Antiretroviral drug levels and interactions affect lipid, lipoprotein, and glucose metabolism in HIV-1 seronegative subjects: A pharmacokinetic- pharmacodynamic analysis

BACKGROUND: HIV-infected patients treated with antiretroviral medications (ARVs) develop undesirable changes in lipid and glucose metabolism that mimic the metabolic syndrome and may be proatherogenic. Antiretroviral drug levels and their interactions may contribute to these metabolic alterations. METHODS: Fifty-six HIV-seronegative adults were enrolled in an open-label, randomized, pharmacokinetic interaction study, and received a non-nucleoside reverse transcriptase inhibitor (efavirenz on days 1-21) plus a protease inhibitor (PI; amprenavir on days 11-21), with a second PI on days 15-21 (saquinavir, nelfinavir, indinavir, or ritonavir). Fasting triglycerides, total, LDL- and HDL-cholesterol, glucose, insulin and C-peptide levels were measured on days 0, 14, 21, and 2-3 weeks after discontinuing drugs. Regression models were used to estimate changes in these parameters and associations between these changes and circulating levels of study drugs. RESULTS: Short-term efavirenz and amprenavir administration significantly increased cholesterol, triglycerides and glucose levels. Addition of a second protease inhibitor further increased triglycerides, total- and LDL-cholesterol levels. Higher amprenavir levels predicted larger increases in triglycerides, total and LDL-cholesterol. Two weeks after all study drugs were stopped, total, LDL- and HDL-cholesterol remained elevated above baseline. CONCLUSIONS: ARV regimens that include a non-nucleoside reverse transcriptase inhibitor plus single or boosted PIs are becoming more common, but the pharmacodynamic interactions associated with these regimens can result in persistent, undesirable alterations in serum lipid/lipoprotein levels. Additional pharmacodynamic studies are needed to examine the metabolic effects of ritonavir-boosted regimens, with and without efavirenz

The Design of Single-Arm Clinical Trials of Combination Antiretroviral Regimens for Treatment-Naive HIV-Infected Patients

Single-arm clinical trials are useful to evaluate antiretroviral regimens in certain populations of HIV-infected treatment-naive patients for whom a randomized controlled trial is not feasible or desirable. They can also be useful to establish initial estimates of efficacy and safety/tolerability of novel regimens to inform the design of large phase III trials. In this article, we discuss key design considerations for such single-arm studies

Amprenavir and efavirenz pharmacokinetics before and after the addition of nelfinavir, indinavir, ritonavir, or saquinavir in seronegative individuals

Adult AIDS Clinical Trials Group 5043 examined pharmacokinetic (PK) interactions between amprenavir (APV) and efavirenz (EFV) both by themselves and when nelfinavir (NFV), indinavir (IDV), ritonavir (RTV), or saquinavir (SQV) is added. A PK study was conducted after the administration of single doses of APV (day 0). Subjects (n = 56) received 600 mg of EFV every 24 h (q24h) for 10 days and restarted APV with EFV for days 11 to 13 with a PK study on day 14. A second protease inhibitor (PI) (NFV, 1,250 mg, q12h; IDV, 1,200 mg, q12h; RTV, 100 mg, q12h; or SQV, 1,600 mg, q12h) was added to APV and EFV on day 15, and a PK study was conducted on day 21. Controls continued APV and EFV without a second PI. Among subjects, the APV areas under the curve (AUCs) on days 0, 14, and 21 were compared using the Wilcoxon signed-rank test. Ninety-percent confidence intervals around the geometric mean ratios (GMR) were calculated. APV AUCs were 46% to 61% lower (median percentage of AUC) with EFV (day 14 versus day 0; P values of <0.05). In the NFV, IDV, and RTV groups, day 21 APV AUCs with EFV were higher than AUCs for EFV alone. Ninety-percent confidence intervals around the GMR were 3.5 to 5.3 for NFV (P < 0.001), 2.8 to 4.5 for IDV (P < 0.001), and 7.8 to 11.5 for RTV (P = 0.004). Saquinavir modestly increased the APV AUCs (GMR, 1.0 to 1.4; P = 0.106). Control group AUCs were lower on day 21 compared to those on day 14 (GMR, 0.7 to 1.0; P = 0.042). African-American non-Hispanics had higher day 14 efavirenz AUCs than white non-Hispanics. We conclude that EFV lowered APV AUCs, but nelfinavir, indinavir, or ritonavir compensated for EFV induction

Compartmental pharmacokinetic analysis of oral amprenavir with secondary peaks

Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring

A seasonal periodicity in relapses of multiple sclerosis? A single-center, population-based, preliminary study conducted in Bologna, Italy

Fabrizio Salvi, Ilaria Bartolomei, Angelo Lorusso, and Elena Barbarossa are with the Department of Neuroscience, Multiple Sclerosis Center, Bellaria Hospital, Bologna, Italy -- Michael H. Smolensky is with the Department of Biomedical Engineering, the University of Texas at Austin, USA -- Ann Maria Malagoni, Paolo Zamboni, and Roberto Manfredini are with the Vascular Diseases Center, University of Ferrara, Italy -- Roberto Manfredini is with the Department of Internal Medicine, Hospital of the Delta, Azienda Unità Sanitaria Locale, Ferrara, Italy and the Department of Clinical and Experimental Medicine, Clinica Medica and Vascular Diseases Center, University of Ferrara, ItalyBackground: Temporal, i.e., 24-hour, weekly, and seasonal patterns in the occurrence of acute cardiovascular and cerebrovascular events are well documented; however, little is known about temporal, especially seasonal, variation in multiple sclerosis (MS) and its relapses. This study investigated, by means of a validated chronobiological method, whether severe relapses of MS, ones requiring medical specialty consultation, display seasonal differences, and whether they are linked with seasonal differences in local meteorological variables. Results: We considered 96 consecutive patients with severe MS relapse (29 men, 67 women, mean age 38.5 ± 8.8 years), referred to the Multiple Sclerosis Center, Bellaria Hospital, Bologna, Italy, between January 1, 2007 and December 31, 2008. Overall, we analyzed 164 relapses (56 in men, 108 in women; 115 in patients aged < 40 years, 49 in patients ≥40 years). Relapses were more frequent in May and June (12.2% each) and the least frequent in September (3.7%). Chronobiological analysis showed a biphasic pattern (major peak in May-June, secondary peak in November-December, p = 0.030). Analysis of monthly mean meteorological data showed a significant seasonal pattern in ambient temperature (peak in July, p < 0.001), relative humidity (peak in January, p < 0.001), and wind speed (peak in June, p = 0.011). Conclusions: In this Italian setting we found a biphasic pattern, peaks in spring and autumn, in severe MS relapses requiring medical consultation by doctors of the MS specialty center apparently unrelated to meteorological variables. Confirmations of the findings on larger multi-center populations residing in different climatic conditions are needed to further explore the potential seasonality of MS relapses and associated environmental triggers.Biomedical [email protected]

Dinâmicas comunitárias em deslocados e não deslocados residentes em áreas de exclusão social em Barranquilla (Colômbia)

El sentido de comunidad, la participación y el empoderamiento permiten comprender el proceso de desplazamiento y reasentamiento en el contexto de recepción, así como las consecuencias derivadas de ambos fenómenos. Los objetivos de la investigación son a) evaluar los tres constructos mencionados, b) analizar la sinergia que existe entre estos y c) proponer estrategias para aumentar su capacidad de influencia en los procesos de toma de decisiones. Llevamos a cabo una investigación exploratoria y transversal con población desplazada (n=30) y no desplazada (n=32) en dos localidades de bajos ingresos en Barranquilla (Colombia). Existe retroalimentación positiva entre los procesos evaluados, aunque no se observan diferencias significativas entre el grupo de desplazados y el de no desplazados. La dimensión Pertenencia (sentido de comunidad) es la que mejor explica la varianza del empoderamiento y de la participación en ambos grupos. Presentamos iniciativas para reforzar el sentido de comunidad y facilitar el acceso a los recursos socio-comunitarios en población desplazada.The sense of community, participation and empowerment enable us to understand the process of displacement and resettlement in the context of reception, as well as the consequences of both phenomena. Our objectives are a) to assess the three constructs mentioned above, b) to analyze the synergy existing among them and c) to propose strategies for increasing their capacity to influence the decision-making processes. We carried out a cross-sectional exploratory study with displaced (n=30) and non-displaced (n=32) people in two low-income districts of Barranquilla (Colombia). There is positive feedback between the processes evaluated, although no significant differences are observed between the displaced and the non-displaced groups. The dimension of belonging (sense of community) is the one that best explains the variance of empowerment and participation in both groups. Finally, we present a set of initiatives to reinforce the sense of community and to facilitate access to the community’s social resources for the displaced population.O sentido de comunidade, a participação e o empoderamento permitem compreender o processo de deslocamento e reassentamento no contexto de recepção bem como as consequências derivadas de ambos os fenômenos. Os objetivos desta pesquisa são: a) avaliar os três construtos mencionados; b) analisar a sinergia que existe entre estes e c) propor estratégias para aumentar sua capacidade de influência nos processos de tomada de decisões. Realizamos uma pesquisa exploratória e transversal com população deslocada (n=30) e não deslocada (n=32) em duas localidades de baixa renda em Barranquilla (Colômbia). Existe retroalimentação positiva entre os processos avaliados, embora não se observem diferenças significativas entre o grupo de deslocados e o de não deslocados. A dimensão Pertencimento (sentido de comunidade) é a que melhor explica a variância do empoderamento e da participação em ambos os grupos. Apresentamos iniciativas para reforçar o sentido de comunidade e facilitar o acesso aos recursos sociocomunitários em população deslocada

Evolutionary relationships among barley and <i>Arabidopsis</i> core circadian clock and clock-associated genes

The circadian clock regulates a multitude of plant developmental and metabolic processes. In crop species, it contributes significantly to plant performance and productivity and to the adaptation and geographical range over which crops can be grown. To understand the clock in barley and how it relates to the components in the Arabidopsis thaliana clock, we have performed a systematic analysis of core circadian clock and clock-associated genes in barley, Arabidopsis and another eight species including tomato, potato, a range of monocotyledonous species and the moss, Physcomitrella patens. We have identified orthologues and paralogues of Arabidopsis genes which are conserved in all species, monocot/dicot differences, species-specific differences and variation in gene copy number (e.g. gene duplications among the various species). We propose that the common ancestor of barley and Arabidopsis had two-thirds of the key clock components identified in Arabidopsis prior to the separation of the monocot/dicot groups. After this separation, multiple independent gene duplication events took place in both monocot and dicot ancestors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00239-015-9665-0) contains supplementary material, which is available to authorized users

No Evidence for Decay of the Latent Reservoir in HIV‐1–Infected Patients Receiving Intensive Enfuvirtide‐Containing Antiretroviral Therapy

Human immunodeficiency virus type 1 (HIV-1) persists in a latent reservoir of infected resting memory CD4 cells in patients receiving antiretroviral therapy. We assessed whether multitarget therapy with enfuvirtide, 2 reverse-transcriptase inhibitors, and a ritonavir-boosted protease inhibitor leads to decay of this reservoir. Nineteen treatment-naive patients initiated this regimen; 9 experienced virologic suppression and continued enfuvirtide-containing therapy for at least 48 weeks. In enfuvirtide-treated patients with virological suppression, there was no decay of the latent reservoir (95% confidence interval for half-life, 11 months to infinity). The stability of the latent reservoir despite intensive therapy suggests that new strategies are needed to eradicate HIV-1 from this reservoir

Impact of chemotherapy for HIV-1 related lymphoma on residual viremia and cellular HIV-1 DNA in patients on suppressive antiretroviral therapy

The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-Thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs) in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20) pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0) post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median prechemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence. © 2014 Cillo et al

Phase I/II Trial of the Anti-HIV Activity of Mifepristone in HIV-Infected Subjects ACTG 5200

Mifepristone is a glucocorticoid receptor inhibitor shown in vitro to have anti-HIV activity and anti-simian immunodeficiency virus activity in a macaque model. A phase I/II trial was performed to assess the drug’s safety and anti-HIV activity