Cervical carcinoma shares many of the same risk factors as HIV
infection.[23,24] As a result, the observed increase in cervical cancer in the
HIV-infected population may be secondary to several confounders, including
number of sexual partners, history of sexually transmitted diseases, tobacco
use, age, and ethnicity. Nonetheless, the clinical course of cervical cancer
in HIV-infected individuals seemed to be more aggressive and refractory to
conventional treatments than in the HIV-negative population.[23,25]
Consequently, in 1993, the Centers for Disease Control and Prevention (CDC)
added cervical cancer to its list of AIDS-defining conditions. Whether cervical
cancer should remain an AIDS-defining condition remains a controversial topic.
Epidemiology and Pathogenesis
Despite data demonstrating a fourfold risk of cervical cancer for
HIV-infected women compared to the general population, several facts argue
against a causal relationship between HIV infection and cervical cancer.
Unlike KS and NHL, there was not an increased incidence of cervical cancer
coincident with the AIDS epidemic. Similarly, there does not seem to be a
progressive risk of invasive cervical cancer in HIV-infected women as they
become more immunocompromised. Data from the AIDS-cancer linkage studies
indicate that the fourfold relative risk of cervical cancer remains stable from
5 years prior to an AIDS diagnosis to 2 years after an AIDS diagnosis.[23,26,27]
Cervical dysplasia, however, may be more influenced by immunosuppression than
invasive cancer. Maiman et al reported that HIV-infected women with cervical
intraepithelial neoplasia had lower CD4 counts than HIV-infected women without
cervical intraepithelial neoplasia. Frisch and colleagues attempted to
investigate the interactions of immunosuppression and human papillomavirus
(HPV)-associated neoplasia in their study of 51,760 HIV-infected women in the
National AIDS-Cancer Match registry. This group reported a relative risk of
4.6 for in situ cancers of the cervix diagnosed in the post-AIDS time period as
compared to prior to an AIDS diagnosis. Clearly, increased surveillance may have
been a significant confounder.
At the molecular level, a potential contribution of HIV to cervical cancer
development is plausible. A critical role for HPV in the pathogenesis of
cervical neoplasia is well-described. HPV subtypes 16, 18, and 31 are
particularly oncogenic. This oncogenicity may result from the affinity of HPV
peptides E6 and E7 for the tumor suppressor genes p53 and Rb.[30,31]
Inactivation of these tumor suppressor genes leads to dysregulation of cell
cycling, defective DNA repair, and increased cellular proliferation. Tumor
evolution may be enhanced by interactions between HIV and HPV, including
decreased cellular immunity, altered cytokine expression, and transactivation of
HPV genes by HIV-encoded proteins (eg, tat).
Several reports indicate that HIV-associated cervical neoplasia may be more
aggressive and refractory to standard treatments than cervical neoplasia in
HIV-negative women.[25,32] Maiman and colleagues compared 44 HIV-infected women
treated for cervical intraepithelial neoplasia to 125 HIV-negative women with
cervical intraepithelial neoplasia. Nearly 40% of HIV-infected women
developed recurrence after standard treatment (cone biopsy, laser ablation, or
cryotherapy), compared to 9% of HIV-negative women. Wright and colleagues
confirmed this, noting cervical intraepithelial neoplasia recurrence rates
of 59% in HIV-infected women compared to 13% in HIV-negative women.
There are some data showing that the higher recurrence rates for cervical
intraepithelial neoplasia in HIV-infected women may be a consequence of more
extensive dysplasia compared to seronegative women. Severity of
immunosuppression may be an additional risk factor for recurrence.[31,34]
Fruchter and colleagues found that the median CD4 count of HIV-infected women
with recurrent dysplasia was lower than that of HIV-positive women without
Prior to HAART, Maiman and colleagues described a cohort of seven
HIV-infected women with cervical cancer, all of whom developed recurrent disease
after appropriate therapy and eventually died from metastatic cervical cancer
with a median survival of 10 months. This compares to a 5-year survival rate
of 35% to 60% for HIV-negative women diagnosed with locally advanced cervical
cancer. This same group found that HIV-infected women were significantly
less likely than HIV-negative women to have early-stage cervical carcinoma at
Again, confounders may be responsible for the observed differences in
presentation between HIV-infected and -uninfected individuals. Fruchter et al
compared the clinical characteristics of 132 HIV-negative women with cervical
cancer to those of 28 HIV-infected women with cervical cancer. Although
univariate analysis showed that HIV infection was associated with a threefold
increased likelihood of advanced disease at presentation, multivariate analysis
showed that only lack of Pap smear and duration of symptoms were predictive of
advanced disease at diagnosis.
Impact of HAART
Few data exist on the impact of HAART on the incidence or clinical course of
cervical carcinoma. Most studies comparing incidences of AIDS-associated
malignancies in the pre- and post-HAART eras focus on changes in KS and NHL.
Given the long natural history of progression from cervical intraepithelial
neoplasia to invasive cancer and the relative infrequency of cervical cancer,
changes in its incidence are difficult to demonstrate.
In a meta-analysis of over 20 cohort and case-control studies, Beral and
colleagues found no significant decline in the incidence of cervical cancer in
the HAART era compared to the period before the widespread use of HAART. In
fact, this group reported a rate ratio of 1.9 (99% confidence interval [CI]:
0.77-4.56) for invasive cervical cancer diagnosed in the 1997 to 1999 period
as compared to the 1992 through 1996 period (incidence of 1.1/1,000
patient-years for 1992 through 1996 vs 2.1/1,000 patient-years for 1997 through
The improved immune function resulting from HAART would be expected to result
in regression and reduced incidence of dysplasia. Indeed, there are some data
showing that HAART may be affecting the incidence and clinical course of
cervical dysplasia. Delmas and colleagues reported that women undergoing
HAART had approximately half the risk of developing cervical intraepithelial
neoplasia as HIV-infected women not undergoing HAART. Heard and colleagues
reported a decreased prevalence of cervical intraepithelial neoplasia after 5
months of potent antiviral therapy.
According to the CDC’s proposed guidelines for cervical neoplasia
screening, when HIV infection is first diagnosed, a cervical Pap smear should be
part of the initial evaluation.. Further recommendations are as follows:
- If the initial Pap smear is normal, a second Pap smear could be repeated
at approximately 6 months.
- If both Pap smears are normal, annual Pap smears could follow (some
clinicians recommend semiannual Pap smears).
- If any Pap smear reveals atypical squamous cells of unknown origin (ASCUS)
or cervical intraepithelial neoplasia, refer the individual for colposcopy with
biopsy of abnormal area.
Treatment of cervical dysplasia in HIV-infected women is not significantly
different than treatment of seronegative women, with the caveat that recurrence
is more common. Institution of HAART may decrease the recurrence rate.
Robinson found a recurrence rate of 17.6% after standard excisional therapy for
cervical intraepithelial neoplasia in HIV-infected women treated with HAART
compared to a 70% recurrence rate in women not treated with HAART.
A recent randomized study by Maiman established a
role for topical fluorouracil (5-FU) in decreasing risk of recurrent
dysplasia. A total of 101 HIV-infected women with cervical intraepithelial
neoplasia were randomly assigned to treatment with 6 months of biweekly 5-FU (2
g) vs observation after standard excisional or ablative therapy. After 18 months
of follow-up, women treated with 5-FU were significantly less likely to have
recurrence than controls (28% vs 47%, P = .04). Furthermore, women in the
observation-only arm were more likely to have high-grade dysplasia at
recurrence. A subset analysis demonstrated that time to recurrence was longer in
women simultaneously treated with HAART.
Invasive Cervical Carcinoma
Treatment recommendations for seropositive
women with invasive cervical cancer are no different than for seronegative
women. Surgical therapy for early-stage disease and chemoradiotherapy for more
advanced tumors with curative intent is appropriate. There are few data to
show whether HIV-infected women are more likely to experience complications of
therapyspecifically, myelosuppression and radiation proctitisthan their
HIV-negative counterparts. Similarly, the impact of HAART on treatment
outcomes is unknown. At the very least, the combination of HAART with standard
therapy is expected to have acceptable toxicity and result in fewer intercurrent
opportunistic infections, as has been demonstrated in treatment of KS and NHL.
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