Tuberculosis burden in households of Tuberculosis burden in households of patients with multi drug-resistant patients with multi drug-resistant

and extensively drug-resistant and extensively drug-resistant tuberculosis: a retrospective cohort tuberculosis: a retrospective cohort

studystudy

Chairperson:Chairperson:

Dr. Satya Ranjan SutradharDr. Satya Ranjan SutradharFCPS (Medicine), MD (Endocrinology)FCPS (Medicine), MD (Endocrinology)

Associate professor and HeadAssociate professor and Head

Department of MedicineDepartment of Medicine

Mymensingh Medical College HospitalMymensingh Medical College Hospital

Speaker:Speaker:

Dr. Minhaj Uddin AhmedDr. Minhaj Uddin Ahmed

RegistrarRegistrar

MU-IIMU-II

The study was published on:

The Lancet 2011; 377: 147–52

Published Online December 9, 2010

Department of Global Health and Social Medicine, Harvard

Medical School, Boston, MA, USA (M C Becerra ScD, S C

Appleton ScM, M F Franke ScD, J Bayona MD,C D Mitnick ScD);

Introduction:Introduction:

After treatment of patients with active TB “contact investigation” - is After treatment of patients with active TB “contact investigation” - is

the top priority for TB control programme because close contact of the top priority for TB control programme because close contact of

known TB patients have a higher risk of developing active TB.known TB patients have a higher risk of developing active TB.

National TB programme are often unable to do contact investigation National TB programme are often unable to do contact investigation

because of inadequate resources and staffing.because of inadequate resources and staffing.

MDR TB:MDR TB: TB strain resistant to at least isoniazide and refampicin. TB strain resistant to at least isoniazide and refampicin.

INH is a proven treatment for latent infection but there is no proven INH is a proven treatment for latent infection but there is no proven

preventive treatment for latent infection with MDR TB.preventive treatment for latent infection with MDR TB.

So when patients are diagnosed with MDR TB, early detection and So when patients are diagnosed with MDR TB, early detection and

treatment of active TB in their close contact is important.treatment of active TB in their close contact is important.

International guidelines recommend that close contacts of patients with International guidelines recommend that close contacts of patients with

MDR TB should be carefully monitored for at least 2 years.MDR TB should be carefully monitored for at least 2 years.

MDR TB and XDR TB have emerged as major global health threatsMDR TB and XDR TB have emerged as major global health threats

Aim of the study:Aim of the study:

To asses the burden of TB disease in household contacts To asses the burden of TB disease in household contacts

Estimate the occurrence of active tuberculosis in household contacts of

patients with MDR tuberculosis and to examine whether the occurrence

of active tuberculosis in household contacts differed according to

whether an index patient had MDR or XDR tuberculosis.

Methods:Methods:

Patients and study designPatients and study design

Beginning in 1996, Peru’s national TB programmed treat patients Beginning in 1996, Peru’s national TB programmed treat patients

with active MDR TB with supervised, individualized treatment with active MDR TB with supervised, individualized treatment

regimens delivered on an outpatient basis.regimens delivered on an outpatient basis.

A retrospective cohort study was undertaken of household contacts of A retrospective cohort study was undertaken of household contacts of

patients treated for MDR or XDR TB in Lima, Peru, in 1996–2003.patients treated for MDR or XDR TB in Lima, Peru, in 1996–2003.

The primary outcome was active tuberculosis in household The primary outcome was active tuberculosis in household

contacts at the time the index patient began MDR TB contacts at the time the index patient began MDR TB

treatment and during the 4-year follow-up. treatment and during the 4-year follow-up.

It was examined whether the occurrence of active TB in the It was examined whether the occurrence of active TB in the

household contacts differed by resistance pattern of the household contacts differed by resistance pattern of the

index patient: either MDR or XDR tuberculosis.index patient: either MDR or XDR tuberculosis.

Household contacts of patients initiating treatment for MDR Household contacts of patients initiating treatment for MDR

TB were tested for active TB.TB were tested for active TB.

Index patients:Index patients: First patient in each household to began an First patient in each household to began an

individualized MDR TB treatment regimen between Sept. 9, 1996 and individualized MDR TB treatment regimen between Sept. 9, 1996 and

Sept. 9, 2003.Sept. 9, 2003.

Household contacts:Household contacts: Living with the index patient on the date that the Living with the index patient on the date that the

MDR TB regimen was initiated.MDR TB regimen was initiated.

Retrospective cohort study of household contacts was done to identify Retrospective cohort study of household contacts was done to identify

the presence of active TB at the time the index patient began their the presence of active TB at the time the index patient began their

treatment regimen (co-prevalent TB) and the occurrence of active TB treatment regimen (co-prevalent TB) and the occurrence of active TB

in the subsequent 4 years (incident TB) in the subsequent 4 years (incident TB)

They excluded households located outside the metropolitan Lima They excluded households located outside the metropolitan Lima

region and households in which the index patient was not tested for region and households in which the index patient was not tested for

XDR TB.XDR TB.

This study protocol was approved by the research ethics committee of This study protocol was approved by the research ethics committee of

the Harvard Medical school and the National Institute of Health of the Harvard Medical school and the National Institute of Health of

Peru.Peru.

Written informed consent was obtained from participants. Written informed consent was obtained from participants.

Between 2004 and 2006, a study team did household visits to gather Between 2004 and 2006, a study team did household visits to gather

demographic data, TB treatment history of household members, and demographic data, TB treatment history of household members, and

data for the physical characteristics of the dwelling and the number of data for the physical characteristics of the dwelling and the number of

people sharing a bedroom and to identify individuals living with the people sharing a bedroom and to identify individuals living with the

index patient at the time they began their MDR tuberculosis regimen.index patient at the time they began their MDR tuberculosis regimen.

Substandard Housing conditions:Substandard Housing conditions: Dirt floor; walls or roof made of Dirt floor; walls or roof made of

straw matting, plastic, or plywood; or no access to water in the house.straw matting, plastic, or plywood; or no access to water in the house.

For index patients information about HIV co-infection and cavitary For index patients information about HIV co-infection and cavitary

disease at the start of the MDR tuberculosis regimen were recorded.disease at the start of the MDR tuberculosis regimen were recorded.

XDR TB:XDR TB: M tuberculosis M tuberculosis strain resistant to at least isoniazid, strain resistant to at least isoniazid,

rifampicin, a fluoroquinolone, and a second-line injectable drug rifampicin, a fluoroquinolone, and a second-line injectable drug

(amikacin, capreomycin, or kanamycin).(amikacin, capreomycin, or kanamycin).

Beginning in 1996, patients who were referred to the MDR Beginning in 1996, patients who were referred to the MDR

tuberculosis treatment programme had isolates routinely tested at the tuberculosis treatment programme had isolates routinely tested at the

Massachusetts State Laboratory Institute, which also tested isolates Massachusetts State Laboratory Institute, which also tested isolates

for resistance against a wider range of drugs, including a for resistance against a wider range of drugs, including a

fluoroquinolone and second-line injectable drugs.fluoroquinolone and second-line injectable drugs.

TB regimens were designed by a Ministry of Health physician TB regimens were designed by a Ministry of Health physician

according to national tuberculosis programme guidelines.according to national tuberculosis programme guidelines.

Prevalent TBPrevalent TB: a case of active TB disease in a household contact in : a case of active TB disease in a household contact in

the baseline window (defined as up to 180 days before and 30 days the baseline window (defined as up to 180 days before and 30 days

after the date on which the index patient initiated MDR tuberculosis after the date on which the index patient initiated MDR tuberculosis

treatment). treatment).

Incident TBIncident TB: a case of active TB in a household contact during the : a case of active TB in a household contact during the

follow-up, which began 31 days after the index patient started MDR follow-up, which began 31 days after the index patient started MDR

treatment, and ended on the date of the household interview or 4 years treatment, and ended on the date of the household interview or 4 years

after the index patient started MDR treatment, whichever came first. after the index patient started MDR treatment, whichever came first.

Statistical analysisStatistical analysis

Prevalent and incident TB in household contacts according to whether Prevalent and incident TB in household contacts according to whether

the index patient had XDR or MDR tuberculosis was compared.the index patient had XDR or MDR tuberculosis was compared.

The imbalanced factors were identified between households of index The imbalanced factors were identified between households of index patients with MDR TB and households of index patients with XDR patients with MDR TB and households of index patients with XDR TB (sex of index patient, receipt of three or more previous regimens TB (sex of index patient, receipt of three or more previous regimens by the index patient, bilateral cavitary disease in the index patient, by the index patient, bilateral cavitary disease in the index patient, number of people in the household, and substandard housing number of people in the household, and substandard housing conditions), and was included in analysis. conditions), and was included in analysis.

Data were double entered into a relational database designed in Data were double entered into a relational database designed in Microsoft Access 2003 and were analyzed with SAS 9.1, and Stata SE Microsoft Access 2003 and were analyzed with SAS 9.1, and Stata SE 10.1. 10.1.

To obtain the estimates of the incidence rate ratios adjusted for To obtain the estimates of the incidence rate ratios adjusted for household clustering, R 2.8.1 was used (R Foundation for Statistical household clustering, R 2.8.1 was used (R Foundation for Statistical Computing, Vienna, Austria).Computing, Vienna, Austria).

Role of funding source:Role of funding source:

The sponsors had no role in the study design, data collection, data The sponsors had no role in the study design, data collection, data analysis, data interpretation, or writing of this report.analysis, data interpretation, or writing of this report.

MCB had full access to all data and final responsibility to submit for MCB had full access to all data and final responsibility to submit for publication.publication.

Results:Results: Study profileStudy profile

Household contacts of index patients with confirmed MDR TBHousehold contacts of index patients with confirmed MDR TB

4943 contacts 4943 contacts

758 households758 households

Household contacts of index patients tested for XDR TBHousehold contacts of index patients tested for XDR TB

Yes NoYes No

4503 contacts 440 contacts4503 contacts 440 contacts

693 households 65 households693 households 65 households

Household contacts of index patients with confirmed XDR TBHousehold contacts of index patients with confirmed XDR TB

Yes NoYes No

312 contacts 4191 contacts312 contacts 4191 contacts

48 households 645 households48 households 645 households

Household contacts with prevalent TBHousehold contacts with prevalent TB

8 contacts 109 contacts8 contacts 109 contacts

2.56% prevalence 2.60% prevalence 2.56% prevalence 2.60% prevalence

Index MDR and XDR Index MDR but not Index MDR and XDR Index MDR but not XDRXDR

(n=48) (n=645) (n=48) (n=645)

Age of index patient (years) 28·5 (9·7) 28·4 (12·8)Age of index patient (years) 28·5 (9·7) 28·4 (12·8)Sex of index patient (female) 20 (41·7%) 263 (40·8%)Sex of index patient (female) 20 (41·7%) 263 (40·8%)Index patient had 3 or moreIndex patient had 3 or more

previous treatment regimens 38 (80·9%) 400 (62·5%)previous treatment regimens 38 (80·9%) 400 (62·5%)Index patient had cavitary Index patient had cavitary

disease at study baseline 37 (77·1%) 415 (64·3%)disease at study baseline 37 (77·1%) 415 (64·3%)Index patient had HIV Index patient had HIV

at study baseline 0 (0%) 6 (0·9%)at study baseline 0 (0%) 6 (0·9%)Number of people living in theNumber of people living in the

household per bedroom 7·5 (3·3) 7·0 (3·7)household per bedroom 7·5 (3·3) 7·0 (3·7)Housing with sub-standardHousing with sub-standard

conditions 12 (25·5%) 174 (28·5%) conditions 12 (25·5%) 174 (28·5%)

Table 2: Table 2: Household characteristics when index patient began Household characteristics when index patient began treatment regimentreatment regimen

Overall Index XDR Index MDR Adjusted hazard Overall Index XDR Index MDR Adjusted hazard ratio (95% CI)*ratio (95% CI)* Incidence rate per Cases Person-years Incidence rate per Cases Person-years Incidence rate per Cases Person-years Incidence rate per Cases Person-years Incidence rate per Cases Person-years Incidence rate per Cases Person-years 100 000 person-years 100 000 person-years 100 000 person-years100 000 person-years 100 000 person-years 100 000 person-years

Year 1 3165 140 4423 4252 13 306 3084 127 4117 1·24 (0·57–Year 1 3165 140 4423 4252 13 306 3084 127 4117 1·24 (0·57–2·66)2·66)Year 2 1092 47 4303 2714 8 295 973 39 4008 2·44 (1·09–Year 2 1092 47 4303 2714 8 295 973 39 4008 2·44 (1·09–5·46)5·46)Year 3 764 30 3927 1816 5 275 685 25 3651 2·67 (0·99–Year 3 764 30 3927 1816 5 275 685 25 3651 2·67 (0·99–7·20)7·20)Year 4 1112 25 2247 2734 5 183 969 20 2065 2·81 (0·89–Year 4 1112 25 2247 2734 5 183 969 20 2065 2·81 (0·89–8·83)8·83)Overall 1624 242 14 900 2928 31 1059 1524 211 13 841 1·88 (1·10–Overall 1624 242 14 900 2928 31 1059 1524 211 13 841 1·88 (1·10–3·21) 3·21)

(years 1–4)(years 1–4)

Table 3: Table 3: Incidence of active tuberculosis in household contacts Incidence of active tuberculosis in household contacts during 4-year follow-up periodduring 4-year follow-up period

Of the 4503 household contacts, 117 (2·60%) had active TB at the

time the index patient began MDR TB treatment—there was no

difference in prevalence between XDR and MDR TB households.

During the 4-year follow-up, 242 contacts developed active TB—the

frequency of active TB was nearly two times higher in contacts of

patients with XDR TB than it was in contacts of patients with MDR

TB (hazard ratio 1·88, 95% CI 1·10–3·21). In the 359 contacts with

active TB, 142 (40%) had had isolates tested for resistance against

first-line drugs, of whom 129 (90·9%, 95% CI 85·0–94·6) had MDR

TB.

Discussion:Discussion:

This study provides unique empirical evidence afforded by a large This study provides unique empirical evidence afforded by a large

cohort, a follow-up period of 4 years, almost 15 000 person-years of cohort, a follow-up period of 4 years, almost 15 000 person-years of

follow-up, and data for patients with both MDR and XDR TB and follow-up, and data for patients with both MDR and XDR TB and

their household contacts.their household contacts.

The study shows a very high prevalence of TB in household contacts The study shows a very high prevalence of TB in household contacts

of patients with XDR or MDR TB in metropolitan Lima, Peru. of patients with XDR or MDR TB in metropolitan Lima, Peru.

Almost 40% of household contacts with active TB had drug-Almost 40% of household contacts with active TB had drug-

susceptibility test results, more than 90% of whom had MDR TB. Of susceptibility test results, more than 90% of whom had MDR TB. Of

those household contacts with MDRTB, almost two-thirds had drug-those household contacts with MDRTB, almost two-thirds had drug-

susceptibility test results for ethambutol and streptomycin that susceptibility test results for ethambutol and streptomycin that

matched with their respective index patient. matched with their respective index patient.

These findings lend support to international guidelines that These findings lend support to international guidelines that

recommend prompt assessment of close contacts of all patients with recommend prompt assessment of close contacts of all patients with

MDR TB, and to suspect a close contact presenting with active TB as MDR TB, and to suspect a close contact presenting with active TB as

having MDR TB until proven otherwise.having MDR TB until proven otherwise.

It was recorded that a high tuberculosis disease burden in household It was recorded that a high tuberculosis disease burden in household

contacts not only during the baseline window, but also during the 4 contacts not only during the baseline window, but also during the 4

years of follow up. years of follow up.

This finding suggests that guidelines which recommend that people This finding suggests that guidelines which recommend that people

who have been exposed to MDR tuberculosis should be monitored for who have been exposed to MDR tuberculosis should be monitored for

at least 2 years to detect active disease, might not be sufficient. at least 2 years to detect active disease, might not be sufficient.

More work is needed to establish for how long a contact should be More work is needed to establish for how long a contact should be

monitored.monitored.

Limitations of the study:Limitations of the study:

There was no difference in the prevalence of TB among household There was no difference in the prevalence of TB among household

contacts (during the baseline window) between households of index contacts (during the baseline window) between households of index

patients with MDR TB and households of index patients with XDR patients with MDR TB and households of index patients with XDR

TB.TB.

Absence of genotypingAbsence of genotyping

Absence of HIV testing for the household members.Absence of HIV testing for the household members.

Interpretation :Interpretation :

In view of the high risk of disease recorded in household contacts of In view of the high risk of disease recorded in household contacts of

patients with MDR or XDR TB, TB programmes should implement patients with MDR or XDR TB, TB programmes should implement

systematic household contact investigations for all patients identified systematic household contact investigations for all patients identified

as having MDR or XDR TB.as having MDR or XDR TB.

If shown to have active TB, these household contacts should be If shown to have active TB, these household contacts should be

suspected as having MDR TB until proven otherwise.suspected as having MDR TB until proven otherwise.

TB programmers should implement systematic contact investigations TB programmers should implement systematic contact investigations

for all patients identified as having MDR or XDR TB.for all patients identified as having MDR or XDR TB.