Description of the condition
The World Health Organization (WHO) estimated that in 2010 there were 2.7 million (2.4 to 2.9 million) people who became newly infected with HIV (WHO 2011a). Of these, an estimated 390 000 [340 000–450 000] were children less than 15 years old. This is a 30% decrease in global figures since 2002 and can largely be attributed to the expansion in access to services for preventing mother-to-child transmission of HIV, the primary route of HIV acquisition in children.
Sub-Saharan Africa is disproportionately represented in the epidemic with 68% of the global total of people living with HIV (WHO 2011a). An estimated 90% of the world’s children living with HIV live in sub-Saharan Africa (UNAIDS 2010). At the end of 2010, 47% of the 14.2 million people (adults and children) in need of treatment in low- and middle-income countries were receiving antiretroviral therapy (WHO 2011a). However, in sub-Saharan Africa, antiretroviral therapy coverage of children in the region is far below the global average, at just 21%.
Description of the intervention
The use of combination antiretroviral therapy (cART) comprising three antiretroviral medications from at least two classes of drugs is the current standard treatment for HIV infection in adults and children (WHO 2010b). Availability of cART has changed the course of paediatric HIV infection with significant reductions observed in mortality over long-term follow-up (Patel 2008). Determining the optimal point at which to initiate cART in children is challenging for several reasons. As children develop, the organs involved in drug metabolism mature. As a result, the pharmacokinetic environment is dynamic and treatment needs differ according to age (Heidari 2012). If malnutrition is present or treatment for co-infections such as tuberculosis or malaria is required, the drug pharmacokinetics may be further altered (Heidari 2012). Markers of disease progression, such as the CD4 count, are unreliable in young children limiting disease monitoring (Prendergast 2012). Given that treatment is life-long, the risk of drug resistance is high and the potential for long-term toxicity exists (Heidari 2012). Determining the optimal time to initiate cART in children is therefore critical.
Current World Health Organization (WHO) guidelines for antiretroviral therapy recommend early treatment regardless of immunologic or clinical thresholds for all infants (less than one years of age) and children under the age of two years (WHO 2010b). The decision to initiate early treatment in infants was based on evidence from the Children with HIV Early Antiretroviral Therapy trial (CHER) (Violari 2008) and supported by a Cochrane review (Penazzato 2012). The subsequent extension of this guideline to children under the age of two years was based on the high risk of disease progression and death and the poor predictive quality of immunological markers in this age group, as well as the fact that early initiation improves retention in care (Prendergast 2012).
For children aged 24 to 59 months (two to five years) current WHO guidelines recommend that clinical and immunological thresholds be used to identify those children aged 24 to 59 months who need to start cART (WHO 2010b). Specifically, treatment should be initiated for all HIV-infected children with WHO HIV clinical stages 3 and 4, irrespective of CD4 count. In children aged 24 to 59 months (2 to 5 years in age), cART should be initiated when CD4 counts <= 750 cells/mm3 or %CD4 <= 25%, irrespective of the WHO clinical stage. These recommendations are acknowledged to be based on low or very low quality evidence.
Why it is important to do this review
The World Health Organization (WHO) Antiretroviral Therapy Guideline is the main normative cART tool at global level and is used by regional and national programme managers to develop local treatment guidelines. The first guideline was produced in 2002 (WHO 2002), then revised in 2003 (WHO 2003). In 2006, and then again in 2010, separate sets of recommendations – one for adults and adolescents (WHO 2006a; WHO 2010a) and another for children (WHO 2006b; WHO 2010b) - were published as two guideline documents. In 2011, WHO/UNAIDS established a new initiative, Treatment 2.0, that advocates for the development and expanded use of more simplified, less toxic drug regimens, with high barriers to drug resistance, that require minimal clinical monitoring while maintaining therapeutic efficacy (WHO 2011b). Treatment 2.0 aims to expand access to treatment and applies equally to both adults and children. Revisions of these recommendations are planned for 2013 and WHO will re-examine the evidence – both clinical and programmatic - around the question of when to start cART in infants and children. A completed Cochrane review focuses on the effectiveness of cART in children aged under two years (Penazzato 2012). This Cochrane review will inform the revision of the WHO antiretroviral therapy guidelines specifically for when to initiate cART in children aged two to five years old.
To assess the evidence for the optimal time to initiate cART in treatment-naive, HIV-positive children aged 24 to 59 months (2 to 5 years old).
Criteria for considering studies for this review
Types of studies
- Randomised controlled trials (RCTs)
- Prospective cohort studies which followed children from enrolment to start of cARTand for at least a median of one year on cART
Cohort studies in which children are all immediately commenced on cART at enrolment and followed will be excluded.
Types of participants
Children with confirmed HIV infection (HIV PCR-positive (either RNA or DNA) if diagnosed at age<18 months or HIV ELISA-positive if diagnosed after 18 months of age) aged between 24 and 59 months (two to five years in age) who are treatment-naïve (except for exposure to drugs to prevent mother-to-child transmission) at commencement of the study.
Studies which include the above age group within a larger age range will be included. We will then contact trial authors to attempt to obtain the specific age range 24 to 59 months.
Studies in children with tuberculosis and other opportunistic illnesses will be included.
Studies focused only on infants (less than one year in age) will be excluded. These are included in another Cochrane review (Penazzato 2012).
For RCTs, at study entry, children must not have fulfilled guideline criteria for commencing antiretroviral treatment current at the time of the study.
Types of interventions
Studies which compare initiating triple cART at different thresholds.
- In RCTs, the intervention group will initiate triple cART irrespective of clinical stage or CD4 count (immediate initiation). The control group will initiate cART using clinical and immunological criteria to determine the time for initiation (deferred initiation) current at the time of the study.
- In cohort studies, children starting at different CD4 percent or CD4 counts are compared. Analysis must have included adjustment for time-dependent confounding and lead-time bias specifically to evaluate the effect of timing of cART initiation on outcomes.
Types of outcome measures
- Clinical occurrence of new HIV-related events (death or AIDS-defining illness)
- Time to event of new HIV-related events (death or AIDS-defining illness)
- Immunological response (change in mean or median CD4+ cell count (mean or median relative change (percent) or mean or median absolute change, compared with baseline, and standard deviation or range as appropriate)
- Virologic response (proportion of patients achieving and maintaining an undetectable viral load, as defined by the trial; change in HIV-RNA levels (mean relative change (percent) or mean absolute change, compared with baseline, and standard deviations)
- HIV drug resistance
Severe adverse events are reported. If classified according to grade 1 to 4 of the Adverse Event Toxicity Scale, we report grade 3 and 4 events. Using this scale, grade 1 and 2 denote mild to moderate symptoms, grade 3 denote serious symptoms and grade 4 denote life-threatening events requiring significant clinical intervention. Grade 5 denotes death (DAIDS 2009).
Search methods for identification of studies
See: HIV/AIDS Collaborative Review Group search strategy.
We developed the search strategy with the assistance of the HIV/AIDS Review Group Trials Search Co-ordinator. We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant randomised controlled trials and cohort 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.
For the RCT search, we combined the RCT strategy developed by The Cochrane Collaboration and detailed in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009) in combination with terms specific to initiation of antiretroviral therapy and children. The search was iterative and a number of trial searches were run first as there are no database-specific terms for 'initiation' of treatment and so we used many free text terms. This increased the yield and hence the search sensitivity but reduced the precision.
As there are no validated search strategies for cohort studies, our strategy was informed by the cohort strategy developed by BMJ Clinical Evidence (http://clinicalevidence.bmj.com/x/set/static/ebm/learn/665076.html).
We will search the following databases:
1. Journal databases
For RCT Identification:
- Medline via Pubmed - see search strategy in Appendix 1
- EmBase - see search strategy in Appendix 2
- Cochrane Central Register of Controlled Trials (CENTRAL) - see search strategy in Appendix 3
For cohort identification:
- Medline via Pubmed
2. Conference databases:
We will search the AEGIS database (www.aegis.org) which contains abstracts from the following major related conferences: 1st-5th International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment and Prevention (2001-2009); 10th-17th International AIDS Conference (IAC) (1994-2008); 1st-16th Conference of Retrovirus and Opportunistic Infections (CROI) (1994-2009); US National HIV Prevention Conference; 7th-14th British HIV Association (2001-2008); and 8th-9th European AIDS Clinical Society Conference (2001, 2003).
AEGIS does not allow for multiple search strings and so, in order to search the database effectively, a separate search was done for relevant terms combined with the term [random*] to identify relevant trials:
ANTIRETROVIRAL* AND RANDOM* AND (child* OR infant* OR toddler* OR pediatric* OR paediatric*)
The more recent conferences (up to 2012) will be covered by searching the conference web-sites of the International AIDS Society, the International AIDS Conference and the CROI. The abstracts of the 2nd, 3rd and 4th International Workshop on HIV Pediatrics will also be searched. These abstracts have been published in Reviews in Antiviral Therapy & Infectious Diseases.
3. Ongoing trials:
To identify ongoing RCTs we searched ClinicalTrials.gov (http://clinicaltrials.gov/) and the World Health Organization International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/).
Searching other resources
We also checked the reference lists of all studies identified by the above methods and examined any systematic reviews, meta-analyses, or guidelines we identified during the search process for references.
We are in close contact with individual researchers working in the field, and policymakers based in inter-governmental organizations including the World Health Organization (WHO) and UNAIDS.
We will not conduct hand-searching of specific journals other than those searched by the Cochrane HIV/AIDS Review Group and already included in CENTRAL.
Data collection and analysis
Selection of studies
NS and ME will read the titles, abstracts and descriptor terms of all downloaded material from the electronic searches to identify potentially eligible reports. Full text articles will be obtained for all citations identified as potentially eligible and NS and ME will independently inspect these to establish the relevance of the article according to the pre-specified criteria. Where there is any uncertainty as to the eligibility of the record, we will obtain the full article.
NS and ME will independently apply the inclusion criteria, and any differences arising will be resolved by discussions with the third reviewer, MD. Studies will be reviewed for relevance based on study design, types of participants, exposures and outcome measures.
Data extraction and management
NS and ME will independently extract data into a standardised data extraction form. The following characteristics will be extracted from each included study.
- Administrative details: Trial or study identification number; author(s); published or unpublished; year of publication; number of studies included in paper; year in which study was conducted; details of other relevant papers cited;
- Details of the study: Study design; type, duration and completeness of follow-up; country and location of study (e.g. higher-income vs. lower-income country); informed consent and ethics approval;
- Details of participants: Setting, numbers, relevant baseline characteristics including CD4 count and viral load;age range;
- Details of intervention: CD4 count and age at which treatment was initiated; drug combinations; additional co-interventions; and
- Details of outcomes: Mortality; HIV-related morbidity; HIV-RNA viral load measurements and proposed levels for suppression, as defined by the authors; clinical disease progression; CD4+ cell counts; adverse events and toxicity.
- Details of the analysis: For RCTs, details of the type of analysis (intention-to-treat or per protocol); for cohort studies, details of the type of adjustment performed in the analysis.
Assessment of risk of bias in included studies
For both RCTs and cohort studies, NS and ME will independently examine the components of each included study for risk of bias using a standard form. This includes 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 trials will be assessed and classified as at a high, low or unclear risk of bias as per the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). Where differences arise, these will be resolved by discussions with the third reviewer, MD.
- Adequate: 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
- 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/date of birth, hospital or clinic record number
- Unclear: insufficient information to permit judgment of the sequence generation process
- 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 (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
- Adequate: 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.
- Inadequate: no blinding, incomplete blinding and 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
- 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
- Adequate: a protocol is available which clearly states the primary outcome as 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
Control of time-dependent confounding (cohort studies only)
The use of standard regression models for the analysis of cohort studies with time-updated measurements may result in biased estimates of treatment effects if time-dependent confounders are present (Robins 2000). In cohorts of HIV-infected patients CD4 cell percentage or CD4 cell counts are measured regularly to assess the patients' eligibility for cART and, once on cART, to monitor therapy. CD4 count is a time-dependent confounder because it predicts both future cART and outcome, and is influenced by past antiretroviral therapy. In other words, CD4 count is on the causal pathway between treatment and the outcome.
- Adequate: appropriate methods were used to control for time-dependent confounding (e.g. marginal structural models)
- Inadequate: there was no control for time-dependent confounding
- Unclear: insufficient reporting to determine whether there was control for time-dependent confounding
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
Measures of treatment effect
Data analysis will be conducted using (RevMan) version 5.1.7.
For RCT data, outcome measures for dichotomous data (e.g. death, virological suppression) will be calculated as relative risks with 95% confidence intervals. For continuous data (e.g. CD4+ cell counts, HIV-RNA viral loads) we will calculate the mean difference and standard deviation where means are reported.
For cohort data, we will report on the adjusted analysis using the estimate of effect reported in the study rather than calculating estimates of effects based on the crude data.
Unit of analysis issues
We do not anticipate cluster or cross-over trials, with the potential for unit of analysis issues, being conducted to investigate this question.
Dealing with missing data
Where data is missing, we will contact study authors and request additional data. Should this not be possible, we will state explicitly where calculations are based on assumptions regarding missing data.
In trials which include participants from the within a larger age range, we will contact trial authors to attempt to obtain the specific age range 24 to 59 months. Where this data is not available, we will use the entire age range for analysis purposes.
Assessment of heterogeneity
Where RCTs are found to be methodologically or clinically comparable, we will pool trial results in a meta-analysis. As we anticipate the presence of statistical heterogeneity we will combine the data using the random effects model.
Where cohort studies are found to be methodologically or clinically comparable, we will also pool the results in a meta-analysis using the generic inverse variance function in RevMan to allow adjusted data to be used in the analysis. We will anticipate heterogeneity due to the likelihood of different analytical techniques and different adjusted variables and will combine studies using the random effects model.
For both RCT and cohort meta-analyses, we will formally test for statistical heterogeneity using the Chi-square test for statistical homogeneity with a 10% level of significance as the cut-off. The impact of any statistical heterogeneity will be quantified using the I² statistic (Higgins 2002).
Where studies do not have combinable outcomes, we will provide the data in a narrative form.
For meta-analysis of RCTs, we will combine the results and calculate the relative risk and 95% confidence intervals using a random effects model for dichotomous data. For continuous data, we will combine the mean differences to calculate a weighted mean difference and standard deviation. If time-to-event data is available, we will combine the hazard ratios reported in the RCTs using the generic inverse variance function.
For cohort studies, we will combine the adjusted estimates of effects using the generic inverse variance function in RevMan and report on the overall estimate and variance effect.
Subgroup analysis and investigation of heterogeneity
We anticipate statistical heterogeneity due to differences between studies conducted in resource-constrained compared with resource-rich settings, and will present the results according to these sub-groups.
We will perform a sub-analysis restricted to children less than 5 years old who have a CD4 above 25% to best inform the current (2012) WHO guideline processes.
For RCTs, we will explore the effect of study quality on the results by excluding those studies where allocation concealment was unclear or inadequate from the meta-analysis and assessing the effect of this on the overall results. For cohort studies we will examine the effect of adjustments for confounding and in particular confounding by indication. We will also conduct the meta-analyses using the fixed effects model and observe if results differ to the random effects model results.
GradePro 2008 will be used to create Summary of Findings and Evidence Profile tables. GradePro software was developed as part of a larger initiative led by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. GRADE offers a system for rating quality of evidence in systematic reviews and guidelines and grading strength of recommendations in guidelines (Guyatt 2011). Use of GradePro within a Cochrane systematic review facilitates the process of presenting and grading evidence transparently (http://ims.cochrane.org/revman/other-resources/gradepro/about-gradepro).
In determining the level of evidence for each outcome, both the efficacy results and the assessment of the risk of bias was integrated into a final assessment of the level of evidence and full details of the decision provided in footnotes.
We are grateful to Joy Oliver, Trial Search Coordinator, for developing the search strategy and for conducting the searches. We thank Tara Hovarth, Managing Editor, for her guidance, especially regarding conference searching.
Appendix 1. Medline search strategy for RCT records
Appendix 2. EmBase search strategy for RCT records
Appendix 3. CENTRAL search strategy for RCT records
Contributions of authors
All authors conceived the aim of the protocol. NS drafted the protocol and MD and ME provided comment and guidance.
Declarations of interest
NS has no conflict of interest. ME and MD are investigators in the collaborative IeDEA cohort studies which evaluate the effects of cART on outcomes in HIV-positive children.
Sources of support
- Centre for Infectious Disease Epidemiology and Research, School of Public Health, University of Cape Town, South Africa.Salary and material support
- Institute of Social Medicine, Institute of Social and Preventive Medicine, Bern, Switzerland.Salary and material support
- No sources of support supplied