Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies.
BACKGROUND
Sputum culture conversion is often used as an early microbiological endpoint in phase 2 clinical trials of tuberculosis treatment on the basis of its assumed predictive value for end-of-treatment outcome, particularly in patients with drug-susceptible tuberculosis. We aimed to assess the validity of sputum culture conversion on solid media at varying timepoints, and the time to conversion, as prognostic markers for end-of-treatment outcome in patients with multidrug-resistant (MDR) tuberculosis.


METHODS
We analysed data from two large cohort studies of patients with MDR tuberculosis. We defined sputum culture conversion as two or more consecutive negative cultures from sputum samples obtained at least 30 days apart. To estimate the association of 2 month and 6 month conversion with successful treatment outcome, we calculated odds ratios (ORs) and 95% CIs with random-effects multivariable logistic regression. We calculated predictive values with bivariate random-effects generalised linear mixed modelling.


RESULTS
We assessed data for 1712 patients who had treatment success, treatment failure, or who died. Among patients with treatment success, median time to sputum culture conversion was significantly shorter than in those who had poor outcomes (2 months [IQR 1-3] vs 7 months [3 to ≥24]; log-rank p<0·0001). Furthermore, conversion status at 6 months (adjusted OR 14·07 [95% CI 10·05-19·71]) was significantly associated with treatment success compared with failure or death. Sputum culture conversion status at 2 months was significantly associated with treatment success only in patients who were HIV negative (adjusted OR 4·12 [95% CI 2·25-7·54]) or who had unknown HIV infection (3·59 [1·96-6·58]), but not in those who were HIV positive (0·38 [0·12-1·18]). Thus, the overall association of sputum culture conversion with a successful outcome was substantially greater at 6 months than at 2 months. 2 month conversion had low sensitivity (27·3% [95% confidence limit 16·6-41·4]) and high specificity (89·8% [82·3-94·4]) for prediction of treatment success. Conversely, 6 month sputum culture conversion status had high sensitivity (91·8% [85·9-95·4]), but moderate specificity (57·8% [42·5-71·6]). The maximum combined sensitivity and specificity for sputum culture conversion was reached between month 6 and month 10 of treatment.


CONCLUSIONS
Time to sputum culture conversion, conversion status at 6 months, and conversion status at 2 months in patients without known HIV infection can be considered as proxy markers of end-of-treatment outcome in patients with MDR tuberculosis, although the overall association with treatment success is substantially stronger for 6 month than for 2 month conversion status. Investigators should consider these results regarding the validity of sputum culture conversion at various timepoints as an early predictor of treatment efficacy when designing phase 2 studies before investing substantial resources in large, long-term, phase 3 trials of new treatments for MDR tuberculosis.


BACKGROUND
US Agency for International Development, US Centers for Disease Control and Prevention, Division of Intramural Research of the US National Institute of Allergy and Infectious Diseases, Korea Centers for Disease Control and Prevention.
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: ekurbatova@cdc.gov.
Ekaterina V
EV
Kurbatova
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
J Peter
JP
Cegielski
WHO, Geneva, Switzerland.
Christian
C
Lienhardt
Office of Disease Prevention and Control, Region 7, Ubon Ratchathani, Thailand.
Rattanawadee
R
Akksilp
Harvard Medical School and Partners In Health, Boston, MA, USA.
Jaime
J
Bayona
Harvard Medical School and Partners In Health, Boston, MA, USA.
Mercedes C
MC
Becerra
Tropical Disease Foundation, Manila, Philippines.
Janice
J
Caoili
Socios en Salud Sucursal, Lima, Peru.
Carmen
C
Contreras
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Tracy
T
Dalton
Tartu University Hospital, Tartu, Estonia.
Manfred
M
Danilovits
Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russia.
Olga V
OV
Demikhova
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Julia
J
Ershova
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Victoria M
VM
Gammino
Harvard Medical School and Partners In Health, Boston, MA, USA.
Irina
I
Gelmanova
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Charles M
CM
Heilig
Reference Laboratory of Mycobacteriology, Taiwan Centers for Disease Control, Taipei, Taiwan.
Ruwen
R
Jou
Orel Oblast Tuberculosis Dispensary, Orel, Russia.
Boris
B
Kazennyy
Harvard Medical School and Partners In Health, Boston, MA, USA.
Salmaan
S
Keshavjee
Korean Institute of Tuberculosis, Seoul, South Korea.
Hee Jin
HJ
Kim
Tartu University Hospital, Tartu, Estonia.
Kai
K
Kliiman
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Charlotte
C
Kvasnovsky
Riga East University Hospital, Tuberculosis and Lung Disease Center, Riga, Latvia.
Vaira
V
Leimane
Harvard Medical School and Partners In Health, Boston, MA, USA.
Carole D
CD
Mitnick
Tropical Disease Foundation, Manila, Philippines.
Imelda
I
Quelapio
Riga East University Hospital, Tuberculosis and Lung Disease Center, Riga, Latvia.
Vija
V
Riekstina
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Sarah E
SE
Smith
Tropical Disease Foundation, Manila, Philippines.
Thelma
T
Tupasi
Medical Research Council, Pretoria, South Africa.
Martie
M
van der Walt
Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russia.
Irina A
IA
Vasilyeva
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Laura E
LE
Via
National Tuberculosis Registry, National Institute for Health Development, Tallinn, Estonia.
Piret
P
Viiklepp
Vladimir Oblast Tuberculosis Dispensary, Vladimir, Russia.
Grigory
G
Volchenkov
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Allison Taylor
AT
Walker
Division of Tuberculosis Elimination, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Melanie
M
Wolfgang
National Institute of Health, Lima, Peru.
Martin
M
Yagui
WHO, Geneva, Switzerland.
Matteo
M
Zignol
D000293:Adolescent; D000328:Adult; D000368:Aged; D006801:Humans; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D011446:Prospective Studies; D013183:Sputum / Q000382:microbiology*; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*; D055815:Young Adult