Incidence of Cervical Squamous Intraepithelial Lesions

Associated With HIV Serostatus, CD4 Cell Counts, and

Human Papillomavirus Test Results
Online article and related content
current as of November 25, 2009. Tiffany G. Harris; Robert D. Burk; Joel M. Palefsky; et al.
JAMA. 2005;293(12):1471-1476 (doi:10.1001/jama.293.12.1471)

http://jama.ama-assn.org/cgi/content/full/293/12/1471

Correction Contact me if this article is corrected.

Citations This article has been cited 31 times.

Contact me when this article is cited.

Topic collections HIV/AIDS; Oncology; Cervical Cancer; Women's Health; Gynecology; Women's
Health, Other; Infectious Diseases
Contact me when new articles are published in these topic areas.

Subscribe Email Alerts

http://jama.com/subscribe http://jamaarchives.com/alerts

Permissions Reprints/E-prints
permissions@ama-assn.org reprints@ama-assn.org
http://pubs.ama-assn.org/misc/permissions.dtl

Downloaded from www.jama.com by guest on November 25, 2009

 ORIGINAL CONTRIBUTION
Incidence of Cervical Squamous
Intraepithelial Lesions Associated With
HIV Serostatus, CD4 Cell Counts, and
Human Papillomavirus Test Results
Tiffany G. Harris, PhD
Robert D. Burk, MD
Joel M. Palefsky, MD
L. Stewart Massad, MD
Ji Yon Bang, MS
Kathryn Anastos, MD
Howard Minkoff, MD
Charles B. Hall, PhD
Melanie C. Bacon, RN, MPH
Alexandra M. Levine, MD
D. Heather Watts, MD
Michael J. Silverberg, MPH, PhD
Xiaonan Xue, PhD
Sandra L. Melnick, DrPH
Howard D. Strickler, MD, MPH
C
ERVICAL CANCER SCREENING
recommendations in the
United States have been
recently updated and now
advise using an interval of 3 years
between screenings in healthy women
30 years or older who have normal
cytology results and who test negative
for oncogenic (cancer-associated)
human papillomavirus (HPV) DNA.1,2
The recommended interval is 6 to 12
months for women with normal cytol-
ogy results and detectable oncogenic
HPV. If no HPV test is conducted, 3
consecutive normal annual Papanico-
laou (Pap) smear results are required
before the Pap smear frequency is
changed to once every 2 or 3 years.
Support for these recommendations
©2005 American Medical Association. All rights reserved.
Downloaded from www.jama.com by guest on November 25, 2009
Context Recent cervical cancer screening guidelines state that the interval between
screenings can be safely extended to 3 years in healthy women 30 years or older who
have normal cytology results and have negative test results for oncogenic human pap-
illomavirus (HPV) DNA.
Objective To determine the incidence of squamous intraepithelial lesions (SILs) in
HIV-seropositive women with normal cytology results, by baseline HPV DNA results.
Design, Setting, and Patients Participants were HIV-seropositive (n=855; mean
age, 36 years) and HIV-seronegative (n=343; mean age, 34 years) US women with
normal baseline cervical cytology who were enrolled in the Women’s Interagency HIV
Study (WIHS), a large, multi-institutional prospective cohort study. Since their recruit-
ment during 1994-1995, WIHS participants have been followed up semi-annually with
repeated Pap smears for a median of 7 years.
Main Outcome Measure The cumulative incidence of any SIL and high-grade SIL
or cancer (HSIL⫹) was estimated according to baseline HPV DNA results, stratified by
HIV serostatus and CD4 T-cell count.
Results Development of any SIL in women with negative HPV results (both onco-
genic and nononcogenic) at 2 years was as follows: in HIV-seropositive women with
CD4 counts less than 200/µL, 9% (95% CI, 1%-18%); with CD4 counts between
200/µL and 500/µL, 9% (95% CI, 4%-13%); and with CD4 counts greater than 500/
µL, 4% (95% CI, 1%-7%). The CIs for these estimates overlapped with those for HIV-
seronegative women with normal baseline cytology who were HPV-negative (3%; 95%
CI, 1%-5%), indicating that at 2 years, there were no large absolute differences in
the cumulative incidence of any SIL between groups. Furthermore, no HPV-negative
participants in any group developed HSIL⫹ lesions within 3 years. Multivariate Cox
models showed that on a relative scale, the incidence of any SIL among HIV-
seropositive women with CD4 counts greater than 500/µL (hazard ratio [HR], 1.2;
95% CI, 0.5-3.0), but not those with CD4 counts less than or equal to 500/µL (HR,
2.9; 95% CI, 1.2-7.1), was similar to that in HIV-seronegative women.
Conclusion The similar low cumulative incidence of any SIL among HIV-
seronegative and HIV-seropositive women with CD4 counts greater than 500/µL and
who had normal cervical cytology and HPV-negative test results suggests that similar
cervical cancer screening practices may be applicable to both groups, although this
strategy warrants evaluation in an appropriate clinical trial.
JAMA. 2005;293:1471-1476 www.jama.com
comes from several large observa- Author Affiliations are listed at the end of this
article.
tional studies.1-5 Corresponding Author: Tiffany G. Harris, PhD, De-
However, guidelines for human immu- partment of Epidemiology and Population Health, Al-
bert Einstein College of Medicine, 1300 Morris Park
nodeficiency virus (HIV)–seropositive Ave, Belfer 1308A, Bronx, NY 10461 (tharris@aecom
women have not been revised since .yu.edu).
(Reprinted) JAMA, March 23/30, 2005—Vol 293, No. 12 1471
CERVICAL LESIONS, HIV STATUS, AND HPV RESULTS
19951,2,6,7 and state that HIV-seroposi- women who were enrolled in the Wom-
tive women should obtain 2 Pap smears en’s Interagency HIV Study (WIHS) and
6 months apart after the initial HIV diag- had normal cervical cytology at base-
nosis and, if results of both are normal, line. The cohort has been described in
should undergo annual cytologic screen- detail elsewhere.9-11 Briefly, 2059 HIV-
ing. Human papillomavirus test results seropositive women and 569 HIV-
are not considered,1,2,6 even though eco- seronegative women were enrolled dur-
nomic models have suggested that HPV ing 1994-1995 from similar clinical and
testing in HIV-seropositive women might outreach sources in New York City, Chi-
be cost-effective.8 In this study, we deter- cago, Ill, Los Angeles and San Fran-
mined the cumulative incidence of cer- cisco, Calif, and the District of Colum-
vical squamous intraepithelial lesions bia. All participants provided written
(SILs) among HIV-seropositive and HIV- informed consent, and the study proto-
seronegative women according to base- col was approved by each local institu-
line HPV results in a large prospective tional review board. The HIV-seroposi-
cohort. We sought to determine, in keep- tive cohort has been previously shown
ing with recommendations for HIV- to have demographic characteristics and
seronegative women, whether a single risk behaviors similar to those of US
initial HPV test result can be used to women with AIDS nationwide.9
determine the appropriate cervical can- Participants were not included in the
cer screening interval in an HIV- current analysis if (1) their baseline Pap
seropositive woman with normal cervi- smear was abnormal or missing (834
cal cytology. HIV-seropositive, 106 HIV-seronega-
tive); (2) they were missing informa-
METHODS tion on baseline HPV status (126 HIV-
Participants were HIV-seropositive seropositive, 33 HIV-seronegative) or
(n=855) and HIV-seronegative (n=343) CD4 T-cell count (35 HIV-seroposi-
Table 1. Baseline Characteristics of HIV-Seropositive and HIV-Seronegative Participants
With Normal Baseline Cytology in the Women’s Interagency HIV Study*
HIV-Seropositive HIV-Seronegative
Characteristic (n = 855) (n = 343)
Age, y
Mean (SD) 36 (8) 34 (8)
Median (IQR) 37 (31-41) 34 (28-40)
Race/ethnicity, No. (%)
Black 446 (52) 172 (50)
Hispanic 212 (25) 101 (30)
White 178 (21) 57 (16)
Other 19 (2) 12 (4)
Sexually active in the last 6 mo, No. (%)‡
Yes 497 (59) 228 (67)
No 348 (41) 113 (33)
Injected drugs in the last 6 mo, No. (%)
Yes 40 (5) 19 (6)
No 806 (95) 322 (94)
HPV DNA test results, No. (%)
Negative 412 (48) 251 (73)
Nononcogenic 280 (33) 75 (22)
Oncogenic 163 (19) 17 (5)
CD4 T-cell count, cells/µL
⬍200 174 (20)
200-500 387 (45)
⬎500 294 (35)
Abbreviations: HIV, human immunodeficiency virus; HPV, human papillomavirus; IQR, interquartile range.
*Some data were missing at baseline for specific participants.
†P value (2-sided) for t test (means), Wilcoxon rank-sum test (medians), or ␹2 test (proportions) comparing HIV-
seropositive and HIV-seronegative participants.
‡Defined as any insertional vaginal or anal intercourse or oral-genital contact with a male partner.
1472 JAMA, March 23/30, 2005—Vol 293, No. 12 (Reprinted) ©2005 American Medical Association. All rights reserved.
Downloaded from www.jama.com by guest on November 25, 2009
tive); (3) they did not have an intact cer-
vix at baseline (113 HIV-seropositive,
31 HIV-seronegative); (4) follow-up
data were unavailable (96 HIV-
seropositive, 43 HIV-seronegative); or
(5) they HIV-seroconverted during fol-
low-up (13 HIV-seronegative). Race and
ethnicity information was obtained via
questionnaire. Study participants were
asked whether they were Hispanic and
to identify their race from the follow-
ing choices: black, white, Asian/
Pacific Islander, Native American/
Alaskan Native, or other. We then
categorized the women further as His-
panic, black (non-Hispanic), white
(non-Hispanic), and other. Race and
ethnicity were included in the analy-
sis because they may be related to HIV
serostatus and the risk of SIL.
At baseline and semi-annual clinical
visits, WIHS participants underwent a
pelvic examination with collection of a
cervicovaginal lavage for HPV testing,
followed by a Pap smear using a wooden
Ayres spatula and cytologic brush. All
Pap smears were interpreted centrally
with the 1991 Bethesda System12 crite-
ria. Two independent cytotechnolo-
gists examined each Pap smear, and all
P smears identified as abnormal by either
Value† technologist, as well as 10% of all nega-
tive smears, were evaluated by a cyto-
⬍.001
pathologist. The WIHS protocol calls for
⬍.001
colposcopy for all women with an ab-
normal Pap smear result, but compli-
ance with colposcopy has been incom-
.11
plete (approximately 70%) in this high-
risk population, and there is no central
review of histologic results. For these
.01 reasons, we used cytology to define end
points in our analysis. Cytology is pri-
marily subject to false-negative results
.55
(ie, it is insensitive),13-16 and occasional
low-grade SILs are known to contain
high-grade lesions when evaluated by bi-
⬍.001
opsy.17-20 Therefore, we used “any SIL”
as our main end point and high-grade
SIL or cancer (HSIL⫹) as a secondary
end point.
HPV DNA testing was conducted us-
ing a well-established MY09/MY11
polymerase chain reaction assay.10,11
HPV types 16, 18, 31, 33, 35, 39, 45,
51, 52, 56, 58, 59, 68, and 73 were con-
 CERVICAL LESIONS, HIV STATUS, AND HPV RESULTS

sidered oncogenic. All other HPVs, in- seronegative women in the WIHS who dence interval [CI], 1%-18%) with CD4
cluding types 6, 11, 13, 26, 32, 34, 40, had normal cytology at baseline and counts less than 200/µL, 9% (CI, 4%-
42, 53, 54, 55, 57, 61, 62, 64, 66, 67, were included in the current analysis. 13%) with CD4 counts of 200/µL to
69, 70, 71 (AE8), 72, 81 (AE7), 82 Mean age was 36 years (range 18-66 500/µL, and 4% (CI, 1%-7%) with CD4
(W13B and AE2), 83 (PAP291), 84 years) and 34 years (range 17-55 years) counts greater than 500/µL developed
(PAP155),85 (AE5) 89 (AE6), AE9, and among the HIV-seropositive and HIV- any SIL within 2 years (TABLE 2). The
AE10, as well as all those HPVs that hy- seronegative women, respectively. Ap- CIs for these estimates overlapped with
bridized only with the consensus probe, proximately 50% of the participants cat- that in HIV-seronegative participants
were considered nononcogenic. egorized themselves as black and 25% who were HPV-negative (3%; CI, 1%-
Standard life-table methods were to 30% as Hispanic. HIV-seronegative 5%), indicating that after 2 years there
used to estimate the cumulative inci- women were somewhat more likely to were no large or significant absolute dif-
dence of any SIL and HSIL⫹ accord- be currently sexually active than HIV- ferences in the cumulative incidence of
ing to baseline HPV DNA test results, seropositive women. Participants in any SIL between groups (all P⬎.25).
stratified by HIV serostatus and CD4 T- both groups were followed up for a me- At 3 years, however, those with less
cell count.21 Cox models were used to dian of 7 years. The main analyses were than 200/µL and 200/µL to 500/µL CD4
conduct multivariate analyses after truncated at 5 years, however, be- T cells at baseline had a cumulative in-
demonstration that the proportional cause a longer interval was not thought cidence of any SIL of 29% (95% CI,
hazard assumption applied to this data to be relevant, given the 3-year inter- 15%-44%) and 14% (95% CI, 8%-
set (data not shown).22 Participants who val recommended for Pap-smear screen- 20%), respectively. HIV-seropositive/
had a hysterectomy (n = 14) after their ing in HIV-seronegative women. HPV-negative women with CD4 T cell
baseline visit were censored at the visit Among the HIV-seropositive women counts greater than 500/µL continued
before the procedure. In the analysis of who had normal cytology results and to have a low rate of any SIL through 3
HSIL⫹, women were additionally cen- were HPV-negative, 9% (95% confi- years of follow-up (6%; 95% CI, 2%-
sored if they reported cervical treat-
ment. Treatment of low-grade lesions
Table 2. Cumulative Incidence of Any SIL and HSIL⫹ Among Women With Normal Cytology
is at the discretion of the physician in Results and HPV-Negative at Baseline
the WIHS, but high-grade lesions must
Any SIL
be treated. For analytic purposes, we
considered as treated any woman who No. at Cumulative
Baseline HIV and Start of No. of Incidence No. of
answered affirmatively to the ques- CD4 Count Status Interval, y Interval New SILs (95% CI) New HSILs⫹*
tion, “Since your last study visit, were HIV seropositive
you treated for any cervical or other ab- CD4 ⬍200/µL 0-1 61 1 2 (1-9)† 0
normality?” Although self-report is not 1-2 42 3 9 (1-18) 0
entirely reliable, we used this broad 2-3 35 7 29 (15-44) 0
definition to be conservative; we could 3-4 21 2 37 (20-53) 0
not exclude the possibility that some 4-5 16 4 53 (35-71) 0
women who received treatment pri- CD4 200-500/µL 0-1 180 5 3 (1-6)† 0
vately did so without this information 1-2 155 9 9 (4-13) 0
being captured by our medical record 2-3 137 7 14 (8-20) 0
review. In the footnotes to the tables, 3-4 102 5 18 (12-25) 0
we report not only the number cen- 4-5 92 9 26 (19-34) 0
sored because of a self-report of treat- CD4 ⬎500/µL 0-1 171 2 1 (1-4)† 0
ment but also the number of these 1-2 147 4 4 (1-7) 0
women who had an abnormal biopsy 2-3 133 3 6 (2-10) 0
3-4 111 6 12 (6-17) 2
result (ie, those most likely to have ac-
4-5 98 1 13 (7-18) 0
tually received treatment).
HIV seronegative 0-1 251 4 2 (1-4)† 0
P⬍.05 was set for significance. Analy-
1-2 214 3 3 (1-5) 0
ses were conducted with SAS version
2-3 187 4 5 (2-9) 0
8.2 (SAS Institute Inc, Cary, NC) and
3-4 153 2 7 (3-10) 1
StatXact version 6.0 (Cytel Software,
4-5 135 0 7 (3-10) 0
Cambridge, Mass).
Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; HPV, human papillomavirus; HSIL⫹, high-
grade squamous intraepithelial lesion or cancer; SIL, squamous intraepithelial lesion.
RESULTS *Four of 14 women with CD4 ⬍200/µL, 5 of 31 women with CD4 200/µL-500/µL, 8 of 33 women with CD4 ⬎500/µL,
and 3 of 29 HIV-seronegative women who were censored for a self-report of having gynecologic treatment had ab-
TABLE 1 shows the baseline character- normal cervical histology results during the period of observation shown in the table.
†Exact Clopper-Pearson confidence interval.
istics of the HIV-seropositive and HIV-
©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, March 23/30, 2005—Vol 293, No. 12 1473

Downloaded from www.jama.com by guest on November 25, 2009

CERVICAL LESIONS, HIV STATUS, AND HPV RESULTS

10%), a cumulative incidence compa- women (8%; 95% CI, 1%-15%). Few in- tive incidence of any SIL was similar in
rable to that in HIV-seronegative cident HSILs and no cancers were ob- HIV-seropositive women with CD4
women (5%; 95% CI, 2%-9%). There served throughout follow-up in the counts greater than 500/µL (9%; 95% CI,
were no cases of HSIL or cancer dur- nononcogenic HPV-positive sub- 5%-13%) and HIV-seronegative women
ing the first 3 years of follow-up in any group. (6%; 95% CI, 3%-9%). HIV-seroposi-
HPV-negative subgroup. In fact, there Using the commercially available test tive women positive for an oncogenic
were no cases of cancer through the en- for HPV, HPV test results are clinically HPV type at baseline had the highest cu-
tire 7-year follow-up period. considered negative if no oncogenic HPV mulative incidence of any SIL, and even
The risk of any SIL was greater for type is detected (ie, women who are HPV those with CD4 counts greater than
participants positive for a nononco- DNA negative and those with a nonon- 500/µL had a markedly higher rate than
genic HPV type at baseline (TABLE 3) cogenic HPV type are grouped to- HIV-seronegative women (TABLE 4).
compared with that for the HPV- gether). HIV-seropositive women with Multivariate Cox models that con-
negative women. At 2 years of follow- CD4 counts less than 200/µL and 200/µL trolled for age and race/ethnicity largely
up, HIV-seropositive women with a to 500/µL who were negative for an on- corroborated the above results: through
nononcogenic HPV infection and CD4 cogenic HPV had a 2-year cumulative in- 3 years of follow-up, the incidence of
counts less than 200/µL had a cumu- cidence of any SIL of 21% (95% CI, 13%- any SIL was similar in HIV-seronega-
lative incidence rate of 31% (95% CI, 29%) and 15% (95% CI, 11%-20%), tive and HIV-seropositive women with
19%-42%) and those with 200/µL to respectively. HIV-seropositive women CD4 counts greater than 500/µL who
500/µL had a rate of 24% (95% CI, 17%- with CD4 counts greater than 500/µL had negative results for oncogenic HPV
32%). The rate was much lower among had a 2-year rate (5%; 95% CI, 2%-7%) (hazard ratio [HR], 1.4; 95% CI, 0.7-
HIV-seropositive women with greater similar to the low rate in HIV- 2.7) or all HPV (HR, 1.2; 95% CI, 0.5-
than 500/µL CD4 T cells (6%; 95% CI, seronegative women (4%; 95% CI, 2%- 3.0). HIV-seropositive women with
1%-11%) and in HIV-seronegative 7%), and even at 3 years the cumula- CD4 counts of 500/µL or less, how-
ever, had a greater incidence of any SIL
relative to HIV-seronegative partici-
Table 3. Cumulative Incidence of Any SIL and HSIL⫹ Among Women With Normal Cytology
Results and Positive for a Nononcogenic HPV at Baseline
pants after just 2 years, even among
women with negative test results for all
Any SIL
HPVs (HR, 2.9; CI, 1.2-7.1). Last, we
No. at Cumulative measured the strength of association of
Baseline HIV and Start of No. of Incidence No. of New
CD4 Count Status Interval, y Interval New SILs (95% CI) HSILs⫹* incident SIL with nononcogenic (HR,
HIV seropositive 1.6; 95% CI, 1.2-2.1) and oncogenic
CD4 ⬍200/µL 0-1 65 8 13 (4-21) 0 (HR, 2.7; 95% CI, 2.0-3.7) HPV infec-
1-2 53 10 31 (19-42) 0 tion at baseline, controlling for HIV se-
2-3 35 1 33 (20-45) 0 rostatus, CD4 T-cell count, age, and
3-4 28 3 40 (27-54) 0 race/ethnicity and using all 5 years of
4-5 22 3 49 (34-63) 0 data in this study. For HSIL⫹, the cor-
CD4 200-500/µL 0-1 131 11 9 (4-14) 0 responding HRs were 1.7 (95% CI, 0.3-
1-2 109 18 24 (17-32) 0 8.9) for nononcogenic and 10.2 (95%
2-3 85 8 32 (23-40) 1 CI, 2.3-44.5) for oncogenic HPV.
3-4 70 3 35 (26-43) 1
4-5 63 4 39 (30-48) 0 COMMENT
CD4 ⬎500/µL 0-1 84 1 1 (1-6)† 0 In this observational cohort study, HIV-
1-2 72 3 6 (1-11) 0 seronegative and HIV-seropositive
2-3 65 6 15 (6-23) 0 women who had normal cytology re-
3-4 54 3 20 (10-29) 0
sults with CD4 counts greater than
4-5 45 0 20 (10-29) 0
500/µL and who had negative test re-
HIV seronegative 0-1 75 2 3 (1-9)† 0
sults for HPV at baseline had a similar
1-2 61 3 8 (1-15) 0
low cumulative incidence of any SIL for
2-3 52 1 10 (2-17) 1
3 years or more. If these findings are
3-4 40 1 12 (4-21) 0
confirmed, comparable risk of cervi-
4-5 36 0 12 (4-21) 0
cal lesions would suggest that compa-
Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; HPV, human papillomavirus; HSIL⫹, high-
grade squamous intraepithelial lesion or cancer; SIL, squamous intraepithelial lesion. rable cancer-screening practices may be
*Three of 17 women with CD4 ⬍200/µL, 7 of 22 women with CD4 200/µL-500/µL, 3 of 19 women with CD4 ⬎500/µL,
and 0 of 11 HIV-seronegative women who were censored for a self-report of having gynecologic treatment had ab-
applicable to both groups. Current cer-
normal cervical histology results during the period of observation shown in the table. vical cancer screening recommenda-
†Exact Clopper-Pearson confidence interval.
tions for HIV-seronegative women 30
1474 JAMA, March 23/30, 2005—Vol 293, No. 12 (Reprinted) ©2005 American Medical Association. All rights reserved.

Downloaded from www.jama.com by guest on November 25, 2009

 CERVICAL LESIONS, HIV STATUS, AND HPV RESULTS

years of age or older advise using an in- be cautious in interpreting the find- albeit well established and widely used,
terval of 3 years between screenings ings of our study. is not a commercial, clinically ap-
among those who have normal cytol- Furthermore, our study has impor- proved test.10,11 In fact, in cervical can-
ogy results and negative test results for tant limitations. First, it is possible that cer screening, the HPV DNA test cur-
oncogenic HPV.1,2 Most women in our we have underestimated the rate of neo- rently approved by the US Food and
study were aged 30 years or older. How- plasia in the cohort because our end Drug Administration is approved only
ever, only an adequately powered clini- points of SIL and HSIL⫹ were deter- for the detection of oncogenic HPV
cal trial can determine whether the cer- mined by using cytology without his- types. Therefore, unlike in our study,
vical cancer screening strategy in HIV- tologic confirmation, and there was no women who are infected with nonon-
seronegative women can be safely used end-of-study colposcopy or blind bi- cogenic HPV would be considered as
in HIV-seropositive women with CD4 opsy to seek occult lesions. However, testing negative with the approved test
counts greater than 500/µL. in a population in which low-grade SIL as it is generally used. With reagents
Among women with negative test re- is uncommon and there is little or no available from the manufacturer, how-
sults for all HPVs, the absolute differ- HSIL detected, we believe that we can ever, this HPV DNA test can detect a
ence in the cumulative incidence of any be reasonably certain that few cases of wide range of oncogenic and nonon-
SIL in HIV-seropositive women with high-grade neoplasia have been missed. cogenic HPV types, which is of inter-
CD4 counts of 500/µL or less (9% cu- Given that participants were also evalu- est because our data showed that in
mulative incidence) compared with that ated every 6 months for more than 5 HIV-seropositive women with CD4
in HIV-seronegative women (3% cu- years, it would seem unlikely that much counts of 500/µL or less, only those who
mulative incidence) was only 6%. There significant disease went undetected. A were negative for both oncogenic and
were also no cases of HSIL⫹ in any second major concern is that the poly- nononcogenic HPV had low rates of
HPV-negative women for 3 or more merase chain reaction assay we used, any SIL.
years. Whether HPV DNA testing might
be useful in determining the appropri-
ate frequency of cervical cancer screen- Table 4. Cumulative Incidence of Any SIL and HSIL⫹ Among Women With Normal Cytology
ing among HIV-seropositive women Results and Positive for an Oncogenic HPV at Baseline
with normal cytology results and CD4 Any SIL
counts of 500/µL or less may also war- No. at Cumulative
rant formal evaluation in a clinical trial. Baseline HIV and Start of No. of Incidence No. of New
CD4 Count Status Interval, y Interval New SILs (95% CI) HSILs⫹*
There has, to our knowledge, been
HIV seropositive
little published about the risk of SIL CD4 ⬍200/µL 0-1 48 8 18 (7-29) 0
among HIV-seropositive women with 1-2 34 11 45 (30-60) 0
normal cytology results as stratified by 2-3 21 4 56 (41-72) 0
HPV test results. Ellerbrock et al23 re- 3-4 14 4 69 (54-85) 0
ported a low cumulative incidence of 4-5 9 1 73 (58-88) 0
SIL (approximately 5% at 24 months) CD4 200-500/µL 0-1 76 13 18 (9-27) 2
among HIV-seropositive women who 1-2 57 7 28 (18-39) 0
were HPV negative at baseline, consis- 2-3 45 8 42 (30-54) 2†
tent with our results. Conversely, Del- 3-4 31 3 48 (35-60) 0
mas et al24 reported that at 18 months, 4-5 26 3 54 (41-67) 0
23% of HIV-seropositive women who CD4 ⬎500/µL 0-1 39 5 13 (2-24) 1
were HPV negative at baseline had de- 1-2 32 5 27 (13-42) 0
veloped a cervical lesion. Younger age 2-3 24 1 31 (15-46) 0
(eg, ⬍35 years) is an established risk 3-4 21 2 37 (21-53) 0
factor for incident HPV infection and 4-5 19 1 41 (24-58) 0
SIL, and the women in the study by Del- HIV seronegative 0-1 17 0 0 (0-20)‡ 0
mas et al24 were younger than those in 1-2 13 0 0 (0-22)‡ 0
either the study by Ellerbrock et al23 or 2-3 11 1 11 (1-34) 0
our study; the median age in the study 3-4 6 0 11 (1-38) 0
by Ellerbrock et al was approximately 4-5 5 0 11 (1-41) 0
35 years, and it was 37 years in our Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; HPV, human papillomavirus; HSIL⫹, high-
grade squamous intraepithelial lesion or cancer; SIL, squamous intraepithelial lesion.
study, whereas only a third of women *Seven of 13 women with CD4 ⬍200/µL, 10 of 20 women with CD4 200/µL-500/µL, 3 of 10 women with CD4 ⬎500/
µL, and 3 of 5 HIV-seronegative women who were censored for a self-report of having gynecologic treatment had
in the study by Delmas et al were 34 abnormal cervical histology results during the period of observation shown in the table.
years or older. Nonetheless, given the †Includes 1 cervical squamous carcinoma.
‡Exact Clopper-Pearson confidence interval.
conflicting reports, it is appropriate to
©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, March 23/30, 2005—Vol 293, No. 12 1475

Downloaded from www.jama.com by guest on November 25, 2009

CERVICAL LESIONS, HIV STATUS, AND HPV RESULTS
Another possible limitation of our
investigation is that we did not con-
sider changes in HPV and immune
status over time in our analyses. The
similarity, though, in the 3-year cumu-
lative incidence rate of any SIL in HIV-
seronegative and HIV-seropositive
women with CD4 cell counts greater
than 500/µL who were oncogenic
HPV-negative at baseline suggests that
this was not a major concern, at least
among HIV-seropositive women who
were fairly immunocompetent at the
time of evaluation. In any case,
changes in HPV and immune status
over time were not highly relevant to
our research question, whether a
single initial HPV test result can be
used to determine the appropriate
interval between Pap smears in HIV-
seropositive women.
Finally, the most important limita-
tion to our study was its observational
design. Consideration will also need to
be given to the psychosocial costs of a
positive HPV test in HIV-seropositive
women, many of whom will not de-
velop SIL. However, according to the
REFERENCES
1. Wright TC Jr, Schiffman M, Solomon D, et al. In-
terim guidance for the use of human papillomavirus
DNA testing as an adjunct to cervical cytology for
screening. Obstet Gynecol. 2004;103:304-309.
2. Practice Bulletin ACOG. Clinical management guide-
lines for obstetrician-gynecologists: number 45, Au-
gust 2003: cervical cytology screening (replaces com-
mittee opinion 152, March 1995). Obstet Gynecol.
2003;102:417-427.
3. Rozendaal L, Westerga J, van der Linden JC, et al.
PCR based high risk HPV testing is superior to neural
network based screening for predicting incident CIN
III in women with normal cytology and borderline
changes. J Clin Pathol. 2000;53:606-611.
4. Sherman ME, Lorincz AT, Scott DR, et al. Baseline
cytology, human papillomavirus testing, and risk for
cervical neoplasia: a 10-year cohort analysis. J Natl Can-
cer Inst. 2003;95:46-52.
5. Clavel C, Cucherousset J, Lorenzato M, et al. Nega-
tive human papillomavirus testing in normal smears
selects a population at low risk for developing high-
grade cervical lesions. Br J Cancer. 2004;90:1803-1808.
6. Kaplan JE, Masur H, Holmes KK; for the Infectious
Diseases Society of America. Guidelines for prevent-
ing opportunistic infections among HIV-infected per-
sons—2002: recommendations of the U.S. Public
Health Service and the Infectious Diseases Society of
America. MMWR Recomm Rep. 2002;51:1-52.
7. USPHS/IDSA Prevention of Opportunistic Infec-
tions Working Group. USPHS/IDSA guidelines for the
prevention of opportunistic infections in persons in-
fected with human immunodeficiency virus: disease-
specific recommendations. Clin Infect Dis. 1995;
21(suppl 1):S32-S43.
1476 JAMA, March 23/30, 2005—Vol 293, No. 12 (Reprinted)
Downloaded from www.jama.com by guest on November 25, 2009
results of our study, we believe that the
use of HPV testing in HIV-seroposi-
tive women warrants evaluation in a
formal clinical trial.
Author Affiliations: Albert Einstein College of Medi-
cine, Bronx, NY (Drs Harris, Burk, Anastos, Hall, Xue,
and Strickler and Ms Bang); University of California,
San Francisco (Dr Palefsky); Southern Illinois Univer-
sity School of Medicine, Springfield (Dr Massad); Mai-
monides Medical Center, Brooklyn, NY (Dr Minkoff );
Georgetown University Medical Center, Washing-
ton, DC (Ms Bacon); University of Southern Califor-
nia, Los Angeles (Dr Levine); National Institute of Child
Health and Human Development, Bethesda, Md (Dr
Watts); Johns Hopkins University, Baltimore, Md (Dr
Silverberg); and National Cancer Institute, Bethesda,
Md (Dr Melnick). Ms Bacon is now with the National
Institute of Allergy and Infectious Diseases, Bethesda,
Md, Dr Silverberg is now with Kaiser Permanente, Oak-
land, Calif, and Dr Melnick is now with the Center for
Scientific Review, Bethesda, Md.
Author Contributions: Dr Harris had full access to all of
the data in the study and takes responsibility for the integ-
rity of the data and the accuracy of the data analysis.
Study concept and design: Harris, Burk, Palefsky,
Strickler.
Acquisition of data: Burk, Palefsky, Massad, Anastos,
Minkoff, Bacon, Levine, Strickler.
Analysis and interpretation of data: Harris, Burk, Palef-
sky, Massad, Bang, Hall, Bacon, Watts, Silverberg, Xue,
Melnick, Strickler.
Drafting of the manuscript: Harris, Burk, Palefsky, Bang,
Xue, Strickler.
Critical revision of the manuscript for important in-
tellectual content: Harris, Burk, Palefsky, Massad, Anas-
tos, Minkoff, Hall, Bacon, Levine, Watts, Silverberg,
Xue, Melnick, Strickler.
8. Goldie SJ, Freedberg KA, Weinstein MC, Wright
TC, Kuntz KM. Cost effectiveness of human papillo-
mavirus testing to augment cervical cancer screening
in women infected with the human immunodefi-
ciency virus. Am J Med. 2001;111:140-149.
9. Barkan SE, Melnick SL, Preston-Martin S, et al. The
Women’s Interagency HIV Study: WIHS Collabora-
tive Study Group. Epidemiology. 1998;9:117-125.
10. Palefsky JM, Minkoff H, Kalish LA, et al. Cervi-
covaginal human papillomavirus infection in human
immunodeficiency virus-1 (HIV)-positive and high-
risk HIV-negative women. J Natl Cancer Inst. 1999;91:
226-236.
11. Strickler HD, Palefsky JM, Shah KV, et al. Hu-
man papillomavirus type 16 and immune status in hu-
man immunodeficiency virus-seropositive women.
J Natl Cancer Inst. 2003;95:1062-1071.
12. The Bethesda System for reporting cervical/
vaginal cytologic diagnoses: revised after the second
National Cancer Institute Workshop, April 29-30, 1991.
Acta Cytol. 1993;37:115-124.
13. Kulasingam SL, Hughes JP, Kiviat NB, et al. Evalu-
ation of human papillomavirus testing in primary
screening for cervical abnormalities: comparison of sen-
sitivity, specificity, and frequency of referral. JAMA.
2002;288:1749-1757.
14. Ratnam S, Franco EL, Ferenczy A. Human papil-
lomavirus testing for primary screening of cervical can-
cer precursors. Cancer Epidemiol Biomarkers Prev.
2000;9:945-951.
15. Schneider A, Hoyer H, Lotz B, et al. Screening for
high-grade cervical intra-epithelial neoplasia and can-
cer by testing for high-risk HPV, routine cytology or
colposcopy. Int J Cancer. 2000;89:529-534.
©2005 American Medical Association. All rights reserved.
Statistical analysis: Harris, Burk, Palefsky, Bang, Hall,
Silverberg, Xue, Strickler.
Obtained funding: Burk, Palefsky, Anastos, Minkoff,
Levine, Watts, Strickler.
Administrative, technical, or material support: Burk,
Palefsky, Anastos, Bacon, Levine, Watts, Strickler.
Study supervision: Burk, Palefsky, Watts, Strickler.
Financial Disclosures: None reported.
Funding/Support: HPV DNA testing is funded through
R01-CA-085178. All specimens and other data in this
study were collected by the Women’s Interagency HIV
Study (WIHS) Collaborative Study Group with cen-
ters (principal investigators) at New York City/Bronx
Consortium (Kathryn Anastos, MD); Brooklyn, NY
(Howard Minkoff, MD); Washington, DC Metropoli-
tan Consortium (Mary Young, MD); The Connie Wofsy
Study Consortium of Northern California (Ruth Green-
blatt, MD); Los Angeles County/Southern California
Consortium (Alexandra Levine, MD); Chicago Con-
sortium (Mardge Cohen, MD); Data Coordinating Cen-
ter (Stephen Gange, MD). The WIHS is funded by the
National Institute of Allergy and Infectious Diseases
with supplemental funding from the National Cancer
Institute and the National Institute on Drug Abuse
(U01-AI-35004, U01-AI-31834, U01-AI-34994, U01-
AI-34989, U01-AI-34993, and U01-AI-42590). Fund-
ing is also provided by the National Institute of Child
Health and Human Development (U01-CH-32632)
and the National Center for Research Resources (M01-
RR-00071, M01-RR-00079, M01-RR-00083).
Role of the Sponsors: The WIHS is an NIH-funded mul-
ticenter cohort study, and the funding sources had a
role in the WIHS study design; in the collection, analy-
sis, and interpretation of data; and in the prepara-
tion, review, and approval of the manuscript.
Previous Presentation: Presented in part at the 8th In-
ternational Conference on Malignancies in AIDS and
Other Immunodeficiencies (ICMAOI): Basic, Epide-
miologic and Clinical Research; April 29-30, 2004;
Bethesda, Md.
16. Nanda K, McCrory DC, Myers ER, et al. Accu-
racy of the Papanicolaou test in screening for and fol-
low-up of cervical cytologic abnormalities: a system-
atic review. Ann Intern Med. 2000;132:810-819.
17. ASCUS LSIL Triage Study (ALTS) Group. A ran-
domized trial on the management of low-grade squa-
mous intraepithelial lesion cytology interpretations. Am
J Obstet Gynecol. 2003;188:1393-1400.
18. Kinney WK, Manos MM, Hurley LB, Ransley JE.
Where’s the high-grade cervical neoplasia? the im-
portance of minimally abnormal Papanicolaou
diagnoses. Obstet Gynecol. 1998;91:973-976.
19. Wright TC, Sun XW, Koulos J. Comparison of man-
agement algorithms for the evaluation of women with
low-grade cytologic abnormalities. Obstet Gynecol.
1995;85:202-210.
20. Lonky NM, Navarre GL, Saunders S, Sadeghi M,
Wolde-Tsadik G. Low-grade Papanicolaou smears and
the Bethesda system: a prospective cytohistopatho-
logic analysis. Obstet Gynecol. 1995;85:716-720.
21. Lawless JF. Statistical Models and Methods for
Lifetime Data. New York, NY: John Wiley & Sons;
1982.
22. Cox DR. Regression models and life-tables. J R
Stat Soc B Stat Methodol. 1972;34:187-220.
23. Ellerbrock TV, Chiasson MA, Bush TJ, et al.
Incidence of cervical squamous intraepithelial
lesions in HIV-infected women. JAMA. 2000;283:
1031-1037.
24. Delmas MC, Larsen C, van Benthem B, et al.
Cervical squamous intraepithelial lesions in HIV-
infected women: prevalence, incidence and regres-
sion: European Study Group on Natural History of
HIV Infection in Women. AIDS. 2000;14:1775-1784.