Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
Add more filters










Database
Language
Publication year range
1.
AIDS ; 33(6): 1089-1093, 2019 05 01.
Article in English | MEDLINE | ID: mdl-30946163

ABSTRACT

: Product labels for cobicistat with atazanavir or darunavir, and for elvitegravir/cobicistat/emtricitabine/tenofovir (alafenamide or disoproxil fumarate) were recently updated to state that these products are not recommended for initiation during pregnancy, and an alternative regimen is recommended for those who become pregnant during therapy with these products. Herein, we present the rationale for these recommendations, which are based on studies in pregnant women evaluating the pharmacokinetics and antiviral activity of darunavir/cobicistat or elvitegravir/cobicistat-containing antiretroviral regimens. In these studies, mean steady-state minimum concentrations in the second and third trimester versus postpartum of cobicistat, darunavir, and elvitegravir were reduced by 61-83%, 89-92%, and 82-86%, respectively. In the absence of data with atazanavir/cobicistat, we leveraged the available data with darunavir/cobicistat and elvitegravir/cobicistat to make recommendations for atazanavir/cobicistat. Darunavir/ritonavir and atazanavir/ritonavir remain viable treatment options for pregnant women.


Subject(s)
Anti-HIV Agents/administration & dosage , Anti-HIV Agents/pharmacokinetics , Antiretroviral Therapy, Highly Active/methods , Cobicistat/administration & dosage , Cobicistat/pharmacokinetics , HIV Infections/drug therapy , Pregnancy Complications, Infectious/drug therapy , Female , Humans , Pregnancy , Treatment Outcome
2.
Clin Drug Investig ; 37(4): 317-326, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28102520

ABSTRACT

Elbasvir/grazoprevir demonstrated high sustained virologic response rates 12 weeks after the end of treatment (SVR12) across five clinical trials in subjects infected with chronic hepatitis C virus (HCV) genotype 1, including those with advanced chronic kidney disease (CKD), and GT4. Despite favorable results overall, the US Food and Drug Administration (FDA) encountered challenging regulatory issues due to the limitations of clinical trial data in certain subpopulations. In GT1a-infected subjects, baseline NS5A resistance-associated polymorphisms emerged as the strongest baseline characteristic associated with diminished SVR12 rates following 12 weeks of elbasvir/grazoprevir treatment. The decision for recommending 16 weeks of elbasvir/grazoprevir + ribavirin in this population and for extrapolating these recommendations to patients with advanced CKD was based on benefit-versus-risk analyses using the available data. Conversely, FDA had insufficient data to define a specific elbasvir/grazoprevir treatment regimen for GT1a-infected subjects with baseline NS5A resistance-associated polymorphisms who failed prior treatment with pegylated interferon + ribavirin (PR) and either boceprevir, simeprevir, or telaprevir. For GT4 PR-experienced patients, leveraging of data in related populations and additional pooled analyses were employed to support labeling for elbasvir/grazoprevir. This article describes FDA's rationale for labeling determinations in situations where limited data made these decisions challenging.


Subject(s)
Antiviral Agents/administration & dosage , Benzofurans/administration & dosage , Hepatitis C, Chronic/drug therapy , Imidazoles/administration & dosage , Quinoxalines/administration & dosage , Antiviral Agents/therapeutic use , Drug Combinations , Genotype , Hepacivirus/genetics , Humans , Renal Insufficiency, Chronic/drug therapy , Ribavirin/administration & dosage , Ribavirin/therapeutic use , Treatment Outcome
3.
Gastroenterology ; 152(3): 586-597, 2017 02.
Article in English | MEDLINE | ID: mdl-27773808

ABSTRACT

BACKGROUND & AIMS: Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) are direct-acting antiviral agents recently approved in the United States for treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infections, as a fixed-dose combination. Trials of elbasvir and grazoprevir, with or without ribavirin, demonstrated high rates of sustained virologic response 12 weeks after treatment ended (SVR12). However, 12 weeks of treatment with elbasvir and grazoprevir failed in a small proportion of patients with HCV genotype 1 infection. We summarize findings from independent US Food and Drug Administration analyses of drug resistance data from trials of elbasvir and grazoprevir, with and without ribavirin. METHODS: We independently analyzed HCV drug resistance and HCV RNA measurement results that were submitted to the US Food and Drug Administration to support the regulatory approval of elbasvir and grazoprevir. These data were reported from selected phase 2 and 3 clinical trials of elbasvir and grazoprevir, with and without ribavirin. Genotypic resistance analyses were conducted using Sanger population nucleotide sequencing data derived from blood samples from study patients. RESULTS: In 56 of 506 (11%) patients with HCV genotype 1a infection who received elbasvir and grazoprevir for 12 weeks, baseline HCV genetic variants encoding amino acid polymorphisms in NS5A (M28, Q30, L31, or Y93) reduced treatment efficacy; rates of SVR12 were 70% and 98% for patients with or without NS5A polymorphisms, respectively (P < .0001). Most patients with treatment failure acquired resistance-associated substitutions in NS3 and/or NS5A. Based on data from a small number of patients (n = 6), an intensified 16-week regimen of elbasvir and grazoprevir plus ribavirin could increase efficacy in patients with HCV genotype 1a infection with NS5A polymorphisms. Among patients with HCV genotype 4a or 4d infections with NS5A polymorphisms, all 26 who received the elbasvir and grazoprevir regimens recommended in prescribing information achieved an SVR12. CONCLUSIONS: The combination of elbasvir and grazoprevir, with or without ribavirin is safe and effective for patients with HCV genotype 1 or 4 infections. In patients with HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the efficacy of this direct-acting antiviral regimen, and pretreatment resistance analyses can optimize treatment selection.


Subject(s)
Benzofurans/therapeutic use , Drug Resistance, Viral/genetics , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Imidazoles/therapeutic use , Quinoxalines/therapeutic use , RNA, Viral/genetics , Viral Nonstructural Proteins/genetics , Antiviral Agents/therapeutic use , Clinical Trials as Topic , Drug Combinations , Drug Therapy, Combination , Genotype , Hepatitis C, Chronic/virology , Humans , Polymorphism, Genetic , Ribavirin/therapeutic use , Treatment Failure , Treatment Outcome
4.
J Acquir Immune Defic Syndr ; 63(3): 355-61, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23535292

ABSTRACT

OBJECTIVE: To identify an alternative inhaled corticosteroid to fluticasone propionate that can be safely coadministered with HIV protease inhibitors, the safety and pharmacokinetics of beclomethasone dipropionate (BDP) and its active metabolite, beclomethasone 17-monopropionate (17-BMP), in combination with ritonavir (RTV) and darunavir/ritonavir (DRV/r) were assessed. DESIGN: Open-label, prospective, randomized pharmacokinetic and pharmacodynamic study in healthy volunteers. METHODS: Thirty healthy volunteers received inhaled 160 µg bid BDP for 14 days and were then randomized (1:1:1) into 3 groups: group 1 (control) remained on BDP alone for 28 days, group 2 received 100 mg bid BDP + RTV for 28 days, and group 3 received 600/100 mg bid BDP + DRV/r for 28 days. Pharmacokinetic sampling for 17-BMP was performed on days 14 and 28, and pharmacokinetic parameter values were compared within patients and between groups. Cortisol stimulation testing was also performed on days 1, 14, 28, and 42 and compared within and between groups. RESULTS: Geometric mean ratios (day 28:day 14) (90% confidence interval) for 17-BMP area under the concentration-time curve in groups 1, 2, and 3, respectively, were 0.93 (0.81 to 1.06, P = 0.27), 2.08 (1.52 to 2.65, P = 0.006), and 0.89 (0.68 to 1.09, P = 0.61). There were no significant reductions in serum cortisol levels within or between groups (P > 0.05). CONCLUSIONS: DRV/r did not increase 17-BMP exposure, whereas RTV alone produced a statistically significant but clinically inconsequential 2-fold increase in 17-BMP exposure. Adrenal suppression was not observed in any of the study groups. These data suggest that BDP can be safely coadministered with DRV/r and likely other RTV-boosted protease inhibitors.


Subject(s)
Anti-Inflammatory Agents/pharmacokinetics , Beclomethasone/pharmacokinetics , Ritonavir/administration & dosage , Sulfonamides/administration & dosage , Adolescent , Adult , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Beclomethasone/administration & dosage , Beclomethasone/analogs & derivatives , Beclomethasone/blood , Beclomethasone/therapeutic use , Darunavir , Drug Interactions , Female , HIV Infections/drug therapy , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/therapeutic use , Humans , Male , Middle Aged , Ritonavir/adverse effects , Ritonavir/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Young Adult
5.
Pharmacotherapy ; 32(1): e1-6, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22392831

ABSTRACT

Current product labels for maraviroc and raltegravir provide no dosing guidance for patients with end-stage liver disease and worsening renal function. We describe a 41-year-old man with human immunodeficiency virus (HIV) infection and rapidly progressive liver failure and vanishing bile duct syndrome at presentation. Despite discontinuation of all potential offending drugs, the patient's liver function continued to deteriorate. To achieve and maintain HIV suppression while awaiting liver transplantation, a regimen consisting of maraviroc, raltegravir, and enfuvirtide was started. These agents were chosen because the patient was not exposed to them before the onset of liver failure. While receiving product label-recommended twice-daily dosing of these drugs, he achieved and maintained HIV suppression. During a complicated and prolonged hospitalization, the patient also developed renal dysfunction. As hepatic metabolism is the primary route of clearance of maraviroc and raltegravir, we predicted that using approved doses of these drugs could result in significant drug accumulation. Since the safety profiles of supratherapeutic concentrations of these agents are not well defined, we chose to use therapeutic drug monitoring to guide further dosing. The reported concentrations showed severely impaired metabolic clearance of both drugs, with markedly prolonged elimination half-lives of 189 hours for maraviroc and 61 hours for raltegravir. Previously reported half-lives for maraviroc and raltegravir in HIV-infected patients with normal hepatic and renal function are 14-18 hours and 9-12 hours, respectively. Based on these results, the dosing intervals were extended from twice/day to twice/week for maraviroc and every 48 hours for raltegravir. Unfortunately, the patient's clinical condition continued to deteriorate, and he eventually died of complications related to end-stage liver disease. This case illustrates the difficulties in managing antiretroviral therapy in an HIV-infected patient with combined severe liver and renal failure. Prolonged excessively high exposure to maraviroc and raltegravir is likely to result in some level of concentration-dependent toxicity. Until more data are available, therapeutic drug monitoring remains the only evidence-based approach to optimize dosage selection of these drugs in this patient population.


Subject(s)
Cyclohexanes/pharmacokinetics , End Stage Liver Disease/complications , HIV Infections/complications , Pyrrolidinones/pharmacokinetics , Renal Insufficiency/complications , Triazoles/pharmacokinetics , Adult , Cyclohexanes/therapeutic use , Disease Management , End Stage Liver Disease/drug therapy , Fatal Outcome , HIV Infections/drug therapy , Humans , Male , Maraviroc , Metabolic Clearance Rate , Pyrrolidinones/therapeutic use , Raltegravir Potassium , Renal Insufficiency/drug therapy , Triazoles/therapeutic use
6.
Am J Health Syst Pharm ; 68(11): 991-1001, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21593227

ABSTRACT

PURPOSE: The most current guidelines issued by the Department of Health and Human Services (DHHS) on the management of human immunodeficiency virus (HIV) infection in treatment-naive patients are reviewed. SUMMARY: Treatment guidelines are updated frequently because of the emergence of data demonstrating the risks and benefits of antiretroviral therapy. The DHHS guidelines strongly recommend initiating therapy in patients with certain conditions regardless of CD4 cell count and in patients with CD4 cell counts of <350 cells/mm(3). Although supporting data are less definitive, treatment is also recommended for patients with CD4 cell counts of 350-500 cells/mm(3). Treatment for patients with CD4 cell counts of >500 cells/mm(3) is controversial. Although cumulative observational data and biological evidence support treatment at higher CD4 cell counts, randomized controlled trial data to support this are not available, and the risk of antiretroviral toxicities, resistance, non-adherence, and cost should be considered in individual patients. The preferred regimens have been consolidated to four options, including a dual-nucleoside reverse transcriptase inhibitor backbone (tenofovir plus emtricitabine) with a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir plus ritonavir or darunavir plus ritonavir), or an integrase strand-transfer inhibitor (raltegravir). Regimens are classified as alternative or acceptable when they have potential safety or efficacy concerns, have higher pill burdens, or require more-frequent administration compared with preferred regimens. CONCLUSION: The DHHS 2011 guidelines advocate earlier antiretroviral therapy initiation than recommended in recent years, and preferred regimens have been refined to maximize efficacy, safety, and quality of life for treatment-naive HIV-infected patients.


Subject(s)
Anti-HIV Agents/therapeutic use , Practice Guidelines as Topic , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , CD4 Lymphocyte Count , Drug Therapy, Combination , HIV Infections/drug therapy , HIV Infections/immunology , Humans , Quality of Life , Time Factors , United States , United States Dept. of Health and Human Services
7.
Antivir Ther ; 16(2): 257-61, 2011.
Article in English | MEDLINE | ID: mdl-21447876

ABSTRACT

Here, we describe an HIV-infected patient with pretreatment resistance to raltegravir, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors, and the ultimate ability to achieve viral suppression. Pretreatment integrase resistance testing is not routinely performed because transmitted integrase mutations conferring resistance to raltegravir are currently thought to be negligible. We suggest obtaining a pretreatment integrase genotype in patients with transmitted multiclass drug resistance in order to create an optimal first regimen and increase the chance for virological suppression.


Subject(s)
Drug Resistance, Viral , HIV Infections/transmission , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Pyrrolidinones/pharmacology , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Drug Resistance, Viral/genetics , Female , Genotype , HIV Infections/drug therapy , HIV Infections/virology , HIV Integrase Inhibitors/therapeutic use , HIV-1/enzymology , HIV-1/genetics , Humans , Middle Aged , Mutation , Pyrrolidinones/therapeutic use , Raltegravir Potassium , Viral Load
SELECTION OF CITATIONS
SEARCH DETAIL
...