There are more than 100 identified strains of HPV. Some types, including 6 and 11, cause warts, both common skin warts and genital warts (condyloma). Oncogenic, or "high-risk," types -- especially 16 and 18 -- can cause cancer of the anogenital area, including the cervix and anus, and (more rarely) the vulva, vagina, and penis; in the NHANES study, about 2% of women had HPV type 16 or 18. A person may be infected with multiple types, including both wart-causing and cancer-causing varieties.
Oncogenic HPV can cause dysplasia, or abnormal precancerous cell changes. Over time, dysplasia can progress to cervical or anal intraepithelial neoplasia (CIN or AIN; classified as grade 1, 2, or 3), also known as squamous intraepithelial lesions (SIL; classified as low-grade or high-grade). If left untreated, intraepithelial neoplasia may progress to noninvasive carcinoma in situ, and eventually to invasive cervical or anal cancer. In addition, a recently published study showed that oral HPV infection -- especially with type 16 -- is a major risk factor for cancers of the mouth and throat, and that people who have oral sex with multiple partners are at highest risk.
While it is generally considered a sexually transmitted infection, HPV may also be spread through nonsexual skin-to-skin contact. Condoms are only partially effective in preventing HPV transmission, since infection can occur through uncovered areas. Infected individuals may transmit the virus even if they have no visible external warts. Infants born to infected mothers may also contract HPV during delivery.
Anal HPV infection appears to be most common among men who have sex with men, but it also occurs in women and in men who do not practice anal sex (see "Not For Women Only," below). A recent study by Susan Cu-Uvin, MD, and colleagues found that anal HPV infection was more common than cervical infection in HIV positive women, including those who did not have anal sex. On the whole, more women develop anal cancer each year than men, but they are less likely to be diagnosed during its early stages.
|Cervical and Anal Cancer Prevention Tips|
Experts disagree about how often HIV positive women should receive Pap tests. Some recommend every six months, while others believe women with high CD4 cell counts who have had at least two normal tests can lengthen the interval to once per year. The recommended interval for healthy HIV negative women with consistently normal tests is once every three years.
HPV DNA tests are also available that detect oncogenic types, but there remains some controversy about their usefulness, since many infections are transient and asymptomatic, and there is no treatment for HPV infection itself.
If a Pap smear shows evidence of abnormal cells, the next step is a procedure called colposcopy (for the cervix) or anoscopy (for the anus), in which the affected area is examined using a lighted microscope; in addition, a tissue biopsy sample may be taken for further analysis.
Since there is no treatment for HPV infection, therapy involves removal or destruction of affected tissue. Genital warts and areas of intraepithelial neoplasia may be removed using a variety of methods, including heat (electrocautery), lasers, freezing (cryosurgery), or surgical excision.
Chemical therapies include imiquimod (Aldara), 5-fluorouracil (Efudex), podofilox (Condylox), and interferon alpha. Other agents are under study, including diindolylmethane, cidofovir (Vistide), and green tea extract. Once invasive cancer has developed, the usual treatment is a combination of chemotherapy, radiation, and surgery. But even after affected areas are removed, HPV may persist in surrounding tissue. Since the infection is not considered "cured," screening should be continued to detect relapses.
In most healthy HIV negative individuals, the immune system is able to keep HPV under control and the infection is asymptomatic. But HIV positive people -- especially those with advanced disease -- have more persistent HPV, are more likely to develop HPV-related dysplasia, have a faster rate of progression to cancer, and are more likely to experience recurrence after treatment.
HIV positive people are also more likely to harbor multiple HPV types. A recent meta-analysis of data from 20 studies including nearly 5600 subjects worldwide found that 41% of HIV positive women with high-grade SIL had more than one type of HPV, compared with 7% of women in the general population. Further, HIV positive women with SIL were less likely to have oncogenic HPV type 16, but more likely to have other high-risk types such as 18, 51, 52, and 58.
Several studies have shown that HIV positive women are more likely than their HIV negative counterparts to develop CIN. In the HIV Epidemiology Research Study, women with HIV also had more vulvar, vaginal, and perianal lesions. Though invasive cervical cancer is considered an AIDS-defining condition, HIV positive women in developed countries do not appear to be at higher risk for invasive carcinoma, probably because they receive regular Pap smears. But in resource-poor countries where such care is lacking, HIV positive women have a high rate of advanced cervical neoplasia and cancer.
Research has produced conflicting data regarding the influence of CD4 cell count and antiretroviral therapy on HPV infection and development of intraepithelial neoplasia. Epidemiological studies indicate that rates of cervical and anal neoplasia and cancer have not decreased in the HAART era; on the contrary, as effective antiretroviral therapy allows HIV positive people to live longer, they have more time to develop progressive HPV-related disease.
An analysis of 855 HIV positive and 343 HIV negative women enrolled in the Women's Interagency HIV Study (WIHS) showed that among those with normal Pap tests and undetectable HPV at baseline, 29% of HIV positive women with CD4 cell counts below 200 cells/mm3 developed CIN over three years, compared with 14% of those with 200-500 cells/mm3, 6% of those with more than 500 cells/mm3, and 5% of HIV negative women. In contrast, two recent French studies found that development of cervical or anal intraepithelial neoplasia was not associated with either current or nadir (lowest-ever) CD4 cell count.
In general, studies suggest that antiretroviral therapy has, at most, a minimal impact on HPV-related disease progression. One French study, for example, found that use of HAART did not lead to the regression of precancerous anal lesions or HPV clearance in HIV positive men. Similarly, an Italian study of 201 HIV positive women showed that over six years of follow-up, antiretroviral therapy did not prevent development of HPV-associated lesions, although women receiving HAART were more likely to experience regression of low-grade SIL. But in another French study, the incidence of SIL decreased modestly (from 10.7 to 6.5 cases per 100 person-years) in women receiving HAART. And in the WIHS trial, the chances of experiencing SIL regression increased from 0% in the pre-HAART era to 12.5% after the introduction of HAART.
Gardasil -- a series of three intramuscular injections given over six months -- is approved for prevention of HPV-associated genital warts, CIN, and cervical, vulvar, and vaginal cancer in females aged 9-26 years. Approval was based on data from randomized, placebo-controlled trials involving more than 20,000 women and girls in both developed and resource-poor countries; the studies did not, however, include HIV positive women.
As reported in the May 10, 2007, New England Journal of Medicine (NEJM), three-year data from the FUTURE I study, which enrolled 5455 HIV negative women aged 16-24 years, showed that the vaccine was 100% effective in preventing HPV-associated anogenital lesions (warts, intraepithelial neoplasia, or cancer) in women who were not infected with HPV at baseline and received all three doses of the vaccine as scheduled. But in a "real world" analysis that included women already infected with HPV types 6, 11, 16, and/or 18 at baseline, the vaccine had only 73% efficacy in preventing external anogenital or vaginal lesions, and 55% efficacy in preventing cervical lesions caused by these HPV types. The vaccine was even less effective (20%-34%) in preventing lesions caused by other HPV types.
Similarly, the FUTURE II trial, which included more than 12,000 HIV negative women aged 15-26 years, found that the vaccine was 98% effective in preventing grade 2 or 3 CIN or cervical carcinoma in situ caused by HPV types 16 or 18 in previously uninfected women who received the full vaccine series as scheduled. Among women previously infected with type 16 or 18 HPV, efficacy dropped to 44% in preventing high-grade CIN caused by these types, and 17% in preventing CIN caused by any type of HPV.
In studies to date, the vaccine was generally well tolerated, with the most frequent side effects being injection site soreness, fainting or dizziness, and flu-like symptoms. An analysis of Gardasil-related adverse events reported to the National Vaccine Information Center found that 14% were fainting episodes, and 8% involved tingling, numbness, loss of sensation, facial paralysis, or Guillain-Barré syndrome (a rare paralyzing autoimmune condition).
GlaxoSmithKline is also developing a preventive HPV vaccine called Cervarix, which targets types 16 and 18. As reported in the April 15, 2006, issue of The Lancet (and updated at the American Association for Cancer Research meeting this past April), a randomized, placebo-controlled trial of more than 1000 women aged 15-25 years showed that over 5.5 years of follow-up, Cervarix was 97% effective in preventing infection with HPV type 16 or 18, 100% effective against CIN associated with these types, and 68% effective against lesions due to any type of HPV. Though not designed to do so, the vaccine also provided cross-protection against HPV types 31 and 45, which are responsible for another 10% of cervical cancer cases.
Importantly, since Gardasil and Cervarix cannot prevent all anogenital cancer, and because the duration of protection is not yet known, regular Pap smears will still be needed to detect abnormal cell changes at an early, treatable stage. According to Diane Harper, MD, who worked on trials of both vaccines, "neither physicians nor women should be lulled into a false sense of security."
While neither Gardasil nor Cervarix protect against neoplasia or cancer in individuals who are already infected with HPV, therapeutic vaccines designed to prevent progression of HPV-related disease after infection are also under study. Transgene and Roche are collaborating on a therapeutic vaccine, designated TG-4001, for the treatment of high-grade CIN. In a Phase II trial that enrolled 21 women with type 16 HPV and grade 2 or 3 CIN, half the participants experienced CIN regression and HPV clearance after six months. And in a small study by Joel Palefsky, MD, and colleagues, 13 men and two women with high-grade AIN received a therapeutic HPV type 16 vaccine known as SGN-00101. After 48 weeks, four patients experienced partial regression of AIN by 1-2 grades, while a fifth achieved more complete regression; three of the responders also demonstrated anal HPV clearance. These promising results suggest that therapeutic HPV vaccines warrant larger studies.
|Not For Women Only|
HIV positive men who have sex with men (MSM) are more likely than their HIV negative counterparts to have HPV infection, anal dysplasia, and anal cancer. The rate of anal cancer among gay and bisexual men is estimated to be 35 times greater than that of the general population, while HIV positive MSM have an 80-fold risk. In a study of 357 HIV positive MSM in San Francisco, for example, Joel Palefsky, MD, and colleagues found that 95% had anal HPV infection and 52% had grade 2 or 3 AIN. Yet invasive anal cancer -- unlike cervical cancer -- is not currently considered an AIDS-defining condition.
As with cervical dysplasia, precancerous anal cell changes can be detected through routine Pap screening. Because the test is simple, inexpensive, and effective, a growing number of experts believe anal Pap smears should become a part of routine care for at-risk individuals, including MSM.
"We haven't proven it yet, but we believe [testing is] likely to prevent anal cancer," says Palefsky, who expects to present data from a study of anal cancer prevention later this year. He recommends that at-risk HIV positive men should get an anal Pap smear each year, while HIV negative men should be tested every 2-3 years.
Given the effectiveness of Gardasil and Cervarix in females, the vaccines are also being tested in males -- both heterosexual and MSM -- and data so far indicate young men will benefit, as well. Some clinicians report that gay men are already requesting off-label Gardasil (which is approved for boys aged 9-15 years in the European Union). But, as with women, the vaccine will only be effective for men who are not already infected with HPV, suggesting that it should be administered before they become sexually active.
This recommendation has generated considerable controversy around proposed policies to mandate vaccination for all girls in this age group. Beyond moral concerns about sexual abstinence, some critics also worry that the vaccine has not been in use long enough to determine if there might be long-term side effects. Critics also contend that HPV is not communicable in social settings such as schools, and that cervical cancer can already be prevented through routine Pap testing. Further, vaccination against some HPV types could encourage the emergence of other strains, with unknown consequences.
According to Karen McCune, MD, of the University of San Francisco, "To be discussing mandatory vaccination when the main clinical trials are still ongoing seems extremely premature."
At the same time, there is concern that the expensive vaccine (which costs about $360 for the three-dose series in the U.S.) will not be available to women in poor countries, who are at greatest risk of dying from cervical cancer. Cervical cancer accounts for some 275,000 deaths per year worldwide, representing the largest cause of years of life lost to cancer in the developing world.
"Although achieving broad coverage of young adolescents, negotiating tiered pricing, and securing financing will be challenging, it is sobering to realize that with every five-year delay in bringing vaccination to developing countries, 1.5 million to 2 million more women will die," wrote public health experts Jan Agosti, MD, and Sue Goldie, MD, MPH, in an editorial in the May 10, 2007, NEJM. "Let us hope that a committed global effort makes fulfillment of the promise of the new vaccine possible."
Liz Highleyman (firstname.lastname@example.org) is a freelance medical writer and editor based in San Francisco.
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