Precancerous anal lesions may be very common in some populations: protease inhibitor therapy may help

Two presentations at the EACS Conference in Cologne investigating anal cancer have found very different levels of the anal dysplasia (cellular changes) that may lead to anal cancer in HIV-positive patients.

A study from Spain of men who had no previous history of HPV related pathology found that 42% of those on antiretroviral therapy (ART) had some degree of anal dysplasia, and no fewer than 59% of those not on ART.

This study found somewhat lower rates of dysplasia in patients taking protease inhibitors (PIs), which backs up previous studies suggesting that PIs have some activity against human papilloma virus (HPV), the causative agent of anal dysplasia and cancer.

In contrast a study from Italy which looked at 205 male and female patients (80% male) consecutively enrolled at a single clinic found a rate of dysplasia of 11%.

It also found that there were high levels of infection with high risk-types of HPV other than types 16 and 18, the ones for which vaccines have been developed.

The study presented by Guillem Sirera of the Independent University of Barcelona studied 269 male patients enrolled in a new cohort of gay men called CARH-MEN. Notably, men with a documented previous history of anal dysplasia were excluded from the cohort.

The men were stratified according to whether they were ARV-naive and, if not, whether they had taken regimens containing PIs, NNRTIs, or both. Anal biopsies were taken and tests for HPV infection, HPV genotype, and anal cytology were performed.

Of the 269 men enrolled, 76% were treatment-experienced. Of these 205, 57 (28%) had only taken PI-containing regimens, 13% only NNRTI-containing regimens, and 60% both.

There were very high rates of HPV infection, with 89% of the treatment-naive men and 74% of those on ART infected. This difference in infection rates was statistically significant. Only 65% of those who had ever taken PIs were infected; this was significant in univariate analysis.

There was an extraordinarily high level of anal dysplasia in this group with over 40% of treatment-experienced and 60% of treatment-naive men with ‘anal precancerous lesions’. The rate in men who had taken PIs was 35% and this was significantly different both from the drug-naive and from men who had never taken PIs: the researchers calculated that PI treatment reduced the odds of having dysplasia by 64%.

On the other hand, ever having taken a treatment interruption was associated with a 75% increase in the odds of having dysplasia, and treatment interruption was also associated with a 4.4-fold times greater risk of infection with the most common cancer-causing variety of HPV, type 16, though being treatment-naive was not.

Dr Sirera, answering a question from the audience, said it was difficult to say why the anal dysplasia rates in this study were so high, though men at higher risk might be more motivated to volunteer for a cohort study.

Infection and dysplasia rates were lower in the second anal cancer study presented. In this Dr Andrea de Luca and colleagues from the Gemelli Polyclinic in Rome enrolled 189 consecutively-diagnosed patients. Patients still had to consent to anal biopsies, but Dr de Luca commented that few patients refused consent to be enrolled.

Of the group, 80% were men and 56% gay men. Fifty-three per cent of patients had had receptive anal intercourse. Although a quarter had had an AIDS diagnosis, their current CD4 count was 534 and CD4 nadir was not especially low (204). At baseline 89% were on ART.

De Luca and colleagues performed similar infection and cytology tests but also did genetic activation tests to look for the expression of the HPV genes E6 and E7. When these are expressed they enhance the chances of cancer and are usually expressed at much higher rates in HPV 16 and 18, the two riskiest types and the ones covered by the Gardasil and Cervarix vaccines.

Patients were re-tested a year later to measure progression or regression of HPV infection and dysplasia.

As might be expected from a consecutive sample, this was a varied group with 14% having had no sexual partners in the last year and 13% over 20 partners; 53% had never had receptive anal sex while 19% had had it with over 100 partners.

Fifty-eight per cent of the group had evidence of HPV infection and 44% had infection with multiple high-risk HPV types. Although the predominant high-risk type was HPV 16, infection with three high-risk subtypes (31, 33 and 35) not covered by vaccines were found in around a quarter of patients each.

In 90 (44%) of patients the HPV genetic activity could be measured and it was found that cancer genes were active in nearly three-quarters of patients with high-risk HPV. The genes expressed belonged to HPV 16 and 18, but also came from other subtypes: a third expressed cancer genes from HPV 45 and 20% from HPV 35.

Although men had a greater risk of high-risk HPV and heterosexuals 62% less, only previous AIDS was associated with infection in a multivariate model. Infection did not appear to be related to the frequency of anal intercourse. ART, unlike in the Spanish study, was not associated with lower levels of HPV infection or dysplasia.

As we said above, 11% of patients infected by HPV (19 patients) had anal dysplasia. Fifty-nine patients were followed-up after 12 months. The good news is that new infections with HPV were outnumbered by patients who became negative for infection, and progression of dysplasia was relatively uncommon. Five patients who were HPV negative became positive while ten who had been positive became negative. Seven patients developed new anal dysplasia but two who had had dysplasia were normal at follow-up.

Dr de Luca commented that the high frequency of cancer-gene expression was unexpected, and rare in HIV negative patients. His may explain why, as another cohort study from Belgium reported (de Wit), anal cancer is 46 times more common in people with HIV than in the general population.