HPV16 highly prevalent among HIV-positive MSM in France and strongly associated with high-grade pre-cancerous anal lesions

Michael Carter
Published: 19 February 2018

HIV-positive gay men in France have a very high prevalence of anal infection with strains of human papillomavirus (HPV) associated with a high risk of anal cancer, investigators report in The Journal of Infectious Diseases. HPV16 was the most commonly detected high-risk HPV (HR-HPV) strain.

Overall, 70% of participants in the study had a high-risk anal HPV infection, with 29% having HPV16, the type of HPV most strongly associated with anal cancer.

“Anal HPV16 and HR-HPV infection was confirmed to be highly prevalent,” comment the authors. “HPV16, the most common anal HR-HPV type in this population, predominated over other HR-HPV types.”

Prevalence of HPV16 increased with the severity of pre-cancerous anal cell changes and lesions. Cell changes in the anus are classified as low-grade intraepithelial lesions, high-grade intraepithelial lesions or anal cancer. High-grade lesions are less likely to disappear without treatment and more likely to lead to the development of anal cancer (although anal cancer remains a relatively rare cancer).

“Our cross-sectional data confirm HPV16 as an important determinant of high-grade lesions,” emphasise the investigators, who suggest that detection of HPV16 and vaccination against HPV16 should be a priority in anal cancer prevention.

A separately published meta-analysis and systematic review found a similar association between HPV16 and pre-cancerous lesions in people with HIV.

Infection with HR-HPV accounts for 90% of all cases of anal cancer. Prevalence of anal HPV infection and incidence of anal cancer are higher among HIV-positive gay and other men who have sex with men (MSM).  

However, information on the risk factors and disease course of anal HPV infection in HIV-positive MSM is scarce. The French ANRS EP57 APACHES study was therefore established to better characterise the prevalence and evolution of anal HPV infection and HPV-related lesions in HIV-positive MSM. As a first step, investigators examined baseline prevalence of HR-HPV, especially HPV16, and their risk factors.

Recruitment to the study occurred between December 2014 and June 2016. The total population consisted of 490 HIV-positive MSM aged 35 and older. Doctors asked participants about sexual behaviour (number of lifetime and recent partners with whom patients had had receptive anal sex) and history of smoking. Data on CD4 cell counts, viral load, HIV-related disease and use of combination antiretroviral therapy (cART) were obtained from medical records. The study excluded anyone with anal cancer or men treated for high-grade AIN (anal intraepithelial neoplasia) in the previous 12 months.

Two anal swabs were taken from each person, one for cytology the other for HPV DNA tests. Individuals also had a digital-rectal examination and high-resolution anoscopy, during which any lesions were biopsied.

The participants had a median age of 51 years. Approximately two-thirds were current or former smokers. Over half reported 40 or more lifetime receptive anal sex partners and 78% reported receptive anal sex within the year before inclusion in the study. Only 4% were not taking cART and approximately a fifth had a history of an AIDS-defining condition. Median CD4 cell count was normal at 685 cells/mm3 and 92% had an undetectable viral load. Previous anal swabs for cytology and/or biopsy were reported by 201 men, with 39 stating these had detected high-grade lesions.

The overall prevalence of HPV16 and HR-HPV were 29% and 70%, respectively. HPV16 was the most common HR-HPV type (29%), followed by HPV69 (16%) and HPV33 (13%). Multiple HPV strains were detected in 47% of samples overall and in 67% of those where HR-HPV was present.

Prevalence of HPV16 and HR-HPV did not vary significantly by age, number of sexual partners, CD4 cell count, duration of HIV infection, or duration of cART. However, HR-HPV prevalence was higher among smokers (OR = 1.8; 95% CI, 1.2-2.7). Prevalence of HPV16 (OR = 4.5; 95% CI, 1.9-10.6) and of HR-HPV (OR = 9.3; 95% CI, 2.9-29.3) were significantly higher among participants previously diagnosed with high-grade anal lesions compared to those without such lesions.

Anal cytology was successful in 479 men. Results were negative in 41% of these individuals. In 17% of participants, atypical cells of undetermined significance were detected. Low- and high-grade cell changes were present in 1% and 7%, respectively.

High-resolution anoscopy was normal in 54% of men. AIN1 was diagnosed in 21%, AIN2 in 5% and AIN3 in 6%.

Combining cytology-histology showed that 37% of men were negative for HPV-related disease, 48% had low-grade disease and 15% had high-grade disease.

Prevalence of HPV16 and HR-HPV increased significantly from cytology-negative participants (23% and 57%, respectively) to individuals with high-grade cell changes (61% and 100%, respectively). A similar increase was observed according to histology results from negative (15% and 63%, respectively) to AIN2 (78% and 100%, respectively).

Composite results indicated that HPV16 increased from 19% among individuals who were negative or had low-grade disease to 63% for individuals with high-grade lesions.

“Given the strong link between HPV16 and anal cancer, HPV prevalence can arguably be used as a proxy of higher probability of developing anal cancer,” write the authors. “HPV16 prevalence increased strongly according to severity of anal diagnosis, both according to the severity of past anal diagnosis, and according to cytology and histological findings.”

Other recent research also showed the important role of HPV16 in anal cancer.

A systematic review and meta-analysis of the prevalence of HPV16 and other HPV types in anal lesions published in The Lancet Infectious Diseases in November 2017 found that as lesions became more severe, HPV16 was more likely to be detected, regardless of patients’ HIV infection status. HPV16 was present in 24% of HIV-positive people without anal lesions and in 67% of those with anal cancer. It was also present in 18% of HIV-negative people and in 86% of those with anal cancer.

The authors of the systematic review concluded that HPV16 is by far the most carcinogenic HPV type and that the presence of HPV16 in anal lesions suggests a greater likelihood of progression to anal cancer.

Although a third of anal cancers in HIV-positive people did not contain HPV16, no other single HPV type predominated in these cancers. The authors of the meta-analysis believe their findings have implications for HPV vaccination strategies in people with HIV, concluding “nine-valent would provide a larger gain in HIV-positive than HIV-negative individuals.”

Reference

Combes J-D et al. Prevalence and risk factors for anal human papillomavirus infection in HIV-positive men who have sex with men. J Infect Dis, online edition, 2018.

Lin C et al. Human papillomavirus types from infection to cancer of the anus according to sex and HIV status: a systematic review and meta-analysis. The Lancet Inf Dis, published online, 17 November 2017.

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