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Meta-Analysis
. 2014 May 22;2014(5):CD004772.
doi: 10.1002/14651858.CD004772.pub4.

Optimisation of antiretroviral therapy in HIV-infected children under 3 years of age

Martina Penazzato  1 , Andrew J Prendergast, Lulu M Muhe, Denis Tindyebwa, Elaine Abrams
Affiliations
Meta-Analysis

Optimisation of antiretroviral therapy in HIV-infected children under 3 years of age

Martina Penazzato et al. Cochrane Database Syst Rev. .

Abstract

Background: In the absence of antiretroviral therapy (ART), over 50% of HIV-infected infants progress to AIDS and death by 2 years of age. However, there are challenges to initiation of ART in early life, including the possibility of drug resistance in the context of prevention of mother-to-child transmission (PMTCT) programs, a paucity of drug choices , uncertain dosing for some medications and long-term toxicities. Key management decisions include when to start ART, what regimen to start, and whether and when to substitute drugs or interrupt therapy. This review, an update of a previous review, aims to summarize the currently available evidence on this topic and inform the ART management in HIV-infected children less than 3 years of age.

Objectives: To evaluate 1) when to start ART in young children (less than 3 years); 2) what ART to start with, comparing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)-based regimens; and 3) whether alternative strategies should be used to optimize antiretroviral treatment in this population: induction (initiation with 4 drugs rather than 3 drugs) followed by maintenance ART, interruption of ART and substitution of PI with NNRTI drugs once virological suppression is achieved on a PI-based regimen.

Search methods: Search methodsWe searched for published studies in the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, Pubmed, EMBASE and CENTRAL. We screened abstracts from relevant conference proceedings and searched for unpublished and ongoing trials in clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform).

Selection criteria: We identified RCTs that recruited perinatally HIV-infected children under 3 years of age without restriction of setting. We rejected trials that did not include children less than 3 years of age, did not provide stratified outcomes for those less than 3 years or did not evaluate either timing of ART initiation, choice of drug regimen or treatment switch/interruption strategy.

Data collection and analysis: Two reviewers independently applied study selection criteria, assessed study quality and extracted data. Effects were assessed using the hazard ratio (HR) for time-to-event outcomes, relative risk for dichotomous outcomes and weighted mean difference for continuous outcomes.

Main results: A search of the databases identified a total of 735 unique, previously unreviewed studies, of which 731 were excluded to leave 4 new studies to incorporate into the review. Four additional studies were identified in conference proceedings, for a total of 8 studies addressing when to start treatment (n=2), what to start (n=3), whether to substitute lopinavir/ritonavir (LPV/r) with nevirapine (NVP) (n=1), whether to use an induction-maintenance ART strategy (n=1) and whether to interrupt treatment (n=1).Treatment initiation in asymptomatic infants with good immunological status was associated with a 75% reduction (HR=0.25; 95%CI 0.12-0.51; p=0.0002) in mortality or disease progression in the one trial with sufficient power to address this question. In a smaller pilot trial, median CD4 cell count was not significantly different between early and deferred treatment groups 12 months after ART.Regardless of previous exposure to nevirapine for PMTCT, the hazard for treatment failure at 24 weeks was 1.79 (95%CI 1.33, 2.41) times higher in children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0001) with no clear difference in the effect observed for children younger or older than 1 year. The hazard for virological failure at 24 weeks was overall 1.84 (95%CI 1.29, 2.63) times higher for children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0008) with a larger difference in time to virological failure (or death) between the NVP and LPV/r-based regimens when ART was initiated in the first year of life.Infants starting a LPV/r regimen and achieving sustained virological suppression who then substituted LPV/r with NVP after median 9 months on LPV/r were less likely to develop virological failure (defined as at least one VL greater than 50 copies/mL) compared with infants who started and stayed on LPV/r (HR=0.62, 95%CI 0.41, 0.92, p=0.02). However the hazard for confirmed failure at a higher viral load (>1000 copies/mL) was greater among children who switched to NVP compared to those who remained on LPV/r (HR=10.19, 95% CI 2.36, 43.94, p=0.002).Children undergoing an induction-maintenance ART approach with a 4-drug NNRTI-based regimen for 36 weeks, followed by 3-drug ART, had significantly greater CD4 rise than children receiving a standard 3-drug NNRTI-based ART at 36 weeks (mean difference 1.70 [95%CI 0.61, 2.79] p=0.002) and significantly better viral load response at 24 weeks (OR 1.99 [95%CI 1.09, 3.62] p=0.02). However, the immunological and virological benefits were short-term.The one trial of treatment interruption that compared children initiating continuous ART from infancy with children interrupting ART was terminated early because the duration of treatment interruption was less than 3 months in most infants. Children interrupting treatment had similar growth and occurrence of serious adverse events as those in the continuous arm.

Authors' conclusions: ART initiation in asymptomatic children under 1 year of age reduces morbidity and mortality, but it remains unclear whether there are clinical benefits to starting ART in asymptomatic children diagnosed with HIV infection between 1-3 years.The available evidence shows that a LPV/r-based first-line regimen is more efficacious than a NVP-based regimen, regardless of PMTCT exposure status. New formulations of LPV/r are urgently required to enable new WHO recommendations to be implemented. An alternative approach to long-term LPV/r is substituting LPV/r with NVP once virological suppression is achieved. This strategy looked promising in the one trial undertaken, but may be difficult to implement in the absence of routine viral load testing.A 4-drug induction-maintenance approach showed short-term virological and immunological benefits during the induction phase but, in the absence of sustained benefits, is not recommended as a routine treatment strategy. Treatment interruption following early ART initiation in infancy was challenging for children who were severely immunocompromised in the context of poor clinical immunological condition at ART initiation due to the short duration of interruption, and is therefore not practical in ART treatment programmes where close monitoring is not feasible.

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Conflict of interest statement

AJP is a co‐investigator on the PEHSS and ARROW trials. EJA is a co‐investigator on the P1060 and NEVEREST trials.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Early vs Deferred antiretroviral treatment, outcome: 1.1 Mortality.
5
5
Forest plot of comparison: 1 Early vs Deferred antiretroviral treatment, outcome: 1.2 Mortality or disease progression.
6
6
Forest plot of comparison: 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, outcome: 2.1 Treatment failure (virological failure or treatment discontinuation).
7
7
Forest plot of comparison: 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, outcome: 2.2 Treatment failure (virological failure or treatment discontinuation).
8
8
Forest plot of comparison: 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, outcome: 2.3 Virological failure or death.
9
9
Forest plot of comparison: 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, outcome: 2.4 Virological failure or death.
10
10
Forest plot of comparison: 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, outcome: 2.5 Change in CD4% from baseline.
11
11
Forest plot of comparison: 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, outcome: 2.6 Change in weight z‐score from baseline.
12
12
Forest plot of comparison: 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, outcome: 2.7 Change in height z‐score from baseline.
13
13
Forest plot of comparison: 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, outcome: 2.8 Adverse events.
14
14
Forest plot of comparison: 3 Switch to NVP vs continue on LPV/r, outcome: 3.2 Virological failure (any VL>50 copies/mL).
15
15
Forest plot of comparison: 3 Switch to NVP vs continue on LPV/r, outcome: 3.3 Virological failure (confirmed VL>1000 copies/mL).
16
16
Forest plot of comparison: 3 Switch to NVP vs continue on LPV/r, outcome: 3.4 Decline by 10% in CD4% at week 52.
17
17
Forest plot of comparison: 3 Switch to NVP vs continue on LPV/r, outcome: 3.5 Decline by 1 z‐score in weight‐for‐age at week 52.
18
18
Forest plot of comparison: 4 Switch to NVP vs continue on LPV/r, outcome: 4.5 ALT increase (Grade 3/4).
19
19
Forest plot of comparison: 4 Switch to NVP vs continue on LPV/r, outcome: 4.6 Neutropenia (grade 3/4).
20
20
Forest plot of comparison: 6 Induction‐Maintance strategy, outcome: 6.2 Increase in CD4% from baseline at week 72.
21
21
Forest plot of comparison: 6 Induction‐Maintance strategy, outcome: 6.3 Increase in CD4% from baseline at week 144.
22
22
Forest plot of comparison: 6 Induction‐Maintance strategy, outcome: 6.1 Increase in CD4% from baseline at week 36.
23
23
Forest plot of comparison: 5 Induction‐Maintance strategy, outcome: 5.4 Virologic response (VL<400 copies/ml) at 24 weeks.
24
24
Forest plot of comparison: 5 Induction‐Maintance strategy, outcome: 5.7 Virologic response (VL<400 copies/ml) at 144 weeks.
25
25
Forest plot of comparison: 6 Induction‐Maintance strategy, outcome: 6.5 Mortality.
26
26
Forest plot of comparison: 6 Induction‐Maintance strategy, outcome: 6.6 New WHO 4/death event‐free survival.
27
27
Forest plot of comparison: 6 Induction‐Maintance strategy, outcome: 6.7 New WHO 3/4/death event‐free survival.
28
28
Forest plot of comparison: 5 Planned treatment interruption strategy, outcome: 5.1 Change in WAZ z‐score.
29
29
Forest plot of comparison: 5 Planned treatment interruption strategy, outcome: 5.2 Change in HAZ z‐score.
30
30
Forest plot of comparison: 5 Planned treatment interruption strategy, outcome: 5.3 Change in WHZ z‐score.
31
31
Forest plot of comparison: 5 Planned treatment interruption strategy, outcome: 5.4 Serious adverse events.
1.1
1.1. Analysis
Comparison 1 Early vs Deferred antiretroviral treatment, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Early vs Deferred antiretroviral treatment, Outcome 2 Mortality or disease progression.
2.1
2.1. Analysis
Comparison 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, Outcome 1 Treatment failure (virological failure or treatment discontinuation).
2.2
2.2. Analysis
Comparison 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, Outcome 2 Treatment failure (virological failure or treatment discontinuation).
2.3
2.3. Analysis
Comparison 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, Outcome 3 Virological failure or death.
2.4
2.4. Analysis
Comparison 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, Outcome 4 Virological failure or death.
2.5
2.5. Analysis
Comparison 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, Outcome 5 Change in CD4% from baseline.
2.6
2.6. Analysis
Comparison 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, Outcome 6 Change in weight z‐score from baseline.
2.7
2.7. Analysis
Comparison 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, Outcome 7 Change in height z‐score from baseline.
2.8
2.8. Analysis
Comparison 2 NVP‐based vs LPV/r‐based first line antiretroviral therapy, Outcome 8 Adverse events.
3.1
3.1. Analysis
Comparison 3 Switch to NVP vs continue on LPV/r, Outcome 1 Virological failure (any VL>50 copie/ml).
3.2
3.2. Analysis
Comparison 3 Switch to NVP vs continue on LPV/r, Outcome 2 Virological failure (confirmed VL>1000 copies/ml).
3.3
3.3. Analysis
Comparison 3 Switch to NVP vs continue on LPV/r, Outcome 3 Decline by 10% in CD4% at week 52.
3.4
3.4. Analysis
Comparison 3 Switch to NVP vs continue on LPV/r, Outcome 4 Decline by 1 z‐score in weight‐for‐age at week 52.
3.5
3.5. Analysis
Comparison 3 Switch to NVP vs continue on LPV/r, Outcome 5 ALT increase (Grade 3/4).
3.6
3.6. Analysis
Comparison 3 Switch to NVP vs continue on LPV/r, Outcome 6 Neutropenia (grade 3/4).
4.1
4.1. Analysis
Comparison 4 Induction‐Maintance strategy, Outcome 1 Increase in CD4% from baseline at week 36.
4.2
4.2. Analysis
Comparison 4 Induction‐Maintance strategy, Outcome 2 Increase in CD4% from baseline at week 72.
4.3
4.3. Analysis
Comparison 4 Induction‐Maintance strategy, Outcome 3 Increase in CD4% from baseline at week 144.
4.4
4.4. Analysis
Comparison 4 Induction‐Maintance strategy, Outcome 4 Virologic response (VL<400 copies/ml) at 24 weeks.
4.5
4.5. Analysis
Comparison 4 Induction‐Maintance strategy, Outcome 5 Virologic response (VL<400 copies/ml) at 36 weeks.
4.6
4.6. Analysis
Comparison 4 Induction‐Maintance strategy, Outcome 6 Virologic response (VL<400 copies/ml) at 48 weeks.
4.7
4.7. Analysis
Comparison 4 Induction‐Maintance strategy, Outcome 7 Virologic response (VL<400 copies/ml) at 144 weeks.
4.8
4.8. Analysis
Comparison 4 Induction‐Maintance strategy, Outcome 8 Mortality.
4.9
4.9. Analysis
Comparison 4 Induction‐Maintance strategy, Outcome 9 New WHO 4/death event‐free survival.
4.10
4.10. Analysis
Comparison 4 Induction‐Maintance strategy, Outcome 10 New WHO 3/4/death event‐free survival.
5.1
5.1. Analysis
Comparison 5 Planned treatment interruption strategy, Outcome 1 Change in WAZ z‐score.
5.2
5.2. Analysis
Comparison 5 Planned treatment interruption strategy, Outcome 2 Change in HAZ z‐score.
5.3
5.3. Analysis
Comparison 5 Planned treatment interruption strategy, Outcome 3 Change in WHZ z‐score.
5.4
5.4. Analysis
Comparison 5 Planned treatment interruption strategy, Outcome 4 Serious adverse events.
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