July 12, 2002
HAART has led to declines in the incidence of other malignancies such as Kaposi's sarcoma and non-Hodgkin's lymphoma, but its effect on HPV-associated anogenital cancers is unclear. Dr. Palefsky reported that the incidence of anal cancer is 37-fold higher among HIV-positive men who have sex with men (MSM) compared with the general population of men. Anal cancer is most likely preceded by anal intraepithelial neoplasia (AIN) 3. The purpose of this study was to determine the effect of HAART on the prevalence and incidence of AIN 3 among HIV-positive MSM.
Of note, the abstract on the poster and the methods section on the poster, did not match. It was confusing to me why Dr. Palefsky chose to compare the current HIV-positive cohort with the historical controls from one of his previous studies rather than the 15 percent of the current population that is not on HAART.
Dr. Palefsky and colleagues have been prospectively following a cohort of HIV-positive MSM with AIN at the University of California, San Francisco. At baseline, and every six months, a questionnaire was administered to patients to obtain data on behavioral and medical risk factors for AIN including use of HAART. At each visit, an anal cytology and high-resolution anoscopy with biopsy of visible lesions were obtained. The level of AIN was classified using the more severe result of cytology and histology.
This is where the data becomes confusing. According to the abstract on the poster, 433 HIV-positive men enrolled at baseline, 15 percent were not on any HAART regimen. Twelve percent were diagnosed with AIN 3 at baseline. The risk of prevalent AIN 3 was 2.6 (95 percent CI 1.3-5.3) for men on HAART compared with those not on HAART after adjustment for CD4+ level. Over a 24-month follow-up period, 51 percent (95 percent CI 43-59) of HIV-positive men on HAART developed AIN 3 compared with 37 percent (95 percent CI 25-50) of men not on HAART (p = .11). (Comparison made on historical controls?)
However, in the text of the poster and during his oral presentation, Dr. Palefsky presented data on 357 men. Does this exclude the 15 percent (n = 65) not on HAART, plus others or are the men not on HAART included in this 357? Unfortunately, no one was present at their poster and I did not see any of the investigators to clarify these results. The results of the anal pap smears of the 357 men are as follows: normal = 10 percent, atypical squamous cells of undetermined significance = 7 percent, AIN 1 or condyloma = 29 percent, AIN 2 = 39 percent and AIN 3 = 13 percent.
Dr. Palefsky then compared this data to historical controls rather than the 15 percent ART-naive population or from a matched antiretroviral-naive control group at a primary care clinic. I think it is very important to recognize that these findings cannot be generalized to the average clinical practice. Dr. Palefsky has a referral clinic and therefore this is a biased population obtained either by advertising for their studies or referral from outside primary care physicians.
Dr. Palefsky concluded that the prevalence and incidence of AIN 3 were higher among HIV-positive men on HAART compared with HIV-positive men not on HAART -- even after adjustment for CD4+ level. HAART did not reduce the incidence of AIN 3 among HIV-positive MSM in this study. This is an observational cohort study and subjects were not randomized to HAART. The proportion of men with AIN 3 who will progress to cancer if left untreated is unknown. AIN 3 may take several years to progress. He suggested that the incidence of anal cancer will continue to rise in the HAART era as men with AIN 3 live longer.
As a former physician at San Francisco General, and after speaking with colleagues from the San Francisco area, we all commented that we had not seen that many cases of actual anal cancer. It remains unclear what the natural history of AIN 3 is. Dr. Palefsky did not present any data showing the risk of developing anal cancer. As he stated, the proportion of men who will go on to develop anal cancer is unknown and we do not know if treating AIN 3 will reduce the risk of developing anal cancer. There is concern among primary care providers about mandating screening programs to identify and treat AIN 3 before progression to cancer for HIV-positive MSM in the absence of knowing what the true outcomes are and effective treatment modalities.
There are insufficient data suggesting that treatment of AIN 3 will alter the natural history of the disease. In fact, it is unclear what the treatment for AIN 3 is and Dr. Palefsky did not discuss this. For AIN, there is insufficient data to recommend a treatment and the efficacy of treatment (widespread surgical fulguration?) to prevent anal cancer is unknown. Whereas, for anal cancer, combined chemoradiation leads to a cure in over 80 percent of patients. Given the lack of data and guidance for management of AIN 3, might it not be better to screen at-risk lesions and treat anal cancer early rather than have potential complications from radiation, chemotherapy or surgery for AIN 3 with uncertain benefit?
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