Xpert MTB/RIF vs microscopy as the first line TB test in South Africa: mortality, yield, initial loss to follow up and proportion treated. The ...
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Xpert MTB/RIF vs microscopy as the first
line TB test in South Africa: mortality,
yield, initial loss to follow up and
proportion treated. The XTEND study
GJ Churchyard
On behalf of the XTEND team
(Xpert for TB - Evaluating a New Diagnostic)
Prof Churchyard has no financial relationships with commercial entities to disclose
Background: Xpert MTB/RIF
Improved diagnosis of TB is a global priority for TB control
Xpert is a rapid, molecular, cartridge-based TB test with
greater sensitivity than sputum smear microscopy
an immediate rifampicin resistance result
WHO conditional recommendation (2013):
Xpert MTB/RIF recommended initial diagnostic test for adults
investigated for TB
Impact of Xpert MTB/RIF will depend on the health system
in which it is used
Evidence concerning patient, program and cost-
effectiveness outcomes are required to inform policy
Background: South Africa (SA)
SA has the third largest number of TB cases globally
Since 2011, SA replaced sputum smear microscopy
with Xpert MTB/RIF as the first-line test for TB
The SA Xpert MTB/RIF program
is the largest in the world
accounts for >50% of all cartridges
procured globally
A pragmatic, cluster-randomized
trial was embedded within the
Xpert MTB/RIF national roll out to
evaluate patient and programme
relevant outcomes
Background: South Africa (SA)
SA has the third largest number of TB cases globally
Since 2011, SA replaced sputum smear microscopy
with Xpert MTB/RIF as the first-line test for TB
The SA Xpert MTB/RIF program
is the largest in the world
accounts for >50% of all cartridges
procured globally
A pragmatic, cluster-randomized
trial was embedded within the
Xpert MTB/RIF national roll out to
evaluate patient and programme
relevant outcomes
XTEND trial: primary objective To evaluate the effect of Xpert MTB/RIF implementation on mortality among adults investigated for TB
XTEND trial: secondary objectives To compare, in the XTEND study, by study arm: Among clinic attendees investigated for TB Proportion index test positive Proportion starting TB treatment by 6 months Among those with a positive index test result Proportion initially lost to follow-up
Study clusters
Cluster defined as a lab and 2 primary care clinics
(PHC) served by, but not co-located with, that lab
20 laboratories in medium-burden districts in 4
provinces were identified
2 PHCs served by each lab were selected
Xpert arm (10 clusters) Microscopy arm (10 clusters)
laboratory laboratory
Clinic 1 Clinic 2 Clinic 1 Clinic 2Xpert MTB/RIF implementation in
participating laboratories
GX 16-module instruments were introduced into
Xpert arm laboratories
Laboratory staff received training on Xpert MTB/RIF
use from the NHLS
Microscopy arm laboratories continued using smear
microscopy during enrolment of participants,
implementing Xpert MTB/RIF ~6 months later
Participant enrolment in the Xpert arm was
initiated a median of 3.6 (range 1-7.4) months
after starting routine use of GeneXpertCohort of persons investigated for TB
Clinic clients
TB symptoms
Sputum
requested
Cohort of persons investigated for TB
Enrolled
phone or home
Contacted by
1 week
Month 1
visit
Month 2
Month 4
6 month review of participants or nominated
contacts
Alive/Dead Treated for TB: Yes/NoCohort of persons investigated for TB
Clinic clients
Persons investigated for
TB by clinic staff
TB symptoms
Xpert arm: 1 sputum
Sputum
requested specimen collected for
Xpert MTB/RIF
microscopy arm: 2
Cohort of persons investigated for TB
Enrolled
sputum specimens
phone or home
Contacted by
1 week
Month 1 collected for fluorescence
visit
Month 2 microscopy
Month 4
CXR/ sputum for culture
6 month review of participants or nominated
contacts
if requested by clinic
staff, guided by relevant
Alive/Dead Treated for TB: Yes/No algorithmCohort of persons investigated for TB
Clinic clients
TB symptoms
Sputum
A systematic sample of
requested
adults, not on TB
treatment, who had
Cohort of persons investigated for TB had a sputum specimen
Enrolled
phone or home
requested by clinic staff
Contacted by
1 week
Month 1
visit
Month 2 to investigate for
Month 4
possible TB were
6 month review of participants or nominated
contacts
recruited by study staff
Alive/Dead Treated for TB: Yes/NoCohort of persons investigated for TB
Clinic clients
At enrolment, personal
TB symptoms
identifiers, including SA
Sputum
requested identity number,
locator information,
Cohort of persons investigated for TB
demographic and
Enrolled clinical data relevant to
phone or home
Contacted by
1 week
Month 1
TB and mortality risk
visit
Month 2
Month 4
were collected
6 month review of participants or nominated No extra tests for study
contacts
purposes
Alive/Dead Treated for TB: Yes/NoCohort of persons investigated for TB
Clinic clients
TB symptoms
Sputum Participants were
requested
contacted
telephonically by study
Cohort of persons investigated for TB
Enrolled
staff in order to
phone or home
Contacted by
1 week
Month 1
maintain contact and
visit
Month 2
update locator
Month 4
information
6 month review of participants or nominated
contacts
Alive/Dead Treated for TB: Yes/NoCohort of persons investigated for TB
Clinic clients
TB symptoms Prior to the 6-month
Sputum
requested
interview, study staff
reviewed patients’
clinic records for
Cohort of persons investigated for TB
Enrolled information such as
phone or home
Contacted by
1 week
Month 1 results of index and
visit
Month 2
Month 4
subsequent tests and
TB treatment and/or
6 month review of participants or nominated
contacts ART start dates
Alive/Dead Treated for TB: Yes/NoCohort of persons investigated for TB
Clinic clients
6 months after
TB symptoms
enrolment, study staff
Sputum
requested interviewed
participants
Cohort of persons investigated for TB telephonically, or by
Enrolled
home visit, to ascertain
phone or home
Contacted by
1 week
Month 1
whether they had
visit
Month 2
Month 4 started TB treatment or
6 month review of participants or nominated ART and treatment
contacts
start dates
Alive/Dead Treated for TB: Yes/NoPrimary outcome Deaths were ascertained through Reports from participant-nominated contacts Clinic staff National vital statistics database using SA ID numbers
Secondary outcomes Among clinic attendees investigated for TB Proportion index test positive Index specimen – sputum taken at enrolment Result obtained from National Health Laboratory Service or record review Proportion starting TB treatment within 6 months Based on participant self-report and/or record review
Secondary outcomes Among those index test positive Initial loss to follow-up defined as not starting TB treatment within 28 days from enrolment
Analysis Analysis was conducted using methods appropriate to the trial design, with a small number of clusters Adjustment for individual-level baseline factors showing imbalance by study arm
20 clusters
N=4,972 “people
Xpert investigated for TB”
Microscopy
Screened
10 clusters 10 clusters
2,541 participants 2,431 participants
Not eligible/did not
consent:
Xpert: N=197
Microscopy: N=63
10 clusters Enrolled 10 clusters
2,344 participants 2,368 participants
Withdrawn:
Xpert: N=20
Microscopy: N=36
10 clusters In analysis 10 clusters
2,324 participants 2,332 participants
N=4,656 “people
investigated for TB”Baseline characteristics
Xpert (n=2324) Microscopy (n=2332)
Age (median (IQR)) 35 (28-45) 37 (29-48)
Female (%) 64.2% 59.9%
HIV status, self-report (%)
Known 72.8% 79.4%
HIV positive 62.2% 62.3%
HIV+, ART ever (%) 33.5% 32.7%
CD4 count (median (IQR)) 303 (171-457) 315 (192-480)
Body mass index (%)
25 45.6% 41.5%
# TB symptoms (%)
0 9.8% 6.0%
1 23.5% 19.6%
2 32.4% 27.0%
≥3 34.3% 47.5%Baseline characteristics
Xpert (n=2324) Microscopy (n=2332)
Age (median (IQR)) 35 (28-45) 37 (29-48)
Female (%) 64.2% 59.9%
HIV status, self-report (%)
Known 72.8% 79.4%
HIV positive 62.2% 62.3%
HIV+, ART ever (%) 33.5% 32.7%
CD4 count (median (IQR)) 303 (171-457) 315 (192-480)
Body mass index (%)
25 45.6% 41.5%
# TB symptoms (%)
0 9.8% 6.0%
1 23.5% 19.6%
2 32.4% 27.0%
≥3 34.3% 47.5%Ascertainment of vital status at 6 months
Xpert Microscopy
(n=2324) (n=2332)
% n % n
Vital status known 98.9% 2299 99.0% 2309
Lost to follow-up 1.1% 25 1.0% 23Effect of Xpert MTB/RIF on mortality risk
over 6 months
Xpert Microscopy Risk ratio (95% CI)
Deaths/N %1 Deaths/N %1 Unadjusted Adjusted2
91/2324 3.9% 116/2332 5.0% 0.86 (0.56-1.28) 1.10 (0.75-1.62)
1summary ignores cluster, 2adjusted for age group, sex, body mass index
group, number of TB symptoms and HIV statusEffect of Xpert MTB/RIF on mortality risk
over 6 months
Xpert Microscopy Risk ratio (95% CI)
Deaths/N %1 Deaths/N %1 Unadjusted Adjusted2
91/2324 3.9% 116/2332 5.0% 0.86 (0.56-1.28) 1.10 (0.75-1.62)
1summary ignores cluster, 2adjusted for age group, sex, body mass index
group, number of TB symptoms and HIV status
.
0.00 0.02 0.04 0.06 0.08 0.10
Kaplan-Meier failure
Cumulative proportion dying
curves for mortality
among all study
participants
(N=4656), by study
0 1 2 3 4 5 6
arm
Months since enrolment
Number at risk (deaths)
Microscopy 2193 (63) 2121 (31) 2083 (20) 0
Xpert 2097 (45) 2041 (30) 2008 (16) 0
Microscopy XpertRisk factor analysis for mortality
(six months from enrolment)
OR aOR 95% CI P-value
Positive index test No 1 1 0.06
Yes 2.25 1.49 0.99-2.24
Gender Female 1 1 0.001
Male 2.37 1.69 1.22-2.33
AgeRisk factor analysis for mortality
(six months from enrolment)
OR aOR 95% CI P-value
Positive index test No 1 1 0.06
Yes 2.25 1.49 0.99-2.24
Gender Female 1 1 0.001
Male 2.37 1.69 1.22-2.33
AgeRisk factor analysis for mortality
(six months from enrolment)
OR aOR 95% CI P-value
Positive index test No 1 1 0.06
Yes 2.25 1.49 0.99-2.24
Gender Female 1 1 0.001
Male 2.37 1.69 1.22-2.33
AgeRisk factor analysis for mortality
(six months from enrolment)
OR aOR 95% CI P-value
# TB symptoms 0 0.18 0.23 0.05-0.98Risk factor analysis for mortality
(six months from enrolment)
OR aOR 95% CI P-value
# TB symptoms 0 0.18 0.23 0.05-0.98Risk factor analysis for mortality
(six months from enrolment)
OR aOR 95% CI P-value
# TB symptoms 0 0.18 0.23 0.05-0.98Proportion index test positive
97% (4411/4656) had index specimen result
available
Xpert Microscopy Prevalence ratio (95% CI)
positive % positive % Unadjusted Adjusted1
/N /N
200/2176 9.2% 174/2235 7.8% 1.27 (0.81-2.00) 1.49 (1.00-2.23)
1adjusted
for age group, sex, body mass index group and number of tuberculosis
symptomsProportion index test positive
97% (4411/4656) had index specimen result
available
Xpert Microscopy Prevalence ratio (95% CI)
positive % positive % Unadjusted Adjusted1
/N /N
200/2176 9.2% 174/2235 7.8% 1.27 (0.81-2.00) 1.49 (1.00-2.23)
1adjusted
for age group, sex, body mass index group and number of tuberculosis
symptomsInitial loss to follow-up
(No evidence of starting TB treatment within 28 days from enrolment)
Among 374 with a positive index test result
Xpert Microscopy Risk ratio (95% CI)
no TB Rx % no TB Rx % Unadjusted Adjusted1
/N /N
34/200 17.0% 26/174 14.9% 0.97 (0.48-1.96) 0.96 (0.48-1.93)
1adjusted for body mass index group and number of tuberculosis symptoms
.
1.00
Cumulative proportion starting TB treatment
Kaplan-Meier curves -
0.75
time to starting TB
treatment, among those
0.50
test positive
0.00 0.25
0 7 14 21 28
Days from enrolment
Microscopy XpertProportion rifampicin resistant In the Xpert arm, of the 200 participants with a positive index result, 8 (4%) had a rifampicin resistance signal
Proportion treated for TB
Overall 11.6 % (541/4656) were treated for TB
over the 6 month follow-up period
Xpert Microscopy Risk ratio (95% CI)
TB rx/N % TB rx/N % Unadjusted Adjusted1
250/2324 10.8% 291/2332 12.5% 0.88 (0.60-1.29) 1.04 (0.76-1.43)
1adjusted for age group, sex, body mass index group and number of tuberculosis symptoms
Cumulative proportion starting TB treatment
.
0.15 0.20
Kaplan-Meier curves -
time to starting TB
0.10
treatment , among clinic
attendees investigated
0.05
for TB
0.00
0 1 2 3 4 5 6
Months since enrolment
Number at risk (TB)
Microscopy 2332 (246) 2021 (33) 1961 (12) 0
Xpert 2324 (216) 2058 (23) 2003 (11) 0
Microscopy XpertProportion with microbiological
confirmation among those treated for TB
Microbiological confirmation: as any positive Xpert,
microscopy or culture
Overall 71.1 % (385/541) of individuals treated for TB
had microbiological confirmation
Xpert Microscopy Prevalence ratio (95% CI)
micro+/N % micro+/N % Unadjusted Adjusted1
196/250 78.4% 189/291 65.0% 1.21 (0.99-1.47) 1.20 (0.98-1.47)
1adjusted for age group, sex, body mass index group and number of tuberculosis symptomsProportion with microbiological
confirmation among those treated for TB
Microbiological confirmation: as any positive Xpert,
microscopy or culture
Overall 71.1 % (385/541) of individuals treated for TB
had microbiological confirmation
Xpert Microscopy Prevalence ratio (95% CI)
micro+/N % micro+/N % Unadjusted Adjusted1
196/250 78.4% 189/291 65.0% 1.21 (0.99-1.47) 1.20 (0.98-1.47)
1adjusted for age group, sex, body mass index group and number of tuberculosis symptomsLimitations
Small numbers of rifampicin resistant samples
we cannot comment on the effect of Xpert
MTB/RIF on outcomes for drug resistant TB
Analysis of costing data is in progress
Population level impact will be determined
through mathematical modelingConclusion Mortality among persons investigated for TB was high Mortality was not reduced after implementation of Xpert MTB/RIF Unknown HIV status, or positive status but not taking ART, were important determinants of mortality
Conclusion
People being investigated for TB should know their
HIV status, and linkage to HIV care improved
The relatively constant death rate over 6 months of
follow-up suggests opportunities to intervene
Those at highest risk of mortality are
Older age
Multiple TB symptoms
HIV status:
Unknown
HIV positive not taking ARTConclusion
Xpert, compared with microscopy
increased the proportion test positive by 50%:
may facilitate rapid initiation of TB treatment by nurses;
potential to result in cost savings both for patients and
for TB programs
did not reduce initial loss to follow-up
did not increase proportion starting TB treatment
increased the proportion of bacteriologically-confirmed
TB cases among those starting treatment by 20%Key message Scale-up of a more sensitive diagnostic test requires strengthened health systems, particularly ensuring that people know their HIV status and those eligible, start ART promptly people with confirmed TB start treatment quickly
XTEND investigators Aurum Institute University of Cape Town Gavin Churchyard Mark Nicol Kerrigan McCarthy Helen Cox Violet Chihota Edina Sinanovic National Department of Health London School of Hygiene & Lerole D. Mametja Tropical Medicine Norbert Ndjeka Anna Vassall Lindiwe Mvusi Katherine Fielding National Health Laboratory Alison Grant Service World Health Organization Wendy Stevens Christopher Dye Linda Erasmus
Acknowledgements
The thousand of participants in the XTEND trial
XTEND study team:
Jo’burg: Sibuse Ginindza, Sarah Yates, Joseph Makhura, Bandile Ndlazi, Siphokazi Mngcomzelo, Nolundi Msheshwe,
Bongiwe Nxumalo, Samantha Naicker, Dumisane Mlotshwa, Puleng Marokane, Flora Popane
Eastern Cape: Lungile Vezi, Asanda Mgoli, Akhona Mseleni , Nomtu Gladys Qabaka, Nombuso Nofelitho, Makiwe
Mbelu, Ntandokazi Ngoma, Mandisa Matanzima, Simpiwe Memela, Nobendiba Euriam Gqola, Tumse Oriental
Ngqokwe, Nondumiso Mtshwelo, Nonhlanhla Teti Mpakama, Busiswa Dyariwe, Ntsika Mahlutshana,
Lizwilombulelo Mtwecu, Sanele Mkhutshwa, Americana Bullie Camba, Bongani Nkaqa, Nicholas Ziqubu,
Ntombizikhona Mkalipi, Olwethu Sogoni, Somikazi Mgwebi, Silulami Zweni, Lindiwe Mnyukana, Nwabisa Ngqube,
Khayakazi Biko, Nomava Tembisa Ncandana
Free State: Tombomzi Motsoeneng ,Julia Motahane, Emily Lekitlane, Modikeng Mapeka, Pulane Matsime, Maria
Mopeli, Itumeleng Moloi, Elizah Makhaeng Hlasa, Moeti Leseba,
Gauteng: Zanele Nthebe, Ntokozo Ndlovu, Belinda Dambuza, Nombuso Mokone, Tshegofatso Kelefetswe, Nonhlanhla
Uwazureke , Nondumiso Khanyile, Gugulethu Kunene, Kanyesile Radebe, Muzi Mkhwanazi, Anna Mpoelang, Malusi
Tshitsha, Agnes Koena, Xolani Nkosi, Soneni Maphosa, Tankiso Molefe, Rosinah Maponyane, Sannah Mokgobo
Motau, France Kgoale, Duduzile Radebe, Macy Mavundza, Miyelani Ngobeni, Xoliswa Mbanjwa, Mmoni Mothupi,
Gloria Ndlovu, Pauline Maswagane, Matome Ntjana , Khutso Pako, Makhanana Mawila, Tshepiso Monakale, Lucille
Motsapi, Lebo Dlamini
Mpumalanga: Edith Becka, Fikile Khoza,Bongumusa Dlamini,Mary-Faith Mabitsela, Morabane
Malesoena, Ntoana Mbete, Solani MthimunyePartners and funders
Funders
Bill and Melinda Gates Foundation
Partners
Eastern Cape Department of Health: Ms Miyakazi
Nokwe, Ms Nomvume Ndinisa
Free State Department of Health: Ms Tshidi Morigihlane
Gauteng Department of Health: Dr Dimakatso Moli
City of JHB: Ms Antonia Barnard
City of Tshwane: Ms Julia Mokale
Ekurhuleni: Ms Sibongile Mokoena
Mpumalanga Department of Health: Ms Duduzile
MbamboSummary of XTEND results
Primary outcome n Xpert Microscopy Adjusted Risk ratio
% % (95% CI)
Mortality risk over 6 4656 3.9% 5.0% 1.10 (0.75-1.62)
months
Secondary outcomes n Xpert Microscopy Adjusted Effect
% % measure (95% CI)
Index test positive 4412 9.2% 7.8% 1.49 (1.00, 2.23)
Initial loss to follow-up, 374 17.0% 14.9% 0.96 (048-1.93)
over 28 days
% treated for TB over 6 4656 10.8% 12.5% 1.04 (0.76-1.43)
months
% with microbiological 541 78.5% 65.0% 1.20 (0.98- 1.47)
confirmation, among
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