Howard Minkoff; Linda Ahdieha; L. Stewart Massadb; Kathryn Anastosc; D.
Heather Wattsd; Sandra Melnicke; Laila Muderspachf; Robert Burkg; Joel
From the departments of Obstetrics and Gynecology, Maimonides Medical Center
and State University of New York Health Sciences at Brooklyn, New York, the
aDivision of Epidemiology, Johns Hopkins School of Public Health, Baltimore,
Maryland, bDepartment of Obstetrics and Gynecology, Cook County Hospital and
Rush Medical College, Chicago, Illinois, cDepartment of Medicine, Montefiore
Medical Center and Lincoln Medical and Mental Health Center, Bronx, New York,
the dNational Institute of Child Health and Human Development, the eNational
Cancer Institute, Bethesda, Maryland, the fDepartment of Obstetrics and
Gynecology, University of Southern California, the gDepartment of Pediatrics,
Microbiology & Immunology and Social Medicine, Albert Einstein College of
Medicine, and the hDepartment of Medicine, University of California at San
Francisco, San Francisco, California, USA.
Objective: Cervical intraepithelial neoplasia (CIN), a common condition among
HIV-infected women, has been linked to HIV load and immune status. Highly
active antiretroviral therapy (HAART) improves immunologic and virologic
status. This study was undertaken to determine the relationship between HAART
use and CIN.
Design: Cohort study. The Women's Interagency HIV Study (WIHS) in five cities
in the USA (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois;
Los Angeles, California; San Francisco Bay area, California; Washington,
District of Columbia).
Methods: HIV-infected women were followed every 6 months with Papanicolaou
smears and cervicovaginal lavage for human papillomavirus (HPV) DNA testing.
To characterize exposures that changed over time and to capture the dynamic
nature of cytologic changes, Papanicolaou smear findings from each
participant's consecutive visits were defined as a pair. We determined the
proportion of all pairs that exhibited either regression or progression,
according to HAART exposure, HPV results and Papanicolaou smear status. As
participants could contribute multiple pairs, inferences were based on robust
methods to adjust for correlated observations.
Results: Women with persistent HPV infection were more likely to have
progression of their lesions. After adjustment for CD4 cell count and
Papanicolaou smear status, women on HAART were 40% (95% confidence interval,
481%) more likely to demonstrate regression and less likely (odds ratio,
0.68; 95% confidence interval, 0.520.88) to demonstrate progression
Conclusions: HAART altered the course of HPV disease in HIV-infected women,
reducing progression and increasing regression. As HPV disease is a common
sex-specific manifestation of HIV disease this effect of HAART would be a
major additional benefit from this modality of therapy.
editorial note: so this raises a question regarding when is the best time for
a woman to begin HIV therapy, does it differ from men. The risk for HPV
related disease appears to me to be a consideration. CD4 and viral load were
important to improved outcome in this study.
With the introduction of more effective antiretroviral therapy, the spectrum
of disease in the AIDS epidemic has been
shifting. It is projected that 2040% of HIV-infected individuals will be
diagnosed with a malignancy . One malignancy
that is unique to women is cervical cancer, the end stage of human
papillomavirus (HPV)-associated cervical intraepithelial lesions. Numerous
studies have shown that HIV-infected women, particularly those with advanced
disease, have a greatly increased risk for the precursors to cervical cancer,
both those measured by histology [cervical intraepithelial neoplasia (CIN)]
and by cytology [squamous intraepithelial lesions (SIL)] . Recent data
have suggested that as many as one in five HIV-infected women with no
evidence of cervical disease will develop SIL within 3 years. These data
suggest a need to assess determinants of cytologic progression and to develop
interventions. The effect of HAART on
HIV-associated malignancies, particularly cervical lesions, has not been
HAART has the potential to influence the relationship between HIV and
cervical cancer precursors in two contrasting ways. First, by prolonging
lives it may lengthen exposure to HPV, thereby allowing the accumulation of
genetic somatic mutations that increase the likelihood of cervical disease.
Conversely, because HAART can decrease HIV viral load, and can partially
restore immune competence, HAART may mitigate the effect of HIV on the course
of HPV disease. To date, these possibilities have been assessed only in small
case series [23,24] and the implications of antiretroviral therapy for
cervical neoplasia are unclear. Therefore, to determine if HAART can
influence the course of HPV disease the following study was undertaken.
The Women's Interagency HIV Study (WIHS) is a prospective study of the
natural and treated history of HIV infection in women that enrolled 2059
HIV-seroprevalent participants at six clinical consortia (Bronx, New York;
Brooklyn, New York; Chicago; Los Angeles; San Francisco; Washington) between
October 1994 and November 1995. The recruitment methods and data collection
procedures for WIHS have been described previously . In brief,
participants undergo visits every 6 months that include an
interview-administered questionnaire, a physical examination, and the
collection of plasma, Papanicolaou smears, and cervicovaginal lavages for HPV
The primary goal of our analysis was to identify whether exposure to HAART
impacted rates of short-term (6 month) cytologic regression and progression.
The study population for our analysis of the impact of HAART on short-term
cytological regression and progression
analysis was composed of 1779 HIV-seropositive participants who had at least
one study visit after 1 October 1995 (the approximate date at which HAART
became available) and were tested for HPV infection during the 1 year
following their enrollment. The study's primary analyses were limited to
those individuals who had an oncognenic HPV infection (defined above). In
addition, we compared short-term cytological progression and regression rates
between those with and without an oncogenic HPV infection. Those with at
least one oncogenic infection were further characterized as having 1/3, 2/3
or 3/3 oncogenic HPV infections.
There were 741 women (41.6% of participants) with at least one oncogenic HPV
at visits one through three. Among women who had HPV tests at all three
baseline visits and who had at least one positive test (n = 507), oncogenic
HPV was detected at one, two, and three visits in 189 (37.3%), 145 (28.6%),
and 173 (34.2%) women respectively.
The group with oncogenic HPV was younger and more likely to smoke, to report
HIV treatment, to have SIL at baseline, to be younger at first coitus, and to
have more sexual partners. This group also had lower CD4 cell counts and
higher HIV viral loads. None of these variables were found to be associated
with cytologic progression or regression. In addition, ethnicity and report
of a prior sexually transmitted disease were not associated with these
Regression was more frequent (P < 0.001) and progression less common (P <
0.001) among women with no oncogenic HPV. Further, persistent HPV infection
significantly decreased regression rates and increased progression rates.
Among those with three measurements, regression rates among those with 1/3,
2/3, and 3/3 positive oncogenic HPV infections were 39.3%, 30.7% and 24.7%
respectively; overall progression rates were 16.2%, 23.6% and 24.6%
respectively (P < 0.001).
Cytological regression was also more likely among pairs characterized by HIV
RNA levels < 4000 copies/ml (39.4%) compared to pairs characterized by RNA
levels of 400020 000 copies/ml (27.7%), 20 000100 000 copies/ml (29.9%),
and > 100 000 copies/ml (22.7%) (P < 0.001).
Cytological regression was also more likely among pairs characterized by CD4
cell counts > 500 compared to pairs characterized by CD4 cell counts of
200500 and < 200 (21.6%) (P < 0.001).
Cytological progression was less likely among pairs of measurements where the
RNA level at the index visit was < 4000 copies/ml (16.4%) compared to RNA
levels of 400020 000 copies/ml (19.8%), 20 000100 000 copies/ml (23.4%)
and > 100 000/ml (27.5%) (P < 0.001). There was no association noted between
CD4 cell count and progression; specifically, 17.9% of pairs with CD4 cell
counts > 500 progressed, as compared to 21.8% of pairs with CD4 cell counts
200500 ? and 21.2% of pairs with < 200.
Overall, pairs of measurements were 1.4 times [95% confidence interval (CI),
1.041.82] more likely to demonstrate regression on HAART. A beneficial
effect of HAART was observed on progression. Pairs of visits on HAART
demonstrated a 0.68 times (95% CI, 0.520.8) likelihood of
progression of disease, i.e., pairs contributed off HAART were 1.5 times (95%
CI, 1.31.9) more likely to progress as compared to pairs contributed on
In this large cohort of HIV-infected women with high-risk HPV DNA, we found
that the use of HAART was associated with significantly increased cytological
regression and decreased cytological progression, after controlling for stage
of HIV disease and severity of cytological disease. We also confirmed
previous reports that found high rates of HPV carriage,
which were often persistent, among HIV-infected women. Ho reported that
persistence of infection with HPV was related to the risk of persistent
cervical dysplasia using similar methods . We found that among
HIV-infected women persistent carriage of HPV and high viral load were
associated with cytologic progression and that low viral load and high CD4
count were associated with regression.
Relatively little attention has been paid to the relationship of HAART to
malignancies in general or to cervical disease in particular. Since the
introduction of HAART, some studies have shown stable levels of non-Hodgkin's
lymphoma and other cancers, and declining rates of Kaposi's sarcoma and
primary brain lymphoma among HIV-infected individuals [22,40]. Individual
cases in which human herpes virus type 8 (HHV-8) was cleared from peripheral
blood mononuclear cells following initiation of antiretroviral therapy have
also been reported . Conversely, at least one study suggested that few
anal SIL regress in response to HAART .
In our cohort, the regression rate among women with high-grade and low-grade
lesions who did not receive HAART were similar to, or greater than, those
seen among women receiving protease inhibitors in the Heard study. However,
when the rates of progression and regression among women with high-risk HPV
who were on HAART were contrasted with changes among similar women not on HAAR
T, the beneficial effect of antiretroviral therapy became clear. These
results are particularly striking as women in both groups were comparably at
risk in terms of the presence of oncogenic HPV. These results were also
supported by multivariate analysis that included markers of HIV disease stage
as well as other factors linked to changes in Papanicolaou smears over time.
The association between HIV disease and both HPV infections and SIL has been
widely noted .Sun detected HPV at an initial examination in 56% of
HIV-seropositive women and 31% of HIV-seronegative women . Minkoff
reported a prevalence of oncogenic HPV in 32.5% of HIV-infected and 17.0% of
HIV-uninfected women . Palefsky noted a correlation between HPV detection
and low CD4 cell counts and high HIV viral loads in an earlier report of
from this cohort . Other authors have reported a similar inverse
association between immune status and HPV detection rates [15,4648].
Several investigators have demonstrated that in addition to an increased
frequency of HPV infection, there is an increased frequency and severity of
HPV-associated cervical lesions among HIV-infected women. Massad found that
rates of SIL were five times greater among HIV-infected than uninfected women
. Mandelblatt, in a review of 15 studies comparing the association between
HIV, HPV and CIN found that the odds ratio for CIN was eight times greater
for HPV-infected women and that there was an interaction between HPV and HIV
(P = 0.001) .
The clinical course of CIN has been noted to be marked by more progression
and less regression among HIV-infected women [3,48]. Ellerbrock has recently
reported that among 328 HIV-infected women without SIL at baseline 20%
developed SIL during approximately 30 months of follow-up. That rate of
progression was significantly greater than among uninfected women .
Massad, in an analysis of women in this cohort has shown that progression of
SIL was linked to HIV serostatus and to viral load and CD4 cell count .
As noted, we have also found that progression and regression may be linked to
immune status and viral load.
One possible explanation for the linkage of both serostatus and immune status
to malignancies may be that HIV-associated products up-regulate cell
proliferation . Reduction of viral load and restoration of host immunity
thus might retard the progression of these neoplasias.
It is impossible, however, to be certain that the association between the use
of HAART and a less aggressive course of HPV disease is mediated simply by a
reduced HIV viral load that results in less up-regulation of HPV. That HAART
could have a direct antiviral effect on HPV has been suggested as a possibile
explanation of the lack of correlation between decreases in HIV viral load
and regression of cytologic abnormalities in women on HAART.
A similar mechanism has been posited as an explanation for the
clearance of HHV-8 in a woman on HAART . The resurgent immune system of
the treated woman might also be better
able to control' HPV infections. Burk has shown a reduced rate of HPV as
women age, even when controlling for the number of lifetime sexual partners
, suggesting that there might be acquired immunity to HPV from past
exposure' . This mechanism has been proposed to explain the loss of
cytomegalovirus (CMV) viremia following HAART therapy, even in the absence of
specific anti-CMV therapy . Similarly, Ahdieh, who reported that the
likelihood of chronic carriage of HPV is linked to immune status, has
suggested that the reversal of immunosuppression possible in the current era
of potent antiretroviral therapy may reduce HPV persistence and consequently
the increased risk for cervical neoplasia' .
If these findings are confirmed, it would suggest that HAART may reduce the
need for colposcopy, biopsy and therapeutic interventions among HIV-infected
women, much as it has been reported by others to reduce the need for
chemoprophylaxis against opportunistic infections . Furthermore, it
underscores the importance of full access to HAART by those for whom it is