Transcript 401_06_Lx9
HPV, Zoster, TB, Etc. MedCh 401 Lecture 9 2Jun06 KL Vadheim Lecture 9 1 Human Papillomavirus • • • • • Papillomaviridae; ds DNA genome ~100 different types Produces warts on various body parts 30-40 types infect genital tissue Low risk: types 6 and 11, e.g. – genital warts • High risk: ~ 15 types – 16, 18, 31, 45 cause most cancers 2Jun06 KL Vadheim Lecture 9 2 HPV infections • • • • • • Most common STD worldwide ~20 million infected in U.S. ~5.5 million new infections annually Often asymptomatic Most infections spontaneously resolve Infects cervix, vagina, vulva, anus, penis 2Jun06 KL Vadheim Lecture 9 3 High Risk HPVs • Cause intraepithelial neoplasias • Can progress to cancer if undetected/untreated • HPV viral sequences (oncogenes) integrated in cellular DNA • Viral E6 protein binds/degrades p53, a tumor suppressor gene 2Jun06 KL Vadheim Lecture 9 4 HPV Vaccines Under Review • Merck - Gardasil – Quadravalent (6, 11, 16, 18) – Recombinant – Recommended for approval by VRPAC • GSK – Bivalent (16 and 18) – Phase III trials ongoing 2Jun06 KL Vadheim Lecture 9 5 Merck’s Gardasil • Targeted for women 9-26 years of age • 100% effective in preventing type 16 and 18 infection (~70% cervical CA) • 99% effective in preventing type 6 and 11 infection (90% of genital warts) • Complement to - not a replacement for Pap smears • $300 - $500 per vaccination 2Jun06 KL Vadheim Lecture 9 6 Cervical Cancer in U.S. • >9,000 women diagnosed annually • ~3,700 deaths • Risk factors for development of cervical CA – – – – – 2Jun06 high-risk type HPV infection smoking having many children long-term oral contraceptive use HIV infection KL Vadheim Lecture 9 7 Zostavax • Merck’s shingles vaccine • Licensed May 25, 2006 • Reduce risk of herpes zoster in people >60 – 50% efficacy in all people >60 – 64% efficacy in people 60-69 • Three-year efficacy trial 2Jun06 KL Vadheim Lecture 9 8 Merck’s Zostavax & Varivax • Oka/Merck strain of live, attenuated VZV • Initially obtained from child with natural varicella infection • Attenuation – Human embryonic lung cells – Embryonic guinea pig cells – Human diploid cells (WI-38) • Lyophilized • Subcutaneous administration 2Jun06 KL Vadheim Lecture 9 9 Varicella zoster Vaccines Component, per dose VZV Sucrose Hydrolyzed porcine gelatin NaCl Monosodium L-glutamate Sodium Phosphate Dibasic Potassium Phosphate Monobasic KCl Neomycin Fetal calf serum Sodium phosphate monobasic EDTA Residual MRC-5 cell components (DNA/protein) 2Jun06 Zostervax 0.65-ml dose 19,400 PFU 31.16 mg 15.58 mg 3.99 mg 0.62 mg 0.57 mg 0.10 mg 0.10 mg Trace Trace Trace KL Vadheim Lecture 9 Varivax 0.5-ml dose 1,350 PFU 25 mg 12.5 mg 3.2 mg 0.5 mg 0.45 mg 0.08 mg 0.08 mg Trace Trace Trace Trace Trace 10 Tuberculosis • • • • 2 billion people are infected worldwide 2 million deaths annually worldwide 1 in 10 infected will develop active TB 98% of deaths are in the developing world, affecting primarily young adults • 8.8 million new TB cases in 2003 – 80% in 22 countries 2Jun06 KL Vadheim Lecture 9 11 Pandemic TB • Global incidence is growing at 1% per year • 25% of all cases are in Africa • 50% of new cases are in six Asian countries – – – – – – 2Jun06 Bangladesh China India Indonesia Pakistan The Philippines KL Vadheim Lecture 9 12 TB Transmission • Airborne • No animal vector known 2Jun06 KL Vadheim Lecture 9 13 Multi-Drug Resistance in TB • Curable, but 5,000 people die daily • MDR-TB present in nearly all 109 countries surveyed by WHO • 425,000 new MDR-TB cases every year – highest rates in former USSR and China – up to 14% of all new cases are not responding to standard drug treatment 2Jun06 KL Vadheim Lecture 9 14 TB control strategies • U.S. – Test and treat – Mantoux test (PPD skin reactivity test) • Europe – BCG vaccination • attenuated TB strain – Dubious efficacy – Recent studies place efficacy near zero 2Jun06 KL Vadheim Lecture 9 15 New TB control strategies (WHO) • Government commitment to TB control • Diagnosis through bacteriology and an effective lab network • Standardized short-course chemotherapy with full patient support • Uninterrupted supply of quality-assured drugs • Documenting patient outcomes 2Jun06 KL Vadheim Lecture 9 16 Malaria • • • • • >1 million deaths annually 300-500 million acute illnesses each year Endemic in >100 countries >80% of deaths in sub-Saharan Africa Most deaths in infants and young children – 3,000 children die of malaria every day 2Jun06 KL Vadheim Lecture 9 17 Malaria transmission • Single-celled parasite carried by Anopheles mosquito • Many animal hosts in addition to humans • Complex life cycle makes control difficult 2Jun06 KL Vadheim Lecture 9 18 Malaria Control • Insecticide-laced mosquito nets – reduces childhood deaths ~20% • Chloroquine – effective against P. vivax, ~30% of cases • Sulphadoxin-Pyrimethamine (SP) – P. falciparum • Drug resistance a problem • Artemisinin-based Combination Therapy (ACT) 2Jun06 KL Vadheim Lecture 9 19 Malaria Vaccine Development • PATH – Malaria Vaccine Initiative • GSK’s candidate vaccine ~50% efficacy against most lethal forms of disease 2Jun06 KL Vadheim Lecture 9 20 Specific Immune Globulins • • • • • • • 2Jun06 Botulinum antitoxin Botulism IGIV Cytomegalovirus IG IV Hepatitis B IGIV Rabies IG (Human) RSV IGIV (Human) Tetanus IG (Human) KL Vadheim Lecture 9 21 Non-specific IGIV • Immune Globulin (Human) • Immune Globulin IV (Human) • Immune Globulin Subcutaneous (Human) – can be self-administered 2Jun06 KL Vadheim Lecture 9 22 Non-specific IGIVs • Highly purified IgG preparation • Made from donated human plasma • Used to treat people with insufficient antibody production • Usually given every 3-4 weeks • Treatment may be life-long 2Jun06 KL Vadheim Lecture 9 23 Schedule 2, 4, 6 months ~15 months 4-6 years Vaccine HepB (10 g) DTaP (Up to 58 g + D + T) Hib (7.5 – 10 g) Conjugate (24-125 g) IPV PCV (16g psacc) (20 g CRM197) HepB DTaP Hib IPV MMR Varicella PCV Influenza HepA HepB DTaP IPV MMR Varicella 2Jun06 KL Vadheim Lecture 9 # Antigens 1 (10 g) Up to 7 (>58 g) 2 (225 g) 3 8 (36 g) Total # antigens 21 (>329 g) 1 (10 g) 7 (>58 g) 2 (225 g) 3 3 1 8 (36 g) 3 (45 g) 1 1 (10 g) 28 (>374 g) 5 (>58g) 3 3 1 13 (>68 g) 24 Complaints • Call or write the manufacturer • Provide as much information as possible • Expect an investigation and written response 2Jun06 KL Vadheim Lecture 9 25 Recalls and Withdrawals • www.fda.gov/cber/recalls 2Jun06 KL Vadheim Lecture 9 26 Adverse Events (AEs) • Adverse event - any untoward medical occurrence in a patient administered a medicinal product and which does not necessarily have to have a causal relationship with this treatment • Adverse Drug Reaction - all noxious and unintended responses to a medicinal product • Adverse Reaction - implies causal relationship; aka side effect 2Jun06 KL Vadheim Lecture 9 27 AEs • Local, systemic, allergic • Serious AE – – – – – results in death is life-threatening requires hospitalization results in persistenr or significant disability is a congenital anomaly/birth defect • Unexpected v. expected (labeled) 2Jun06 KL Vadheim Lecture 9 28 Pharmacovigilence • All scientific and data gathering activities relating to the detection, assessment and understanding of AEs • Involves identification and evaluation of safety signals 2Jun06 KL Vadheim Lecture 9 29 Safety signals • A concern about an excess of AEs compared to what is expected with that product • Single event • Group of events that indicate the need for further investigations - e.g., intussesception with RotaShield 2Jun06 KL Vadheim Lecture 9 30 Safety Signals • • • • New, serious AEs Increase in severity of labeled AE Increase in frequency of serious AE New product-product, product-diet supplement interactions • Identification of previously unrecognized at-risk populations • Misuse of a product 2Jun06 KL Vadheim Lecture 9 31 Good Case Reports • Complete description of event • Product therapy details - dose, lot #, schedule, dates, dietary supplements or OTC meds taken, etc. • Patient characteristics • Documentation of diagnosis of the event(s) • Clinical course and patient outcomes • Relevant therapeutic measure and lab data during and after therapy • Any other relevant information 2Jun06 KL Vadheim Lecture 9 32 Pharmacovigilence • ICH Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, April 2005 • ICH Guidance for Industry: Pharmacovigilance Planning, April 2005 • Guidance for Industry: How to Complete the VAERS Form, Sept. 1998 • www.fda.gov/cber/guidelines 2Jun06 KL Vadheim Lecture 9 33