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

Abstract

BackgroundThe 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.MethodsThe 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).ResultsBetween 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.ConclusionsAt 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 ...

Pharmacokinetics of Efavirenz at a High Dose of 25 Milligrams per Kilogram per Day in Children 2 to 3 Years Old

“…We did not notice any clinical seizures in terms of central nervous system (CNS) toxicity among the 52 children switched onto EFV, but 1 child had persistent daytime and nighttime sleeping disorders. EFV treatment of this child was then substituted after 9 months of treatment (18). At the PK evaluation visits, this child was not overexposed with regard to EFV because his C 12 h value was estimated at 1.9 mg/liter with the 25 mg/kg EFV dose and at 1.4 mg/liter with the 2016 FDA recommended dose.…”

“…The recent FDA recommendations for children who are 3 months to 3 years of age, released in 2016, take weight into account (Table 1) (4). Genetic covariates found include the polymorphic nature of cytochrome P450 2B6 (CYP2B6: rs3745274) and other isoforms responsible for EFV metabolism (17,18). Department of Health and Human Services (DHHS) guidelines include a "research" dose of EFV for children aged 3 months to Ͻ3 years according to CYP2B6 genotype (using data generated in IMPAACT P1070: protocol P1070) (17) (Table 1).…”

Suboptimal cotrimoxazole prophylactic concentrations in HIV‐infected children according to the WHO guidelines

“…Our study of PK/PD survival showed no SMX (on the left) and TMP (on the right) prediction-corrected visual predictive check: comparison between the 5th (lower dashed line), 50th (solid line) and 95th (upper dashed line) percentiles obtained from 1000 simulations and the observed data (points) for SMX or TMP concentrations correlation between the SMX or the TMP AUCs and the infection occurrence. This could be explained by the lack of statistical power due to the number of events in these children already on antiretroviral therapy for 6 months with an increased immunological response [29]. Even if the cotrimoxazole has proved its effect, there are still hospital admissions due to opportunistic infections.…”

“…Our study of PK/PD survival showed no correlation between the SMX or the TMP AUCs and the infection occurrence. This could be explained by the lack of statistical power due to the number of events in these children already on antiretroviral therapy for 6 months with an increased immunological response . Even if the cotrimoxazole has proved its effect, there are still hospital admissions due to opportunistic infections.…”

“…MONOD‐ANRS‐12206 was conducted in Ouagadougou, Burkina‐Faso and Abidjan, Côte d'Ivoire (http://ClinicalTrial.gov registry number: NCT01127204) . This randomized, non‐inferiority, and open label phase 3 trial was approved by the ‘Comité d'Ethique pour la Recherche en santé du Burkina Faso’, and the ‘Comité National d'Ethique et de la Recherche en Côte d'Ivoire’.…”