Background
For
treating multidrug-resistant tuberculosis (MDR TB), the World Health
Organization (WHO) recommends a regimen of at least four second-line drugs that
are likely to be effective as well as pyrazinamide. WHO guidelines indicate
only marginal benefit for regimens based directly on drug susceptibility
testing (DST) results. Recent evidence from isolated cohorts suggests that
regimens containing more drugs may be beneficial, and that DST results are
predictive of regimen effectiveness. The objective of our study was to gain
insight into how regimen design affects treatment response by analyzing the
association between time to sputum culture conversion and both the number of
potentially effective drugs included in a regimen and the DST results of the
drugs in the regimen.
Methods and Findings
We
analyzed data from the Preserving Effective Tuberculosis Treatment Study
(PETTS), a prospective observational study of 1,659 adults treated for MDR TB
during 2005–2010 in nine countries: Estonia, Latvia, Peru, Philippines, Russian
Federation, South Africa, South Korea, Thailand, and Taiwan. For all patients,
monthly sputum samples were collected, and DST was performed on baseline
isolates at the US Centers for Disease Control and Prevention. We included
1,137 patients in our analysis based on their having known baseline DST results
for at least fluoroquinolones and second-line injectable drugs, and not having
extensively drug-resistant TB. These patients were followed for a median of 20
mo (interquartile range 16–23 mo) after MDR TB treatment initiation. The
primary outcome of interest was initial sputum culture conversion. We used Cox
proportional hazards regression, stratifying by country to control for
setting-associated confounders, and adjusting for the number of drugs to which
patients’ baseline isolates were resistant, baseline resistance pattern,
previous treatment history, sputum smear result, and extent of disease on chest
radiograph.
In
multivariable analysis, receiving an average of at least six potentially
effective drugs (defined as drugs without a DST result indicating resistance)
per day was associated with a 36% greater likelihood of sputum culture
conversion than receiving an average of at least five but fewer than six
potentially effective drugs per day (adjusted hazard ratio [aHR] 1.36, 95% CI
1.09–1.69). Inclusion of pyrazinamide (aHR 2.00, 95% CI 1.65–2.41) or more
drugs to which baseline DST indicated susceptibility (aHR 1.65, 95% CI
1.48–1.84, per drug) in regimens was associated with greater increases in the
likelihood of sputum culture conversion than including more drugs to which
baseline DST indicated resistance (aHR 1.33, 95% CI 1.18–1.51, per drug).
Including in the regimen more drugs for which DST was not performed was
beneficial only if a minimum of three effective drugs was present in the
regimen (aHR 1.39, 95% CI 1.09–1.76, per drug when three effective drugs
present in regimen).
The
main limitation of this analysis is that it is based on observational data, not
a randomized trial, and drug regimens varied across sites. However, PETTS was a
uniquely large and rigorous observational study in terms of both the number of
patients enrolled and the standardization of laboratory testing. Other
limitations include the assumption of equivalent efficacy across drugs in a
category, incomplete data on adherence, and the fact that the analysis
considers only initial sputum culture conversion, not reversion or long-term
relapse.
Conclusions
MDR TB regimens including more potentially effective
drugs than the minimum of five currently recommended by WHO may encourage
improved response to treatment in patients with MDR TB. Rapid access to
high-quality DST results could facilitate the design of more effective
individualized regimens. Randomized controlled trials are necessary to confirm
whether individualized regimens with more than five drugs can indeed achieve
better cure rates than current recommended regimens.
Below: Time to initial
sputum culture conversion by average number of potentially effective drugs
received per day. Initial sputum culture conversion was defined as at
least two consecutive negative cultures of sputum samples collected at least 30
d apart.
Full article at: http://goo.gl/LHeQRH
By:
Courtney M. Yuen, Ekaterina V. Kurbatova, Janice Campos
Caoili, Charlotte Kvasnovsky, Julia Ershova, Tracy Dalton, J. Peter Cegielski
Centers for Disease Control and
Prevention, Atlanta, Georgia, United States of America
Thelma Tupasi, Janice Campos Caoili
Tropical Disease Foundation,
Manila, Philippines
Martie Van Der Walt, Charlotte Kvasnovsky
Medical Research Council,
Pretoria, South Africa
Martin Yagui
National Institute of Health,
Lima, Peru
Jaime Bayona
Partners In Health, Boston,
Massachusetts, United States of America
Carmen Contreras
Socios en Salud Sucursal, Lima,
Peru
Vaira Leimane
Riga East University Hospital
Centre of Tuberculosis and Lung Diseases, Riga, Latvia
Laura E. Via
National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, Maryland,
United States of America
HeeJin Kim
Korean Institute of
Tuberculosis, Seoul, Republic of Korea
Somsak Akksilp
Department of Disease Control,
Ministry of Public Health, Bangkok, Thailand
Boris Y. Kazennyy
Orel Oblast Tuberculosis
Dispensary, Orel, Russian Federation
Grigory V. Volchenkov
Vladimir Oblast Tuberculosis
Dispensary, Vladimir, Russian Federation
Ruwen Jou
Taiwan Centers for Disease
Control, Taipei, Taiwan
Kai Kliiman
Tartu University Hospital,
Tartu, Estonia
Olga V. Demikhova, Irina A. Vasilyeva
Central Tuberculosis Research
Institute, Russian Academy of Medical Sciences, Moscow, Russian Federation
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