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Studies Shed Further Light on HPV Infection and Anal Cancer in HIV+ People

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Human papillomavirus (HPV) infection, which is common in both HIV positive and HIV negative people, can trigger abnormal cell proliferation. Some types cause warts, while certain "high-risk" types (e.g., 16, 18) can cause oral, genital, cervical, and anal cancer.

Research indicates that HIV positive people are more likely to have persistent HPV infection and more likely to develop genital or anal tissue abnormalities (known variously as dysplasia, intraepithelial neoplasia, or squamous intraepithelial lesions), but some study data have been conflicting, including the influence of CD4 cell count.

HPV and Anal Lesions in Women with HIV

Invasive cervical cancer is considered an AIDS-defining condition; anal cancer is not so classified, but it is caused by the same oncogenic HPV types, and many experts believe it should be. Women with HIV are advised to receive regular Papanicolau ("Pap") smears for cervical cancer screening, but they -- like HIV positive men, both gay/bisexual and heterosexual -- are also at risk for anal cancer.

As reported in the January 2, 2009 issue of AIDS, Nancy Hessol from the University of California at San Francisco (UCSF) and colleagues analyzed pre-cancerous anal intraepithelial neoplasia (AIN) and its associations with anal and cervical HPV, cervical intraepithelial neoplasia (CIN), immune status, and demographic and behavioral risk factors in HIV positive women with and those at risk for HIV infection.

The study included 470 HIV positive and 185 HIV negative women seen at 3 clinical centers -- in Brooklyn, Chicago, and San Francisco -- participating in the Women's Interagency HIV Study (WIHS). Overall, 70% were African-American, and 13% were white, and about half smoked tobacco (a known risk factor for cervical cancer). A similar proportion in both groups (46%-47%) reported receptive anal intercourse (a risk factor for anal cancer). HIV positive women were more likely to have a history of injection drug use.

Between 2001 and 2003, participants were interviewed, received a gynecological examination, and underwent anal and cervical cytology (cell) testing. If cytology results were abnormal, they received a biopsy of visible lesions guided by colposcopy or anoscopy (using lighted magnifying instruments).

Results

• HIV positive women were more likely than HIV negative women to have anal, cervical, and both anal and cervical HPV infection.
• Anal HPV infection was common in both groups (80% for HIV positive, 50% for HIV negative women).
• Anal HPV infection in HIV positive women was more common than cervical HPV infection (45%).
• HIV positive women were significantly more likely than HIV negative women to have abnormal anal cells or tissue (31% vs 9%).
• HIV positive women were also significantly more likely to have cervical abnormalities (34% vs 19%).
• 12% of HIV positive and 5% of HIV negative women had low-grade anal intraepithelial neoplasia.
• 9% and 1%, respectively, had high-grade AIN.
• In adjusted analyses of the HIV positive group, risk factors for low-grade AIN were:
• younger age (odds ratio [OR] 0.59);
• history of receptive anal intercourse (OR 3.2);
• anal HPV infection (OR 11 for both oncogenic types only and for oncogenic + non-oncogenic types);
• cervical HPV infection (OR 3.5 for oncogenic and non-oncogenic types).
• In multivariate analyses, the only significant risk factor for high-grade AIN in HIV positive women was anal HPV infection (OR 7.6 for oncogenic and non-oncogenic types).
• In adjusted analyses, smoking was not significantly associated with increased risk of anal lesions.

"Even in the era of highly active antiviral therapy, the prevalence of anal intraepithelial neoplasia was 16% in HIV-infected women," the study authors concluded. "After controlling for potential confounders, several risk factors for low-grade anal intraepithelial neoplasia differed from risk factors for high-grade anal intraepithelial neoplasia."

"[T]he true prevalence of AIN and CIN is likely to be even higher than what we observed because some of the women with normal cytological findings may have had a false-negative cytology result," they added in their discussion of the results. "Although this represents the largest group of HIV-infected women to be studied to date for AIN, in some of the subgroup analyses the samples sizes were small."

In a related study published in the January 9, 2009 advance online edition of the Journal of Acquired Immune Deficiency Syndromes, Sebastian Videla and colleagues with the Spanish HIV-HPV Study Group reported results from a retrospective epidemiological analysis of HPV types in cervical samples from 93 HIV positive women with at least 2 normal Pap smears.

At baseline, HPV prevalence was 63% using polymerase chain reaction (PCR) testing and 41% using an HC-2 assay. The most common high-risk HPV types were 16 (28%), 33 (18%), 52 (12%), 58 (11%), and 39 (11%). More than 40% had multiple HPV types. HPV infection persisted at follow-up in 86% of the women according to PCR testing and 76% according to HC-2 testing. More than half still had persistent HPV infection in samples available beyond 3 years.

The investigators concluded that, "HPV infection is highly prevalent and persistent among HIV-1-infected women with normal Papanicolau smears. High-risk HPV genotypes other than HPV-16 (HPV-33, HPV-52) are frequently detected in HIV-infected women."

In a third study, reported in the February 2009 Journal of Medical Virology, Dianne Marais from University of Cape Town in South Africa and colleagues looked at changes in cervical HPV types and immune response against oncogenic HPV-16 in female sex workers newly infected with HIV. Analysis of HPV DNA from cervical cells was done prior to HIV seroconversion, within 1 year after seroconversion, and again more than 2 years after seroconversion.

Of the 104 women in the cohort, 38% became HIV positive during the course of the study. Shortly after HIV seroconversion, a significant increase in infection with multiple HPV types was observed compared with women who remained HIV negative. The newly HIV positive women also had reduced serum HPV-16 IgA antibodies and cervicovaginal IgA and IgG antibodies, but increased serum IgG antibodies.

In conclusion, the authors wrote, "HIV-1 seroconversion in sex workers rapidly increased cervical HPV infection and caused a reduced ability to produce cervical HPV-16 antibodies, but a continued ability to generate serum IgG antibodies."

HPV Types in HIV Positive Men

As reported in the October 1, 2008 issue of AIDS, Alessandra Pierangeli and colleagues characterizes anal HPV genotype prevalence and type-specific HPV DNA viral load in 36 HIV positive men attending a proctology clinic at a university hospital in Rome between November 2004 and July 2007. A group of 25 HIV negative men seen at the same clinic served as control subjects.

The HIV positive men had well controlled HIV disease, with a median CD4 count of about 400 cells/mm3 and 86% with HIV viral load < 50 copies/mL. None of the men had abnormal anal cytology or a history of anal cancer.

Results

• HPV DNA of some type was detected in 81% of the HIV positive men and 61% of the HIV negative men.
• Men with HPV were more likely to be homosexual and to have a larger number of sexual partners.
• Almost all the homosexual men were HPV-infected, both HIV positive (94%) and HIV negative (89%).
• The rate of infection with low-risk HPV types (6, 61, 70, and 74) was greater than for high-risk types (16, 18, 31, 33 and 35) in both the HIV positive and HIV negative groups.
• HIV positive men, however, were more likely than HIV negative men to have high-risk HPV types (48% vs 33%).
• 12% of HIV positive men, but no HIV negative men, were infected with 2 or more HPV types.
• HPV viral load levels varied greatly between samples, but did not differ significantly between HIV positive and HIV negative men.
• In many samples, viral loads of low-risk HPV types and high-risk types were comparable.

Based on these findings, the study authors concluded, "Type-specific HPV DNA copies at baseline appear to be independent of patient immune status and of HPV genotype."

They added that, "HPV genotype risk and viral load should be further evaluated for their potential predictive role in persistence and progression."

Gardasil HPV Vaccine

The Gardasil HPV vaccine, developed by Merck, has been shown to dramatically reduce the risk of infection with 4 HPV types (6, 11, 16, and 18) that can lead to genital warts and cervical, vaginal, and vulvar cancer when administered to young women before they become sexually active; it is currently approved for ages 9 to 26.

Earlier this month, the U.S. Food and Drug Administration (FDA) denied approval of Merck's application for use of the vaccine in women aged 27 to 45. A majority of women are exposed to HPV before their late twenties, and the vaccine is much less effective -- and perhaps not cost-effective -- for older women. The FDA indicated that it will wait until an ongoing 4-year trial of the vaccine is completed before it considers approval for older women; completion is expected by the end of 2009.

On the other hand, interim study data presented at the European Research Organization on Genital Infection and Neoplasia (EUROGIN) conference this past November showed that the Gardasil vaccine is effective in preventing HPV-related disease in young men. Merck recently applied for FDA approval of the vaccine for young men aged 9 to 26.

In this placebo-controlled Phase 3 trial -- which included 4065 young men aged 16-26 years (both heterosexual and men who have sex with men) -- 3 doses of the vaccine prevented 90% of external genital lesions caused by HPV types 6, 11, 16, and 18 after an average 29 months of follow-up. The vaccine also reduced the prevalence of persistent HPV infection. No vaccine-related serious adverse events were observed, although more participants in the vaccine group reported injection site reactions.

According to Joel Palefsky of UCSF, widespread HPV vaccination could prevent anal cancer in gay/bisexual men, and by inducing so-called "herd immunity," it could help reduce transmission of HPV between heterosexual men and women.

1/20/09

References

N Hessol, E Holly, J Efird, and others. Anal intraepithelial neoplasia in a multisite study of HIV-infected and high-risk HIV-uninfected women. AIDS 23(1): 59-70. January 2, 2009. (Abstract).

S Videla, L Darwich, MP Canadas, and others. Epidemiological Data of Different Human Papillomavirus Genotypes in Cervical Specimens of HIV-1-Infected Women without History of Cervical Pathology. Journal of Acquired Immune Deficiency Syndromes. January 7, 2009 [Epub ahead of print].

DJ Marais, H Carrara, G Ramjee, and others. HIV-1 seroconversion promotes rapid changes in cervical human papillomavirus (HPV) prevalence and HPV-16 antibodies in female sex workers. Journal of Medical Virology 81(2): 203-210. February 2009. (Abstract).

A Pierangeli, C Scagnolari, AM Degener, and others. Type-specific human papillomavirus-DNA load in anal infection in HIV-positive men. AIDS 22(15): 1929-1935. October 1, 2008. (Abstract).

Other sources

P Loftus. Merck hits another delay for wider Gardasil use. MarketWatch. January 9, 2009.

J Norris. In Young Men, HPV Vaccine Prevents Conditions That Lead to Cancer. UCSF Today. November 20, 2008.

Merck and Co. Gardasil, Merck's Cervical Cancer Vaccine, Demonstrated Efficacy in Preventing HPV-Related Disease in Males in Phase III Study. Press release. November 13, 2008.