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HPV, Zoster, TB, Etc.

HPV, Zoster, TB, Etc. MedCh 401 Lecture 9. 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

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HPV, Zoster, TB, Etc.

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  1. HPV, Zoster, TB, Etc. MedCh 401 Lecture 9 KL Vadheim Lecture 9

  2. 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 KL Vadheim Lecture 9

  3. 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 KL Vadheim Lecture 9

  4. 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 KL Vadheim Lecture 9

  5. 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 KL Vadheim Lecture 9

  6. 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 KL Vadheim Lecture 9

  7. Cervical Cancer in U.S. • >9,000 women diagnosed annually • ~3,700 deaths • Risk factors for development of cervical CA • high-risk type HPV infection • smoking • having many children • long-term oral contraceptive use • HIV infection KL Vadheim Lecture 9

  8. 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 KL Vadheim Lecture 9

  9. 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 KL Vadheim Lecture 9

  10. Varicella zoster Vaccines KL Vadheim Lecture 9

  11. 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 KL Vadheim Lecture 9

  12. 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 • Bangladesh • China • India • Indonesia • Pakistan • The Philippines KL Vadheim Lecture 9

  13. TB Transmission • Airborne • No animal vector known KL Vadheim Lecture 9

  14. 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 KL Vadheim Lecture 9

  15. 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 KL Vadheim Lecture 9

  16. 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 KL Vadheim Lecture 9

  17. 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 KL Vadheim Lecture 9

  18. Malaria transmission • Single-celled parasite carried by Anopheles mosquito • Many animal hosts in addition to humans • Complex life cycle makes control difficult KL Vadheim Lecture 9

  19. 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) KL Vadheim Lecture 9

  20. Malaria Vaccine Development • PATH • Malaria Vaccine Initiative • GSK’s candidate vaccine ~50% efficacy against most lethal forms of disease KL Vadheim Lecture 9

  21. Specific Immune Globulins • Botulinum antitoxin • Botulism IGIV • Cytomegalovirus IG IV • Hepatitis B IGIV • Rabies IG (Human) • RSV IGIV (Human) • Tetanus IG (Human) KL Vadheim Lecture 9

  22. Non-specific IGIV • Immune Globulin (Human) • Immune Globulin IV (Human) • Immune Globulin Subcutaneous (Human) • can be self-administered KL Vadheim Lecture 9

  23. 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 KL Vadheim Lecture 9

  24. KL Vadheim Lecture 9

  25. Complaints • Call or write the manufacturer • Provide as much information as possible • Expect an investigation and written response KL Vadheim Lecture 9

  26. Recalls and Withdrawals • www.fda.gov/cber/recalls KL Vadheim Lecture 9

  27. 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 KL Vadheim Lecture 9

  28. 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) KL Vadheim Lecture 9

  29. Pharmacovigilence • All scientific and data gathering activities relating to the detection, assessment and understanding of AEs • Involves identification and evaluation of safety signals KL Vadheim Lecture 9

  30. 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 KL Vadheim Lecture 9

  31. 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 KL Vadheim Lecture 9

  32. 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 KL Vadheim Lecture 9

  33. 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 KL Vadheim Lecture 9

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