1. 2Jun06KL Vadheim Lecture 91 HPV, Zoster, TB, Etc. MedCh 401 Lecture 9

2. 2Jun06KL Vadheim Lecture 92 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

3. 2Jun06KL Vadheim Lecture 93 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

4. 2Jun06KL Vadheim Lecture 94 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

5. 2Jun06KL Vadheim Lecture 95 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

6. 2Jun06KL Vadheim Lecture 96 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

7. 2Jun06KL Vadheim Lecture 97 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

8. 2Jun06KL Vadheim Lecture 98 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

9. 2Jun06KL Vadheim Lecture 99 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

10. 2Jun06KL Vadheim Lecture 910 Varicella zoster Vaccines

11. 2Jun06KL Vadheim Lecture 911 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

12. 2Jun06KL Vadheim Lecture 912 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

13. 2Jun06KL Vadheim Lecture 913 TB Transmission Airborne No animal vector known

14. 2Jun06KL Vadheim Lecture 914 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

15. 2Jun06KL Vadheim Lecture 915 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

16. 2Jun06KL Vadheim Lecture 916 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

17. 2Jun06KL Vadheim Lecture 917 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

18. 2Jun06KL Vadheim Lecture 918 Malaria transmission Single-celled parasite carried by Anopheles mosquito Many animal hosts in addition to humans Complex life cycle makes control difficult

19. 2Jun06KL Vadheim Lecture 919 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)

20. 2Jun06KL Vadheim Lecture 920 Malaria Vaccine Development PATH –Malaria Vaccine Initiative GSK’s candidate vaccine ~50% efficacy against most lethal forms of disease

21. 2Jun06KL Vadheim Lecture 921 Specific Immune Globulins Botulinum antitoxin Botulism IGIV Cytomegalovirus IG IV Hepatitis B IGIV Rabies IG (Human) RSV IGIV (Human) Tetanus IG (Human)

22. 2Jun06KL Vadheim Lecture 922 Non-specific IGIV Immune Globulin (Human) Immune Globulin IV (Human) Immune Globulin Subcutaneous (Human) –can be self-administered

23. 2Jun06KL Vadheim Lecture 923 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

24. 2Jun06KL Vadheim Lecture 924

25. 2Jun06KL Vadheim Lecture 925 Complaints Call or write the manufacturer Provide as much information as possible Expect an investigation and written response

26. 2Jun06KL Vadheim Lecture 926 Recalls and Withdrawals www.fda.gov/cber/recalls

27. 2Jun06KL Vadheim Lecture 927 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

28. 2Jun06KL Vadheim Lecture 928 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)

29. 2Jun06KL Vadheim Lecture 929 Pharmacovigilence All scientific and data gathering activities relating to the detection, assessment and understanding of AEs Involves identification and evaluation of safety signals

30. 2Jun06KL Vadheim Lecture 930 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

31. 2Jun06KL Vadheim Lecture 931 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

32. 2Jun06KL Vadheim Lecture 932 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

33. 2Jun06KL Vadheim Lecture 933 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