Transcript Human papillomaviruses

HPV and Infectious Disease
HHD 2015
Joel Palefsky, M.D.
Professor of Medicine
UCSF
Infectious Virus Particle of HPV1,2
Capsid proteins:
L1
L2
Viral DNA
Viral exterior
1. Baker TS, et al. Biophys J. 1991;60:1445–1456.
2. Chen XS, et al. Mol Cell. 2000;5:557–567.
Viral interior
Estimated Annual Burden of
HPV-Related Diagnoses in the United States
9,710 new cases of cervical cancer1
3,700 deaths
estimated
in 20061
330,000 new cases of high-grade
cervical dysplasia (CIN 2/3)2
1.4 million new cases of
low-grade cervical dysplasia
(CIN 1)2
1 million new cases
of genital warts3
1. American Cancer Society. Cancer Facts and Figures 2006. Atlanta, Ga: American Cancer Society; 2006:4.
2.
Schiffman M, Solomon D. Findings to date from the ASCUS-LSIL Triage Study (ALTS). Arch Pathol Lab Med.
2003;127:946–949. 3. Fleischer AB, Parrish CA, Glenn R, Feldman SR. Condylomata acuminata (genital warts): Patient
demographics and treating physicians. Sex Transm Dis. 2001;28:643–647.
Oncogenic HPV types

16, 18, 31, 33, 35

39, 45, 51, 52, 56, 58, 70
Non- oncogenic HPV types


HPV 6, 11- genital warts
HPV 1, 2 and 4- plantar and palmar warts
HPV Infection and Productive Life Cycle
Virus introduced
through microabrasion
Infectious virions shed
Virion assembly
Viral DNA replication
Late HPV protein
production
L1 & L2
Virus
infection
Early HPV protein
production
E1, E2, E4, E5, E6, & E7
Adapted from Doorbar J. J Clin Virol. 2005;32S:S7–S15.
E6 leads to degradation of p53
p53
E6-AP
X
Ubiquitin
E6
Ubiquitin
Binding of E7 to RB releases E2F
E2F
E7
RB
RB
E7
Cell Cycle
E2F
E1 and E2


E1 is responsible for coordinating the
division of the viral DNA with that of cell
division
E2 has many functions


Works with E1
Regulates expression of E6 and E7
E4 and E5

E4 is found in the cytoplasm, is
associated with the cell cytoskeleton


? Leads to collapse and ?effect on
infectivity?
E5 works with E6 and E7 to increase
malignant transformation

Leads to reduced turnover of EGF
receptors on cell surface
E5 and EGF
EGF
EGF
EGF
EGF
EGF
E5
EGF
EGF
EGF
EGF
EGF
EGF
EGF
EGF
2-tiered system: LSIL & HSIL
Reflects HPV biology and clinical management
Infection
Precancer
HPV infection
Low-grade CIN
High-grade CIN
Cervical cancer
Schiffman, MH. J Natl Cancer Inst. 1992; 84:394-98
HPV testing for screening
•
•
•
Cervical cytology has limited sensitivity
HPV testing is now approved for primary
cervical screening in women over age
25 years
Can increase the screening interval in
women who test negative
Risk factors for development
of HPV-associated lesions







Sexual activity
Younger age
Smoking
Other sexually transmitted diseases,
especially chlamydia trachomatis
Immune suppression
HPV strain variant
Genetic background
Incidence of oropharynx and
cervical cancers
Chaturvedi A et al. J Clin Oncol 2011; 29: 4294-4301
22
Incidence of HPV-positive and
HPV-negative oropharynx cancers
Chaturvedi A et al. J Clin Oncol 2011; 29: 4294-4301
23
Penile cancer

About 40% of cases are HPVrelated
•
Associated mortality of 41%2


Survival is 2 years without
treatment.3

Patients often seek treatment late.3
Treatment is associated with
substantial psychological and
sexual dysfunction4
Image used with permission from Alex Ferenczy, MD.
1. Hernandez BY et al. Cancer. 2008;113(suppl 10):2883–2891. 2. Rippentrop JM et al. Cancer. 2004;101:
1357–1363; 3. Misra S et al. Lancet Oncol. 2004;5:240–247. 4. Maddineni S et al. BMC Urology. 2009;9:8.
24
Anal and cervical cancer incidence
•
Cervical cancer prior to cervical cytology
screening: 40-50/100,000
•
Cervical cancer currently: 8/100,000
•
Anal cancer among HIV- MSM: up to
37/100,000
28
Anal cancer rates in North American
AIDS Cohort Collaboration on Research
and Design) (NA-ACCORD) 1996-2007
Incidence/100,000 (85% CI)
•HIV-infected
•
•
•
MSM
MSW
Women
131 (109-157)
46 (25-77)
30 (17-50)
Silverberg M et al. CID, e-pub Jan 2012
Prevalence of AIN among MSM
Prevalence, %
Population-based data
All participants
HIV-negative
participants
HIV-positive
participants
Chin-Hong et al. Ann Int Med. 2008;149;300-6.
30
Anal and cervical HPV infection
in HIV-positive women
90
80
70
60
50
40
30
20
10
0
Anal
Cervical
HIV-
HIV+ CD4 HIV+ CD4 HIV+ CD4
<200
200-500
>500
Palefsky JM et al. J Infect Dis. 2001;183:383-391.
San Francisco Giants
2010, 2012 and 2014 World
Series Champions
Treatment of
condyloma/warts


Expectant- many will resolve
spontaneously
Patient-applied therapies



Podophyllotoxin (Condylox™) gel applied 3
days on/4 days off
Imiquimod (Aldara ™) cream applied 3
times/week
Sinecatechin (Veregen™) cream applied 3
times daily until clearance
Treatment of
condyloma/warts

Clinician-applied therapies







Liquid nitrogen
80% trichloroacetic acid
Surgical excision
Laser
Thermocoagulation/infrared coagulation
Loop electrosurgical excision procedure (LEEP)
Intralesional interferon
Treatment of
low-grade lesions

Most clinicians would follow carefully
without treatment since many resolve
spontaneously
Treatment of cervical
high-grade lesions




Loop electroexcision procedure
Cryotherapy
Surgical cone biopsy
Laser
The nonavalent HPV vaccine
Schiller J. Lancet Oncol 2015;16(5):e217-25
Quadrivalent vaccine in males: efficacy against HPV
6/11/16/18-related external genital lesions (HM+MSM)1
Per-Protocol Efficacy Population
50
Related Cases
40
Quadrivalent vaccine
90.6%
Reduction
(70, 98)
Placebo
32
30
20
10
3
0
n=1,394 n=1,404
HPV 6-, 11-, 16-, or 18-Related
External Genital Lesions
1Giuliano
A, Palefsky J et al. NEJM 2011 Feb 3;364(5):401-11
42
Quadrivalent vaccine in males: efficacy against HPV
6/11/16/18-related AIN and anal cancer in MSM1
Per-Protocol Efficacy Population
50
Quadrivalent vaccine
Placebo
Related Cases
40
30
77.5%
Reduction
(40, 93)
24
20
10
5
0
n=194
n=208
HPV 6-, 11-, 16-, or 18-Related
AIN and Anal Cancer
n = number of subjects who have at least 1 follow-up visit after month 7.
1Palefsky
J, Giuliano et al. NEJM 2011, 365: 1576-85
44
The nonavalent HPV vaccine
MMWR / March 27, 2015 / Vol. 64 / No. 11
ACIP recommendations
for HPV vaccine in women
•
9vHPV, 4vHPV or 2vHPV can be used for:
•
•
•
routine vaccination of females aged 11 or 12
females through age 26 years who have not been
vaccinated previously or who have not completed
the 3-dose series
If providers do not know or do not have available
the HPV vaccine product previously administered,
or are in settings transitioning to 9vHPV, any
available HPV vaccine product may be used to
continue or complete the series for females for
protection against HPV 16 and 18
HPV vaccination of men


Vaccine approved for routine use in boys and
men age 9-21 years to prevent HPV 6/11related genital warts and anal HPV infection,
AIN and anal cancer due to vaccine types
Approved for routine use in MSM and HIV+
men age 22-26 years
s
Ali et al, BMJ 2013
HPV prevalence in the pre- and
post-HPV vaccination eras
Markowitz L et al. JID 2013; 208: 383-93
Conclusions



Vaccines are effective to prevent cervical and
vulvovaginal HPV infection and associated disease
due to vaccine types
Vaccine prevents anal HPV infection and AIN in boys
and men due to the types most commonly found in
anal cancer
Secondary prevention for those already infected with
HPV
The future


Implementation of vaccine in developing
countries
Two-dose vs. three dose
International research program
Joel Palefsky, M.D., Program director
www.ddcf.org
[email protected]
415-476-1574