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.

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.

Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates.

The aim of the present study was to describe the nevirapine (NVP) pharmacokinetics (PK) in pregnant women and their neonates and to evaluate the transplacental drug transfer and administration scheme for the prevention of mother-to-child transmission. Thirty-eight HIV-1-infected pregnant women were administered one tablet of NVP (200 mg) and two tablets of tenofovir-emtricitabine (Truvada) at the initiation of labor. Children were given NVP syrup (2 mg/kg of body weight) as a single dose (sdNVP) on the first day of life. By pair, NVP concentrations were measured in 11 maternal, 1 cord blood, and 2 neonatal plasma samples and analyzed by a population approach. A one-compartment model was used for mothers and neonates; the absorption rate constants for mothers and neonates were 0.95 h(-1) (intersubject variability, 111%) and 0.39 h(-1), respectively; the apparent elimination clearances were 1.42 liter·h(-1) (intersubject variability, 22%) and 0.035 liter·h(-1), respectively; and apparent volumes of distribution were 87.3 liters (intersubject variability, 25%) and 5.65 liters, respectively. An effect compartment was linked to maternal circulation by mother-to-cord and cord-to-mother rate constants of 1.10 h(-1) and 1.43 h(-1), respectively. Placental transfer, expressed as the fetal-to-maternal area under the curve ratio, was 75%. Neonates had a very long half-lives (110 h) compared to adults. In the 38 mothers, the simulated median individual predicted time during which the NVP concentration remained above the half-maximal inhibitory concentration (IC(50)) was 13.2 days (range, 12 to 19.2 days). Thus, the administration of tenofovir-emtricitabine for at least 3 weeks after delivery should be considered to prevent the emergence of resistant viruses. The neonate must receive sdNVP immediately after birth when the infant is born less than 30 min after maternal drug intake to keep NVP concentrations above the IC(50).

Concentrations of tenofovir and emtricitabine in breast milk of HIV-1-infected women in Abidjan, Cote d'Ivoire, in the ANRS 12109 TEmAA Study, Step 2.

The aim was to evaluate emtricitabine (FTC) and tenofovir (TFV) neonatal ingestion through breast milk. Median TFV and FTC breast milk doses represented 0.03% and 2%, respectively, of the proposed oral infant doses. Neonatal simulated plasma concentrations were extremely low for TFV but between the half-maximal inhibitory concentration and the adult minimal expected concentration for FTC. The rare children who will acquire HIV despite TDF-FTC therapy will need to be monitored for viral resistance acquisition.

Plasma and intracellular tenofovir pharmacokinetics in the neonate (ANRS 12109 trial, step 2).

The objective of this study was to investigate for the first time tenofovir (TFV) pharmacokinetics in plasma and peripheral blood mononuclear cells (PBMCs) of the neonate. HIV-1-infected pregnant women received two tablets of tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) at onset of labor and then one tablet daily for 7 days postpartum. A single dose of 13 mg/kg of body weight of TDF was administered to 36 neonates within 12 h of life after the HIV-1-infected mothers had been administered two tablets of TDF-emtricitabine at delivery. A total of 626 samples collected within the 2 days after the drug administration were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and analyzed by a population approach. In the neonate, the median TFV plasma area under the curve and minimal and maximal concentrations, respectively, were 3.73 mg/liter · h and 0.076 and 0.29 mg/liter. In PBMCs, TFV concentrations were detectable in all fetuses, whereas tenofovir diphosphate (TFV-DP) was quantifiable in only two fetuses, suggesting a lag in appearance of TFV-DP. The median TFV-DP neonatal concentration was 146 fmol/106 cells (interquartile range [IQR], 53 to 430 fmol/106 cells); two neonates had very high TFV-DP concentrations (1,530 and 2963 fmol/106 cells). The 13-mg/kg TDF dose given to neonates produced plasma TFV and intracellular active TFV-DP concentrations similar to those in adults. This dose should be given immediately after birth to reduce the delay before the active compound TFV-DP appears in cells.

Population pharmacokinetics of emtricitabine in human immunodeficiency virus type 1-infected pregnant women and their neonates.

The objectives of this study were to evaluate emtricitabine (FTC) pharmacokinetics in pregnant women and their neonates and to determine the optimal prophylactic dose for neonates after birth to prevent mother-to-child transmission of human immunodeficiency virus (HIV). A total of 38 HIV-infected pregnant women were administered tenofovir disoproxyl fumarate (300 mg)-FTC (200 mg) tablets-two tablets at the initiation of labor and one daily for 7 days postpartum. By pair, 11 maternal, one cord blood, and two neonatal FTC concentrations were measured using a high-performance liquid chromatography-tandem mass spectrometry validated method and analyzed by a population approach. Model and mean estimates (interpatient variability) were a two-compartment model for mothers, with an absorption rate constant of 0.54 h(-1) (61%), apparent elimination and intercompartmental clearances of 23.2 (17%) and 6.04 liters x h(-1), and apparent central and peripheral volumes of 127 and 237 liters, respectively; an effect compartment linked to maternal circulation for cord blood and a neonatal compartment disconnected, after delivery, with a 10.6-h half-life (30%). After the 400-mg FTC administration, the median population area under the concentration-time curve and the minimal and maximal plasma FTC concentrations in pregnant women were 14.3 mg x liter(-1) x h and 1.68 and 0.076 mg/liter, respectively. At delivery, median (range) predicted maternal and cord blood FTC concentrations were, respectively, 1.16 (0.14 to 1.99) and 0.72 (0.05 to 1.19) mg x liter(-1). We concluded that the 400-mg FTC administration in pregnant women produces higher exposition than does the 200-mg administration in other adults, at steady state. FTC was shown to have good placental transfer (80%). Administering 1 mg FTC/kg as soon as possible after birth or 2 mg/kg 12 h after birth should produce neonatal concentrations comparable to the concentrations observed in adults.

Costs of Care of HIV-Infected Children Initiating Lopinavir/Ritonavir-Based Antiretroviral Therapy before the Age of Two in Cote d'Ivoire.

OBJECTIVES: To access the costs of care for Ivoirian children before and after initiating LPV/r-based antiretroviral therapy (ART) before the age of two. METHODS: We assessed the direct costs of care for all HIV-infected children over the first 12 months on LPV/r-based ART initiated <2 years of age in Abidjan. We recorded all drug prescriptions, ART and cotrimoxazole prophylaxis delivery, medical analyses/examinations and hospital admissions. We compared these costs to those accrued in the month prior to ART initiation. Costs and 95% confidence intervals (95%CI) were estimated per child-month, according to severe morbidity. RESULTS: Of the 114 children screened, 99 initiated LPV/r-based ART at a median age of 13.5 months (IQR: 6.8-18.6); 45% had reached World Health Organization stage 3 or 4. During the first 12 months on ART, 5% died and 3% were lost to follow-up. In the month before ART initiation, the mean cost of care per child-month reached $123.39 (95%CI:$121.02-$125.74). After ART initiation, it was $42.53 (95%CI:$42.15-$42.91); 50% were ART costs. The remaining costs were non-antiretroviral drugs (18%) and medical analyses/examinations (14%). Mean costs were significantly higher within the first three months on ART ($48.76, 95%CI:$47.95-$49.56) and in children experiencing severe morbidity ($49.76, 95%CI:$48.61-50.90). CONCLUSION: ART reduces the overall monthly cost of care of HIV-infected children < 2 years. Because children were treated at an advanced HIV disease stage, the additional costs of treating severe morbidity on ART remain substantial. Strategies for treating HIV-infected children as early as possible must remain a priority in Côte d'Ivoire.

CD4-specific mortality rates among HIV-infected adults with high CD4 counts and no antiretroviral treatment in West Africa.

BACKGROUND: CD4-specific rates of mortality in sub-Saharan African adults with high CD4 counts have rarely been estimated. This estimation is useful to the when to start antiretroviral treatment (ART) debate. METHODS: We pooled data from National Agency for Research on AIDS and Viral Hepatitis (ANRS)-funded research cohorts or associated partners in West Africa. All HIV-infected adults (≥18 years) with available follow-up time off ART were eligible. We used a joint model to estimate CD4 count evolution. We estimated CD4-specific rates of mortality, loss-to-follow-up (LTFU) and ART initiation by dividing the number of first event by the follow-up time off ART within each CD4 category. RESULTS: Between 1996 and 2009, 2588 adults (80% women) from 5 cohorts in Cote d'Ivoire and Burkina Faso were followed off ART during 6862 person-years. In the 201-350, 351-500, 501-650, and >650 cells per cubic millimeter CD4 categories, mortality rates were: 3.0, 1.5, 0.4, 0.2 per 100 person-years; LTFU rates: 6.0, 4.6, 6.1, 6.0 per 100 person-years; and ART initiation rates: 18.1, 2.7, 0.5, 0.5 per 100 person-years, respectively. All estimates varied across cohorts; mortality rates were higher when rates of LFTU and ART initiation were lower; LTFU rates were 2-40 times higher than mortality rates. CONCLUSIONS: Among untreated West African adults with high CD4 counts, mortality and LTFU rates were substantial. Even when data are collected under research conditions, informative censoring due to ART initiation and LTFU could lead to significantly underestimate mortality figures.

Maternal and nenonatal tenofovir and emtricitabine to prevent vertical transmission of HIV-1: tolerance and resistance.

OBJECTIVE: Viral resistance occurs with a high frequency after single-dose nevirapine. We aimed to evaluate the tolerance and resistance profiles of a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) given to HIV-1-infected delivering women and their newborns. DESIGN: An open-label phase I/II trial in Cambodia, Côte d'Ivoire and South Africa. METHODS: HIV-1-infected pregnant women received zidovudine from the enrollment until the beginning of labor, when single-dose nevirapine and two tablets of TDF/FTC were given. One daily tablet of TDF/FTC was then administered for 7 days postpartum. All infants received single-dose nevirapine with single-dose TDF (13 mg/kg) and single-dose FTC (2 mg/kg) and 1 week of zidovudine. Mothers and infants were followed for 2 months. Serious adverse events, kinetic of maternal plasma HIV-1 RNA, pediatric HIV infection and genotypic resistance and viral subtype were assessed. RESULTS: Thirty-six HIV-1-infected pregnant women were enrolled: median age 28 years (interquartile range: 26-31 years), median CD4 cell count 462 cells/µl (interquartile range: 376-632) and median HIV-1 RNA 3.7 log10 copies/ml (interquartile range: 2.95-4.11). Two infants had clinical serious adverse events, including one who died (neonatal sepsis). One transient grade 3 neutropenia and two grade 3/4 hyperbilirubinemia were also reported in neonates. One HIV pediatric in-utero infection was diagnosed (2.8%; 95% confidence interval 0-15.4%). Genotypic viral resistance to nevirapine was detected in one mother out of 34 (2.9%) at one month postpartum, but was also detectable at enrollment. CONCLUSION: The combination of TDF/FTC to delivering women and their neonates appears well tolerated and to minimize the occurrence of nevirapine viral resistance.

Tolerance and viral resistance after single-dose nevirapine with tenofovir and emtricitabine to prevent vertical transmission of HIV-1.

OBJECTIVE: Viral resistance occurs with high frequency after single-dose nevirapine. We aimed to evaluate the safety and resistance profiles of a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) in HIV-1-infected pregnant women and their newborns. DESIGN: An open-label phase I/II trial in Côte d'Ivoire, Cambodia and South Africa. METHODS: Women received antenatal zidovudine, intrapartum single-dose nevirapine and two tablets of TDF/FTC and one daily tablet of TDF/FTC during the 7 days postpartum. Their infants received single-dose nevirapine and zidovudine for 1 week. Serious adverse events (SAEs), kinetic of maternal plasma HIV-1 RNA viral load, genotypic resistance at 28 days postpartum and paediatric HIV-1 infection at 3, 28 and 45 days of life were assessed. RESULTS: Thirty-eight HIV-1-infected pregnant women were enrolled (19 in Abidjan, 12 in Phnom Penh and seven in Soweto) with a median CD4 cell count of 450 cells/microl and median viral load of 4.08 log10 copies/ml. Women received TDF/FTC 4.9 h in median before delivery. Biological SAEs occurred in nine women. Among 39 live births, nine infants had clinical SAEs, including four deaths, and two developed severe anaemia. These SAEs were not likely to be related to TDF/FTC. Maternal viral load decreased by a median of 0.90 log10 copies/ml at 2 days postpartum and returned to baseline value at 28 days. No intrapartum HIV transmission was reported. No genotypic resistance mutation to zidovudine, nevirapine, FTC or TDF was detected. CONCLUSION: The TDF/FTC combination was well tolerated in delivering women and exposed newborns. Nevirapine viral resistance appears to have been avoided by the intrapartum and 7-day postpartum TDF/FTC regimen.