Putative HIV-1 Reverse Transcriptase Inhibitors: Design, Synthesis, in Vitro Evaluation and in Silico Analysis
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Failure of Initial Antiretroviral Treatment Regimens
An update of Current Research January, 1999 The Forum for Collaborative HIV Research, (FCHR) situated within the Center for Health Policy Research (CHPR) at The George Washington University School of Public Health & Health Services, is an independent public-private partnership composed of representatives from multiple interests in the HIV clinical research arena. The FCHR primarily facilitates ongoing discussion and collaboration between appropriate stakeholders on the development and implementation of new clinical studies in HIV and on the transfer of the results of research into clinical practice. The main purpose of the FCHR is to enhance collaboration between interested groups in order to address the critical unanswered questions regarding the optimal medical management of HIV disease. By encouraging coordination among public and private HIV/AIDS clinical research efforts, the FCHR hopes to integrate these efforts into HIV/AIDS medical care settings. Therefore, studies performed by these various research entities, separately or in cooperation, can begin faster; duplication of efforts can be reduced; patient enrollment and retention can be further facilitated; and costs of getting answers to the critical questions can be shared. At present,the FCHR is staffed by three persons and consists of over one hundred members, representing all facets of the field. These include pharmaceutical companies; public and private third-party payors; health care delivery system groups; government agencies; clinical research centers; and patient advocacy groups. The Director of the FCHR is David Barr. For further information about the Forum for Collaborative HIV Research and its projects, please call William Gist at 202-530-2334 or visit our website at: www.gwumc.edu/chpr and click on HIV Research. -
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New Antiretrovirals in Development: Reprinted from The PRN Notebook,™ june 2002. Dr. James F. Braun, Editor-in-Chief. Tim Horn, Executive Editor. Published in New York City by the Physicians’ Research Network, Inc.,® John Graham Brown, Executive Director. For further information and other articles The View in 2002 available online, visit http://www.PRN.org All rights reserved. © june 2002. Roy “Trip” Gulick, md, mph Associate Professor of Medicine, Weill Medical College of Cornell University Director, Cornell Clinical Trials Unit, New York, New York Summary by Tim Horn Edited by Scott Hammer, md espite the fact that 16 antiretro- tiviral activity of emtricitabine was estab- Preliminary results from two random- virals are approved for use in the lished, with total daily doses of 200 mg or ized studies—FTC-302 and FTC-303—were United States, there is an indis- more producing the greatest median viral reported by Dr. Charles van der Horst and putable need for new anti-hiv com- load suppression: 1.72-1.92 log. Based on his colleagues at the 8th croi, held in Feb- pounds that have potent and these data, a once-daily dose of 200 mg ruary 2001 in Chicago (van der Horst, durable efficacy profiles, unique re- was selected for further long-term clinical 2001). FTC-302 was a blinded comparison sistance patterns, patient-friendly dosing study. “This is what we’re looking forward of emtricitabine and lamivudine, both in schedules, and minimal toxicities. To pro- to with emtricitabine,” commented Dr. combination with stavudine (Zerit) and vide prn with a glimpse of drugs current- Gulick. -
TRIZIVIR® (Abacavir Sulfate, Lamivudine, and Zidovudine) Tablets
NDA 21-205/S-011 Page 4 PRESCRIBING INFORMATION TRIZIVIR® (abacavir sulfate, lamivudine, and zidovudine) Tablets WARNINGS TRIZIVIR contains 3 nucleoside analogues (abacavir sulfate, lamivudine, and zidovudine) and is intended only for patients whose regimen would otherwise include these 3 components. Hypersensitivity Reactions: Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir sulfate, a component of TRIZIVIR. Hypersensitivity to abacavir is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups: (1) fever, (2) rash, (3) gastrointestinal (including nausea, vomiting, diarrhea, or abdominal pain), (4) constitutional (including generalized malaise, fatigue, or achiness), and (5) respiratory (including dyspnea, cough, or pharyngitis). Discontinue TRIZIVIR as soon as a hypersensitivity reaction is suspected. Permanently discontinue TRIZIVIR if hypersensitivity cannot be ruled out, even when other diagnoses are possible. Following a hypersensitivity reaction to abacavir, NEVER restart TRIZIVIR or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death. Reintroduction of TRIZIVIR or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions. Such reactions can occur within hours (see WARNINGS and PRECAUTIONS: Information -
Ep 2531027 B1
(19) TZZ ¥_Z _T (11) EP 2 531 027 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4985 (2006.01) A61K 31/52 (2006.01) 06.05.2015 Bulletin 2015/19 A61K 31/536 (2006.01) A61K 31/513 (2006.01) A61K 38/55 (2006.01) A61P 31/18 (2006.01) (21) Application number: 11737484.3 (86) International application number: (22) Date of filing: 24.01.2011 PCT/US2011/022219 (87) International publication number: WO 2011/094150 (04.08.2011 Gazette 2011/31) (54) Therapeutic combination comprising dolutegravir, abacavir and lamivudine Therapeutische Zusammensetzung enthaltend Dolutegravir, Abacavir und Lamivudine Combinaison thérapeutique comprenant du dolutégravir, de l’abacavir et de la lamivudine (84) Designated Contracting States: (74) Representative: Gladwin, Amanda Rachel AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GlaxoSmithKline GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Global Patents (CN925.1) PL PT RO RS SE SI SK SM TR 980 Great West Road Designated Extension States: Brentford, Middlesex TW8 9GS (GB) BA ME (56) References cited: (30) Priority: 27.01.2010 US 298589 P WO-A1-2010/011812 WO-A2-2009/148600 US-A1- 2006 084 627 US-A1- 2006 084 627 (43) Date of publication of application: US-A1- 2008 076 738 US-A1- 2009 318 421 12.12.2012 Bulletin 2012/50 US-A1- 2009 318 421 US-B1- 6 544 961 (73) Proprietor: VIIV Healthcare Company • SONG1 et al: "The Effect of Ritonavir-Boosted Research Triangle Park, NC 27709 (US) ProteaseInhibitors on the HIV Integrase Inhibitor, S/GSK1349572,in Healthy Subjects", INTERNET , (72) Inventor: UNDERWOOD, Mark, Richard 15 September 2009 (2009-09-15), XP002697436, Research Triangle Park Retrieved from the Internet: URL:http: North Carolina 27709 (US) //www.natap.org/2009/ICCAC/ICCAC_ 52.htm [retrieved on 2013-05-21] Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. -
ZIAGEN Safely and Effectively
HIGHLIGHTS OF PRESCRIBING INFORMATION • Patients With Hepatic Impairment: Mild hepatic impairment – 200 mg These highlights do not include all the information needed to use twice daily; moderate/severe hepatic impairment – contraindicated. (2.3) ZIAGEN safely and effectively. See full prescribing information for --------------------- DOSAGE FORMS AND STRENGTHS -------------- ZIAGEN. Tablets: 300 mg; Oral Solution: 20 mg/mL (3) ZIAGEN® (abacavir sulfate) Tablets and Oral Solution -------------------------------CONTRAINDICATIONS------------------------ Initial U.S. Approval: 1998 • Previously demonstrated hypersensitivity to abacavir. (4, 5.1) • Moderate or severe hepatic impairment. (4) WARNING: HYPERSENSITIVITY REACTIONS/LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY ----------------------- WARNINGS AND PRECAUTIONS ---------------- • Hypersensitivity: Serious and sometime fatal hypersensitivity reactions See full prescribing information for complete boxed warning. have been associated with ZIAGEN and other abacavir-containing • Serious and sometimes fatal hypersensitivity reactions have been products. Read full prescribing information section 5.1 before associated with ZIAGEN (abacavir sulfate). (5.1) prescribing ZIAGEN. (5.1) • Hypersensitivity to abacavir is a multi-organ clinical syndrome. • Lactic acidosis and severe hepatomegaly with steatosis have been (5.1) reported with the use of nucleoside analogues. (5.2) • Patients who carry the HLA-B*5701 allele are at high risk for • Immune reconstitution syndrome (5.3) and redistribution/accumulation -
( 12 ) United States Patent
US010426780B2 (12 ) United States Patent (10 ) Patent No. : US 10 ,426 , 780 B2 Underwood (45 ) Date of Patent : Oct . 1 , 2019 ( 54 ) ANTIVIRAL THERAPY 5 ,089 , 500 A 2 / 1992 Daluge 5 ,519 ,021 A 5 / 1996 Young et al. 5 ,641 , 889 A 6 / 1997 Daluge et al . (71 ) Applicant : VIIV HEALTHCARE COMPANY , 5 ,663 , 169 A 9 /1997 Young et al. Wilmington , DE (US ) 5 ,663 , 320 A 9 / 1997 Mansour et al. 5 ,693 ,787 A 12 / 1997 Mansour et al. (72 ) Inventor : Mark Richard Underwood , Research 5 ,696 ,254 A 12 / 1997 Mansour et al. Triangle Park , NC (US ) 5 , 808 , 147 A 9 / 1998 Daluge et al. 5 ,811 , 423 A 9 / 1998 Young et al . 5 , 840 , 990 A 11/ 1998 Daluge et al . ( 73 ) Assignee : ViiV Healthcare Company , 5 , 849 , 911 A 12 / 1998 Fassler et al. Wilmington , DE (US ) 5 , 905 , 082 A 5 / 1999 Roberts et al. 5 , 914 , 332 A 6 / 1999 Sham et al . ( * ) Notice : Subject to any disclaimer , the term of this 5 ,917 ,041 A 6 / 1999 Daluge et al. patent is extended or adjusted under 35 5 ,917 , 042 A 6 / 1999 Daluge et al . 5 ,919 ,941 A 7 / 1999 Daluge et al. U . S . C . 154 (b ) by 0 days. 5 , 922 ,695 A 7 / 1999 Arimilli et al. 5 , 935 , 94 A 8 / 1999 Munger et al . (21 ) Appl. No. : 15 / 366 , 442 5 ,977 ,089 A 11/ 1999 Arimilli et al . 6 ,043 ,230 A 3 / 2000 Arimilli et al . ( 22 ) Filed : Dec . -
Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis
Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis Centers for Disease Control and Prevention Office of Infectious Diseases National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination June 2013 This document is accessible online at http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm Suggested citation: CDC. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis [online]. 2013. Available from URL: http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm Table of Contents Introduction 1 Methodology for Preparation of these Guidelines 2 The Role of Rifamycins in Tuberculosis Treatment 4 Managing Drug Interactions with Antivirals and Rifampin 5 Managing Drug Interactions with Antivirals and Rifabutin 9 Treatment of Latent TB Infection with Rifampin or Rifapentine 10 Treating Pregnant Women with Tuberculosis and HIV Co-infection 10 Treating Children with HIV-associated Tuberculosis 12 Co-treatment of Multidrug-resistant Tuberculosis and HIV 14 Limitations of these Guidelines 14 HIV-TB Drug Interaction Guideline Development Group 15 References 17 Table 1a. Recommendations for regimens for the concomitant treatment of tuberculosis and HIV infection in adults 21 Table 1b. Recommendations for regimens for the concomitant treatment of tuberculosis and HIV infection in children 22 Table 2a. Recommendations for co-administering antiretroviral drugs with RIFAMPIN in adults 23 Table 2b. Recommendations for co-administering antiretroviral drugs with RIFAMPIN in children 25 Table 3. Recommendations for co-administering antiretroviral drugs with RIFABUTIN in adults 26 ii Introduction Worldwide, tuberculosis is the most common serious opportunistic infection among people with HIV infection. -
Lamivudine in Combination with Zidovudine, Stavudine, Or Didanosine in Patients with HIV-1 Infection
Lamivudine in combination with zidovudine, stavudine, or didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial Daniel R. Kuritzkes*, Ian Marschner†, Victoria A. Johnson‡, Roland Bassett†, Joseph J. Eron§, Margaret A. FischlII, Robert L. Murphy¶, Kenneth Fife**, Janine Maenza††, Mary E. Rosandich*, Dawn Bell‡‡, Ken Wood§§, Jean-Pierre Sommadossi‡, Carla PettinelliII II and the National Institute of Allergy and Infectious Disease AIDS Clinical Trials Group Protocol 306 Investigators Objective: To study the antiviral activity of lamivudine (3TC) plus zidovudine (ZDV), didanosine (ddI), or stavudine (d4T). Design: Randomized, placebo-controlled, partially double-blinded multicenter study. Setting: Adult AIDS Clinical Trials Units. Patients: Treatment-naive HIV-infected adults with 200–600 × 106 CD4 T lymphocytes/l. Interventions: Patients were openly randomized to a d4T or a ddI limb, then randomized in a blinded manner to receive: d4T (80 mg/day), d4T plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos; or ddI (400 mg/day), ddI plus 3TC (300 mg/day), or ZDV (600 mg/day) plus 3TC, with matching placebos. After 24 weeks 3TC was added for patients assigned to the monotherapy arms. Main outcome measure: The reduction in plasma HIV-1 RNA level at weeks 24 and 48. From the *University of Colorado Health Sciences Center and Veterans Affairs Medical Center, Denver, Colorado, the †Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts, the -
Dolutegravir-Abacavir-Lamivudine (Triumeq)
© National HIV Curriculum PDF created September 24, 2021, 7:23 pm Dolutegravir-Abacavir-Lamivudine (Triumeq) Table of Contents Dolutegravir-Abacavir-Lamivudine Triumeq Summary Drug Summary Key Clinical Trials Resistance Key Drug Interactions Drug Summary Dolutegravir-abacavir-lamivudine is a single-tablet regimen that is used primarily for treatment-naïve individuals. It has high potency, a relatively robust barrier to resistance (due to the dolutegravir component), and few drug interactions. It may be especially advantageous for individuals with renal insufficiency or risk factors for renal disease or osteoporosis, as it avoids the use of tenofovir DF. In certain treatment- experienced individuals, dolutegravir-abacavir-lamivudine may provide an option for switch or simplification of therapy. Abacavir can cause a life-threatening hypersensitivity reaction in individuals who are HLA-B*5701 positive; all patients need to undergo testing for HLA-B*5701 prior to receiving dolutegravir-abacavir- lamivudine and those who test positive for HLA-B*5701 should not receive this single tablet regimen. Dolutegravir blocks tubular secretion of creatinine and therefore causes a small increase in serum creatinine in the first 4 to 8 weeks of use; this increase is benign and does not indicate a change in true creatinine clearance. Key Clinical Trials In antiretroviral-naïve individuals, dolutegravir plus abacavir-lamivudine demonstrated superior virologic responses when compared with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine [SINGLE], with superiority largely driven by the greater tolerability of the dolutegravir plus abacavir-lamivudine regimen. In a comparison of 2 NRTIs plus either dolutegravir or raltegravir in treatment-naïve patients, virologic responses in the subset of patients who received dolutegravir plus abacavir-lamivudine were equivalent to those receiving raltegravir plus either tenofovir DF-emtricitabine or abacavir-lamivudine [SPRING-2]. -
Recent Advances in Antiviral Therapy J Clin Pathol: First Published As 10.1136/Jcp.52.2.89 on 1 February 1999
J Clin Pathol 1999;52:89–94 89 Recent advances in antiviral therapy J Clin Pathol: first published as 10.1136/jcp.52.2.89 on 1 February 1999. Downloaded from Derek Kinchington Abstract indicated that using a combination of drugs In the early 1980s many institutions in might overcome this problem. The only Britain were seriously considering available drugs during the late 1980s were two whether there was a need for specialist other nucleotide reverse transcriptase inhibi- departments of virology. The arrival of tors (NRTI) which also targeted HIV reverse HIV changed that perception and since transcriptase (HIV-RT): 2',3'-dideoxycytidine then virology and antiviral chemotherapy (ddC) and 2',3'-dideoxyinosine (ddI).56 In have become two very active areas of bio- vitro combination studies gave surprising medical research. Cloning and sequencing results: those viruses that became highly resist- have provided tools to identify viral en- ant to ZDV remained sensitive to both ddC zymes and have brought the day of the and ddI.7 Furthermore, neither cross resistance “designer drug” nearer to reality. At the nor interference between the drugs was an other end of the spectrum of drug discov- issue, and subsequent clinical experience ery, huge numbers of compounds for showed that patients benefited when these two screening can now be generated by combi- compounds were used in combination with natorial chemistry. The impetus to find ZDV.8 It was also found by in vitro studies that drugs eVective against HIV has also virus isolated from patients on long term ZDV stimulated research into novel treatments monotherapy had become insensitive to ZDV, for other virus infections including her- but regained sensitivity when these patients pesvirus, respiratory infections, and were switched to ddI monotherapy. -
AVT-080205-Ait-Khaled
Antiviral Therapy 8:111-120 HIV-1 reverse transcriptase and protease resistance mutations selected during 16–72 weeks of therapy in isolates from antiretroviral therapy-experienced patients receiving abacavir/efavirenz/amprenavir in the CNA2007 study Mounir Ait-Khaled1*, Abdelrahim Rakik2, Philip Griffin2, Chris Stone2, Naomi Richards3, Deborah Thomas4, Judith Falloon5 and Margaret Tisdale2 for the CNA2007 international study team 1GlaxoSmithKline, HIV Clinical Development and Medical Affairs Europe, Greenford, UK 2GlaxoSmithKline, International Clinical Virology, Stevenage, UK 3GlaxoSmithKline, Statistics, Greenford, UK 4GlaxSmithKline, North American Medical Affairs, Research Triangle Park, NC, USA 5National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., USA *Corresponding author: Tel: +44 208 966 2703; Fax: +44 208 966 4514; E-mail: [email protected] Objective: To determine HIV-1 reverse transcriptase (RT) TAMs were observed, new L74V or I mutations developed and protease (PRO) mutations selected in isolates from in 39 and 16% of isolates, respectively, however, new antiretroviral therapy (ART)-experienced patients receiving M184V mutations were only detected in isolates from two an efavirenz/abacavir/amprenavir salvage regimen. patients, one of whom had added lamivudine + didano- Methods: Open-label, single arm of abacavir, 300 mg sine. M184V was common at baseline (55%) and twice daily, amprenavir, 1200 mg twice daily and maintained in 22/27 (81%) isolates (five of these 22 efavirenz, 600 mg once daily, in ART-experienced added lamivudine or didanosine, or both). The PRO muta- patients of which 42% were non-nucleoside reverse tran- tions selected were in accordance with the distinct scriptase inhibitor-naive. The virology population resistance profile of amprenavir compared with other examined consisted of all patients who took at least 16 protease inhibitors. -
Bictegravir-Tenofovir Alafenamide-Emtricitabine (Biktarvy)
© National HIV Curriculum PDF created September 25, 2021, 12:10 pm Bictegravir-Tenofovir alafenamide-Emtricitabine (Biktarvy) Table of Contents Bictegravir-Tenofovir alafenamide-Emtricitabine Biktarvy Summary Drug Summary Key Clinical Trials Key Drug Interactions Figures Drug Summary Bictegravir-tenofovir alafenamide-emtricitabine is a single-tablet regimen that is comprised of an integrase strand transfer inhibitor (bictegravir) combined with two nucleoside reverse transcriptase inhibitors (tenofovir alafenamide and emtricitabine). Bictegravir, which is not FDA-approved as an individual antiretroviral medication, has a high barrier to resistance, is well tolerated, and, extrapolating from the phase 3 data, has virologic efficacy comparable to dolutegravir. Bictegravir levels can be reduced with medications or oral supplement that contain polyvalent cations (e.g. Ca, Mg, Al, Fe). Bictegravir blocks tubular secretion of creatinine and typically raises serum creatinine by about 0.1 mg/dL, but without affecting renal glomerular function. Phase 3 trials in antiretroviral-naïve persons as well as switch trials in persons with virologic suppression have shown excellent efficacy with bictegravir-tenofovir alafenamide-emtricitabine. Available data suggest that bictegravir has a high genetic barrier to resistance. Key Clinical Trials In a phase 3 trial, 629 antiretroviral-naïve adults were randomized to receive bictegravir-tenofovir alafenamide-emtricitabine or dolutegravir-abacavir-lamivudine; after 48 weeks, there was no significant difference