Continuous nevirapine may be associated with increased toxicity among HIV-1-infected pregnant women with CD4 cell counts greater than 250 cells/microL, as has been observed in non-pregnant women.

STUDY OBJECTIVE The optimal pharmacodynamic parameter for the prediction of efficacy of vancomycin is the area under the concentration-time curve (AUC), and current published data indicate that dosing based on vancomycin trough concentrations is an inaccurate substitute. In this study, our objective was to compare the achievement of therapeutic target attainment after switching from a trough-based to an AUC-based dosing strategy as a part of our institution's vancomycin-per-pharmacy protocol. DESIGN Prospective observational quality assurance study. SETTING Academic medical center. PATIENTS A total of 296 hospitalized adults who received vancomycin and monitoring under our institution's vancomycin-per-pharmacy protocol were included in the analysis. The preimplementation retrospective comparison group consisted of 179 patients in whom vancomycin was initiated using a trough-based dosing strategy between November 22, 2017, and January 22, 2018. The postimplementation group included 117 patients in whom vancomycin was initiated using an AUC-based dosing strategy using two-point sampling between June 19, 2018, and July 19, 2018, after hospital-wide implementation of this protocol on June 19, 2018. MEASUREMENTS AND MAIN RESULTS AUC values were calculated from two vancomycin concentrations (peak and trough). The primary outcome was achievement of therapeutic AUC values (400-800 mgÁhr/L) in the postimplementation group or therapeutic trough level values (10-20 mg/L) in the preimplementation group. Only 98 (55%) of 179 initial trough values were therapeutic in the preimplementation group (trough-only dosing method) versus 86 (73.5%) of 117 initial AUC values in the postimplementation group (AUC-based dosing method) (p=0.0014). A lower proportion of supratherapeutic AUC values was observed in the postimplementation group compared with supratherapeutic trough concentrations in the preimplementation group (1.7% vs 18%, p<0.0001). Overall, 62% of patients with initially therapeutic AUC values had subsequent trough value increases of 25% or greater, occurring at a median of 6 days of vancomycin therapy. Nephrotoxicity occurred in 11% of patients in the preimplementation versus 9.4% in the postimplementation group (p=0.70). CONCLUSION Compared with a trough concentration-based dosing strategy, AUC-based dosing using two-point sampling improved therapeutic target attainment. Implementation is feasible at any hospital that performs vancomycin peak concentration testing and is a workable alternative to using Bayesian software for estimating AUC. This approach should also be directly compared with AUC-based dosing using Bayesian software.

Marine mussels and barnacles are sessile biofouling organisms that adhere to a number of surfaces in wet environments and maintain remarkably strong bonds. Previous synthetic approaches to mimic biological wet adhesive properties have focused mainly on the catechol moiety, present in mussel foot proteins (mfps), and especially rich in the interfacial mfps, for example, mfp-3 and -5, found at the interface between the mussel plaque and substrate. Barnacles, however, do not use Dopa for their wet adhesion, but are instead rich in noncatecholic aromatic residues. Due to this anomaly, we were intrigued to study the initial contact adhesion properties of copolymerized acrylate films containing the key functionalities of barnacle cement proteins and interfacial mfps, for example, aromatic (catecholic or noncatecholic), cationic, anionic, and nonpolar residues. The initial wet contact adhesion of the copolymers was measured using a probe tack testing apparatus with a flat-punch contact geometry. The wet contact adhesion of an optimized, bioinspired copolymer film was ∼15.0 N/cm(2) in deionized water and ∼9.0 N/cm(2) in artificial seawater, up to 150 times greater than commercial pressure-sensitive adhesive (PSA) tapes (∼0.1 N/cm(2)). Furthermore, maximum wet contact adhesion was obtained at ∼pH 7, suggesting viability for biomedical applications.

RET proto-oncogene encodes a receptor tyrosine kinase whose ligand is glial cell line-derived neurotrophic factor (GDNF), and its polymorphism at G691S juxtamembrane region (RETp) is a germline polymorphism. Cutaneous melanomas, particularly the desmoplastic subtype, are highly neurotropic; thus we sought to determine the frequency of RETp in cutaneous melanoma and its functional responsiveness to GDNF. RETp was assessed in 71 non-desmoplastic cutaneous melanomas (non-DMs) and 70 desmoplastic melanomas (DMs). Melanoma cell lines with RETp, RET wild-type (RETwt), BRAF V600E mutation (BRAFmt) or BRAF wild-type (BRAFwt) were assessed for functional activity. RETp frequency was significantly higher in DMs (61%) than in non-DMs (31%, P<0.001). BRAFmt was detected in only 11% of DMs. GDNF stimulation significantly amplified cell proliferation, migration, and invasion in RETp, but not in RETwt melanoma cells. GDNF stimulation of RETp cell lines enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt of the RET-RAS-RAF-ERK and RET-phosphatidylinositol 3-kinase (PI3K)-Akt pathways, respectively. GDNF response of RETp cells in signal transduction and other functional studies were not affected by BRAFmt. The study demonstrates that RETp are frequently found in cutaneous melanoma, particularly desmoplastic subtypes, and responds to GDNF inducing events favorable for tumor progression.

The physiologic changes that occur during pregnancy make it difficult to predict antiretroviral pharmacokinetics (PKs), but few data exist on the PKs of protease inhibitors in human immunodeficiency virus (HIV)-infected pregnant women. The objective of the present study was to determine the PKs of ritonavir (RTV)-enhanced saquinavir (SQV) in HIV-infected pregnant women by an area under the curve (AUC)-targeted approach. A phase I, formal PK evaluation was conducted with HIV-infected pregnant woman during gestation, during labor and delivery, and at 6 weeks postpartum. The SQV-RTV regimen was 800/100 mg twice a day (b.i.d.), and nucleoside analogs were administered concomitantly. The SQV exposure targeted was an AUC at 24 h of 10,000 ng ⅐ h/ml. Participants were evaluated for 12-h steady-state PKs at each time period. Thirteen subjects completed the PK evaluations during gestation, 7 completed the PK evaluations at labor and delivery, and 12 completed the PK evaluations postpartum. The mean baseline weight was 67.4 kg, and the median length of gestation was 23.3 weeks. All subjects achieved SQV exposures in excess of the target AUC. The SQV AUCs at 12 h (AUC 12 s) during gestation (29,373 ؎ 17,524 ng ⅐ h/ml [mean ؎ standard deviation]), during labor and delivery (26,189 ؎ 22,138 ng ⅐ h/ml), and during the postpartum period (35,376 ؎ 26,379 ng ⅐ h/ml) were not significantly different. The mean values of the PK parameters for RTV were lower during gestation than during the postpartum period: for AUC 12 , 7,811 and 13,127 ng ⅐ h/ml, respectively; for trough concentrations, 376 and 632 ng/ml, respectively; and for maximum concentrations, 1,256 and 2,252 ng/ml, respectively (P < 0.05 for all comparisons). This is the first formal PK evaluation of a dual protease inhibitor regimen with HIV-infected pregnant women. The level of SQV exposure was sufficient at each time of evaluation. These data demonstrate large variability in SQV and RTV concentrations and suggest that RTV concentrations are altered by pregnancy. These PK results suggest that SQV-RTV at 800/100 mg b.i.d. appears to be a reasonable treatment option for this population.It is well established that the pharmacokinetics of drugs may be altered during pregnancy (9, 10). Factors that may lead to pregnancy-induced changes in drug absorption and disposition include increased gastric and intestinal emptying times, reductions in the levels of gastric acid secretion, increases in the levels of mucus secretion, plasma volume expansion, increased cardiac output, changes in organ blood flow, stimulation of hepatic microsomal enzymes, and inhibition of microsomal oxidases. Many of these physiologic changes begin during the second trimester and become marked during the third trimester. These changes make prediction of the effect of pregnancy on the pharmacokinetics of drugs difficult.Considerable data indicate that there is a significant association between antiretroviral drug concentrations and the virologic response or toxicity, particularly for the protease inhibitor...

Objective Although HIV-infected children are recommended to receive quadrivalent human papillo-mavirus vaccine (QHPV) there is limited information on their response to QHPV. This study in HIV-infected children, evaluated the magnitude and duration of immune responses to QHPV. This report describes type-specific serum antibody responses over a 4-to-5 year period after either 3 or 4 doses of QHPV. Design/methods HIV-infected children, ages 7-to-11 years, received 3 doses of QHPV (n = 96) or placebo (n = 30). At 72 weeks QHPV recipients received a fourth dose (n = 84), while placebo recipients began the 3-dose QHPV schedule (n = 27). HPV serotype-specific antibody was determined, by competitive Luminex immunoassay (cLIA) and IgG Luminex immunoassay, at 2, 3.5, and 4-to-5 years after the last dose of QHPV in each treatment arm. Results At 4-to-5 years after the last dose of QHPV, antibody titers were significantly higher in 4-dose than in 3-dose group. However, the proportion of vaccinees with a seroresponse in the cLIA assay was not different between the two groups (86–93% for HPV types 6, 11, and 16, and 64% for HPV type 18). These results were very similar to the seroresponse rate in these HIV-infected children at 1 month after completing vaccination. Conclusions Children with well-controlled HIV infection who receive 3 doses of the QHPV vaccine maintain seropositivity and antibody levels that are generally similar to children of the same age who are not HIV-infected. Antibody titer correlated strongly with low log HIV RNA, low CD8%, and high CD4%. Additionally, a fourth dose of vaccine in HIV-infected children produces a marked rise in antibody characteristic of an anamnestic response and persistence of high antibody levels. Conclusions Study identification: IMPAACT P1085 (V501-021). CLINICALTRIALS.GOV identifier: NCT01206556.

Tyrosinase-related protein-2 (TRP2) is a weak antigen expressed in murine and human melanomas. Induction of antibody (Ab) response and T-cell immunity toward TRP2 with DNA plasmid vaccines has not been efficient to date. Recent studies have suggested that a chemokine ligand for the CCR7 (CCL21) present on T-cells and dendritic cells is important in activating and regulating immunity. We investigated the effectiveness of CCL21 as an adjuvant with an HVJ anionic liposomal TRP2 DNA (plasmid) vaccine to enhance anti-TRP2 Ab, cytokines, delayed-type hypersensitivity, T-cell responses, and tumor protection against B16 melanoma cells. Induction of anti-TRP2 immunity depended mainly on cell-mediated immunity, which was regulated by timing and route of CCL21 administration with DNA vaccine. The optimum protocol was to administer CCL21 im 24 h before DNA vaccine at the same vaccination site. Two vaccinations (prime/boost) were essential for induction of strong anti-TRP2 cell-mediated immunity. CCL21 administration 3 days before or 24 h after DNA vaccine, simultaneous with DNA vaccine, or at different sites (iv, opposite leg) was not effective. This study demonstrated that CCL21 was an effective adjuvant to enhance TRP2-specific immunity induced by a plasmid DNA cancer vaccine.

Human immunodeficiency virus-infected women (n ‫؍‬ 16) received indinavir (800 mg three times a day) plus zidovudine plus lamivudine from 14 to 28 weeks of gestation to 12 weeks postpartum. Two women and eight infants experienced grade 3 or 4 toxicities that were possibly treatment related. Indinavir area under the plasma concentration-time curve was 68% lower antepartum versus postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy.Current antiretroviral guidelines recommend triple combination highly active antiretroviral therapy during pregnancy for the treatment of the mother and the prevention of mother-toinfant transmission of human immunodeficiency virus (HIV) (4). During pregnancy, physiological changes occur that have the potential to change the pharmacokinetics of drugs (8) and hence lead to decreased virologic efficacy. This study was initiated to determine the pharmacokinetics and safety of indinavir (IDV), coadministered with zidovudine (ZDV) and lamivudine (3TC), in HIV-infected women during pregnancy and postpartum.Women with a singleton, uncomplicated pregnancy between 14 and 28 weeks of gestation according to menstrual and ultrasound dating were enrolled after signing institutional human subjects committee-approved informed consent statements. Exclusion criteria included prior treatment with a protease inhibitor of Ͼ3 weeks, nonnucleoside reverse transcriptase inhibitor use within 3 weeks, Ͼ3 weeks of prior 3TC usage unless taken for Ͼ3 months with a stable HIV RNA and CD4 ϩ cell count, or intolerance to ZDV or 3TC. Women received 800 mg IDV three times daily according to standard instructions with ZDV (300 mg twice a day or 200 mg three times daily) and 150 mg 3TC twice daily through 12 weeks postpartum. During labor, IDV was temporarily discontinued, oral 3TC was continued, and ZDV was given intravenously (7).Infants received orally 2 mg/kg 3TC twice daily and 2.6 mg/kg ZDV three times daily (or 2.0 mg/kg intravenously every 8 h) until 6 weeks. Infants did not receive IDV because of the concern for increases in indirect bilirubin concentrations.Maternal and infant study visits for safety and efficacy evaluations occurred every 1 to 2 weeks antepartum, at delivery, at 6 and 12 weeks postpartum, and at 1, 6, 12, and 24 weeks of life, respectively. Adverse events were graded according to the National Institute of Allergy and Infectious Diseases Division of AIDS toxicity grading tables (1). Maternal blood samples for IDV pharmacokinetics were obtained predose and at 0.5, 1.0, 1.5, 2, 4, 6, and 8 h postdose at 30 to 32 weeks of gestation and 6 weeks postpartum. Infant IDV plasma concentrations were obtained at birth and at 1, 2, 4, and 6 h of life. IDV plasma concentrations (as free base) were determined by a high-performance liquid chromatography-UV and, at later stages of the study, by the more sensitive high-performance liquid chromatography-mass spectrometry assay (University of California at San Diego PACTG Pharmacology Laboratory). For both assays, the inter-...