Transmission of extensively drug-resistant tuberculosis in South Africa

N. Sarita Shah, Sara C. Auld, James C.M. Brust, Barun Mathema, Nazir Ismail, Pravi Moodley, Koleka Mlisana, Salim Allana, Angela Campbell, Thuli Mthiyane, Natashia Morris, Primrose Mpangase, Hermina Van Der Meulen, Shaheed V. Omar, Tyler S. Brown, Apurva Narechania, Elena Shaskina, Thandi Kapwata, Barry Kreiswirth, Neel R. Gandhi

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Abstract

BACKGROUND Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions. METHODS We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants' history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment- length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrugresistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission. RESULTS Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%). CONCLUSIONS The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission.

Original languageEnglish (US)
Pages (from-to)243-253
Number of pages11
JournalNew England Journal of Medicine
Volume376
Issue number3
DOIs
StatePublished - Jan 19 2017

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Extensively Drug-Resistant Tuberculosis
South Africa
Tuberculosis
Virus Diseases
Multidrug-Resistant Tuberculosis
HIV
Social Support
Insertional Mutagenesis
Community Hospital
Therapeutics
CD4 Lymphocyte Count
Mycobacterium tuberculosis
Restriction Fragment Length Polymorphisms
Medical Records
Hospitalization
Public Health
Genome
Prospective Studies
Interviews

ASJC Scopus subject areas

  • Medicine(all)

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Shah, N. S., Auld, S. C., Brust, J. C. M., Mathema, B., Ismail, N., Moodley, P., ... Gandhi, N. R. (2017). Transmission of extensively drug-resistant tuberculosis in South Africa. New England Journal of Medicine, 376(3), 243-253. https://doi.org/10.1056/NEJMoa1604544

Transmission of extensively drug-resistant tuberculosis in South Africa. / Shah, N. Sarita; Auld, Sara C.; Brust, James C.M.; Mathema, Barun; Ismail, Nazir; Moodley, Pravi; Mlisana, Koleka; Allana, Salim; Campbell, Angela; Mthiyane, Thuli; Morris, Natashia; Mpangase, Primrose; Van Der Meulen, Hermina; Omar, Shaheed V.; Brown, Tyler S.; Narechania, Apurva; Shaskina, Elena; Kapwata, Thandi; Kreiswirth, Barry; Gandhi, Neel R.

In: New England Journal of Medicine, Vol. 376, No. 3, 19.01.2017, p. 243-253.

Research output: Contribution to journalArticle

Shah, NS, Auld, SC, Brust, JCM, Mathema, B, Ismail, N, Moodley, P, Mlisana, K, Allana, S, Campbell, A, Mthiyane, T, Morris, N, Mpangase, P, Van Der Meulen, H, Omar, SV, Brown, TS, Narechania, A, Shaskina, E, Kapwata, T, Kreiswirth, B & Gandhi, NR 2017, 'Transmission of extensively drug-resistant tuberculosis in South Africa', New England Journal of Medicine, vol. 376, no. 3, pp. 243-253. https://doi.org/10.1056/NEJMoa1604544
Shah, N. Sarita ; Auld, Sara C. ; Brust, James C.M. ; Mathema, Barun ; Ismail, Nazir ; Moodley, Pravi ; Mlisana, Koleka ; Allana, Salim ; Campbell, Angela ; Mthiyane, Thuli ; Morris, Natashia ; Mpangase, Primrose ; Van Der Meulen, Hermina ; Omar, Shaheed V. ; Brown, Tyler S. ; Narechania, Apurva ; Shaskina, Elena ; Kapwata, Thandi ; Kreiswirth, Barry ; Gandhi, Neel R. / Transmission of extensively drug-resistant tuberculosis in South Africa. In: New England Journal of Medicine. 2017 ; Vol. 376, No. 3. pp. 243-253.
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AU - Shah, N. Sarita

AU - Auld, Sara C.

AU - Brust, James C.M.

AU - Mathema, Barun

AU - Ismail, Nazir

AU - Moodley, Pravi

AU - Mlisana, Koleka

AU - Allana, Salim

AU - Campbell, Angela

AU - Mthiyane, Thuli

AU - Morris, Natashia

AU - Mpangase, Primrose

AU - Van Der Meulen, Hermina

AU - Omar, Shaheed V.

AU - Brown, Tyler S.

AU - Narechania, Apurva

AU - Shaskina, Elena

AU - Kapwata, Thandi

AU - Kreiswirth, Barry

AU - Gandhi, Neel R.

PY - 2017/1/19

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N2 - BACKGROUND Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions. METHODS We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants' history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment- length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrugresistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission. RESULTS Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%). CONCLUSIONS The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission.

AB - BACKGROUND Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions. METHODS We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants' history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment- length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrugresistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission. RESULTS Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%). CONCLUSIONS The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission.

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