Effectiveness of antiretroviral therapy in HIV-infected children under 2 years of age

  • Review
  • Intervention

Authors


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 initiate 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 switch or interrupt therapy. This review aims to summarize the currently available evidence on this topic and inform the ART management in HIV-infected children less than 2 years of age.

Objectives

To evaluate 1) when to start ART in young children; 2) what ART to start with, comparing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) and PI-based regimens; and 3) whether and when ART should be stopped or switched from a PI-based regimen to an NNRTI-based regimen.

Search methods

We 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 We screened abstracts from relevant conference proceedings and searched for unpublished and ongoing trials in clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform).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 2 years of age without restriction of setting. We rejected trials that did not include children less than 2 years of age, 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

Of 1921 records retrieved, 5 studies were eligible for inclusion in the review, addressing when to start treatment (n=2), what to start (n=2) and whether to switch regimen (n=1). Three ongoing studies that address the question of treatment interruption were also identified.

Early infant treatment 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 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 was 2.01 (95%CI 1.47, 2.77) 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 effect by age group. The hazard for virological failure was overall 2.28 (95%CI 1.55, 3.34) times higher for children starting ART with a NVP-based regimen compared to those starting with a LPV/r-based regimen (p=0.0005) 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. By contrast, increases in weight z-score (MD=0.37, 95%CI 0.08, 0.65, p=0.01) and height z-score (MD=0.23, 95%CI 0.04, 0.42, p=0.02) were larger in the NVP arm compared to the LPV/r arm .

Infants starting on a LPV/r regimen but who then switched to a NVP-based regimen after a median time of 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 higher 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).

Authors' conclusions

Immediate ART reduces morbidity and mortality among infants and may improve neurodevelopmental outcome.  However It remains unclear whether all children diagnosed with HIV infection between 1-2 years of age should start ART, as has been recommended by the World Health Organization on practical grounds.

The available evidence suggests that a LPV/r-based first-line regimen is more potent than NVP, regardless of PMTCT exposure status. However, this finding provides a dilemma to policy-makers because  higher cost, poor palatability, inconvenient formulation and cold chain requirements make  LPV/r a more  costly and challenging first-line regimen. An alternative approach to long-term  LPV/r is switching to NVP (maintaining the NRTI backbone) once virological suppression is achieved. This strategy looked promising  in the one trial undertaken, but may be difficult to implement in the absence of VL testing.  

Ongoing trials are exploring the possibility of starting early ART and interrupting treatment beyond the critical period of rapid disease progression and neurological development. Further evidence is urgently required to better inform policy on first-line treatment recommendations in young children and more robust data addressing non-virological outcomes are also needed.

Plain language summary

Using antiretroviral drugs to treat children under 2 years old who have HIV infection

HIV-infected children  under  two years of age  have  a high risk of dying without antiretroviral  therapy, but treatment in this age  group is challenging because  there  are few suitable drug choices. Infants are often exposed to the antiretroviral drug nevirapine around the time of birth as part of strategies to reduce mother-to-child HIV transmission, and resistance to this class of drug is rapidly acquired. Results from this systematic review show that starting  ART soon after birth is preferable to delaying  treatment, because infants are less  likely to die or become sick. Starting  a first-line combination of treatment that includes the drug lopinavir/ritonavir (a protease inhibitor) rather  than nevirapine (a non-nucleoside reverse transcriptase inhibitor) seems to be preferable, because infants are less  likely to discontinue treatment, whether or not they had previously  been exposed to nevirapine. However, lopinavir/ritonavir is more  expensive than nevirapine, tastes more  bitter, and is currently only available as an inconvenient liquid which has  to be refrigerated, making it difficult to recommend lopinavir/ritonavir as first-line treatment in all parts  of the world. It may be possible to switch from lopinavir/ritonavir to nevirapine once  the HIV virus levels are  under  control, but tests to measure the amount of virus in the blood are expensive and often unavailable. Other  ongoing trials are exploring  other ways to give a stronger drug combination to infants and the possibility of starting  ART soon after birth but then stopping medication after 1-2 years.