Lopinavir and tenofovir interaction observed in non-pregnant adults altered during pregnancy.

WHAT IS KNOWN AND OBJECTIVE: Tenofovir exposure is increased in non-pregnant adults when tenofovir disoproxil fumarate is coadministered with lopinavir/ritonavir. In pregnant women, tenofovir exposure is decreased. Our objective is to describe the effect of lopinavir/ritonavir on tenofovir pharmacokinetics during pregnancy. METHODS: Data were collected through the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s protocol. This was a nonrandomized, open-label, parallel-group and multicentre phase-IV prospective study in pregnant women with HIV. Intensive steady-state 24-h pharmacokinetic profiles were collected during the third trimester of pregnancy and postpartum. Tenofovir was measured in plasma using validated liquid chromatography-mass spectrometry method (quantification limit: 10 ng/ml). Statistical tests compared paired and between group pharmacokinetic data. RESULTS AND DISCUSSION: In women not receiving lopinavir/ritonavir (n = 28), tenofovir AUC0-24 was 27% lower (2.2 mcg·h/ml vs 2.8 mcg·h/ml, p = 0.002) and oral clearance was 27% higher (61 L/h vs 48 L/h, p = 0.001) during the third trimester compared to paired postpartum data. In women receiving lopinavir/ritonavir (n = 10), tenofovir AUC0-24 and oral clearance were not different antepartum compared to postpartum. Women with and women without concomitant lopinavir/ritonavir displayed no significant differences in postpartum tenofovir pharmacokinetics. WHAT IS NEW AND CONCLUSION: Tenofovir exposure during the third trimester was reduced compared to postpartum in pregnant women not receiving lopinavir/ritonavir, but not in pregnant women also receiving lopinavir/ritonavir. Our findings suggest that pregnancy confounds the expected decrease in tenofovir exposure with concomitant lopinavir/ritonavir in non-pregnant adults. These findings illustrate the need for drug-drug interaction studies in pregnant women as drug disposition differs significantly in pregnant women compared to non-pregnant adults.

Evaluating Predictive Value of Surgical Resected Proximal Bone Margins in Diabetic Foot Osteomyelitis With Clinical Outcomes at 1 Year.

Background: Osteomyelitis of the diabetic foot remains a significant complication that may result in the need for amputation. Proximal surgical margin histopathology after limb-sparing amputation could be used to guide antimicrobial duration and prognostic management but remains debatable. Here we evaluate if negative proximal bone margins predict outcomes of diabetic foot osteomyelitis at 1 year. Methods: A retrospective study assessed adults with diabetes undergoing limb-sparing foot amputations from September 2016 to September 2019. Patients required histopathology confirmation of osteomyelitis, proximal margin histopathology report, and documented electronic medical record follow-up through 12 months. The primary outcome evaluated if no further amputation at the same site was required in the following 12 months. Results: Of 92 patients, 57 (61.9%) had pathology-confirmed negative margins for osteomyelitis. Patients with negative margins required less frequent subsequent amputations at the same site within 12 months compared to positive margins (86.0% vs 65.7%; P = .003). Antibiotic duration was shorter in patients with negative margins (mean, 18 vs 30 days; P = .001). Negative-margin patients also noted lower rates of readmission at 12 months (26.3% vs 51.4%; P = .015) for site-specific complications. Staphylococcus aureus was more predominant in patients with positive versus negative margins (57.1% vs 29.8%; P = .017). Conclusions: Negative proximal bone margin by histopathology was associated with lower frequency of further amputations at the index surgical site within 12 months. This group also received shorter courses of antibiotic therapy. It was also associated with lower rates of readmission at 12 months for surgical-site complications. Proximal margin histopathology results potentially can be integrated to guide antimicrobial duration and decrease the frequency of further amputation at the original site.

Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV.

OBJECTIVE: To evaluate dolutegravir pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery. DESIGN: Ongoing, nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and infants. METHODS: Intensive steady-state 24 h pharmacokinetic profiles after dolutegravir 50 mg once-daily were performed during the second trimester (2T), third trimester (3T) and postpartum. Maternal delivery and postnatal infant samples were collected after birth. Dolutegravir was measured by validated LC-MS/MS; quantitation limit was 0.005 µg/ml. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-subject comparisons. RESULTS: Twenty-nine enrolled participants had a median age of 32 years (range 21-42). Pharmacokinetic data were available for 15 (2T), 28 (3T) and 23 (postpartum) women. Median dolutegravir AUC0-24,Cmax and C24 were 25-51% lower in the 2T and 3T compared with postpartum. The median cord blood/maternal plasma concentration ratio was 1.25 (n = 18). In 21 infants, median elimination half-life was 32.8 h after in utero exposure. Viral load at delivery was less than 50 copies/ml for 27/29 women (93%). Twenty-nine infants were HIV-negative. Renal abnormalities noted on ultrasound in two infants were deemed possibly related to dolutegravir. CONCLUSION: Dolutegravir exposure is lower in pregnancy compared with postpartum in the same women on once-daily dosing. Median AUC0-24 during pregnancy was similar to, whereas trough concentrations were lower than, those seen in nonpregnant adults. Trough concentrations in pregnancy were well above dolutegravir EC90 (0.064 µg/ml). Dolutegravir readily crosses the placenta. Infant elimination is prolonged, with half-life over twice that of historical adult controls.

Etravirine Pharmacokinetics in HIV-Infected Pregnant Women.

BACKGROUND: The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women. METHODS: IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL). RESULTS: Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0-12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19-4.25) and no perinatal transmission occurred. CONCLUSION: Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available. CLINICAL TRIAL REGISTRATION: The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929.