High frequency of recurrent high-grade pre-cancerous anal lesions in HIV-positive MSM

A high proportion of HIV-positive men who have sex with men (MSM) successfully treated for high-grade pre-cancerous anal lesions experience a recurrence of disease within 18 months, investigators from Barcelona report in the online edition of AIDS.

Risk factors for the recurrence of high-grade anal intraepithelial neoplasia (HGAIN) included a low nadir CD4 cell count, co-infection with hepatitis C virus (HCV), size of previously treated lesion and infection with two or more cancer-associated strains of human papillomavirus (HPV). Follow-up with high-resolution anoscopy (HRA) successfully detected all cases of disease recurrence.

“The risk of recurrence of HGAIN for HIV-infected MSM, despite undergoing effective treatment, is high,” write the authors. “To our knowledge, our study is the first to assess risk factors of recurrence including HPV infection, HIV infection, and characteristics of HGAIN.”

HIV-positive gay and other MSM have a high prevalence of anal infection with cancer-associated strains of HPV. Persistent infection can lead to the development of HGAIN, a precursor to anal cancer.

A systematic review and meta-analysis published in 2012 estimated that between 8% and 15% of men who have sex with men living with HIV developed HGAIN each year, and 3% - 6% of MSM without HIV. Dorothy Machalek and colleagues calculated that one in 377 men with HIV diagnosed with HGAIN would go on to develop anal cancer each year, and one in 4196 MSM without HIV.

Early diagnosis and prompt treatment of pre-cancerous lesions is therefore important. However, there is some evidence that even after successful therapy, a proportion of men experience recurrence of HGAIN.

Investigators from Barcelona, Spain, wanted to clarify the circumstances associated with disease recurrence and the best surveillance strategies.

They therefore designed an observational study involving 100 HIV-positive MSM with HGAIN who had a partial or complete response to electrocautery therapy to remove a lesion. The men were then followed at intervals of three to six months using HRA and anal cytology to see if there was a recurrence of HGAIN.

The study period was 2009 to 2016. The men had a median age of 43 years and the median time since diagnosis with HIV was a little under five years. The majority of men (84%) were taking antiretroviral therapy. Median current CD4 cell count was 629 cells/mm³ and 70% of men had an undetectable viral load.

As regards sexual behaviour, the men reported a median of 100 lifetime sexual partners and 66% reported a history of sexually transmitted infections.

Three-quarters of men had anal infection with an HPV type associated with a high risk of cancerous cell changes. The median number of electrocautery sessions was three per person, resulting in a complete response in 52% of men and a partial response in 48%.

Study participants were followed for a mean of 17.6 months (median 13.6 months) after treatment response. During this time, 39 individuals experienced a recurrence of HGAIN. In 24 people, recurrence was at the site of the previously treated disease, and was at a new site in the other 15.

The probability of recurrence was 24% after 12 months and 54% at 24 months.

Persistent infection with cancer-associated HPV strains was detected in 88% of men with disease recurrence compared to 51% of men without recurrence (p < 0.001).

Six men with recurrence had HCV antibodies (five with detectable HCV RNA). In contrast, only one man in the group without HGAIN recurrence had HCV antibodies (without HCV RNA) (p < 0.014).

After controlling for potential confounders, risk factors for HGAIN recurrence were a nadir CD4 cell count below 200 cells/mm³ (HR = 2.61; 95% CI, 1.06-6.44; p = 0.038), HCV co-infection (HR = 2.79; 95% CI, 1.04-7.53; p = 0.042) and large HGAIN lesions (HR = 8.27; 95% CI, 1.10-62.02; p = 0.04). Infection with at least two high-risk HPV types was of borderline significance (HR = 2.30; 95% CI, 0.98-5.42).

Disease recurrence at the same site was associated with low nadir CD4 cell count and large previous lesions. The emergence of lesions at a new site was associated with low nadir CD4 cell count.

In terms of monitoring strategies, HRA detected 100% of the cases of disease recurrence, with 79% detected because of abnormal anal cytology, with histology detecting 21% of cases.

“No cases that could not be detected via HRA were detected via anal cytology,” note the investigators.

“Patients with previously treated HGAIN are at a high risk of recurrence of the disease,” conclude the investigators. “The low nadir CD4 cell count, hepatitis C infection, and large HGAIN lesions were found as independent risk factors of recurrence. Regular posttreatment follow-up of these at-risk patients are mandatory, and HRA appears to be the best follow-up strategy.”