About cervical cancer

HPV and cervical cancer

Mother and daughtersIn the low-resource countries of the world, 700 women die every day from cervical cancer, leaving behind families and communities that depended on them. Cervical cancer is the second most common cancer in women worldwide and the leading cause of cancer deaths in women in developing countries. With screening, vaccination, and political willpower, cervical cancer can be prevented.1–5

The worldwide burden

  • Nearly 500,000 women are diagnosed with invasive cervical cancer every year.
  • 275,000 women die every year.
  • 80% to 85% of deaths occur in developing countries.
  • The highest incidence and mortality rates are in sub-Saharan Africa, Latin America, and South/Southeast Asia (Figure 1).
  • Most cervical cancer in developing countries occurs in women who take care of children, provide income for families, and work in their communities.
  • Poor women in industrialized countries have a higher incidence of cervical cancer than their wealthier neighbors.

Figure 1 Reference 2

The opportunities

  • Cervical cancer is caused by human papillomaviruses (HPV).6,7 Safe and effective vaccines have been developed against the HPV types responsible for most of the cancers.
  • These vaccines are now available for girls and young women; HPV vaccine has also been approved for boys in some countries (see information about vaccinating boys in the Vaccination strategies section below).
  • Screening adult women for cancer or precancer continues to be a vital strategy.
  • Developing countries need strong and persistent advocates for cervical cancer screening and vaccination programs.

HPV, the cause of cervical cancer

In recent years, investigators have found that some viruses cause cancer. Among these are the hepatitis B and C viruses, which cause liver cancer, and the Epstein-Barr virus, which is responsible for several forms of lymphoma. In the early 1980s, certain HPV types were identified as the cause of cervical cancer by zur Hausen and colleagues. HPV is associated with virtually all cervical cancers.8

Prevalence of HPV

Papillomaviruses are easily transmissible, highly prevalent, tissue-specific DNA viruses. In fact, HPV is the most common sexually transmitted infection. There is no treatment once a person acquires an HPV infection, but recently approved vaccines can prevent infection if given before sexual activity begins.

About 630 million people worldwide are believed to be infected with HPV.6,9 In the United States, about 40% of young women become infected with HPV within three years of sexual debut, and globally, 50% to 80% of sexually active women are infected by HPV at least once in their lives.10,11 Fortunately, in most cases, these infections clear through natural immune responses. The vast majority of HPV infections are transient, becoming undetectable with molecular assays after a period of 4 to 18 months.12-14

Usually women contract HPV between their late teenage years and early 30s, with the peak of infection coinciding with the onset of sexual activity. Most often, cervical cancer is found much later, usually after age 40 (Figure 2), with peak incidence around age 45 and peak mortality in the late 50s. Thus, there is typically a long delay between infection and invasive cancer.13,15,16 This is the reason that screening programs can be so effective, as discussed in the Screening and treatment section.

Figure 2 Reference 2

HPV types

Human papillomaviruses comprise a large family of viruses, with more than 100 types known.17 Some types have a high potential for causing cancer (high-risk types), whereas others have a lower potential (low-risk types).

  • High-risk types cause most anogenital cancers.
  • Low-risk types cause genital warts, abnormal cervical cytology, recurrent respiratory papillomatosis, or, most commonly, infections that go unnoticed and eventually clear up.6
  • HPV 16 and 18 are two types of high-risk HPV associated with about 70% of all cases of cervical cancer.16,18
  • At least 11 other HPV types are also high risk. Among these, HPV 45 and 31 account for about 4% of cases each.

While types 16 and 18 are the most common cancer-causing types worldwide, their prevalence varies slightly in different geographic areas. For example, the combined HPV 16/18 prevalence in cervical cancer lesions is slightly higher in Europe, North America, and Australia (74 to 77%) than in Africa, Asia, and South/Central America (65 to 70%). The next most common HPV types are the same on each continent, namely HPV 31, 33, 35, 45, 52, and 58, although their relative importance differs by region.16,18

Progression from HPV infection to cervical cancer

Cervical cancer begins with HPV infection of the cervix (see short video, "Cervical Cancer, Cervical Dysplasia, Genital Warts"). The cervix is the lower portion of the uterus; it connects the uterus with the vagina (Figure 3). The vagina and the lower part of the cervix are lined with flat (squamous) cells, while the inner surface of the canal to the uterus consists of tall column-like cells. (During a Papanicolaou or "Pap" test, some of the squamous cells are scraped off the surface of the cervix and examined.)

The area where the flat and columnar cells meet is called the transformation zone, and this area is particularly vulnerable to attack by HPV viruses. Both pre-cancer and cancer usually arise in the transformation zone, which is larger during puberty.3 In older women, the transformation zone is deeper inside the canal, and the epithelium is not as susceptible to infection.

Figure 3

Normally, the surface layers of the cervix die and slough off, with a controlled stream of new cells constantly forming and pushing upward from below, in a manner similar to skin renewal. With persistent HPV infection, however, this process is disrupted; cells from the lower layer continue multiplying as they move toward the surface, rather than maturing and eventually dying. They first become abnormal (precancerous), and after a time, they develop cancerous properties. When they invade the deep muscle and fibrous tissue, and then the organs surrounding the uterus, the patient has invasive cancer.

Most HPV infections clear up spontaneously, but 5 to 10% of women who encounter high-risk types develop persistent infections, and this can lead to precancerous changes called lesions.18,19 Neither incident nor persistent infections have symptoms, so women must be screened periodically to see if lesions have developed. Some lesions resolve spontaneously, but others can progress to invasive cervical cancer (Figure 4). See the Screening and treatment section for further information.

Figure 4

Because progression from HPV infection to invasive cancer is slow, usually taking decades, cancer is seen more frequently in women in their 40s and 50s.2,20-22

Risk factors for developing cervical cancer after HPV infection

Most women are infected with a high-risk type of HPV at some time in their lives, but, as mentioned above, only a small portion develop cancer. Risk factors that may affect whether or not an infected woman develops cancer include the following:2,17,23

  • Early age at first sexual intercourse.
  • Early age at first delivery.
  • High number of pregnancies.
  • Smoking.
  • Failure to be screened and treated for precancerous lesions.
  • Long-term use of hormonal contraceptives.
  • Many sexual partners; high-risk partners.
  • Infection with human immunodeficiency virus (HIV) or other sexually transmitted infections (e.g., herpes virus or Chlamydia trachomatis).
  • Immunosuppression due to HIV, other diseases, chemotherapy, or other causes.

Because HPV, like HIV, is sexually transmitted, people sometimes assume that interventions effective in preventing HIV infection—such as using condoms and reducing the number of sexual partners—work just as well for HPV prevention. But this is not true, because HPV resides in the skin, not in body fluids, and the virus can be present in genital regions not covered by a condom sheath. Even when used correctly with every act of sexual conduct, condoms are only about 70% effective in preventing HPV.24

For both men and women, the risk of contracting HPV infection is affected primarily by sexual activity; their own or that of their partners. But while risk of HIV infection increases dramatically as the number of sexual partners increases, the situation with HPV is more complex. HPV viruses are so prevalent that a recent US study found that the chance that a woman would contract HPV after her first sexual partner was nearly 30% in her first year of sexual activity and 50% within three years.25

Thus it is very difficult to avoid HPV infection. If a person has more than one partner (concurrently or serially), the risk goes up. Further, people who have had many sexual partners, have other sexually transmitted infections, or are immunosuppressed are more likely to have active HPV infections and to transmit them.

Being faithful to a partner and regularly using condoms are not sufficient precautions for significantly reducing rates of cervical cancer. Women can decrease their chances of developing cervical cancer by reducing some of the risk factors in the list above, but vaccination of adolescent girls against HPV and screening of adult women are the best ways of preventing this disease.

Best methods for preventing cervical cancer

Cervical cancer can be prevented either by avoiding HPV infection, or by periodic monitoring (screening) for infection and lesions.

Preventing HPV infection

  • Avoid exposure to the virus through abstinence from sexual activity or through mutual monogamy forever, provided both partners are consistently monogamous and were not previously infected (but this is not considered practical for most people).
  • Get the HPV vaccine before beginning sexual activity. The new vaccines are discussed in the Vaccines against HPV section below. These vaccines do not protect against all HPV viruses that can cause cervical cancer, so screening is still necessary.

Preventing development of invasive cancer through screening and treatment

  • The most familiar method of cervical cancer screening worldwide is the Pap test, but new alternatives have been shown to be as effective, or more effective, than Pap, often at a lower cost. Tests for HPV DNA have become available and may become a more common way of screening for infection. Screening options are discussed in the Screening and treatment section. Because cervical cancer develops slowly, over years, regular screening, along with removal of any lesions, is very effective in preventing invasive cancer.

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Vaccines against HPV

Two approved HPV vaccines

In June 2006, the first vaccine against HPV infection was approved and marketed—Merck & Co. Inc.’s Gardasil.® Since that time, Gardasil and the GlaxoSmithKline vaccine, Cervarix,® have been licensed in more than 100 countries worldwide.

Gardasil prevents infection with two of the most common cancer-causing types of HPV, types 16 and 18. Around 70% of cervical cancer cases are associated with these two HPV types. This vaccine also protects against two types of HPV that do not cause cancer—types 6 and 11—but cause about 90% of genital warts. This quadrivalent vaccine is given in a series of three 0.5-mL intramuscular injections over six months, with the second dose given two months after the first and the third about six months after the first.26

Cervarix also protects against infection with HPV types 16 and 18, but does not include protection against any other HPV types. It is also given in a series of three 0.5-mL injections, but the dosing differs slightly from that for Gardasil, with the second dose given one month after the first and the third given six months after the first.27 See Table 1 for further information on the two vaccines.

Table 1 Click for reference list

Effectiveness and safety of the vaccines

Protection against cervical cancer

Clinical trials of the two HPV vaccines used cervical lesions (cervical intraepithelial dysplasia 2+) as their primary endpoint; that is, they compared the number of cases of precancerous lesions in vaccine and control groups to determine how effective the vaccines were.28,29 They did not wait for cases of cervical cancer to develop because that would have taken several decades and would have been unethical. It is well-known from years of research that cancer is preceded by these precancerous lesions.

Efficacy for preventing precancerous lesions for both vaccines is greater than 92% in women who have not been previously infected.28,29 In all primary analyses for Gardasil and Cervarix, vaccine efficacy was very high; that is, the vaccines are very effective in preventing infection and lesions caused by HPV 16 or 18 if the woman has not been infected previously with those types. These types cause 70% of all cervical cancers.

Duration of effectiveness

Clinical trials show that HPV vaccines are effective for at least five to six years (the duration to date, based on follow-up data from the major trials), but they are likely to be effective for much longer.30,31

Preliminary results from a trial of the HPV 16 component of the quadrivalent vaccine indicate that it is effective for up to 8.5 years.32 During the long-term follow-up, there has been no evidence of decreased efficacy for prevention of infection or lesions. While the two vaccines cannot be compared directly because of differences in the way antibody levels are measured for the clinical trials, they both produce levels between 10 and 80 times that found in natural infections.

Further, a booster shot of the HPV vaccine stimulated a response similar to vaccines that provide long-lasting protection, such as the hepatitis B vaccine.33 These findings suggest that the duration of effectiveness could be long lasting, but definitive data will become available only when clinical trial participants have been followed for a longer time.

Cross-protection against non-vaccine HPV types

Both Gardasil and Cervarix appear to offer some protection against HPV types that are not specifically targeted by the vaccines (types 16 and 18), mainly against type 31, which is related to type 16. Gardasil was 70% effective, and Cervarix 92% effective, against lesions caused by HPV 31 in study participants naïve to that virus. In all women in the clinical trials, including those who had already been exposed to viruses, Gardasil was about 20% effective against all HPV types, while Cervarix was about 30% effective, and statistical analyses showed a lower level of confidence in the results.29,34

Safety and side effects

The safety of drugs, including vaccines, is assessed in two ways: from data in clinical trials and from reports posted by the public after medicines are approved and in use. Data from randomized clinical trials are highly reliable, since reports of serious adverse events can be investigated and verified and there is a built-in control group for comparison.

Reports from the public after vaccine approval can be made to the Vaccine Adverse Event Reporting System (VAERS) in the United States. These reports provide a signal of possible side effects related to a particular vaccine, which authorities can investigate. A similar system, the Yellow Card Scheme, is used in the United Kingdom (Cervarix is currently the dominant vaccine in the United Kingdom). Both VAERS and Yellow Card reports are available to the public as posted, and without verification. The side effects reported should not be interpreted as confirmed side effects of a vaccine. They are intended to give a signal to investigators that further monitoring may be warranted.

No serious adverse events and no deaths have been verified to have been caused by HPV vaccine in any of the clinical trials, even after more than five years of follow-up.

Some people in low-resource countries have expressed concern that the HPV vaccines are being tested on girls in their communities. In fact, thousands of young women in the United States and Europe, as well as in Asia and Latin America, received vaccine in the clinical trials that led to approval. The vaccines are no longer being tested; they have been approved as safe and effective. As of April 2009, more than 16 million doses of Gardasil had been given in the United States, with a very low rate of adverse events. From September 2008 to September 2009, 1.4 million doses of Cervarix were administered across the United Kingdom, also with a low side effect rate.

Gardasil

In clinical trial reports for Gardasil,26 the most common side effect was discomfort at the injection site. About 60% of recipients had pain, swelling, itching, bruising, or redness at the injection site; however, about 50% of participants who received the vaccine adjuvant (a mixture of aluminum salts) also had these symptoms, as did about 25% of those receiving a simple salt solution. Other common side effects were headache, fever, nausea, dizziness, vomiting, and fainting. Fainting after any injection is common in adolescents. Other reactions tended to pass within a day or two. Out of the entire study population involved in Gardasil clinical trials at the time of approval (25,274 subjects), only 0.05% of the reported serious systemic adverse reactions were judged to be vaccine related by the study investigator (but still have not been proven). For all of these events, a similar number of cases were seen in the control groups.

While fainting itself is not usually dangerous, falling may cause serious problems such as head injuries. Because of the reports of fainting, in June 2009, the US Food and Drug Administration required Merck to add a warning to the Gardasil package insert stating that individuals should be watched carefully for 15 minutes after vaccination to avoid potential injury from a fall.

In the VAERS reporting system for tracking Gardasil, the most commonly reported adverse events following HPV immunization have been similar to those found in clinical trials: discomfort at the injection site, fainting, dizziness, nausea, and headache. In regard to serious side effects, these accounted for only 6% of all VAERS reports—and remember, these were not confirmed to be caused by the vaccine. US Centers for Disease Control and Prevention investigators published a review of the data and stated:35
A major limitation of VAERS data is that there is no proven causal association between the vaccine and the adverse event. The only association is in time, meaning that the adverse event occurred sometime after vaccination. Therefore we cannot conclude that the events reported to VAERS were caused by the vaccine.

Cervarix

Side effects for Cervarix are similar to those reported for Gardasil. In clinical trials,27 injection site reactions were the most common side effect. Other frequent effects were headache, nausea, vomiting, and muscle aches. The most common side effects reported in the Yellow Card Scheme have been pain and redness at the injection site, allergic reactions (rash, itching), fainting, dizziness, nausea, headache, and low fever.

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HPV vaccination strategies

World Health Organization recommendations

According to the World Health Organization, routine HPV vaccination should be included in national immunization programs when:

…prevention of cervical cancer or other HPV-related diseases, or both, constitutes a public health priority; vaccine introduction is programmatically feasible; sustainable financing can be secured; and the cost effectiveness of vaccination strategies in the country or region is considered. HPV vaccines are most efficacious in females who are naive to vaccine-related HPV types; therefore, the primary target population should be selected based on data on the age of initiation of sexual activity and the feasibility of reaching young adolescent girls through schools, health-care facilities or community-based settings. The primary target population is likely to be girls within the age range of 9 or 10 years through to 13 years.

Programmes introduced to prevent cervical cancer should initially prioritize high coverage in the primary target population of young adolescent girls. Vaccination of secondary target populations of older adolescent females or young women is recommended only if this is feasible, affordable, cost effective, does not divert resources from vaccinating the primary target population or effective cervical cancer screening programmes, and if a significant proportion of the secondary target population is likely to be naive to vaccine-related HPV types.36

Age for vaccination

Many countries have adopted policies that support vaccination of female adolescents before sexual debut (usually around ages 10 to 14). Although vaccination even earlier in life poses no theoretical risk, no studies have yet been published to support vaccination of very young girls or infants. Thus far, it is not recommended that sexually active, older women be vaccinated, since both vaccines show much lower effectiveness after HPV infection. Rather, cervical screening is the best approach for this group.1,36 Because the incidence of cervical cancer is highest in women more than 40 years of age, screening is especially important in older women (see Continued need for screening below).

Subsidies for vaccines

In low-resource countries, vaccination with current vaccines will be possible only with substantial vaccine subsidies. The GAVI Alliance37 is considering providing HPV vaccine at a reduced cost to the poorest countries in the world.

Strategies for vaccinating girls currently are being explored in PATH-led HPV vaccination demonstration projects in India, Peru, Uganda, and Vietnam.38 The strategies include:

  • Vaccinating girls in school settings (with outreach to out-of-school girls).
  • Vaccinating as part of a campaign to reach older children with other health interventions (such as Uganda’s semi-annual Child Days Plus program).
  • Vaccinating girls in community health clinics.

Lessons learned from these demonstration vaccination programs will help give countries the tools they need to develop effective local programs. Forecasting and delivery strategies (in schools or community programs) can also be guided by this information.

Ensuring access to HPV vaccine

Young adolescents do not routinely interact with health systems in most developing countries, and ensuring access will be a challenge. One promising suggestion is to strengthen school health programs, especially because of the recent increase in primary school attendance in some countries. Where many young girls drop out of school at an early age, community programs might help to fill the gap.

Once effective strategies have been developed to reach these girls, they can be used to provide additional health interventions appropriate for older children, such as other immunizations, deworming, malaria intermittent preventive treatment, provision of bed nets, nutritional supplementation, and general health and life skills education. Using one system to deliver multiple interventions—at the same time as HPV vaccination or at different times—will lower the cost of all the interventions.

Continued need for screening

Although the new HPV vaccines are expected to significantly reduce the risk and incidence of cervical cancer, they will not replace screening; rather, use of the vaccines in partnership with screening will maximize effectiveness.39,40 Screening is needed for the millions of women aged 30 or older in whom HPV infection has likely occurred if they have been sexually active sometime in their lives. Because the new vaccines are not therapeutic, they cannot benefit women who are already infected. In these women, the effects would be much smaller, probably protecting against the type not yet encountered.

Countries with screening programs already in place should continue to support screening even if a vaccination program is instituted. In countries without screening programs, policymakers should consider initiating screening of women aged 30 and older once or twice in their lifetimes, in conjunction with vaccination of girls and young women who are not yet sexually active.15,40,41 To learn more, visit the Screening and treatment section.

Vaccinating boys

Vaccinating boys is not cost-effective in the developing world.
Boys can become infected with HPV, they can infect female partners, and they can develop HPV-associated diseases such as penile, anal, and oral cancers or genital warts. Some experts believe that vaccinating both males and females would benefit women because women are infected by male sexual partners, but computer models suggest that this strategy may not be cost-effective unless vaccine coverage of girls is low.42

Unanswered questions about HPV vaccines

Current research projects and clinical trials are addressing questions:

  • Will booster shots be necessary, and if so, when and how often?
  • What is the optimal dosing regimen? Can protection be achieved with fewer than three doses? Can doses be delivered on schedules different from the current ones?
  • Are the vaccines safe in pregnant and breastfeeding women?
  • Is co-administration with other adolescent vaccines safe and effective?

Future vaccines

Second-generation prophylactic vaccines

A key goal for the future is to develop preventive vaccines that are more suitable to resource-limited areas. Some features that would improve current vaccines include:
  • Lower price.
  • Longer shelf life.
  • Stable at a range of temperatures.
  • Effective after only one or two doses.
  • Function when given nasally or orally.
  • Effective against multiple high-risk HPV types.
  • Confer long-lasting immunity without boosters.

Investigators are working on second generation prophylactic vaccines that may address some of these needs.43,44

Therapeutic vaccines

Currently, no therapies are available for active HPV infections, but researchers are working on vaccines that may prevent cancer in women who have persistent HPV infections. These vaccines could be used alone or in combination with other treatments, and would be designed to stop the progression of low-grade lesions to invasive cancer, or to prevent the recurrence of previously treated lesions or cancer.43,45,46

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Screening and treatment of precancerous lesions

Screening

Cervical cancer screening of sexually active or formerly sexually active women can determine whether they are at risk of developing cervical cancer. This determination can be made by examining the cells gently scraped from the cervix using the Pap test; by examining the surface layer of the cervix through visual inspection; or by detecting HPV DNA from cervical swabs.39,47 The Alliance for Cervical Cancer Prevention promotes ten findings and recommendations for effective cervical cancer screening programs.

Cytologic screening (Pap)

Since its introduction more than 50 years ago, the Pap or cervical smear has been used throughout the world to identify precancerous lesions for treatment or follow-up. Routine use of Pap smear screening in the industrialized world has contributed to the 70% to 80% reduction of cervical cancer incidence in developed countries since the 1960s.48 Even in industrialized countries, however, the level of success can vary. For example, in the United States, where an overall decline in the number of cervical cancer cases has occurred, rates nonetheless remain high in impoverished areas.49

Lack of similar success in developing countries can be attributed to limited resources (i.e., supplies, trained personnel, equipment, quality control, health care infrastructure, and effective follow-up procedures).48 As noted earlier, screening programs in developing countries either do not exist or have not proven to be sustainable or effective.1 One estimate is that about 75% of women in industrialized countries have been screened within the preceding five years. In contrast, a survey in India found that only 2.6% of women had been screened.50 Estimates in Kenya suggest that only 1% of participants had ever undergone any screening, despite numerous efforts to improve screening programs. One factor compounding the problem is that both women and health care workers often lack information about cervical disease and how to prevent it.51,52

Pap smear

Limitations of cytology

A single cytologic screening results in a high rate of false-negatives—that is, it lacks sensitivity and cannot detect many cervical abnormalities, making repeat screening necessary. Pap smear failure can be a consequence of the health care provider’s sampling technique or ability to read the smears. In addition, the need for follow-up medical appointments to present the results and manage any abnormalities can negatively affect treatment rates when women are unable to return for treatment appointments.15,39

Efforts to improve the reliability of Pap smears in the last ten years include the development of liquid-based cytology, which uses a small amount of fluid to preserve cells collected from the cervix, rather than directly smearing the cell sample onto a glass microscope slide. This method has greater laboratory efficiency, but in some countries, it adds to the cost of the test, has not been shown to have better accuracy, and requires additional instruments. For these reasons, it may not be well-suited for use in many low-resource settings.48,53 In addition, computer technology is now being used to identify the most abnormal areas on a Pap smear slide, thereby reducing the subjectivity of assessments and increasing the test’s sensitivity—however, this technology is also quite expensive.

Alternatives to cytology

Several new types of screening methods are either available now or under development. Ideally, the most effective screening method would be accurate, inexpensive, painless, and simple to perform; socially and culturally acceptable; without adverse effects; and able to provide immediate results. Some promising new methods may bring cervical cancer screening closer to this ideal.48,51,53

Visual inspection with acetic acid

Visual inspection with acetic acid (VIA) can be an alternative to cytologic testing or can be used along with Pap or HPV DNA screening. VIA involves washing the cervix with 3% to 5% acetic acid (vinegar) for one minute and observing the cervix with the naked eye afterward. If characteristic, well-defined white areas are seen near the transformation zone, the test is considered positive for precancerous cell changes or early invasive cancer. VIA does not require a laboratory or intensive staff training. The results are immediately available, allowing treatment at a single visit and thus reducing loss to patient follow-up. VIA’s sensitivity is as good as or better than that of the Pap smear, but like the Pap smear, visual inspection is subjective, and supervision is needed for quality control of visual inspection methods. VIA does not work as well in postmenopausal women because the transformation zone recedes into the cervical canal at menopause and cannot be seen with VIA.51,54

An additional advantage of VIA not offered by Pap or HPV DNA tests is that it allows providers to identify the small proportion of positive lesions that are unsuitable for treatment with cryotherapy, a mode of treatment appropriate for limited-resource settings (see Treatment of precancerous lesions below). An implication of this is that whether primary screening is done by Pap, VIA, or HPV testing, the decision not to treat with cryotherapy can be made only with VIA (unless a colposcope is available). VIA therefore can be used as a primary screening test or for treatment triage subsequent to primary Pap or HPV testing.

Visual inspection with Lugol’s iodine (VILI) is similar to VIA. However, data on VILI’s sensitivity and specificity remain limited.

HPV DNA testing

New tests can detect DNA from cancer-causing HPV types in vaginal or cervical smears. A sample of cells is collected from the cervix or vagina using a small brush or swab, and the specimen is sent to a laboratory for processing. One advantage of HPV DNA testing is that when conditions are ideal, it is not as subjective as visual and cytologic screening. A review of studies concluded that HPV DNA testing is particularly valuable in detecting high-grade precancerous lesions in women older than 30. HPV infections in women younger than 30 are likely to clear up by themselves, so testing women at that age would lead to frequent overtreatment.55,56

The Cervista™ HPV tests

The United States Food and Drug Administration has approved an HPV DNA test called Cervista HPV 16/18 (Hologic™, Inc.), which detects DNA for HPV types 16 and 18. Another test, the Cervista HPV HR (High Risk) test, which detects most oncologic HPV types, also has been approved.57

The Hybrid Capture® 2 test

The US FDA has approved the HPV DNA detection assay Hybrid Capture 2, which was developed by QIAGEN, Inc. (formerly Digene). This test can detect 13 high-risk types of HPV and 5 low-risk types. It is more sensitive than visual inspection methods and cytology, but it is unaffordable for low-resource areas. In addition, the test requires laboratory facilities, special equipment, and trained personnel.58,59

The careHPV™ test

A new test called careHPV™ (QIAGEN, Inc.), based on Hybrid Capture 2 technology, has been developed specifically for use in low-resource settings. This test is able to detect DNA from 14 cancer-causing types of HPV, with test results available in two to four hours. CareHPV should become available commercially sometime in 2010 or 2011, and if it proves to be simple, rapid, accurate, and affordable, it may be a suitable screening tool for low-resource settings.59 One issue regarding both the careHPV™ test and the Hybrid Capture 2 test is that they are designed to test many samples at the same time, which might affect how programs will use them.

In addition to these tests, other molecular HPV tests are under development and are likely to be evaluated soon for clinical use.

Treatment of precancerous lesions of the cervix

Women with precancerous lesions who receive treatment have a high survival rate. The affected area of the cervix may be frozen with a cold probe (cryotherapy) or removed using a heated wire loop as a knife (loop electrosurgical excision procedure or LEEP). These are both outpatient procedures that can be used in developing countries, but LEEP is quite expensive and requires more training than cryotherapy (see descriptions in Table 2). If cryotherapy is restricted to lesions that are small (i.e., about 20 mm or less), and the entire lesion is visible (does not extend into the cervical canal), treatment efficacy is 85% to 95%. Both cryotherapy and LEEP are less radical than the previous standard treatment, cold-knife cone biopsy. Although no longer the standard, cone biopsy is still used for precancerous lesions that cannot be otherwise treated, or when cancer (squamous carcinoma or adenocarcinoma) is suspected.20,60,61

Table 2 Click for reference list.

Screen-and-treat programs

In developing countries, a promising method called screen-and-treat is being used. Women who test positive on VIA or HPV DNA tests do not undergo further diagnostic testing; instead, they are treated immediately or shortly after screening with cryotherapy or LEEP.20 The screen-and-treat approach is especially appealing where transportation, time, and other access issues make follow-up visits difficult. The main benefit is that women are less likely to be lost to treatment because they cannot return to the clinic.47 Screen-and-treat programs have been evaluated in Ghana, South Africa, and Thailand with good results. The data show that VIA and cryotherapy done in one or two clinical visits, without an intermediary colposcopic and biopsy diagnostic step, is one of the most cost-effective alternatives to conventional multi-visit strategies.62-64

New paradigms for screening in the age of HPV vaccination

The success of VIA, HPV DNA testing, and cryotherapy in field settings signals new potential for cervical cancer control in places where cytology programs are not feasible or sustainable. Single-visit approaches using VIA to screen can be offered now, and screen-and-treat approaches using HPV DNA tests for primary screening and VIA for triage may be possible in the near future in many low- to medium-resource settings.

Once HPV vaccination becomes routine, and more sensitive tests than Pap or VIA are in widespread use, it is likely that the screening strategies common today (such as Pap smears repeated every one to three years, as in the United States, or every three to five years, as in other countries) will change. One proposed scenario is to vaccinate prior to sexual debut, then screen only a few times when the woman is in her 30s and 40s using HPV DNA testing (or other future molecular tests that may give a better indication of which women are at highest risk of pre-cancer).65 Such a strategy would be feasible in low-resource settings and would save considerable costs in wealthier countries.

Another concern for the future is what will happen when the current generation of newly vaccinated girls reaches the appropriate age for screening. The vaccines protect against the two HPV types that cause 70% of cervical cancer, but not against those that cause the other 30%. Some epidemiologists have raised concerns that the vaccines will diminish the quality of Pap-based screening programs. According to this thinking, as cervical lesions become less prevalent, technicians will lose their skills of interpreting specimens, so the accuracy of Pap screening will fall. In this sense, the clear and objective results of the new HPV DNA or other molecular tests will provide an advantage. More generally, the principles of public health screening will help to determine how resources should be allocated in future decades, taking into consideration factors such as vaccine coverage and cervical cancer prevalence.

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Invasive cervical cancer

Diagnosis of invasive cervical cancer

In industrialized countries, women who test positive by either Pap smear or HPV DNA tests then undergo diagnostic testing, with colposcopy, for example. Colposcopy is an examination of the vagina and cervix using a magnifying device with a powerful light source to identify abnormal areas on the cervix and to guide sampling of cervical tissue (biopsy).66 Colposcopy must be performed by trained providers, and colposcopes are expensive. In addition, the biopsy samples must be transported to a laboratory staffed by a pathologist, which is often impossible in low-resource countries. If a woman has an abnormal Pap smear but no abnormal areas are seen by colposcopy, or the colposcopic examination is inadequate (i.e., the entire transformation zone is not seen), cells from the cervical canal can be sampled and sent to the laboratory. This procedure is called endocervical curettage.20,67

Treatment of invasive cervical cancer

If detected early, invasive cervical cancer can be treated successfully; five-year survival for women with cancer in the earliest stage (stage 1A, in which the cancer has had minimal spread to the inside of the cervix) is estimated at 92%.3 Radical hysterectomy and radiotherapy are the recommended primary treatments for the early stages of cervical cancer but should not be used to treat precancerous lesions. For advanced disease, radiotherapy (radiation) is frequently used to cure or ease symptoms, but in developing countries it is not widely available or accessible. Radiotherapy aims to destroy cancer cells while preserving normal cells. Adverse effects include inflammation of the skin, diarrhea, and nausea. Its effectiveness depends on how far the cancer has spread beyond the cervix. Chemotherapy may also be used with hysterectomy and radiotherapy.15,20

Adjunctive nonmedical care can include traditional or cultural practices, provided they do not cause harm (e.g., massage, prayer, counseling, emotional support). Pain control for women with advanced cervical cancer is often inadequate in developing countries. There are, however, effective and inexpensive options for providing pain control, such as the use of morphine. This palliative aspect of patient care should be a priority for implementation by both clinical and home care providers.15,68

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Financing and cost-effectiveness

Financing and cost-effectiveness of cervical cancer prevention

Costs for delivering the HPV vaccine probably will be greater than those for existing infant vaccination programs. Financing for health care in developing countries is already limited; therefore, financing for HPV vaccine and pre-cancer screening and treatment programs will require sustained, strong advocacy efforts and innovative strategies.39,69

Program costs

The price of the vaccine itself is not the only cost—there are programmatic costs as well—and this is equally true for screening programs. Most adolescents and older women do not routinely participate in health care to the same extent as younger children and infants, and new strategies must be developed to reach both of these groups.

The cost-effectiveness of vaccination and screening programs in developing countries will be influenced by the cost of instituting programs for widespread coverage of the target populations; the duration of protection the vaccine provides; and the degree of participation in the programs.70-74 An important component in the cost-effectiveness of prevention will be eventual savings in treatment of cervical cancer and other HPV-related diseases. A number of studies have been published that use computer models to estimate the cost-effectiveness of various combinations of HPV vaccination of girls and screening and treatment of adult women, including for developing-world countries such as Brazil, India, and Vietnam.75-78

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Advocacy, communication, and training

Advocating and training for cervical cancer prevention

Accurate information is essential to improving understanding of both HPV and cervical cancer among health care workers, educators, policymakers, parents, and patients. Many do not know the cause and burden of cervical cancer and may not be able to understand the value of HPV vaccines or cervical screening for improving the current situation. Without such understanding and strong advocacy, individuals are unlikely to support these interventions.5,53,71

To improve knowledge, it is advisable first to decide how best to “frame” the information by considering sociocultural realities. Effective framing can help to avoid social resistance from, for example, groups that fear that HPV vaccines will promote promiscuity (even though studies have shown that sex education has the opposite effect).5,79,80 Community readiness and acceptance will help to ensure access to vaccination and screening programs, so community leaders should be involved in the design and implementation from the beginning.

HPV vaccine is well accepted in many communities

Recent experience in India, Peru, Uganda, and Vietnam provides guidance in ways to frame HPV vaccination in developing countries. Based on the results of extensive audience and systems research, all four country programs made the strategic decision to emphasize the protective effect of the vaccine against cancer rather than emphasizing the mode of transmission (sexual activity) or the disease agent (HPV) when educating community members. Posters, local radio spots, brochures, and other media for the general public promote “cervical cancer vaccine.” (But when communicating with more educated health professionals, materials use the phrase “HPV vaccine” since these individuals are more likely to understand that term.) This strategic choice seems to have paid off, as community acceptance rates of the vaccine are much higher than expected for a new vaccine that had not been part of the routine government immunization program. Project staff believe that once parents understand the basics of cervical cancer, they reason along these lines: (1) in general, communities have faith in immunization; (2) they are concerned about cancer, even when they are not very knowledgeable about it; and (3) they say that if a vaccine against cervical cancer is safe, effective, and affordable, they want their daughters vaccinated.38

The country teams also have been pleased to find that potential sociocultural concerns have not arisen. Possible concerns included the fear that parents would distrust a vaccine offered only to girls or that they would worry that giving their daughters a vaccine against a sexually transmitted infection could disinhibit the girls from early sexual experimentation. There also was concern that conservative religious leaders might take a stand against HPV vaccination for the same reasons. But none of these scenarios has developed significantly in the four countries. This is likely due to the extensive educational work done in the communities prior to vaccine introduction. In villages or schools where pre-introduction communication was weaker, coverage tended to be low until additional educational outreach was implemented.

One unanticipated challenge arose during field work—confusion between HPV and HIV. As mentioned in the HPV and cervical cancer section above, sometimes people assume that because both HIV and HPV are sexually transmitted, prevention strategies would be similar. However, while reducing numbers of sexual partners and consistent use of condoms can dramatically reduce HIV infection, those strategies are not as effective against HPV. Explaining this difference has been added as a key message in the PATH programs. Further, the use of the term “cervical cancer vaccine” can lessen confusion between the abbreviations HPV, HIV, and HBV (hepatitis B virus).

Educating health care workers

Because clinicians are often the primary source of information for both parents and adolescents, educating clinicians helps parents to understand the benefits of any vaccine.5,52 Health care workers in many developing countries might not have a clear understanding of HPV infection and its relationship to cervical cancer development and prevention. This situation is exacerbated by the “silent nature” of cervical cancer—the fact that symptoms are not present until the cancer is at an advanced stage. Health workers need to be educated about how to help patients understand the enormous advantages offered by both screening and vaccination.52,81,82

In both industrialized and developing countries, it is unclear which types of providers will deliver the vaccines—community health workers, general physicians or nurses, pediatricians, nurse midwives, or obstetricians and gynecologists. Obstetricians and gynecologists have not traditionally administered vaccines. Conversely, the immunization community may have limited knowledge of cervical cancer and HPV. Therefore, some additional training with both groups will be necessary to implement HPV vaccination programs.83,84

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