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BMC Med. 2017 Apr 24;15(1):85. doi: 10.1186/s12916-017-0842-4.

Efavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and Côte d'Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial.

Author information

1
MONOD Project, ANRS 12206, Centre de Recherche Internationale pour la Santé, Ouagadougou, Burkina Faso.
2
Centre Muraz, Bobo-Dioulasso, Burkina Faso.
3
Inserm, Unité U1219, Université de Bordeaux, Bordeaux, France.
4
Paediatric Department, Centre Hospitalier Universitaire of Cocody, Abidjan, Côte d'Ivoire.
5
PACCI Programme, Site ANRS, Projet MONOD, Abidjan, Côte d'Ivoire.
6
Department of Infection and Immunity, Luxembourg Institute of Health, Luxembourg City, Luxembourg.
7
Laboratory CeDReS, Abidjan, Côte d'Ivoire.
8
Laboratory, Centre Hospitalier Universitaire de Ouagadougou, Ouagadougou, Burkina Faso.
9
EA 8, Université Paris Descartes, Paris, France.
10
Immunology, Hematology, Rhumatologie Unit, Hopital Necker-Enfants Malades-Assistance Publique-Hopitaux de Paris, Paris, France.
11
Paediatric Department, Centre Hospitalier Universitaire Yalgado Ouédraogo, Ouagadougou, Burkina Faso.
12
Paediatric Department, Centre Hospitalier Universitaire de Yopougon, Abidjan, Côte d'Ivoire.
13
Paediatric Department, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
14
Paediatric Department, Centre Hospitalier Universitaire Charles de Gaulle, Ouagadougou, Burkina Faso.
15
UMR 1058, Pathogenesis and control of chronic infections, Inserm/Université de Montpellier/EFS, Montpellier, France.
16
Department of Bacteriology-Virology, CHU Montpellier, Montpellier, France.
17
CePReF-enfants, Yopougon, Abidjan, Côte d'Ivoire.
18
University of Ouagadougou, Ouagadougou, Burkina Faso.
19
Inserm, Unité U1027, Université Toulouse 3, Toulouse, France. valeriane.leroy@inserm.fr.

Abstract

BACKGROUND:

The 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years.

METHODS:

The MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d'Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12-15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test).

RESULTS:

Between May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12-15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), -11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, -13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation.

CONCLUSIONS:

At the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored.

TRIAL REGISTRATION:

ClinicalTrial.gov registry n° NCT01127204 , 19 May 2010.

KEYWORDS:

Africa; Early antiretroviral treatment; Efavirenz; HIV; Infants; Lopinavir; Protease inhibitors; Randomised clinical trial; Treatment simplification; Virological outcomes

PMID:
28434406
PMCID:
PMC5402051
DOI:
10.1186/s12916-017-0842-4
[Indexed for MEDLINE]
Free PMC Article

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