IAS: HPV diversity suggests value of HIV-positive gay men receiving Gardasil

Michael Carter
Published: 09 August 2007

Investigators from the United States are suggesting that there is a case for all HIV-positive gay men (indeed all gay men, regardless of their HIV infection status) to receive the Gardasil vaccine against the cancer-causing strains of human papilloma virus (HPV).

In research presented to the recent International AIDS Society Conference in Sydney, doctors from the US Department of Veterans Affairs and Northwestern University in Illinois found that 41% of HIV-positive gay men were infected with HPV strains 16 and 18, which are implicated in 70% of cases of anal cancer and are covered by the recently-approved Gardasil HPV vaccine.

Given the prevalence of HPV-16 and -18 infection, the investigators nevertheless believe that mass HPV vaccination of gay men would be justified and could prevent many cases of anal cancer in gay men.

The investigators also found that DNA screening of cells obtained from anal PAP smears would help detect a higher number of patients with potentially cancerous cells changes in the anus. Furthermore, they found that men with abnormal anal cells had significantly lower CD4 cell counts than men with normal anal cytology.

A second study presented to the Sydney conference found considerable diversity of HPV infection in HIV-positive men, and a separately published Australian study has found a much higher than expected incidence of pre-cancerous cell changes in surgically removed anal/perianal warts, particularly in HIV-positive men. They suggest that this could indicate that cases of anal cancer are likely to increase in the future.

HPV diversity amongst US gay men

The incidence of anal cancer in gay men exceeds that of cervical cancer in women, and HIV-positive gay men have a particularly high risk of anal cancer. Cancerous and pre-cancerous cell changes in the anus are related to HPV infection and the same strains of HPV that are associated with a high risk of cervical cancer are also associated with anal cancer.

Only two studies have looked at the prevalence of HPV infection in HIV-positive gay men and both these studies were conducted within a few years of potent antiretroviral therapy becoming available. Investigators therefore designed a pilot study using PAP smears to screen HIV-positive gay men for abnormal anal cells. The results of these PAP smears were then tested further using HPV DNA testing, and an analysis was undertaken to determine the prevalence of the cancer-causing HPV genotypes 16 and 18 which the Gardasil vaccine provides protection against.

A total of 70 individuals who were receiving HIV outpatient care from the US Department of Veterans Affairs were enrolled in the study. The men had a median age of 53 years and a median CD4 cell count of 535 cells/mm3.

In all, a third of patients (23/70, 33%) had abnormal anal PAP smear result. However, significantly more patients, 47% (33/70) had a positive HPV test result.

Of the 23 patients with an abnormal PAP smear, 70% (16/23) had a positive HPV test. The investigators also found that over a third (17/47, 36%) of individuals with a normal PAP smear were positive for HPV. The percentage of patients with either an abnormal PAP smear or a positive HPV test was 57%, suggesting that using HPV testing in addition to PAP smears would lead to the diagnosis of more patients with potentially pre-cancerous or cancerous call changes in the anus.

Genotypic testing was performed on 32 of the 33 samples positive for HPV. The investigators found that 31% (10/32) were positive for the cancer-causing HPV-16. A further four samples (3%) were positive for HPV-18, which is also associated with a high risk of cancer and 7% (2/32) were dually infected with both HPV-16 and HPV-18. However, the majority of individuals (59%, 19/32) with anal HPV infection had infection with a strain of HPV other than HPV-16 or HPV-18.

In further analysis, the investigators found that patients with normal anal cytology had significantly higher CD4 cell counts than men with abnormal cells in the anus (mean 618 cells/mm3 versus 458 cells/mm3, p = 0.04). They suggest that “when the CD4 cell count has dropped to a low enough point, the patient does not (or cannot) clear HPV infection and thus it (HPV) is more likely to cause cytological abnormalities.”

The investigators note that the safety and efficacy of the Gardasil HPV vaccine in men is currently being examined in a large clinical study. Should the results of this trial be favourable, the 41% prevalence of HPV genotypes 16 and 18 in their study suggests to the investigators a “strong rationale” for vaccinating all HIV-positive gay men, indeed all HIV-negative gay men with Gardasil. They suggest that such a strategy would yield “significant decreases in morbidity and mortality.” The investigators also argue that more individuals with abnormal anal cells would be diagnosed if HPV DNA testing was used in conjunction with PAP smears.

HPV and HIV-positive men in Italy

A second study presented to the Sydney conference also looked at the distribution of HPV genotypes in men with both HIV and HPV. The study was performed in Milan and detected 30 different HPV genotypes in 278 HIV-positive men with HPV. The most commonly observed HPV genotypes were HPV-6 (20%), HPV-16 (19%), HPV-11 (18%), HPV-58 (5%), HPV-30 (5%) and HPV-18 (2). Multiple HPV infections were found in 47% of men. The investigators also found that patients with multiple HPV infections were significantly more likely to have infection with potentially cancer-causing strains of HPV (p < 0.0001), as did patients infected with HPV-16 or -18 (p < 0.0001).

Reference

Berman S et al. HPV DNA screening as an adjunct to standard PAP testing in identifying a subset of HIV-positive males at higher risk of developing anal neoplasia – a pilot study. Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, abstract MOPEB087, Sydney, 2007.

Orlando, G et al. Human papilloma typing in a cohort of HIV-1-infected men in Milan, Italy. Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, abstract MOPEB106, Sydney, 2007.

McCloskey JC et al. Frequency of high-grade intraepithelial neoplasia in anal/perianal warts is higher than previously recognized. International Journal of STD and AIDS 18: 538 – 542, 2007.

Is there going to be an increase in the incidence of anal cancer?

And a recently published study, from Perth, Australia, looked at the prevalence of pre-cancerous cell changes in surgically removed anal/perianal warts. It found that 78% of HIV-positive men had pre-cancerous cell changes in the anus (52%, high grade), as did a third of HIV-negative men (20%, high grade) and 8% of women (3%, high grade). The investigators note that such a prevalence of pre-cancerous cell changes in anal/perianal warts was higher than expected and suggests that there may be an increase in the incidence of anal cancer in the future.

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