Suchergebnisse

IntroductionAntiretroviral therapy is recommended during pregnancy for prevention of mother‐to‐child transmission (MTCT) of HIV. Physiological changes during pregnancy are known to affect the pharmacokinetics (PK) of protease inhibitors (PIs), leading to lower exposures in pregnant women. Here we examine the PK of DRV/r 800/100 mg once daily (OD) over the course of pregnancy and postpartum (PP).Material and MethodsIn this prospective open‐labelled study, HIV‐positive pregnant women receiving darunavir/ritonavir as part of their routine maternity care were enrolled. DRV plasma trough concentrations [DRV] were determined in the first (T1) and/or second (T2) and/or third (T3) trimester and PP using a validated HPLC‐MS/MS methodology (Lab21, Cambridge UK). Where possible paired maternal and cord blood samples were taken at delivery.ResultsTo date 20 women (12 black African, 8 Caucasian) have been enrolled. Median (range) baseline CD4 count was 338 cells/µL (108–715), and median baseline plasma viral load was 555 copies/mL (<40–8,188,943). All but 2 women were virally suppressed at time of delivery (114 and 176 copies/mL; 1 sub‐therapeutic at T3) and median CD4 count was 410 cells/µL (92–947). There were 20 live births, all term deliveries and there were no cases of MTCT. [DRV] (geometric mean; 95% CI) was 3790 ng/mL at T1 (n=1); 1288 ng/mL (663–1913) at T2 (n=9); 1086 ng/mL (745–1428) at T3 (n=18, 1 undetectable) and 2324 ng/mL (1369–3279) at PP (n=14, 1 undetectable). There was no significant difference in [DRV] between T2 and PP (p=0.158); however, there was between T3 and PP (p=0.021). Nineteen of twenty (95%) and 16 of 20 (80%) women achieved [DRV] above the estimated MEC for WT (55 ng/mL) and PI resistant HIV‐1 (550 ng/mL) throughout pregnancy. Maternal and cord [DRV] were available for 10 mother–baby pairs. Mean maternal [DRV] at delivery was 2235 ng/mL (±1557 ng/mL), while mean cord [DRV] was 337 ng/mL (±217 ng/mL). The median cord to maternal blood ratio (C/M) was 0.11 (0.06–0.49).ConclusionsIn most cases examined, DRV/r 800/100 mg once daily was effective at achieving adequate therapeutic drug levels (>550 ng/ml) during pregnancy. However, reduced DRV plasma concentrations in the second/third trimesters highlights the need for TDM in this population and warrants further study of pregnancy‐associated changes in DRV pharmacokinetics. The low C/M ratios reported here are consistent with previous reports [1] and suggest low transplacental transfer of DRV.

IntroductionDarunavir/r (DRV/r) is currently used at a dose of 800/100 mg once daily (OD) in a high proportion of patients. Pharmacokinetic data suggest that 600/100 OD may be effective, reducing toxicity and cost. However, drug concentrations in reservoirs such as cerebrospinal fluid (CSF) might not be adequate to inhibit viral replication. We aimed to evaluate concentrations of DRV and HIV‐1 viral load (VL) in CSF patients receiving DRV 600/100 mg OD.MethodsDRV600 is an ongoing randomized open study comparing DRV/r 800/100 mg (DRV800) vs 600/100 mg (DRV600) OD plus TDF/FTC or ABC/3TC in 100 virologically suppressed patients (eudraCT 2011‐006272‐39). Here we present the results of a CSF sub‐study. A lumbar puncture (LP) was performed in participating patients after at least six months of inclusion in the study, 20–28 hours after a dose of DRV/r. VL (PCR, LOD 40 copies/mL) was determined in CSF and in plasma. DRV concentrations were quantified in CSF by liquid chromatography mass spectrometry (LC/MS/MS) and in plasma using high‐performance liquid chromatography (HPLC).ResultsSixteen patients were included (eight in each arm). All DRV600 patients and four out of eight DRV800 patients received TDF/FTC, and the other four ABC/3TC. 75% were males, median (range) age was 48 (17–71) years, CD4 cell count 532 cells/mL (190–1,394). Median total time on DRV/r was 30 (11–57) months, and since the beginning of the study 8 (6–12) months in DRV800 and 10 (7–12) months in DRV600 patients. LP was performed a median of 26 (24–28) hours after the last DRV/r+TVD or KVX dose. In DRV600 patients the median DRV plasma levels were 1,674 (326–3,742) ng/mL, CSF levels 17.08 (5.79–30.19) ng/mL and DRV CSF:plasma ratio 0.0084 (0.0028–0.0388), while in the DRV800 arm, median DRV plasma levels were 1,707 (958–3,910) ng/mL, CSF levels 13.23 (3.47–32.98) ng/mL and DRV CSF:plasma ratio 0.0104 (0.0018–0.0262). All patients had VL<40 copies/mL in plasma and 14 patients VL<40 copies/mL in CSF. Two patients (1 in each arm, and taking TDF/FTC) had detectable VL in CSF (280 and 159 c/mL). These patients had the lowest CSF DRV concentrations (5.47 and 3.47 ng/mL), with plasma DRV concentrations of 802 and 958 ng/mL respectively.ConclusionsCSF DRV concentrations and CSF VL were similar between patients receiving DRV/r 800/100 mg or 600/100 mg OD. Low CSF DRV concentrations might be associated with viral escape in CNS. This may be taken into account in patients receiving OD DRV/r. Larger studies should confirm these findings.

IntroductionSub‐dermal hormone implants, such as levonorgestrel (LNG), are a safe and desirable form of long‐acting contraception, but their use among HIV‐positive women on antiretroviral therapy (ART) may be compromised given the potential for a cytochrome P450 3A‐mediated drug–drug interaction. Our study aimed to characterize the pharmacokinetics of LNG released from a sub‐dermal implant over six months in HIV‐positive Ugandan women on nevirapine (NVP)‐ or efavirenz (EFV)‐based ART.Material and MethodsThis non‐randomized, parallel group study compared LNG pharmacokinetics between HIV‐positive Ugandan women not yet eligible for ART (control group, n=18) and those on stable NVP‐ (n=20) or EFV‐ (n=20) based ART. The two‐rod (75 mg/rod) LNG sub‐dermal implant was inserted at study enrolment. LNG sampling was obtained pre‐implant and at weeks 1, 4, 12 and 24 post‐insertion. LNG concentrations were analyzed using a validated LC‐MS/MS method, with an assay calibration range of 50–1500 pg/mL. Safety monitoring, including a pregnancy test, was conducted at each study visit.ResultsAt enrolment, participants had a mean age of 31 years; CD4+ cell counts were similar between the control, NVP and EFV groups (758, 645 and 568 cells/mm3, respectively; p=0.09); all women in the NVP and EFV groups had an undetectable HIV‐RNA. Women in the control group had a higher baseline body weight (73 kg) compared to those in the NVP (63 kg; p=0.03) or EFV groups (60 kg; p<0.01). By linear regression, weight was a significant predictor of LNG concentrations (1 kg increase in weight=5 pg/mL decrease in LNG, p=0.03). LNG concentrations are reported in the table.ConclusionsOver a 24‐week period, LNG concentrations were 40–54% lower in women on EFV‐based ART, despite their having a significantly lower body weight, compared to those not on ART. In women on NVP‐based ART, LNG concentrations were 32–39% higher than those observed in the control group, a difference partially explained by body weight. These data confirm a significant drug interaction occurs between the LNG implant and EFV, adding to growing concern for reduced contraceptive efficacy with their combined use. In contrast, these data support use of the LNG implant with NVP‐based ART.