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Tratamiento de observación directa para la tuberculosis

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Directly observed therapy for treating tuberculosis

Tuberculosis is a leading cause of death in low- and middle-income countries, despite the availability of effective treatments. In the latest update of the Cochrane Review of one of the methods that might help in the delivery of these treatments, Jamlick Karumbi and Paul Garner have brought together the latest evidence on directly observed therapy. Jamlick, from the SIRCLE collaboration based in Nairobi in Kenya, tells us what they found in the review that was published in May 2015.

Factors influencing adherence and possible intervention points.
Figuras y tablas -
Figure 1

Factors influencing adherence and possible intervention points.

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
Figuras y tablas -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.
Figuras y tablas -
Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included trials.

Comparison 1 Directly observed versus self‐administered, Outcome 1 Cure (negative sputum smear in last month of Rx in patients +ve initially).
Figuras y tablas -
Analysis 1.1

Comparison 1 Directly observed versus self‐administered, Outcome 1 Cure (negative sputum smear in last month of Rx in patients +ve initially).

Comparison 1 Directly observed versus self‐administered, Outcome 2 Cure (by intensity of monitoring in control group).
Figuras y tablas -
Analysis 1.2

Comparison 1 Directly observed versus self‐administered, Outcome 2 Cure (by intensity of monitoring in control group).

Comparison 1 Directly observed versus self‐administered, Outcome 3 Treatment completion (both with smear sputum test at end and those without).
Figuras y tablas -
Analysis 1.3

Comparison 1 Directly observed versus self‐administered, Outcome 3 Treatment completion (both with smear sputum test at end and those without).

Comparison 1 Directly observed versus self‐administered, Outcome 4 Treatment completion (grouped by frequency of monitoring in the self‐administered therapy group).
Figuras y tablas -
Analysis 1.4

Comparison 1 Directly observed versus self‐administered, Outcome 4 Treatment completion (grouped by frequency of monitoring in the self‐administered therapy group).

Comparison 2 Home observed versus clinic observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).
Figuras y tablas -
Analysis 2.1

Comparison 2 Home observed versus clinic observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).

Comparison 2 Home observed versus clinic observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).
Figuras y tablas -
Analysis 2.2

Comparison 2 Home observed versus clinic observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).

Comparison 2 Home observed versus clinic observed, Outcome 3 Cure (stratified by intensity of observation).
Figuras y tablas -
Analysis 2.3

Comparison 2 Home observed versus clinic observed, Outcome 3 Cure (stratified by intensity of observation).

Comparison 3 Community observed vs family observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).
Figuras y tablas -
Analysis 3.1

Comparison 3 Community observed vs family observed, Outcome 1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially).

Comparison 3 Community observed vs family observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).
Figuras y tablas -
Analysis 3.2

Comparison 3 Community observed vs family observed, Outcome 2 Treatment completion (both with smear sputum test at end and those without).

Comparison 4 Injecting drug users, Outcome 1 Treatment completion.
Figuras y tablas -
Analysis 4.1

Comparison 4 Injecting drug users, Outcome 1 Treatment completion.

Summary of findings for the main comparison. Directly observed therapy (DOT) versus self‐administered TB treatment

Directly observed therapy (DOT) versus self‐administered TB treatment

Patient or population: Patients on TB treatment
Settings: Low‐, middle‐ or high‐income countries
Intervention: DOT
Comparison: Self‐administered therapy

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Self‐administered therapy

DOT

Cure
Follow‐up: up to 6 months

617 per 1000

666 per 1000
(561 to 784)

RR 1.08
(0.91 to 1.27)

1645
(5 trials)

⊕⊕⊕⊝
moderate1,2,3,4

Treatment completion

Follow‐up: 2 to 8 months5

709 per 1000

751 per 1000
(680 to 829)

RR 1.07
(0.96 to 1.19)

1839
(6 trials)

⊕⊕⊕⊝
moderate1,2,3,4

The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; DOT: directly observed therapy; TB: tuberculosis.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1No serious risk of bias: three trials adequately described allocation concealment. Exclusion of trials at unclear or high risk of bias did not substantially change the result.
2Downgraded by 1 for inconsistency: trials include qualitative differences in effect size and direction. The benefit reached standard levels of statistical significance in the two trials where those receiving self‐administered therapy had less frequent contact with health services compared to the directly observed group, so any effect probably due to confounding.
3No serious indirectness: The trials were conducted in low‐, middle‐ and high‐income countries between 1995 and 2008.
4No serious imprecision: The analysis is adequately powered to detect clinically important differences between treatment arms.
5Some trials checked for completion of intensive phase treatment and others the completion of the whole therapy, hence the 2 to 8 months.

Figuras y tablas -
Summary of findings for the main comparison. Directly observed therapy (DOT) versus self‐administered TB treatment
Summary of findings 2. Home DOT versus clinic DOT

Home DOT versus clinic DOT

Patient or population: Patients with TB treatment
Settings: Low‐, middle‐ or high‐income countries
Intervention: Home observation
Comparison: Clinic observation

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Clinic observation

Home observation

Cure
Follow‐up: up to 6 months

492 per 1000

502 per 1000
(433 to 580)

RR 1.02
(0.88 to 1.18)

1556
(4 trials)

⊕⊕⊕⊝
moderate1,2,3

Treatment completion4
Follow‐up: 2 to 6 months

751 per 1000

781 per 1000
(684 to 879)

RR 1.04
(0.91 to 1.17)

1029
(3 trials)

⊕⊕⊕⊝
moderate1,2,3

The basis for the assumed risk is the median control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; DOT: directly observed therapy; TB: tuberculosis.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Downgraded by 1 for risk of bias: selection bias is probable in one trial, Wandwalo 2004 TZA, as there was no blinding and no allocation concealment. In Lwilla 2003 TZA, sequence generation and allocation concealment were unclear and there was no blinding. This could bias the measurement of treatment completion.
2No serious indirectness: The trials were conducted in low‐, middle‐ and high‐income countries between 1995 and 2008.
3No serious imprecision: The analysis is adequately powered to detect clinically important differences between treatment arms.
4Some trials checked for completion of intensive phase treatment and others the completion of the whole therapy, hence the 2 to 6 months.

Figuras y tablas -
Summary of findings 2. Home DOT versus clinic DOT
Summary of findings 3. Summary of findings table 3

Community DOT versus family DOT

Patient or population: Patients on TB treatment
Settings: Low‐, middle‐ or high‐income countries
Intervention: Community DOT
Comparison: Family DOT

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Family DOT

Community DOT

Cure

Follow‐up: up to 6 months

766 per 1000

781 per 1000
(659 to 927)

RR 1.02 (0.86 to 1.21)

1493

(2 trials)

⊕⊕⊕⊝
moderate1

Treatment completion

Follow‐up: 2 to 6 months

827 per 1000

869 per 1000
(744 to 1000)

RR 1.05 (0.90 to 1.22)

1493

(2 trials)

⊕⊕⊝⊝
low1,2

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; DOT: directly observed therapy; TB: tuberculosis.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Downgraded by 1 for risk of bias. Both trials had unclear random sequence generation and recruitment bias could not be ruled out for Newell 2006 NPL.
2Downgraded by 1 for risk of bias for the outcome of treatment completion as there was no allocation concealment and selective reporting could not be ruled out in Wright 2004 SWZ.

Figuras y tablas -
Summary of findings 3. Summary of findings table 3
Summary of findings 4. DOT versus self‐administered therapy for intravenous drug users

DOT versus self‐administered therapy for intravenous drug users

Patient or population: Patients on TB treatment
Settings: Low‐, middle‐ or high‐income countries
Intervention: DOT
Comparison: Self‐administered treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(trials)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Self‐administered therapy

DOT

Treatment completion

Follow‐up for 6 months

79 per 100

79 per 1000
(70 to 89)

RR 1.00 (0.88 to 1.13)

300
(1 trial)

⊕⊕⊝⊝
low1,2,3

*The basis for the assumed risk (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio; DOT: directly observed therapy; TB: tuberculosis.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Downgraded by 1 for risk of bias. There was no blinding of outcome assessment and allocation concealment was unclear and treatment completion can be a bit subjective hence the results might be biased. The level of completeness to follow‐up was 88%.
2Downgraded by 1 for indirectness. The self‐administered group had a 10 dollar stipend which is may have enhanced adherence in this group.
3There may have been some imprecision. The study was had a small sample size and may have been underpowered to detect clinically important differences.

Figuras y tablas -
Summary of findings 4. DOT versus self‐administered therapy for intravenous drug users
Table 1. Summary of interventions in trials of DOT versus self‐administered

Trial ID

DOT

Self administered therapy

Who observed?

Where?

How often?

Adherence recorded at each contact

Cure

Frequency of contact with health service

Adherence recorded at each contact

Cure

Intensive phase

Consolidation phase

Zwarenstein 1998 ZAF

Nurses

Clinic

5 times per week

3 times per week

Yes

38%

(42/111)

Weekly

Yes

51%

(31/61

Zwarenstein 2000 ZAF

Nurse

Clinic

5 times per week

3 times per week

Yes

57%

(31/54)

Weekly

Yes

41%

(9/22)

Lay health worker

Lay health workers home

Kamolratanakul 1999 THA1

Healthcare worker

Clinic

Daily

Daily

Yes

76%
(315/414)

Monthly

Unclear

67%

(283/422)

Community health worker

Home

Daily

Daily

Family member

Home

Daily

Daily

Walley 2001 PAK

Healthcare worker

Clinic

6 times per week

2 times per month

Yes

59%

(199/335)

Every two weeks

Unclear

62%

(100/162)

Community health worker

Home

Family member

Home

Daily

Daily

MacIntyre 2003 AUS2

Family member

Home

Daily

Daily

Yes

Not reported

Monthly

Yes

Not reported

Hsieh 2008 TWN3

Case manager or

Hospital care

Hospital

Daily

Once per week

Yes

94%

(30/32)

Monthly unscheduled visit

Yes

69%

(22/32)

1In Kamolratanakul 1999 THA patients could choose which observer they preferred and there a more intense supervision of observers in the intensive phase.
2In MacIntyre 2003 AUS nurses made weekly calls to the patients who were observed by a family member.
3In Hsieh 2008 TWN the case manager directly supervised medicine intake for first two months (Intensive phase), then self‐administration with weekly unscheduled visit.

Figuras y tablas -
Table 1. Summary of interventions in trials of DOT versus self‐administered
Table 2. Interventions comparing home versus clinic direct observation

Trial ID

DOT at patient's home

DOT at clinic

Who observed?

How often?

Supervision of observer

Cure

Who observed?

How often?

Cure

Intensive phase

Consolidation phase

Intensive phase

Consolidation phase

Walley 2001 PAK1

Family member

Daily

Not described

Observers collected drugs from the clinic every 2 weeks

55%

(91/165)

Health worker

6 times per week

Self‐supervised

64%

(108/170)

Wandwalo 2004 TZA1

Family member or former TB patient

Daily

Self‐supervised

Observers collected drugs from clinic weekly and spot checks were conducted by health worker

43%

(111/260)

Health worker

Daily

Self‐supervised

43%

(141/327)

Zwarenstein 2000 ZAF

Lay health worker2

'Several times a week'

Not described

Observer collected drugs monthly

57%

(31/54)

Health worker

5 times a week

3 times a week

41%

(24/58)

Lwilla 2003 TZA1

Community volunteer

Daily

Self‐supervised

Observer was visited every two weeks by the health worker and every month by the district co‐ordinator3

53%

(117/221)

Health worker

Daily

Self‐supervised

49%

(148/301)

1In Lwilla 2003 TZA, Walley 2001 PAK and Wandwalo 2004 TZA observation was during the intensive phase, while in the clinic observation arm of Zwarenstein 2000 ZAF it continued in the consolidated phase.
2In Zwarenstein 2000 ZAF the observation took place in the lay health worker's home, not the patient's home.
3In Lwilla 2003 TZA there was additional supervision by the district coordinator.

Figuras y tablas -
Table 2. Interventions comparing home versus clinic direct observation
Table 3. Interventions comparing family‐administered DOT versus community health worker DOT

Trial ID

Who observed?

Where?

How often?

Additional intervention

Who observed?

Where?

How often?

Intensive phase

Consolidation phase

Intensive phase

Consolidation phase

Newell 2006 NPL

Family member

Patient's home

Daily

Daily

Drugs supplied to supervisor every week

Community health worker

Patient's home1

Daily

Daily

Wright 2004 SWZ

Family member

Patient's home

Daily

Daily

Patient reviewed at the diagnostic centre once per month

Recorded in a patient adherence card

Community health worker

Community health worker's home

Daily

Daily

1In Newell 2006 NPL the community health worker mainly visited the patients at their homes but occasionally the patients came to the health worker's home.

Figuras y tablas -
Table 3. Interventions comparing family‐administered DOT versus community health worker DOT
Comparison 1. Directly observed versus self‐administered

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cure (negative sputum smear in last month of Rx in patients +ve initially) Show forest plot

5

1645

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.91, 1.27]

2 Cure (by intensity of monitoring in control group) Show forest plot

5

1645

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [1.00, 1.15]

2.1 Monthly monitoring of patients in self administered group

2

900

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.06, 1.25]

2.2 Once every two weeks monitoring of patients in self‐administered group

1

497

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.83, 1.12]

2.3 Weekly monitoring of patients in self‐administered group

2

248

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.68, 1.21]

3 Treatment completion (both with smear sputum test at end and those without) Show forest plot

6

1839

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.96, 1.19]

4 Treatment completion (grouped by frequency of monitoring in the self‐administered therapy group) Show forest plot

6

1839

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.96, 1.19]

4.1 Monthly monitoring of self‐administered treatment

3

1073

Risk Ratio (M‐H, Random, 95% CI)

1.12 [0.95, 1.31]

4.2 Once every two weeks monitoring of self‐administered treatment

1

497

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.87, 1.14]

4.3 Weekly monitoring of self‐administered treatment

2

269

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.74, 1.46]

Figuras y tablas -
Comparison 1. Directly observed versus self‐administered
Comparison 2. Home observed versus clinic observed

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially) Show forest plot

4

1556

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.88, 1.18]

2 Treatment completion (both with smear sputum test at end and those without) Show forest plot

3

1034

Risk Ratio (M‐H, Random, 95% CI)

1.04 [0.91, 1.17]

3 Cure (stratified by intensity of observation) Show forest plot

4

1556

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.91, 1.11]

3.1 DOT (Intense supervision of observer)

1

522

Risk Ratio (M‐H, Fixed, 95% CI)

1.08 [0.91, 1.28]

3.2 Routine supervision of DOT

3

1034

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.86, 1.10]

Figuras y tablas -
Comparison 2. Home observed versus clinic observed
Comparison 3. Community observed vs family observed

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cure (having a negative sputum smear test in the last month of treatment having been smear‐positive initially) Show forest plot

2

1493

Risk Ratio (M‐H, Random, 95% CI)

1.02 [0.86, 1.21]

2 Treatment completion (both with smear sputum test at end and those without) Show forest plot

2

1493

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.90, 1.22]

Figuras y tablas -
Comparison 3. Community observed vs family observed
Comparison 4. Injecting drug users

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment completion Show forest plot

1

300

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.88, 1.13]

Figuras y tablas -
Comparison 4. Injecting drug users