Progression of anal neoplasia is common among gay men with HIV

Nearly 40% of HIV-positive men with low-grade anal neoplasia may progress to high-grade neoplasia or anal cancer, according to a Spanish study presented on Wednesday at the 52^nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco. Younger age and shorter duration of HIV infection were risk factors for worsening disease.

Anal cancer caused by human papillomavirus (HPV) is more common among HIV-positive gay men, compared with the general population. While AIDS-defining cancers have declined since the advent of effective combination antiretroviral therapy, some studies indicate that anal cancer has become more common as people with HIV live longer.

HPV triggers abnormal cell growth including warts and neoplasia. Certain 'high-risk' or oncogenic types – in particular HPV-16 and HPV-18 – are the usual cause of anal and cervical cancer. But oncogenic HPV infection does not always result in tissue abnormalities, mild or low-grade dysplasia (abnormal tissue) does not always progress to more severe or high-grade neoplasia, and high-grade neoplasia does not always lead to cancer.

Carmen Hidalgo from Hospital Universitario Virgen de las Nieves in Granada, Spain, and colleagues looked at predictors of progression from low-grade anal intraepithelial neoplasia (AIN) to high-grade AIN or anal carcinoma in situ (localised cancer). They also evaluated the role of different screening methods for detecting high-grade AIN or anal cancer.

This prospective cohort study included 163 HIV-positive men who have sex with men seen at the hospital between April 2010 and April 2012 who participated in an anal neoplasia screening program.

The participants' average age was 36 years and they had been diagnosed with HIV for a median of 54 months. They reported a median of one sexual partner during the past year and nearly 75% said they used condoms. Only 3% were co-infected with hepatitis B or C. Half were smokers.

Participants had well-preserved immune function, with a current median CD4 cell count of about 600 cells/mm³ and a nadir (lowest-ever) count of 375 cells/mm³. Three-quarters were on antiretroviral therapy and 85% had an undetectable HIV viral load.

The men underwent baseline and follow-up evaluations that included anal cytology tests (examination of a cell sample under a microscope, better known as a Pap smear), PCR tests for HPV and anoscopy (visual examination using a lighted magnifying instrument, with application of vinegar to make lesions turn white).

PCR testing showed that 81% of participants had HPV infection; 68% had high-risk HPV types, 69% had low-risk types and 47% had both. The most common types were HPV-16 (26%); HPV-53 and HPV-6 (15% for both); and HPV-11, HPV-18 and HPV-51 (14% for each).

About two-thirds of participants received cytology tests by the time of data analysis. Within this group, 71% were classified as having modest cell abnormalities (referred to as low-grade squamous intraepithelial lesions, or LSIL), 3% had serious abnormalities (high-grade squamous intraepithelial lesions, or HSIL) and 27% had atypical squamous cells of undetermined significance (ASCUS).

Half of the participants underwent anoscopy by the time of analysis. Of these, 28% were normal, 47% were classified as having low-grade AIN (sometimes referred to as grade 1, as neoplasia staging terminology is not consistent), 17% were classified as having high-grade AIN (sometimes called grade 2/3) and 8% had anal cancer in situ.

The researchers calculated incidence rates of 14.9 cases per 1000 patient-months over a median of eleven months for high-grade AIN and 3.3 cases per 1000 patient-months for anal cancer.

Participants diagnosed with low-grade AIN received annual check-ups, and half had completed follow-up at the time of analysis. Follow-up anoscopies over a median of eleven months revealed that 33% progressed from low-grade to high-grade AIN, for a progression rate of 14.3 per 1000 patient-months. In addition, 5% progressed from low-grade AIN to anal cancer, a progression rate of 2.0 per 1000 patient-months. Hidalgo did not report how many people experienced regression or improvement of neoplasia.

The only two factors significantly associated with progression of low-grade to high-grade AIN or anal cancer were younger age and shorter time since HIV diagnosis. Progressors had an average age of 29.5 years compared with 34.1 years for non-progressors. Intervals since HIV diagnosis were 44 and 60 months, respectively.

Other analysed factors – including AIDS stage, HIV viral load, baseline and nadir CD4 count, use of antiretroviral therapy, HPV types, number of sexual partners, presence of other sexually transmitted infections, alcohol use and smoking – were not found to be independent predictors of progression.

This finding conflicts with previous studies that have seen a link between anal neoplasia and several of these factors, in particular HPV type and degree of immune deficiency. However, only 21 people with low-grade AIN completed follow-up and small samples sizes make it more difficult to demonstrate statistical significance.

Turning to the accuracy of screening methods, the researchers found that the sensitivity, or ability to identify true cases, of anal cytology alone for detecting high-grade AIN or anal carcinoma in situ was 80%, high-risk HPV testing was 93% and the two tests combined reached 100%. Positive predictive values were 18%, 22% and 19%, respectively.

Specificity, or ability to rule out false cases, was 34% for cytology alone, 23% for HPV testing alone and 8% for the two together. Negative predictive values were 90, 93 and 100%, respectively.

Combining the two tests was also highly accurate for diagnosing any degree of anal dysplasia, with a sensitivity of 98% and a negative predictive value of 80%.

Anal cytology and high-risk HPV testing together have good sensitivity and negative predictive value, the researchers said, concluding that if both tests are normal, a patient can be presumed not have neoplasia, allowing them to avoid unnecessary anoscopy.

Offering a different opinion at an ICAAC 'meet-the-experts' session earlier in the week, Joel Palefsky from the University of California at San Francisco recommended that all HIV-positive gay and bisexual men over age 30 should be screened for anal neoplasia using both cytology testing and digital-rectal examination.

Some abnormalities that do not show up on a Pap smear may be felt by a manual exam and vice-versa, he explained. HPV testing may be less useful because its prevalence in this population is "almost 100%".

Palefsky added that in his opinion an individual with any degree of abnormality should be followed up with anoscopy, not just those with suspected high-grade neoplasia. He acknowledged, however, that cost and limited "people power" can make this difficult to put into practice.

Hidalgo Tenorio C et al. Risk factors in the progression of low grade intraepithelial neoplasia (LGAIN) to high grade intraepithelial neoplasia (HGAIN) in a cohort of HIV-MSM.52^nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, abstract H-1921, 2012. View the abstract on the conference website.