2jun06kl vadheim lecture 91 hpv, zoster, tb, etc. medch 401 lecture 9

2Jun06 KL Vadheim Lecture 9 1

HPV, Zoster, TB, Etc.

MedCh 401

Lecture 9

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 KL Vadheim Lecture 9 10

Varicella zoster VaccinesComponent, per dose Zostervax

0.65-ml doseVarivax0.5-ml dose

VZV 19,400 PFU 1,350 PFUSucrose 31.16 mg 25 mgHydrolyzed porcine gelatin 15.58 mg 12.5 mgNaCl 3.99 mg 3.2 mgMonosodium L-glutamate 0.62 mg 0.5 mgSodium Phosphate Dibasic 0.57 mg 0.45 mgPotassium Phosphate Monobasic 0.10 mg 0.08 mgKCl 0.10 mg 0.08 mg

Neomycin Trace TraceFetal calf serum Trace TraceSodium phosphate monobasic TraceEDTA TraceResidual MRC-5 cell components(DNA/protein)

Trace Trace

2Jun06 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

2Jun06 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

2Jun06 KL Vadheim Lecture 9 13

TB Transmission

• Airborne

• No animal vector known

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 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)

2Jun06 KL Vadheim Lecture 9 20

Malaria Vaccine Development

• PATH– Malaria Vaccine Initiative

• GSK’s candidate vaccine ~50% efficacy against most lethal forms of disease

2Jun06 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)

2Jun06 KL Vadheim Lecture 9 22

Non-specific IGIV

• Immune Globulin (Human)

• Immune Globulin IV (Human)

• Immune Globulin Subcutaneous (Human)– can be self-administered

2Jun06 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

2Jun06 KL Vadheim Lecture 9 24

Schedule Vaccine #Antigens

Total #antigens

HepB(10 g)

1(10 g)

DTaP(Up to 58 g + D + T)

Up to 7(>58 g)

Hib (7.5 – 10 g)Conjugate (24-125 g)

2(225 g)

IPV 3

2, 4, 6months

PCV(16g psacc)(20 g CRM197)

8(36 g)

21(>329 g)

HepB 1 (10 g)DTaP 7 (>58 g)Hib 2 (225 g)IPV 3MMR 3Varicella 1PCV 8 (36 g)Influenza 3 (45 g)

~15months

HepA 1

28(>374 g)

HepB 1 (10 g)

DTaP 5 (>58g)

IPV 3MMR 3

4-6 years

Varicella 1

13(>68 g)

2Jun06 KL Vadheim Lecture 9 25

Complaints

• Call or write the manufacturer

• Provide as much information as possible

• Expect an investigation and written response

2Jun06 KL Vadheim Lecture 9 26

Recalls and Withdrawals

• www.fda.gov/cber/recalls

2Jun06 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

2Jun06 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)

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 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

2Jun06 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