hpv and cervical cancer screening vietnam longer (eng)

HPV Vaccine and Cervical
Cancer Screening
Rebecca Jackson, MD
Associate Professor
Obstetrics, Gynecology & Reproductive Sciences and
Epidemiology & Biostatistics
San Francisco General Hospital

Preview

Effectiveness of HPV vaccine (in the US)

Effectiveness of Cervical Cancer
Screening Programs

Which to choose?

Part 1
Effectiveness of HPV vaccine in
screened populations

HPV and Cervical Cancer

Cervical cancer is due to persistent high
risk HPV infection

67%: HPV types 16 & 18

33%: other high risk HPV types
(30s, 40s, 50s)


Infections are sexually acquired in
teens, twenties

Most HPV infections are transient

Genital warts: caused by HPV 6 & 11

HPV Vaccine

Logic for vaccine

Once HPV infection cleared, immune
to HPV type

16 & 18 antigen: prevent cervical
cancer

6 & 11 antigen: prevent genital
warts

Merck Gardasil quadravalent vaccine
active against HPV 6,11,16,18.

Gardasil HPV Vaccine

FDA approved in June 2006

Contains virus-like particles
(not live virus)


3 shots: 0, 2 and 6 months

Booster shot?: high titers for 5
years of study, but no longer
term data so don’t know if need
booster shot.

Gardasil Study Populations
Per Protocol Efficacy

HPV seronegative at entry

HPV DNA (PCR) negative
during vaccination phase

All 3 injections completed

No protocol violation

Case counting 1 month
after dose 3
General Population Impact

Seropositive or
seronegative on day 1

73% negative for all 4
types


20% positive for 1 type

<1% positive for all 4
types

Any PCR + during
vaccination phase

Any Pap>ASC-US on day 1

Protocol violators

Gardasil Study Populations
Per Protocol Efficacy

Best case scenario

Maximum effectiveness
General Population
Impact

How the vaccine would
work in a real population
including women already
sexually active (some HPV
positive)

Minimum effectiveness

Terminology of abnormal

cervical lesions
Main outcomes of study were:
1. Decrease in advanced (high-grade)
cervical lesions due to HPV 16/18.

Called “CIN 2/3 and AIS”
2. Decrease in high and low grade cervical
lesions due to HPV 16/18

Called “CIN 1/2/3 and AIS”
3. Decrease in warts due to HPV 16/18

Gardasil Efficacy* Studies
Vaccinated vs. Placebo
Efficacy against
lesions at 3-4 years
Per Protocol Efficacy
(virus naïve only)
CIN 2/3 + AIS* 100% (93-100%)
CIN 1/2/3 + AIS* 95.2% (87-99%)
Genital Warts 98.9% (94-100%)
*Only lesions due to vaccine HPV types; does not
*Only lesions due to vaccine HPV types; does not
include disease due to nonvaccine HPV types
include disease due to nonvaccine HPV types

Gardasil Efficacy* Studies
Vaccinated vs. Placebo
Efficacy against
lesions at 3-4

years
Per Protocol
(virus naïve
only)
General
population
CIN 2/3 + AIS* 100% 39.0%
CIN 1/2/3 + AIS* 95.2% 46.4%
Genital Warts* 98.9% 68.5%
*Only lesions due to vaccine HPV types; does not include
*Only lesions due to vaccine HPV types; does not include
disease due to nonvaccine HPV types
disease due to nonvaccine HPV types

What about cervical lesions
not due to 16/18?

Vaccine only active against 16/18 but 20
other HPV types also cause cancer.

What if suppressing HPV 16 and 18
allows these other viruses to multiply?
(This is called replacement).

So, what we really want to know is the
total number of dysplasia lesions in
placebo compared to vaccine

How Effective is Gardasil?
Reduction in CIN 2/3 +

AIS
HPV 16/18
lesions
All HPV type
lesions
Per Protocol Efficacy
“Best case”
100% Unpublished
General Population
Impact*
“Typical case”
39% 12%
•


It is unknown how much Gardasil will decrease total
It is unknown how much Gardasil will decrease total
precursor lesions (not just 16/18 lesions).
precursor lesions (not just 16/18 lesions).
•


Replacement of HPV 16/18 by other virus types is a
Replacement of HPV 16/18 by other virus types is a
theoretic possibility that would decrease overall efficacy
theoretic possibility that would decrease overall efficacy

Impact of Gardasil
®

in the General Population

Gardasil is a prophylactic vaccine

There was no clear evidence of protection
from disease caused by HPV types for
which subjects were PCR positive and/or
seropositive at baseline

Individuals who were already infected with
1 or more vaccine-related HPV types prior
to vaccination were less likely to develop
clinical disease caused by the remaining
vaccine HPV types

Is it safe?
Injection site (1-5 days postvaccination)
Gardasil
(N=5,088)
Placebo: Al
(N=3,470)
Placebo:
NaCl (N=320)
Pain 83.9% 75.4% 48.6%
Swelling 25.4% 15.8% 7.3%
Erythema 24.6% 18.4% 12.1%
Pruritus 3.1% 2.8% 0.6%
Systemic adverse event (1-15 days postvaccination)
Gardasil (N=5,088) PBO (N=3,790)
Fever 10.3% 8.6%

•
Few subjects (0.1%) discontinued due to adverse experiences.

Benefits of Quad HPV
Vaccine

Decrease cervical cancer cases and death rates

Reduce hysterectomies, radiation
treatment, infertility

Reduce loss of productive years of life

Decrease cases of external genital warts

Less physical discomfort, stigmatization,
cost

Decrease need for colposcopy, treatment of SIL

Fewer false positive Paps

Less detection and treatment of
pseudodisease (non-progressive high
grade CIN)

Decrease Cervical Cancer
Rates

2006 US rates of cervical cancer


Incident cases per year: 9,710

Deaths: 3,700

HPV vaccine will not prevent all of these cases

Some US women will choose not to be vaccinated

Many immigrant women will not be vaccinated

Some develop cervical cancer even if vaccinated

Conclusions

Optimistic: “Vaccine saves women’s lives”

Pessimistic: “Vaccine is unnecessary
because cervical cancer has already been
successfully controlled in the US”

Decrease External Genital
Warts

Prevalence: 1% reproductive aged women

US Incidence: 0.4% (1 case /250 persons/
year)

Burden of illness


Many asymptomatic cases; no treatment needed

Can be cosmetically ugly; anxiety-provoking;
Rare case requires surgery

Do we really need a vaccine to prevent a
cosmetic condition?

In the US, the answer is probably no.

What about in Viet Nam—how much of a
problem are warts here in Viet Nam.

Reduce (Unnecessary) Evaluation
and Treatment

False positive Pap smears

ASC-US: 3-10% have CIN 2/3+

LSIL: 10-20% have CIN 2/3+

Vaccine expected to sharply reduce transient
high risk HPV infections that cause abnormal
Paps

But, the false positives do not become cancer

Conclusions


Vaccine prevents invasive diagnostic
evaluation and treatment. This only
applys in a screened population like the
US.

Ideal Target Group

WHO

11-12 year old girls

Virginal women up to 26 years old

WHY

Immunization before sexual
exposure to HPV

Before the onset of squamous
metaplasia

More robust immune response
than later on

If vaccine has limited durability,
will cover the most vulnerable
time for HPV infection

For discussion:


In Viet Nam, what would be the ideal
age for vaccination?

Assumptions:

Most effective prior to start of sexual
activity

Need to give it no more than 5-7 years
before onset of sex because we don’t
know how long it remains effective

Efficacy in women already
exposed to HPV?

Vaccine will not affect progress of an
already acquired HPV infection (it is
prophylactic, not therapeutic)

But, if < 26 years and < 4 sexual
partners, 73% are virus naïve; so
vaccine can still be moderately
effective

From the population impact study:

39% HPV 16/18 CIN 2▼
+


12% all HPV type CIN 2▼
+

HPV Vaccine can’t replace
screening (in the US)

1/3 of cervical cancers due to HPV types
other than 16 and 18

Vaccine is not 100% effective

Not all will receive it

Unclear if replacement of HPV 16/18 by
other virus types will occur thus
decreasing the benefit of the vaccine

Vaccine Cost?

One of the most expensive vaccines ever

US $360 for 3 courses (does not include
administration fees)

In the US, cost effectiveness analyses show it
can be cost effective in conjunction with
reduced screening.

Unclear cost/benefit in countries without

effective screening programs in place.

The benefits of HPV vaccine are decades away
due to natural history of the disease and due
to time required to implement a vaccination
program.

Barriers to HPV immunization
in developing countries

Takes an average of 10-20 years to bring new
vaccine to developing countries (mostly due to
high cost)

Can’t use existing vaccine systems because
this is a different age group than targeted by
existing vaccine programs

Cultural barriers occur because it is only for
girls/women and is for a sexually transmitted
infection

Competition with other new childhood vaccines
which have more immediate results