DOCSLIB.ORG

Rate of Thymidine Analogue Resistance Mutation Accumulation with Zidovudine- Or Stavudine-Based Regimens

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Rate of Thymidine Analogue Resistance Mutation Accumulation with Zidovudine- Or Stavudine-Based Regimens BRIEF REPORT:CLINICAL SCIENCE Rate of Thymidine Analogue Resistance Mutation Accumulation With Zidovudine- or Stavudine-Based Regimens Daniel R. Kuritzkes, MD,* Roland L. Bassett, MS,† J. Darren Hazelwood, BS,‡ Heidi Barrett, MT( ASCP), CLS,* Ruth A. Rhodes, BS, MPH,‡ Russell K. Young, MS,* and Victoria A. Johnson, MD,‡ for the Adult ACTG Protocol 306 and 370 Teams ment with ZDV or d4T, but the specific pattern of mutations may Abstract: Zidovudine (ZDV) and stavudine (d4T) select for the differ somewhat in patients treated with these thymidine analogues. same set of thymidine analogue resistance mutations (TAMs). To compare the rate at which TAMs emerge, genotypic analysis of Key Words: zidovudine, stavudine, drug resistance, thymidine ana- HIV-1 was performed on serial plasma samples from treatment-naive logues subjects randomly assigned to receive ZDV or d4T in combination (J Acquir Immune Defic Syndr 2004;36:600–603) with lamivudine. After 72 weeks of follow-up, TAMs were detected in samples from 50% of ZDV-treated subjects and 45% of d4T- treated subjects (P = 0.79). The frequency of K70R and T215Y or F ucleoside analogue inhibitors of HIV-1 reverse transcrip- mutations was similar in both groups, although M41L was observed tase (RT) are a mainstay of antiretroviral therapy. The more frequently in samples from ZDV-treated subjects. This random- N efficacy of these regimens may be limited, however, by the ized study shows that TAMs accumulate at similar rates during treat- emergence of drug resistance. Particular interest has been fo- cused on cross-resistance between the 2 thymidine analogues Received for publication October 2, 2003; accepted February 10, 2004. From *University of Colorado Health Sciences Center, Denver, CO; †Harvard in clinical use, stavudine (d4T) and zidovudine (ZDV). Resis- School of Public Health, Boston, MA; and ‡Birmingham Veterans Affairs tance to ZDV emerges in a step-wise manner by the ordered Medical Center and University of Alabama at Birmingham School of accumulation of mutations at RT codons 41, 67, 70, 210, 215, Medicine, Birmingham, AL. and 219 (reviewed in Hirsch et al.1). Drs. Johnson and Kuritzkes acknowledge the following grant support from the Analysis of HIV-1 isolates from subjects treated with National Institutes of Health: AI32770, AI 32775, AI38855, AI38858, AI40876, AI42567, RR00051, and RR16482. Dr. Johnson also acknowl- d4T-containing regimens has identified the presence of muta- 2,3 edges BVAMC and CFAR core laboratory research facilities. Partial sup- tions classically associated with ZDV resistance. It is now port for the genotypic analysis was provided by a grant from Bristol-Myers recognized that these mutations, referred to as nucleoside- Squibb. associated mutations (NAMs) or thymidine analogue– Dr. Kuritzkes has received grant/research support, speaker’s honoraria, and/or associated mutations (TAMs), can result in a pattern of cross- is on the clinical advisory boards of: Bayer, Bristol-Myers, Squibb, Glaxo- SmithKline, ViroLogic, and Visible Genetics (Bayer). Dr. Johnson has resistance to all nucleoside and nucleotide reverse transcrip- 4 received grant/research support, speaker’s honoraria, and/or is on the clini- tase inhibitors (NRTIs). Although these studies demonstrate cal advisory boards of: Bristol-Myers, Squibb, GlaxoSmithKline, Virco that TAMs can be selected by d4T-containing regimens, the Lab, ViroLogic, and Visible Genetics (Bayer). frequency with which these mutations emerge in virus from GenBank Accession #AY527818-AY528222. subjects receiving d4T- or ZDV-based regimens has not di- Presented in part at the following meetings: 4th International Workshop on HIV Drug Resistance and Treatment Strategies, Sitges, Spain, June 12–16, rectly been compared. To address this question we performed 2000 (abstract 57); 40th Interscience Conference on Antimicrobial Agents genotypic resistance testing of serial plasma virus samples and Chemotherapy, Toronto, Canada, September 17–20, 2000 (abstract from subjects randomly assigned to receive ZDV or d4T in #2111); and XIth International HIV Drug Resistance Workshop, Seville, Adult AIDS Clinical Trials Group (ACTG) protocol 306 and Spain, July 2–5, 2002 (abstract 36). followed until entry into a rollover study, ACTG protocol 370. Informed consent was obtained from all subjects participating in this study. Conduct of this study conformed to human experimentation guidelines of the US Department of Health and Human Services. METHODS Reprints: Daniel R. Kuritzkes, Section of Retroviral Therapeutics, Brigham and Women’s Hospital, 65 Landsdowne Street, Room 449, Cambridge Subjects and Study Design MA 02139 (e-mail: [email protected]). Adult ACTG protocol 306 was a multicenter, random- Copyright © 2004 by Lippincott Williams & Wilkins ized, placebo-controlled trial conducted by 21 collaborating 600 J Acquir Immune Defic Syndr • Volume 36, Number 1, May 1 2004 J Acquir Immune Defic Syndr • Volume 36, Number 1, May 1 2004 Thymidine Analogue Resistance in HIV-1 Adult AIDS Clinical Trials Units. That study compared the in the resistance analyses were 4.54 log10 copies/mL at entry safety and efficacy of monotherapy with didanosine (ddI) or into ACTG 306 and 3.73 log10 copies/mL at entry into ACTG d4T to that of dual-nucleoside regimens consisting of either 370. Median CD4 cell counts for these subjects were 388 × 106 ZDV plus lamivudine (3TC), d4T + 3TC, or ddI + 3TC in treat- cells/L at entry into ACTG 306 and 497 × 106 cells/L at entry ment-naive subjects with 200 × 106 to 600 × 106 CD4 cells/L.5 into ACTG 370. Median duration of NRTI therapy at entry into At week 24, 3TC was added to the regimen of subjects initially ACTG 370 was 79 weeks (range, 61–94 weeks). Baseline assigned to ddI or d4T monotherapy. Subjects who success- characteristics of subjects with resistance test results did not fully completed at least 48 weeks of treatment in ACTG 306 differ from those of the respective ACTG 306 or 370 study and remained on their assigned study regimen were eligible for populations as a whole. entry into a rollover study (ACTG 370). 6 Baseline data from ACTG 370 are included to provide for longer follow-up on the Accumulation of TAMs on Thymidine ACTG 306 regimens. Genotypic resistance testing was per- Analogue Therapy formed on samples from subjects in the ZDV- and d4T- Samples from 4 subjects (1 in the ZDV/3TC arm and 3 in containing arms of ACTG 306 who had plasma HIV-1 RNA the d4T or d4T/3TC arms) had Ն1 TAMs at entry into ACTG levels >500 copies/mL (Quantiplex HIV-1 RNA assay version 306 (Table 1). At week 24, samples from 4 of 48 subjects (8%) 2.0; Bayer Nucleic Acid Diagnostics, Norwood, MA) at study in the ZDV-containing arms vs. 4 of 39 subjects (10%) in the entry and at one or more time points at weeks 24, 48, and/or d4T-containing arms had accumulated Ն1 TAM (P = 1.00). week 72. In addition, genotypic resistance testing was per- (Because results from the initial d4T monotherapy and formed on samples from subjects with plasma HIV-1 RNA d4T/3TC arms were similar, data from these 2 arms were levels > 500 copies/mL (ultrasensitive HIV-1 Monitor assay pooled.) At week 48, samples from 7 of 40 ZDV-treated sub- version 1.0, Roche Molecular Systems, Branchburg, NJ) at en- jects (18%) vs. 6 of 29 d4T-treated subjects (21%) had Ն1 try into ACTG 370. TAM (P = 0.76). At week 72, samples from 17 of 34 ZDV- treated subjects (50%) vs. 10 of 22 d4T-treated subjects (45%) Nucleotide Sequencing and Analysis had Ն1 TAM (P = 0.79). At entry into ACTG 370, Ն1 TAM Sequencing of HIV-1 pol (codons 41–237 of RT) was had accumulated in samples from 17 of 34 ZDV-treated sub- performed using the TruGene HIV-1 Sequencing Kit and OpenGene DNA Sequence Analysis System (Bayer Nucleic Acid Diagnostics).7 Phylogenetic trees of the aligned, manu- ally edited sequences were constructed using PHYLIP8 and TABLE 1. Emergence of Thymidine Analogue Resistance 9 Mutations During ACTG 306 According to Treeview to verify that each patient’s viral sequence was Treatment Assignment unique. ZDV resistance was assessed as the number of ZDV resistance–associated mutations (41L, 67N, 70R, 210W, 215Y Number of TAMs Treatment Study or F, 219Q). Arm Week 0 1 2345Total Statistical Analyses ZDV/3TC 0 65 0 0100 66 Fisher exact tests were used to compare the proportion of 24* 4440000 48 samples containing TAMs at each time point. The distribution 48 3341101 40 of the number of TAMs was compared between treatment 72 17106001 34 groups using a Wilcoxon test. 370 baseline† 1778101 34 d4T/3TC 0 31 1 1000 33 RESULTS 24* 2110000 22 Two hundred subjects were enrolled into the ZDV- or 48 1521000 18 d4T-containing arms of ACTG 306; the analyses presented 72 8 21100 12 here are limited to the 120 subjects who had plasma HIV-1 370 baseline† 1230000 15 RNA levels >500 copies/mL at the time points of interest. d4T‡ 0 2010000 21 Similarly, 75 subjects from the ZDV- and d4T-containing 24* 1430000 17 arms of ACTG 306 enrolled into ACTG 370 with plasma 48 8 30000 11 HIV-1 RNA >500 copies/mL; genotypic resistance data from 72 4 51000 10 65 subjects are presented here. (Resistance data from the re- 370 baseline† 5 51000 11 maining subjects were not obtained either because baseline, as *Data for weeks 24, 48, and 72 exclude TAMs present at week 0. opposed to screening, plasma HIV-1 RNA levels were <500 †Entry into ACTG 370 (median time on ACTG 306 = 79 weeks, range copies/mL, or because genotypic testing failed to yield a re- 61–94 weeks). ‡3TC added at week 24. sult.) Median plasma HIV-1 RNA levels for subjects included © 2004 Lippincott Williams & Wilkins 601 Kuritzkes et al J Acquir Immune Defic Syndr • Volume 36, Number 1, May 1 2004 jects (50%) and in samples from 9 of 26 d4T-treated subjects monotherapy arm of ACTG 306 received 6 months of d4T (35%) (P = 0.30).
Load more

Recommended publications
  • Treatment-Drugs
    © National HIV Curriculum PDF created September 23, 2021, 9:14 am Stavudine (Zerit) Table of Contents Stavudine Zerit Summary Drug Summary Key Clinical Trials Resistance Key Drug Interactions Drug Summary Stavudine, an early nucleoside reverse transcriptase inhibitor (NRTI), was used as part of combination antiretroviral therapy for years, but now has become obsolete and replaced by better-tolerated and safer options. Stavudine poses risk of serious toxicity, including peripheral neuropathy (which can be permanent), pancreatitis, lipoatrophy, and lactic acidosis. Fatal and nonfatal cases of pancreatitis and lactic acidosis have been reported, especially when stavudine was combined with didanosine. According to the Adult and Adolescent ARV Guidelines, stavudine is no longer recommended for the treatment of HIV infection due to potential severe toxicity. Further, all persons currently taking stavudine should be strongly encouraged to switch to a safer medication. The sale and distribution of all strengths of stavudine will be discontinued and removed from the market in the United States in 2020. Key Clinical Trials Stavudine was studied for treatment-naïve patients as part of triple therapy, such as with lamivudine plus indinavir [START I], lamivudine plus lopinavir-ritonavir [M98-863], and lamivudine plus efavirenz [DART II]. Several studies demonstrated benefits of switching stavudine to newer NRTI agents, such as tenofovir disoproxil fumarate; the switch led to decreased rates of metabolic complications and mitochondrial toxicity [903E, SNAP, and ACTG 5142]. Resistance For a listing of the most common clinically significant mutations associated with stavudine (d4T) resistance, see the NRTI Resistance Notes on the Stanford University HIV Drug Resistance Database. Page 1/2 Key Drug Interactions For complete information on stavudine-related drug interactions, see the Drug Interactions section in the Stavudine (Zerit) Prescribing Information.
    [Show full text]
  • Eparate Formulations According to the Prescribed Dosing Recommendations for These Products
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Lamivudine/Zidovudine Teva 150 mg/300 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 150 mg lamivudine and 300 mg zidovudine. For the full list of excipients see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet White, capsule shaped, biconvex, film-coated scored tablet – engraved with “L/Z” on one side and “150/300” on the other side. The tablet can be divided into equal halves. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Lamivudine/Zidovudine Teva is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection (see section 4.2). 4.2 Posology and method of administration Therapy should be initiated by a physician experienced in the management of HIV infection. Lamivudine/Zidovudine Teva may be administered with or without food. To ensure administration of the entire dose, the tablet(s) should ideally be swallowed without crushing. For patients who are unable to swallow tablets, tablets may be crushed and added to a small amount of semi-solid food or liquid, all of which should be consumed immediately (see section 5.2). Adults and adolescents weighing at least 30 kg: the recommended oral dose of Lamivudine/Zidovudine Teva is one tablet twice daily. Children weighing between 21 kg and 30 kg: the recommended oral dose of Lamivudine/Zidovudine Teva is one-half tablet taken in the morning and one whole tablet taken in the evening. Children weighing from 14 kg to 21 kg: the recommended oral dose of Lamivudine/Zidovudine Teva is one-half tablet taken twice daily.
    [Show full text]
  • Product Monograph for CELSENTRI
    PRODUCT MONOGRAPH PrCELSENTRI maraviroc Tablets 150 and 300 mg CCR5 antagonist ViiV Healthcare ULC 245, boulevard Armand-Frappier Laval, Quebec H7V 4A7 Date of Revision: July 05, 2019 Submission Control No: 226222 © 2019 ViiV Healthcare group of companies or its licensor. Trademarks are owned by or licensed to the ViiV Healthcare group of companies. Page 1 of 60 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION.........................................................3 SUMMARY PRODUCT INFORMATION ........................................................................3 INDICATIONS AND CLINICAL USE..............................................................................3 CONTRAINDICATIONS ...................................................................................................3 WARNINGS AND PRECAUTIONS..................................................................................4 ADVERSE REACTIONS....................................................................................................9 DRUG INTERACTIONS ..................................................................................................19 DOSAGE AND ADMINISTRATION..............................................................................28 OVERDOSAGE ................................................................................................................31 ACTION AND CLINICAL PHARMACOLOGY ............................................................31 STORAGE AND STABILITY..........................................................................................36
    [Show full text]
  • 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
    [Show full text]
  • Emtricitabine and Tenofovir Alafenamide
    HIGHLIGHTS OF PRESCRIBING INFORMATION ------------------------DOSAGE AND ADMINISTRATION----------------------­ These highlights do not include all the information needed to use • Testing: Prior to initiation of DESCOVY, patients should be tested for DESCOVY safely and effectively. See full prescribing information hepatitis B virus infection, and estimated creatinine clearance, urine for DESCOVY. glucose and urine protein should be obtained. (2.1) • ® Recommended dosage: One tablet taken once daily with or without DESCOVY (emtricitabine and tenofovir alafenamide) tablets, for food in patients with body weight at least 25 kg and a creatinine oral use clearance greater than or equal to 30 mL per minute. (2.2) Initial U.S. Approval: 2015 • Renal impairment: DESCOVY is not recommended in patients with WARNING: POST TREATMENT ACUTE EXACERBATION OF estimated creatinine clearance below 30 mL per minute. (2.3) HEPATITIS B ----------------------DOSAGE FORMS AND STRENGTHS--------------------­ See full prescribing information for complete boxed warning. Tablets: 200 mg of FTC and 25 mg of TAF (3) • DESCOVY is not approved for the treatment of chronic -------------------------------CONTRAINDICATIONS------------------------------­ hepatitis B virus (HBV) infection. Severe acute None. exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have -----------------------WARNINGS AND PRECAUTIONS-----------------------­ discontinued products containing emtricitabine (FTC) • Immune reconstitution syndrome: May necessitate further evaluation and/or tenofovir disoproxil fumarate (TDF), and may occur and treatment.(5.2) with discontinuation of DESCOVY. Hepatic function should • New onset or worsening renal impairment: Assess creatinine be monitored closely in these patients. If appropriate, clearance, urine glucose, and urine protein in all patients before initiation of anti-hepatitis B therapy may be warranted.
    [Show full text]
  • SYMTUZA™ (Darunavir, Cobicistat, Emtricitabine, Tenofovir Alafenamide) Oral
    PHARMACY COVERAGE GUIDELINES ORIGINAL EFFECTIVE DATE: 9/20/2018 SECTION: DRUGS LAST REVIEW DATE: 8/19/2021 LAST CRITERIA REVISION DATE: 8/19/2021 ARCHIVE DATE: SYMTUZA™ (darunavir, cobicistat, emtricitabine, tenofovir alafenamide) oral Coverage for services, procedures, medical devices and drugs are dependent upon benefit eligibility as outlined in the member's specific benefit plan. This Pharmacy Coverage Guideline must be read in its entirety to determine coverage eligibility, if any. This Pharmacy Coverage Guideline provides information related to coverage determinations only and does not imply that a service or treatment is clinically appropriate or inappropriate. The provider and the member are responsible for all decisions regarding the appropriateness of care. Providers should provide BCBSAZ complete medical rationale when requesting any exceptions to these guidelines. The section identified as “Description” defines or describes a service, procedure, medical device or drug and is in no way intended as a statement of medical necessity and/or coverage. The section identified as “Criteria” defines criteria to determine whether a service, procedure, medical device or drug is considered medically necessary or experimental or investigational. State or federal mandates, e.g., FEP program, may dictate that any drug, device or biological product approved by the U.S. Food and Drug Administration (FDA) may not be considered experimental or investigational and thus the drug, device or biological product may be assessed only on the basis of medical necessity. Pharmacy Coverage Guidelines are subject to change as new information becomes available. For purposes of this Pharmacy Coverage Guideline, the terms "experimental" and "investigational" are considered to be interchangeable.
    [Show full text]
  • Stavudine and Lamivudine Tablets RX Only
    Stavudine and Lamivudine Tablets RX only WARNING LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUES ALONE OR IN COMBINATION, INCLUDING STAVUDINE, LAMIVUDINE AND OTHER ANTIRETROVIRALS (SEE WARNINGS). FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF STAVUDINE AND DIDANOSINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF STAVUDINE AND DIDANOSINE SHOULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS: PREGNANCY). FATAL AND NONFATAL PANCREATITIS HAVE OCCURED DURING THERAPY WHEN STAVUDINE WAS PART OF A COMBINATION REGIMEN THAT INCLUDED DIDANOSINE, WITH OR WITHOUT HYDROXYUREA, IN BOTH TREATMENT–NAIVE AND TREATMENT EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF 1 IMMUNOSUPPRESSION (SEE WARNINGS). SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV AND HAVE DISCONTINUED LAMIVUDINE. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY WITH BOTH CLINICAL AND LABORATORY FOLLOW UP FOR AT LEAST SEVERAL MONTHS IN PATIENTS WHO DISCONTINUE LAMIVUDINE AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED (SEE WARNINGS). DESCRIPTION Stavudine and lamivudine tablets are for oral administration. Each uncoated tablet contains the active ingredients 40mg of stavudine and 150mg of lamivudine, and the inactive ingredients microcrystalline cellulose, colloidal anhydrous silica, croscarmellose sodium, ferric oxide red, povidone, magnesium stearate and purified water. Stavudine (d4T) is a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus (HIV). Lamivudine (3TC) is a synthetic nucleoside analogue with activity against HIV-1 and HBV.
    [Show full text]
  • Managing Side Effects of HIV Medications | 1 Managing Side Effects of HIV Medications | 2 Your Doctor Can Also Help You Prepare for Any Side Effects
    Managing Side Eects of HIV MEDICATIONS Table of Contents What are side effects?..........................................................................................1 Side effects of different classes of HIV drugs ....................................................9 Why do I need to know about side effects of HIV medications? ......................2 Protease inhibitors ..................................................................................................................9 Fat problems (lipodystrophy) ..............................................................................................9 What questions should I ask when my doctor first prescribes an HIV medication? .............................................................................................2 Metabolic problems ................................................................................................................9 Make sure you understand what the medication does and the best way Heart disease, heart attacks, stroke ...................................................................................9 to take it ......................................................................................................................................2 Diabetes ................................................................................................................................... 10 Your doctor can also help you prepare for any side effects .....................................3 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) .............................................
    [Show full text]
  • Application for Inclusion of Emtricitabine and Tenofovir Alafenamide Fixed Dose Combination Tablets (Descovy®) on the WHO Model List of Essential Medicines
    Application for Inclusion of Emtricitabine and Tenofovir Alafenamide Fixed Dose Combination Tablets (Descovy®) on the WHO Model List of Essential Medicines Submitted by Gilead Sciences Inc. December 2016 Gilead Sciences Inc. 333 Lakeside Drive Foster City California 94404 USA Gilead Sciences Submission Reference number: GSI-DSY-161201 1 Application for inclusion of Descovy tablets in the WHO Model List of Essential Medicines, December 2016 Contents 1. Summary statement of the proposal for inclusion ................................................... 5 2. Name of the focal point in WHO submitting or supporting the application ................. 7 3. Name of the organization(s) consulted and/or supporting the application ................. 7 4. International Nonproprietary Name (INN, generic name) of the medicine ................. 7 5. Formulation proposed for inclusion ........................................................................ 8 6. International availability ....................................................................................... 9 7. Listing type requested ........................................................................................ 11 8. Information supporting the public health relevance ............................................... 12 8.1 Epidemiological information on disease burden 12 9. Treatment details ............................................................................................... 15 9.1 Indications and usage 15 9.2 Dosage and administration 16 9.2.1 Special populations 16
    [Show full text]
  • Is There a True Difference in Efficacy and Safety?
    Journal of Virus Eradication 2018; 4: 73–80 ORIGINAL RESEARCH Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety? Andrew Hill1*, Sophie L Hughes2, Dzintars Gotham2 and Anton L Pozniak3 1 Department of Pharmacology and Therapeutics, University of Liverpool, UK 2 Faculty of Medicine, Imperial College London, UK 3 Chelsea and Westminster Hospital NHS Foundation Trust, London, UK Abstract Background: Higher plasma tenofovir concentrations are associated with higher risks of renal and bone adverse events. The pharmacokinetic boosters ritonavir (RTV) and cobicistat (COBI) significantly increase plasma area under the curve (AUC) concentrations of tenofovir disoproxil fumarate (TDF), by 25–37%. When combined with RTV or COBI, the dose of tenofovir alafenamide (TAF) is lowered from 25 mg to 10 mg daily, but the TDF dose is maintained at 300 mg daily. Objective: To assess the differences in safety and efficacy between tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) in regimens with and without the pharmacokinetic boosters RTV and COBI. Methods: A PubMed/Embase search inclusive of dates up to 17 July 2017 identified 11 randomised head-to-head trials (8111 patients) of TDF versus TAF. The Mantel–Haenszel method was used to calculate pooled risk differences and 95% confidence intervals using random-effects models. A pre-defined sub-group analysis compared TAF with TDF, either when boosted with RTV or COBI, or when unboosted. Results: Nine clinical trials compared TAF and TDF for treatment of HIV-1 and two were for hepatitis B treatment. The eleven clinical trials documented 4574 patients with boosting RTV or COBI in both arms, covering 7198 patient-years of follow-up.
    [Show full text]
  • PREZCOBIX-Pi.Pdf
    PREZCOBIX® PREZCOBIX (darunavir and cobicistat) tablets (darunavir and cobicistat) tablets, for oral use • Skin reactions ranging from mild to severe, including Stevens-Johnson Highlights of Prescribing Information Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic These highlights do not include all the information needed to use PREZCOBIX symptoms and acute generalized exanthematous pustulosis, can occur with safely and effectively. See full prescribing information for PREZCOBIX. PREZCOBIX. Discontinue treatment if severe reaction develops. (5.2) PREZCOBIX® (darunavir and cobicistat) tablets, for oral use • When PREZCOBIX is used in combination with a tenofovir disoproxil fumarate Initial U.S. Approval: 2015 (tenofovir DF) containing regimen, cases of acute renal failure and Fanconi syndrome have been reported. (5.4) --------------------------------RECENT MAJOR CHANGES--------------------------------- • PREZCOBIX is not recommended in combination with other antiretroviral drugs Warnings and Precautions, that require pharmacokinetic boosting. (5.6) Risk of Serious Adverse Reactions or Loss of • Monitor in patients with a known sulfonamide allergy. (5.7) Virologic Response Due to Drug Interactions (5.5) 12/2020 • Patients receiving PREZCOBIX may develop new onset or exacerbations of --------------------------------INDICATIONS AND USAGE--------------------------------- diabetes mellitus/hyperglycemia (5.8), redistribution/accumulation of body fat PREZCOBIX is a two-drug combination of darunavir, a human immunodeficiency
    [Show full text]
  • REYATAZ Rx Only
    ® REYATAZ Rx only (atazanavir sulfate) Capsules (Patient Information Leaflet Included) DESCRIPTION REYATAZ® (atazanavir sulfate) is an azapeptide inhibitor of HIV-1 protease. The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1- dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]- 2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7•H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula: Atazanavir sulfate is a white to pale yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3° C. REYATAZ Capsules are available for oral administration in strengths containing the equivalent of 100 mg, 150 mg, or 200 mg of atazanavir as atazanavir sulfate and the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue #2, and titanium dioxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue #2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol. 1 of 47 Approved v1.0 CLINICAL PHARMACOLOGY Microbiology Mechanism of Action Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.
    [Show full text]