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Interventions for the prevention of mycobacterium avium complex in adults and children with HIV

  1. Muhammed Mubashir B Uthman1,2,*,
  2. Olalekan A Uthman3,
  3. Ismail Yahaya4,5

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 30 APR 2013

Assessed as up-to-date: 11 JAN 2013

DOI: 10.1002/14651858.CD007191.pub2


How to Cite

Uthman MMB, Uthman OA, Yahaya I. Interventions for the prevention of mycobacterium avium complex in adults and children with HIV. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD007191. DOI: 10.1002/14651858.CD007191.pub2.

Author Information

  1. 1

    University of Ilorin, Department of Epidemiology & Community Health, Faculty of Clinical Sciences, College of Health Sciences, Ilorin, Kwara, Nigeria

  2. 2

    University of Ilorin Teaching Hospital (UITH), Ilorin, Nigeria

  3. 3

    Division of Health Sciences, Warwick Medical School, The University of Warwick, Warwick-Centre for Applied Health Research and Delivery (WCAHRD), Warwick, UK

  4. 4

    Mid-Sweden University, Department of Public Health, Sundsvall, Sweden

  5. 5

    Heart of England NHS Foundation Trust, Birmingham, UK

*Muhammed Mubashir B Uthman, uthmanmb@yahoo.com. mubashiruthman@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 30 APR 2013

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Characteristics of included studies [ordered by study ID]
Abrams 1993

MethodsRCT


ParticipantsPatients with advanced HIV


Interventions50mg/day clofazimine vs. no treatment


OutcomesPrimary outcomes

  1. Disseminated MAC infection (diagnosed by blood culture positive for acid-fast bacilli or positive bone marrow biopsy)
  2. Death


NotesCommunity-based clinical trial conducted in USA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described in the study

Allocation concealment (selection bias)Unclear riskNot described in the study

Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study

Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label study

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in number across groups.

Selective reporting (reporting bias)Low riskCompares favourably with protocol on www.ClinicalTrials.gov (Identifier: NCT00002058)

Other biasUnclear riskThere was no sufficient information to determine whether there is a risk of other potential sources of bias

Benson 2000

MethodsRCT


ParticipantsHIV-infected persons with ≤ 100 CD4 T lymphocytes/ʯL


InterventionsClarithromycin (500mg 2 times a day) vs. rifabutin (450mg once per day) vs. clarithromycin plus rifabutin


OutcomesPrimary outcome

  1. Development of MAC infection as defined by a single blood culture positive for MAC after randomisation or the isolation of MAC from another normally sterile site plus at least 1 sign or symptom of MAC infection, as previously defined


Secondary outcome

  1. Death
  2. treatment-limiting adverse effects


NotesMulticenter study conducted in USA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"... use permuted blocks of six"

Allocation concealment (selection bias)Low risk"randomisation was done centrally by ..."

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"... patients .. remained blinded to treatment assignment and dose..."

Blinding of outcome assessment (detection bias)
All outcomes
Low risk".. participating clinicians remained blinded to treatment assignment..."

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo published information on the study was found.

Selective reporting (reporting bias)Low riskCompares favourably with protocol on www.ClinicalTrials.gov (Identifier: NCT00001030)

Other biasLow riskNo other potential sources of bias identified

Currier 2000

MethodsRCT


ParticipantsDocumented HIV infection and CD4+ cell counts of 0.05 X 109 cells/L or less followed by a documented increase in CD4+ cell count to 0.10X109 cells/L or more on two separate occasions at least 4 weeks apart, with no intervening values less than 0.10 X109 cells/L.


InterventionsAzithromycin (1200mg once weekly) vs. matching placebo


OutcomesPrimary outcome

  1. development of MAC infection, defined by growth from a usually sterile site, such as blood, lymph node, liver, or bone marrow.


Secondary outcome

  1. Death


NotesMulticenter study conducted in USA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomisation process was appropriate.

Allocation concealment (selection bias)Unclear riskNo published information on the study was found.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Both participants and staff were blinded to treatment assignment throughout the study"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Both participants and staff were blinded to treatment assignment throughout the study"

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in number across groups.

Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting

Other biasLow riskNo other potential sources of bias identified

El-Sadr 2000

MethodsRCT


ParticipantsHIV-infected patients with CD4+ cell count of less than 50 per cubic millimeter (at any time in the past), followed by a count of more than 100 cells per cubic millimeter on two consecutive occasions in response to antiretroviral therapy


InterventionsAzithromycin (1200mg once weekly) vs. matching placebo


OutcomesPrimary outcome

  1. development of confirmed MAC infection


Secondary outcome

  1. Death


NotesMulticenter study conducted in USA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo published information on the study was found.

Allocation concealment (selection bias)Unclear riskNo published information on the study was found.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information was provided on who was masked, though the study was described as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information was provided on who was masked, though the study was described as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in number across groups.

Selective reporting (reporting bias)Low riskCompares favourably with protocol on www.ClinicalTrials.gov (Identifier: NCT00000947)

Other biasLow riskNo other potential sources of bias identified.

Havlir 1996

MethodsRCT


ParticipantsHIV-infected patients with fewer than 100 CD4 cell per cubic millimeter


InterventionsRifabutin (300mg daily) vs. azithromycin (1200mg weekly) vs. rifabutin plus azithromycin


OutcomesPrimary outcome

  1. Development of MAC infection, which was diagnosed on the basis of a positive culture of MAC from blood or another sterile body site


NotesMulticenter study conducted in USA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNo published information on the study was found.

Allocation concealment (selection bias)Unclear riskNo published information on the study was found.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information was provided on who was masked, though the study was described as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information was provided on who was masked, though the study was described as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo published information on the study was found.

Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting

Other biasUnclear riskThere was no sufficient information to determine whether there is a risk of other potential sources of bias

Nightingale 1993

MethodsRCT


ParticipantsHIV-infected patients with ≤ 200 CD4 cell per cubic millimeter


InterventionsRifabutin (300mg daily) vs. placebo


OutcomesPrimary outcome

  1. Development of MAC infection


Secondary outcome

  1. Death


NotesMulticenter study conducted in USA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPermuted block

Allocation concealment (selection bias)Unclear riskNo published information on the study was found.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information was provided on who was masked, though the study was described as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information was provided on who was masked, though the study was described as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in number across groups.

Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting

Other biasUnclear riskThere was no sufficient information to determine whether there is a risk of other potential sources of bias

Oldfield 1998

MethodsRCT


ParticipantsHIV-infected with one documented CD4 cell count <100/mm3 within the preceding 12 months


InterventionsAzithromycin (300-mg weekly) vs. matching placebo


OutcomesPrimary outcome

Development of MAC infection documented by culture of a specimen


NotesMulticenter study conducted in USA


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskPatients were randomly assigned in one-to-one ratio by a computer-generated random code

Allocation concealment (selection bias)Unclear riskNo published information on the study was found.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo published information on the study was found.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo published information on the study was found.

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in number across groups.

Selective reporting (reporting bias)Low riskCompares favourably with protocol on www.ClinicalTrials.gov (Identifier: NCT00002309)

Other biasUnclear riskNo published information on the study was found.

Pierce 1996

MethodsRCT


ParticipantsHIV-infected patients with CD4 count 100 or less per cubic millimeter


InterventionsClarithromycin (500mg) vs. matching placebo


OutcomesPrimary outcome

  1. development of disseminated MAC infection as confirmed by a positive culture from blood or another sterile site


Secondary outcome

  1. All-cause mortality


NotesMulticenter study conducted in USA and Europe


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk... use a computer-generated randomisation sequence

Allocation concealment (selection bias)Unclear riskNo published information on the study was found.

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information was provided on who was masked, though the study was described as double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information was provided on who was masked, though the study was described as double-blind

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in number across groups.

Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting

Other biasHigh riskLarge proportion of patients withdrew from the study

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Chu 2011Systematic review

Cohn 1997Review article

Currier 1997Review article

Dube 1997Not a prophylaxis study, prevention of lapse of MAC

Dube 1999Non-RCT

Green 2004Non-RCT

McNabb 2000No relevant outcome, not efficacy study

Moore 1995Re-analysis of Nightingale 1993

Ong 1999Review article

Ostroff 1995Review article

Siegal 1996Review article

 
Comparison 1. Monotherapy versus no treatment or placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Development of MAC disease6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Clofazimine vs. no treatment
199Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.37, 2.80]

    1.2 Rifabutin vs. placebo
11146Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.35, 0.67]

    1.3 Azithromycin vs. placebo
31337Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.19, 0.74]

    1.4 Clarithromycin vs. placebo
1667Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.21, 0.58]

 2 All-cause mortality6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Clofazimine vs. no treatment
199Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.41, 2.32]

    2.2 Rifabutin vs. placebo
11146Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.78, 1.05]

    2.3 Azithromycin vs. placebo
31337Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.69, 1.32]

    2.4 Clarithromycin vs. placebo
1667Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.64, 0.96]

 
Comparison 2. Monotherapy versus monotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Development of MAC disease2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Clarithromycin vs.rifabutin
1789Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.41, 0.89]

    1.2 Azithromycin vs. rifabutin
1446Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.40, 0.89]

 2 All-cause mortality2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Clarithromycin vs.rifabutin
1789Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.83, 1.15]

    2.2 Azithromycin vs. rifabutin
1446Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.77, 1.24]

 
Comparison 3. Combination therapy versus monotherapy

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Development of MAC disease2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Rifabutin plus Clarithromycin vs. clarithromycin
1787Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.46, 1.20]

    1.2 Rifabutin plus Clarithromycin vs. rifabutin
1780Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.29, 0.69]

    1.3 Rifabutin plus azithromycin vs. azithromycin
1441Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.34, 1.03]

    1.4 Rifabutin plus azithromycin vs. rifabutin
1441Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.21, 0.59]

 2 All-cause mortality2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Rifabutin plus Clarithromycin vs. clarithromycin
1787Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.94, 1.28]

    2.2 Rifabutin plus Clarithromycin vs. rifabutin
1780Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.92, 1.25]

    2.3 Rifabutin plus azithromycin vs. azithromycin
1441Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.78, 1.27]

    2.4 Rifabutin plus azithromycin vs. rifabutin
1441Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.77, 1.24]

 
Table 1. Search strategy for MEDLINE

NumberSearch terms

#1HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw]))

#2"mycobacterium avium complex" [Mesh] OR mycobacterium avium complex [tw] OR mycobacterium avium OR MAC

#3#1 OR #2

#4randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ( placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh] OR prospective studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animals [mh] NOT human [mh])

#5#3 AND #4

#6#5 Field: All Fields, Limits: from 1980 to 2008, HUMAN

 
Table 2. Search strategy for EMBASE

NumberSearch terms

#1'human immunodeficiency virus infection'/exp

#2'human immunodeficiency virus'/exp

#3hiv:ti OR hiv:ab

#4'hiv-1':ti OR 'hiv-1':ab

#5'hiv-2':ti OR 'hiv-2':ab

#6'human immunodeficiency virus':ti OR 'human immuno deficiency':ab

#7'human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab

#8'human immunedeficiency virus':ti OR 'human immune deficiency virus':ab

#9'human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab

#10'acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab

#11'acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab

#12'acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab

#13'acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab

#14#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13

#15'mycobacterium avium complex'

#16Mac

#17' mycobacterium avium'

#18#15 OR #16 OR #17

#19random*:ti OR random*:ab

#20factorial*:ti OR factorial*:ab

#21cross ?over*:ti OR cross?over:ab OR crossover*:ti OR crossover *:ab

#22placebo*:ti OR placebo*:ab

#23((doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab))

#24((singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab))

#25assign*:ti OR assign*:ab

#26volunteer*:ti OR volunteer*:ab

#27'crossover procedure'/de

#28'double-blind procedure'/de

#29'single-blind procedure'/de

#30'randomized controlled trial'/de

#31allocat*:ti OR allocat*:ab

#32#19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31

#33#14 AND #18 AND #32

 
Table 3. Search strategy for CENTRAL


NumberSearch terms

#1hiv OR hiv-1* OR hiv-2* OR hiv1 OR hiv2 OR (HIV INFECT*) OR (HUMAN IMMUNODEFICIENCY VIRUS) OR (HUMAN IMMUNEDEFICIENCY
VIRUS) OR (HUMAN IMMUNE-DEFICIENCY VIRUS) OR (HUMAN IMMUNO-DEFICIENCY VIRUS) OR (HUMAN IMMUN* DEFICIENCY VIRUS) OR
(ACQUIRED IMMUNODEFICIENCY SYNDROME) OR (ACQUIRED IMMUNEDEFICIENCY SYNDROME) OR (ACQUIRED IMMUNO-DEFICIENCY
SYNDROME) OR (ACQUIRED IMMUNE-DEFICIENCY SYNDROME) OR (ACQUIRED IMMUN* DEFICIENCY SYNDROME) in All Fields in all products

#2MeSH descriptor HIV Infections explode all trees in MeSH products

#3MeSH descriptor HIV explode all trees in MeSH products

#4(#1 OR #2 OR #3)

#5(MYCOBACTERIUM AVIUM COMPLEX) OR (MYCOBACTERIUM AVIUM) in All Fields in all products

#6(#4 AND #5)

 
Table 4. Loss to follow-up

Study IDInterventionLoss to follow-up (%)P-value

Abrams 1993   

 Clofazamine3.70.048

 No treatment15.2 

Nightingale 1993   

 Rifabutin6.10.518

 Placebo7.1 

Havlir 1996   

 Rifabutin5.50.316

 Azithromycin4.3 

 Combination2.7 

Pierce 1996   

 Clarithromycin6.60.921

 Placebo6.9 

Currier 2000   

 Azithromycin9.30.681

 Placebo10.3 

El-Sadr 2000   

 Azithromycin1.60.688

 Placebo1.2