International Journal of STD & AIDS 2006; 17: 507–511

REVIEW

The recurrence of cervical intraepithelial

neoplasia in HIV-positive women: a review
of the literature

Pierre Marie Tebeu MD1,2, Attila L Major MD1, Paulette Mhawech

3 4
MD and Elisabetta Rapiti MD MPH
1
Department of Obstetrics and Gynaecology, Geneva University Hospitals, Geneva,
Switzerland; 2Department of Obstetrics and Gynaecology, Provincial Hospital, Maroua,
Cameroon; 3Department of Pathology and Laboratory Medicine at Roswell Park Cancer
Institute, NY, USA; 4Geneva Cancer Registry, Institute of Social and Preventive Medicine,
University of Geneva, Geneva, Switzerland

Summary: The objective of this study was to assess the available evidence on the
outcome of cervical intraepithelial neoplasia (CIN) in HIV-positive women after
conization. We performed a literature search of Medline and Cochrane libraries to
locate published articles reporting about the rate of recurrence of CIN after
excisional treatment in patients with negative surgical margins. Out of 15 articles,
five studies reported recurrence rate of CIN in margin negative patients. The
recurrence rate of CIN after conization in HIV-infected women ranges from 20% to
75%. No conclusions can be drawn about the impact of CD4 cell counts on the
recurrence rate. Available evidence suggests that standard excisional treatments for
CIN are associated with high rates of recurrence in HIV-positive women. Despite
the fact that the evidence is limited because of the few number of eligible studies,
this issue should be considered in the management of HIV-positive patient with
CIN.
Keywords: CIN, HIV, excision, recurrence

Introduction outcome of CIN in HIV-positive women after

Women infected with HIV have a five-fold higher
risk of developing a cervical intraepithelial neopla-
sia (CIN) in comparison to HIV-seronegative
women.1–6 The prevalence and the severity of
dysplasia correlate significantly with the immune
status of HIV-infected patients. Thus, women
having low CD4 þ lymphocyte counts are at higher
risk of presenting with high-grade dysplasia.7,8 In
addition, the severity of immunosuppression as
reflected by CD4 cells counts seemed to be
associated with the rate of disease progression
and the rate of its recurrence after treatment.9
Treatment failures of CIN in HIV-positive wo-
men have been described in several studies.
However, some of these studies did not discrimi-
nate between persistence of CIN and recurrence of
the disease as primary treatment outcome. Further-
more, the results of these studies were often not
categorized by treatment modality such as ablative
or excisional; thus few data were available on the
Correspondence to: Dr Elisabetta Rapiti, Geneva Cancer Registry, 55,
Bd de la Cluse, CH-1205, Geneva, Switzerland.
Email: Elisabetta.Rapiti@imsp.unige.ch
excisional treatment.
We conducted a review of the published litera-
ture to assess the available evidence on disease
recurrence after conization of cervical intraepithe-
lial lesions in HIV-positive women.
Methods
Data sources
We conducted a search of the literature to identify
all relevant articles published in the period
1980–2004 in the following bibliographic databases:
Medline (Pubmed, Ovid), Cochrane Trials Register,
Cumulative Index to Nursing and Allied Health.
We conducted a variety of searches using a
combination of the following medical terms and
MeSH headings: cervix dysplasia, squamous in-
traepithelial lesion, cervical intraepithelial lesion,
recurrence, persistence, HIV, conization. In addi-
tion, potentially relevant publications were identi-
fied from the reference lists of identified articles
and from review articles. No attempt was made to
identify unpublished studies.

507
508 International Journal of STD & AIDS Volume 17 August 2006

Study selection patients, length of follow-up, type of treatment,

Descriptive or analytic studies providing persis-
tence and/or recurrence rates of CIN in HIV-
positive women, or comparing persistence and/or
recurrence rates in HIV-positive and HIV-negative
women were initially eligible for inclusion. After
identification of potentially relevant studies, each
of these studies was reviewed in detail and
additional exclusion criteria were applied. The
criteria for inclusion were as follows: (1) The
documentation of CIN recurrence rate in HIV þ
patients with well-established negative surgical
margins assessed by histology examination after
excision. (2) Treatment modalities included laser
cone biopsy, cold-knife conization (CKC), or loop
electrosurgical excision procedure (LEEP). The
criteria for exclusion were as follows: (1) CIN
lesions treated by destructive or ablative techni-
ques such as laser vaporization, cryotherapy, cold
coagulation; (2) women with positive surgical
margins or for which the surgical margin status
was unknown; (3) single case report.
Data extraction and analysis
From these works, we considered the following
variables for the review: study design, age of the
margin status, CD4 cell count and use of antire-
troviral treatment.
Results
We found 15 studies that evaluated the persistence
and/or the recurrence rate of CIN after conization
in HIV-infected women.10–24 Table 1 shows selected
characteristics of the studies initially identified.
Afterwards, 10 reports were excluded for the
following reasons: five studies did not report the
surgical margin status after conization.10,11,15,19,22 In
two studies, it was not possible to distinguish
patients treated with one of the excisional techni-
ques from patients treated with an ablative
modality.17,20 In one study, the outcome after
invasive treatment was reported together for HIV
infection and allograft recipient patients.13 In one
study, the outcome after the conization was
ascertained only through cytologic examination.24
In one study, patients were the same as those
reported in a subsequent article12,16 (therefore, we
only considered for the analysis the most recent
report16).
Of the five studies considered eligible for the
review (Table 2), two had a prospective design16,18

Table 1 Studies reporting the outcome of CIN in HIV-positive women treated with conization

Surgical
Year of Year of margins
Author publication study Study design Treatment status Outcome
10
Spinillo 1992 NR Prospective Electrocauterization, CKC Unknown Recurrence
Adachi11 1993 1988–91 Prospective Cone biopsy, cryosurgery Unknown Progression,
recurrence
Maiman12 1993 NR Prospective Cryosurgery, laser vaporization, Reported Recurrence
CKC
Petry13 1994 1989–93 Prospective CKC, laser cone Reported Recurrence
Wright14 1994 1991–92 Retrospective LEEP Reported Persistence,
recurrence
Kuppers15 1994 1991–93 Retrospective Laser cone, CO2-laser Unknown Recurrence
Fruchter16 1996 1988–93 Prospective Cryosurgery, laser vaporization, Reported Progression,
CKC, LEEP, cone biopsy recurrence
Maiman17 1999 1993–97 Prospective Cryosurgery, laser vaporization, Reported Recurrence
Randomized trial LEEP, cone biopsy +5-FU
Holcomb18 1999 1991–98 Prospective LEEP, CKC, laser cone Reported Recurrence
Six19 1998 1993–95 Prospective Cryosurgery, conization Unknown Progression,
persistence,
recurrence
Ahr20 2000 1990–97 Retrospective Conization, hysterectomy Reported Relapse
Robinson21 2001 NR Retrospective LEEP, cone biopsy, hysterectomy Reported Persistence,
progression,
recurrence
Ferrero22 2002 1991–2001 Retrospective LEEP, cone biopsy, laser Unknown Persistence,
vaporization recurrence
Tate23 2002 1996–2000 Retrospective Cryosurgery, laser vaporization, Reported Recurrence
LEEP, cone biopsy, hysterectomy
Gilles24 2005 1995–2002 Retrospective Conization Reported Pathological
smears at
follow-up
NR=not reported
CKC=Cold knife conization
LEEP=Loop electrosurgical excision procedure
 Tebeu et al. CIN recurrence in HIV þ women 509

and three were retrospective.14,21,23 Three studies

Yes 17.6%;
No 70.3%;
Po0.05
evaluated the recurrence rate of CIN in HIV-

HAART
Use of positive and HIV-negative patients, one study in
HIV-positive patients and patients whose HIV

4/47 (8.5%) 9/17 (53%) >200; p200 crude

status was unknown, and one study only assessed

Po0.05; adjusted
the recurrence rate among HIV-positive patients.

o200; >200;
2/4 (50%) >500; p500

All of the studies considered all the degrees of CIN.

Continuous;
Follow-up ranged from 6 to 73 months. All the
margins
ve margins +ve by CD4

P=0.002
Analysis

P=0.13

studied populations came from the USA. Follow-

P=NS

P=NS
up strategies included cytology and colposcopy,
and cytology/colposcopy and biopsy.
Recurrence Recurrence

The rate of recurrence of CIN in HIV-positive

in HIV

women with negative margins after conization

ranged from 20% to 75%. In comparison, the
NA

NA
NR
recurrence rate in women HIV-negative or with
5/5 (100%) 8/76w (11%)

undetermined HIV status and negative margins

8/49 (16%) varied between 8.5% and 16%. The reported
in HIV

recurrence/persistence rate of women with posi-

NA

NR

tive margins after conization ranged between 55%

and 100% in HIV-positive women and around 55%
7/8 (88%)
22/59 (37.3%) 10/18 (55%)

21/43 (48.8%) 15/24 (63%)

margins +ve

among women with HIV-negative or undeter-

Recurrence

mined status. Only one study reported the risk of

in HIV+

recurrence by CD4 cell count in women with

NA

known marginal status treated by excision. Frutch-

Table 2 Studies reporting the recurrence rate of cervical intraepithelial in HIV-positive women treated with conization

er et al.16 reported a CD4 lymphocyte count within

1/5 (20%)
14/29 (48%)

21/28 (75%)
margins ascertainment margins
ve

three months of the treatment of CIN to the time of

Recurrence

recurrence. Their study revealed a significant

in HIV+

increase in the recurrence rate, both in univariate

and multivariate models, for patients with CD4
counts o200 cells/mm3 compared with those with
CD4 counts X200 cells/mm3, when including in
colposcopy,
6–27 HIV
w 76 HIV
w colposcopy

colposcopy
6–26 HIV+ 29 HIV+ Cytology,

Cytology,

Cytology,

Cytology,

Cytology,
Negative Means of

histology

the analysis of both ablative and excisional mod-

biopsy

biopsy

biopsy

alities of treatment. When considering the exci-

sional treatment group alone, a low CD4 cell count
Only the study by Robinson et al. reports the recurrence incidence rates by CD4 counts adjusting by margin status

was still a strong determinant of recurrence (crude

HAART=highly active antiretroviral therapy; NR=not reported; NA=not applicable; NS=not statistically significant
47 HIV

49 HIV

59 HIV+

43 HIV+

28 HIV+
8 HIV

rate ratio 2.0, 95% confidence interval [CI]: 1.0–4.1,

5 HIV+

Po0.05). However, after adjustment for residual

CIN, the estimate was no longer significant
(adjusted rate ratio 1.9, 95% CI: 0.9–3.9). The other
6–73 HIV

24.2 HIV+,
19.9 HIV

6–64 HIV+
cases cases Age of the Follow-up
(months)

reviewed studies did not report the recurrence

Mean
7–74

rates by level of CD4 separately by negative and

24

positive margin status.

63% HIV

63% HIV

Only one study reported the outcome of patients

193 54% HIV+

59% HIV+
28 HIV
w

Mean 34
32 HIV+
patients

with CIN treated by use of antiviral therapy.

30–39
80w Mean

o30,
o30

Robinson et al.21 found that patients who were

NR

treated by highly active antiretroviral therapy

HIV+ HIV

(HAART) had a recurrence rate of 17.6% as

35

49
(n)

compared with those who did not receive HAART

(70.6%). However, this finding was not reported
127
34

66

19

28
Study design (n)

separately for negative and positive margins.

Retrospective

Retrospective

1996–2000 Retrospective
Prospective

Prospective

Discussion
HIV status of these cases was unknown

Excisional modalities such as LEEP, laser cone and

cold-knife cone biopsies are currently preferred
over ablative methods, such as cryotherapy and
1991–92

1988–93

Holcomb, 1991–98
Year of

laser vaporization in the treatment of CIN in HIV-

study

positive women.6,9,13 Excisional methods have the

Robinson, NR

advantage of a histology examination to document

Fruchter,

negative margins, which is of particular impor-

Author,

Wright,
199414

199616

199918

200121

200223

tance in HIV-positive women in whom disease may

Tate,
year

be more extensive. Involved margins after coniza-

w
510 International Journal of STD & AIDS Volume 17 August 2006
tion are known to be one of the risk factors for
persistence/recurrence of CIN in HIV-negative
women, with incidence rate of recurrence ranging
from 8.7% to 40% in patients with incomplete
resection.25–29 We only included in the review
recurrence rates estimated from populations with
known free resection margins to avoid including
cases with persistent disease. Nevertheless, the
recurrence rates in HIV-infected patients were even
higher than those in HIV-negative patients with
involved margins.
Only one study reported the risk of recurrence by
CD4 cell count in women treated by excision by
margin status.16 This study suggests that after
excisional treatment with or without residual
disease, lower CD4 counts predict higher recur-
rence rates. The authors fail to show an impact
when adjusting for margin status. This result could
indicate that the risk of recurrence is not influenced
by immune status when the CIN is adequately
treated, or could simply reflect a lack of power of
the study. Additional studies are needed before
drawing any conclusions regarding the impact of
immunosuppression on CIN recurrence rate.
Very scarce data exist regarding the use of
HAART in patients with CIN.30,31 HAART may
have a role both as adjuvant therapy for CIN and as
primary therapy for HIV. The definition of the
effect of HAART on CIN is of utmost importance,
because with the use of HAART, a higher number
and higher grade of CIN might be expected, as a
consequence of longer survival of HIV-infected
patients. In our search, we only found one study
showing a strong association between the effect of
HAART antiviral therapy and decreased risk of
both disease recurrence and progression consid-
ered together as outcome.21
Persistent infection with certain types of human
papilloma virus (HPV) is thought to be necessary for
the development of high-grade squamous intrae-
pithelial lesions and cervical cancer.32 Although
factors that influence persistence of HPV are not
yet well understood, several studies suggest that
alterations in cell-mediated immune responses play
a large role in persistence of HPV.33,34 HIV infection,
HIV-associated immunosuppression, or both seem
to increase a woman’s susceptibility to HPV infec-
tion or alter the natural history of pre-existing HPV
infection, thus leading to increased incidence of
CIN, CIN lesions that are more difficult to treat, and
high rate of recurrence.33–36 However, none of the
studies examined for this review has reported the
HPV status of the patients.
Our review has some limitations due mainly to
limitations of the original studies. First, our review
may be subject to publication and selection bias as
we were unable to identify unpublished studies
and we did not contact the authors or other experts
to have access to grey literature. Second, few
studies met the criteria for inclusion in the review,
with most studies being excluded because of the
lack of information on the status of the margins.
Even eligible studies had substantial limitations.
Third, the small size of study populations and high
number of patients lost to follow-up may have
biased findings. Finally, all the study populations
were from the USA, which raises concerns about
generalizability of these data.
In general, CIN grade, duration of follow-up, and
conization methods were highly variable and not
always clearly reported. All the studies, however,
consistently found a high incidence of recurrence of
CIN after conization in HIV-infected women in
comparison to HIV-negative women. The variability
between the estimates can be attributed to metho-
dological differences of the studies.
In summary, available evidence suggests that
eradication of CIN is difficult to achieve with
standard therapy in HIV-infected women. CIN
recurrence rates in HIV-infected women are con-
sistently higher than in HIV-negative women, even
after a complete excision of the lesion and negative
margins. Not enough evidence is available to
conclude about the impact on the recurrence rate
of immunosuppression or the use of HAART.
Overall, this review has identified several areas
that need to be adequately studied in the research
of effective treatments of CIN disease in HIV-
infected patients.
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