Protocol. Investigators. Marriott Nliwasa. Ankur Gupta-Wright. Peter MacPherson. Liz Corbett. Katherine Hurton. April 2015

Transcription

1 The Prevalence of HIV and Subsequent Risk of Early Mortality in Adults with Cough Presenting for TB Diagnosis in Low- and Middle- Income Countries: A Systematic Literature Review Protocol Investigators Marriott Nliwasa Ankur Gupta-Wright Peter MacPherson Liz Corbett Katherine Hurton April 2015 Mortality in TB Protocol v1.2 Page 1 of 17 Last updated 10/04/15 by MN

2 Table of Contents 1 Introduction Objective Methods Protocol and registration Eligibility criteria Information sources Search strategy Study selection Data collection process Data items Assessment of methodological quality Summary measures Planned methods of analysis Results Presentation of Results of Study Selection Results of individual studies Dissemination of Results Review Team: Affiliation, Source of Funding and Conflict of Interest Project Administration and Timelines Ethics statement References Tables and Figures Mortality in TB Protocol v1.2 Page 2 of 17 Last updated 10/04/15 by MN

3 1 Introduction Cough and other symptoms including fever, weight loss, night sweats, haemoptysis are used to define people with suspected tuberculosis (TB). 1, 2 Cough is an easily recognised symptom and is commonly the symptom that prompts people to seek care for TB. In addition, cough is an important symptom to with regard to TB transmission in congregate settings. Cough is associated with high prevalence of HIV in TB surveys in sub-saharan Africa. The prevalence of HIV is in adults with cough at community level is as high as 32% and 46%. 2, 3 Adults with cough and other symptoms of TB in high HIV prevalence settings also have a high risk of death by 2 months. This risk of death is variable and dependent on the level of care. The risk of death by two months in adults with suspected TB is <1% to 6% in primary care settings 4, 5, 4% to 7% in antiretroviral therapy cohorts 6, 7 and 13% to 30% among HIV positive hospital inpatients. 8, 9 The prevalence of HIV in adults with cough in low- and middle- income countries (LMICs) and subsequent risk of death have not been systematically investigated. Adults with cough who present for TB diagnosis and are subsequently linked to care can be considered lives saved. When TB is not confirmed in adults with cough a variety of underlying conditions may be responsible for the cough; definitive diagnosis for such conditions is not usually available in programmes of systematic screening of TB. Non-HIV related lung diseases for example asthma, chronic obstructive pulmonary disease also cause cough but they tend to have prolonged course and the immediate risk of death is not high. However, other HIV related lung diseases including pneumonia and pneumocystis jiroveci pnemonia carry a high risk of death in the short-term. Furthermore, with advancing HIV disease, a host of severe diseases and worsening health status puts people at an even higher risk of death. ART is expected to reverse this high risk of death in HIV positive adults with cough. The differences in these underlying factors can be understood by stratifying people with suspected TB by HIV and investigating their risk of death. This review is the first to systematically investigate early mortality in adults with cough undergoing TB diagnosis and adds to the knowledge reported in reviews among TB patients 10 in general and also those with focus on HIV associated TB 11. This review aims to describe the burden of HIV in adults with suspected TB and the importance of HIV in influencing risk of early mortality. In the past decade there have been major improvements in TB prevention and care including introduction of more vigorous strategies of systematic screening for TB in communities, increasing availability of molecular tests for TB in resource constrained settings and increased availability of antiretroviral therapy (ART). Access to these services remains a challenge especially in low- and middle- income countries (LMICs) and impact of these strategies in improving survival of adults with suspected TB remains uncertain. Mortality in TB Protocol v1.2 Page 3 of 17 Last updated 10/04/15 by MN

4 2 Objective The objective is to investigate the prevalence of HIV and how HIV (including disease stage marked by CD4 cell count and ART status) influences risk of early mortality (up to 12 months) in adults with cough presenting for TB diagnosis at different levels of care in LMICs. 3 Methods 3.1 Protocol and registration This systematic review protocol will be submitted to the International Prospective Register of Systematic Reviews (PROSPERO). 3.2 Eligibility criteria Population The review focuses on adults ( 16 years) presenting with cough in different contexts including systematic screening for TB in the general population, in primary care clinics, specialised outpatient respiratory clinics, and hospitals. All potential participant populations will be included i.e. general patient population as well as specific high-risk groups e.g. prisoners, miners and other high risk occupation. Pregnant women will also be included. Children (age 15 years) will be excluded. We will exclude studies where the participant population is only that of extra-pulmonary TB or multidrug resistant TB. We will exclude studies of diagnosed TB patients. Exposure The exposure status is having current cough of any duration with or without other symptoms or signs suggestive of TB including fever, cough, weight loss, night sweats or haemoptysis. Outcomes The outcomes of interest are: o HIV prevalence HIV prevalence will be determined participants with cough in the included studies. HIV prevalence will be determined based on duration of cough depending on the reporting of the studies i.e. any duration or cough 2 weeks. o Risk of all-cause mortality Risk of all-cause mortality will be determined as a proportion of adults with cough and other symptoms of TB who die at intervals specified by the individual study i.e. 2 weeks, 4 weeks, 8 weeks, 12 weeks, 6 months or 12 months. Mortality in TB Protocol v1.2 Page 4 of 17 Last updated 10/04/15 by MN

5 Stratification The prevalence of HIV in adults with cough will be described for different levels of care; community, primary care, and hospital (outpatients and inpatients). The risk of death in people with cough will be assessed based on the following: by HIV status, CD 4 cell count level and ART status; and by level of health system at presentation. The following HIV status categories will be recognised; HIV positive, HIV negative, HIV status unknown. Where possible, the HIV positive participants will also be categorised by CD4 cell count level and duration on ART ( 6 months, > 6 months to 1 year, > 1year) We will compare mortality in adults with cough also based on level of the health system. Setting The review focuses on studies in low- and middle income countries as defined by the World Bank 12 or in any of the 22 countries with a high burden of TB as defined by the STOP TB department of the WHO 13. Type of studies The studies to be included will be studies involving people undergoing diagnosis of TB and where HIV testing is offered and clinical outcomes are reported. This will include crosssectional TB surveys, operational research on TB screening of health facility attenders, randomised controlled trials of TB screening strategies (mortality will be presented for each arm of the trial), studies of evaluation of TB diagnostic tests and studies of TB screening in HIV clinics. Different types of randomised controlled trials are expected. Cluster randomised trials of community interventions of systematic TB screening will usually have a cohort of people with suspected TB on whom outcomes are reported. 14, 15 Trials where participants are being randomised to particular TB diagnostic algorithms will usually report patient outcomes and will be included in the review. Studies have been conducted on new TB diagnostics tests that have become available for use since 2003; such studies usually have a cohort of TB patients on whom outcomes are reported. We expect to include studies of diagnostic evaluation of new tests including Xpert MTB/RIF and tests for detecting lipoarabinomannan in urine (Determine TB-LAM) 16. We will exclude community-level vital registration studies or other mortality surveys where individual-level data of HIV status are usually unavailable. Restriction by Time Language and Publication status The reporting time of the studies is 1 January 2003 to reflect time since the ART scale-up in We will include peer-reviewed articles and relevant grey literature published in English. Non- English languages will be excluded because the investigators are English-speaking and there are no resources for translation of other languages available for this review. Mortality in TB Protocol v1.2 Page 5 of 17 Last updated 10/04/15 by MN

6 A summary of the inclusion and exclusion criteria is presented in Table Information sources The following electronic databases will be searched on Ovid platform: MEDLINE, Embase and Global Health. We will also search for other systematic reviews on mortality in TB published since 1 January 2003 in the Cochrane database of systematic reviews. Reference lists from selected studies will be hand searched for relevant studies. Authors will be contacted where appropriate for input on any potential missing information. We will also ask experts in the field for addition of any obviously missing studies in the review. Abstracts of academic conferences from 1 January 2012 will be hand searched. The abstracts of the following conferences will be searched: the International Union against Tuberculosis and Lung Disease and International AIDS society (IAS). 3.4 Search strategy The following search concepts will be used: tuberculosis, symptoms, HIV, and mortality. Appropriate Boolean operators and truncation will be used on synonyms. We will use both medical subject and key word searches. Limits of the publication year of 2003 will be set in the search. Refer to Table 2 for an example of search strategy run in Ovid Medline. This search will be adapted for searching Embase and Global health. All search results from the three databases will be imported into EndNote X7 and duplicate citations will be removed. 3.5 Study selection Three reviewers MN, PM and AGW will independently screen abstracts of the studies retrieved from the literature search for relevance. MN will review all the abstracts while PM and AGW will review half of the abstracts each. The full text of relevant studies will be obtained and independently assessed by the three reviewers against the inclusion and exclusion criteria. Queries on study design and study quality will be discussed with a fourth reviewer, ELC. A final list of studies to be included in analysis will be arrived as consensus of all four reviewers. 3.6 Data collection process Data will be recorded in a data extraction form. The data will be independently extracted by three reviewers MN, PM and AGW. Disagreements will be resolved by discussion and by a fourth reviewer (ELC), where necessary. Data will be entered using Google Forms. 3.7 Data items The following general descriptive variables will be recorded: author; title; year of publication; year of study, country; population; study design and study setting (includes whether routine care, research or NGO), and level of care i.e. community, primary care, hospital outpatient/inpatient and HIV care clinic. We will also extract information on methodology of the studies including TB diagnostic procedures and methods of HIV testing. The description of methods of TB diagnosis will include screening criteria (i.e. symptoms and/or radiography), diagnostic tools (i.e Mortality in TB Protocol v1.2 Page 6 of 17 Last updated 10/04/15 by MN

7 microscopy, culture, molecular tests or other), and case definitions. The description of methods of HIV testing will include whether HIV testing was offered to all participants or participants diagnosed with TB only, provider of the test and whether ART was offered as part of the study. Procedures of follow-up and ascertainment of clinical outcomes will also be described. The group of participants followed up for clinical outcomes will also be described; whether it was all participants or participants with symptoms only. Information on the number of participants at each stage of the study will be extracted. We will extract the reported sample size, the number of participants screened for TB, the number of participants screened for HIV, the distribution of participants by HIV test results (i.e. positive, negative and unknown). We will also extract reported information on the initiations of ART and TB treatment in the studies. Information regarding mortality will be extracted from the included studies but will depend on the level of disaggregation of data in the included studies. Where available, information will be extracted to an individual-level categorised by HIV status. We will report vital status by HIV status (positive, negative and unknown) and the respective follow-up times. 3.8 Assessment of methodological quality There are many potential sources of bias in studies of HIV and TB screening. Studies may include adults with cough and different combinations of other symptoms of TB. The combination of symptoms allowed by the study will affect the risk of death since some symptom combinations may represent more severe disease. Refusal of HIV and TB screening may result in underestimation of true risk of death. A group of participants at high risk of death may systematically be refusing procedures of the study. Loss to follow-up will tend to underestimate the true risk of death, since the people with unascertained outcome may well have died. Misclassification of the outcome of death would occur if there are poor methods of ascertainment of death. Most community based studies conducted in countries with no vital registration systems depend on verbal autopsies as a method of ascertainment of death. Even in formal health care, records of death may not be easily be available and outcomes cannot be correctly be ascertained. We will use the Newcastle Ottawa scale, a star scoring system, to evaluate included studies Table 3. We will assess studies on the following; selection procedures; ascertainment of cough status and mortality; and adequacy of follow-up (duration and attrition). 3.9 Summary measures The primary summary measures are: 1) prevalence of HIV and 2) the risk of death expressed as proportion of adults with cough dying at specified intervals (2, 4, 8, and 12 weeks or 6 and 12 months). Mortality in TB Protocol v1.2 Page 7 of 17 Last updated 10/04/15 by MN

8 3.10 Planned methods of analysis When appropriate, meta-analyses will be considered for HIV prevalence and of risk of the death. The following will be considered before meta-analysis can be done: stage of disease of participants included in the study (i.e. presence of other symptoms in addition to cough) and availability of supportive care. The outcome of interest (mortality) is clear cut and expected to have minimal clinical diversity. We will primarily use the fixed-effect metaanalysis. Results of the analysis will be presented in a Forrest plot. Heterogeneity will be assessed using the I 2 Statistic. Heterogeneity is expected to arise from differences in the participant population participants having known or unknown comorbidities. Diversity in study methodology will also result in heterogeneity. For example, we will include cluster randomised trials, thus by nature of the design will be different from other RCTs due to difference in level of randomisation, and also to observational studies. Where significant heterogeneity exists we will conduct random-effects meta-analysis. We will use the cut-offs suggested by the Cochrane collaboration, where heterogeneity of greater than 50% is viewed as substantial heterogeneity. 17 Meta analysis will be considered inappropriate if considerable heterogeneity. Missing information is expected to be a problem in some included studies. Some of the included studies are expected not to have information to the level of disaggregation to allow determination of risk of death by HIV status. When attempts to contact authors have not been successful, such studies will be excluded from the meta-analysis. Publication bias will be assessed using a funnel plot and Eggers test. All statistical analyses will be done using Stata version Results 4.1 Presentation of Results of Study Selection Results of the selection of studies will be presented following guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). 4.2 Results of individual studies The following will be presented: author, year, country, population, and sample size, uptake of TB screening, and uptake of HIV testing, number of TB patients, overall HIV prevalence, HIV prevalence in adults with cough, risk of death at intervals 2 weeks, 4 weeks, 8 weeks, 12 weeks, 6 months or 12 months. 5 Dissemination of Results The results of this systematic literature review will be submitted for online publication. Part of the work on the systematic review will also be included in a PhD thesis to the London School of Hygiene and Tropical Medicine (LSHTM) by one of the investigators, MN. 6 Review Team: Affiliation, Source of Funding and Conflict of Interest The investigators are affiliated to LSHTM, the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) and the Liverpool school of Tropical medicine (LSTM). The Mortality in TB Protocol v1.2 Page 8 of 17 Last updated 10/04/15 by MN

9 roles of the investigators have been presented in Table 5. The investigators are closely linked to various TB research groups around the World including the WHO and TB centre under the LSHTM. These collaborations would facilitate input on any missed studies and also ease contact to authors of included studies. The investigators have no conflict of interest to declare for conducting this systematic literature review. 7 Project Administration and Timelines There will be enough resources available for conducting this systematic review. There will be will be full access to online bibliographic databases access provided by the LSHTM and the College of Medicine Malawi. Data entry and data management support will be available within the MLW. The proposed timelines for various activities in the systematic review have been presented in the in Table 6. 8 Ethics statement Ethical approval is not required for this study. Mortality in TB Protocol v1.2 Page 9 of 17 Last updated 10/04/15 by MN

10 9 References 1. World Health Organisation (WHO). Definitions and reporting framework for tuberculosis revision 2013 [cited March 2015]. Available from: 2. Corbett EL, Zezai A, Cheung YB, Bandason T, Dauya E, Munyati SS, et al. Providerinitiated symptom screening for tuberculosis in Zimbabwe: diagnostic value and the effect of HIV status. Bull World Health Organ. 2010;88(1): Ayles H, Schaap A, Nota A, Sismanidis C, Tembwe R, De Haas P, et al. Prevalence of tuberculosis, HIV and respiratory symptoms in two Zambian communities: implications for tuberculosis control in the era of HIV. PloS one. 2009;4(5):e Hanrahan CF, Selibas K, Deery CB, Dansey H, Clouse K, Bassett J, et al. Time to treatment and patient outcomes among TB suspects screened by a single point-of-care xpert MTB/RIF at a primary care clinic in Johannesburg, South Africa. PloS one. 2013;8(6):e 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): Worodria W, Massinga-Loembe M, Mayanja-Kizza H, Namaganda J, Kambugu A, Manabe YC, et al. Antiretroviral treatment-associated tuberculosis in a prospective cohort of HIV-infected patients starting ART. Clin Dev Immunol. 2011;2011: Lawn SD, Kerkhoff AD, Vogt M, Ghebrekristos Y, Whitelaw A, Wood R. Characteristics and early outcomes of patients with Xpert MTB/RIF-negative pulmonary tuberculosis diagnosed during screening before antiretroviral therapy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2012;54(8): Feasey NA, Banada PP, Howson W, Sloan DJ, Mdolo A, Boehme C, et al. Evaluation of Xpert MTB/RIF for detection of tuberculosis from blood samples of HIV-infected adults confirms Mycobacterium tuberculosis bacteremia as an indicator of poor prognosis. J Clin Microbiol. 2013;51(7): Talbot E, Munseri P, Teixeira P, Matee M, Bakari M, Lahey T, et al. Test characteristics of urinary lipoarabinomannan and predictors of mortality among hospitalized HIV-infected tuberculosis suspects in Tanzania. PloS one. 2012;7(3):e Waitt CJ, Squire SB. A systematic review of risk factors for death in adults during and after tuberculosis treatment. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2011;15(7): Harries AD, Zachariah R, Corbett EL, Lawn SD, Santos-Filho ET, Chimzizi R, et al. The HIV-associated tuberculosis epidemic--when will we act? Lancet. 2010;375(9729): Bank. TW. GNI, Atlas method (current US$) [cited May 2015]. Available from: WHO. Global Tuberculosis Report Geneva: World Health Organization; Corbett EL, Bandason T, Duong T, Dauya E, Makamure B, Churchyard GJ, et al. Comparison of two active case-finding strategies for community-based diagnosis of symptomatic smear-positive tuberculosis and control of infectious tuberculosis in Harare, Zimbabwe (DETECTB): a cluster-randomised trial. Lancet. 2010;376(9748): Mortality in TB Protocol v1.2 Page 10 of 17 Last updated 10/04/15 by MN

11 15. Churchyard GJ, Fielding K, Roux S, Corbett EL, Chaisson RE, De Cock KM, et al. Twelve-monthly versus six-monthly radiological screening for active case-finding of tuberculosis: a randomised controlled trial. Thorax. 2011;66(2): Lawn SD, Kerkhoff AD, Vogt M, Wood R. HIV-associated tuberculosis: relationship between disease severity and the sensitivity of new sputum-based and urine-based diagnostic assays. BMC Med. 2013;11(1): JPT H, S G. Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011]: The Cochrane Collaboration; Available from: Mortality in TB Protocol v1.2 Page 11 of 17 Last updated 10/04/15 by MN

12 10 Tables and Figures Table 1. Summary of inclusion and exclusion criteria Inclusion criteria Participants Adults ( 15 years) With cough and other symptoms High risk groups or general population, including pregnant women Type of reporting Individual-level data on HIV and mortality Exclusion criteria Participants Children (<15 years) Extra-pulmonary TB only studies MDR or XDR TB only studies Study types Studies with no individual level information on death and HIV status Study types Cross-sectional Cohort Randomised controlled trials Evaluation of diagnostic tests Systematic screening for TB Case control Geographical (Refer to Appendix A) Low- and middle- income countries WHO s 22 High TB burden countries Publication status Peer reviewed Relevant grey literature Conference abstracts English language Time Study published since 1 January 2003 to current 1 January 2015 Mortality in TB Protocol v1.2 Page 12 of 17 Last updated 10/04/15 by MN

13 Table 2. Search strategy in Ovid Medline; strategy will be adapted for other databases Concepts Set Search terms Tuberculosis 1-3 exp *Tuberculosis/ OR Tuberculosis.mp. OR TB.mp 4 1 or 2 or 3 Symptoms of TB 5-9 suspect*.mp OR presumpt*.mp OR probabl*.mp OR (chronic adj1 cough*).mp OR symptom*.mp 10 5 or 6 or 7 or 8 or 9 HIV exp HIV/ or exp HIV-2/ or exp HIV-1/ or exp HIV Infections/ OR human immunodeficiency virus.mp OR human immune deficiency virus.mp OR human immuno-deficiency virus.mp OR human immune-deficiency virus.mp OR acquired immunodeficiency syndrome.mp OR acquired immune deficiency syndrome.mp OR acquired immune-deficiency syndrome.mp OR HIV.mp. OR (HIV adj2 infect*).mp OR AIDS mp or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 Context of study exp Mass Screening/ OR screen*.mp. OR exp Diagnosis/ OR diagnos*.mp. OR detect*.mp. OR (active adj1 case adj1 find*).mp. OR (enhanced adj1 case adj1 find*).mp. OR (new adj2 diagnos*).mp. OR (diagnos* adj2 evaluat*).mp. OR (diagnos* adj2 implement*).mp. OR (prevalence adj1 survey).mp. OR contact tracing.mp. OR microscop*.mp. OR (LED adj1 microscopy).mp. OR (smear adj1 microscopy).mp. OR "xpert MTB/Rif".mp. OR exp Polymerase Chain Reaction/ or exp Molecular Diagnostic Techniques/ or exp Nucleic Acid Amplification Techniques/ OR xpert.mp. OR x-ray.mp. OR exp Radiology/ or exp Radiography/ OR radiolog*.mp. Lipoarabinomannan.mp. OR Loop mediated isothermal amplif*.mp. OR exp Culture Techniques/ OR culture.mp OR MGIT.mp. OR randomized controlled trial.pt OR controlled clinical trial.pt OR randomized controlled trials/ OR random allocation/ OR double blind method/ OR Cohort Studies/ or Cohort Effect/ or cohort.mp OR Prospective Studies/ or Treatment Outcome/ or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 Mortality exp Hospital Mortality/ or exp Mortality/ OR mortality.mp. OR death.mp. OR exp Death/ OR die.mp. OR dead.mp OR dying.mp. OR exp Fatal Outcome/ OR fatal*.mp. OR surviv*.mp OR (live or alive or living).mp. OR exp Prognosis/ OR prognos*.mp. OR exp Treatment Outcome/ OR outcome.mp. OR exp Autopsy/ OR autopsy.mp or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 or 69 or 71 or 72 or or and and 74 and limit 77 to yr="2003 -Current" 79 limit 78 to english language Mortality in TB Protocol v1.2 Page 13 of 17 Last updated 10/04/15 by MN

14 Table 3 Methodological quality assessment of included studies Newcastle Ottawa Scale for cohort studies Selection Representativeness of the exposed cohort Truly representative of an average adult with cough in setting* Somewhat representative of the average adult with cough in setting* Only high risk (select) group No description of derivation of participants Selection of non-exposed cohort Drawn from the same community as exposed cohort Drawn from a different source No description of derivation of non-exposed cohort Ascertainment of cough status or TB symptoms Symptom screening questionnaire used in the study* Self-presenting with symtoms* Participants referred from other sites as having suspected TB based on clinical judgement alone by the referring site No description Comparability Comparability of the cohorts on the basis of design or analysis Study describes age range of participants with cough* Study describes other characteristics of participants with cough* Outcome Assessment of Mortality Independent and blinded assessment of death* Linkage to vital registration systems or other autopsy reports* Other methods of death reports No description Was follow-up long enough for outcome of death Yes ( follow-up time of at least 4 weeks)* No Adequacy of follow-up of cohorts Complete follow-up* Follow-up > 80%* Follow-up < 80% No description *Represents the star scoring system of the scale Section of the scale that does not apply to the review Mortality in TB Protocol v1.2 Page 14 of 17 Last updated 10/04/15 by MN

15 Table 4 Presentation of results from included studies Author, year Country Setting Study design Sample Size (n) HIV yield n(%) TB yield n(%) Prevalence of HIV in adults with cough All-cause mortality N (%) 4 wks n (%) 8 wks n (%) Mortality by HIV status HIV-positive n (%) HIV-negative n (%) HIV-unknown n (%) 6 mons n (%) 12 mons n (%) Per person years fu Mortality in TB Protocol v1.2 Page 15 of 17 Last updated 10/04/15 by MN

16 Table 5 Roles of investigators Initials Source of funding and affiliation Conflict of Interest Roles Protocol Search strategy Conducting search Study selection Data extraction Arbitration Dr Marriott Nliwasa MN a,b,c None * * * * * * Dr Peter PM c, d None * * * * * * MacPherson Dr Ankur Gupta- AGW a, c None * * * * * * Wright Prof Liz Corbett ELC a,b,c None * * * Affiliation a. London School of Hygiene and Tropical Medicine b. Helse Nord TB Initiative, College of Medicine, Malawi c. Malawi-Liverpool-Wellcome Trust Clinical Research Programme d. Liverpool School of Tropical Medicine Final Report Mortality in TB Protocol v1.2 Page 16 of 17 Last updated 10/04/15 by MN

17 Table 6. Timeline for progress of review Activity Deadline 1. Protocol and Search strategy agreed March Registration of protocol to April 2015 PROSPERO 3. Running Search in databases March Selection of Abstracts April May Selected studies Agreed June Data extraction June to August Write-up August to December Submission to January 2016 Mortality in TB Protocol v1.2 Page 17 of 17 Last updated 10/04/15 by MN