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Artemisinin‐based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether‐lumefantrine in HIV‐uninfected and HIV‐infected children living in a high‐transmission region of Uganda. HIV‐infected children were on efavirenz‐, nevirapine‐, or lopinavir‐ritonavir‐based antiretroviral regimens, with daily trimethoprim‐sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42‐day follow‐up and incorporated genotyping into a time‐to‐event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy‐seven children contributed 364 episodes to the model (186 HIV‐uninfected and 178 HIV‐infected), with recurrent microscopy‐detectable parasitemia detected in 176 episodes by day 42. The final model was a two‐compartment model with first‐order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir‐ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV‐uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5‐fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV‐infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa. [ABSTRACT FROM AUTHOR]

Background: HIV-1 transmission rates have been reduced over the last decade, an estimated 2 million new infections per year arise, including 220,000 paediatric cases. The main post-natal HIV exposure is through breastfeeding, where both its duration and modality (exclusive or not) are associated with postnatal transmission. The ANRS 12174 trial compared HIV-1 postnatal transmission of 2 prophylaxis drugs for infants during lactation (lamivudine and lopinavir-ritonavir). Our objective has been to examine the feeding practices and the determinants of exclusive/ predominant (EPBF) or any breastfeeding among the participants of this trial in Burkina Faso, South Africa, Uganda and Zambia. Methods: Mothers infected with HIV-1 and their uninfected offspring were followed from day 7 after birth for 50 weeks, keeping monthly records of their feeding patterns. Feeding was classified into 3 categories: 1) exclusive breastfeeding during the first six months, only breast-milk being given to infant for 6 months, 2) predominant breastfeeding, breast-milk with liquid-based items being given, and 3) mixed feeding, other non-breast milk or solid food being given in addition to breast milk with or without liquid-based items. The categories were merged into 2 groups: EPBF applying to infants aged <6 months and mixed feeding applying to infants of any age. The feeding patterns have been given as Kaplan-Meier curves. A flexible parametric multiple regression model was used to identify the determinants of the mothers' feeding behaviour. Results: A total of 1,225 mother-infant pairs provided feeding data from Burkina Faso (N = 204), South Africa (N = 213), Uganda (N = 274) and Zambia (N = 534) between November 2009 and March 2013. The mean maternal age was 27.4 years and the mean BMI was 24.5. 57.7 and 93.9% of mothers initiated breastfeeding within the first hour and first day, respectively. Overall, the median durations of any form of breastfeeding and EPBF were 40.6, and 20.9 weeks, respectively. Babies randomized to the lopinavir/ ritonavir group in South Africa tended to do less EPBF than those in the lamivudine group. Overall the group of mothers aged between 25 and 30 years, those married, employed or multiparous tended to stop early EPBF. Mothers living in Uganda or Zambia, those aged between 25 -30 years, better educated (at least secondary school level), employed or having undergone C-section stopped any breastfeeding early. Conclusions: There is a need to improve breastfeeding and complementary feeding practices of children, particularly those exposed to HIV and anti-retrovirals, taking into account context and socio-demographic factors. Trial registration: Clinical trial registration: NCT00640263. [ABSTRACT FROM AUTHOR]

Pregnancy and food insecurity may impact antiretroviral (ART) pharmacokinetics (PK), adherence and response. We sought to quantify and characterize the PK of lopinavir/ritonavir (LPV/r) and efavirenz (EFV) by pregnancy and nutritional status among HIV-infected women in Tororo, Uganda. In 2011, 62/225 ante-partum/post-partum single dried blood spot samples DBS and 43 post-partum hair samples for LPV/r were derived from 116 women, 51/194 ante-/post-partum DBS and 53 post-partum hair samples for EFV from 105 women. Eighty percent of Ugandan participants were severely food insecure, 26% lost weight ante-partum, and median BMI post-partum was only 20.2 kg/m2. Rich PK-data of normally nourished (pregnant) women and healthy Ugandans established prior information. Overall, drug exposure was reduced (LPV −33%, EFV −15%, ritonavir −17%) compared to well-nourished controls ( P < 0.001), attributable to decreased bioavailability. Pregnancy increased LPV/r clearance 68% ( P < 0.001), whereas EFV clearance remained unchanged. Hair concentrations correlated with plasma-exposure ( P < 0.001), explaining 29% PK-variability. In conclusion, pregnancy and food insecurity were associated with lower ART exposures in this cohort of predominantly underweight women, compared to well-nourished women. Much variability in plasma-exposure was quantified using hair concentrations. Addressing malnutrition as well as ART-PK in this setting should be a priority. [ABSTRACT FROM AUTHOR]

Background: Postnatal transmission of HIV-1 through breast milk remains an unsolved challenge in many resource-poor settings where replacement feeding is not a safe alternative. WHO now recommends breastfeeding of infants born to HIV-infected mothers until 12 months of age, with either maternal highly active antiretroviral therapy (HAART) or peri-exposure prophylaxis (PEP) in infants using nevirapine. As PEP, lamivudine showed a similar efficacy and safety as nevirapine, but with an expected lower rate of resistant HIV strains emerging in infants who fail PEP, and lower restrictions for future HIV treatment. Lopinavir/ritonavir (LPV/r) is an attractive PEP candidate with presumably higher efficacy against HIV than nevirapine or lamivudine, and a higher genetic barrier to resistance selection. It showed an acceptable safety profile for the treatment of very young HIV-infected infants. The ANRS12174 study aims to compare the risk of HIV-1 transmission during and safety of prolonged infant PEP with LPV/r (40/10 mg twice daily if 2-4 kg and 80/20 mg twice daily if >4 kg) versus Lamivudine (7,5 mg twice daily if 2-4 kg, 25 mg twice daily if 4-8 kg and 50 mg twice daily if >8 kg) from day 7 until one week after cessation of BF (maximum 50 weeks of prophylaxis) to prevent postnatal HIV-1 acquisition between 7 days and 50 weeks of age. Methods: The ANRS 12174 study is a multinational, randomised controlled clinical trial conducted on 1,500 mother-infant pairs in Burkina Faso, South Africa, Uganda and Zambia. We will recommend exclusive breastfeeding (EBF) until 26th week of life and cessation of breastfeeding at a maximum of 49 weeks in both trial arms. HIV-uninfected infants at day 7 (± 2 days) born to HIV-1 infected mothers not eligible for HAART who choose to breastfeed their infants. The primary endpoint is the acquisition of HIV-1 (as assessed by HIV-1 DNA PCR) between day 7 and 50 weeks of age. Secondary endpoints are safety (including resistance, adverse events and growth) until 50 weeks and HIV-1-free survival until 50 weeks. Discussion: This study will provide a new evidence-based intervention to support HIV-1-infected women not eligible for HAART to safely breastfeed their babies. Trial registration number (www.clinicaltrials.gov): NCT00640263 [ABSTRACT FROM AUTHOR]

Background. We aimed to assess cardiac conduction safety of coadministration of the CYP3A4 inhibitor lopinavir/ritonavir (LPV/r) and the CYP3A4 substrate artemether-lumefantrine (AL) in HIV-positive Ugandans. Methods. Open-label safety study of HIVpositive adults administered single-dose AL (80/400 mg) alone or with LPV/r (400/100 mg). Cardiac function was monitored using continuous electrocardiograph (ECG). Results. Thirty-two patients were enrolled; 16 taking LPV/r -based ART and 16 ART naïve. All took single dose AL. No serious adverse events were observed. ECG parameters in milliseconds remained within normal limits. QTc measurements did not change significantly over 72 hours although were higher in LPV/r arm at 24 (424 versus 406; P = .02) and 72 hours (424 versus 408; P = .004) after AL intake. Conclusion. Coadministration of single dose of AL with LPV/r was safe; however, safety of six-dose AL regimen with LPV/r should be investigated. [ABSTRACT FROM AUTHOR]