Genomic epidemiology of extensively drug-resistant tubercul - PowerPoint Presentation

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Genomic epidemiology of extensively drug-resistant tuberculosis in KwaZulu-Natal, South AfricaDemographic expansion and genetic determinants of epidemiological success in a high HIV prevalence setting Tyler S. Brown, M.D.Columbia University Medical CenterDepartment of Medicine @DrTSBSlide2

Extensively drug-resistant (XDR)-TB: Major threat to global TB control: costly and toxic drugs, high case mortality Resistance to isoniazid, rifampin, fluroquinolones, & 2nd-line

injectables

First XDR-TB isolate in KwaZulu-Natal (KZN) reported in 2001:Evolved from well-described multi-drug resistant strain LAM4/KZNResponsible for high-mortality outbreak among co-hospitalized HIV patients in Tugela Ferry (2005-2006)High HIV prevalence setting (approximately 40%)Incidence: 3.5 cases of XDR-TB per 100,000 in 2011-2012Cases are geographically widespread across provinceMajority of new XDR-TB cases are due to transmission rather than de novo acquisition of drug resistance while on treatment

BackgroundSlide3

When did XDR-TB emerge in KwaZulu-Natal? What was the extent of transmission in the community before the Tugela Ferry outbreak? (Was Tugela Ferry a sentinel event or an initiating event for widespread community transmission?)What pathogen-specific biological factors may have contributed to the emergence and spread of XDR-TB in KZN?

How did HIV co-infection and

TB transmission in a high HIV prevalence setting influence the epidemiology and evolutionary history of XDR-TB?Research QuestionsSlide4

WGS  evolutionary history  epidemiological historyWhole genome sequencing, targeted sequencing, & RFLP-genotyping of 296 Mtb clinical

isolates from KZN

(1994-2014)Bayesian evolutionary analysis to infer phylogenetic trees and estimate dates for drug resistance mutations (time to most recent common ancestor)Bayesian Skyline Analysis to estimate prior bacterial population history

MethodsSlide5

5Bayesian phylogenetic analysisSlide6

6Bayesian Skyline Plot: Estimates (bacterial) effective population size over timeSlide7

7Slide8

8Mtb clinical isolates:190 XDRSlide9

9Mtb clinical isolates:190 XDR 54 MDR52 drug-susceptibleSlide10

10LAM4/KZN

Mtb

clinical isolates:190 XDR 54 MDR52 drug-susceptibleHIV prevalence 70-79% among XDR-TB cases Highly diverse: XDR-TB arose independently in 11 different RFLP strain families (distantly related)Majority of isolates are KZN/LAMSlide11

Stepwise evolution of drug-resistance in LAM4/KZN katG (isoniazid): 1962 (1947-1972)Slide12

Stepwise evolution of drug-resistance in LAM4/KZNkatG (isoniazid): 1962 (1947-1972)inhA (isoniazid): 1975 (1964 -1983)Slide13

Stepwise evolution of drug-resistance in LAM4/KZNkatG (isoniazid): 1962 (1947-1972)inhA (isoniazid): 1975

(1964

-1983)MDR (rpoB L452P  rifampin): 1985 (1977-1991)Slide14

Stepwise evolution of drug-resistance in LAM4/KZNkatG (isoniazid): 1962 (1947-1972)inhA (isoniazid): 1975 (1964

-

1983)MDR (rpoB L452P  rifampin): 1985 (1977-1991)XDR:rpoB D435G (rifampin drug-resistance)rpoB I1106T (not associated with DR)gyrA A90V (fluroquinolone resistance)rrs A1401G (kanamycin resistance)1993 (1988-1998)

Consistent with prior estimates

(Cohen,

Abeel

et al 2015)Slide15

15Effective bacterial population size (Ne) of HP/LAM4/KZN

via Bayesian Skyline analysisNe increases 4-5 years before first reported XDR isolate10 years before Tugela Ferry outbreak*TMRCA: time to most recent common ancestorSlide16

16Effective bacterial population size (Ne) of HP/LAM4/KZN via Bayesian Skyline analysisN

e

increases 4-5 years before first reported XDR isolate10 years before Tugela Ferry outbreakConcurrent with increase in overall incidence of all TB cases in South Africa*TMRCA: time to most recent common ancestorSlide17

17Effective bacterial population size (Ne) of HP/LAM4/KZN via Bayesian Skyline analysisNe increases 4-5 years before first reported XDR isolate

10 years before Tugela Ferry outbreak

Concurrent with increase in overall incidence of all TB cases in South AfricaConcurrent with increase in HIV prevalence 1990-2010*TMRCA: time to most recent common ancestorSlide18

18Extensively drug-resistant subpopulations of M. tuberculosis expanded well before the Tugela Ferry outbreak, suggesting ongoing community transmission prior to detection via public health surveillanceSlide19

LimitationsCross-sectional sampling may under-represent non-LAM4/KZN XDR isolates if these isolates are clustered in under-sampled populations, or if infections with these isolates are less likely to cause fulminant clinical diseaseEffective population size is at best a proxy measure for incidence or total number of infectionsSlide20

20\Summary When did XDR-TB emerge in KwaZulu-Natal? Most likely in 1993

, 8 years before the first isolate reported in KZN and 12 years before the Tugela Ferry outbreak.

Bacterial population expansion before 2001-2005, suggesting ongoing transmission of this strain before detection via public health surveillance What pathogen-specific biological factors may have contributed to the emergence and spread of XDR-TB in KZN?Unique set of rpoB mutations in the epidemiologically successful KZN/LAM4: ?selective advantage associated with additional rpoB mutation(s)How did HIV co-infection and transmission in a high HIV prevalence setting influence the epidemiology and evolutionary history of XDR-TB?

Close temporal association between increasing HIV prevalence, increasing incidence of all TB cases, and XDR-TB bacterial population

size.

HIV likely facilitated the spread of XDR-TB Slide21

Implications HIV treatment likely a cornerstone to preventing further spread of XDR-TB Prioritize pharmacosurveillance

, include new anti-TB medications (

bedaquiline, delamanid) in drug susceptibility testing now Evolution happens fast (even in TB): whole genome sequencing is an important tool for early detection of emerging drug resistanceSlide22

Acknowledgements

Sergios-Orestis

KolokotronisSara C. AuldShaheed OmarApurva Narechania N. Sarita ShahKristin N

. NelsonNazir Ismail

Barry N

.

Kreiswirth

James C.M

.

Brust

Pravi

Moodley

,

Neel R

. Gandhi

Barun Mathema*

e

mail:

tsbrown@mgh.harvard.edu