Download SUPPLEMENTAL DIGITAL CONTENT 2

SUPPLEMENTAL DIGITAL CONTENT 2. ASSUMPTIONS ON THE NATURAL HISTORY
OF HPV INFECTION AND PERFORMANCE OF SCREENING TESTS
1. All cases of cervical cancer arise from a HR-HPV infection; all women targeted to be
detected by screening (CIN2) are HR-HPV positive.
2. The incidence of new HPV infections varies with age. The peak rate is at 20 years of
age, it declines until the age of 35 and it gradually increases thereafter until the age
of 50, reaching finally a nadir at about 65 years (1). Therefore, for each initial (i.e. at
22 years of age) incidence, we followed the time-dependent tendencies as described
above.
3. The likelihood of a HR-HPV positive woman with an initially negative Pap test to clear
the infection in one year is estimated at 40% for HPV16, 60% for HPV18 and 50% for
non-16 or -18 HR-HPV types (2, 3). For the transition tree we accepted a likelihood of
50% for both groups (i.e. 16/18 and other HR). Although clearance rates vary with
age, the variation is not expected to be significant in the young age range we study.
4. In persisting infection, the risk of progression to CIN2 in one year was extrapolated
from Berkhof et al. (4), accepting that the incidence of HPV16-, HPV18- and other HR
HPV type-related development of CIN2 within the first 12 months represents 66%,
66% and 100% of its 18-months cumulative incidence respectively (5). Therefore, the
calculated 1-year incidence of CIN2 was 8.2% for HPV16/18 and 2.6% for the rest
HR types.
5. In persisting infection, the risk of progression to CIN3/Ca in one year (first year
following infection) for women <30 years old is 6.2% for patients with HPV 16, 1% for
women with HPV18 and 0.8% for other high-risk types included in HC2. (6). Given
that the rate of incident HPV16:18 infection is approximately 2:1, we used an overall
figure of 4.4% in the matrix for HPV16/18. For women 30 years old, the
corresponding figures are 6.0% for HPV16/18 and 0.8% for other HR types (6).
6. The risk of progression of CIN2 depends on the underlying HPV type; CIN2 cases
with an underlying HPV16 infection are greatest risk, followed by HPV16-related
types, whereas non-HPV16-related high risk types only carry minimal risk (7)
Historical data from untreated cases show that progression of CIN2 to CIN3 appears
to follow a logarithmic pattern, and the likelihood of progression within a year is
approximately 10% (8). Given that HPV16/18 infection underlies about 60% of CIN2
lesions in the same geographical region (9, 10), the calculated 1-year risk for
progression is 12.5% for HPV16/18 –related CIN2 and 6.2% for other HRHPV types –
related CIN2.
7. Regression of CIN2 appears to follow a polynomial (quadratic) pattern and the
likelihood of true regression (one negative smear, adjusted for 80% sensitivity of
cytology) within a year is approximately 10% (8). Similarly to progression, regression
rates of CIN2 depend on the underlying type of HPV. Given that HSIL lesions caused
by other HR types than 16/18 are twice as likely to regress than HPV16-related
lesions (11), the regression rate within a year is calculated as 7.1% for CIN2 related
to HPV 16/18 and 14.2% for lesions related to other HR types.
8. In order to simplify the model, we accepted CIN3+ as an endpoint, omitting the
potential regression of CIN3 lesions and accepting it as a unified category together
with carcinoma an situ and invasive cancer. This is based on the consensus that all
lesions CIN3 should be treated. We have also dismissed the state of CIN1 because
of its little clinical relevance. Finally, we pooled HPV16 and HPV18, despite their
differing natural histories, as the implementation of prophylactic vaccination is
expected to affect both in the same way.
9. We accepted 96% sensitivity of HPV DNA testing for diagnosing CIN2+ (12). Using
LSIL as a cutoff, Pap test has a sensitivity of 81.0% for diagnosing CIN2+, for a
23.0% false-positive rate (FPR) (calculations for studies with minimal verification
bias) (13). The sensitivity of diagnostic colposcopy for distinguishing normal from
abnormal (all grades) epithelium is 96% (for an FPR of 52%). Setting the cutoff at
HSIL decreases the sensitivity to 85% and the FPR to 31% (14). The sensitivity of
combined cytologic and colposcopic screening may reach 95% (15-17) for a false
positive rate (any test) of 35% (expert opinion).
Table of transition rates and test performance estimators
Transition
Rate / year
References
Well to HPV16/18
Variable initial rate (modelling), changing with age
(1)
Well to Other HR
Variable initial rate (modelling), changing with age
(1)
HPV16/18 to Well
50.0%
(2, 3)
HPV16/18 to 16/18CIN2
8.2%
(4, 5)
HPV16/18 to CIN3+
4.4% (women <30), 6.0% (women 30)
(6)
16/18CIN2 to CIN3+
12.5%
(7, 8)
16/18CIN2 to HPV16/18
7.1%
(8, 11)
Other HR to Well
50.0%
(2, 3)
Other HR to other HR
2.6%
(4, 5)
Other HR to CIN3+
0.8%
(6)
OtherHR CIN2 to CIN3+
6.2%
(7, 8)
Other HR CIN2 to other
14.2%
(8, 11)
CIN2
HR HPV
Test / target
Sensitivity / False positive rate
HPV test / HPV infection
96% / 0%
(12)
Cytology / CIN2+
81% / 23%
(13)
Colposcopy /CIN2+
85% / 31%
(14)
Combined cytology +
95% / 35%
(15-17)
colposcopy
References
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