Types of studies

For the primary purpose of determining the effects of any intervention, only randomised controlled clinical trials (RCTs) of preventive treatments will be considered, irrespective of whether the control group received a placebo. We will exclude quasi‐randomised studies.

Types of participants

HIV‐infected adults and children.

Types of interventions

Any intervention aimed at preventing HIV‐related MAC infection, including:

• Macrolides (clarithromycin, azithromycin)

• Ethambutol

• Rifabutin

• Fluoroquinolones

• Amikacin

• Clofazimine

The intervention may be a single drug or a combination. Also, the Interventions may be combined with ART as long as the intervention and control group both receive the same antiretroviral therapy.

Types of outcome measures

Primary outcome:

• Detection of disseminated MAC infection as evidenced by a positive culture from blood or other normally sterile site

Secondary outcome:

• All‐cause mortality

• Any adverse events ‐ any drug‐related adverse events will be reported.

Electronic searches

See: HIV/AIDS Cochrane Review Group search strategy.

Identification of studies was done with the assistance of the HIV/AIDS Review Group Trials Search coordinator. We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (i.e. published, unpublished, in press, and in progress).

We searched the following electronic databases in December 2012

1. PubMed, 1 January 1980 to 20 December 2012

2. EMBASE, 1 January 1980 to 20 December 2012

3. The Cochrane Central Register of Controlled Trials (Issue 12 2012)

The detailed search strategy for each of the databases are documented in Table 1; Table 2; and Table 3 respectively.

Searching other resources

We also searched the WHO International Clinical Trials Registry Platform. In addition, we checked the reference lists of all studies identified by the above methods and examined any systematic reviews, meta‐analyses or treatment guidelines we identified.

Selection of studies

Two authors (MU and OU) independently read the titles, abstracts, and descriptor terms of the search output from the different databases to identify potentially eligible studies. Full text articles were obtained for all citations identified as potentially eligible. Both authors (MU and OU) independently inspected these to establish the relevance of the articles according to the pre‐specified criteria. The studies were reviewed for relevance based on study design, types of participants, interventions, and outcome measures. We gave reasons for excluding potentially relevant studies in an excluded studies table.

Data extraction and management

We extracted data independently using the form we designed and agreed upon. Both authors verified the extracted data. Extracted information included the study, participant, intervention and outcome details. We summarized the eligible study using the RevMan software.The authors independently extracted the data, entered them into RevMan; and all disagreements were resolved by discussion.

Assessment of risk of bias in included studies

MU and OU independently examined the components of each included trial for risk of bias using a standard form. This included information on the sequence generation, allocation concealment, blinding (participants, personnel, and outcome assessor), incomplete outcome data, selective outcome reporting, and other sources of bias. The methodological components of the studies were assessed and classified as adequate, inadequate, or unclear as per the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). Where differences arose, they were resolved by discussions with the third reviewer (IY).

Sequence generation

• Low risk of bias: investigators described a random component in the sequence generation process such as the use of random number table, coin tossing, cards or envelops shuffling, etc.

• High risk of bias: investigators described a non‐random component in the sequence generation process such as the use of odd or even date of birth, algorithm based on the day/date of birth, hospital or clinic record number.

• Unclear: insufficient information to permit judgment of the sequence generation process.

Allocation concealment

• Low risk of bias: participants and the investigators enrolling participants cannot foresee assignment (e.g. central allocation; or sequentially numbered, opaque, sealed envelopes).

• High risk of bias: participants and investigators enrolling participants can foresee upcoming assignment (e.g. an open random allocation schedule (e.g. a list of random numbers); or envelopes were unsealed or non­opaque or not sequentially numbered).

• Unclear: insufficient information to permit judgment of the allocation concealment or the method not described.

Blinding

• Low risk of bias: blinding of the participants, key study personnel and outcome assessor, and unlikely that the blinding could have been broken. Or lack of blinding unlikely to introduce bias. No blinding in the situation where non‐blinding is not likely to introduce bias.

• High risk of bias: no blinding, incomplete blinding and the outcome is likely to be influenced by the lack of blinding.

• Unclear: insufficient information to permit judgment of adequacy or otherwise of the blinding.

Incomplete outcome data

• Low risk of bias: no missing outcome data, reasons for missing outcome data unlikely to be related to true outcome, or missing outcome data balanced in number across groups.

• High risk of bias: reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data.

• Unclear: insufficient reporting of attrition or exclusions.

Selective Reporting

• Low risk of bias: a protocol is available which clearly states the primary outcome as the same as in the final trial report.

• High risk of bias: the primary outcome differs between the protocol and final trial report.

• Unclear: no trial protocol is available or there is insufficient reporting to determine if selective reporting is present.

Other forms of bias

• Low risk of bias: there is no evidence of bias from other sources.

• High risk of bias: there is potential bias present from other sources (e.g. early stopping of trial, fraudulent activity, extreme baseline imbalance or bias related to specific study design).

• Unclear: insufficient information to permit judgment of adequacy or otherwise of other forms of bias.

Measures of treatment effect

Outcome measures for dichotomous data (e.g. development of MAC infection and death) were calculated as a relative risk with 95% confidence intervals.

Assessment of heterogeneity

We did not have a sufficient number of studies to perform a meta‐analysis. Therefore we could not assess statistical heterogeneity. However, the included studies differed in terms of the prophylactic agents used.

Data synthesis

MU and OU independently extracted data from the included studies. The data were summarised in RevMan 5.1. All of the entries were checked by both authors.