Hivassociated Squamous Cell Cancer Of The Cervix Epidemiology of HIVAssociated Cervical Cancer

Since 1993, invasive cervical cancer has been listed by the CDC guidelines as an "AIDS-defining" condition. However, quantifying the contribution of HIV infection in the development of cervical cancer among HIV-infected women remains unclear. Although immunosuppression after organ transplantation has been shown to enhance the onset and progression of HPV-related tumors,289 a 1996 study by the International Agency for Research on Cancer (IARC) which evaluated the relationship between HIV and cervical cancer found no conclusive evidence that HIV per se increased the risk of cervical cancer among HIV-infected women.289 Subsequent studies continue to yield conflicting results. In developed countries, with access to HAART, there have been several studies that have shown an increased risk of cervical cancer. Studies conducted in Southern European countries have found that the increased risk of invasive cervical cancer ranged from 3.1 to 15.5 among HIV-infected women.116,290,291 In addition, using a national

AIDS-cancer linked registry database of cases through 1998, Frisch et al.280 found a relative risk of 5.4 for invasive cervical cancer among HIV-positive women compared with the general population. Data from South Africa have also shown an increased risk of cervical cancer.292 However, no increase in cervical cancer has been noted among case-control studies from multiple African countries where endemic rates of cervical cancer are higher and women have shorter survival, such as Rwanda, Cote d'Ivoire, Zambia, or Kenya.293-296

There appears to have been little change in the incidence of invasive cervical cancer in recent years associated with HAART. A study conducted by the International Collaboration on HIV and Cancer 2000 compiled 23 studies from North America, Europe, and Australia, evaluating the incidence of cervical cancer among HIV-infected women from 1992 to 1999. No significant increase in the incidence rate of cervical cancer was noted during the study period, particularly since the widespread use of HAART.297 However, longer follow-up time is necessary before definitive conclusions are drawn regarding the effect of HAART on invasive cervical cancer incidence.

Epidemiology of CIN in HIV-Infected Women

The relationship between HIV-infection and increased prevalence of CIN has been shown in many studies. Mandelblatt et al.298 performed a meta-analysis of 15 cross-sectional studies published between 1986 and 1998 that evaluated prevalence of cervical neoplasia, HPV infection and HIV infection among women. They found that among women infected with HPV, HIV-infected women were significantly more likely to develop cervical neoplasia, and that this effect was related to degree of immunodeficiency. Several other recent studies have also shown that HIV-infected women are at higher risk for CIN. A cross-sectional study conducted by the Women's Interagency Health Study (WIHS) group299 found that 38% of HIV-positive women had abnormal cytologic findings compared with 16% of HIV-negative women. In another cross-sectional multicenter study, Duerr et al.300 also found that HIV-positive women were more likely than HIV-negative women to present with atypical cervical cytology. Finally, Ahdieh et al.301 found that 13% of HIV-positive women versus 2% of HIV-negative women had abnormal cytological findings. They also found that HIV-positive women had a much lower rate of HPV clearance on follow-up exams, and that in a multivariate model, the increased rate of CIN among HIV-positive women was fully accounted for by HPV persistence.

Screening Guidelines for HIV-Infected Women

Current United States Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA) guidelines302 recommend that HIV-positive women undergo a complete history, and pelvic exam as part of cervical cytologic assessment at the time of initial evaluation.A pap smear every 6 months is recommended for the first year after HIV diagnosis, and if both are normal, a yearly pap smear may be obtained thereafter.Women with abnormal pap smears should undergo colposcopy and can be subsequently managed according to published universal guidelines.303 In addition, Tate et al.304 found that the recurrence rates of CIN are high among HIV-infected women, but a separate study found that HAART may decrease the recurrence of CIN among HIV-infected women after therapy.305

Effect of HAART on Cervical Cancer and CIN

Although HAART has significantly improved the survival of HIV-infected individuals through immune reconstitution and has decreased the incidence of opportunistic infections, the effects of HAART on HPV infection and CIN among HIV-infected women remain unclear. While three small retrospective studies did not find a significant reduction in risk of cervical dysplasia among women on HAART,306-308 several other studies have found a reduction in cervical dysplasia risk related to HAART. In a cross-sectional study, Heard et al.309 did not find any change in prevalence of HPV infection 5 months after HAART initiation in 73 HIV-positive women, but the prevalence of CIN decreased significantly. Greater increases in CD4 cell counts after initiating HAART were also associated with CIN regression. The largest retrospective analysis performed by the WIHS group found that among 741 HIV-positive women, women on HAART were 40% (95% CI, 4-81) more likely to exhibit a regression of cervical lesions and were also significantly less likely to have progression of CIN (OR 0.68).310 Heard et al.311 conducted another prospective analysis evaluating the effect on HAART on time to regression of CIN in 168 women and found that the hazard ratio for the regression of CIN was 1.93 (95% CI, 1.14-3.20) for women on HAART compared with those on less effective or no therapy.

The conflicting observations regarding the effect of HAART on cervical squa-mous intraepithelial lesions (SIL) or CIN from these reports are likely in part due to the design differences, differences in inclusion criteria, differences in end points, and different statistical methodologies employed by the authors. However, taken together, it appears that HAART has a modest beneficial effect on progression of HPV-related cervical disease.

Treatment of Cervical Cancer in HIV-Positive Women

Women with AIDS and cervical cancer have been shown to have a significantly higher mortality than those without AIDS. In the pre-HAART era, data from the National Center for Health Certificates from 1990 through 1995 found that relative risk of cervical cancer for women aged 25-44, adjusted for race, was 5.5 for in HIV-infected women compared with HIV-negative women.312 In the postHAART era (1996-2000), a recent study linking the New York state cancer registry and the New York City HIV/AIDS registry found that the 24 month survival for women with AIDS was 64% compared with 74% among women without AIDS. The adjusted hazard ratio of death at 24 months for women with AIDS was 1.8 (95% CI 1.1-3.2) compared with women without AIDS.

Invasive cervical cancer diagnosed in women with HIV infection is treated using the same criteria and protocols as those women without HIV infection, as long as no other contraindications for treatment exist. In addition, close post-treatment surveillance is also recommended.

HIV-ASSOCIATED SQUAMOUS CELL CANCER OF THE ANUS Epidemiology of HIV-Associated Anal Cancer

In the 1960s, the annual incidence of squamous cell cancer of the anus (SCCA) among men in the United States was relatively low and stable, with approximately 0.5 cases per 100,000 persons.313,314 The disease was primarily found among older persons, with a 2:1 female to male ratio.313,314 However, a recent US population based analysis of the Surveillance, Epidemiology and End Results (SEER) program data found that the incidence of SCCA in the US among men increased from 1.06 per 100,000 in 1973-1979 to 2.04 per 100,000 in 1996-2004.315 Other recent studies have shown a steady increase in the incidence of SCCA during the past three decades,313,314 with significant increases among never married men in the San Francisco Bay Area.314,316

In addition, large retrospective AIDS-Cancer Registry Match studies and prospective studies of HIV-infected cohorts have shown an increased risk of SCCA among HIV-infected individuals. Compared to the general population, the relative risk for SCCA in the national US AIDS Cancer Registry match was 37.9 (33.0-43.4) for men and 6.8 (2.7-14) for women.158 The incidence of SCCA among HIV-infected populations reported from prospective cohort studies ranged from 3.9 to 92 per 100,000 and the relative risks reported ranged from 33.4 to 115. In addition, the widespread introduction of HAART in industrialized nations does not appear to have changed the incidence of SCCA in these studies.317-319

Epidemiology of HIV-Associated Anal Intraepithelial Neoplasia

There have been many studies that have reported the prevalence of AIN among HIV-infected men and women. Sixteen studies demonstrated that between 41 and 97% of HIV-infected men are found to have anal dysplasia on anal pap smear screening.320-333 Palefsky et al.334 also found that the relative risk (RR) of developing high grade squamous intraepithelial lesions (HSIL) was 3.7; (95% CI 2.6-5.7) for HIV-positive men who have sex with men (MSM) compared to HIV-negative MSMs. In addition, five studies have shown that between 14 and 28% of HIV-

infected women are found to have anal dysplasia.276,335-338 In a study evaluating the prevalence of HPV DNA in anal swabs of HIV-positive and HIV-negative women, 76% of HIV-infected and 42% of HIV-negative women had HPV detected.336

Screening for Anal Cancer

As shown in the previous section, HIV-infected individuals are at an increased risk for SCCA and AIN. In addition, SCCA shares many biologic similarities with cervical cancer, including detectable dysplastic precursor lesions and high-risk HPV

infection. Thus, the institution of annual anal pap screening for HIV-infected patients has been recommended.339,340 Anal pap smears are obtained by randomly obtaining squamous cells from the anal canal using a Dacron swab. They are then fixed in liquid fixative medium. Similar to cervical cytology protocols, abnormal anal cytologic findings are confirmed by high-resolution anoscopy (HRA) directed biopsy of visualized lesions.The 2001 revised Bethesda System of cytologic classification includes a basic primer on anal cytology and uses the system of cervical cytologic classification as an accepted means for classifying anal cytology.341 Anal pap smears have a similar sensitivity and specificity to cervical pap smears.342-346 Although there are no definitive clinical studies showing that anal pap smears decrease SCCA-related morbidity and mortality among HIV-infected individuals, a recent cost-effectiveness analysis found that the incremental cost-effectiveness ratio per quality-adjusted life year saved was $16,000, which is similar to other widely accepted screening procedures.347

Effect of HAART on Anal Cancer and Anal Dysplasia

Only eight small case series (ranging from 4 to 26 patients) describe outcomes of HIV-associated SCCA, with 5-year survival ranging from 47 to 60%.348-355 The majority of cases were diagnosed at either stage 1 or 2 (localized tumor without lymph node invasion) and received combined chemoradiotherapy. Most series reported some toxicity associated with therapy and with one reporting up to 50% of patients unable to complete planned therapy.356-362 Among three studies that specifically compared survival among patients with SCCA in the pre-HAART versus HAART eras, there was a nonsignificant trend toward improved survival, better tolerability of chemoradiotherapy, and improved local tumor control in the HAART era.319,356,357,362 However, a recent study linking the New York state cancer registry with the New York city HIV/AIDS registry found that in the HAART era (1990-1996) the 24-month survival was 76% for patients with AIDS, compared to 78% for patients without AIDS, suggesting that in the HAART era, HIV-infected patients with SCCA have equivalent survival with HIV-negative patients.368

Like studies evaluating the effect of HAART on cervical dysplasia, studies evaluating the effect of HAART on anal dysplasia also report conflicting results, likely related to the significant design and methodological differences among these studies. Palefsky et al.320 compared the rates of progression and regression of anal dys-plasia after 6 months of HAART. They found that the likelihood of lesion progression or regression was not affected by HAART initiation, but they noted that among the patients starting HAART at higher CD4 counts, HAART demonstrated a nonsignificant benefit on anal dysplasia lesions. In a subsequent study, Palefsky et al.363 performed a cross-sectional analysis on the prevalence of AIN 3 among a cohort of 433 HIV-positive men. They found that men on HAART had an increased risk of 12.6 (95% CI, 2.4-64) for AIN 2 or 3 after adjustment for CD4 count. In contrast,Wilkin et al.323 conducted a cross-sectional study evaluating anal HPV infection and anal dysplasia in 98 HIV-positive men. In a multivariate analysis they found that HAART and higher nadir CD4 count were significantly protective for anal dysplasia by histology, but were not protective of anal HPV infection. Therefore, it remains unclear if HAART initiation influences the natural history of AIN in HIV-infected individuals.

Treatment outcomes for anal dysplasia have only been reported for small case series. Current treatment options are similar for HIV-positive and HIV-negative individuals. These treatments include surgical ablation, infrared coagulation, imiquimod, and topical 5-FU.364-367

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