Effects of patient tracing on estimates of lost to follow-up, mortality and retention in antiretroviral therapy programs

in low-middle income countries: a systematic review

James H. McMahon1,2, Julian H. Elliott1,3,4, Steven Y. Hong2, Michael R. Jordan2

1Infectious Diseases Unit, Alfred Hospital, Melbourne, Australia; 2Department of

Public Health and Community Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA; 3Department of Medicine, Monash University, and

4Burnet Institute, Melbourne, Australia

1

Background

• Frequently reported outcomes for populations receiving ART include the number of patients: – Alive and on ART– Died– Transferring care from one facility to another

(‘transfer out’)– Stopping ART (physician directed or patient

initiated) but remaining in care– Lost to follow-up (LTFU)

2

Background - Definitions• LTFU - generic term for patients initiating ART with unknown

treatment outcomes– Unreported deaths– Unknown transfer of care without documentation– Disengagement from care

• Retention on ART: patients alive and receiving ART 1

– Retained on ART = 1 – LTFU - died - stopped ART

• Retention at the original site: individuals retained on ART and excludes transfers out 1

– Retained at the original site = 1 – LTFU – died – stopped ART – transfer out

31 Fox TMIH 2010, Rosen PLoS Med 2007

Background• Patient Tracing - Potential benefits:

– Improved classification of unknown outcomes– Linking patients disengaged from care back into the health

system

• Methods of tracing:– Telephone tracing– Physical tracing

• Prior reviews1 provide summary estimates of LTFU, mortality and retention but have not incorporated the potential for patient tracing to affect these outcomes

Or combination of both

1 Fox TMIH 2010, Rosen PLoS Med 2007, Gupta PLoS One 2011, Lawn AIDS 20084

Objective

• Compare summary estimates of LTFU, mortality and retention in low- and middle-income countries (LMICs) 12 months after ART initiation in cohorts of patients with and without physical tracing

5

Methods• Systematic review for studies in LMIC programmatic settings

– MEDLINE (2003-2011) – HIV conferences (CROI and IAS 2009-2011)

• MeSH and search terms for LTFU and retention

• Included studies: reported proportion LTFU 12-months after ART initiation

• Excluded studies: majority children, patients received mono- or dual-therapy, not performed in LMICs, clinical trials (non-programmatic setting)

6

Methods• Tracing activities determined from studies or

contacting study authors– Classified as tracing study if physical tracing available for

majority of patients

• Summary estimates – Medians (IQR) if estimates non-normally distributed or;– Weighted means (± SD) if normally distributed

• Weighting of proportions was by the inverse of its variance [1/(p x [1-p]/n); where p is proportion and n is sample size]

– Compared by Student’s t-test if normally distributed, or Wilcoxon rank sum test if non-normal

7

Identified studies• 261 papers

Identified studies• 616 conference

abstracts

Excluded after reviewing titles and abstracts• 149 papers

Excluded after reviewing titles• 334 conference abstracts

Full text review• 112 papers

Included in the review• 32 papers

Full text review• 282 conference abstracts

Included in the review• 7 conference abstracts

32 papers and 7 conference abstracts included in the review

Search strategy and study selection

8

Excluded after reviewing full text• 80 papers

Excluded after reviewing full text• 275 conference abstracts

Comparison of summary estimates with and without physical tracing

Outcome ofinterest

With tracing Without tracingP

value#Cohorts (n)

Starting ART (n)

Range of estimates

(%)Summary

estimate* (%)Cohorts

(n)Starting ART (n)

Range of estimates

(%)Summary

estimate* (%)

LTFU 25 62791 0.3 - 15.0 7.6 ± 1.1 29 124875 0.8 - 34.8 15.1 ± 1.7 < 0.001

Mortality 25 62791 4.2 – 29.7 10.5 (7.0 – 12.7) 25 113693 1.1 - 15.3 6.6

(4.3 – 9.6) 0.006

Stopped ART 13 43975 0.5 – 5.8 2.8 ± 0.2 7 10841 0.8 – 8.5 3.2 ± 0.8 0.5

Transfer out 5 6945 1.0 – 14.0 2.7 ± 1.9 7 6195 1.2 – 14.5 3.9 ± 1.3 0.6

Retention on ART 25 62791 58.4 – 88.5 80.0

(76.5 – 84.5) 25 113693 58.5 – 91.0 75.8 (70.0 – 81.2) 0.04

Retention at original site 25 62791 47.5 – 88.5 80.0

(76.0 – 84.0) 25 113693 58.5 – 90.6 72.9 (68.5 – 79.8) 0.02

* Values represent median (Q1–Q3), or weighted mean ± SE (estimates weighted by the inverse of their variance)# Comparing summary estimates for the 2 groups of studies (tracing and non-tracing) by Wilcoxon rank-sum test for medians or student’s t test for weighted means Notes: LTFU, lost to follow up; ART, antiretroviral therapy

9

Discussion

• LTFU and mortality with physical tracing– Uncertain by how much the LTFU was a result of

re-engagement into care versus re-classification of unknown outcomes

• However, in addition to LTFU and mortality, we report in retention at the original site– Suggests tracing may re-engagement in care

• Retention at the original site definition accounts for re-classification of lost patients as died or transferred out

10

Discussion

• re-engagement would lead to beneficial effects of ART 1

– survival, fewer opportunistic infections, limiting treatment interruptions (minimizing emergence of HIV drug resistance), in community HIV viral load

• Cost-effectiveness (CE) of tracing not known– Prior CE analyses on reducing LTFU have not

considered tracing 2

111 Pallella NEJM 1998, Parienti CID 2004, Oyugi AIDS 2007, Das PLoS One 2010, Montaner JAIDS 2010, Andrews JID 2012. 2 Losina PLoS Med 2009

Discussion

• Difference in summary estimates emphasizes the importance of knowing whether physical tracing occurs within an ART program or clinic when interpreting LTFU, mortality or retention data 1

121 2006 WHO IMAI guidelines, 2010 WHO HIVDR Early Warning Indicators, 2009 UNGASS indicators, 2009 PEPFAR indicators

Limitations• ART clinics with physical tracing may have resources

resulting in improved outcomes– Review of randomized controlled trials (RCTs) with tracing

interventions may provide more accurate assessments of the impact of tracing on LTFU, mortality and retention

– RCTs not found Needed to quantify benefits and CE

• Transfer out data available in a minority of studies – Estimates of retention at the original site could differ if

complete transfer out data available– Emphasises the importance of understanding transfer out to

accurately interpret estimates of retention 13

Conclusions• Physical tracing leads to:

– unknown outcomes – Suggests improved re-engagement in care

• Critical need for studies to assess tracing interventions for:– Ability to improve re-engagement of patients on ART– Optimal methods of tracing– Cost effectiveness

• Programs providing ART in LMICs should consider physically tracing patients who have unknown outcomes as an intervention to improve individual outcomes and programmatic evaluation of populations receiving ART 14

Acknowledgements• Financial support

– National Health and Medical Research Council• Postgraduate Scholarship - J.H.M

– National Institutes of Health• 5K23AI074423-04 - M.R.J., 1K23AI097010-01A1 - S.Y.H.

• In addition to study authors– Tufts Medical Center / Tufts University

• Christine Wanke– Alfred Hospital / Monash University

• Sharon Lewin– World Health Organization, HIV Department

• Silvia Bertagnolio15