DOCSLIB.ORG

Short Communication Compilation and Prevalence of Mutations Associated with Resistance to Non-Nucleoside Reverse Transcriptase Inhibitors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Short Communication Compilation and Prevalence of Mutations Associated with Resistance to Non-Nucleoside Reverse Transcriptase Inhibitors Antiviral Therapy 14:103–109 Short communication Compilation and prevalence of mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors Lotke Tambuyzer1*, Hilde Azijn1, Laurence T Rimsky1, Johan Vingerhoets1, Pierre Lecocq2, Guenter Kraus1, Gaston Picchio3 and Marie-Pierre de Béthune1 1Tibotec BVBA, Mechelen, Belgium 2Virco BVBA, Mechelen, Belgium 3Tibotec Inc., Yardley, PA, USA *Corresponding author: E-mail: [email protected] Background: Non-nucleoside reverse transcriptase inhibi- Results: In total, 44 NNRTI RAMs were identified. These tors (NNRTIs) are an important component of antiretroviral included V90I, A98G, L100I, K101E/P/Q, K103H/N/S/T, therapy for HIV type-1 (HIV-1)-infected patients. Develop- V106A/I/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/ ment of NNRTI resistance can lead to treatment failure I/V, Y188C/H/L, V189I, G190A/C/E/Q/S, H221Y, P225H, and is conferred by the presence of specific resistance- F227C/L, M230I/L, P236L, K238N/T and Y318F. These associated mutations (RAMs) in the reverse transcriptase. NNRTI RAMs were observed, either alone or in combi- In addition to the widely used list of NNRTI RAMs provided nation with others, ranging in frequency from 0.02% to by the International AIDS Society-USA HIV-1 Drug Resist- 56.96% in a panel of 101,679 NNRTI-resistant isolates ance Mutation Group, which were identified on the basis submitted to Virco BVBA (Mechelen, Belgium) for routine of clinical experience with the approved NNRTIs, a more clinical resistance testing. Phenotypical data from site- comprehensive list of NNRTI RAMs is needed to guide the directed mutants helped to establish the contribution of study of baseline and emerging resistance to new NNRTIs. each mutation to NNRTI resistance. Methods: We conducted an extensive review of the exist- Conclusions: The list of 44 NNRTI RAMs compiled in this ing literature on NNRTI resistance, together with several study provides a comprehensive overview of mutations in vitro and in vivo studies on the mechanism of HIV-1 that play a role in HIV-1 NNRTI resistance and can be resistance to approved NNRTIs and to NNRTIs formerly or used to guide further in vitro and in vivo research on the currently in clinical development. mechanisms of HIV-1 NNRTI resistance. Introduction Non-nucleoside reverse transcriptase inhibitors first-line antiretroviral (ARV) therapy for patients (NNRTIs) target the viral reverse transcriptase (RT) infected by HIV type-1 (HIV-1), mainly because of responsible for the conversion of the single-stranded their proven efficacy and favourable safety and tol- RNA genome into double-stranded DNA, which is erability profiles. However, EFV, NVP and the other subsequently integrated into the host genomic DNA first-generation NNRTI, delavirdine (DLV), are char- [1,2]. NNRTIs are non-competitive inhibitors of acterized by a low genetic barrier to the development the RT enzyme and bind into a hydrophobic pocket of resistance and extensive cross-resistance, prevent- located in the p66 subunit domain, at 10 Å from ing sequential treatment with these NNRTIs [3,4]. the active site, and overlapping with the p66/p51 Recently, a next-generation NNRTI, etravirine (ETR; heterodimer interface [3]. Specific mutations in the TMC125), was approved in the United States [5] and NNRTI binding pocket cause resistance to NNRTIs the European Union [6] for the treatment of ARV and might lead to treatment failure. therapy- experienced adult patients. ETR exhibits a The first-generation NNRTIs, efavirenz (EFV) high genetic barrier to the development of resistance and nevirapine (NVP), are recommended as part of [7] and is an important new option for constructing © 2009 International Medical Press 1359-6535 103 Tambuyzer.indd 103 5/2/09 14:23:38 L Tambuyzer et al. an active ARV regimen because the prevalence of effective concentration [FC]) for the HIV-1/HXB2 site- NNRTI resistance in ARV-treated patients appears to directed mutant harbouring the single mutation in the be substantial [8] and the transmission of NNRTI-re- RT [7] and genotypical and phenotypical resistance sistant HIV-1 (primary resistance) has been reported information of HIV-1 isolates from patients who par- with an overall prevalence of 10–15% [9,10]. ticipated in the Tibotec clinical trials and were on an NNRTI resistance involves specific mutations, NNRTI-containing treatment regimen. either alone or in multiple and complex patterns. The The prevalence of each NNRTI RAM was determined International AIDS Society (IAS)-USA HIV-1 drug in a panel of 237,958 recombinant HIV-1 isolates sub- resistance mutations update provides a list of NNRTI mitted to Virco BVBA for routine clinical resistance resistance-associated mutations (RAMs), which were testing between January 1999 and June 2007 and in two identified on the basis of clinical experience with the subsets of this panel. The first subset included 101,679 approved NNRTIs [11,12]. In addition, several in NNRTI-resistant isolates for which the predicted FC vitro studies have identified RAMs that are directly for any first- generation NNRTI (EFV, NVP or DLV) associated with NNRTI resistance [13–15]. There is was greater than the respective virco®TYPE biological expanding evidence on new mutations that play a cutoff and the second subset contained the remaining role in NNRTI resistance; therefore, the present study 136,279 isolates that were not NNRTI resistant. aimed to compile a comprehensive list of RAMs to aid the study of resistance to new NNRTIs. Results Methods At the time of the analysis, 44 amino acid changes at 20 different positions along the RT were identified An extensive review of the existing literature on based on an extensive review of the existing literature in vitro and in vivo NNRTI resistance data was on NNRTI resistance data together with several in conducted in early to mid 2007. Bibliographical vitro and in vivo studies on the mechanism of HIV-1 searches on the mechanism of HIV-1 resistance to the resistance to approved NNRTIs and to NNRTIs for- approved NNRTIs (DLV, EFV, NVP and ETR) and to merly or currently in clinical development. The 44 the NNRTIs currently (TMC278 [rilpivirine], RDEA NNRTI RAMs included in the list were V90I, A98G, 806 and BILR 355 BS) or formerly (HEPT-, TIBO- L100I, K101E, K101P, K101Q, K103H, K103N, and BHAP derivatives, capravirine, emivirine and K103S, K103T, V106A, V106I, V106M, V108I, loviride) in clinical development, were included. E138G, E138K, E138Q, V179D, V179E, V179F, Several listings of NNRTI RAMs are available V179G, V179I, Y181C, Y181I, Y181V, Y188C, today. The IAS-USA 2007 drug resistance mutations Y188H, Y188L, V189I, G190A, G190C, G190E, update outlines 21 NNRTI RAMs at 12 different G190Q, G190S, H221Y, P225H, F227C, F227L, positions in the RT that might contribute to a reduced M230I, M230L, P236L, K238N, K238T and Y318F. virological response to DLV, EFV, NVP and ETR [11]. Results for each NNRTI RAM appear in Table 1 The NNRTI resistance matrix from the Stanford Uni- [7,11,14–16,18–53] and Figure 1. The prevalence of versity HIV Drug Resistance Database comprises 29 the NNRTI RAM in the total panel of 237,958 HIV-1 NNRTI RAMs at 16 different positions in the RT clinical isolates is shown. K103N had the highest prev- [16]. Mutational patterns including RT mutations at alence (24.34%) followed by Y181C (10.66%), V179I different positions have been described for the gener- (8.55%), G190A (8.16%) and V108I (4.81%). The ation of a quantitative phenotypical prediction (fold lowest prevalence was observed for F227C (0.01%). change) by the virco®TYPE (Virco BVBA, Mechelen, Table 1 also shows the prevalence of the NNRTI Belgium) analysis [17]. In the HIV Sequence Compen- RAM in the subset of 101,679 NNRTI-resistant HIV-1 dium 2006/2007 published by Los Alamos National clinical isolates. The five most prevalent NNRTI Laboratory (Los Alamos, NM, USA), 57 mutations at RAMs in this subset were K103N (56.96%), Y181C 28 different positions in the RT gene were considered (24.95%), G190A (19.09%), V179I (11.82%) and to be associated with NNRTI resistance [18]. V108I (10.68%) and were the same as in the whole In addition to this literature study and the com- panel. F227C also showed the lowest prevalence parison of different mutation listings, mutations were (0.02%) in this subset. included in the list of NNRTI RAMs on the basis of The five most prevalent NNRTI RAMs in the phenotypical evidence of NNRTI resistance using one remaining 136,279 HIV-1 clinical isolates that were or more of the following criteria: the selection of the not NNRTI resistant were V179I (6.11%), V90I mutation in vitro in selection experiments starting (3.06%), V106I (1.98%), V189I (0.93%) and K101Q from wild-type or mutant HIV-1 strains [7], a decrease (0.84%). Twenty-four NNRTI RAMs were not in phenotypical susceptibility (fold change in 50% present in this subset. 104 © 2009 International Medical Press Tambuyzer.indd 104 5/2/09 14:23:38 Extended list of NNRTI RAMs Table 1 shows the number of nucleotide substitutions B subtypes (91%). This number could give an indication needed for the HIV-1/HXB2 wild-type amino acid to of the genetic barrier to develop a particular RAM. switch to the mutant amino acid, using the most preva- The FC values for EFV, NVP and ETR obtained lent codon in a genotype database including mainly clade using HIV-1/HXB2 site-directed mutants harbouring Table 1. Mutations associated with resistance to NNRTIs Prevalence in samples for RCRT, % NNRTI- Not NNRTI- Number of NNRTI
Load more

Recommended publications
  • HIV-Infected Patients
    New Drugs for the Treatment-Experienced Patient Joseph Eron, md Associate Professor of Medicine and Director, Clinical Core unc Center for aids Research, University of North Carolina at Chapel Hill Summary by Tim Horn Edited by Jay Dobkin, md; Michael Saag, md reatment options for antiretro- humans by adenosine deaminase into D- Deeks and his colleagues in 1998 demon- viral-experienced patients leave a dioxolane guanine (dxg), a metabolite that strated a 1 log reduction in hiv-rna in hiv- lot to be desired. According to Dr. has potent activity against hiv and hbv. infected patients—more than 50% of whom Joe Eron, patients who have treat- According to in vitro data presented at were treatment-experienced—who received ment experience in all three classes the 3rd International Workshop on hiv tenofovir df 300 mg once daily as of currently available antiretrovi- Drug Resistance and Treatment Strategies, monotherapy for 28 days (Deeks, 1998). Trals have, at best, a 30% chance of re- held in June 1999, dapd was found to in- According to in vitro data presented by ducing their viral load to levels below 400 hibit wild-type and mutant isolates resistant Gilead’s Dr. Michael Miller at the recent copies/mL upon initiating a salvage regi- to azt (Retrovir) and 3TC (Borroto-Esoda, 4th International Resistance Workshop, the men. Cross-resistance within each class of 1999). The drug was also reported to be ac- resistance pattern for tenofovir df is simi- drugs, particularly the protease inhibitors tive against strains collected from patients lar to that of its chemical predecessor adefo- (pis) and non-nucleoside reverse tran- who have failed various nrti and nnrti vir, a compound no longer in development scriptase inhibitors (nnrtis), essentially combination therapies, including those for the treatment of hiv (Miller, 2000).
    [Show full text]
  • ( 12 ) United States Patent
    US010385067B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 385, 067 B2 Carra et al. (45 ) Date of Patent: Aug. 20 , 2019 (54 ) SODIUM (2R , 55 , 13AR ) - 7 , 9 -DIOX0 - 10 ( 56 ) References Cited ( 2 , 4 ,6 - TRIFLUOROBENZYL )CARBAMOYL ) 2 , 3 , 4 , 5 , 7 , 9 , 13 , 13A -OCTAHYDRO - 2 , 5 U . S . PATENT DOCUMENTS METHANOPYRIDO [ 1 ' , 2 ' : 4 , 5 ]PYRAZINO 5 , 814 ,639 A 9 / 1998 Liotta et al . [ 2 , 1 - B ] [ 1 , 3 ]OXAZEPIN - 8 - OLATE 5 , 914 , 331 A 6 / 1999 Liotta et al . 5 ,922 ,695 A 7 / 1999 Arimilli et al . 5 , 935 , 946 A 8 / 1999 Munger, Jr . et al. (71 ) Applicant: Gilead Sciences , Inc ., Foster Ctiy , CA 5 , 977 , 089 A 11/ 1999 Arimilli et al. (US ) 6 ,043 , 230 A 3 / 2000 Arimilli et al. 6 ,620 , 841 B1 9 / 2003 Fujishita et al . (72 ) Inventors : Ernest A . Carra , Foster City , CA ( US ) ; 6 ,642 , 245 B1 11/ 2003 Liotta et al. 6 , 703 , 396 B1 3 / 2004 Liotta et al . Irene Chen , San Mateo , CA (US ) ; 7 , 176 , 220 B2 2 /2007 Satoh et al. Vahid Zia , Palo Alto , CA (US ) 7 ,419 , 969 B2 9 / 2008 Naidu et al. 7 , 550 , 463 B2 6 / 2009 Yoshida (73 ) Assignee : Gilead Sciences , Inc. , Foster City , CA 7 ,635 , 704 B2 12 /2009 Satoh et al. 7 , 858 , 788 B2 12 / 2010 Yoshida et al . (US ) 8 , 129 , 385 B2 3 / 2012 Johns et al . 8 , 148 , 374 B2 4 / 2012 Desai et al. ( * ) Notice : Subject to any disclaimer , the term of this 8 , 188 , 271 B2 5 / 2012 Yoshida et al .
    [Show full text]
  • Canadian HIV/AIDS Pharmacists Network (CHAP) Newsletter – April 2000
    1 Canadian HIV/AIDS Pharmacists Network (CHAP) Newsletter – April 2000 Happy Spring! It is pouring cats and dogs here in “sunny” Alberta today, but the good news is that the grass and trees are green (yes I am an optimist). I even had to shake off the dust from my umbrella! I won’t complain because Spring is finally here……. Hurray! As you know, I have officially taken over the Chair from Kathy Slayter (aka “Mom”). This is my first attempt at a newsletter so please be patient with me! Social News Well I am sure everyone has heard the good news but I would like to officially congratulate Kathy and Mike on the birth of their little boy, Ethan James Tucker, on December 11, 1999. Congratulations Kathy! New Members I would like to officially welcome the following new members: Laura Park-Wyllie who has taken over Michelle Foisy’s position as HIV Primary Care Pharmacist at the St. Michael’s Hospital, Health Centre at 410 (formerly Wellesley Health Centre). Deborah Kelly who is as an Assistant Professor of Clinical Pharmacy at Memorial University in Newfoundland and Clinical Pharmacy Specialist at Health Care Corp of St. John’s. Kimberly Montgomery who is a Pharmacist at the Southern Alberta Clinic (taking over from Nikola Ostrop). Unfortunately, Kim will not be with us long. She is getting married in August and then will be moving to Newfoundland. Her last day at the clinic will be June 30, 2000. Congratulations on your upcoming wedding Kim! For those of you interested, there is an opening at the SAC and you can contact Kimberly for more details… 2 CAHR Update I thought the CAHR conference was excellent and the Network meeting went well (considering all of the problems we had arranging the first Network meeting of the millenium!).
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2016/0058872 A1 Crew Et Al
    US 2016.0058872A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0058872 A1 Crew et al. (43) Pub. Date: Mar. 3, 2016 (54) IMIDE-BASED MODULATORS OF A613 L/426 (2006.01) PROTEOLYSIS AND ASSOCATED METHODS A 6LX3 L/505 (2006.01) OF USE A613 L/454 (2006.01) A613 L/55 (2006.01) (71) Applicant: Arvinas, Inc., New Haven, CT (US) C07D40 L/4 (2006.01) A6II 45/06 (2006.01) (72) Inventors: Andrew P. Crew, Guilford, CT (US); (52) U.S. Cl. Craig Crews, New Haven, CT (US), CPC ............ A61K 47/481 (2013.01); C07D401/14 Hanging Dong, Madison, CT (US); Jing (2013.01); C07D 495/14 (2013.01); C07D Wang, Milford, CT (US); Yimin Qian, 417/14 (2013.01); A61K 45/06 (2013.01); Plainsboro, NJ (US); Kam Siu Milford, A6 IK3I/505 (2013.01); A61 K3I/454 CT (US); Meizhong Jin, East Northport, (2013.01); A61 K3I/551 (2013.01); A61 K NY (US) 3 1/426 (2013.01) (21) Appl. No.: 14/792,414 (57) ABSTRACT (22) Filed: Jul. 6, 2015 The description relates to imide-based compounds, including Related U.S. Application Data bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially (63) Continuation-in-part of application No. 14/686.640, inhibitors of a variety of polypeptides and other proteins filed on Apr. 14, 2015. which are degraded and/or otherwise inhibited by bifunc (60) Provisional application No. 61/979,351, filed on Apr. tional compounds according to the present invention. In par 14, 2014, provisional application No.
    [Show full text]
  • Meeting Report: 26Th International Conference on Antiviral Research Q
    Antiviral Research 100 (2013) 276–285 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Review Meeting report: 26th International Conference on Antiviral Research q R. Anthony Vere Hodge Vere Hodge Antivirals Ltd, Old Denshott, Leigh, Reigate, Surrey, UK article info abstract Article history: The 26th International Conference on Antiviral Research (ICAR) was held in San Francisco, California from Received 2 August 2013 May 11 to 15, 2013. This article summarizes the principal invited lectures at the meeting. The opening Accepted 8 August 2013 symposium on the legacy of the late Antonín Holy´ included presentations on his pioneering work with Available online 21 August 2013 nucleotide analogs, which led to the development of several antiviral drugs including tenofovir. This drug has transformed the treatment of HIV infection and has recently become the first-line therapy for chronic Keywords: hepatitis B. The Gertrude Elion Award lecturer described the anti-HIV activities of the CCR5 inhibitor Human immunodeficiency virus cenicriviroc and the reverse transcriptase inhibitor festinavirÒ, and also reviewed the evaluation of bio- Hepatitis B degradable nanoparticles with adjuvant activity. The William Prusoff Award winner reported on the cre- Hepatitis C Herpesviruses ation of NAOMI, a computer model with 21 enzymes to predict the activity of nucleoside analogs against Antiviral therapy hepatitis C virus (HCV). Other invited lecturers discussed the development of countermeasures against severe dengue and the potential of RNA virus capping and repair enzymes as drug targets. Topics in the clinical symposium included the current status of the anti-HCV compounds sovaprevir, ACH-3102, miravirsen and ALS-2200; the evaluation of single-tablet regimens for HIV infection; and the investiga- tion of cytomegalovirus resistance to CMX001.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances
    WHO/PSM/QSM/2006.3 The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances 2006 Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Medicines Policy and Standards The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0250896 A1 Zhao (43) Pub
    US 20150250896A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0250896 A1 Zhao (43) Pub. Date: Sep. 10, 2015 (54) HYDROPHILIC LINKERS AND THEIR USES Publication Classification FOR CONUGATION OF DRUGS TO A CELL (51) Int. Cl BNDING MOLECULES A647/48 (2006.01) (71) Applicant: Yongxin R. ZHAO, Henan (CN) Ek E. 30.8 C07D 207/216 (2006.01) (72) Inventor: R. Yongxin Zhao, Lexington, MA (US) C07D 40/12 (2006.01) C07F 9/30 (2006.01) C07F 9/572 (2006.01) (73) Assignee: Hangzhou DAC Biotech Co., Ltd., (52) U.S. Cl. Hangzhou City, ZJ (CN) CPC ........... A61K47/48715 (2013.01); C07F 9/301 (2013.01); C07F 9/65583 (2013.01); C07F (21) Appl. No.: 14/432,073 9/5721 (2013.01); C07D 207/46 (2013.01); C07D 401/12 (2013.01); A61 K3I/454 (22) PCT Filed: Nov. 24, 2012 (2013.01) (86). PCT No.: PCT/B2O12/0567OO Cell(57) binding- agent-drugABSTRACT conjugates comprising hydrophilic- S371 (c)(1), linkers, and methods of using Such linkers and conjugates are (2) Date: Mar. 27, 2015 provided. Patent Application Publication Sep. 10, 2015 Sheet 1 of 23 US 2015/0250896 A1 O HMDS OSiMe 2n O Br H-B-H HPC 3 2 COOEt essiop-\5. E B to NH 120 °C, 2h OsiMe3 J 50 °C, 2h eSiO OEt 120 oC, sh 1 2 3. 42% from 1 Bra-11a1'oet - Brn 11-1 or a 1-1 or ÓH 140 °C ÓEt ÓEt 4 5 6 - --Messio. 8 B1a-Br aus 20 cc, hP-1}^-'ot Br1-Y.
    [Show full text]
  • This Project Has Been Supported with Unrestriced Grants from Abbvie Gilead Sciences HEXAL Janssen-Cilag MSD Viiv Healthcare By
    This project has been supported with unrestriced grants from AbbVie Gilead Sciences HEXAL Janssen-Cilag MSD ViiV Healthcare By Marcus Altfeld, Hamburg/Boston (USA) Achim Barmeyer, Dortmund Georg Behrens, Hannover Dirk Berzow, Hamburg Christoph Boesecke, Bonn Patrick Braun, Aachen Thomas Buhk, Hamburg Rob Camp, Barcelona (Spain/USA) Rika Draenert, Munich Christian Eggers, Linz (Austria) Stefan Esser, Essen Gerd Fätkenheuer, Cologne Gunar Günther, Windhoek (Namibia) Thomas Harrer, Erlangen Christian Herzmann, Borstel Christian Hoffmann, Hamburg Heinz-August Horst, Kiel Martin Hower, Dortmund Christoph Lange, Borstel Thore Lorenzen, Hamburg Tim Niehues, Krefeld Christian Noah, Hamburg Ramona Pauli, Munich Ansgar Rieke, Koblenz Jürgen Kurt Rockstroh, Bonn Thorsten Rosenkranz, Hamburg Bernhard Schaaf, Dortmund Ulrike Sonnenberg-Schwan, Munich Christoph D. Spinner, Munich Thomas Splettstoesser (Figures), Berlin Matthias Stoll, Hannover Hendrik Streeck, Essen/Boston (USA) Jan Thoden, Freiburg Markus Unnewehr, Dortmund Mechthild Vocks-Hauck, Berlin Jan-Christian Wasmuth, Bonn Michael Weigel, Schweinfurt Thomas Weitzel, Santiago (Chile) Eva Wolf, Munich HIV 2015/16 www.hivbook.com Edited by Christian Hoffmann and Jürgen K. Rockstroh Medizin Fokus Verlag IV Christian Hoffmann, M.D., Ph.D. ICH Stadtmitte (Infektionsmedizinisches Centrum Hamburg) Glockengiesserwall 1 20095 Hamburg, Germany Phone: + 49 40 2800 4200 Fax: + 49 40 2800 42020 [email protected] Jürgen K. Rockstroh, M.D., Ph.D. Department of Medicine I University of Bonn Sigmund-Freud-Strasse 25 53105 Bonn, Germany Phone: + 49 228 287 6558 Fax: + 49 228 287 5034 [email protected] HIV Medicine is an ever-changing field. The editors and authors of HIV 2015/16 have made every effort to provide information that is accurate and complete as of the date of publication.
    [Show full text]
  • TREATMENT B U L L E T I N
    ISSN 1472-4863 HIV-treatment bulletin VOLUME 2 NO.2 MARCH 2001 FORMERLYh- Doctor Fax tb H I V i - B a s e TREATMENT bulletin. 2 Volume 2 No.2 - MARCH 2001 TREATMENT ACCESS • Capravirine clinical trials restricted: Additional safety evaluation required • From Talk to Action in Fighting AIDS in the Developing Countries: 8th Retrovirus Conference opening session • Gilead announces start of early access program for investigational anti-HIV agent tenofovir DF in US and France • UNAIDS calls for new deal between pharmaceutical companies and society • Mortality from liver disease increasing in HIV-positive patients • US trade action threatens Brazilian AIDS programme TREATMENT GUIDELINES • Brazil May Flout Trade Laws to Keep AIDS Drugs Free • Roche Open to Discuss Patent Rights of AIDS Drug With Brazil • First European guidelines for HIV-1 drug resistance testing • Crusading Indian firm takes on might of Glaxo SmithKline: • U.S.A HIV treatment guidelines updated for adults and Cipla is offers anti-HIV drugs at a fraction of rivals’ prices adolescents • GSK to review drug pricing policy: Pharmaceuticals giant • U.S.A. Perinatal Treatment Guidelines Updated, Jan. 24, 2001 reacts to criticism over costs to poor countries • Oxfam launches stinging attack on drug industry over cheap CONFERENCE REPORTS medicines ban 8th Conference on Retroviruses and Opportunistic Infections • Companies Weigh Offer of Royalties for AIDS Drugs for Africa February 4 – 8, 2001. Chicago IL. OTHER NEWS • Differentiating within and between drug classes: Sometimes it’s toxicity,
    [Show full text]
  • L:\0901 with Peru\0901PHARMAPPX.Wpd
    Harmonized Tariff Schedule of the United States (2009) (Rev. 1) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2009) (Rev. 1) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. ABACAVIR 136470-78-5 ACEXAMIC ACID 57-08-9 ABAFUNGIN 129639-79-8 ACICLOVIR 59277-89-3 ABAMECTIN 65195-55-3 ACIFRAN 72420-38-3 ABANOQUIL 90402-40-7 ACIPIMOX 51037-30-0 ABAPERIDONE 183849-43-6 ACITAZANOLAST 114607-46-4 ABARELIX 183552-38-7 ACITEMATE 101197-99-3 ABATACEPT 332348-12-6 ACITRETIN 55079-83-9 ABCIXIMAB 143653-53-6 ACIVICIN 42228-92-2 ABECARNIL 111841-85-1 ACLANTATE 39633-62-0 ABETIMUS 167362-48-3 ACLARUBICIN 57576-44-0 ABIRATERONE 154229-19-3 ACLATONIUM NAPADISILATE 55077-30-0 ABITESARTAN 137882-98-5 ACODAZOLE 79152-85-5 ABLUKAST 96566-25-5 ACOLBIFENE 182167-02-8 ABRINEURIN 178535-93-8 ACONIAZIDE 13410-86-1 ABUNIDAZOLE 91017-58-2 ACOTIAMIDE 185106-16-5 ACADESINE 2627-69-2 ACOXATRINE 748-44-7 ACAMPROSATE 77337-76-9 ACREOZAST 123548-56-1 ACAPRAZINE 55485-20-6
    [Show full text]