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The potential of human papillomavirus vaccines

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Commentary by Arthur Ammann, MD and Sahai Burrowes, MALD

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What is HPV?

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Human papilloma virus (HPV) refers to a group of very common viruses that cause warts or abnormal growths on the skin and mucous membranes. More than 100 different types of HPV have been detected, many of which are transmitted sexually. Individuals may be infected with more than one type of HPV at a time. In recent years, there has been increasing evidence that HPV infections are extremely widespread among sexually active adults. Experts estimate that more than 50% of sexually active adults have been infected with HPV at some point in their lives, but that these infections usually are transient.( 1 )

Nonsexual transmission of HPV may occur but documentation of this phenomenon is not very strong. There is evidence of HPV transmission from mothers to infants and of juvenile-onset recurrent respiratory papillomatosis as a consequence of respiratory exposure during delivery. There also have been cases of genital HPV infection in virginal females and transmission by casual contact with inanimate objects.( 2 )

The risk factors for HPV transmission include having a large number of sexual partners, smoking, the presence of other genital tract infections such as bacterial vaginosis, having sex with men who have had many sexual partners, and being <40 years of age.( 3 , 4 )

Preventing HPV infection is difficult. Barrier contraceptive methods, such as the use of condoms, are not fully effective because the virus can exist on areas of the genital region that are not covered by male condoms.

Approximately 30 types of HPV cause genital and anal mucosal infections. In women, HPV may cause abnormal growths on the cervix, the vulva, the uretra and the anus. These growths usually are classified into 2 groups: genital warts and cervical or anal dysplasia. Cervical dysplasia is an abnormality in the size, shape, and organization of the cells on the surface of the cervix. These changes are graded on a scale ranging from normal to severe. If left untreated, these abnormalities can progress to carcinoma in situ and invasive cervical cancer. The severity of cervical dysplasia is graded by 2 systems:

transparent gif bullet The Bethesda or SIL (squamous intraepithelial lesion) system, which measures the degree of abnormalities in the individual cells.
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transparent gif bullet The CIN (cervical intraepithelial neoplasia) system, which measures both the degree of abnormality and how deep below the surface (epithelium) of the cervix the cell abnormalities reside.
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CIN Bethesda Explanation
-- -- Atypical squamous cells of undetermined significance (ASCUS) Not all cells look normal; the cervix may be inflamed but clinicians are not sure if the cells are normal or abnormal. Clinicians usually repeat Pap smear in a few weeks.
Mild dysplasia CIN 1 Low-grade squamous intraepithelial lesion (LSIL) There are mild abnormalities in the shape of the cells. Cells usually return to normal on their own within a few months or years. Clinicians usually monitor the patient closely, particularly if she is HIV infected.
Moderate dysplasia CIN 2 High-grade squamous intraepithelial lesion (HSIL) About two thirds of the cells are abnormal or about half the thickness of the surface lining of the cervix.
Severe dysplasia or carcinoma in situ CIN 3 The entire thickness of cells is abnormal, but the abnormal cells have not yet spread below the surface of the cervix.
Adapted from: Public Health Agency of Canada. CATIE Factsheet Cervical Dysplasia; March 2000.
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HPV and Cervical Cancer

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Papilloma viruses are members of the Papovaviridae family of DNA viruses, all of which are considered to be potentially carcinogenic. Certain strains of HPV (HPV 16, 18, 31, 33, 35, 39, 45, 51, and 52) are more likely to lead to low- and high-grade squamous intraepithelial lesions (LSIL and HSIL) and invasive cancer. High-risk HPV types are found in >90% of cervical cancers worldwide; HPV 16 is present in 50% of cervical cancer cases and HPV 18, 31, and 45 in an additional 30%.( 5 ) Low-risk HPV types (HPV 6, 11, 42, 43, and 44) are associated primarily with genital warts, LSIL, and recurrent respiratory papillomatosis.( 2 )

The evidence linking high-risk HPV types and cervical carcinoma is sufficiently strong to conclude that they act as carcinogens in the development of cervical cancer and it is generally recognized that HPV has contributed significantly to the increased incidence of cervical cancer worldwide.( 6 ) With the exception of HIV/AIDS, it is estimated that HPV results in more deaths worldwide from sequelae of infection than all other sexually transmitted infections combined.( 6 ) However, the fact that the vast majority of women with HPV infection do not develop cervical cancer suggests that other cofactors such as smoking, genetic predisposition, the presence of genital tract infections, HIV infection, and hormonal exposure through contraceptive use or multiple pregnancies, also may contribute to the development of cervical cancer in women infected with HPV.( 7 )

One the most consistent predictors of cervical cancer is sexual activity. Both the number of lifetime partners and the number of recent partners correlate with risk of cervical cancer.( 8 ) Anal cancer in men is associated with similar risk factors.( 9 ) Women who develop cervical cancer tend to come from low-income groups, have an early sexual debut (<20 years old), have a high parity (>4 births), and have a history of multiple sexual partners (>5).( 10 )

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Natural History

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The highest prevalence HPV infection with carcinogenic types occurs in women between ages 15 and 20, shortly after the initiation of sexual activity (see Figure 1). ( 11 ) Precancerous cervical lesions reach their highest prevalence approximately 10 years later, followed by a peak of invasive cervical cancer between ages 40 to 50.

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Figure 1. The Natural History of HPV Infection and Cervical Cancer

The promise of global cervical-cancer prevention

Source: Schiffman M, Castle PE. The promise of global cervical-cancer prevention. N Engl J Med. 2005 Nov 17;353(20):2101-4. All rights reserved. Reprinted with permission.

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Papanicolaou testing (Pap smear) is used to detect abnormal, precancerous cells in the cervix or anus. This test, which is used for the early detection of cervical cancer, involves staining exfoliated cells by a special technique. Conducting Pap smears is the primary cervical cancer screening method in resource-rich countries. Although the method was developed almost 50 years ago, it is not used widely in resource-poor countries, and cervical cancer remains the primary cause of cancer deaths among women in these settings.

Specific diagnoses of HPV types can be made using DNA detection techniques. Current HPV DNA tests use cervical cell samples with hybrid capture methods.

There is an inverse relationship between peak detection of HPV infection and age. Peak rates of infection are observed in women <25 years of age, suggesting that the passage of time and an effective immune response to HPV results in clearance of the virus.( 12 ) Additional studies suggest that infection with multiple HPV types and older ages are associated with persistent infection.( 13 )

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There are many parallels between the epidemic of HIV and the epidemic of HPV-related cervical cancer. In both epidemics, the disproportionate burden of disease is born by women in resource-poor countries. Each year there are 471,000 new cases of cervical cancer worldwide, 233,000 of which result in death--80% of these cases occur in resource-poor countries. These countries have only 5% of global cancer diagnostic capabilities and care.( 14 )

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Figure 2. Worldwide Age-Standardized Incidence of Cervical Cancer per 100,000 Population

The promise of global cervical-cancer prevention

Source: International Association of Cancer Registries, GLOBOCAN 2002. Reprinted in Schiffman M, Castle PE. The promise of global cervical-cancer prevention. N Engl J Med. 2005 Nov 17;353(20):2101-4.

These two epidemics not only parallel each other, they also may reinforce each other. Women infected with HIV have higher prevalence and incidence of HPV infection, more persistent HPV infection, greater difficultly clearing HPV, and a greater likelihood than their HIV-negative counterparts of progressing to a disease caused by HPV.

The American Women's Interagency HIV Study (WIHS) has found that 63% of HIV-infected women were infected with HPV, compared with 30% of noninfected women, and that women with more advanced HIV disease had the highest risk of infection.( 15 ) In this study, HIV-infected women also were more likely to be infected with more than 1 type of HPV.

There is clear evidence that HIV-infected women are more likely than HIV-negative women to have abnormal Pap smears and neoplasia and that the seriousness of abnormalities increases with the degree of immunosuppression. However, there is no firm evidence that HIV-infected women are at greater risk than HIV-negative women of invasive cervical cancer.( 16 ) HIV-infected women who do develop invasive cervical cancer tend to have disease that is more aggressive than that found in their non-HIV-infected counterparts.( 17 ) The disease also tends to be more difficult to treat in HIV-infected women and is more likely to metastasize to unusual locations such as the psoas muscle or the clitoris. The U.S. Centers for Disease Control and Prevention (CDC) has included invasive cervical cancer as an AIDS-defining illness.

The evidence on whether antiretroviral treatment of HIV-infected women affects the development and progression of HPV-related abnormalities is inconclusive. It seems that immune system restoration as a result of treatment may not be sufficient to halt the progression of HPV-related abnormalities.

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Cervical Cancer Screening

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Strategies to reduce death from cervical cancer include repeated Pap smears beginning at 20 years of age and HPV DNA testing at 35 and 40 years of age.

Because of the association between HPV and HIV, all women who are diagnosed as having HPV infection or cervical cancer also should be tested for HIV, and women who are HIV infected should undergo regular cervical cancer screening.

In the United States, it is recommended that HIV-infected women receive Pap smears 6 months apart after HIV diagnosis and annual Pap smears thereafter if results are normal.

When HPV vaccines become available, women who are identified as being at increased risk for sexually transmitted infections also should be considered as candidates for HPV immunization, especially if they are young and have not previously had HPV infection.

There are many barriers to effective screening for cervical cancer including poverty, lack of health insurance, lack of transportation, language difficulties, poor infrastructure, lack of adequate communication, and cultural attitudes that view vaginal examinations as inappropriate.

Limited attempts have been made to estimate the annual cost of cervical cancer and HPV screening and treatment in the United States. These estimates range from $1.6 billion to $6 billion, making genital HPV the second most costly sexually transmitted infection after HIV.(18) Costs for single-visit cervical cancer screening in resource-poor countries were estimated by Goldie et al and ranged from $28 to $110.( 18 )

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Screening in Resource-Poor Countries

There is a marked contrast between cervical cancer screening programs in resource-rich and resource-poor countries.

transparent gif bullet Countries with adequate health care resources use multiple clinic visits for screening, confirmation, diagnosis, and finally treatment of HPV-related abnormalities. This approach is not possible in most resource-poor countries. Failure to return for one or more of the follow-up visits in resource-poor countries is a major contributor to low rates of cervical cancer diagnosis and treatment in these settings.( 19 )
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transparent gif bullet Screening based on Pap smears has reduced cervical cancer markedly in resource-rich countries. Performing these tests is challenging in resource-poor countries because high-quality cytological laboratories are difficult to establish and maintain. This results in inaccurate diagnoses and delays in treatment.
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transparent gif bullet To ensure an accurate diagnosis before initiating treatment, screening programs in resource-rich countries visually inspect the vagina using colposcopy, with biopsy of suspicious lesions.( 19 ) However, colposcopy and histopathological laboratory services generally are not available in resource poor-countries.
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Several recent studies have examined the usefulness of less complex approaches to cervical cancer screening in resource-poor settings.( 19 , 20 , 21 ) Denny et al in South Africa demonstrated that both visual inspection with acetic acid or HPV DNA screening followed by cryotherapy reduce the prevalence of high-grade cervical intraepithelial neoplasia (>CIN 2).( 20 ) They also demonstrated that there was no increase in HIV acquisition following cryotherapy in women, an important safety concern for women at high risk for HIV infection.

An abbreviated approach to cervical cancer screening was evaluated by Brewster et al in a primarily poor Latina population in Southern California.( 21 ) The researchers used a single-visit screening program in which women with an abnormal Pap smear were treated with large loop electrosurgical excision during the initial visit. Provision of treatment based on precancerous findings in a single visit greatly increased patient satisfaction and their perception of how well they were informed regarding their health care status. Although this approach has appeal for resource-poor countries, immediate processing of the Pap smear was required, which would be difficult to achieve in settings with limited infrastructure.

HPV testing for primary cancer screening is a complex issue that nevertheless has great potential benefit. Used in conjunction with Pap smears, it increases the sensitivity for a specific diagnosis and has the potential of improving cost- effectiveness of screening programs. This improvement in cost-effectiveness would facilitate increased screening in resource-poor countries.( 19 , 20 ) HPV DNA testing is more sensitive and reproducible than cytological methods such as the Pap smear and colposcopy. Once-in-a-lifetime HPV testing might be more feasible and cost-effective than cytological single-visit screening and treatment programs.( 18 )

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HPV Vaccines

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The approval of an HPV vaccine would represent a major public health advance in the prevention of cervical cancer and cancer of the anus, penis, vagina, and vulva. Although the majority of the estimated 6 million new genital HPV infections are asymptomatic, cervical cancer is the 11th most common cancer among women in United States with an estimated 10,300 new cases and 3,700 deaths in 2005. Worldwide, 471,000 new cases of cervical cancer occur each year, with 233,000 deaths.( 19 )

Significant progress has been made in developing a vaccine for HPV infection. A major breakthrough in the development of an HPV vaccine was reported by Harper et al in 2004.( 22 ) The investigators used HPV viruslike particles (VLPs) for immunization. These vaccines mimic the structure of the virion and induce strong antibody responses. Two of the most important carcinogenic HPV types are HPV 16 and HPV 18. The use of a combined HPV 16 and HPV 18 VLP vaccine was evaluated in HIV-uninfected women over a 26-month period using cytological examination of cervical vaginal samples as end points. The vaccine was found to be 91% effective against new HPV infections and 100% effective against persistent infection.

Recent studies have lead to submission of 2 HPV vaccine candidates to the U.S. Food and Drug Administration for approval. A quadrivalent vaccine has been developed by Merck that would be administered in 3 doses at 0, 2, and 6 months.( 23 ) The vaccine is directed toward HPV types 16 and 18, responsible for 70% of cervical, anal, and genital cancers and HPV types 6 and 11, which cause an estimated 90% of genital warts. The latter HPV types also are implicated in 90% of cases of recurrent respiratory papillomatosis. GlaxoSmithKline has developed a bivalent HPV vaccine containing HPV types 16 and 18 that also would be administered in 3 doses. Both vaccines use the immunization technology described above.( 22 )

The target recipients of the vaccines differ: Merck has targeted both men and women with the intent of preventing cancer and genital warts in both groups and also of immunizing men in order to prevent them from transmitting HPV to women or other men. GlaxoSmithKline has focused on women as the target, primarily to prevent infection with HPV types associated with cervical cancer.

In spite of the enthusiasm regarding the potential public health benefit of these vaccines, several important challenges remain:

transparent gif bullet It is not yet known how long immunity to HPV will last following immunization.
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transparent gif bullet The projected cost of the vaccines is high, estimated to be approximately $300-$500 for the 3-dose series, an amount that would be unaffordable in resource-poor countries, where 80% of cervical cancers occur.( 23 ) It is anticipated that the savings derived from the decreased need for follow-up diagnostic studies and treatment potentially could offset the cost of immunization programs.
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transparent gif bullet An additional issue relates to incomplete protection against other HPV types that are associated with cancer. Although 75% of cervical cancers theoretically could be prevented, 25% of cervical cancers are related to HPV types that are not currently in the vaccines.( 22 , 23 ) This would mean that cervical cancer screening still would be necessary, incurring continued costs for screening programs.
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There are also several ethical and cultural issues related to mass HPV immunization programs. It is not clear whether immunization of males for the protection of females would be widely acceptable. Currently, the only other vaccine that is used in a similar manner is rubella immunization, which is given to all children regardless of gender in order to prevent rubella infection of pregnant women and subsequent congenital rubella syndrome.

Once HPV infection occurs, neither vaccine would be of use for the prevention of cervical or anal cancer.( 23 ) Because HPV infection tends to occur shortly after people become sexually active, HPV vaccines would need to be administered prior to sexual debut in order to be effective for the prevention of cervical or anal cancer. This would require immunization of young girls (and boys) in anticipation that they might become sexually active during early puberty and teenage years.

In addition, it would take several generations before an HPV vaccine would have an impact on reduction of cervical cancer risk overall. In the meantime, women who are currently HPV infected would remain at risk for cervical cancer and would still require cervical cancer screening.

Finally, the impact of mass immunization programs with a vaccine to prevent a sexually transmitted disease on behavior and acquisition of other sexually transmitted diseases is unknown.

There are additional questions that relate to the reduction of the risk of cervical and anal cancer in HIV-infected individuals. Women in resource-poor countries bear the burden of HPV-related cervical cancer and of HIV infection. Theoretically, an HPV vaccine could significantly reduce cervical cancer, a major complication of HPV and HIV coinfection. However, an effective HPV preventative vaccine would not be expected to benefit individuals already coinfected with HPV and HIV. In the majority of patients, once HIV is diagnosed, they already are infected with HPV. It also is not known whether HPV immunization in populations at high risk for HIV infection could prevent the development of cancer. Studies are required to analyze the prophylactic value of HPV vaccines in young women and men at risk for HIV and HPV and the development of HPV-associated malignancies.

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