Effect of tuberculosis screening and retention interventions on early antiretroviral therapy mortality in Botswana: a stepped-wedge cluster randomized trial

Andrew F Auld, Tefera Agizew, Anikie Mathoma, Rosanna Boyd, Anand Date, Sherri L Pals, Christopher Serumola, Unami Mathebula, Heather Alexander, Tedd V Ellerbrock, Goabaone Rankgoane-Pono, Pontsho Pono, James C Shepherd, Katherine Fielding, Alison D Grant, Alyssa Finlay, Andrew F Auld, Tefera Agizew, Anikie Mathoma, Rosanna Boyd, Anand Date, Sherri L Pals, Christopher Serumola, Unami Mathebula, Heather Alexander, Tedd V Ellerbrock, Goabaone Rankgoane-Pono, Pontsho Pono, James C Shepherd, Katherine Fielding, Alison D Grant, Alyssa Finlay

Abstract

Background: Undiagnosed tuberculosis (TB) remains the most common cause of HIV-related mortality. Xpert MTB/RIF (Xpert) is being rolled out globally to improve TB diagnostic capacity. However, previous Xpert impact trials have reported that health system weaknesses blunted impact of this improved diagnostic tool. During phased Xpert rollout in Botswana, we evaluated the impact of a package of interventions comprising (1) additional support for intensified TB case finding (ICF), (2) active tracing for patients missing clinic appointments to support retention, and (3) Xpert replacing sputum-smear microscopy, on early (6-month) antiretroviral therapy (ART) mortality.

Methods: At 22 clinics, ART enrollees > 12 years old were eligible for inclusion in three phases: a retrospective standard of care (SOC), prospective enhanced care (EC), and prospective EC plus Xpert (EC+X) phase. EC and EC+X phases were implemented as a stepped-wedge trial. Participants in the EC phase received SOC plus components 1 (strengthened ICF) and 2 (active tracing) of the intervention package, and participants in the EC+X phase received SOC plus all three intervention package components. Primary and secondary objectives were to compare all-cause 6-month ART mortality between SOC and EC+X and between EC and EC+X phases, respectively. We used adjusted analyses, appropriate for study design, to control for baseline differences in individual-level factors and intra-facility correlation.

Results: We enrolled 14,963 eligible patients: 8980 in SOC, 1768 in EC, and 4215 in EC+X phases. Median age of ART enrollees was 35 and 64% were female. Median CD4 cell count was lower in SOC than subsequent phases (184/μL in SOC, 246/μL in EC, and 241/μL in EC+X). By 6 months of ART, 461 (5.3%) of SOC, 54 (3.2%) of EC, and 121 (3.0%) of EC+X enrollees had died. Compared with SOC, 6-month mortality was lower in the EC+X phase (adjusted hazard ratio, 0.77; 95% confidence interval, 0.61-0.97, p = 0.029). Compared with EC enrollees, 6-month mortality was similar among EC+X enrollees.

Conclusions: Interventions to strengthen ICF and retention were associated with lower early ART mortality. This new evidence highlights the need to strengthen ICF and retention in many similar settings. Similar to other trials, no additional mortality benefit of replacing sputum-smear microscopy with Xpert was observed.

Trial registration: Retrospectively registered: ClinicalTrials.gov (NCT02538952).

Keywords: Intensified tuberculosis case finding; Mortality; Tuberculosis; Xpert MTB/RIF.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study design for the Xpert Package Rollout Evaluation using a Stepped-wedge design (XPRES). Abbreviations: SOC, standard of care phase; EC, enhanced care phase; EC+X, enhanced care plus Xpert phase
Fig. 2
Fig. 2
Trial profile
Fig. 3
Fig. 3
Kaplan-Meier curves showing cumulative 6-month mortality among ART enrollees in SOC, EC, and EC+X phases
Fig. 4
Fig. 4
Intensified TB case finding (ICF) cascade among ART enrollees in SOC, EC, and EC+X phases. Abbreviations: SOC, standard of care phase, EC, enhanced care phase, EC+X, enhanced care plus Xpert phase

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. Gupta A, Nadkarni G, Yang WT, Chandrasekhar A, Gupte N, Bisson GP, et al. Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and meta-analysis. PLoS One. 2011;6(12):e28691. doi: 10.1371/journal.pone.0028691.
    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):817–824. doi: 10.1016/S0140-6736(06)68337-2.
    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):e47542. doi: 10.1371/journal.pone.0047542.
    1. World Health Organisation. Rapid Implementation of the Xpert MTB/RIF diagnostic test. . Accessed 10 Aug 2019.
    1. Auld AF, Agizew T, Pals S, Finlay A, Ndwapi N, Boyd R, et al. 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. BMC Infect Dis. 2016;16(1):606. doi: 10.1186/s12879-016-1905-4.
    1. Date A, Modi S. TB screening among people living with HIV/AIDS in resource-limited settings. J Acquir Immune Defic Syndr. 2015;68(Suppl 3):S270–S273. doi: 10.1097/QAI.0000000000000485.
    1. Auld AF, Fielding KL, Gupta-Wright A, Lawn SD. Xpert MTB/RIF - why the lack of morbidity and mortality impact in intervention trials? Trans R Soc Trop Med Hyg. 2016;110(8):432–444. doi: 10.1093/trstmh/trw056.
    1. Albert H, Nathavitharana RR, Isaacs C, Pai M, Denkinger CM, Boehme CC. Development, roll-out and impact of Xpert MTB/RIF for tuberculosis: what lessons have we learnt and how can we do better? Eur Respir J. 2016;48(2):516–525. doi: 10.1183/13993003.00543-2016.
    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–e457. doi: 10.1016/S2214-109X(15)00100-X.
    1. Dryden-Peterson S, Lockman S, Zash R, Lei Q, Chen JY, Souda S, et al. Initial programmatic implementation of WHO option B in Botswana associated with increased projected MTCT. J Acquir Immune Defic Syndr. 2015;68(3):245–249. doi: 10.1097/QAI.0000000000000482.
    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):e1000391. doi: 10.1371/journal.pmed.1000391.
    1. Brinkhof MW, Pujades-Rodriguez M, Egger M. Mortality of patients lost to follow-up in antiretroviral treatment programmes in resource-limited settings: systematic review and meta-analysis. PLoS One. 2009;4(6):e5790. doi: 10.1371/journal.pone.0005790.
    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):190–199. doi: 10.1177/1740774507076937.
    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):e1725. doi: 10.1371/journal.pone.0001725.
    1. May M, Boulle A, Phiri S, Messou E, Myer L, Wood R, et al. Prognosis of patients with HIV-1 infection starting antiretroviral therapy in sub-Saharan Africa: a collaborative analysis of scale-up programmes. Lancet. 2010;376(9739):449–457. doi: 10.1016/S0140-6736(10)60666-6.
    1. Farahani M, Price N, El-Halabi S, Mlaudzi N, Keapoletswe K, Lebelonyane R, et al. Trends and determinants of survival for over 200 000 patients on antiretroviral treatment in the Botswana National Program: 2002-2013. AIDS. 2016;30(3):477–485.
    1. Hemming K, Haines TP, Chilton PJ, Girling AJ, Lilford RJ. The stepped wedge cluster randomised trial: rationale, design, analysis, and reporting. BMJ. 2015;350:h391. doi: 10.1136/bmj.h391.
    1. Johnson LF, Mossong J, Dorrington RE, Schomaker M, Hoffmann CJ, Keiser O, et al. Life expectancies of South African adults starting antiretroviral treatment: collaborative analysis of cohort studies. PLoS Med. 2013;10(4):e1001418. doi: 10.1371/journal.pmed.1001418.
    1. World Health Organisation. Guidelines for Intensified Tuberculosis Case-Finding and Isoniazid Preventive Therapy for People Living with HIV in Resource Constrained Settings. Available at: . Accessed 10 Aug 2019.
    1. Ngwira LG, Corbett EL, Khundi M, Barnes GL, Nkhoma A, Murowa M, et al. Screening for tuberculosis with Xpert MTB/RIF versus fluorescent microscopy among adults newly diagnosed with HIV in rural Malawi: a cluster randomized trial (CHEPETSA) Clin Infect Dis. 2018;68(7):1176–1183. doi: 10.1093/cid/ciy590.
    1. Auld AF, Blain M, Ekra KA, Kouakou JS, Ettiegne-Traore V, Tuho MZ, et al. Wide variations in compliance with tuberculosis screening guidelines and tuberculosis incidence between antiretroviral therapy facilities - Cote d’Ivoire. PLoS One. 2016;11(6):e0157059. doi: 10.1371/journal.pone.0157059.
    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):e0138149. doi: 10.1371/journal.pone.0138149.
    1. Hamada Y, Lujan J, Schenkel K, Ford N, Getahun H. Sensitivity and specificity of WHO's recommended four-symptom screening rule for tuberculosis in people living with HIV: a systematic review and meta-analysis. Lancet HIV. 2018;5(9):e515–e523. doi: 10.1016/S2352-3018(18)30137-1.
    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):e54665. doi: 10.1371/journal.pone.0054665.
    1. Ndwiga C, Birungi H, Undie CC, Weyenga H, Sitienei J. Feasibility and effect of integrating tuberculosis screening and detection in postnatal care services: an operations research study. BMC Health Serv Res. 2013;13:99. doi: 10.1186/1472-6963-13-99.
    1. Christian Carmen, Gerdtham Ulf-G., Hompashe Dumisani, Smith Anja, Burger Ronelle. Measuring Quality Gaps in TB Screening in South Africa Using Standardised Patient Analysis. International Journal of Environmental Research and Public Health. 2018;15(4):729. doi: 10.3390/ijerph15040729.
    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):424–435. doi: 10.1016/S0140-6736(13)62073-5.
    1. Lawn SD, Nicol MP, Corbett EL. Effect of empirical treatment on outcomes of clinical trials of diagnostic assays for tuberculosis. Lancet Infect Dis. 2015;15(1):17–18. doi: 10.1016/S1473-3099(14)71049-7.
    1. Agizew T, Nyirenda S, Mathoma A, Mathebula U, Date A, Kgwaadira B, et al. Comparison of pre- and post-Xpert tuberculosis treatment outcomes among people living with HIV in Botswana. (Abstract # PC-1124-06). 46th World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease. Cape Town, 2–6 December 2015. Available at: . Accessed 30 Nov 2019.
    1. Di Tanna GL, Khaki AR, Theron G, McCarthy K, Cox H, Mupfumi L, et al. Effect of Xpert MTB/RIF on clinical outcomes in routine care settings: individual patient data meta-analysis. Lancet Glob Health. 2019;7(2):e191–e199. doi: 10.1016/S2214-109X(18)30458-3.
    1. Haas Andreas D, Zaniewski Elizabeth, Anderegg Nanina, Ford Nathan, Fox Matthew P, Vinikoor Michael, Dabis François, Nash Denis, Sinayobye Jean d'Amour, Niyongabo Thêodore, Tanon Aristophane, Poda Armel, Adedimeji Adebola A, Edmonds Andrew, Davies Mary-Ann, Egger Matthias. Retention and mortality on antiretroviral therapy in sub-Saharan Africa: collaborative analyses of HIV treatment programmes. Journal of the International AIDS Society. 2018;21(2):e25084. doi: 10.1002/jia2.25084.
    1. Holmes CB, Sikazwe I, Sikombe K, Eshun-Wilson I, Czaicki N, Beres LK, et al. Estimated mortality on HIV treatment among active patients and patients lost to follow-up in 4 provinces of Zambia: findings from a multistage sampling-based survey. PLoS Med. 2018;15(1):e1002489. doi: 10.1371/journal.pmed.1002489.
    1. Mfinanga S, Chanda D, Kivuyo SL, Guinness L, Bottomley C, Simms V, et al. Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet. 2015;385(9983):2173–2182. doi: 10.1016/S0140-6736(15)60164-7.
    1. World Health Organisation. Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy. In: Guidelines for Managing Advanced HIV Disease and Rapid Initiation of Antiretroviral Therapy. edn. Geneva; 2017.
    1. Auld AF, Shiraishi RW, Oboho I, Ross C, Bateganya M, Pelletier V, et al. Trends in prevalence of advanced HIV disease at antiretroviral therapy enrollment - 10 countries, 2004-2015. MMWR Morb Mortal Wkly Rep. 2017;66(21):558–563. doi: 10.15585/mmwr.mm6621a3.
    1. NIH. Key Dates & Policy Notices - Clinical Research/Trial Policies & Effective Dates. Available at: . Accessed 10 Aug 2019.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner