HIV and COVID-19 No 8
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Pros and Cons of Entry and Fusion Inhibitors (Review)
MOLECULAR MEDICINE REPORTS 19: 1987-1995, 2019 Investigational drugs in HIV: Pros and cons of entry and fusion inhibitors (Review) EMMANUELE VENANZI RULLO1,2, MANUELA CECCARELLI1, FABRIZIO CONDORELLI3, ALESSIO FACCIOLÀ1, GIUSEPPA VISALLI4, FRANCESCO D'ALEO1, IVANA PAOLUCCI1, BRUNO CACOPARDO5, MARILIA RITA PINZONE2-5, MICHELE DI ROSA6, GIUSEPPE NUNNARI1 and GIOVANNI F. PELLICANÒ7 1Department of Clinical and Experimental Medicine, Unit of Infectious Diseases, University of Messina, I-90124 Messina, Italy; 2Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; 3Department of Pharmacological Sciences, University of Eastern Piedmont ‘A. Avogadro’, I-13100 Novara; 4Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, I-90124 Messina; 5Department of Clinical and Experimental Medicine, University of Catania, I-95123 Catania; 6Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, University of Catania, I-95123 Catania; 7Department of Human Pathology of the Adult and the Developmental Age ‘G. Barresi’, Unit of Infectious Diseases, University of Messina, I-98122 Messina, Italy Received September 2, 2018; Accepted November 29, 2018 DOI: 10.3892/mmr.2019.9840 Abstract. Despite the profound changes and improve- 4. Gp41 antagonists ments reached in the field of HIV treatment, tolerability and 5. CD4 antagonists adherence to highly active antiretroviral therapy remains a 6. Discussion challenge. Furthermore, multi-experienced patients could take advantage of drugs with different mechanisms of action to combat the spread of resistance to actual therapy. For these 1. Introduction reasons identification of new HIV drugs is crucial. Among all the molecules that at present are under investigation, entry HIV continues to be an important challenge and a major and fusion inhibitors pose an interesting class owing to their global public health issue. -
Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients
antibodies Review Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients Andrew T. Lucas 1,2,3,*, Ryan Robinson 3, Allison N. Schorzman 2, Joseph A. Piscitelli 1, Juan F. Razo 1 and William C. Zamboni 1,2,3 1 University of North Carolina (UNC), Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA; [email protected] (J.A.P.); [email protected] (J.F.R.); [email protected] (W.C.Z.) 2 Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] 3 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-919-966-5242; Fax: +1-919-966-5863 Received: 30 November 2018; Accepted: 22 December 2018; Published: 1 January 2019 Abstract: The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small molecule drugs, though their clinical use still requires optimization. The pharmacology of mAbs/ADCs is complex and because ADCs are comprised of multiple components, individual agent characteristics and patient variables can affect their disposition. To further improve the clinical use and rational development of these agents, it is imperative to comprehend the complex mechanisms employed by antibody-based agents in traversing numerous biological barriers and how agent/patient factors affect tumor delivery, toxicities, efficacy, and ultimately, biodistribution. -
Altering Cell Death Pathways As an Approach to Cure HIV Infection
Citation: Cell Death and Disease (2013) 4, e718; doi:10.1038/cddis.2013.248 OPEN & 2013 Macmillan Publishers Limited All rights reserved 2041-4889/13 www.nature.com/cddis Review Altering cell death pathways as an approach to cure HIV infection AD Badley*,1,2, A Sainski2,3, F Wightman4,5 and SR Lewin4,5 Recent cases of successful control of human immunodeficiency virus (HIV) by bone marrow transplant in combination with suppressive antiretroviral therapy (ART) and very early initiation of ART have provided proof of concept that HIV infection might now be cured. Current efforts focusing on gene therapy, boosting HIV-specific immunity, reducing inflammation and activation of latency have all been the subject of recent excellent reviews. We now propose an additional avenue of research towards a cure for HIV: targeting HIV apoptosis regulatory pathways. The central enigma of HIV disease is that HIV infection kills most of the CD4 T cells that it infects, but those cells that are spared subsequently become a latent reservoir for HIV against which current medications are ineffective. We propose that if strategies could be devised which would favor the death of all cells which HIV infects, or if all latently infected cells that release HIV would succumb to viral-induced cytotoxicity, then these approaches combined with effective ART to prevent spreading infection, would together result in a cure for HIV. This premise is supported by observations in other viral systems where the relationship between productive infection, apoptosis resistance, and the development of latency or persistence has been established. Therefore we propose that research focused at understanding the mechanisms by which HIV induces apoptosis of infected cells, and ways that some cells escape the pro-apoptotic effects of productive HIV infection are critical to devising novel and rational approaches to cure HIV infection. -
Keeping up with FDA Drug Approvals: 60 New Drugs in 60 Minutes Elizabeth A
Keeping Up with FDA Drug Approvals: 60 New Drugs in 60 Minutes Elizabeth A. Shlom, PharmD, BCPS Senior Vice President & Director Clinical Pharmacy Program | Acurity, Inc. Privileged and Confidential April 10, 2019 Privileged and Confidential Program Objectives By the end of the presentation, the pharmacist or pharmacy technician participant will be able to: ▪ Identify orphan drugs and first-in-class medications approved by the FDA in 2018. ▪ List five new drugs and their indications. ▪ Identify the place in therapy for three novel monoclonal antibodies. ▪ Discuss at least two new medications that address public health concerns. Dr. Shlom does not have any conflicts of interest in regard to this presentation. Both trade names and generic names will be discussed throughout the presentation Privileged and Confidential 2018 NDA Approvals (NMEs/BLAs) ▪ Lutathera (lutetium Lu 177 dotatate) ▪ Braftovi (encorafenib) ▪ Vizimpro (dacomitinib) ▪ Biktarvy (bictegravir, emtricitabine, ▪ TPOXX (tecovirimat) ▪ Libtayo (cemiplimab-rwic) tenofovir, ▪ Tibsovo (ivosidenib) ▪ Seysara (sarecycline) alafenamide) ▪ Krintafel (tafenoquine) ▪ Nuzyra (omadacycline) ▪ Symdeko (tezacaftor, ivacaftor) ▪ Orilissa (elagolix sodium) ▪ Revcovi (elapegademase-lvir) ▪ Erleada (apalutamide) ▪ Omegaven (fish oil triglycerides) ▪ Tegsedi (inotersen) ▪ Trogarzo (ibalizumab-uiyk) ▪ Mulpleta (lusutrombopag) ▪ Talzenna (talazoparib) ▪ Ilumya (tildrakizumab-asmn) ▪ Poteligeo (mogamulizumab-kpkc) ▪ Xofluza (baloxavir marboxil) ▪ Tavalisse (fostamatinib disodium) ▪ Onpattro (patisiran) -
HPTN 083 – Injectable Cabotegravir (CAB) for Prep
CROI 2021 Update: Evaluating Options for Long-Acting PreP 4/15/2021 Nicholas Yared, M.D. Infectious Disease Senior Staff Henry Ford Health System HPTN 083 – Injectable Cabotegravir (CAB) for PrEP • HPTN 083 showed 66% reduction in HIV incidence in men who have sex with men (MSM) and transgender women (TGW) randomized to CAB 600mg every 8 weeks vs. daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) • 58 incident infections among 4566 participants • 13 in CAB group, annual incidence 0.41% • 39 in TDF/FTC group, annual incidence 1.22% • Marzinke et al. used data from HPTN 083 to characterize the 58 cases where infection occurred Marzinke M, et al. Laboratory analysis of HIV infections in HPTN 083: Injectable CAB for PrEP Lab Analysis of HPTN 083 – Methods • Plasma concentrations of CAB and TFV-diphosphate • Concentrations from dried blood spots (DBS) using liquid chromatography-tandem mass spectrometry • HIV Ag/Ab test, HIV discriminatory test, and RNA assays for HIV status and timing • Resistance testing to look for resistance-associated mutations (RAMs) if HIV-1 RNA level > 500 copies/mL Marzinke M, et al. Laboratory analysis of HIV infections in HPTN 083: Injectable CAB for PrEP Results of Lab Analysis of Incident HIV Cases in HPTN 083 – Cabotegravir Arm • 12 incident infections • 5 with no recent CAB dosing • 4 occurred despite on-time CAB injections & targeted CAB concentrations • 3 occurred in oral lead-in phase (1 had no CAB detected) • RAMs • 5 had INSTI-related mutations (Q148 or R263K) • 1 had NNRTI mutations only • 1 had NRTI & NNRTI mutations Marzinke M, et al. -
The Importance of Community Engagement in Hiv Cure Research
tagline Vol. 26, No. 1, May 2019 SCIENTIFIC COMPLEXITY AND ETHICAL UNCERTAINTIES: THE IMPORTANCE OF COMMUNITY ENGAGEMENT IN HIV CURE RESEARCH By Richard Jefferys Introduction The past decade has seen a major expansion of the research Recent presentations at the March 2019 CROI indicate that effort to develop a cure for HIV infection. The U.S. National two additional people may have joined Brown,6,7 but follow-up Institutes of Health (NIH), the world’s largest biomedical is far shorter: One of the individuals has been off ART without research funder, has identified the pursuit of a cure as one of evidence of HIV rebound for 18 months, while the other is at five primary priorities for HIV.1 Total global financial support about four months. increased substantially in the period 2012–2017, from $88 million to $288.8 million.2 In 2014, TAG launched an online Translating to a Wider Community listing of cure-related clinical research drawn from registries (primarily ClinicalTrials.gov). The list initially contained less These additional cases of possible cures are encouraging, than 50 entries; it currently includes 98 clinical trials and 34 but the method used to achieve this outcome cannot be observational studies that are ongoing.3 Over 7,000 people used in most people with HIV, who do not require stem cell are expected to enroll in these studies. transplants for cancer (the high mortality risk associated with transplantation precludes its use outside of this setting). As with other areas of HIV research, engagement of the community of people living with HIV and their advocates is In the absence of any known safe alternatives for obtaining vital for ensuring that the conduct of cure-related studies is similarly robust depletion of HIV from the body, investigators ethical, appropriate, and responsive to community priorities. -
An HIV Clinician's View
HIV Meets Oncology: An HIV Clinician’s View Merceditas S. Villanueva MD Director, HIV/AIDS Program Yale University School of Medicine HIV and Cancer Retreat April 30, 2019 Financial Disclosures • None Case Presentation • 58 year old man diagnosed with HIV in 1996 • Early years: serial ART mono and dual therapy with multidrug resistance • Moved to CT 2005-worked in pharmaceutical field (ART development) • I met him in 2009-applying for disability ART Over Time Saquinavir Tenofovir Emtricitabine Stavudine Ritonavir Atazanavir Maraviroc Elvitegravir Zidovudine Doravirine Indinavir Enfuvirtide Raltegravir Nelfinavir Ibalizumab 1985 1990 1995 2000 2005 2010 2015 2018 Didanosine Tenofovir Lamivudine Efavirenz Darunavir Rilpivirine alafenamide Abacavir Fosemprenavir Dolutegravir Nevirapine Lopinavir+Ritonavir Etravirine ART in Single Tablet Regimen Now 1 pill a Day 2-3 ARVs co-formulated ART Simpler and Safer AN AIDS TIMELINE: The 1st Decade RONALD REAGAN GEORGE H.W. BUSH 1981-1989 1989-1993 ’85 ’87 AZT ’82 First approved HIV “AIDS” ’83 Virus test isolation 1981 AN AIDS TIMELINE: The 2nd Decade GEORGE H.W. BUSH WILLIAM CLINTON 1989-1993 1993-2000 92’ ddl/ddC 93’ d4t Dual NRTI’s HAART ’97: NEL, DLV, Combivir ’95: Saquinavir ’96: NVP, IDV, RIT ’92 AIDS ’96 HIV leading cause viral load of death approved adults 25-44 yrs old AIDS Deaths Red down Ribbon 40% due Tony to Awards HAART 19901 1994 1995 ‘96 My Pt was diagnosed HIV+ AN AIDS TIMELINE: THE 3rd Decade … GEORGE W. BUSH BARACK H. OBAMA 2001-2008 2009 - 2016 ’00 ’01 ’03 ‘04 ’05 ‘06 Darunavir ’07 ’08 Trizivir Tenofo Fuzeon Truvada Tipranavir Maraviroc Etravirine -Atripla vir Raltegravir Lopinavir ’00 13th Int’l AIDS : Conf in PEPFAR 25 30 Durban SA $15B/5 yrs years years 2000 AN AIDS TIMELINE: THE 4th Decade … DONALD J. -
Long-Acting Subcutaneous Lenacapavir Dosed Every 6 Months
Long-acting Subcutaneous Lenacapavir Dosed Every 6 Months as part of a Combination Regimen in Treatment-Naïve People with HIV: Interim 16-week Results of a Randomized, Open-label, Phase 2 Induction-Maintenance Study (CALIBRATE) Samir K. Gupta,1 Mezgebe Berhe,2 Gordon Crofoot,3 James Sims,4 Paul Benson,5 Moti Ramgopal,6 William E. Sanchez,7 Peter Ruane,8 Cheryl McDonald,9 Anita Scribner,10 Hui Wang,11 Laurie VanderVeen,11 Hadas Dvory-Sobol,11 Robert H. Hyland,11 Martin S. Rhee,11 Jared M. Baeten,11 Diana M. Brainard,11 Ellen Koenig12 1Indiana University School of Medicine, Indianapolis, USA; 2North Texas Infectious Diseases Consultants, Dallas, USA; 3The Crofoot Research Center, Inc., Houston, USA; 4St. Hope Foundation, Bellaire, USA; 5Be Well Medical Center, Berkley, USA; 6Midway Specialty Care Center, Fort Pierce, USA; 7Floridian Clinical Research, Hialeah, USA; 8Ruane Clinical Research Group, Los Angeles, USA; 9Texas Centers for Infectious Disease Associates, Fort Worth, USA; 10Diagnostic Clinic of Longview Center for Clinical Research, Longview, USA; 11Gilead Sciences Inc., Foster City, USA; 12Instituto Dominicano de Estudios Virológicos, Santo Domingo, Dominican Republic Disclosures SKG receives unrestricted research grant support from the NIH, Indiana University School of Medicine, and GSK/ViiV and receives advisory board fees from Gilead Sciences, Inc., and GSK/ViiV. 2 Acknowledgments We extend our thanks to: The study participants and their families Participating study investigators and staff: Dominican Republic: E Koenig United States: P Benson; DS Berger; M Berhe; C Brinson; P Cook; DR Coulston; GE Crofoot; FA Cruickshank; D Cunningham; E DeJesus; C Dietz; V Drelichman; E Gardner; A Gaur; D Goldstein; SK Gupta; D Hagins; R Hengel; T Hodge; C-B Hsiao; A Khalsa; CA Kinder; P Kumar; C McDonald; A Mills; JO Morales-Ramirez; C Newman; G Oguchi; O Osiyemi; MN Ramgopal; PJ Ruane; W Sanchez; JL Santana-Bagur; L Santiago; A Scribner; J Sims; GI Sinclair; JL Stephens; M Wohlfeiler; AK Wurapa This study was funded by Gilead Sciences, Inc. -
TROGARZO (Ibalizumab-Uiyk) RATIONALE for INCLUSION IN
TROGARZO (ibalizumab-uiyk) RATIONALE FOR INCLUSION IN PA PROGRAM Background Trogarzo (ibalizumab-uiyk) is a recombinant humanized monoclonal antibody that blocks HIV-1 from infecting CD4+ T-cells. This medication blocks the HIV-1 virus from entering the host cell by interfering with post-attachment steps required for the entry of HIV-1 virus that occurs via cell fusion. The binding specificity of ibalizumab-uiyk to domain 2 of CD4 allows ibalizumab-uiyk to block viral entry into host cells without causing immunosuppression (1). Regulatory Status FDA approved indication: Trogarzo, a CD4-directed post-attachment HIV-1 inhibitor, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen (1). Immune reconstitution inflammatory syndrome has been reported in one patient treated with Trogarzo in combination with other antiretrovirals. During the initial phase of combination antiretroviral therapies, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections, which may necessitate further evaluation and treatment(1). Phenotypic and genotypic test results revealed no evidence of cross-resistance between ibalizumab-uiyk and any of the approved classes of anti-retroviral drugs (CCR5 co-receptor antagonists, gp41 fusion inhibitors, integrase strand transfer inhibitors [INSTIs], non-nucleos(t)ide reverse transcriptase inhibitors [NNRTIs], nucleos(t)ide reverse transcriptase inhibitors [NRTIs], or protease inhibitors [PIs]). Ibalizumab-uiyk is active against HIV-1 resistant to all approved antiretroviral agents and exhibits antiretroviral activity against R5-tropic, X4-tropic, and dual-tropic HIV-1 (1). -
G HIV/AIDS & Immune Evasion Strategies the Year 1981…
Micro 320: Infectious Disease & Defense HIV/AIDS & Immune Evasion Strategiesg Wilmore Webley Dept. of Microbiology The Year 1981… Reported by MS Gottlieb, MD, HM Schanker, MD, PT Fan, MD, A Saxon, MD, JD Weisman, DO, Div of Clinical Immunology-Allergy; Dept of Medicine, UCLA School of Medicine; I Pozalski, MD, Cedars-Mt. Siani Hospital, Los Angeles; Field services Div, Epidemiology Program Office, CDC. First Encounter: Dr. Michael Gottleib http://www.pbs.org/wgbh/pages/frontline/aids/view/ What is AIDS? Acquired Immune Deficiency Syndrome • Acquired means you can get infected with it (not inherited) • Immune Deficiency means a weakness in the body's system that fights diseases. • Syndrome means a group of health problems that make up a disease. The term AIDS refers to an advanced stage of HIV infection, when the immune system has sustained substantial damage. Not everyone who has HIV infection develops AIDS http://www.pbs.org/wgbh/pages/fro ntline/aids/view/ Global Statics of HIV/AIDS Transmission of HIV “Patient Zero” and HIV Transmission Gaëtan Dugas: A Canadian who worked for Air Canada as a flight attendant Claimed to have had over 2,500 sexual partners across North America 1972 Diagnosed with Kaposi's Sarcoma in June 1980 In 1982 the CDC linked him to 9 of the first 19 cases in Los Born February 20, 1953 Angeles, 22 cases in NYC and 9 March 30, 1984 Died (aged 31) more in 8 other cities – Total of 40 Quebec City, Quebec of the first 248 cases in the U.S. Occupation Flight attendant New Model: HIV Traveled to Haiti, Then U.S. -
What's New in Hiv? Highlights & New Data on Hiv Treatment a Presentation for Healthtrust Members June 18, 2021
WHAT'S NEW IN HIV? HIGHLIGHTS & NEW DATA ON HIV TREATMENT A PRESENTATION FOR HEALTHTRUST MEMBERS JUNE 18, 2021 SHIVANI PATEL, PHARMD PGY-1 PHARMACY RESIDENT ROBERT WOOD JOHNSON UNIVERSITY HOSPITAL NAVANEETH NARAYANAN, PHARMD, MPH, BCIDP CLINICAL ASSOCIATE PROFESSOR RUTGERS UNIVERSITY ERNEST MARIO SCHOOL OF PHARMACY CONFLICT OF INTEREST DISCLOSURE There are no relevant financial interest to disclose for myself or my spouse/partner within the last 12 months. The preceptor has a financial interest/arrangement, affiliation or relationship with Astellas and Merck that could be perceived as a real or apparent conflict of interest in the context of the subject of this activity. Note: This program may contain the mention of suppliers, brand products, services, or drugs presented in a case study or comparative format using evidence-based research. Such examples are intended for educational and informational purposes only and should not be perceived as an endorsement of any particular supplier, brand, product, service or drug. 1 2 3 LEARNING Identify new antiretroviral Describe a two-drug regimen Outline key counseling points agents and their role in the for treatment-naïve to a patient receiving new OBJECTIVES management of HIV/AIDS individuals and factors to antiretroviral agents related consider when selecting an to drug administration, initial regimen for an potential side effects, and individual. drug-drug interactions DRUG NAME ABBREVIATIONS Abbreviation Full Name Abbreviation Full Name Abbreviation Full Name 3TC Lamivudine DTG Dolutegravir -
CDER Breakthrough Therapy Designation Approvals Data As of December 31, 2020 Total of 190 Approvals
CDER Breakthrough Therapy Designation Approvals Data as of December 31, 2020 Total of 190 Approvals Submission Application Type and Proprietary Approval Use Number Number Name Established Name Applicant Date Treatment of patients with previously BLA 125486 ORIGINAL-1 GAZYVA OBINUTUZUMAB GENENTECH INC 01-Nov-2013 untreated chronic lymphocytic leukemia in combination with chlorambucil Treatment of patients with mantle cell NDA 205552 ORIGINAL-1 IMBRUVICA IBRUTINIB PHARMACYCLICS LLC 13-Nov-2013 lymphoma (MCL) Treatment of chronic hepatitis C NDA 204671 ORIGINAL-1 SOVALDI SOFOSBUVIR GILEAD SCIENCES INC 06-Dec-2013 infection Treatment of cystic fibrosis patients age VERTEX PHARMACEUTICALS NDA 203188 SUPPLEMENT-4 KALYDECO IVACAFTOR 21-Feb-2014 6 years and older who have mutations INC in the CFTR gene Treatment of previously untreated NOVARTIS patients with chronic lymphocytic BLA 125326 SUPPLEMENT-60 ARZERRA OFATUMUMAB PHARMACEUTICALS 17-Apr-2014 leukemia (CLL) for whom fludarabine- CORPORATION based therapy is considered inappropriate Treatment of patients with anaplastic NOVARTIS lymphoma kinase (ALK)-positive NDA 205755 ORIGINAL-1 ZYKADIA CERITINIB 29-Apr-2014 PHARMACEUTICALS CORP metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib Treatment of relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients NDA 206545 ORIGINAL-1 ZYDELIG IDELALISIB GILEAD SCIENCES INC 23-Jul-2014 for whom rituximab alone would be considered appropriate therapy due to other co-morbidities