Metabolic and cardiac adaptation to chronic pharmacologic blockade of facilitative glucose transport in murine dilated cardiomyopathy and myocardial ischemia

Abstract GLUT transgenic and knockout mice have provided valuable insight into the role of facilitative glucose transporters (GLUTs) in cardiovascular and metabolic disease, but compensatory physiological changes can hinder interpretation of these models. To determine whether adaptations occur in response to GLUT inhibition in the failing adult heart, we chronically treated TG9 mice, a transgenic model of dilated cardiomyopathy and heart failure, with the GLUT inhibitor ritonavir. Glucose tolerance was significantly improved with chronic treatment and correlated with decreased adipose tissue retinol binding protein 4 (RBP4) and resistin. A modest improvement in lifespan was associated with decreased cardiomyocyte brain natriuretic peptide (BNP) expression, a marker of heart failure severity. GLUT1 and −12 protein expression was significantly increased in left ventricular (LV) myocardium in ritonavir-treated animals. Supporting a switch from fatty acid to glucose utilization in these tissues, fatty acid transporter CD36 and fatty acid transcriptional regulator peroxisome proliferator-activated receptor α (PPARα) mRNA were also decreased in LV and soleus muscle. Chronic ritonavir also increased cardiac output and dV/dt-d in C57Bl/6 mice following ischemia-reperfusion injury. Taken together, these data demonstrate compensatory metabolic adaptation in response to chronic GLUT blockade as a means to evade deleterious changes in the failing heart

A solid dispersion based on milk-micelle as a drug-carrier for the enhancement of the aqueous solubility of ritonavir

The goal of present investigation was to evaluate the feasibility of formulating a solid-dispersion using milk-micelles as drug-carriers, to enhance the aqueous solubility of ritonavir

Drug-Drug Interactions Among Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) Medications

One-fourth of individuals diagnosed with the human immunodeficiency virus concomitantly have the hepatitis C virus infection. Since the discovery of highly active antiretroviral therapy, liver complications have become the leading cause of morbidity and mortality in HIV-HCV coinfected individuals. Optimal treatment in this patient population is critical, as coinfection has been linked to deterioration of both disease states. The objective of this review article is to highlight the current literature on drug-drug interactions between HIV and HCV treatments. The management of the treatment of coinfection patients has been covered extensively in numerous other publications

The enhancement of the aqueous solubility of ritonavir via formulation of a drug-phospholipid complex

Objective: To evaluate the enhancement of aqueous solubility of a poorly water soluble drug ritonavir by forming its complex with a phospholipid (Phospholipon®90H)

Personalizing HIV therapy, mission impossible?

Sustained HIV suppression depends on a number of factors including therapy adherence, management of side effects, viral resistance and individual characteristics of patients and therapeutic settings. Treatment response rates range up to 90% in therapy naïve patients but decline to approximately 50% in patients who received several antiretrovirals during treatment history. Furthermore, HIV protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) plasma concentrations display high inter- and intra individual variability and the therapeutic window is comparably narrow. In this therapeutic setting the personalization of dosing regimens has been suggested in many cases to tailor the ARV plasma concentrations with the intention to maximize therapy success and minimize side effects in the individual. However, personalizing therapy by modifying the dosing regimen bears the danger of losing therapeutic efficacy, increasing side effects or causing viral resistance. This topical review identifies pharmacokinetic and pharmacodynamic models of antiretroviral therapy appraising the potential application to HIV therapy and discusses its future in the light of new drug classes and fix-dose combinations

Clinical impact of double protease inhibitor boosting with Lopinavir/Ritonavir and Amprenavir as part of salvage antiretroviral therapy

Purpose: Double protease inhibitor (PI) boosting is being explored as a new strategy in salvage antiretroviral (ARV) therapy. However, if a negative drug interaction leads to decreased drug levels of either or both PIs, double PI boosting could lead to decreased virologic response. A negative drug interaction has been described between amprenavir (APV) and lopinavir/ritonavir (LPV/r). This observational cohort study assessed the virologic impact of the addition of APV to a salvage ARV regimen, which also contains LPV/r, compared to a regimen containing LPV/r alone. Method: Patients initiated on a salvage ARV regimen that included LPV/r obtained from the expanded access program in Toronto, Canada, were evaluated. APV (600-1,200 mg bid) was added at the discretion of the treating physician. Results: Using multivariate Cox proportional hazards models, we found that the addition of APV to a LPV/r-containing salvage regimen was not significantly associated with time to virologic suppression (< 50 copies/mL; adjusted hazard ratio [HR] = 0.75, p = .12) or with time to virologic rebound (adjusted HR = 1.46, p = .34). Those patients who received higher doses of APV had an increased chance of virologic suppression (p = .03). In a subset of 27 patients, the median LPV Ctrough was significantly lower in patients receiving APV (p = .04), and the median APV Ctrough was reduced compared to reported controls. Conclusion: Our data do not support an additional benefit in virologic reduction of double boosting with APV and LPV/r relative to LPV/r alone in salvage ARV therapy. Our study's limitations include its retrospective nature and the imbalance between the two groups potentially confounding the results. Although these factors were adjusted for in the multivariate analysis, a prospective randomized controlled trial is warranted to confirm our findings

Era of direct acting anti-viral agents for the treatment of hepatitis C.

Hepatitis C infection is universal and the most common indication of liver transplantation in the United States. The period of less effective interferon therapy with intolerable side effects has gone. Now we have stepped into the era of direct acting anti-viral agents (DAAs) against hepatitis C virus. Treatment of hepatitis C is now extremely effective, tolerable and requires a short duration of intake of oral agents. Less monitoring is required with the current therapy and drug-drug interactions are less than the previous regimen. The current treatment options of chronic hepatitis C with various DAAs are discussed in this article

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-Week results of a randomized trial

Objectives Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. Methods Patients on 3-drug ART with stable HIV-1 RNA &lt;50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm).Results In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. Conclusion Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therap

Monotherapy with boosted protease inhibitors as antiretroviral treatment simplification strategy in the clinical setting

Antiretroviral treatment simplification with darunavir/ritonavir or lopinavir/ritonavir monotherapy maintains sustained HIV viremia suppression in clinical trials. However, data about the efficacy of this strategy in routine clinical practice is still limited, and no direct comparison between darunavir/ritonavir and lopinavir/ritonavir has been performed to date. We retrospectively studied all HIV-1-infected subjects who initiated monotherapy with darunavir/ritonavir or lopinavir/ritonavir while having plasma VL&#60;50 c/mL, and had at least 1 subsequent follow-up visit in our clinic. When two consecutive PI-monotherapy regimens were used, each regimen was considered separately. The primary endpoint was the percentage of patients who maintained virological suppression (HIV-1 VL &#60;50 c/mL) through follow-up. Virological failure was defined as at least two consecutive HIV-1 VL &#x003E;50 c/mL. We also evaluated other reasons for treatment discontinuation. Analyses were performed considering all regimens (full dataset analysis) either as &#x201C;on treatment&#x201D; or as &#x201C;treatment switch equals failure&#x201D;. Five hundred and seventy-three PI-monotherapy regimens corresponding to 520 subjects were included, 262 with darunavir/ritonavir and 311 with lopinavir/ritonavir. Medians (IQR) follow-up were 50 (26.3&#x2013;107.6) and 85.6 (36.9&#x2013;179.1) weeks for subjects on darunavir/ritonavir and lopinavir/ritonavir, respectively (p&#60;0.001). Overall, 67 (11.7%) subjects experienced virological failure, 23 (8.7%) were on darunavir/ritonavir and 42 (13.5%) were on lopinavir/ritonavir (p=0.796). Two hundred and three (77.5%) patients on darunavir/ritonavir and 154 (49.5%) on lopinavir/ritonavir maintained virological suppression in the &#x201C;treatment switch equals failure&#x201D; (p=0.002). Other reasons for treatment discontinuation were gastrointestinal toxicity and dyslipidemia in 7.2% and 5.9% of cases, respectively. Gastrointestinal toxicities and dyslipidemia leading to treatment discontinuation were more frequent in patients on lopinavir/ritonavir (10.6% and 10.3%, respectively) than in patients on darunavir/ritonavir (3.1% and 0.8%, respectively). Monotherapy with darunavir/ritonavir or lopinavir/ritonavir as simplification strategy appears to be effective and safe in subjects with virological suppression in clinical practice. Virological efficacy seems to be similar between regimens. However, rates of discontinuation due to toxicities were higher in subjects on lopinavir/ritonavir than darunavir/ritonavir

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Although the pathogenesis of human immunodeficiency virus (HIV) infection and the general virologic and immunologic principles underlying the use of antiretroviral therapy are similar for all HIV-infected persons, there are unique considerations needed for HIV-infected infants, children, and adolescents, including; A acquisition of infection through perinatal exposure for many infected children, In utero, intrapartum, and/or postpartum neonatal exposure to zidovudine (ZDV) and other antiretroviral medications in most perinatally infected children, Requirement for use of HIV virologic tests to diagnose perinatal HIV infection in infants under age 15 to 18 months old, Age-specific differences in immunologic markers (i.e., CD4+ T cell count), Changes in pharmacokinetic parameters with age caused by the continuing development and maturation of organ systems involved in drug metabolism and clearance, Differences in the clinical and virologic manifestations of perinatal HIV infection secondary to the occurrence of primary infection in growing, immunologically immature persons, and Special considerations associated with adherence to antiretroviral treatment for infants, children and adolescents. This report addresses the pediatric-specific issues associated with antiretroviral treatment and provides guidelines to health care providers caring for infected infants, children, and adolescents. It is recognized that guidelines for antiretroviral use in pediatric patients are rapidly evolving. The Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children will review new data on an ongoing basis and provide regular updates to the guidelines