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  AIDS 2002 Barcelona
Barcelona, Spain July 7-12 2002
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HAART Did Not Prevent or Reduce Rates of Anal Intraepithelial Neoplasia; Screening Recommended For All
Reported by Jules Levin
  This is not my area of expertise but I'm reporting what Dr Palefsky presented, I think this is important information. Joel Palefsky, MD, (University of California, SF) reported the results of a study in Barcelona at the oral Late Breakers on the effects of HAART on anal intrapithelial neoplasia grade 3. He reported the following as background. Although HAART has led to declines in the incidence of Kaposis sarcoma and non-Hodgkins lymphoma, the effect of HAART on HPV-associated anogenital cancers appears unclear; and it appears that the number of HIV-infected individuals with anal cancer associated with human papillomavirus is rising slowly. The biology of anal cancer is very similar to cervical cancer, they're both associated with HPV. The true pre-canerous lesion in cervical cancer is believed to be CIN 2 and CIN 3. Anal cancer appears to be most likely preceded by detectable changes in the skin of the anus called anal intraepithelial neoplasia (AIN), which are graded from AIN-1 through AIN-3, with the latter the most severe. AIN 2 and 3 are the precursors for anal cancer. The detection and treatment of CIN 2 and 3 are important to the prevention of cervical cancer, and it is likely that the detection and treatment of AIN 2 and 3 will prevent anal cancer.
The incidence of anal carcinoma has been reported to be 37 times higher among HIV+ MSM compared with the general population and may be rising. Pre-HIV anal cancer among MSM was epidemic: 35/100,000. Eventually, AIN may progress to anal carcinoma. The data on the effect of HAART on CIN are mixed. There are few data on the effect of HAART on AIN. Palefsky said HAART initiation is not associated with regression of AIN 2 or 3 within 6 months. So, what is the effect of HAART on the prevalence and incidence of AIN 2 and 3.
One of the challenges of this type of study is that CD4s and viral load can be different between patients on HAART and those not on HAART. These patients were a cohort (group) of patients (357 men HIV+ MSM) followed prospectively enrolled between 1998-2000. The pre-HAART group was 346 HIV+ men enrolled between 1991-1994. These men were used as controls, for comparison.
85% were non-Hispanic Caucasian. Average age 42. 57% college or post-college educated. At baseline and every 6 months patients had interview detailing medical history, drug use, sexual behavior; anal swab for cytology; anal swab for HPV testing- L1 consensus PCR followed by probing for 39 different HPV types; High resolution anoscopy with biopsy; blood for CD4 and viral load; development of AIN 2 or 3. Anal cytology graded using Bethesda cervical cytology criteria. Anal histology graded using standard cervical histology criteria. Results recorded as the more severe of the cytology and histology at a given visit. HAART defined as PI or NNRTI with at least a NRTI. 75% were on HAART, 12% non-HAART, and 14% no ART. CD4s were 200-500 for 47% of men, 37% >500, and 16% <200. Palefsky projected that when CD4s are <200 pre-HAART the incidence of AIN 2 and 3 increases more quickly than when CD4s are higher, and as CD4s increase the incidence decrease, as projected in a graph by him over 4 years; and when CD4s are over 500 pre-HAART the incidence is the lowest over the same 4 year period.
Palefsky conducted a time-point prevalence study and a prospective study in which he followed patients. At baseline 13% (47) had AIN 3; 39% (139) had AIN 2; 29% (102) had AIN 1; 3% indeterminate; 10% normal -- for a total of 357 men. The results showed a trend that being on HAART might increase risk of having AIN 2 or 3, and a trend suggesting that risk increased the longer a patient was on HAART. The risk for men on HAART having AIN 3 was 2.6 times compared to men not on HAART, after adjusting for the CD4 count. That is, regardless of immune function as measured by CD4 count which is considered somewhat of a crude measure of immune status. Using a univariate analysis found a low CD4 count (the highest risk was when cd4 <200) increased risk for developing AIN 2 or 3, and HIV viral load did not. Being on HAART increased risk. The level of consensus probe, which is an indicator of higher viral quantity, was a risk factor; as well, so was the number of specific HPV types detected. So was the presence or absence of HPV. However, using a multivariate analysis model, neither CD4 count or viral load were statistically significant. Two factors remaining significant in the model used were the number of HPV types detected, and whether or not patient was on HAART regimen: Risk was increased on HAART.
In looking at the prospective data, after 24 months of study following patients on or not on HAART the rates of AIN 2 and 3 were very high (2/3 of men had AIN 2 or 3), and were the same whether or not patient was on HAART. In comparing the patients on HAART to the control patient group, men on HAART progressed more quickly to AIN 2 or 3 regardless of whether CD4 count in the control group was >500, 200-500, or <200. Patients in the pre-HAART control group with >500 CD4s progressed the least quickly, patients with 200-500 progressed the next most quickly, and patients in the controls with <200 progressed the most quickly.
Palefsky concluded that in the time-point prevalence and prospective studies the use of HAART was associated with increased risk of AIN 2 or 3. His model left some doubt to him about the contribution of HAART to risk, so the magnitude of the increased risk of AIN 2 or 3 associated with HAART is uncertain. However, he said his take-home message is that "it is very likely that HAART definitely does not decrease the risk of AIN 2 or 3". He went on, HPV-associated anal cancer and AIN do not respond to HAART in the same way as other HIV-related malignancies. And cytology screening to detect AIN 2 or 3 followed by treatment should be strongly considered for HIV+ MSM whether or not they are on HAART to prevent cancer. Follow-up is required to see how long it takes for cancer to develop after AIN 3.


Dr Aberg takes a different view of the study from Dr Palefsky. She questions the reliability of his study findings.
Effect of HAART on Incidence of Anal Intraepithelial Neoplasia Grade 3 Among HIV-Positive Men Who Have Sex With Men
Judith A. Aberg, M.D. Source: The Body Conference coverage www.thebody.com
Effect of HAART on Incidence of Anal Intraepithelial Neoplasia Grade 3 Among HIV-Positive Men Who Have Sex With Men (LbOr21) Authored by Joel Palefsky, Elizabeth Holly, Mary Ralston, Naomi Jay, Michael Berry, Teresa Darragh
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-na´ve 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 AIN 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?