Elsevier

The Lancet

Volume 382, Issue 9904, 9–15 November 2013, Pages 1555-1563
The Lancet

Articles
Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial

https://doi.org/10.1016/S0140-6736(13)61409-9Get rights and content

Summary

Background

Interim results from the children with HIV early antiretroviral (CHER) trial showed that early antiretroviral therapy (ART) was life-saving for infants infected with HIV. In view of the few treatment options and the potential toxicity associated with lifelong ART, in the CHER trial we compared early time-limited ART with deferred ART.

Methods

CHER was an open-label randomised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher. 377 infants were randomly allocated to one of three groups: deferred ART (ART-Def), immediate ART for 40 weeks (ART-40W), or immediate ART for 96 weeks (ART-96W), with subsequent treatment interruption. The randomisation schedule was stratified by clinical site with permuted blocks of random sizes to balance the numbers of infants allocated to each group. Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4% less than 25% in infancy; otherwise, the criteria were CD4% less than 20% or Centers for Disease Control and Prevention severe stage B or stage C disease. Combination therapy of lopinavir–ritonavir, zidovudine, and lamivudine was the first-line treatment regimen at ART initiation and re-initiation. The primary endpoint was time to failure of first-line ART (immunological, clinical, or virological) or death. Comparisons were done by intention-to-treat analysis, with use of time-to-event methods. This trial is registered with ClinicalTrials.gov, number NCT00102960.

Findings

377 infants were enrolled, with a median age of 7·4 weeks, CD4% of 35%, and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years; 34 infants (9%) were lost to follow-up. Median time to ART initiation in the ART-Def group was 20 weeks (IQR 16–25). Time to restarting of ART after interruption was 33 weeks (26–45) in ART-40W and 70 weeks (35–109) in ART-96W; at the end of the trial, 19% of patients in ART-40W and 32% of patients in ART-96W remained off ART. Proportions of follow-up time spent on ART were 81% in the ART-Def group, 70% in the ART-40W group, and 69% in the ART-96W group. 48 (38%) of 125 children in the ART-Def group, 32 (25%) of 126 in the ART-40W group, and 26 (21%) of 126 in the ART-96W group reached the primary endpoint. The hazard ratio, relative to ART-Def, was 0·59 (95% CI 0·38–0·93, p=0·02) for ART-40W and 0·47 (0·27–0·76, p=0·002) for ART-96W. Three children in ART-Def, three in ART-40W, and one in ART-96W switched to second-line ART.

Interpretation

Early time-limited ART had better clinical and immunological outcomes than deferred ART, with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption, with marginally better outcomes.

Funding

US National Institutes of Health.

Introduction

HIV infection causes high mortality and rapid disease progression in infants.1, 2 If untreated, more than a third of infected infants die during infancy and about half by 2 years of age.3, 4 Although early antiretroviral therapy (ART) is life-saving, treatment duration is lifelong. ART options are scarce in resource-poor settings, and even fewer are available for infants because of formulation and pharmacokinetic limitations and the risk of resistance after exposure to drugs used to prevent mother-to-child transmission.5 The cumulative effects of treatment in the growing child are worrying, with long-term pharmacovigilance data unavailable. Therefore, we postulated that compared with deferred ART, a strategy of early time-limited ART initiated close to primary infection would prevent disease progression and safely allow a subsequent period off ART, thus preserving future treatment options.

In 2007, when the median follow-up time of the CHER trial was 40 weeks (IQR 24–58), interim data showed that early ART reduced the risk of death by 75% compared with deferred ART,2 and subsequently became the standard of care.6, 7, 8 Here, we report the 5-year results of the completed CHER trial.

Section snippets

Study design and participants

Infants aged 6–12 weeks with confirmed HIV infection test results and a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher were eligible for inclusion in the study. No previous ART was allowed, apart from treatment for prevention of mother-to-child transmission. Exclusion criteria included birthweight less than 2 kg, grade 3 or 4 laboratory abnormalities (transaminases, neutrophil count, haemoglobin, electrolytes, and creatinine), clinically significant medical events, and

Results

Of 591 HIV-infected infants screened, 411 had CD4% of 25% or higher; of these infants, 377 were enrolled in the study and randomly allocated to ART-Def (n=125), ART-40W (126), or ART-96W (126) between July, 2005, and February, 2007. An additional 34 infants were randomly allocated to ART-40W (17) or ART-96W (17) between September, 2007, and March, 2008, after the Data Safety Monitoring Board recommended that recruitment to ART-Def should be stopped in June, 2007 (figure 1 and appendix).

The

Discussion

The results of the completed CHER trial show that early time-limited ART in young infants is better than deferred ART over an extended period. During planned interruption after primary therapy, the rapid disease course noted with deferred ART2 was not recorded, perhaps because the children given early time-limited ART were older when ART was discontinued than were those who had not started ART in the ART-Def group. Another explanation is that initiation of ART shortly after infection limits

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