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Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis: A Systematic Review and Meta-analysisOptimal Timing of ART for HIV-Infected Adults With TB

Olalekan A. Uthman, MBBS, MPH, PhD; Charles Okwundu, MBBS, MPH; Kayode Gbenga, MBBS, MPH; Jimmy Volmink, MBChB, MPH, PhD; David Dowdy, MD, PhD; Alimuddin Zumla, BSc, MBChB, MSc, PhD; and Jean B. Nachega, MD, MPH, PhD, DTM&H
[+] Article, Author, and Disclosure Information

From Warwick Medical School, Warwick University, Coventry, United Kingdom; Liverpool School of Tropical Medicine, International Health Group, Liverpool, United Kingdom; Stellenbosch University, Stellenbosch, South Africa; South African Medical Research Council, Tygerberg, South Africa; University Medical Center Utrecht, Utrecht, The Netherlands; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; University College London, London, United Kingdom; and University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.

Note: The results of this review were accepted for presentation at the 8th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Vancouver, Canada, 18–22 July 2015. Abstract MOPEB165.

Acknowledgment: The authors thank John L. Johnson, MD (Professor of Medicine at Case Western Reserve University), for critical review of the manuscript.

Grant Support: Dr. Uthman acknowledges support from the Swedish Council for Working Life and Social Research Marie Curie International Postdoctoral fellowship (2012-0064). Dr. Nachega receives research grant support from the National Institute for Allergy and Infectious Disease of the National Institutes of Health, the AIDS Clinical Trial Group, and Stellenbosch University Clinical Trial Unit (2UM1AI069521-08); the Medical Education Partnership Initiative through the U.S. President Emergency Plan for AIDS Relief (T84HA21652-01-00); the European Developing Countries Clinical Trial Partnership Senior Fellowship Award (TA-08-40200-021); and the Wellcome Trust Southern Africa Consortium for Research Excellence (WT087537MA). Dr. Zumla receives support from the European Commission Seventh Framework Programme (Rapid Identification of Respiratory Tract Infections Project) and the National Institutes of Health Research Biomedical Research Centre. Dr. Volmink receives support from Stellenbosch University and the South African Medical Research Council.

Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2979.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Requests for Single Reprints: Olalekan A. Uthman, MBBS, MPH, PhD, Warwick Centre for Applied Health Research and Delivery, Division of Health Sciences, Warwick Medical School, Medical Teaching Centre, Warwick University, Coventry CV4 7AL, United Kingdom; e-mail, olalekan.uthman@warwick.ac.uk.

Current Author Addresses: Dr. Uthman: Warwick Centre for Applied Health Research and Delivery, Division of Health Sciences, Warwick Medical School, Medical Teaching Centre, Coventry CV4 7AL, United Kingdom.

Mr. Okwundu and Dr. Volmink: Centre for Evidence-Based Health Care, Stellenbosch University, Tygerberg 7505, South Africa.

Mr. Gbenga: Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht 3584 CG, The Netherlands.

Dr. Dowdy: Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, 615 North Wolfe Street, Baltimore, MD 21205.

Dr. Zumla: Division of Infection and Immunity, University College London, and NIHR Biomedical Research Centre, University College London Hospital, London WC1E 6BT, United Kingdom.

Dr. Nachega: Pittsburgh Graduate School of Public Health, Department of Epidemiology. 130, DeSoto Street, Parran Hall 503, Pittsburgh, PA 15261.

Authors Contributions: Conception and design: O.A. Uthman, A. Zumla, J.B. Nachega.

Analysis and interpretation of the data: O.A. Uthman, C. Okwundu, K. Gbenga, J. Volmink, D. Dowdy, A. Zumla, J.B. Nachega.

Drafting of the article: O.A. Uthman, C. Okwundu, K. Gbenga, J. Volmink, A. Zumla, J.B. Nachega.

Critical revision of the article for important intellectual content: O.A. Uthman, C. Okwundu, K. Gbenga, J. Volmink, D. Dowdy, A. Zumla, J.B. Nachega.

Final approval of the article: O.A. Uthman, C. Okwundu, K. Gbenga, J. Volmink, D. Dowdy, A. Zumla, J.B. Nachega.

Provision of study materials or patients: O.A. Uthman.

Statistical expertise: O.A. Uthman.

Administrative, technical, or logistic support: O.A. Uthman, J.B. Nachega.

Collection and assembly of data: O.A. Uthman, C. Okwundu, K. Gbenga, A. Zumla.


Ann Intern Med. 2015;163(1):32-39. doi:10.7326/M14-2979
Text Size: A A A

Background: Initiation of antiretroviral therapy (ART) during tuberculosis (TB) treatment remains challenging.

Purpose: To assess evidence from randomized, controlled trials of the timing of ART initiation in HIV-infected adults with newly diagnosed pulmonary TB.

Data Sources: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, conference abstracts, and ClinicalTrials.gov (from January 1980 to May 2015).

Study Selection: Randomized, controlled trials evaluating early versus delayed ART initiation (1 to 4 weeks vs. 8 to 12 weeks after initiation of TB treatment) or deferred ART initiation (after the end of TB treatment).

Data Extraction: Three reviewers independently extracted data and assessed risk of bias. The main outcome measures were all-cause mortality and the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS).

Data Synthesis: The 8 included trials (n = 4568) were conducted in Africa, Asia, and the United States and were generally at low risk of bias for the assessed domains. Overall, early ART reduced mortality compared with delayed ART (relative risk [RR], 0.81 [95% CI, 0.66 to 0.99]; I2 = 0%). In a prespecified subgroup analysis, early ART reduced mortality compared with delayed ART among patients with baseline CD4+ T-cell counts less than 0.050 × 109 cells/L (RR, 0.71 [CI, 0.54 to 0.93]; I2 = 0%). However, a mortality benefit from early ART was not found among those with CD4+ T-cell counts greater than 0.050 × 109 cells/L (RR, 1.05 [CI, 0.68 to 1.61]; I2 = 56%). Early ART was associated with a higher incidence of TB-IRIS than delayed ART (RR, 2.31 [CI, 1.87 to 2.86]; I2 = 19%).

Limitation: Few trials provided sufficient data for subgroup analysis.

Conclusion: Early ART in HIV-infected adults with newly diagnosed TB improves survival in those with CD4+ T-cell counts less than 0.050 × 109 cells/L, although this is associated with a 2-fold higher frequency of TB-IRIS. In patients with CD4+ T-cell counts greater than 0.050 × 109 cells/L, evidence is insufficient to support or refute a survival benefit conferred by early versus delayed ART initiation.

Primary Funding Source: None. (PROSPERO registration: CRD42012001884)

Figures

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Figure 1.

Summary of evidence search and selection.

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Figure 2.

Risk-of-bias assessment of included trials.

CAMELIA = Cambodian Early Versus Late Introduction of Antiretrovirals; SAPiT = Starting ART at Three Points in TB; STRIDE = Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis; TB-HAART = An Evaluation of the Impact of Early Initiation of HAART on TB Treatment Outcomes for TB Patients Co-infected With HIV; TIME = Appropriate Timing of HAART in Co-infected HIV/TB Patients.

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Figure 3.

All-cause mortality comparing early versus delayed initiation of ART.

ART = antiretroviral therapy; CAMELIA = Cambodian Early Versus Late Introduction of Antiretrovirals; M–H = Mantel–Haenszel; SAPiT = Starting ART at Three Points in TB; STRIDE = Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis; TIME = Appropriate Timing of HAART in Co-infected HIV/TB Patients.

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Figure 4.

All-cause mortality comparing early versus delayed initiation of ART, stratified by baseline CD4+ T-cell counts.

ART = antiretroviral therapy; CAMELIA = Cambodian Early Versus Late Introduction of Antiretrovirals; M–H = Mantel–Haenszel; SAPiT = Starting ART at Three Points in TB; TIME = Appropriate Timing of HAART in Co-infected HIV/TB Patients.

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Figure 5.

TB-IRIS comparing early versus delayed initiation of ART.

ART = antiretroviral therapy; CAMELIA = Cambodian Early Versus Late Introduction of Antiretrovirals; M–H = Mantel–Haenszel; SAPiT = Starting ART at Three Points in TB; STRIDE = Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis; TB-IRIS = tuberculosis-associated immune reconstitution inflammatory syndrome; TIME = Appropriate Timing of HAART in Co-infected HIV/TB Patients.

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Appendix Figure 1.

TB-IRIS comparing early versus delayed initiation of ART, stratified by baseline CD4+ T-cell count.

ART = antiretroviral therapy; CAMELIA = Cambodian Early Versus Late Introduction of Antiretrovirals; M–H = Mantel–Haenszel; SAPiT = Starting ART at Three Points in TB; STRIDE = Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis; TB-IRIS = tuberculosis-associated immune reconstitution inflammatory syndrome; TIME = Appropriate Timing of HAART in Co-infected HIV/TB Patients.

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Appendix Figure 2.

Secondary outcomes comparing early versus delayed initiation of ART.

ART = antiretroviral therapy; CAMELIA = Cambodian Early Versus Late Introduction of Antiretrovirals; M–H = Mantel–Haenszel; SAPiT = Starting ART at Three Points in TB; STRIDE = Immediate Versus Deferred Start of Anti-HIV Therapy in HIV-Infected Adults Being Treated for Tuberculosis; TIME = Appropriate Timing of HAART in Co-infected HIV/TB Patients.

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Appendix Figure 3.

Outcomes comparing early versus deferred initiation of ART.

ART = antiretroviral therapy; M–H = Mantel–Haenszel; SAPiT = Starting Antiretroviral Therapy at Three Points in Tuberculosis; TB-HAART = An Evaluation of the Impact of Early Initiation of HAART on TB Treatment Outcomes for TB Patients Co-infected With HIV; TB-IRIS = tuberculosis-associated immune reconstitution inflammatory syndrome.

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Appendix Figure 4.

Outcomes comparing delayed versus deferred initiation of ART.

ART = antiretroviral therapy; M–H = Mantel–Haenszel; SAPiT = Starting Antiretroviral Therapy at Three Points in Tuberculosis; TB-IRIS = tuberculosis-associated immune reconstitution inflammatory syndrome.

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Comment
Posted on August 11, 2015
Reinaldo Espíndola, Jean-François Etard, Sandrine Leroy
University of Montpellier
Conflict of Interest: None Declared
We read with interest Uthman et al. article (1) regarding the optimal timing of antiretroviral therapy (ART) initiation in HIV-TB co-infected patients. The authors conducted a meta-analysis to compare global mortality and IRIS-specific mortality in patients initiating early ART (within 4 weeks after TB-treatment beginning) or delayed ART (in the 8-12 weeks). They demonstrated a significant lower mortality in patients receiving early ART, regardless of the immunodeficiency level. They also pointed out that early ART was associated with a two-fold increased risk of TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) regardless of the immunodeficiency. However, the concern for a clinician, facing a HIV-TB co-infected patient, is to translate mortality risk related to opportunistic infections (OI) due to a longer immunodeficiency if ART initiation is postponed, and TB-IRIS mortality when initiating early ART, into a clinical decision. To help clinicians’ decision making, it would be of interest to complement Uthman’s results by estimating absolute mortality risks related to (i) TB-IRIS, and to (ii) OIs, and for both difference between early and delayed ART. Assuming that mortality not related to TB-IRIS was due to OIs, numbers of opportunistic and TB-IRIS related deaths were extracted from included articles when available (2-6), and respective mortality risks were estimated and compared between treatment groups (early vs. delayed ART). The OI specific mortality risk significantly decreased from 11.7% in delayed ART group to 9.7% in early ART group (risk difference = -2.7%; 95% CI: -5.4 to -0.4; p=0.02). Conversely, the TB-IRIS specific mortality risk slightly but significantly increased from 0% in delayed ART treatment group to 0.8% in early ART group (risk difference = 0.8; 95% CI: 0.3 to 1.3; p=0.003). It means that, even if patients receiving early ART experienced two-fold increase in IRIS rate than those with delayed ART, decrease of OI specific mortality risk difference was higher than the increase in TB-IRIS mortality risk difference. Therefore, it seems to us that this increased frequency of IRIS should not be understood as a major limitation for initiating early ART. To conclude, it would be of interest to better explore the predictive factors that could help clinicians to early identify whose patients would be at high-risk of severe TB-IRIS, in order to reasonably slightly postpone his decision of early ART. Moreover, heterogeneity related to TB-location (pulmonary or extra-pulmonary), and to TB diagnostic methods should be taken into account.



References
1. Uthman OA, Okwundu C, Gbenga K, Volmink J, Dowdy D, Zumla A, et al. Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis: a systematic review and meta-analysis. Ann Intern Med. 2015;163:32-9. [PMID: 26148280] doi: 10.7326/M14-2979.
2. Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, et al. Integration of antiretroviral therapy with tuberculosis treatment.NEngl J Med. 2011;365:1492-501. [PMID: 22010915] doi: 10.1056/NEJMoa1014181
3. Blanc FX, Sok T, Laureillard D, Borand L, Rekacewicz C, Nerrienet E, et al; CAMELIA (ANRS 1295–CIPRA KH001) 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] doi:10.1056/NEJMoa1013911
4. 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] doi:10.1056/NEJMoa1013607
5. Manosuthi W, Mankatitham W, Lueangniyomkul A, Thongyen S, Likanonsakul S, Suwanvattana P, et al; 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] doi:10.1097/QAI.0b013e31825b5e06
6. Sinha S, Shekhar RC, Singh G, Shah N, Ahmad H, Kumar N, et al. Early versus delayed initiation of antiretroviral therapy for Indian HIVInfected individuals with tuberculosis on antituberculosis treatment. BMC Infect Dis. 2012;12:168. [PMID: 22846195]

Reinaldo Espíndola, Jean-François Etard, Sandrine Leroy
Unité Mixte Internationale 233, Institut de Recherche pour le Développement, INSERM U1175, and University of Montpellier, 34394 Montpellier, France
Comment
Posted on August 11, 2015
Jean Joel R. Bigna, Claudia S. Plottel, Eric V. Balti, Mathurin Cyrille Tejiokem, Sinata Koulla-Shiro
Pasteur Center of Cameroun, New York University Langone MC, Brussels Free University-VUB,
Conflict of Interest: None Declared
WHO guidelines recommend that all HIV-infected persons with newly diagnosed tuberculosis (TB) receive antiretroviral therapy (ART) within 8 weeks of starting anti-TB treatment and within the first 2 weeks if the CD4+ T-cell (CD4) count is < 500 cells/µL (1). Early (2-4 weeks) ART initiation in HIV-infected adults with newly diagnosed TB and CD4+ < 50 cells/µL improves survival as compared to delayed ART initiation (8-12 weeks) (REF). In TB-HIV co-infected patients with CD4+ > 50 cells/µL however, current evidence is insufficient to support or refute a survival benefit conferred by early versus delayed/deferred ART initiation.

Given Uthman and colleagues’ findings (2), we conclude that in patients with TB-HIV and CD4+ counts between 50-500 cells/µL, for whom there is no evidence of an overall survival benefit from prescribing ART before 8-12 weeks, clinicians should be vigilant for the development of TB-immune reconstitution inflammatory syndrome (IRIS) when initiating ART within 1-4 weeks of prescribing anti-TB medications. For those with CD4+ counts < 50 cells/µL, early ART initiation is indicated, despite the risk of IRIS, given the overall survival benefit. As the risk of IRIS doubles with early ART initiation, we advocate that the potential for IRIS should serve as an important guide in selecting the optimal time of ART initiation, especially when CD4+ counts are between 50-500 cells/µL. We believe that ART initiation should be delayed/deferred beyond 4 weeks when CD4+ are between 50-500 cells/µL. Additionally, other factors including non-adherence to multiple antiretroviral and anti-TB drugs, adverse drug–drug interactions, and enhanced drug toxicities complicate the early simultaneous prescription of ART and anti-TB medications. All justify moving ART initiation further away from the first month (or two) of anti-TB treatment.

Given our understanding of the course of HIV infection, updated considerations favoring early initiation of ART in asymptomatic persons with HIV, and measures decreasing risks of developing active TB in all those with HIV infection (3, 4), what is the optimal timing of initiating ART in TB patients when HIV co-infection is discovered? The epidemiology and distribution of clinical TB disease in HIV-infected patients in the coming years will likely reflect decreasing TB incidence in those treated with ART earlier in the course of their immunosuppression. Nonetheless, more research is needed to clarify what is the safest and most efficacious window of opportunity for starting ART in co-infected TB-HIV patients with higher CD4+ counts.


References
1. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach: World Health Organization; 2013.
2. Uthman OA, Okwundu C, Gbenga K, Volmink J, Dowdy D, Zumla A, et al. Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis: A Systematic Review and Meta-analysis. Ann Intern Med. 2015;163(1):32-9.
3. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. N Engl J Med. 2015.
4. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015.

Jean Joel R. Bigna1*
Claudia S. Plottel2
Eric V. Balti3
Mathurin Cyrille Tejiokem1
Sinata Koulla-Shiro4, 5

1. Department of Epidemiology and Public Health, Pasteur Center of Cameroun, Yaoundé, Cameroon, Member International Network of the Pasteur Institutes
2. Department of Medicine, New York University Langone Medical Center, New York, New York, United States of America
3. Faculty of Medicine and Pharmacy, Brussels Free University-VUB, Brussels, Belgium
4. Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon
5. Infectious Diseases Unit, Yaoundé Central Hospital, Yaoundé, Cameroon

A question of significance
Posted on September 16, 2015
Dimitri M Drekonja, Nicholas Yared
Minneapolis Veterans Affairs Healthcare System (Dr. Drekonja), University of Minnesota Medical School (Drs. Drekonja and Yared)
Conflict of Interest: None Declared
We read with interest the systematic review and meta-analysis by Uthman et al. assessing the optimal timing of antiretroviral therapy (ART) for HIV infected adults with pulmonary tuberculosis (1). The results show that early ART reduces mortality compared to delayed ART, with a relative risk of 0.81 (95% confidence interval, 0.66 to 0.99). This is clearly stated in the abstract and the results section of the paper.

However, the authors make a confusing statement in the first paragraph of the discussion, where they state the main findings of their study. They write “Across all CD4+ T-cell count strata, patients commencing ART within 1 to 4 weeks versus 8 to 12 weeks after starting TB treatment had lower all-cause mortality, although this effect was not statistically significant.” We are puzzled by why it is stated that the results are not statistically significant, given that the 95% confidence interval of the relative risk is entirely below 1.0, with a P value for overall effect of 0.04. Is this statement an error that was retained from a prior draft, or some other typographical error? If so, it is unfortunately placed, since it occurs in the location many authors use to highlight the key finding of their work. If it is not an error, the authors need to explain why the main finding is not statistically significant.

1. Uthman OA, Okwundu C, Gbenga K, Volmink J, Dowdy D, Zumla A, et al. Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis: a systematic review and meta-analysis. Ann Intern Med. 2015;163:32-9. [PMID: 26148280] doi: 10.7326/M14-2979.
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