HPV type 39 linked to anal dysplasia, better screening needed for HIV+ men and women

About two-thirds of gay men and one-fifth of women tested in Spain were found to have cell or tissue abnormalities that could progress to anal cancer, and both groups could benefit from more widespread and accurate testing, researchers reported at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last week in Denver. The men's study found that human papillomavirus (HPV) type 39 was a key risk factor.

HPV can trigger abnormal cell growth ranging from warts to cancer. Certain high-risk or oncogenic types including HPV 16 and HPV 18 cause anal, cervical, and other genital cancers. These typically begin as low-grade dysplasia (also known as squamous intraepithelial lesions or intraepithelial neoplasia) and can progress to high-grade lesions and carcinoma if left untreated. Low-risk types including HPV 6 and HPV 11 cause genital warts. However, high-risk types do not always cause dysplasia, low-grade neoplasia does always progress to high-grade lesions or cancer and lesions may regress on their own without treatment.

Anal cancer is more common amongst people with HIV than it is in the general population, and is especially high amongst men who have sex with men (MSM). Although cervical cancer is considered an AIDS-defining malignancy, anal cancer is not so classified. Regular cervical cytology (often referred to as Pap or smear tests) is recommended for both HIV-positive and HIV-negative women to catch abnormalities at an early stage, but clinical practices for screening, preventing and treating anal cancer vary widely.

Carmen Hidalgo from Hospital Universitario Virgen de las Nieves in Granada, Spain, and colleagues reported findings from studies looking at HPV infection, anal dysplasia, and predictive factors in men and women with HIV.

Men who have sex with men

The men's study, presented at an oral session, looked at prevalence of and risk factors for high-grade or stage 2 to 3 anal intraepithelial neoplasia (AIN) or anal cancer (carcinoma in situ) among HIV-positive MSM.

The researchers assessed the accuracy of HPV PCR testing for more than a dozen high- and low-risk types, cytology (testing for cell abnormalities, as done with a Pap smear) and anoscopy (examination of anal-rectal tissue with a magnifying device). They also compared anoscope-guided cytology vs cytology samples taken with swab. 

The analysis included 103 participants in a prospective cohort study that screened HIV-positive MSM for anal dysplasia from April 2010 through to September 2012 using all three methods.

The average age was 36 years and the mean and nadir (lowest-ever) CD4 T-cell counts were 645 and 387 cells/mm³, respectively, indicating well-preserved immune function. Most (85%) used antiretroviral therapy (ART). Half were smokers – a known risk factors for HPV-related cancer – and about 40% had anal warts. All the men reported anal sex, they had a median of 1.5 sexual partners during the study, and 70% said they used condoms.

Overall, the researchers found that one-third to one-half of the men had low-grade squamous intraepithelial lesions (LSIL) or stage 1 AIN, and around 5 to 10% had high-grade squamous intraepithelial lesions (HSIL) or stage 2 to 3 AIN, depending on the method used:

Anal cytology using swab:

• LSIL: 53%

• HSIL: 5%

• Atypical squamous cells of undetermined significance (ASCUS): 5%

• Normal: 33%

Anoscopy:

• AIN 1: 44%

• AIN 2-3: 10%

• Carcinoma in situ: 11%

• Normal: 36%

Cytology with anoscope:

• LSIL: 36%

• HSIL: 7%

• ASCUS: 6%

• Normal: 50%

In a univariate analysis looking at separate risk factors, older age and infection with HPV types 6, 39 or 42 predicted high-grade AIN or anal cancer. However, in a multivariate analysis HPV 36 was the only independent risk factor to reach statistical significance, conferring more than a ten-fold higher risk (odds ratio 10.51; p=0.04). Neither smoking nor CD4 count were associated with greater risk in this study, in which CD4 cells were uniformly high.

For each testing method, the researchers calculated sensitivity (ability to detect true cases), specificity (ability to rule out if not present), positive predictive value (PPV, or proportion of correct positive diagnoses) and negative predictive value (NPV, or proportion of correct negative diagnoses): 

• Anal swab cytology: 94%, 42%, 31% and 97%, respectively.

• Cytology with anoscope: 90%, 61%, 40% and 96%, respectively.

• High-risk HPV testing: 83%, 15%, 24% and 77%, respectively.

• Anal swab cytology and high-risk HPV: 79%, 41%, 28% and 88%, respectively.

• Anal swab cytology and/or high-risk HPV: 100%, 15%, 24% and 100% NVP. 

"In our HIV-positive MSM cohort, the association of the oncogenic HPV genotype 39 with other [high risk] HPV genotypes was the main risk factor associated with high-grade AIN and/or carcinoma in situ," the researchers concluded.

With regard to testing methods, "anoscopy-guided cytology does not improve the diagnosis of the dysplastic lesions, and for this reason, we do not think that it should be included in the screening protocol." 

HIV-positive MSM "should be systematically tested for dysplastic lesions with anal cytology and HPV PCR," they summarised.

If cytology is abnormal, irrespective of the grade of dysplasia, histologic evaluation of the lesion should be performed using anoscopy, they added. But if cytology is normal, HPV PCR screening should be done, and if high-risk HPV is found, the patient should also be referred for anoscopy. 

Asked if anal screening could be done less often after a series of negative tests (as is the case for HIV-negative women undergoing cervical screening), Hidalgo Tenorio said she recommends ongoing screening every year for this population.

Session moderator Judith Aberg asked about the unexpectedly high rate of HPV 39, speculating whether vaccination against HPV types 16 and 18 might allow other types to take over as major causes of cancer. Hidalgo Tenorio did not have an answer, but to date HPV vaccines have mostly been given to young women, and more recently young men, so coverage is likely still low in this population of MSM. She noted that new vaccines are under study that will protect against more HPV types.

Women with HIV

Hidalgo Tenorio's team also presented a poster looking at the prevalence of and risk factors for anal dysplasia among a cohort of women in southern Spain, comparing rates to those of men who have sex with men.

While cervical abnormalities are a known risk for women with HIV, anal dysplasia may be equally or more common but is not regularly screened for. The researchers noted that HIV-positive women have a 14-fold higher risk of anal neoplasia than HIV-negative women. 

This cross-sectional analysis looked at HIV-positive women and MSM receiving medical care at a single centre between December 2008 and December 2012. The men were the same group described above.

The 45 women were a bit older, with an average age of 43 years. Mean and nadir CD4 cell counts were 692 and 223, respectively, and most (93%) were taking ART. A majority (71%) were smokers, 22% had anal warts and 27% were coinfected with hepatitis C (compared with just 4% of the men). They reported a median of one sexual partner during the study, 53% said they used condoms and only 22% reported anal sex.

The researchers found that 23% of the women had low-risk HPV types and 34% had high-risk types, compared with 71 and 85%, respectively, amongst the men. Looking at high-risk types amongst women, 5% had HPV 16, 5% had HPV 18, 9% had HPV 51 and 2% had HPV 53. For men, the prevalence rates were 27, 17, 18 and 15%, respectively.

Turning to anal abnormalities, more than three-quarters of the women (79%) had normal cytology by anal swab, compared with one-third of the men. Eight women (19%) had low-grade SIL, none had high-grade SIL and one (2%) had ASCUS. 

In a univariate analysis, significant risk factors for anal dysplasia were presence of either low-risk or high-risk HPV types, with HIV viral load and CD4 count being of borderline significance. However, in a multivariate analysis presence of anal or genital warts was the only independent risk factor (OR 11.5; p=0.046)

Rates of dysplasia and anal HPV infection in this cohort of HIV-positive women were significantly lower than those of HIV-positive MSM, but even so it is enough to justify screening regardless of virological or immunological status, the researchers concluded. 

They did not answer the question put forth in their title – whether anal dysplasia among people with HIV is a matter of sexual behaviour or gender – but HPV is sexually transmitted, and the women in this study were much less likely than the gay men to have had anal sex.