Treatment interventions for diarrhoea in HIV-infected and HIV-exposed children

  • Protocol
  • Intervention

Authors

  • Nkengafac V Motaze,

    Corresponding author
    1. Yaoundé Central Hospital, Centre for Development of Best Practices in Health (CDBPH), Yaoundé, Centre Province, Cameroon
    2. South African Medical Research Council, South African Cochrane Centre, Cape Town, Western Cape, South Africa
    • Nkengafac V Motaze, South African Cochrane Centre, South African Medical Research Council, PO Box 19070, Tygerberg, Cape Town, Western Cape, 7505, South Africa. villyen@yahoo.com.

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  • Chukwuemeka E Nwachukwu,

    1. Excellence & Friends Management Consult (EFMC), Abuja, FCT, Nigeria
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  • Eliza H Humphreys

    1. University of California, San Francisco, Global Health Sciences, San Francisco, California, USA
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

The objective of this review is to evaluate the efficacy of all treatment interventions used in the management of diarrhoea in HIV infected and exposed children.

We will focus on fluid replacement, targeting the causative organism, anti-diarrhoeal agents, replenishing micronutrients and combinations of these.

Background

It is estimated that over 10 million children in developing countries die each year before they reach five years of age. Seventy percent of these deaths are due to acute respiratory infections (mostly pneumonia), diarrhoea, measles, malaria, or malnutrition or a combination of these conditions (WHO 2005a). Diarrhoeal diseases alone account for an estimated 17.5-21% of all deaths in children in this age range, equivalent to 2.5 million deaths per year (Kosek 2003; Boschi-Pinto 2008).This high disease burden persists despite effective prevention strategies like interventions that promote hand washing (Ejemot 2008), improve disposal of human faeces (Clasen 2010) and improve quality of water (Clasen 2006).

According to the Joined United Nations Programme on HIV/AIDS (UNAIDS) 33.3 million people were living with HIV worldwide at the end of 2009 and 2.5 million were children (UNAIDS 2010). Children acquire HIV from their mothers at three distinct periods; during intra-uterine life (when the child is in the womb), during delivery and during breastfeeding. In addition to these, other situations in which HIV transmission can occur, though less frequently, are nosocomial transmission (infection during hospital care) and sexual abuse. In 2009, an estimated 370 000 children contracted HIV during the perinatal and breastfeeding period (UNAIDS 2010). The risk of transmission during breastfeeding alone is about 10%-16% while intrauterine and perinatal (during labour and delivery) transmission account for 25-40% and 60-75% of infections respectively (Bartlett 2008). However, there has been pronounced progress in reducing the incidence and impact of HIV among children younger than 15 years due to progress in prevention strategies like prevention of mother to child transmission (PMTCT) programs through the use of antiretroviral (ARV) drugs. A reflection of these efforts is that 32% fewer children were newly infected and 26% fewer deaths occurred from AIDS-related conditions among children in 2009 compared with 2004 (UNAIDS 2010).

HIV-exposed children are breastfeeding children born to HIV infected mothers and who did not acquire HIV during intra-uterine life or delivery. These children are at higher risk of mortality compared to children who are not exposed to HIV (Marinda 2007; Shapiro 2007). HIV positive mothers usually have to chose between exclusive breastfeeding, exclusive formula feeding, or mixed feeding. Findings from observational studies estimate that the risk of transmission of the HIV virus to the child due to breastfeeding is 14% (Dunn 1992). PMTCT guidelines recommend that children receive anti-retroviral therapy (ART) during the entire breastfeeding period, in order to reduce HIV transmission (WHO 2010a). Exclusive breastfeeding is associated with a reduced risk of HIV transmission compared to mixed feeding (Coovadia 2007). It is estimated that 1.7 million babies have been infected with the HIV virus through breast milk, but that 1.5 million babies die every year because they are not breast fed (Wise 2001). Some children who are born to HIV positive mothers are fed with formula feed. If safe water and adequate sanitation are not available, there will be an increased risk of diarrhoeal disease. An estimated 88% of diarrhoeal deaths worldwide are attributable to unsafe water, inadequate sanitation and poor hygiene (UNICEF/WHO 2009). Therefore, the risk of transmission through breastfeeding has to be weighed against the risk of diarrhoeal diseases when choosing a method of feeding in HIV infected mothers.

Description of the condition

Diarrhoea is defined as the passage of unusually loose or watery stools at least three times in a 24 hour period (WHO 2005b). Emmission of frequent watery stools leads to loss of water from the body resulting in dehydration. Dehydration from diarrhoea is classified as Severe dehydration, Some dehydration and No dehydration (WHO 2005a), depending on the clinical signs that reflect the extent of water lost. Acute diarrhoea is defined as three or more loose or watery stools daily for less than fourteen days and persistent or chronic diarrhoea is defined as the emission of more than two loose or watery stools daily for fourteen days or more (WHO 2005b,UNICEF/WHO 2009). When there is diarrhoea with blood in the stool, with or without mucus, the condition is called dysentery (WHO 2005b,UNICEF/WHO 2009).

HIV infected children can suffer from diarrhoea as a result of opportunistic infections that occur due to HIV-related immune suppression (Bartlett 2008). Some pathogens frequently responsible for diarrhoea are campylobacter, clostridium, enteric viruses (adenovirus, astrovirus, picornavirus, calicivirus). Chronic diarrhoea on the other hand is mostly due to cryptosporidiosis, cytomegalovirus, Entamoeba, Isospora, giardia and Microsporidia (Bartlett 2008). Shigella is responsible for about 60% of dysentery cases and nearly all cases of life-threatening dysentery (WHO 2005a).These agents vary in their disease causing mechanisms since they may be parasites, viruses or bacteria and there is also the possibility of co-infection by more than one agent.

Older children who are no longer breast fed but who are HIV positive and on antiretroviral treatment may present with diarrhoea as a side effect of their medication. Several ARVs, especially protease inhibitors (PI) are known to cause diarrhoea (Bartlett 2008) and this can present management challenges in settings where alternative drugs are not available. Trials investigating the use of paediatric preparations of PIs for PMTCTare ongoing (Nagot 2012) and it will be interesting to see if these preparations have fewer gastro-intestinal side effects since their efficacy against HIV is higher than nevirapine or lamivudine, and they have a higher genetic barrier to resistance selection.

Description of the intervention

The World Health Organization (WHO) has published management guidelines for the treatment of children with diarrhoeal disease in the handbook for Integrated Management of Childhood Illness (IMCI) (WHO 2005a). The assessment and treatment of diarrhoea involves evaluating the degree of dehydration, appropriate fluid replacement, continuation of feeding, zinc supplementation, antibiotics when indicated, appropriate referral and follow up.

Current WHO treatment recommendations for acute diarrhoea include the following:

• Treatment of dehydration with Oral Rehydration solution (ORS) solution or with intravenous electrolyte solution in cases of severe dehydration. The ORS can have different osmolarities (measured in milli-osmoles per litre; mOsm/l), with the two main groups being < 270 mOsm/l and >310 mOsm/l which are glucose-based. The WHO and UNICEF currently recommend an ORS ≤ 270 mOsm/l formulation for treating dehydration caused by all types of diarrhoea (WHO 2004). A systematic review found that in people with cholera, ORS ≤ 270 mOsm/l resulted in more patients developing biochemical hyponatraemia with no clinical benefits compared with the ORS ≥ 310 mOsm/l formula (Musekiwa 2011).
• Feeding should be continued or increased in these children and breastfeeding increased during and after the diarrhoeal episode.
• Antibiotics should be used only when appropriate, for example in the presence of dysentery and zinc supplementation should be carried out. Several antibiotics have been used for treating diarrhoea due to specific types of bacteria, but other agents like probiotics are also available.

Several clinical trials are being carried out to explore other treatment interventions like prebiotics, probiotics and smectite for acute diarrhoea (Johnston 2010). Diosmectite and racecadotril have been shown to reduce stool output in children (Faure 2013)

How the intervention might work

Treatment of diarrhoea involves fluid replacement, reducing intestinal motility, targeting the causative organism and replenishing micronutrients.

Fluid replacement: The basis of rehydration during diarrhoea is to replace body water that is lost through frequent emission of loose stools. Since electrolytes are also lost along with water, several types of glucose-based ORS with different compositions and osmolarities are available that can compensate this loss. Consumption of fluids that have high osmolarities can lead to secretion of water into the intestines and aggravation of dehydration. Decreasing the osmolarity of the ORS solution to 245 mOsm/l by reducing the concentrations of glucose and salt avoids this adverse effect and improves the efficacy of the ORS regimen for children with acute non-cholera diarrhoea (WHO 2004). A new type of ORS, which is a polymer-based ORS, has been shown to decrease the duration of diarrhoea among adults with cholera and lower the risk of unscheduled use of intravenous fluid, compared with a glucose-based ORS >310 mOsm/l (Gregorio 2009).

Targetting the causative organism: Antibiotics for treating specific opportunistic infections that cause diarrhoea (Bartlett 2008), target the causative germs and eradicate them in order to stop the diarrhoeal episode. However, this has to be done concurrently with adequate rehydration and feeding for optimal recovery.

Replacing depleted Micronutrients: When zinc is administered during and until the end of diarrhoea, it has a preventive and long-lasting impact by reducing the number of episodes of diarrhoea in the 2–3 months after the supplementation regimen (WHO 2004).

Anti-diarrhoeal agents: Other treatment interventions like anti motility agents have been shown to benefit children with acute diarrhoea (Li 2007). A recent systematic review found that probiotics administered in addition to rehydration therapy resulted in significant reductions in the duration and severity of acute infectious diarrhoea (Allen 2010), however another review found no benefit in persistent diarrhoea (Bernaola 2010).

In addition to the above management strategies, there are additional considerations for children living with HIV in whom there is a potential for drug interactions with antiretroviral therapy, the possibility of exclusive bottle feeding (hence less breast milk) and the wider variety of pathological agents. This may be aggravated by malnutrition and other infectious diseases which are frequent in children living with HIV.

Why it is important to do this review

Recent Cochrane reviews confirm the benefit of zinc supplementation (Lazzerini 2012), rehydration via oral hydration solution or intravenous solutions and antibiotics for bloody diarrhoea (Hartling 2006; Abba 2009; Atia 2009). However, these reviews do not address subpopulations of HIV infected or exposed children, who may be especially vulnerable to diarrhoeal disease. Infants and children with HIV/AIDS have diarrhoeal disease complicated by immunocompromise, malnutrition, gastrointestinal manifestations of primary HIV disease, and may be treated with ARV drugs, that are associated with gastrointestinal symptoms, among other challenges (Thom 2006; Ramos-Soriano 1996; Guarino 2004). The combination of HIV infection and diarrhoea thus represents a complex and challenging situation that is faced by health workers worldwide and especially in developing countries. WHO has set research on childhood diarrhoea as a priority area in order to meet the United Nation’s Millennium Development goal of reducing childhood mortality by two-thirds between 1990 and 2015 (Fontaine 2009).  Also recognizing that children with HIV require comprehensive care, WHO has initiated a series of systematic reviews that will underlie evidence-based recommendations on the prevention and treatment of common conditions in HIV-infected and exposed children, including diarrhoea (WHO 2010b). In this review, we intend to summarise the evidence and outcomes for the recommended treatment interventions for diarrhoea in infants and children with HIV infection and exposure. 

Objectives

The objective of this review is to evaluate the efficacy of all treatment interventions used in the management of diarrhoea in HIV infected and exposed children.

We will focus on fluid replacement, targeting the causative organism, anti-diarrhoeal agents, replenishing micronutrients and combinations of these.

Methods

Criteria for considering studies for this review

Types of studies

We intend to include randomised controlled trials (RCTs).

Types of participants

Children 0 to less than 15 years of age who are HIV infected or exposed and who have diarrhoea will be included in this review. Different definitions are frequently used for entry criteria into trials involving paediatric diarrhoea (Johnston 2010). Children usually pass frequent stools which could be normal for them but their carers know when they have diarrhoea (WHO 2005b). We will therefore include children with diarrhoea reported by the carer and diarrhoea confirmed by the health professional in this review.

Types of interventions

We will assess all treatment interventions for the management of diarrhoea. These will include:

  • Rehydration (oral rehydration therapy and intravenous rehydration). We will compare different types of ORS (e.g. glucose-based, polymer-based )

  • Anti-infective agents. We will compare different types of anti-infective agents, anti-infective agents to placebo or no treatment.

  • Micronutrient supplementation. We will compare one micronutrient to another, micronutrient(s) to placebo or no treatment.

  • Anti-diarrhoeal agents: for example anti-motility agents, diosmectite, prebiotics and probiotics. These will be compared to one another or to placebo or no treatment.

We will also carry out comparisons in which combinations of these groups of interventions are used.

Types of outcome measures

Primary outcomes
  • Clinical cure. This will be cessation of diarrhoeal episodes.

  • All cause mortality

Secondary outcomes
  • Hospitalisation due to diarrhoea

  • Duration of diarrhoea

  • Severity of diarrhoea (stool output: consistency and frequency).

  • Mortality due to dehydration from diarrhoea.

  • Adverse treatment events: These could be serious adverse events necessitating hospital admission or discontinuation of treatment (for example ileus, lethargy). Other adverse events will be reported (for example vomiting, abdominal pain or nausea).

  • Recurrence of diarrhoea.

Search methods for identification of studies

We will formulate a comprehensive search strategy with the assistance of the HIV/AIDS Review Group Trials Search co-coordinator, in order to identify all relevant studies. We will search for studies regardless of publication status (published, unpublished, in press and in progress). Full details of the Cochrane HIV/AIDS Review Group search methods and the journals handsearched are published in The Cochrane Library in the section on Collaborative Review Groups. Searches will be carried out regardless of the language in which studies are published.

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, and Web of Science. The search period will be from 1 January 1980 to the search date.

Searching other resources

  • Writing to experts: We will contact principal investigators of identified relevant studies to find if they know of other existing relevant studies.

  • Snowballing: Reference lists of identified studies will be screened for potentially relevant studies.

  • Handsearching will be conducted for studies in unindexed or recent journals and conference proceedings. Online archives of abstracts from relevant conference proceedings, e.g. the International AIDS Society conferences and the Conference on Retroviruses and Opportunistic infections (CROI) will be screened for potentially eligible trials. We will contact authors to retrieve unpublished trials. We will search the abstracts of foreign journals that are written in English. We will request for an English language version of the full article if necessary and assess it for inclusion.

  • Ongoing Trials: We will search for unpublished and ongoing studies by considering prospective clinical trial registries (ClinicalTrials.gov and the WHO International Clinical TrialsRegistry Platform).

We will also contact research organizations and experts in the field for any relevant manuscripts that could be in preparation or in press.  The references of published articles found will be screened for additional pertinent material.

Data collection and analysis

Selection of studies

The first two review authors will independently assess identified studies for inclusion. We will resolve any disagreement through discussion and if required, we will consult the third author for a final decision.

Data extraction and management

We will design and test a data extraction form. For each included study, the first two authors will extract the data independently using the agreed form. We will then compare our forms and if we do not agree on any aspect, we will discuss it and consult the third author in order to find a consensus. We will enter data into Revman 5.1.2 software (Revman 2011) and check for accuracy. When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Study information that will be extracted includes:

Study details: citation, start and end dates, location, study design and details

Participant details: study population eligibility (inclusion and exclusion) criteria, ages, population size, attrition rate, details of HIV diagnosis and disease, details of diagnosis and definitions for diarrhoeal disease.

Interventions details: intervention details (drug or supplement name, dose and duration), administration of co-trimoxazole and/or ART in HIV infected or exposed children, co-morbid diagnoses.

Outcome details: mortality (all-cause and diarrhoea-specific), clinical course and outcomes, recurrent diarrhoea, severe or life-threatening adverse events, all other adverse events.

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement through discussion and by consulting the third author.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table, computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth, hospital or clinic record number); or

  • unclear risk of bias. (e.g. in the case of absent relevant information in the paper, non response from the authors)  

 (2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias. (e.g. absence of relevant information in the paper, non response from the authors)  

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received.  We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.  Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.

We will assess methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation. We will consider studies with more that 20% missing data as high risk of bias);

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias.

We will assess whether each study was free of other problems that could put it at risk of bias:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings.  We will explore the impact of the level of bias by undertaking sensitivity analyses. See Sensitivity analysis

Assessment of Quality of Evidence Across Studies
We will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2008). We will define 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 2011). The quality rating across studies has four levels: high, moderate, low or very low. Randomised controlled trials are categorised as high quality but can be downgraded; similarly, other types of controlled trials and observational studies are categorised as low quality but can be upgraded. Factors that decrease the quality of evidence include limitations in design, indirectness of evidence, unexplained heterogeneity or inconsistency of results, imprecision of results, or high probability of publication bias. Factors that can increase the quality level of a body of evidence include having a large magnitude of effect, whether plausible confounding would reduce a demonstrated effect, and if there is a dose-response gradient. 

Measures of treatment effect

For dichotomous outcomes, we will present results as summary risk ratio with 95% confidence intervals. 

For continuous outcomes, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference when combining trials that measure the same outcome using different methods.

Unit of analysis issues

Cluster-randomised trials

We will include cluster-randomised trials in the analyses along with individually randomised trials. We will adjust their sample sizes using the methods described in the Handbook using an estimate of the intra cluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit

Dealing with missing data

For included studies, we will note levels of attrition and explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta-analysis using the Tau, I² and Chi² statistics. We will regard heterogeneity as substantial if I² is greater than 30% and either Tau is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity.

Assessment of reporting biases

If there are 10 or more studies in the meta-analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes we will use the test proposed by Egger (Egger 1997), and for dichotomous outcomes we will use the test proposed by Harbord (Harbord 2006). If asymmetry is detected in any of these tests or is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

The first author will carry out statistical analysis using Revman 5.1.2 software (Revman 2011). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful we will not combine trials.

If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of  T² and I².

Subgroup analysis and investigation of heterogeneity

We intend to carry out the following subgroup analysis.

  1. Children aged under 5 years vs children 5 years of age or older.

  2. HIV infected vs HIV exposed children.

  3. Children on ART versus those not on ART. Children receiving ARVs as part of PMTCT programs will be considered as "children on ART" if they were included in the trial during the period of time they were on ART. Children who had received ART for PMTCT and who were not taking ARVs during the trial will be considered "not on ART".

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful and use random-effects analysis to produce it.

For fixed-effect inverse variance meta-analyses we will assess differences between subgroups by interaction tests. For random-effects and fixed-effect meta-analyses using methods other than inverse variance, we will assess differences between subgroups by inspection of the subgroups’ confidence intervals; non-overlapping confidence intervals indicate a statistically significant difference in treatment effect between the subgroups.

Sensitivity analysis

Sensitivity analysis will be carried out to explore the effect of trial quality, including studies assessed as having adequate controls in place for the prevention of potential bias.

Acknowledgements

We acknowledge the South African Cochrane Centre for supporting this review.

Two editors of the HIV review group provided input as part of the peer-review process.

Contributions of authors

EH and NV wrote the first draft of the protocol. CE reviewed the draft protocol and provided input. All three authors approved the final copy submitted to the review group.

Declarations of interest

The authors have no conflicts of interest.

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