Implementation of a pragmatic, stepped-wedge cluster randomized trial to evaluate impact of Botswana's Xpert MTB/RIF diagnostic algorithm on TB diagnostic sensitivity and early antiretroviral therapy mortality

Andrew F Auld, Tefera Agizew, Sherri Pals, Alyssa Finlay, Ndwapi Ndwapi, Rosanna Boyd, Heather Alexander, Anikie Mathoma, Joyce Basotli, Sambayawo Gwebe-Nyirenda, James Shepherd, Tedd V Ellerbrock, Anand Date, Andrew F Auld, Tefera Agizew, Sherri Pals, Alyssa Finlay, Ndwapi Ndwapi, Rosanna Boyd, Heather Alexander, Anikie Mathoma, Joyce Basotli, Sambayawo Gwebe-Nyirenda, James Shepherd, Tedd V Ellerbrock, Anand Date

Abstract

Background: In 2012, as a pilot for Botswana's national Xpert MTB/RIF (Xpert) rollout plans, intensified tuberculosis (TB) case finding (ICF) activities were strengthened at 22 HIV treatment clinics prior to phased activation of 13 Xpert instruments. Together, the strengthened ICF intervention and Xpert activation are referred to as the "Xpert package".

Methods: The evaluation, called the Xpert Package Rollout Evaluation using a Stepped-wedge design (XPRES), has two key objectives: (1) to compare sensitivity of microscopy-based and Xpert-based pulmonary TB diagnostic algorithms in diagnosing sputum culture-positive TB; and (2) to evaluate impact of the "Xpert package" on all-cause, 6-month, adult antiretroviral therapy (ART) mortality. A pragmatic, stepped-wedge cluster-randomized trial design was chosen. The design involves enrollment of three cohorts: (1) cohort R, a retrospective cohort of all study clinic ART enrollees in the 24 months before study initiation (July 31, 2012); (2) cohort A, a prospective cohort of all consenting patients presenting to study clinics after study initiation, who received the ICF intervention and the microscopy-based TB diagnostic algorithm; and (3) cohort B, a prospective cohort of all consenting patients presenting to study clinics after Xpert activation, who received the ICF intervention and the Xpert-based TB diagnostic algorithm. TB diagnostic sensitivity will be compared between TB culture-positive enrollees in cohorts A and B. All-cause, 6-month ART-mortality will be compared between cohorts R and B. With anticipated cohort R, A, and B sample sizes of about 10,131, 1,878, and 4,258, respectively, the study is estimated to have >80 % power to detect differences in pre-versus post-Xpert TB diagnostic sensitivity if pre-Xpert sensitivity is ≤52.5 % and post-Xpert sensitivity ≥82.5 %, and >80 % power to detect a 40 % reduction in all-cause, 6-month, ART mortality between cohorts R and B if cohort R mortality is ≥13/100 person-years.

Discussion: Only one small previous trial (N = 424) among ART enrolees in Zimbabwe evaluated, in a secondary analysis, Xpert impact on all-cause 6-month ART mortality. No mortality impact was observed. This Botswana trial, with its larger sample size and powered specifically to detect differences in all-cause 6-month ART mortality, remains well-positioned to contribute understanding of Xpert impact.

Trial registration: Retrospectively registered at ClinicalTrials.gov: NCT02538952 .

Keywords: Antiretroviral therapy; Botswana; Diagnostic accuracy; Mortality; People living with HIV; Sensitivity; Stepped-wedge cluster randomized trial; Xpert MTB/RIF.

Figures

Fig. 1
Fig. 1
Study design for the Xpert package rollout evaluation using a stepped wedge design (XPRES)
Fig. 2
Fig. 2
Comparison of pre-X pert and Xpert-based TB diagnostic algorithms in adults
Fig. 3
Fig. 3
Figure showing power to detect a difference in TB diagnostic algorithm sensitivity pre- versus post-Xpert over a range of culture-positive TB prevalence rates at study enrollment according to actual prospective cohort sample size (N = 6,136)
Fig. 4
Fig. 4
Power to detect a 40 % and 50 % difference in all-cause 6-month ART mortality between pre-Xpert retrospective and post-Xpert prospective cohort enrollees over a range of pre-Xpert mortality rates

References

    1. Gupta RK, Lucas SB, Fielding KL, Lawn SD. Prevalence of tuberculosis in post-mortem studies of HIV-infected adults and children in resource-limited settings: a systematic review and meta-analysis. AIDS. 2015;29(15):1987–2002. doi: 10.1097/QAD.0000000000000802.
    1. Cox JA, Lukande RL, Lucas S, Nelson AM, Van Marck E, Colebunders R. Autopsy causes of death in HIV-positive individuals in sub-Saharan Africa and correlation with clinical diagnoses. AIDS Rev. 2010;12(4):183–94.
    1. Lawn SD, Harries AD, Anglaret X, Myer L, Wood R. Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS. 2008;22(15):1897–908. doi: 10.1097/QAD.0b013e32830007cd.
    1. Wong EB, Omar T, Setlhako GJ, Osih R, Feldman C, Murdoch DM, et al. Causes of death on antiretroviral therapy: a post-mortem study from South Africa. PLoS One. 2012;7(10) doi: 10.1371/journal.pone.0047542.
    1. Centers for Disease C, Prevention Differences Between HIV-Infected Men and Women in Antiretroviral Therapy Outcomes - Six African Countries, 2004–2012. MMWR Morb Mortal Wkly Rep. 2013;62(47):946–52.
    1. Lawn SD, Wilkinson RJ, Lipman MC, Wood R. Immune reconstitution and “unmasking” of tuberculosis during antiretroviral therapy. Am J Respir Crit Care Med. 2008;177(7):680–5. doi: 10.1164/rccm.200709-1311PP.
    1. Auld AF, Ekra KA, Shiraishi RW, Tuho MZ, Kouakou JS, Mohamed F, et al. Temporal trends in treatment outcomes for HIV-1 and HIV-2-infected adults enrolled in Cote d’Ivoire’s national antiretroviral therapy program. PLoS One. 2014;9(5) doi: 10.1371/journal.pone.0098183.
    1. Auld AF, Tuho MZ, Ekra KA, Shiraishi RW, Mohamed F, Kouakou JS, et al. Temporal Trends in Mortality and Loss to Follow-up Among Children Enrolled in Cote d’Ivoire’s National Antiretroviral Therapy Program. Pediatr Infect Dis J. 2014;33(11):1134–40. doi: 10.1097/INF.0000000000000457.
    1. Auld AF, Mbofana F, Shiraishi RW, Alfredo C, Sanchez M, Ellerbrock TV, et al. Incidence and determinants of tuberculosis among adults initiating antiretroviral therapy—Mozambique, 2004–2008. PLoS One. 2013;8(1) doi: 10.1371/journal.pone.0054665.
    1. Chihota VN, Ginindza S, McCarthy K, Grant AD, Churchyard G, Fielding K. Missed Opportunities for TB Investigation in Primary Care Clinics in South Africa: Experience from the XTEND Trial. PLoS One. 2015;10(9) doi: 10.1371/journal.pone.0138149.
    1. Parsons LM, Somoskovi A, Gutierrez C, Lee E, Paramasivan CN, Abimiku A, et al. Laboratory diagnosis of tuberculosis in resource-poor countries: challenges and opportunities. Clin Microbiol Rev. 2011;24(2):314–50. doi: 10.1128/CMR.00059-10.
    1. Boehme CC, Nicol MP, Nabeta P, Michael JS, Gotuzzo E, Tahirli R, et al. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet. 2011;377(9776):1495–505. doi: 10.1016/S0140-6736(11)60438-8.
    1. Dheda K, Gumbo T, Gandhi NR, Murray M, Theron G, Udwadia Z, et al. Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis. Lancet Respir Med. 2014;2(4):321–38. doi: 10.1016/S2213-2600(14)70031-1.
    1. Small PM, Pai M. Tuberculosis diagnosis—time for a game change. N Engl J Med. 2010;363(11):1070–1. doi: 10.1056/NEJMe1008496.
    1. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N. Xpert(R) MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev. 2014;1
    1. Lawn SD, Meintjes G, McIlleron H, Harries AD, Wood R. Management of HIV-associated tuberculosis in resource-limited settings: a state-of-the-art review. BMC Med. 2013;11:253. doi: 10.1186/1741-7015-11-253.
    1. Churchyard GJ, Stevens WS, Mametja LD, McCarthy KM, Chihota V, Nicol MP, et al. Xpert MTB/RIF versus sputum microscopy as the initial diagnostic test for tuberculosis: a cluster-randomised trial embedded in South African roll-out of Xpert MTB/RIF. Lancet Glob Health. 2015;3(8):e450–7. doi: 10.1016/S2214-109X(15)00100-X.
    1. Lawn SD, Mwaba P, Bates M, Piatek A, Alexander H, Marais BJ, et al. Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect Dis. 2013;13(4):349–61. doi: 10.1016/S1473-3099(13)70008-2.
    1. Sanson-Fisher RW, D’Este CA, Carey ML, Noble N, Paul CL. Evaluation of systems-oriented public health interventions: alternative research designs. Annu Rev Public Health. 2014;35:9–27. doi: 10.1146/annurev-publhealth-032013-182445.
    1. Lawn SD, Harries AD. Reducing tuberculosis-associated early mortality in antiretroviral treatment programmes in sub-Saharan Africa. AIDS. 2011;25(12):1554–5. doi: 10.1097/QAD.0b013e328348fb61.
    1. Mupfumi L, Makamure B, Chirehwa M, Sagonda T, Zinyowera S, Mason P, et al. Impact of Xpert MTB/RIF on Antiretroviral Therapy-Associated Tuberculosis and Mortality: A Pragmatic Randomized Controlled Trial. Open Forum Infect Dis. 2014;1(1):ofu038. doi: 10.1093/ofid/ofu038.
    1. World Health Organization. Rapid Implementation of the Xpert MTB/RIF diagnostic test: 2011. Available at: . Accessed 18 Aug 2015.
    1. Ministry of Health, Republic of Botswana. National Tuberculosis Programme Manual. Seventh Edition. 2011.
    1. Mdege ND, Man MS, Taylor Nee Brown CA, Torgerson DJ. Systematic review of stepped wedge cluster randomized trials shows that design is particularly used to evaluate interventions during routine implementation. J Clin Epidemiol. 2011;64(9):936–48. doi: 10.1016/j.jclinepi.2010.12.003.
    1. Maclure M. Explaining pragmatic trials to pragmatic policy-makers. CMAJ. 2009;180(10):1001–3. doi: 10.1503/cmaj.090076.
    1. Moulton LH, Golub JE, Durovni B, Cavalcante SC, Pacheco AG, Saraceni V, et al. Statistical design of THRio: a phased implementation clinic-randomized study of a tuberculosis preventive therapy intervention. Clin Trials. 2007;4(2):190–9. doi: 10.1177/1740774507076937.
    1. Hussey MA, Hughes JP. Design and analysis of stepped wedge cluster randomized trials. Contemp Clin Trials. 2007;28(2):182–91. doi: 10.1016/j.cct.2006.05.007.
    1. Hayes R, Moulton LH. Cluster Randomized Trials. Boca Raton: CRC Press; 2009.
    1. Getahun H, Kittikraisak W, Heilig CM, Corbett EL, Ayles H, Cain KP, et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies. PLoS Med. 2011;8(1) doi: 10.1371/journal.pmed.1000391.
    1. Lawn SD, Brooks SV, Kranzer K, Nicol MP, Whitelaw A, Vogt M, et al. Screening for HIV-Associated Tuberculosis and Rifampicin Resistance before Antiretroviral Therapy Using the Xpert MTB/RIF Assay: A Prospective Study. PLoS Med. 2011;8(7) doi: 10.1371/journal.pmed.1001067.
    1. Bassett IV, Wang B, Chetty S, Giddy J, Losina E, Mazibuko M, et al. Intensive tuberculosis screening for HIV-infected patients starting antiretroviral therapy in Durban, South Africa. Clin Infect Dis. 2010;51(7):823–9. doi: 10.1086/656282.
    1. Lawn SD, Edwards DJ, Kranzer K, Vogt M, Bekker LG, Wood R. Urine lipoarabinomannan assay for tuberculosis screening before antiretroviral therapy diagnostic yield and association with immune reconstitution disease. AIDS. 2009;23(14):1875–80. doi: 10.1097/QAD.0b013e32832e05c8.
    1. Lawn SD, Kranzer K, Edwards DJ, McNally M, Bekker LG, Wood R. Tuberculosis during the first year of antiretroviral therapy in a South African cohort using an intensive pretreatment screening strategy. AIDS. 2010;24(9):1323–8.
    1. Shah S, Demissie M, Lambert L, Ahmed J, Leulseged S, Kebede T, et al. Intensified tuberculosis case finding among HIV-Infected persons from a voluntary counseling and testing center in Addis Ababa, Ethiopia. J Acquir Immune Defic Syndr. 2009;50(5):537–45. doi: 10.1097/QAI.0b013e318196761c.
    1. Cain KP, McCarthy KD, Heilig CM, Monkongdee P, Tasaneeyapan T, Kanara N, et al. An algorithm for tuberculosis screening and diagnosis in people with HIV. N Engl J Med. 2010;362(8):707–16. doi: 10.1056/NEJMoa0907488.
    1. World Health Organization. African Health Observatory: Better information, better action for health. Available at: . Accessed 18 Aug 2015.
    1. Ministry of Health, Ethiopia. Incidence of Tuberculosis in Ethiopia. Available at: . Accessed 18 Aug 2015.
    1. World Health Organization. Global Tuberculosis Report-2014. Available at: . Accessed 18 Aug 2015.
    1. Hayes RJ, Bennett S. Simple sample size calculation for cluster-randomized trials. Int J Epidemiol. 1999;28(2):319–26. doi: 10.1093/ije/28.2.319.
    1. Bisson GP, Gaolathe T, Gross R, Rollins C, Bellamy S, Mogorosi M, et al. Overestimates of survival after HAART: implications for global scale-up efforts. PLoS One. 2008;3(3) doi: 10.1371/journal.pone.0001725.
    1. Braitstein P, Brinkhof MW, Dabis F, Schechter M, Boulle A, Miotti P, et al. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Lancet. 2006;367(9513):817–24. doi: 10.1016/S0140-6736(06)68337-2.
    1. Brinkhof MW, Dabis F, Myer L, Bangsberg DR, Boulle A, Nash D, et al. Early loss of HIV-infected patients on potent antiretroviral therapy programmes in lower-income countries. Bull World Health Organ. 2008;86(7):559–67. doi: 10.2471/BLT.07.044248.
    1. Cornell M, Lessells R, Fox MP, Garone DB, Giddy J, Fenner L, et al. Mortality among adults transferred and lost to follow-up from antiretroviral therapy programmes in South Africa: a multicenter cohort study. J Acquir Immune Defic Syndr. 2014;67(2):e67–75. doi: 10.1097/QAI.0000000000000269.
    1. Ansari NA, Kombe AH, Kenyon TA, Hone NM, Tappero JW, Nyirenda ST, et al. Pathology and causes of death in a group of 128 predominantly HIV-positive patients in Botswana, 1997–1998. Int J Tuberc Lung Dis. 2002;6(1):55–63.
    1. Auld AF, Mbofana F, Shiraishi RW, Sanchez M, Alfredo C, Nelson LJ, et al. Four-Year Treatment Outcomes of Adult Patients Enrolled in Mozambique’s Rapidly Expanding Antiretroviral Therapy Program. PLoS One. 2011;6(4) doi: 10.1371/journal.pone.0018453.
    1. Geng EH, Glidden DV, Bangsberg DR, Bwana MB, Musinguzi N, Nash D, et al. A causal framework for understanding the effect of losses to follow-up on epidemiologic analyses in clinic-based cohorts: the case of HIV-infected patients on antiretroviral therapy in Africa. Am J Epidemiol. 2012;175(10):1080–7. doi: 10.1093/aje/kwr444.
    1. Seaman SR, White IR. Review of inverse probability weighting for dealing with missing data. Stat Methods Med Res. 2013;22(3):278–95. doi: 10.1177/0962280210395740.
    1. Lucas RM, McMichael AJ. Association or causation: evaluating links between “environment and disease”. Bull World Health Organ. 2005;83(10):792–5.
    1. Farahani M, Vable A, Lebelonyane R, Seipone K, Anderson M, Avalos A, et al. Outcomes of the Botswana national HIV/AIDS treatment programme from 2002 to 2010: a longitudinal analysis. Lancet Glob Health. 2014;2(1):e44–50. doi: 10.1016/S2214-109X(13)70149-9.
    1. Auld AF, Shiraishi R, Couto A, Mbofana F, Xavier C, Alfredo C, et al. Evaluation of outcome trends and determinants and new models of service delivery among more than 300,000 adults starting antiretroviral therapy in Mozambique during 2004–2013. JAIDS. 2016;(in press).
    1. Durovni B, Saraceni V, Moulton LH, Pacheco AG, Cavalcante SC, King BS, et al. Effect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: a stepped wedge, cluster-randomised trial. Lancet Infect Dis. 2013;13(10):852–8. doi: 10.1016/S1473-3099(13)70187-7.
    1. UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2013. Available at: . Accessed 14 Dec 2015.
    1. Lawn SD, Harries AD, Williams BG, Chaisson RE, Losina E, De Cock KM, et al. Antiretroviral therapy and the control of HIV-associated tuberculosis. Will ART do it? Int J Tuberc Lung Dis. 2011;15(5):571–81. doi: 10.5588/ijtld.10.0483.
    1. Yoon C, Cattamanchi A, Davis JL, Worodria W, den Boon S, Kalema N, et al. Impact of Xpert MTB/RIF testing on tuberculosis management and outcomes in hospitalized patients in Uganda. PLoS One. 2012;7(11) doi: 10.1371/journal.pone.0048599.
    1. Theron G, Zijenah L, Chanda D, Clowes P, Rachow A, Lesosky M, et al. Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. Lancet. 2014;383(9915):424–35. doi: 10.1016/S0140-6736(13)62073-5.
    1. Cox HS, Mbhele S, Mohess N, Whitelaw A, Muller O, Zemanay W, et al. Impact of Xpert MTB/RIF for TB diagnosis in a primary care clinic with high TB and HIV prevalence in South Africa: a pragmatic randomised trial. PLoS Med. 2014;11(11) doi: 10.1371/journal.pmed.1001760.
    1. Calligaro GL, Theron G, Khalfey H, Peter J, Meldau R, Matinyenya B, et al. Burden of tuberculosis in intensive care units in Cape Town, South Africa, and assessment of the accuracy and effect on patient outcomes of the Xpert MTB/RIF test on tracheal aspirate samples for diagnosis of pulmonary tuberculosis: a prospective burden of disease study with a nested randomised controlled trial. Lancet Respir Med. 2015;3(8):621–30. doi: 10.1016/S2213-2600(15)00198-8.
    1. Durovni B, Saraceni V, van den Hof S, Trajman A, Cordeiro-Santos M, Cavalcante S, et al. Impact of replacing smear microscopy with Xpert MTB/RIF for diagnosing tuberculosis in Brazil: a stepped-wedge cluster-randomized trial. PLoS Med. 2014;11(12) doi: 10.1371/journal.pmed.1001766.
    1. van Kampen SC, Susanto NH, Simon S, Astiti SD, Chandra R, Burhan E, et al. Effects of Introducing Xpert MTB/RIF on Diagnosis and Treatment of Drug-Resistant Tuberculosis Patients in Indonesia: A Pre-Post Intervention Study. PLoS One. 2015;10(6) doi: 10.1371/journal.pone.0123536.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren