline Characteristics of Patients Who Withdrew, Died, or Could Not Be Assessed for IRIS
IRIS Incidence in the SAPiT Trial, by Study Group
Kaplan–Meier estimates of cumulative probability of IRIS, by study group.
IRIS = immune reconstitution inflammatory syndrome.
Appendix Table 3.
IRIS Incidence, by Study Group
Proportion of all patients with IRIS who developed clinical signs, symptoms, and radiographic features of IRIS.
IRIS Severity, by Study Group
Appendix Table 4.
IRIS Incidence and Incidence Rate Ratios for Selected Baseline Characteristics, by Study Group
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Leonardo Calza; Michele Bartoletti; Pierluigi Viale
Clinic of Infectious Diseases, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
September 10, 2012
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME IN PATIENTS WITH TUBERCULOSIS AND HIV INFECTION: WHICH TIMING FOR ANTIRETROVIRAL THERAPY?
Dear Sir,the findings from the SAPiT clinical trial recently published by Naidoo K et al. (1) have raised again the question about the most appropriate timing of antiretroviral therapy (ART) in patients with HIV and tuberculosis coinfection. In a secondary analysis of this trial, an early start of ART (within 4 weeks of tuberculosis treatment initiation) resulted in significantly higher incidence of immune reconstitution inflammatory syndrome (IRIS), longer time to resolution, and more severe cases of IRIS requiring hospitalization than a delayed start of ART (within 4 weeks of completion of the intensive phase of tuberculosis treatment or later). Moreover, these findings are more evident in patients with severe immunological damage (CD4+ lymphocyte count <50 cells/mm3). These data seem suggest a more late initiation of ART in this population, but some remarks should be made.Among the most evident limitations of the above-mentioned trial, there is certainly the choice of the study end-points. The Authors have assessed incidence and severity of IRIS, and not the IRIS-associated mortality or the overall mortality. Even though early initiation of ART was associated with higher incidence and severity of IRIS, only 2 out of 80 patients died. Moreover, incidence of IRIS with neurological symptoms (which is the real potentially life-threatening manifestation of IRIS) was limited. Another important limitation is the absence of reliable diagnostic tests for IRIS, and the risk of misclassification bias, as observed by the Authors.Large cohort studies report an IRIS incidence of about 10-20% among patients with advanced HIV infection (2), and ranging between 13% and 40% among subjects with HIV-tuberculosis coinfection (3-5). However, the incidence of IRIS with life-threatening manifestations (such as meningitis) was usually low, and the contribution of IRIS to the observed early mortality was limited (5-7). In a cohort study involving 302 HIV-positive patients with tuberculosis starting ART, in most patients died with IRIS an alternative cause of death was identified. Moreover, no ART use was an independent predictor of mortality, reinforcing the need for timely and joint treatment for both infections (8).In our opinion, it should be advisable to take account of overall mortality as main parameter to evaluate the timing of ART initiation in patients with different stages of HIV infection and immunological deterioration.In patients with severe immune deficiency, some randomized trials have shown that early start of ART is usually associated with a lower rate of new AIDS-defining illnesses and a lower overall mortality. In the CAMELIA randomized study involving 661 Cambodian HIV-infected patients with newly diagnosed tuberculosis and a CD4 T-lymphocyte count <200 cells/mm3, ART has been started 2 weeks or 8 weeks after beginning tuberculosis treatment. After a median follow-up of 25 months, the overall survival was significantly higher among patients with earlier ART initiation (9). The ACTG Study A5221 compared earlier with later ART (started within 2 weeks and within 8-12 weeks after the start of antituberculosis treatment, respectively) in 809 subjects with advanced HIV infection and suspected tuberculosis. After 48 weeks of follow-up, earlier ART was associated with a lower rate of opportunistic infections and death among persons with CD4+ T-cell counts of less than 50/mm3, but not in those with a higher CD4+ T-cell count (10). Also the SAPiT randomized trial assessed the incidence of AIDS or death among 642 ambulatory patients with HIV infection and confirmed tuberculosis in South Africa. In this study, early initiation of ART (within 4 weeks after the start of tuberculosis therapy) increased AIDS-free survival in subjects with CD4+ cell count <50/mm3, while deferral of the ART initiation to the first 4 weeks of the continuation phase of tuberculosis therapy reduced the risk of IRIS without increasing the risk of AIDS or death in patients with higher CD4+ cell count (11). The undeniable advantage in reducing incidence of HIV disease progression of earlier initiation of ART (after 2-4 weeks of starting antituberculosis therapy) in patients with tuberculosis and advanced HIV infection was recently shown also by a randomized trial including 150 patients in India (12). The TIME randomized study involving 156 HIV/tuberculosis coinfected patients in middle-income countries showed that earlier initiation of ART (within 4 weeks of the start of tuberculosis treatment) was not associated with survival advantage when compared to later initiation of ART (at 12 weeks). However, in this study patients had higher CD4+ cell count (<350/mm3), and incidence of IRIS was limited (8.86 per 100 person-months in the 4-week group) (13).Therefore, the point at issue is when to start ART in HIV-infected patients with tuberculosis and a less severe immune suppression (CD4+ T-lymphocyte count ranging from 50 to 200 cells/mm3), because in this population early initiation of ART is not clearly associated with improved survival and the risk of IRIS occurrence is still elevated. The knowledge of circulating biomarkers which can predict the onset of IRIS in this population would be extremely useful to choose earlier or later start of ART.Even though routinely usable predictors of IRIS are not available still today, interesting data originate from recent reports. A case-control study including a cohort of 498 patients in South Africa showed that paradoxical IRIS was associated with lower serum levels of interleukin (IL)-10 and monocyte chemotactic protein-1 (MCP-1), and with higher levels of C-reactive protein (14). The role of natural killer (NK) cells in the onset of IRIS was evaluated among 128 patients enrolled in the CAMELIA study. At baseline, the NK-cell degranulation capacity was significantly higher in subjects who developed IRIS than in non-IRIS patients, and patients with baseline degranulation levels >10.84% had a significantly higher risk of IRIS (15). In a prospective study including 81 HIV-infected patients with tuberculosis starting ART, serum levels of IL-6, IL-8, IL-12p40, IL-18, and tumor necrosis factor (TNF) significantly increased during the first 2 weeks of ART in patients who developed IRIS, while concurrent use of corticosteroid therapy significantly lowered serum levels of cytokines and chemokines (16).Therefore, early initiation of antiretroviral treatment (within 2-4 weeks after beginning antituberculosis therapy) seems mandatory in HIV-infected patients with severe immune deficiency (CD4+ lymphocyte count <50 cells/mm3), owing to the evident advantages in reducing AIDS-associated morbidity and mortality. On the contrary, a later ART initiation (at 8-12 weeks) may be considered in those with a more favourable immunological status (CD4+ lymphocyte count between 50 and 200 cells/mm3), owing to the less evident effects on the overall mortality and the high risk of developing IRIS. Particularly, in this population the evidence of predictors of IRIS at baseline could suggest a delay in ART initiation (at least 12 weeks after beginning tuberculosis therapy), and increased levels of cytokines during the initial phase of ART could orient towards the use of corticosteroids. Certainly, further enlarged study are requested to better define the role of inflammatory biomarkers and corticosteroid therapy in the clinical management of tuberculosis-associated IRIS in HIV-infected patients.In conclusion, the SAPiT trial (1) has emphasized the need of remind the IRIS occurrence as a frequent complication in the clinical management of HIV-tuberculosis coinfection, particularly in patients with a more advanced stage of immune suppression.REFERENCES1. Naidoo K, Yende-Zuma N, Padayatchi N, Naidoo K, Jithoo N, Nair G, et al. The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial. Ann Intern Med. 2012;157:313-24. [PMID: 22944873]2. Novak RM, Richardson JT, Buchacz K, Chmiel JS, Durham MD, Palella FJ, et al; HIV Outpatients Study (HOPS) Investigators. Immune reconstitution inflammatory syndrome: incidence and implications for mortality. AIDS. 2012;26:721-30. [PMID: 22233655]3. Manosuthi W, Van Tieu H, Mankatitham W, Lueangniyomkul A, Ananworanich J, Avihingsanon A, et al; N2R Study Team. Clinical case definition and manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2009;23:2467-71. [PMID: 19898217]4. Elliott JH, Vohith K, Saramony S, Savuth C, Dara C, Sarim C, et al. Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early antiretroviral therapy. J Infect Dis. 2009;200:1736-45. [PMID: 19874177]5. Agarwal U, Kumar A, Behera D, French MA, Price P. Tuberculosis associated immune reconstitution inflammatory syndrome in patients infected with HIV: meningitis a potentially life threatening manifestation. AIDS Res Ther. 2012;9:17. [PMID: 22620862]6. Worodria W, Menten J, Massinga-Loembe M, Mazakpwe D, Bagenda D, Koole O, et al; the TB-IRIS Study Group. Clinical spectrum, risk factors and outcome of immune reconstitution inflammatory syndrome in patients with tuberculosis-HIV coinfection. Antivir Ther 2012;17:841-8. [PMID: 22543224]7. Castelnuovo B, Manabe YC, Kiragga A, Kamya M, Easterbrook P, Kambugu A, et al. Cause-specific mortality and the contribution of immune reconstitution inflammatory syndrome in the first 3 years after antiretroviral therapy initiation in an urban African cohort. Clin Infect Dis. 2009;49:965-72. [PMID: 19673615]8. Worodria W, Massinga-Loembe M, Mazakpwe D, Luzinda K, Menten J, Van Leth F, et al; the TB-IRIS Study Group. Incidence and predictors of mortality and the effect of tuberculosis immune reconstitution inflammatory syndrome in a cohort of TB/HIV patients commencing antiretroviral therapy. J Acquir Immune Defic Syndr. 2011;58:32-7. [PMID: 21654499]9. Blanc FX, Sok T, Laureillard D, Borand L, Rekacewicz C, Nerrienet E, et al; CAMELIA Study Team. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365:1471-81. [PMID: 22010913]10. Havlir DV, Kendall MA, Ive P, Kumwenda J, Swindells S, Qasba SS, et al; AIDS Clinical Trials Group Study A5221. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365:1482-91. [PMID: 22010914]11. Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365:1492-501. [PMID: 22010915]12. Sinha S, Shekhar RC, Singh G, Shah N, Ahmad H, Kumar N, et al. Early versus delayed initiation of antiretroviral therapy for Indian HIV-infected individuals with tuberculosis on antituberculosis treatment. BMC Infect Dis. 2012;12:168. [PMID: 22846195]13. Manosuthi W, Mankatitham W, Lueangniyomkul A, Thongyen S, Likanonsakul S, Suwanvattana P, et al; for the TIME Study Team. Time to initiate antiretroviral therapy between 4 weeks and 12 weeks of tuberculosis treatment in HIV-infected patients: results from the TIME Study. J Acquir Immune Defic Syndr. 2012;60:377-83. [PMID: 22592586]14. Haddow LJ, Dibben O, Moosa MY, Borrow P, Easterbrook P. Circulating inflammatory biomarkers can predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2011;25:1163-74. [PMID: 21505297]15. Pean P, Nerrienet E, Madec Y, Borand L, Laureillard D, Fernandez M, Marcy O, et al; CAMELIA Study Team. Natural killer cell degranulation capacity predicts early onset of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients with tuberculosis. Blood. 2012;119:3315-20. [PMID: 22343919]16. Conesa-Botella A, Meintjes G, Coussens AK, van der Plas H, Goliath R, Schutz C, et al. Corticosteroid therapy, vitamin D status, and inflammatory cytokine profile in the HIV-tuberculosis immune reconstitution inflammatory syndrome. Clin Infect Dis. 2012;55:1004-11. [PMID: 22715179]
Naidoo K, Yende-Zuma N, Padayatchi N, Naidoo K, Jithoo N, Nair G, et al. The Immune Reconstitution Inflammatory Syndrome After Antiretroviral Therapy Initiation in Patients With Tuberculosis: Findings From the SAPiT Trial. Ann Intern Med. ;157:313–324. doi: 10.7326/0003-4819-157-5-201209040-00004
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Published: Ann Intern Med. 2012;157(5):313-324.
HIV, Infectious Disease, Mycobacterial Infections.
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