1. health and fitness
2. disease
3. cancer

Rate of Human Papillomavirus Clearance After
Treatment of Cervical Intraepithelial Neoplasia
Kristina Elfgren, MD, Marcel Jacobs, MD, Jan M. M. Walboomers, PhD,†
Chris J. L. M. Meijer, MD, PhD, and Joakim Dillner, MD, PhD
OBJECTIVE: To investigate the rate of clearance of human
papillomavirus (HPV) infection after surgical treatment
for cervical intraepithelial neoplasia (CIN).
METHODS: One hundred nine women with CIN I–III,
treated with cryosurgery or conization at a university hospital, were observed with cervical HPV deoxyribonucleic
acid (DNA) testing by general primer polymerase chain
reaction and HPV typing at 0, 3, 6, 9, 12, and 24 months
after treatment. Penile HPV DNA was analyzed from
current sexual partners.
RESULTS: Eighty-one percent of evaluable women were
HPV DNA positive at treatment or enrollment. One year
later, seven women (9%) remained positive for the same
HPV type. Most women had cleared the HPV infection
diagnosed at treatment within 3 months. The cryotherapy
group had lower CIN grades, was younger, and had a
slower HPV clearance rate (P < .002). Only four couples
had HPV DNA of the same type detected.
CONCLUSION: Surgical treatment of CIN usually results in
clearance of HPV infection within 3 months. Human papillomavirus DNA testing may be useful as a rapid intermediate end point for monitoring the efficacy of treatments.
(Obstet Gynecol 2002;100:965–71. © 2002 by The American College of Obstetricians and Gynecologists.)
Cervical cancer is the third most common cancer among
women worldwide, with approximately 370,000 cases a
year and 190,000 deaths.1,2 Organized cytologic screenFrom the Department of Obstetrics and Gynecology, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Pathology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands; Department of
Medical Virology, Malmo¨ University Hospital, Malmo¨, Sweden; and School of
Public Health, University of Tampere, Tampere, Finland.
The authors thank Assistant Professor Peter Lidbrink, Department of Dermatovenereology, Huddinge University Hospital, for invaluable help with examining the
male partners; Dr. Ilvars Silins for the statistical analyses; and Ms. Carina Eklund
for excellent technical assistance.
This study was supported by Europe Against Cancer, the Swedish Cancer Society,
the Swedish Society for Medical Research, and Anders Otto Swa¨rd Foundation for
Medical Research. The Swedish Medical Research Council supports JD.
†
JMMW died February 1, 2000.
ing protects against cervical cancer, but there has been a
recent increase of cervical cancer also in a thoroughly
screened population.3 Screening programs today identify women with abnormal cytology for further examination by colposcopy and cervical biopsy and eventually
surgical removal of a histologically verified cervical intraepithelial neoplasia (CIN), the precursor to cervical
cancer. Follow-up after treatment has so far consisted of
repeat cytology and, possibly, colposcopy.
Infection with human papillomavirus (HPV) is established as a prerequisite for the development and maintenance of the vast majority of cervical cancers and
CINs.4 –7 We previously reported that HPV DNA is
usually no longer present 2 years after effective treatment for CIN,8 suggesting that strategies for follow-up
after treatment of CIN based on monitoring the clearance of the major risk factor for CIN (ie, HPV) might be
feasible. To expand on these findings, we observed a
larger group of patients with more frequent HPV DNA
testing after treatment and determined the time course of
HPV clearance and the determinants of HPV persistence after treatment, including examination of the current sexual partners.
MATERIALS AND METHODS
The institutional review board of Huddinge Hospital
approved the study (decision no. 126/95).
For maximum generalizability, all women admitted to
the Department of Gynecology and Obstetrics, Huddinge University Hospital, Stockholm, Sweden, for treatment of CIN I–III (66 women with CIN III, 21 with CIN
II, and 22 with CIN I) from September 1995 to September 1997 and giving informed consent were eligible to be
enrolled. There was no HIV screening. The CIN diagnosis was based on diagnostic biopsy from the cervix and
also, in most cases, endocervical curettage. The lag between the diagnostic biopsy taken at the gynecology
outpatient clinics in the catchment area (southern Stockholm County) and treatment at the hospital was on
average about 2.5 months. The diagnostic biopsies had
VOL. 100, NO. 5, PART 1, NOVEMBER 2002
© 2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.
0029-7844/02/$22.00
PII S0029-7844(02)02280-9
965
been taken because of an abnormal Papanicolaou smear,
taken in either organized or opportunistic screening.
At the time of the study, the main features of the
established regional guidelines for choice of treatment of
CIN were that CIN I and II should be treated by cryotherapy and CIN III by conization.
Seventy-one women (mean age 35 years, range 21–71)
were treated with conization (66 had CIN III and five
had CIN II), and 38 women (mean age 30 years, range
20 –55) were treated with cryotherapy (22 had CIN I and
16 had CIN II).
Of the 109 women, 100 were white, three from the
Middle East, three Latin American, and three Asian.
One woman had immunosuppressive treatment because
of a renal transplant. Two women became pregnant at
the beginning of the study, but continued to participate.
Three women were pregnant at the last visit.
All women were examined by the same gynecologist
(KE) immediately before surgical treatment. A cervical
brush sample (Cytobrush; Medscand, Malmo¨, Sweden)
was collected from the endo- and ectocervices. The
brush was put in a plastic tube with 1 mL of phosphatebuffered saline solution containing a 5-mmol/L ethylenediaminetetra-acetic acid buffer, immediately frozen at
⫺20C, and later transferred to ⫺70C storage for future
analysis side by side with the cervical samples taken at
the follow-up visits.
The conization was performed as an electrosurgical
excision with microneedle diathermy on all 71 women.
Cryotherapy was performed using nitrous oxide as the
refrigerant. The cryosurgical probe was applied to the
cervix and a procedure of 2 ⫻ 3–minute freeze with
thawing in between was carried out.
Follow-up visits were scheduled at 3, 6, 9, 12, and 24
months after treatment. The actual mean times for the
follow-up visits were 3 months and 8 days, 6 months and
8 days, 9 months and 9 days, 13 months and 1 day, and
24 months. Of the initial 109 enrolled patients, 91%
attended the 3-month visit. Three women could not be
sampled because they had had a hysterectomy, because
of the CIN lesion. The attendance rates of the originally
enrolled 109 women were 84.5% at 6 months, 84% at 9
months, and 85% at 12 months. On March 1, 1998,
when the study was closed, only 46 patients had been
observed for 24 months after treatment and were eligible
for invitation. Seventy-three percent of these invited
women attended. The mean length of follow-up for the
eligible women was 15.7 months.
At all follow-up visits, the women were examined by
the same gynecologist (blinded to the HPV DNA status)
who examined them at baseline. Cervical brush sampling was conducted in the same way as at the baseline
visit, before a Papanicolaou smear, colposcopy, and, if
966
Elfgren et al
Rate of HPV Clearance
necessary (ie, in case of colposcopic or cytologic signs of
CIN), a punch biopsy was performed. Altogether 407
follow-up visits were conducted, and at 34 of these visits
(8%) a punch biopsy was taken. Four of these resulted in
a new treatment before the study closed, two conizations
(CIN II, atypical squamous cells of undetermined significance [ASCUS] plus immunosuppression), one cryotherapy (CIN I), and one reconization (CIN II).
At each follow-up visit, all women were asked about
new sexual partners since the previous consultation.
Among the 72 women subjected to conization, there
were 18 changes of male sexual partners (25%). Among
the 38 women in the cryotherapy group, 12 new male
sexual partners (32%) were reported during the follow-up period.
All sexual partners of the women at inclusion and
during follow-up were invited for a single examination
including sampling of HPV DNA by rotating a cytobrush over the glans penis and sulcus coronarius, after
which the same brush was inserted into the urethral
orifice. The brush was thereafter handled in the same
manner as the cervical brushes. Forty-eight (51%) of the
95 reported male partners of the 109 women attended.
Thirty were partners of women treated with conization,
and 18 were partners of women undergoing cryosurgery. Samples from 39 men were ␤-globin positive. The
men were examined after treatment of their female partner. None of the CIN case women reported female
sexual partners in the study.
After the study was closed, all cervical samples from
baseline and follow-up visits were thawed and the tube
was vortexed to dispense mucus and cells from the
brush. The brush was then removed from the tube in a
sterile manner while the remaining mucus and cells on
the brush were pressed towards the edge of the tube.
After vortexing, 350 ␮L of the sample was transferred to
a new tube, frozen, and analyzed for HPV DNA. The
analyzing laboratory was blinded to the identity of the
samples, but an analysis order list ensuring that samples
from the same women were analyzed side by side was
provided.
The brush containing HPV DNA from the male partner was treated in the same manner and analyzed side by
side with the samples from the female patients.
Testing for HPV was performed using an HPV general primer GP5⫹/6⫹-mediated polymerase chain reaction (PCR)– enzyme immunoassay method. The PCR
amplification products were individually probed with
oligonucleotide probes for HPV typing of 14 high-risk(HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68)
and six low-risk (HPV 6, 11, 40, 42, 43, 44) HPV types.
Three times the mean optical density value of the PCRnegative controls was used as a cutoff point. This value
OBSTETRICS & GYNECOLOGY
Table 1. Cervical HPV Infections Before Treatment
Conization*
HPV DNA
Total (n)
6
16
18
31
33
35
39
42
45
51
56
58
66
X
Double infections§
Negative
Not testable㛳
Sum
1
43
3
4
1
3
1
2
1
1
1
1
1
3‡
18
20
5
109
†
No CIN
2
CIN I
3
CIN II
3
1
CIN III
27
1
2
1
3
Microinvasive
cancer
1
4
1
8
2
5
8
1
5
1
2
CIN II
2
1
1
1
1
3
5
3
47
CIN I
1
1
1
1
3
Cryotherapy
1
2
1
1
6
3
23
1
7
3
1
15
* For women treated with conization the histopathologic diagnosis refers to the diagnosis of the cone specimen, whereas for women treated with
cryotherapy the histopathologic diagnosis of the diagnostic biopsy that was taken before referral for treatment is given.
†
The diagnostic biopsy taken before referral for conization showed CIN III or cancer in situ in seven cases and CIN II in the case that contained
HPV 45.
‡
One histopathologic diagnosis of the cone specimen was missing. The diagnostic biopsy before referral showed cancer in situ.
§
The double infections were 16 ⫹ 18 (n ⫽ 6); 18 ⫹ 31 (n ⫽ 2); 31 ⫹ 42 (n ⫽ 2); and 16 ⫹ 31, 16 ⫹ 42, 18 ⫹ 35, 18 ⫹ 42, 31 ⫹ 35, 31 ⫹ 39,
and 56 ⫹ 66, 66 ⫹ 42 (one woman each).
㛳
␤-globin–negative results.
HPV ⫽ human papillomavirus; DNA ⫽ deoxyribonucleic acid; CIN ⫽ cervical intraepithelial neoplasia.
revealed a 100% agreement between enzyme immunoassay results and results from the radioactive method.
Testing for ␤-globin ensured that adequate samples containing intact human DNA had been taken. The method
used is described in detail elsewhere.9 There is also high
interlaboratory agreement of the method (␬ ⫽ 0.88 –
1.0).10
Survival analysis with the Cox-Mantel test analyzed
the clearance rate after treatment.11 Losses to follow-up
and hysterectomies were treated as censored observations.
We defined women as having cleared their HPV
infection if the type of HPV infection at the baseline visit
could not be detected at follow-up. For women positive
for multiple HPV types at baseline, clearance from all
HPV types was required.
RESULTS
One hundred nine women (mean age 32.5 years, range
20 –71) were enrolled in the study. These women were
sampled before treatment of CIN, and 104 women had
an adequate ␤-globin–positive sample. Twenty of 104
women (19%) were negative for HPV DNA. Six of these
VOL. 100, NO. 5, PART 1, NOVEMBER 2002
women became HPV positive in at least one visit during
follow-up.
Among the 84 women with positive HPV DNA tests,
18 double infections were detected, giving a total of 102
cervical infections. Human papillomaviruses 16, 18, and
31 were by far the most common types (Table 1). Four of
the initially HPV DNA–positive women could not be
observed, three because of hysterectomy and one because of a ␤-globin–negative sample at follow-up. Of the
80 HPV-positive women who could be followed up, 49
had had conization and 31 had had cryotherapy.
Among the women treated with conization, only six
remained positive with an HPV DNA type present before therapy at 3 months after treatment. Two women
remained continuously positive during the first year of
follow-up visits. Both of these women had HPV 16
(Figure 1 and Table 2) and involved margins in the cone
specimen.
Fifteen of the 31 women who were treated with cryosurgery had an HPV DNA type at the 3-month follow-up
visit that had also been present before treatment. The
rates of persistence declined gradually during follow-up,
but at the follow-up visit at 12 months five patients were
still persistently HPV positive (Figure 1), four of them
Elfgren et al
Rate of HPV Clearance
967
Figure 1. Time course of type-specific persistence of cervical human papillomavirus (HPV) deoxyribonucleic acid after
treatment of cervical intraepithelial neoplasia. Clearance was slower in the cryotherapy group (P ⬍ .002, Cox-Mantel test).
Elfgren. Rate of HPV Clearance. Obstet Gynecol 2002.
having CIN I in cytology during follow-up (Figure 1 and
Table 2).
By survival analysis the clearance rate was significantly slower in the cryotherapy group (P ⬍ .002) (Figure 1).
Presence of multiple infections was common among
cryotherapy-treated women, both before treatment and
during the follow-up (Tables 1 and 2).
Only four couples had HPV DNA of the same HPV
type detected (three couples with HPV 16 and one
couple with HPV 6). Two women in these couples were
persistently HPV DNA positive with the same type (6 or
16) at all follow-up visits, whereas the other two women
did show clearance at follow-up (odds ratio for HPV
persistence in case of detection of the same HPV DNA
type in the partner ⫽ 10.8 [95% confidence interval 0.55,
164.3]).
During the 2 years of follow-up, all together 17
women (16% of 104) had abnormal cytology at least
once. Seven women treated with conization had cytological CIN I or II in a total of 15 smears. Six of these women
had a positive HPV test and a positive cytology concurrently at least once. Two of them had the same HPV
968
Elfgren et al
Rate of HPV Clearance
type as before treatment, and three women had positive
margins in the cone specimen. Three women had CIN II
(two with a new HPV type and one with persistence).
Ten women from the cryotherapy group had cytologic CIN I, CIN II, or ASCUS in at least one smear of a
total of 21 smears. Eight of these ten women were HPV
positive concurrently with the abnormal smear, four of
them with the same HPV type as before treatment.
DISCUSSION
The objective of the present study was not to investigate
whether HPV infection causes CIN III, as this is already
well known, but to investigate whether HPV can be
cleared after treatment and at what rate. Clearance of
HPV DNA was rapid and usually occurred within 3
months after treatment. Our mean length of follow-up
was only 16 months, but there were few additional
clearances occurring after 6 months. HPV DNA clearance was primarily found in the conization group, suggesting that this type of treatment in this group of women
had indeed resulted in clearance of HPV infection. However, it should be stressed that the purpose of the present
OBSTETRICS & GYNECOLOGY
Table 2. Time Course of HPV DNA Persistence and Concurrent CIN
Persistence
Women with
persistent
HPV*
Percentage of
initially HPV
DNA–positive
women attending
At 3 mo
At 6 mo
At 9 mo
At 12 mo
At 24 mo†
6/47 (13%)
3/41 (7%)
2/45 (4%)
2/39 (5%)
1/12 (8%)
96 (47/49)
84 (41/49)
92 (45/49)
80 (39/49)
63 (12/19)
At 3 mo
15/28 (54%)
90 (28/31)
At 6 mo
10/28 (36%)
90 (28/31)
At 9 mo
7/24 (29%)
77 (24/31)
At 12 mo
5/21 (24%)
68 (21/31)
At 24 mo†
0/7
60 (7/12)
No. of women
with CIN/persistently
HPV positive
HPV types detected
After conization
16 (n ⫽ 2), 31, 45, X, 16 ⫹ 31
16 (n ⫽ 3)
16 (n ⫽ 2)
16 (n ⫽ 2)
16
After cryotherapy
X, 6, 16 (n ⫽ 5), 18, 16 ⫹ 18, 18 ⫹
35, 18 ⫹ 42, 31, 42, 66, 31 ⫹ 42‡
X, 6, 16 (n ⫽ 2), 18 (n ⫽ 2), 16 ⫹ 18,
16 ⫹ 18, 66, 31 ⫹ 42‡
6, 16 (n ⫽ 2), 18 (n ⫽ 2), 16 ⫹ 18, 31
⫹ 42‡
6, 16 ⫹ 18, 18 (n ⫽ 2), 31 ⫹ 42‡
1/6 (CIN I: HPV 16 ⫹ 31)
0
1/2 (CIN II: HPV 16)
1/2 (CIN I: HPV 16)
0
3/15 (CIN I [n ⫽ 3]: HPV X,
HPV6, HPV 66)
3/10 (CIN II: HPV X; CIN I
[n ⫽ 2]: HPV 66, HPV 31
⫹ 42‡)
2/7 (CIN I: HPV 6; ASCUS:
HPV 31 ⫹ 42‡)
2/5 (CIN I: HPV 6; ASCUS:
HPV 31 ⫹ 42‡)
ASCUS ⫽ atypical squamous cells of undetermined significance. Other abbreviations as in Table 1.
* In the conization group 49 of 63 women and in the cryotherapy group 31 of 37 women were HPV DNA positive before treatment.
†
Only 19 HPV DNA–positive women in the conization group and 12 HPV DNA–positive women in the cryotherapy group had completed 24
months of follow-up when the study was closed.
‡
Immunosuppression because of a renal transplant.
study was not to compare treatments per se, but to
describe the rates of HPV clearance in different treatment groups, which is essential for planning of when to
take follow-up samples. Studies comparing different
treatments should be based on randomized allocation of
treatment.
In recent years, several studies have confirmed our
finding that after successful CIN III treatment HPV
DNA is no longer detectable even by highly sensitive
PCR methodology. In our original study of 23 patients
with HPV-positive CIN III,8 only one woman was still
positive for the same HPV type 2 years after treatment.
Similar results were published by Kjellberg et al,12 who
found only three women HPV DNA positive 3 years
after laser conization of 82 initially HPV DNA–positive
women with CIN I–III. All three women had a new HPV
type. In two studies by Bollen et al,13,14 88 –90% of
women treated for CIN had cleared their initial HPV
infection at follow-up 1 year after treatment. Strand et
al15 also found that 27 of 30 women treated for CIN I–III
were negative for HPV DNA at follow-up 6 –12 months
after treatment. Kanamori et al16 found that two of 27
HPV DNA–positive women treated with conization
were HPV DNA positive after conization. Nagai et al17
reported an HPV DNA persistence after conization for
HPV DNA–positive CIN III of 19.6%, and the recurrence of CIN in this group of patients to 46%. None of
the patients with negative HPV DNA tests after treat-
VOL. 100, NO. 5, PART 1, NOVEMBER 2002
ment had recurrence of CIN. Chua and Hjerpe18 analyzed the presence of HPV DNA in normal Papanicolaou smears taken after treatment of CIN and found
HPV DNA in 25 of 26 women who later developed
recurrent disease, whereas none of the 22 treated women
who remained healthy had detectable DNA. Nobbenhuis et al19 found that HPV DNA negativity 6 months
after treatment had a 99% negative predictive value that
CIN II–III would not develop. Tate et al,20 who performed PCR on microdissected specimens, found that
HPV DNA is very uncommon in normal tissue adjacent
to CIN, suggesting that the mechanism of clearance
might simply be removal of the infected cells. Our results, with a more frequent HPV clearance in the conization group, could be interpreted as a more effective
treatment of CIN and the underlying HPV infection.
However, the conization group had a higher CIN grade,
were older, and had a lower rate of sexual partner
change than the cryotherapy group. Several of these
explanations may have contributed to the differences in
HPV clearance. It is possible, for example, that CIN I
may reflect an early infection with substantial production
of virus, whereas CIN III lesions produce less virus and
may be more prone to heal after treatment. The clearance rates of different types could not be studied because
39% of the infections were HPV 16 and the other 12
HPV types were represented only by one to four cases
per type. The fact that two women with a partner posi-
Elfgren et al
Rate of HPV Clearance
969
tive for the same HPV DNA type were persistently
positive at all visits suggests that type-specific reinfection
may also be a determinant of persistence.
Several different treatment strategies exist for the
treatment of CIN. At electrosurgical conization there is a
better control for removal of the CIN lesion, and thus the
HPV infection, relative to the blind surgery of cryotherapy. However, Mitchell et al21 observed no significant
difference in success rate for curing the CIN I–III lesions
when comparing cryosurgery, loop electrosurgical excision, and laser vaporization. Studies comparing different
treatments are hampered by the long follow-up times
required until CIN recurrence is observed and by limited
statistical power because of few recurrent cases. We
suggest that the use of HPV testing after treatment could
be useful as an intermediate end point to achieve more
rapid results and more power when comparing different
CIN treatments.
The majority of pathologic Papanicolaou smears during follow-up in our study were CIN I, which might
reflect true neoplasia but can also be a nonspecific finding
or reflect a recent new HPV infection. The results in our
study show that the CIN treatment strategies used in a
vast majority of cases will result in negative cytology and
eradication of the disease. The fact that some women
become disease free, at least temporarily, but do not clear
the HPV infection after treatment raises questions as to
what the mechanisms of clearance of the virus infection
might be. Of the seven patients persistently HPV positive at 12 months in our study, the two patients from the
conization group had unclear margins in the cone specimen. In the cryotherapy group one had multifocal genital warts and one had immunosuppressive therapy because of an organ transplant. Immunosuppression is a
well-known risk factor for the development, persistence,
and recurrence of HPV infection and disease.22,23 For
the other three patients with persistence, no known risk
factor could be identified. All patients presenting with
CIN II (the true risk group for developing CIN III)
during follow-up had positive HPV tests concurrent with
the CIN II smear. However, there were also patients
with persistently positive HPV DNA tests who did not
show cytologic abnormalities in the Papanicolaou smear
during follow-up. It is well established that the persistent
HPV infection is a prerequisite for the development of
CIN III.7
Our present study extends earlier findings with
smaller patient groups that effective treatment of CIN
will indeed rapidly clear the HPV infection. Our results
imply that removal of the main risk factor for CIN, the
HPV infection, is an attainable goal. They also suggest
that HPV testing could be used as an important interme-
970
Elfgren et al
Rate of HPV Clearance
diate end point in the follow-up after treatment of CIN
for evaluation of efficacy of treatments.
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Address reprint requests to: Kristina Elfgren, MD, Huddinge
University Hospital, Department of Obstetrics and Gynecology, K57, S-141 86 Stockholm, Sweden; E-mail: kristina.elfgren
@obgyn.hs.sll.se.
Received March 14, 2002. Received in revised form June 16, 2002.
Accepted June 27, 2002.
Elfgren et al
Rate of HPV Clearance
971