Tenofovir Disoproxil Fumarate

2003 ◽  
Vol 37 (6) ◽  
pp. 849-859 ◽  
Author(s):  
Shellee A Grim ◽  
Frank Romanelli
Keyword(s):  
Reverse Transcriptase ◽  
Tenofovir Disoproxil Fumarate ◽  
Highly Active Antiretroviral Therapy ◽  
Data Extraction ◽  
Single Agent ◽  
Transcriptase Inhibitor ◽  
Medline Search ◽  
Highly Active ◽  
Cell Counts ◽  
Hiv 1

OBJECTIVE: To review the pharmacology, virology, pharmacokinetics, efficacy, safety, resistance profile, and clinical use of tenofovir disoproxil fumarate. DATA SOURCES: A MEDLINE search was performed (1966–August 2002) using the following terms: tenofovir, tenofovir disoproxil fumarate, PMPA (9-( R)-[2-(phosphonomethoxy)propyl]adenine), and Viread. Abstracts from HIV-related meetings were reviewed. DATA EXTRACTION AND STUDY SELECTION: Publications and meeting abstracts regarding tenofovir were reviewed. The most recent and pertinent items were included. DATA SYNTHESIS: Tenofovir disoproxil fumarate is a nucleotide prodrug that is diphosphorylated to its active moiety, tenofovir diphosphate. In this form, tenofovir acts as a reverse transcriptase inhibitor to inhibit HIV-1 replication. In clinical trials, tenofovir was effective at suppressing HIV-1 RNA and boosting CD4+ cell counts. Tenofovir has a long intracellular half-life, which permits once-daily dosing. Since tenofovir does not interact with the cytochrome P450 pathway, it exhibits minimal drug interactions, with the exception of didanosine. Compared with other reverse transcriptase inhibitors, tenofovir may have advantages in terms of toxicity and medication adherence profiles. Ongoing studies are also analyzing tenofovir's activity against hepatitis B virus. CONCLUSIONS: Tenofovir has been shown to be active against HIV-1 in combination with other antiretrovirals. The drug's benefit as a single-agent intensifier of highly active antiretroviral therapy in treatment-experienced patients has been established, and preliminary data for treatment-naïve patients are encouraging.

scholarly journals The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes

2015 ◽  
Vol 59 (8) ◽  
pp. 4882-4888 ◽  
Author(s):  
Weisi Xu ◽  
Jianxiong Zhao ◽  
Jianping Sun ◽  
Qianqian Yin ◽  
Yan Wang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Therapeutic Index ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Highly Active ◽  
Hiv Drugs ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of the highly active antiretroviral therapy (HAART) used to treat human immunodeficiency type 1 virus (HIV-1). However, because of the emergence of drug resistance and the adverse effects of current anti-HIV drugs, it is essential to develop novel NNRTIs with an excellent safety profile, improved activity against NNRTI-resistant viruses, and enhanced activity against clinical isolates of different subtypes. Here, we have identified 1-[(benzyloxy)methyl]-6-(3,5-dimethylbenzyl)-5-iodopyrimidine-2,4(1H,3H)-dione (WPR-6), a novel NNRTI with a 50% effective concentration (EC50) of 2 to 4 nM against laboratory-adapted HIV-1 strain SF33 and an EC50of 7 to 14 nM against nucleoside reverse transcriptase inhibitor-resistant HIV-1 strain 7391 with a therapeutic index of >1 × 104. A panel of five representative clinical virus isolates of different subtypes circulating predominantly in China was highly sensitive to WPR-6, with EC50s ranging from 1 to 6 nM. In addition, WPR-6 showed excellent antiviral potency against the most prevalent NNRTI-resistant viruses containing the K103N and Y181C mutations. To determine whether WPR-6 selects for novel resistant mutants,in vitroresistance selection was conducted with laboratory-adapted HIV-1 strain SF33 on MT-4 cells. The results demonstrated that V106I and Y188L were the two dominant NNRTI-associated resistance mutations detected in the breakthrough viruses. Taken together, thesein vitrodata indicate that WPR-6 has greater efficacy than the reference HEPT analogue TNK651 and the marketed drug nevirapine against HIV-1. However, to develop it as a new NNRTI, further improvement of its pharmacological properties is warranted.

scholarly journals Lersivirine, a Nonnucleoside Reverse Transcriptase Inhibitor with Activity against Drug-Resistant Human Immunodeficiency Virus Type 1

2010 ◽  
Vol 54 (10) ◽  
pp. 4451-4463 ◽  
Author(s):  
Romuald Corbau ◽  
Julie Mori ◽  
Chris Phillips ◽  
Lesley Fishburn ◽  
Alex Martin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Highly Active Antiretroviral Therapy ◽  
Transcriptase Inhibitor ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The nonnucleoside reverse transcriptase inhibitors (NNRTIs) are key components of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1). A major problem with the first approved NNRTIs was the emergence of mutations in the HIV-1 reverse transcriptase (RT), in particular K103N and Y181C, which led to resistance to the entire class. We adopted an iterative strategy to synthesize and test small molecule inhibitors from a chemical series of pyrazoles against wild-type (wt) RT and the most prevalent NNRTI-resistant mutants. The emerging candidate, lersivirine (UK-453,061), binds the RT enzyme in a novel way (resulting in a unique resistance profile), inhibits over 60% of viruses bearing key RT mutations, with 50% effective concentrations (EC50s) within 10-fold of those for wt viruses, and has excellent selectivity against a range of human targets. Altogether lersivirine is a highly potent and selective NNRTI, with excellent efficacy against NNRTI-resistant viruses.

scholarly journals The Combined Anti-HIV-1 Activities of Emtricitabine and Tenofovir plus the Integrase Inhibitor Elvitegravir or Raltegravir Show High Levels of SynergyIn Vitro

2014 ◽  
Vol 58 (10) ◽  
pp. 6145-6150 ◽  
Author(s):  
Rima Kulkarni ◽  
Rebecca Hluhanich ◽  
Damian M. McColl ◽  
Michael D. Miller ◽  
Kirsten L. White
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Integrase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Strand Transfer ◽  
Antiretroviral Agents ◽  
Highly Active ◽  
Drug Classes ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTHighly active antiretroviral therapy (HAART) involves combination treatment with three or more antiretroviral agents. The antiviral effects of combinations of emtricitabine (FTC) plus tenofovir (TFV) plus antiretroviral agents of all the major drug classes were investigated. Combinations of FTC and TFV with a nonnucleoside reverse transcriptase inhibitor (NNRTI) (efavirenz or rilpivirine) or with a protease inhibitor (PI) (atazanavir, lopinavir, or darunavir) showed additive to synergistic anti-HIV-1 activity. FTC-TFV with an HIV-1 integrase strand transfer inhibitor (INSTI) (elvitegravir or raltegravir) showed the strongest synergy. Anti-HIV-1 synergy suggests enhancement of individual anti-HIV-1 activities within cells that may contribute to potent treatment efficacy and open new areas of research into interactions between reverse transcriptase (RT) and integrase inhibitors.

scholarly journals Combination Therapy with Tenofovir Disoproxil Fumarate/Emtricitabine/Elvitegravir/Cobicistat Plus Darunavir Once Daily in Antiretroviral-Naive and Treatment-Experienced Patients: A Retrospective Review

2018 ◽  
Vol 17 ◽  
pp. 232595741775226 ◽  
Author(s):  
Mark J. Naccarato ◽  
Deborah M. Yoong ◽  
Ignatius W. Fong ◽  
Kevin A. Gough ◽  
Marian A. Ostrowski ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Tenofovir Disoproxil Fumarate ◽  
Retrospective Chart Review ◽  
Transcriptase Inhibitor ◽  
Primary Objective ◽  
Fixed Dose ◽  
Drug Resistant ◽  
Once Daily ◽  
Dose Combination ◽  
Hiv 1

Background: Patients with drug-resistant HIV often require complex antiretroviral regimens. However, combining fixed-dose combination tablets such as tenofovir–disoproxil–fumarate, emtricitabine, and cobicistat-boosted elvitegravir (TDF/FTC/EVG/cobi) with darunavir (DRV) can provide a simple, once-daily (QD), 2-tablet regimen for patients with drug-resistant HIV. Primary objective was to determine the percentage of patients with HIV-1 RNA <40 copies/mL at 48 weeks. Methods: We performed a retrospective chart review of patients initiated on TDF/FTC/EVG/cobi plus DRV. Results: Among the 21 included patients, prior resistance showed a median of 2 nucleoside reverse transcriptase inhibitor mutations, 1 nonnucleoside reverse transcriptase mutation, and 1 protease inhibitor mutation. At week 48, 14 (67%) patients achieved HIV-1 RNA <40 copies/mL, 1 patient experienced viral rebound, and 6 (29%) had missing data or discontinued therapy. No patient discontinued for adverse events. Conclusion: According to this observational study, QD TDF/FTC/EVG/cobi plus DRV is considered safe, well tolerated, and generally effective in suppressing HIV drug-resistant virus.

scholarly journals Antiviral Drug Resistance and the Need for Development of New HIV-1 Reverse Transcriptase Inhibitors

2012 ◽  
Vol 56 (10) ◽  
pp. 5000-5008 ◽  
Author(s):  
Eugene L. Asahchop ◽  
Mark A. Wainberg ◽  
Richard D. Sloan ◽  
Cécile L. Tremblay
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Antiviral Drug ◽  
Transcriptase Inhibitor ◽  
Antiviral Resistance ◽  
Hiv Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Genetic Barrier ◽  
Highly Active ◽  
Underlying Mechanisms

ABSTRACTHighly active antiretroviral therapy (HAART) consists of a combination of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. Despite being the first antivirals described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of HAART. There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first such compounds were developed, viral resistance to them has inevitably been described; this necessitates the continuous development of novel compounds within each class. In this review, we consider the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second-line therapy and describe the patterns of resistance associated with their use as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with a low genetic barrier are more commonly used in resource-limited settings. Their use results in the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings.

Sign in / Sign up

Export Citation Format

Share Document