hpv and cervical cancer screening vietnam longer (eng)

Gardasil Study PopulationsPer Protocol Efficacy Best case scenario Maximum effectiveness General Population Impact How the vaccine would work in a real population including women already

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 ProgramsWhich 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 & 1833%: 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

Gardasil HPV Vaccine

FDA approved in June 2006Contains virus-like particles (not live virus)

3 shots: 0, 2 and 6 monthsBooster 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

Gardasil Efficacy* Studies

only)

General population

What about cervical lesions

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”

• It is unknown how much Gardasil will decrease total

precursor lesions (not just 16/18 lesions)

• Replacement of HPV 16/18 by other virus types is a

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

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

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 nạve; so vaccine can still be moderately

effective From the population impact study:

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% effectiveNot 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

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

For discussion:

How could the vaccine be administered

to adolescent girls before onset of sex?

Are there currently systems in place for seeing these girls or would new systems have to be created?

Do you anticipate any problems with acceptance of the vaccine because this

is a vaccine that prevents a sexually transmitted infection?

Is it worth it?

In the US, it might be worth it although cervical cancer screening alone has been very effective in reducing incidence and mortality

The main benefit in a well-screened population will be in decreasing pre-invasive lesions

What about in a population with less effective screening?

Part 2

Effectiveness of Cervical Cancer

Screening Programs

Cervical Cancer: Nat’l History

Pap smears are the most effective screening test ever invented This is not controversial.

The natural history of cervical cancer is understood and begins with a pre-invasive lesion (dysplasia) that is easily detectable and treatable.

well-Development of invasive cancer occurs in an orderly progression from low grade to high grade dysplasia to invasion This process takes about 10 years.

Pap smear screening: the

obtain the cells

• Read by cytologist: Negative, inflammatory changes, ASCUS, LSIL, HSIL

Work-up of positive test

If LSIL, HSIL

(sometimes ASCUS),

colposcopy done to

look for abnormal

areas on the cervix

If any seen, directed

complicationsThis treatment PREVENTS development

of cancer

Review of sensitivity, specificity,

positive predictive value

Sensitivity: of those with biopsy proven dysplasia, what percent are detected by pap smear

How good the pap smear is in finding disease.

Specificity: of those with no dysplasia, what percent have a normal pap smear

False positive is (1 – specificity) So if specificity

is 98%, 2% of pap smears are falsely positive The pap is abnormal but there is no dysplasia.

Review of sensitivity, specificity,

positive predictive value

Positive predictive value is more useful for clinicians

Positive predictive value: Percent of those with an abnormal pap smear who actually have biopsy proven dysplasia

So, if the PPV is 40% it means for every 100 women with an abnormal pap smear, 40 of these will have dysplasia and 60 will undergo colposcopy and be found not to have dsyplasia

Is the pap smear a good test?

It is far from perfect!

It is acceptable—about 90% of women in the US are screened

It is not very sensitive and specificity

range is wide

Sensitivity: about 80% (as low as 50%) Specificity: about 98% (as low as 78%)

Positive predictive value using 1.6%

prevalence: 43% (pretty good)

Pap smear characteristics

in Viet Nam

In Viet Nam, the prevalence of dysplasia

is higher than in the USThat means that the positive predictive value is much higher here than in the US

concurrent with pap smear screening programs

Many studies in other populations show similar decreases in incidence with

introduction of pap smear

Cervical Cancer in the US

Similar decreases seen in

Nordic countries

Why does pap smear work?

Sensitivity and specificity not so great

BUT Natural history is favorable (precursor exists

and is detectable and 100% treatable; time

course is long)

Thus, there are many opportunities to detect

dysplasia: even if one test is false negative, get another chance

It is cost-effective because many many years of life are saved because cancer is actually

prevented.

For discussion

How can the pap smear screening system be improved in Viet Nam?

Are the correct ages being screened?

Are enough women being screened?

Are colposcopy and treatment readily available for women with abnormal pap smears?

Pap smear vs liquid based

Instead of smearing the cells from the brush

on a slide, the brush is swirled in a bottle of fluid and the bottle is sent to pathologist

The pathologist makes a slide and reads it The fluid can be tested for HPV

Pap smear vs liquid based

Pap smear vs liquid based

cytology (thin-Prep)

For a screening program, especially in

an unscreened population, specificity is more important

Why? Decreased specificity = more false positives which are expensive to work-

up and provide no benefit Thus, no reason to use liquid based cytology

Which to choose: vaccine

or pap smear?

Pap smear screening proven in multiple populations throughout the world to decrease cervical cancer incidence by as much as 75% HPV vaccine has not been proven to decrease cervical cancer but has been proven to

decrease HPV 16/18 precursor lesions (although the actual efficacy for all precursor lesions is unknown)

Pap smear screening will bring benefits faster HPV vaccine will take decades to see benefit Unknown which will be more cost effective and easier to implement in an unscreened

population

For discussion

If Viet Nam needs to choose between

vaccine and Pap:

1. Which will be easier to implement:

vaccine or improved Pap screening?

2. Which will be more acceptable to

women and to physicians?

Thank you! Questions?

jacksonr@obgyn.ucsf.edu