Types of studies

• Randomised controlled trials (RCTs)

• Observational studies with comparison groups (e.g., cohort studies)

We chose to include observational studies for multiple reasons. First, RCTs were not expected to be commonly performed because it would likely be unethical to restrict presumed efficacious treatment to HIV‐infected children. Additionally, we did not anticipate a large body of data and we wanted to be less restrictive in gathering the evidence.

Types of participants

• HIV‐infected infants and children <18 years old treated with ART who have been diagnosed with KS

Types of interventions

• ART plus antineoplastic therapy

• ART alone

• Antineoplastic therapy alone

For purposes of this review antineoplastic therapy includes:

• For extensive skin involvement or disseminated or systemic disease, systemic chemotherapy including: single‐agent liposomal doxorubicin; combination chemotherapy with bleomycin, vincristine and doxorubicin; and single‐agent paclitaxel

• Non‐chemotherapeutic agents including: interferon alfa

• For symptomatic local disease, local therapies including: radiotherapy, intralesional chemotherapy, cryotherapy, surgery, topical therapy and laser and photodynamic treatment

Types of outcome measures

The following are the outcomes of interest we extracted for included studies. However, if a study did not have relevant outcome data but still satisfied our inclusion criteria, we would include it for descriptive purposes.

Electronic searches

We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press and in progress). Full details of the Cochrane HIV/AIDS Review Group methods and the journals hand‐searched are published in the section on Collaborative Review Groups in The Cochrane Library.

We searched the following electronic databases, in the period from 01 January 1980 to the search date (06 January 2014):

• CENTRAL (Cochrane Central Register of Controlled Trials)

• EMBASE

• PubMed

• Web of Science

• World Health Organization (WHO) Global Health Library (http://www.globalhealthlibrary.net), which includes references from AIM (AFRO), LILACS (AMRO/PAHO), IMEMR (EMRO), IMSEAR (SEARO), and WPRIM (WPRO)

Along with appropriate MeSH terms and relevant keywords, we used the Cochrane Highly Sensitive Search Strategy for identifying reports of randomised controlled trials in MEDLINE (Higgins 2008), and the Cochrane HIV/AIDS Group's validated strategies for identifying references relevant to HIV infection and AIDS. The search strategy was iterative, in that references of included studies were searched for additional references. All languages were included.

See Appendix 1 for our PubMed search strategy, which was modified and adapted as needed for use in the other databases.

Conference databases

We searched the Aegis archive of HIV/AIDS conference abstracts, which includes abstracts for the following conferences:

• British HIV/AIDS Association, 2001‐2010

• Conference on Retroviruses and Opportunistic Infections (CROI), 1994‐2008

• European AIDS Society Conference, 2001 and 2003

• International AIDS Society, International AIDS Conference (IAC), 1985‐2006

• International AIDS Society, Conference on HIV Pathogenesis, Treatment and Prevention (IAS), 2001‐2005

• US National HIV Prevention Conference, 1999, 2001, 2003, 2005, 2007, 2009, and 2011

We also searched the CROI and International AIDS Society web sites for abstracts presented at conferences subsequent to those listed above (CROI, 2009‐2013; IAC, 2008‐2012; IAS, 2007‐2013).

Searching other resources

In addition to searching electronic databases, we contacted individual researchers, experts working in the field and authors of major trials to address whether any relevant manuscripts are in preparation or in press. The references of published articles found in the above databases were searched for additional pertinent materials. We searched WHO's International Clinical Trials Registry Platform (ICTRP) and www.clinicaltrials.gov to identify ongoing clinical trials.

Selection of studies

One author performed a broad first cut of all downloaded material from the electronic searches to exclude citations that are plainly irrelevant. Two authors read the titles, abstracts, and descriptor terms of the remaining downloaded citations to identify potentially eligible reports. Full text articles were obtained for all citations identified as potentially eligible and two authors independently inspected these to establish the relevance of the article according to the pre‐specified criteria. Where there was uncertainty as to the eligibility of the record, the full article was obtained. Two authors independently applied the inclusion criteria, and any differences arising were resolved by discussion with a neutral arbiter. Studies were reviewed for relevance based on study design, types of participants, and outcome measures. Studies were included irrespective of their publication status if we were able to identify and obtain unpublished data.

Data extraction and management

Two authors independently extracted data into a standardised, pre‐tested data extraction form. The following characteristics were extracted from each included study:

• Administrative details: trial identification number; author(s); published or unpublished; year of publication; number of studies included in paper; year(s) in which study was conducted; details of other relevant papers cited

• Details of the study: study design; type, duration and completeness of follow up; location/orientation of study (e.g. higher‐income vs. low or middle‐income country; stage of HIV epidemic)

• Details of participants: age range; gender; clinical characteristics if appropriate

• Details of treatment

• Details of outcomes

• Details necessary for risk of bias assessment

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each study using the bias assessment tool described in the Cochrane Handbook (Higgins 2008). We resolved any disagreement by discussion or by involving a neutral third party to adjudicate. The Cochrane approach assesses risk of bias in individual studies across six domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other potential biases.

Sequence generation (checking for selection bias)

• Adequate: investigators described a random component in the sequence generation process, such as the use of random number table, coin tossing, card or envelope shuffling.

• Inadequate: 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 or date of birth, hospital or clinic record number.

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

Allocation concealment (checking for selection bias)

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

• Inadequate: participants and investigators enrolling participants can foresee upcoming assignment (e.g., an open random allocation schedule, a list of random numbers), or envelopes were unsealed, non‐opaque or not sequentially numbered.

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

Blinding (checking for performance bias and detection bias)

• Adequate: blinding of the participants, key study personnel and outcome assessor and unlikely that the blinding could have been broken. Not blinding in the situation where non‐blinding is unlikely to introduce bias.

• Inadequate: no blinding or incomplete blinding when the outcome is likely to be influenced by lack of blinding.

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

Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

• Adequate: 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.

• Inadequate: 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

• Adequate: a protocol is available which clearly states the primary outcome is the same as in the final trial report.

• Inadequate: 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

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

• Inadequate: 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.

For blinding and incomplete outcome data, multiple entries can be made if more than one outcome (or time points) is involved.

We used the Newcastle‐Ottawa Scale (Newcastle‐Ottawa) to assess the quality and risk of bias in non‐randomised studies. Specifically, the scale uses a star system to judge three general areas: selection of study groups, comparability of groups, and ascertainment of outcomes (in the case of cohort studies). As a result, this instrument can assess the quality of non‐randomised studies so that they can be used in a meta‐analysis or systematic review. Please see Figure 1 and Appendix 2 for details.

Figure 1

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

The quality of evidence across the body of evidence was assessed with the GRADE approach (Guyatt 2008), which defines the quality of evidence for each outcome as"the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest" (Higgins 2008). The quality rating across studies has four levels: high, moderate, low, or very low. Randomised trials are considered to be of high quality, but can be downgraded for any of five reasons; similarly, observational studies are considered to be of low quality, but can be upgraded for any of 3 reasons. The 5 factors that decrease the quality of evidence are: 1) limitations in study design; 2) indirectness of evidence; 3) unexplained heterogeneity or inconsistency of results; 4) imprecision of results; or 5) high probability of publication bias. The three factors that can increase the quality level of a body of evidence are: 1) large magnitude of effect; 2) if all plausible confounding would reduce a demonstrated effect; and 3) if there is a dose‐response gradient.

Measures of treatment effect

We extracted the unadjusted relative risk (RR) for dichotomous outcomes and the 95% confidence interval (CI). For continuous data we calculated a weighted mean difference (WMD). When data were not presented in the paper, we calculated RR and WMD.

Dealing with missing data

We contacted study authors if it was necessary to obtain data missing from published reports.

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity among the trials in each analysis. If we identified substantial heterogeneity (I² greater than 50%), we explored potential reasons for the heterogeneity.

Assessment of reporting biases

Where we suspected reporting bias we attempted to contact study authors and ask them to provide missing outcome data.

Data synthesis

Meta‐analysis was conducted, when appropriate. Both fixed effects and random effects models were used in the analysis; if there were discrepancies between the models, we explored potential reasons for the differences. If meta‐analysis was not possible, a narrative synthesis of a particular intervention was undertaken. We also examined data using the GRADEpro software (GRADEpro 2008). GRADE evidence profiles and summary of findings tables were generated.

Subgroup analysis and investigation of heterogeneity

Heterogeneity was explored by analyses per subgroup, which was performed for populations or types of interventions that are dissimilar in a meaningful way. These analyses could include subgroup analyses based on the stage of the epidemic in the study region, higher‐income vs. low‐ or middle‐income country, characteristics of key populations, or other factors. Specifically, we aimed to examine the effects of interventions on KS outcomes among disease staging subgroups.