Xian Wen Jin, MD, PhD, FACP

Yes. Growing evidence demonstrates that the human papillomavirus (HPV) DNA test is more sensitive than the Papanicolaou (Pap) test, with a better negative predictive value—ie, women who have negative test results can be more certain that they are truly free of cervical cancer.^1–3

On April 24, 2014, the US Food and Drug Administration (FDA) approved the Cobas HPV test developed by Roche for use as the first-line screening test for cervical cancer in women age 25 and older.⁴ The approval follows the unanimous recommendation from an independent panel of experts, the Microbiology Devices Panel of the FDA’s Medical Devices Advisory Committee, on March 12, 2014.

PAP-HPV COTESTING IS EFFECTIVE BUT NOT PERFECT

Based on conclusive evidence of a direct link between HPV infection (specifically, infection with certain high-risk HPV genotypes) and almost all cases of invasive cervical cancer,^5,6 the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), US Preventive Services Task Force (USPSTF), and American Congress of Obstetricians and Gynecologists (ACOG) issued a consensus recommendation for Pap-HPV cotesting as the preferred screening strategy starting at age 30 and continuing through age 65.^7–9

Compared with Pap testing alone, cotesting offers improved detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the ability to safely extend the screening interval to every 5 years in women who have negative results on both tests. It is an effective screening strategy and remains the standard of care today.

However, this strategy is not perfect and presents several problems for clinicians. The results of the two tests often conflict—the results of the Pap test might be positive while those of the HPV test are negative, or vice versa. Integrating the results of cotesting into triaging can be confusing and complicated. In addition, performing two tests on all women increases the cost of care. And furthermore, the cotesting strategy increases the number of women who require immediate or short-term follow-up,^1,2,10–12 such as colposcopy, which is unnecessary for many.

THE HPV TEST DETECTS 14 HIGH-RISK GENOTYPES

The FDA-approved HPV test detects 14 high-risk genotypes. The results for 12 of these are pooled and reported collectively as either positive or negative, while the other two—HPV 16 and HPV 18—are reported separately. (HPV 16 and HPV 18 are the highest-risk genotypes, and together they account for more than two-thirds of cases of invasive cervical cancer.)

ADVANTAGES OF HPV-ONLY TESTING: FINDINGS FROM THE ATHENA TRIAL

The FDA’s decision to approve the Cobas HPV test for use by itself for screening was based on the landmark ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial.¹³ ATHENA, the largest prospective study of cervical cancer screening performed in the United States to date, enrolled 47,208 women at 61 sites in 23 states. The study revealed the following findings:

The FDA has approved the test for this indication, and guideline committees are reviewing the data

• The HPV DNA test had higher sensitivity for detecting CIN3+ (37% higher than the Pap test) and equivalent specificity.
• The HPV test’s positive predictive value was nearly twice as high (12.25% vs 6.47%), and it had a higher negative predictive value (99.58% vs 99.41%) in detecting CIN3+ than with the Pap test.
• HPV testing by itself performed better than Pap-HPV cotesting, with positive predictive values of 12.25% vs 11.04% and negative predictive values of 99.58% vs 99.52% (data presented to the FDA Medical Devices Advisory Committee, Microbiology Panel. March 12, 2014. FDA Executive Summary).

For women whose results were negative for HPV 16 and 18 but positive for the 12-genotype pooled panel, the sample was automatically submitted for cytologic (Pap) testing. Reserving Pap testing for samples in this category improved the specificity of the test and resulted in fewer colposcopy referrals. The ATHENA researchers found that 11.4% of the participants who tested positive for either HPV 16 or 18 had CIN2+.¹³ Other large cohort studies^14,15 also showed that the short-term risk of developing CIN3+ reached 10% over 1 to 5 years in women who tested positive for HPV 16 or 18.

The proposed algorithm for screening (Figure 1) takes advantage of the superior sensitivity of the HPV test, the built-in risk stratification of HPV 16 and 18 genotyping, and the excellent specificity of the Pap test in triaging women whose results are positive for high-risk HPV genotypes other than HPV 16 and 18. Thus, women who have a negative HPV test result can be assured of remaining disease-free for 3 years. The algorithm also identifies women who are at highest risk, ie, those who test positive for HPV 16 or 18. In contrast, the current cotesting approach uses the Qiagen Hybrid Capture HPV testing system, which is a panel of 13 high-risk genotypes, but, if the result is positive, it does not tell you which one the patient has. Furthermore, the new algorithm provides efficient triage, using the Pap test, for women who test positive for the 12 other high-risk HPV genotypes.

Data from large clinical trials other than ATHENA are limited.

FDA APPROVAL DOES NOT CHANGE THE GUIDELINES—YET

The cervical cancer screening guidelines are developed by several organizations other than the FDA. The current guidelines issued by the ACS, ASCCP, ASCP, USPSTF, and ACOG in 2012 call for Pap testing every 3 years in women younger than 30 and Pap-HPV cotesting every 5 years in women ages 30 to 65.^7–9 However, FDA approval of the new indication of the HPV DNA test as a stand-alone first-line screening test is an important milestone. It heralds the shifting of the practice paradigm from morphologically based Pap testing to molecular testing in cervical cancer screening.

The ACS and ASCCP have announced that they are reviewing the evidence and may issue updated guidelines for clinicians in the near future.^16,17 We anticipate that other organizations may take similar steps. As primary care physicians, we need to stay tuned and follow the most up-to-date evidence-based practice guidelines to provide the best care for our patients.

Yes. Growing evidence demonstrates that the human papillomavirus (HPV) DNA test is more sensitive than the Papanicolaou (Pap) test, with a better negative predictive value—ie, women who have negative test results can be more certain that they are truly free of cervical cancer.^1–3

On April 24, 2014, the US Food and Drug Administration (FDA) approved the Cobas HPV test developed by Roche for use as the first-line screening test for cervical cancer in women age 25 and older.⁴ The approval follows the unanimous recommendation from an independent panel of experts, the Microbiology Devices Panel of the FDA’s Medical Devices Advisory Committee, on March 12, 2014.

PAP-HPV COTESTING IS EFFECTIVE BUT NOT PERFECT

Based on conclusive evidence of a direct link between HPV infection (specifically, infection with certain high-risk HPV genotypes) and almost all cases of invasive cervical cancer,^5,6 the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), US Preventive Services Task Force (USPSTF), and American Congress of Obstetricians and Gynecologists (ACOG) issued a consensus recommendation for Pap-HPV cotesting as the preferred screening strategy starting at age 30 and continuing through age 65.^7–9

Compared with Pap testing alone, cotesting offers improved detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the ability to safely extend the screening interval to every 5 years in women who have negative results on both tests. It is an effective screening strategy and remains the standard of care today.

However, this strategy is not perfect and presents several problems for clinicians. The results of the two tests often conflict—the results of the Pap test might be positive while those of the HPV test are negative, or vice versa. Integrating the results of cotesting into triaging can be confusing and complicated. In addition, performing two tests on all women increases the cost of care. And furthermore, the cotesting strategy increases the number of women who require immediate or short-term follow-up,^1,2,10–12 such as colposcopy, which is unnecessary for many.

THE HPV TEST DETECTS 14 HIGH-RISK GENOTYPES

The FDA-approved HPV test detects 14 high-risk genotypes. The results for 12 of these are pooled and reported collectively as either positive or negative, while the other two—HPV 16 and HPV 18—are reported separately. (HPV 16 and HPV 18 are the highest-risk genotypes, and together they account for more than two-thirds of cases of invasive cervical cancer.)

ADVANTAGES OF HPV-ONLY TESTING: FINDINGS FROM THE ATHENA TRIAL

The FDA’s decision to approve the Cobas HPV test for use by itself for screening was based on the landmark ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial.¹³ ATHENA, the largest prospective study of cervical cancer screening performed in the United States to date, enrolled 47,208 women at 61 sites in 23 states. The study revealed the following findings:

The FDA has approved the test for this indication, and guideline committees are reviewing the data

• The HPV DNA test had higher sensitivity for detecting CIN3+ (37% higher than the Pap test) and equivalent specificity.
• The HPV test’s positive predictive value was nearly twice as high (12.25% vs 6.47%), and it had a higher negative predictive value (99.58% vs 99.41%) in detecting CIN3+ than with the Pap test.
• HPV testing by itself performed better than Pap-HPV cotesting, with positive predictive values of 12.25% vs 11.04% and negative predictive values of 99.58% vs 99.52% (data presented to the FDA Medical Devices Advisory Committee, Microbiology Panel. March 12, 2014. FDA Executive Summary).

For women whose results were negative for HPV 16 and 18 but positive for the 12-genotype pooled panel, the sample was automatically submitted for cytologic (Pap) testing. Reserving Pap testing for samples in this category improved the specificity of the test and resulted in fewer colposcopy referrals. The ATHENA researchers found that 11.4% of the participants who tested positive for either HPV 16 or 18 had CIN2+.¹³ Other large cohort studies^14,15 also showed that the short-term risk of developing CIN3+ reached 10% over 1 to 5 years in women who tested positive for HPV 16 or 18.

The proposed algorithm for screening (Figure 1) takes advantage of the superior sensitivity of the HPV test, the built-in risk stratification of HPV 16 and 18 genotyping, and the excellent specificity of the Pap test in triaging women whose results are positive for high-risk HPV genotypes other than HPV 16 and 18. Thus, women who have a negative HPV test result can be assured of remaining disease-free for 3 years. The algorithm also identifies women who are at highest risk, ie, those who test positive for HPV 16 or 18. In contrast, the current cotesting approach uses the Qiagen Hybrid Capture HPV testing system, which is a panel of 13 high-risk genotypes, but, if the result is positive, it does not tell you which one the patient has. Furthermore, the new algorithm provides efficient triage, using the Pap test, for women who test positive for the 12 other high-risk HPV genotypes.

Data from large clinical trials other than ATHENA are limited.

FDA APPROVAL DOES NOT CHANGE THE GUIDELINES—YET

The cervical cancer screening guidelines are developed by several organizations other than the FDA. The current guidelines issued by the ACS, ASCCP, ASCP, USPSTF, and ACOG in 2012 call for Pap testing every 3 years in women younger than 30 and Pap-HPV cotesting every 5 years in women ages 30 to 65.^7–9 However, FDA approval of the new indication of the HPV DNA test as a stand-alone first-line screening test is an important milestone. It heralds the shifting of the practice paradigm from morphologically based Pap testing to molecular testing in cervical cancer screening.

The ACS and ASCCP have announced that they are reviewing the evidence and may issue updated guidelines for clinicians in the near future.^16,17 We anticipate that other organizations may take similar steps. As primary care physicians, we need to stay tuned and follow the most up-to-date evidence-based practice guidelines to provide the best care for our patients.

Yes. Growing evidence demonstrates that the human papillomavirus (HPV) DNA test is more sensitive than the Papanicolaou (Pap) test, with a better negative predictive value—ie, women who have negative test results can be more certain that they are truly free of cervical cancer.^1–3

On April 24, 2014, the US Food and Drug Administration (FDA) approved the Cobas HPV test developed by Roche for use as the first-line screening test for cervical cancer in women age 25 and older.⁴ The approval follows the unanimous recommendation from an independent panel of experts, the Microbiology Devices Panel of the FDA’s Medical Devices Advisory Committee, on March 12, 2014.

PAP-HPV COTESTING IS EFFECTIVE BUT NOT PERFECT

Based on conclusive evidence of a direct link between HPV infection (specifically, infection with certain high-risk HPV genotypes) and almost all cases of invasive cervical cancer,^5,6 the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), US Preventive Services Task Force (USPSTF), and American Congress of Obstetricians and Gynecologists (ACOG) issued a consensus recommendation for Pap-HPV cotesting as the preferred screening strategy starting at age 30 and continuing through age 65.^7–9

Compared with Pap testing alone, cotesting offers improved detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the ability to safely extend the screening interval to every 5 years in women who have negative results on both tests. It is an effective screening strategy and remains the standard of care today.

However, this strategy is not perfect and presents several problems for clinicians. The results of the two tests often conflict—the results of the Pap test might be positive while those of the HPV test are negative, or vice versa. Integrating the results of cotesting into triaging can be confusing and complicated. In addition, performing two tests on all women increases the cost of care. And furthermore, the cotesting strategy increases the number of women who require immediate or short-term follow-up,^1,2,10–12 such as colposcopy, which is unnecessary for many.

THE HPV TEST DETECTS 14 HIGH-RISK GENOTYPES

The FDA-approved HPV test detects 14 high-risk genotypes. The results for 12 of these are pooled and reported collectively as either positive or negative, while the other two—HPV 16 and HPV 18—are reported separately. (HPV 16 and HPV 18 are the highest-risk genotypes, and together they account for more than two-thirds of cases of invasive cervical cancer.)

ADVANTAGES OF HPV-ONLY TESTING: FINDINGS FROM THE ATHENA TRIAL

The FDA’s decision to approve the Cobas HPV test for use by itself for screening was based on the landmark ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial.¹³ ATHENA, the largest prospective study of cervical cancer screening performed in the United States to date, enrolled 47,208 women at 61 sites in 23 states. The study revealed the following findings:

The FDA has approved the test for this indication, and guideline committees are reviewing the data

• The HPV DNA test had higher sensitivity for detecting CIN3+ (37% higher than the Pap test) and equivalent specificity.
• The HPV test’s positive predictive value was nearly twice as high (12.25% vs 6.47%), and it had a higher negative predictive value (99.58% vs 99.41%) in detecting CIN3+ than with the Pap test.
• HPV testing by itself performed better than Pap-HPV cotesting, with positive predictive values of 12.25% vs 11.04% and negative predictive values of 99.58% vs 99.52% (data presented to the FDA Medical Devices Advisory Committee, Microbiology Panel. March 12, 2014. FDA Executive Summary).

For women whose results were negative for HPV 16 and 18 but positive for the 12-genotype pooled panel, the sample was automatically submitted for cytologic (Pap) testing. Reserving Pap testing for samples in this category improved the specificity of the test and resulted in fewer colposcopy referrals. The ATHENA researchers found that 11.4% of the participants who tested positive for either HPV 16 or 18 had CIN2+.¹³ Other large cohort studies^14,15 also showed that the short-term risk of developing CIN3+ reached 10% over 1 to 5 years in women who tested positive for HPV 16 or 18.

The proposed algorithm for screening (Figure 1) takes advantage of the superior sensitivity of the HPV test, the built-in risk stratification of HPV 16 and 18 genotyping, and the excellent specificity of the Pap test in triaging women whose results are positive for high-risk HPV genotypes other than HPV 16 and 18. Thus, women who have a negative HPV test result can be assured of remaining disease-free for 3 years. The algorithm also identifies women who are at highest risk, ie, those who test positive for HPV 16 or 18. In contrast, the current cotesting approach uses the Qiagen Hybrid Capture HPV testing system, which is a panel of 13 high-risk genotypes, but, if the result is positive, it does not tell you which one the patient has. Furthermore, the new algorithm provides efficient triage, using the Pap test, for women who test positive for the 12 other high-risk HPV genotypes.

Data from large clinical trials other than ATHENA are limited.

FDA APPROVAL DOES NOT CHANGE THE GUIDELINES—YET

The cervical cancer screening guidelines are developed by several organizations other than the FDA. The current guidelines issued by the ACS, ASCCP, ASCP, USPSTF, and ACOG in 2012 call for Pap testing every 3 years in women younger than 30 and Pap-HPV cotesting every 5 years in women ages 30 to 65.^7–9 However, FDA approval of the new indication of the HPV DNA test as a stand-alone first-line screening test is an important milestone. It heralds the shifting of the practice paradigm from morphologically based Pap testing to molecular testing in cervical cancer screening.

The ACS and ASCCP have announced that they are reviewing the evidence and may issue updated guidelines for clinicians in the near future.^16,17 We anticipate that other organizations may take similar steps. As primary care physicians, we need to stay tuned and follow the most up-to-date evidence-based practice guidelines to provide the best care for our patients.

Advances in our understanding of the pathogenesis of cervical cancer, new tests for human papillomavirus (HPV), and the development of HPV vaccines in the last decade are transforming the way we screen for cervical cancer.

As a result, screening guidelines are evolving rapidly, requiring clinicians to keep up-to-date with the evidence and rationales supporting the latest guidelines to properly convey best practices to patients.^1–3

For example, we must understand why it is safe to extend the screening interval in women at low risk (as recommended in the new guidelines), and we need to be familiar with the options for women who test positive for HPV. Patients and providers may often find such new recommendations frustrating, and patients may feel that they are being denied something necessary by insurers rather than being treated according to scientific evidence.

This article will review the newest screening guidelines and the evidence supporting these recommendations for primary care providers. We will also review the potential role of novel biomarkers, newer HPV tests, and possible future strategies for cervical cancer screening.

WHAT’S NEW IN THE LATEST SCREENING GUIDELINES

Over the years, various organizations have issued separate screening guidelines, sometimes agreeing with each other, sometimes disagreeing.⁴ Now, for the first time, several of these organizations have developed guidelines collaboratively, and we have consensus in the screening recommendations.

Shortly after the American Congress of Obstetricians and Gynecologists (ACOG) issued its screening guidelines in December 2009,¹ the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP) convened an expert panel to review the available evidence and develop a new joint screening guideline. Concurrently, the US Preventive Services Task Force (USPSTF) commissioned a targeted systematic review of the latest evidence.

Both the ACS/ASCCP/ASCP group² and the USPSTF³ released their new guidelines on March 14, 2012. In November 2012, ACOG issued its latest recommendation on cervical cancer screening.⁴ The following discussion highlights the consensus recommendations from these organizations (Table 1).

These guidelines apply to the general population only. They do not apply to women at high risk who may require more intensive screening, such as those who have a history of cervical cancer, are immunocompromised (eg, positive for human immunodeficiency virus [HIV]), or were exposed in utero to diethylstilbestrol.

Start screening at age 21

According to the new guidelines, women younger than 21 years should not be screened, regardless of the age at which they start having sex.^1–3 This is a change from the 2002 and 2003 ACS recommendations, which said screening should begin 3 years after the onset of vaginal intercourse.^5,6

Evidence. The rationale for the recommendation not to screen before age 21 stems from two pieces of evidence:

• Invasive cervical cancer is rare in this age group.⁷
• Screening can cause harm. For example, unnecessary treatment of preinvasive lesions can lead to long-term complications such as cervical stenosis, preterm delivery, and preterm premature rupture of membranes.^8,9

Additionally, one study found that screening before age 21 has little or no impact on the incidence of invasive cervical cancer.¹⁰

Longer screening intervals

The 2012 ACS/ASCCP/ASCP guidelines² and the latest ACOG guidelines⁴ lengthen the interval between cytology (Papanicolaou) testing to every 3 years in women age 21 to 29. Previous recommendations from these groups were to screen every 2 years, and the USPSTF first recommended the 3-year interval in 2003.¹¹

For women age 30 to 65, the ACS/ASCCP/ASCP, ACOG, and the USPSTF now recommend screening every 5 years if the patient’s results on combined cytology and HPV testing are negative. However, cytologic testing alone every 3 years is also acceptable.^2–4

Evidence. The evidence supporting a 3-year screening interval in women age 21 to 29 is primarily from modeling studies—no randomized clinical trial has been done. These studies found no significant difference in outcomes with a 2-year vs a 3-year screening interval.^12,13 In particular, the predicted lifetime risk of cervical cancer in women screened every 3 years was 5 to 8 new cases of cancer per 1,000 women, compared with 4 to 6 cases per 1,000 women screened every 2 years.¹⁴

Similarly, screening women younger than age 30 at 2-year or 3-year intervals carried the same predicted lifetime risk of death from cervical cancer of 0.05 per 1,000 women, yet women screened every 2 years underwent 40% more colposcopies than those screened every 3 years.² Therefore, screening every 3 years offers the best balance of benefits and risks in this age group.

Adding HPV testing to cytologic testing increases the sensitivity of screening—thus the recommendation to lengthen the screening interval to every 5 years in women age 30 to 65 who are at low risk and who have negative results on both tests. (Previously, the interval was 3 years.)

Specifically, adding HPV testing improves the sensitivity of screening for cervical intraepithelial neoplasia grade 3 (CIN3), so that, in subsequent rounds of screening, fewer cases of CIN3 or worse (CIN3+) or cancer are detected.^15–17 The longer diagnostic lead time with combined testing is associated with a lower risk of CIN3+ or cancer following a double-negative test result than screening with cytology alone at shorter intervals. Combined testing at 5-year intervals is associated with a similar or lower cancer risk than cytology-alone screening at 3-year intervals.⁹

Moreover, modeling studies have shown that combined testing of women age 30 and older at 5-year intervals leads to fewer colposcopies and a similar or lower cancer risk than with cytology screening at 3-year intervals.^18,19

Combined cytologic and HPV testing has received its strongest endorsement to date from the ACS/ASCCP/ASCP, ACOG, and USPSTF in their latest guidelines.^2–4

In 2003, ACOG gave HPV and cytology combined testing an “optional” recommendation for women over age 30; in 2009, it upgraded its recommendation to the highest level of recommendation.¹ At that time, the USPSTF did not recommend for or against HPV testing, while the ACS did recommend HPV testing (with cytology testing alone every 2 to 3 years as an alternative screening strategy).⁵

Now, the ACS/ASCCP/ASCP and ACOG recommend HPV and cytology combined testing as the preferred strategy for screening women age 30 or over.^2,4 Similarly, the USPSTF gives combined testing for women age 30 to 65 a grade A (its highest) recommendation.³ (In 2003, it had given it a grade I—insufficient evidence to assess the balance of benefit and harm.)

Evidence. Several recent studies provide compelling evidence that HPV testing has high sensitivity and excellent negative predictive value, supporting the stronger endorsement of HPV testing and longer screening intervals.

The Joint European Cohort study,²⁰ in 24,295 women, conclusively showed that the 6-year risk of CIN3+ following a negative HPV test was significantly lower than that following a negative cytology result alone (0.27% vs 0.97%).

Katki et al,²¹ in another retrospective study, analyzed data from 330,000 women age 30 and older who underwent combined HPV and cytology testing. Looking at the tests separately, they found the risk of CIN3+ was comparable in the 3 years following a negative cytology test by itself and in the 5 years following negative combined HPV and cytology testing. In fact, combined testing at 5- or 6-year intervals offered better protection than cytology alone at 3-year intervals.

Furthermore, combined testing is also more sensitive for detecting cervical adenocarcinoma.²² (Most cancers of the cervix are squamous cell carcinomas, but approximately 10% are adenocarcinomas.)

Stop screening sooner

In 2002, the ACS recommended ending screening at age 70,¹¹ and in 2009 ACOG said to stop at age 65 to 70.¹ Now, the ACS/ASCCP/ASCP group² and ACOG⁴ recommend stopping screening sooner—at age 65—provided that:

• The patient has had adequate negative screening until then. (Adequate negative prior screening is defined as three consecutive negative cytology results or two consecutive negative combined HPV and cytologic testing results within the 10 years before ceasing screening, with the most recent test performed within the last 5 years.)
• The patient has no history of CIN2+ within the last 20 years.
• The patient is not at high risk of cervical cancer, eg, no history of a high-grade precancerous cervical lesion or cervical cancer, in utero exposure to diethylstilbestrol, or immunosuppression (eg, HIV infection).

The USPSTF had already adopted this position.

Evidence. In women over age 65 who have had good screening, cervical cancer is rare and CIN2+ is uncommon.^2,23,24 Kulasingam et al,⁹ in a modeling study performed for the USPSTF, calculated that continuing to screen until age 90 prevents only 1.6 cancer cases and 0.5 cancer deaths and extends life expectancy by only 1 year per 1,000 women.

Other studies also suggest that newly acquired high-risk HPV infection in women age 65 or older is associated with a very low absolute risk of HPV persistence and CIN3+ progression.^25,26

In addition, cervical cancer takes a median of 20 to 25 years to develop after infection with high-risk HPV.² Also, continuing to screen this older population will detect only a very small number of new cases of CIN2+ and may lead to harm from overtreatment.

Finally, postmenopausal women often have smaller and less accessible cervical transformation zones that may require more interventions to obtain adequate samples and to treat.

Stop screening after hysterectomy

The ACS/ASCCP/ASCP group, ACOG, and the USPSTF reaffirmed their recommendation against screening in women who have had a hysterectomy with removal of the cervix for a reason other than cancer and who have had no history of CIN2+ or cervical cancer.^2–4

Evidence. Several lines of evidence suggest stopping screening after a woman has a hysterectomy. The incidence of vaginal cancer is extremely low,²⁷ and the positive predictive value of cytologic testing of the vaginal cuff for vaginal cancer was zero in one study.²⁸ Also, a large cross-sectional study of 5,330 screening cytology tests in women who had a hysterectomy found only one case of dysplasia and no cancer.²⁹

Continue to screen after HPV vaccination

For the first time since HPV vaccines were introduced in 2006, the ACS/ASCCP/ASCP, ACOG, and the USPSTF have had to consider what to do for vaccinated women. All of their new guidelines say to keep screening them.

Evidence. The currently available HPV vaccines protect against cervical cancer,³⁰ but only against cervical cancer caused by HPV types 16 and 18. Other oncogenic types of HPV exist, and the current vaccines do not protect against them.

Furthermore, many women are vaccinated who are already infected. In addition, as of 2010, only about 32% of eligible girls and women in the United States had received all three recommended doses of the vaccine.³¹ And modeling studies predict that the impact of the HPV vaccine will not be apparent for at least another decade.³²

HPV 16/18 genotyping

The ACS/ASCCP/ASCP and ACOG now recommend HPV 16/18 genotyping as a triage option in women who have positive results on HPV testing but negative cytology results, and immediate referral for colposcopy if the genotyping test is positive.² The alternative option in this situation is to repeat combined HPV and cytologic testing in 12 months.^2,33

Evidence. The standard tests for HPV can detect DNA from about a dozen of the oncogenic types of HPV depending on the test, but they do not tell you which one the patient has. This information may be relevant, since not all “high-risk” HPV types are equally bad. HPV 16 and HPV 18 are the worst of all, together accounting for more than 70% of cases of cervical cancer.

Large cohort studies^34,35 have shown that the risk of CIN3 reaches 10% over 1 to 4 years in women who test positive for HPV 16, and over 2 to 5 years if they test positive for HPV 18. This clinically relevant short-term risk supports immediate referral for colposcopy.

In March 2009, the US Food and Drug Administration (FDA) approved a test for HPV 16 and HPV 18—Cervista HPV 16/18 (Hologic, Bedford, MA).³⁶

More recently, researchers from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial,³⁷ in 47,208 women, reported that they found CIN2+ in 11.4% of women who tested positive for either HPV 16 or HPV 18, and CIN3+ in 9.8%. Of those who were positive for HPV 16, 13.6% had CIN2+ and 11.7% had CIN3+.

WHAT’S COMING?

As we gain knowledge of the molecular oncogenesis of cervical cancer, we appreciate more the complex relation between HPV oncoproteins and cervical dysplasia. Recent studies demonstrated the clinical utility of detecting novel markers in women who have positive HPV results.^38,39

At present, however, there is insufficient evidence to integrate these strategies into our standard of care for cervical cancer screening.

Novel biomarkers: p16 and Ki-67

Although HPV testing is sensitive, it has poor specificity and positive predictive value.^40,41 In a primary screening setting, women with normal cytology results who test positive for high-risk HPV may carry a risk of only 3% to 7% for high-grade CIN.^42,43

HPV 16/18 genotyping can be useful in this situation (see above). However, not everyone who carries HPV 16 or 18 goes on to develop CIN or cancer.⁴⁴

A novel biomarker, p16, has been shown to be overexpressed in cervical dysplasia and associated with high-risk HPV oncogenic transformation. Another novel marker, Ki-67, can be regarded as a surrogate marker of deregulated cell proliferation (Figure 1).³⁸

A recent study reported that a combined test for both of these markers (dual-stained cytology) had a sensitivity of 91.9% for detecting CIN2+ and 96.4% for CIN3+. This test was also highly specific: 82.1% for CIN2+ and 76.9% for CIN3+.³⁸

An Italian randomized trial reported that p16 immunostaining improved the specificity of HPV testing in detecting CIN2+.⁴⁵

In addition, the European Equivocal or Mildly Abnormal Papanicolaou Cytology Study⁴⁶ found that the dual-stained cytology test had excellent sensitivity for CIN2+ in women with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) cytology results (92.2% for ASCUS, 94.2% for LSIL). The specificity for CIN2+ in ASCUS and LSIL was 80.6% and 68%, respectively.

A US study also showed that the sensitivity and specificity to detect CIN3+ by using p16/Ki-67 were 97.2% and 60%, respectively, in women age 30 and older.⁴⁷

If confirmed in more studies, p16/Ki-67 dual staining could help us in deciding which women who have positive HPV but negative cytology results should be referred for colposcopy.

HPV oncogene E6/E7 mRNA testing

In October 2011, the FDA approved the clinical use of a new-generation HPV test, the Aptima HPV assay (Hologic Gen-Probe, San Diego, CA), which detects mRNA for the proteins E6 and E7 from high-risk HPV.³⁹

HPV E6/E7 mRNA expression has been found in virtually all HPV-positive cancer cases and demonstrates a stronger correlation with cervical disease than detection of HPV DNA.⁴⁸ High-risk HPV E6 and E7 proteins immortalize and malignantly transform infected cells by inhibiting two host cellular anticancer proteins, p53 and retinoblastoma protein (pRB).^44,49

The recent FDA approval was based on data from the CLEAR (Clinical Evaluation of Aptima HPV RNA) trial.³⁹ In this trial, in more than 11,000 women, the test was as sensitive for detecting CIN2+ as the HPV DNA-based test, and it was more specific. This advantage was statistically significant. The higher specificity may reduce the number of unnecessary colposcopies and allow for more effective management.^50,51

A promising future screening strategy: HPV testing first, then cytology

HPV testing is more sensitive than cytology, while cytology is more specific. Thus, it would be logical to test for HPV first, and then to perform cytologic testing in patients who have positive results on HPV testing.

In the past 5 years, several large randomized clinical trials within national screening programs in Italy, England, Sweden, and the Netherlands examined the value of a primary HPV-based screening strategy.^15–17,52 These studies confirmed the superior sensitivity of HPV testing for detection of CIN2+.

A large Canadian randomized trial⁵³ compared HPV testing and cytologic testing as screening tests in women age 30 to 69. HPV DNA testing was 94.6% sensitive in detecting CIN2 or CIN3, compared with 55.4% for cytology. The specificity of HPV testing was nearly as high as that of cytology, 94.1% vs 96.8%. Furthermore, HPV testing followed (in those positive for HPV) by cytology resulted in a lower referral rate for colposcopy than did either test alone (1.1% vs 2.9% with cytology alone or 6.1% with HPV testing alone).

More randomized trial data are needed to evaluate the validity of this promising new approach in varied populations. The HPV FOCAL trial is comparing HPV-then-cytology testing vs cytology-then (in women with ASCUS)-HPV testing.⁵⁴ In addition, the aforementioned novel biomarkers for HPV oncogenic activity may eventually play a greater role in primary screening.

With the latest evidence-based screening guidelines, we can implement a more sensitive and effective screening strategy for better prevention and early detection of cervical cancer. Newer cutting-edge molecular technologies appear promising; however, their cost-effectiveness needs to be further evaluated.

A MORAL AND ETHICAL RESPONSIBILITY

Our unscreened and underscreened populations carry a higher burden of cervical cancer and of death from cervical cancer. Identifying and reaching out to these women is our moral and ethical responsibility and yet poses the biggest challenge in screening. Arguably, this could have the most significant impact on rates of death from cervical cancer.

Innovative measures in overcoming healthcare barriers and in making testing cheaper will help to close the gap between well-screened and underscreened populations in the United States and globally. Examples would be a low-cost, point-of-care screening test for the general population, and a government-subsidized global vaccination program. It is entirely conceivable that women will no longer die from cervical cancer in the near future, thanks to global effective screening and preventive efforts through widespread HPV vaccination.

Advances in our understanding of the pathogenesis of cervical cancer, new tests for human papillomavirus (HPV), and the development of HPV vaccines in the last decade are transforming the way we screen for cervical cancer.

As a result, screening guidelines are evolving rapidly, requiring clinicians to keep up-to-date with the evidence and rationales supporting the latest guidelines to properly convey best practices to patients.^1–3

For example, we must understand why it is safe to extend the screening interval in women at low risk (as recommended in the new guidelines), and we need to be familiar with the options for women who test positive for HPV. Patients and providers may often find such new recommendations frustrating, and patients may feel that they are being denied something necessary by insurers rather than being treated according to scientific evidence.

This article will review the newest screening guidelines and the evidence supporting these recommendations for primary care providers. We will also review the potential role of novel biomarkers, newer HPV tests, and possible future strategies for cervical cancer screening.

WHAT’S NEW IN THE LATEST SCREENING GUIDELINES

Over the years, various organizations have issued separate screening guidelines, sometimes agreeing with each other, sometimes disagreeing.⁴ Now, for the first time, several of these organizations have developed guidelines collaboratively, and we have consensus in the screening recommendations.

Shortly after the American Congress of Obstetricians and Gynecologists (ACOG) issued its screening guidelines in December 2009,¹ the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP) convened an expert panel to review the available evidence and develop a new joint screening guideline. Concurrently, the US Preventive Services Task Force (USPSTF) commissioned a targeted systematic review of the latest evidence.

Both the ACS/ASCCP/ASCP group² and the USPSTF³ released their new guidelines on March 14, 2012. In November 2012, ACOG issued its latest recommendation on cervical cancer screening.⁴ The following discussion highlights the consensus recommendations from these organizations (Table 1).

These guidelines apply to the general population only. They do not apply to women at high risk who may require more intensive screening, such as those who have a history of cervical cancer, are immunocompromised (eg, positive for human immunodeficiency virus [HIV]), or were exposed in utero to diethylstilbestrol.

Start screening at age 21

According to the new guidelines, women younger than 21 years should not be screened, regardless of the age at which they start having sex.^1–3 This is a change from the 2002 and 2003 ACS recommendations, which said screening should begin 3 years after the onset of vaginal intercourse.^5,6

Evidence. The rationale for the recommendation not to screen before age 21 stems from two pieces of evidence:

• Invasive cervical cancer is rare in this age group.⁷
• Screening can cause harm. For example, unnecessary treatment of preinvasive lesions can lead to long-term complications such as cervical stenosis, preterm delivery, and preterm premature rupture of membranes.^8,9

Additionally, one study found that screening before age 21 has little or no impact on the incidence of invasive cervical cancer.¹⁰

Longer screening intervals

The 2012 ACS/ASCCP/ASCP guidelines² and the latest ACOG guidelines⁴ lengthen the interval between cytology (Papanicolaou) testing to every 3 years in women age 21 to 29. Previous recommendations from these groups were to screen every 2 years, and the USPSTF first recommended the 3-year interval in 2003.¹¹

For women age 30 to 65, the ACS/ASCCP/ASCP, ACOG, and the USPSTF now recommend screening every 5 years if the patient’s results on combined cytology and HPV testing are negative. However, cytologic testing alone every 3 years is also acceptable.^2–4

Evidence. The evidence supporting a 3-year screening interval in women age 21 to 29 is primarily from modeling studies—no randomized clinical trial has been done. These studies found no significant difference in outcomes with a 2-year vs a 3-year screening interval.^12,13 In particular, the predicted lifetime risk of cervical cancer in women screened every 3 years was 5 to 8 new cases of cancer per 1,000 women, compared with 4 to 6 cases per 1,000 women screened every 2 years.¹⁴

Similarly, screening women younger than age 30 at 2-year or 3-year intervals carried the same predicted lifetime risk of death from cervical cancer of 0.05 per 1,000 women, yet women screened every 2 years underwent 40% more colposcopies than those screened every 3 years.² Therefore, screening every 3 years offers the best balance of benefits and risks in this age group.

Adding HPV testing to cytologic testing increases the sensitivity of screening—thus the recommendation to lengthen the screening interval to every 5 years in women age 30 to 65 who are at low risk and who have negative results on both tests. (Previously, the interval was 3 years.)

Specifically, adding HPV testing improves the sensitivity of screening for cervical intraepithelial neoplasia grade 3 (CIN3), so that, in subsequent rounds of screening, fewer cases of CIN3 or worse (CIN3+) or cancer are detected.^15–17 The longer diagnostic lead time with combined testing is associated with a lower risk of CIN3+ or cancer following a double-negative test result than screening with cytology alone at shorter intervals. Combined testing at 5-year intervals is associated with a similar or lower cancer risk than cytology-alone screening at 3-year intervals.⁹

Moreover, modeling studies have shown that combined testing of women age 30 and older at 5-year intervals leads to fewer colposcopies and a similar or lower cancer risk than with cytology screening at 3-year intervals.^18,19

Combined cytologic and HPV testing has received its strongest endorsement to date from the ACS/ASCCP/ASCP, ACOG, and USPSTF in their latest guidelines.^2–4

In 2003, ACOG gave HPV and cytology combined testing an “optional” recommendation for women over age 30; in 2009, it upgraded its recommendation to the highest level of recommendation.¹ At that time, the USPSTF did not recommend for or against HPV testing, while the ACS did recommend HPV testing (with cytology testing alone every 2 to 3 years as an alternative screening strategy).⁵

Now, the ACS/ASCCP/ASCP and ACOG recommend HPV and cytology combined testing as the preferred strategy for screening women age 30 or over.^2,4 Similarly, the USPSTF gives combined testing for women age 30 to 65 a grade A (its highest) recommendation.³ (In 2003, it had given it a grade I—insufficient evidence to assess the balance of benefit and harm.)

Evidence. Several recent studies provide compelling evidence that HPV testing has high sensitivity and excellent negative predictive value, supporting the stronger endorsement of HPV testing and longer screening intervals.

The Joint European Cohort study,²⁰ in 24,295 women, conclusively showed that the 6-year risk of CIN3+ following a negative HPV test was significantly lower than that following a negative cytology result alone (0.27% vs 0.97%).

Katki et al,²¹ in another retrospective study, analyzed data from 330,000 women age 30 and older who underwent combined HPV and cytology testing. Looking at the tests separately, they found the risk of CIN3+ was comparable in the 3 years following a negative cytology test by itself and in the 5 years following negative combined HPV and cytology testing. In fact, combined testing at 5- or 6-year intervals offered better protection than cytology alone at 3-year intervals.

Furthermore, combined testing is also more sensitive for detecting cervical adenocarcinoma.²² (Most cancers of the cervix are squamous cell carcinomas, but approximately 10% are adenocarcinomas.)

Stop screening sooner

In 2002, the ACS recommended ending screening at age 70,¹¹ and in 2009 ACOG said to stop at age 65 to 70.¹ Now, the ACS/ASCCP/ASCP group² and ACOG⁴ recommend stopping screening sooner—at age 65—provided that:

• The patient has had adequate negative screening until then. (Adequate negative prior screening is defined as three consecutive negative cytology results or two consecutive negative combined HPV and cytologic testing results within the 10 years before ceasing screening, with the most recent test performed within the last 5 years.)
• The patient has no history of CIN2+ within the last 20 years.
• The patient is not at high risk of cervical cancer, eg, no history of a high-grade precancerous cervical lesion or cervical cancer, in utero exposure to diethylstilbestrol, or immunosuppression (eg, HIV infection).

The USPSTF had already adopted this position.

Evidence. In women over age 65 who have had good screening, cervical cancer is rare and CIN2+ is uncommon.^2,23,24 Kulasingam et al,⁹ in a modeling study performed for the USPSTF, calculated that continuing to screen until age 90 prevents only 1.6 cancer cases and 0.5 cancer deaths and extends life expectancy by only 1 year per 1,000 women.

Other studies also suggest that newly acquired high-risk HPV infection in women age 65 or older is associated with a very low absolute risk of HPV persistence and CIN3+ progression.^25,26

In addition, cervical cancer takes a median of 20 to 25 years to develop after infection with high-risk HPV.² Also, continuing to screen this older population will detect only a very small number of new cases of CIN2+ and may lead to harm from overtreatment.

Finally, postmenopausal women often have smaller and less accessible cervical transformation zones that may require more interventions to obtain adequate samples and to treat.

Stop screening after hysterectomy

The ACS/ASCCP/ASCP group, ACOG, and the USPSTF reaffirmed their recommendation against screening in women who have had a hysterectomy with removal of the cervix for a reason other than cancer and who have had no history of CIN2+ or cervical cancer.^2–4

Evidence. Several lines of evidence suggest stopping screening after a woman has a hysterectomy. The incidence of vaginal cancer is extremely low,²⁷ and the positive predictive value of cytologic testing of the vaginal cuff for vaginal cancer was zero in one study.²⁸ Also, a large cross-sectional study of 5,330 screening cytology tests in women who had a hysterectomy found only one case of dysplasia and no cancer.²⁹

Continue to screen after HPV vaccination

For the first time since HPV vaccines were introduced in 2006, the ACS/ASCCP/ASCP, ACOG, and the USPSTF have had to consider what to do for vaccinated women. All of their new guidelines say to keep screening them.

Evidence. The currently available HPV vaccines protect against cervical cancer,³⁰ but only against cervical cancer caused by HPV types 16 and 18. Other oncogenic types of HPV exist, and the current vaccines do not protect against them.

Furthermore, many women are vaccinated who are already infected. In addition, as of 2010, only about 32% of eligible girls and women in the United States had received all three recommended doses of the vaccine.³¹ And modeling studies predict that the impact of the HPV vaccine will not be apparent for at least another decade.³²

HPV 16/18 genotyping

The ACS/ASCCP/ASCP and ACOG now recommend HPV 16/18 genotyping as a triage option in women who have positive results on HPV testing but negative cytology results, and immediate referral for colposcopy if the genotyping test is positive.² The alternative option in this situation is to repeat combined HPV and cytologic testing in 12 months.^2,33

Evidence. The standard tests for HPV can detect DNA from about a dozen of the oncogenic types of HPV depending on the test, but they do not tell you which one the patient has. This information may be relevant, since not all “high-risk” HPV types are equally bad. HPV 16 and HPV 18 are the worst of all, together accounting for more than 70% of cases of cervical cancer.

Large cohort studies^34,35 have shown that the risk of CIN3 reaches 10% over 1 to 4 years in women who test positive for HPV 16, and over 2 to 5 years if they test positive for HPV 18. This clinically relevant short-term risk supports immediate referral for colposcopy.

In March 2009, the US Food and Drug Administration (FDA) approved a test for HPV 16 and HPV 18—Cervista HPV 16/18 (Hologic, Bedford, MA).³⁶

More recently, researchers from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial,³⁷ in 47,208 women, reported that they found CIN2+ in 11.4% of women who tested positive for either HPV 16 or HPV 18, and CIN3+ in 9.8%. Of those who were positive for HPV 16, 13.6% had CIN2+ and 11.7% had CIN3+.

WHAT’S COMING?

As we gain knowledge of the molecular oncogenesis of cervical cancer, we appreciate more the complex relation between HPV oncoproteins and cervical dysplasia. Recent studies demonstrated the clinical utility of detecting novel markers in women who have positive HPV results.^38,39

At present, however, there is insufficient evidence to integrate these strategies into our standard of care for cervical cancer screening.

Novel biomarkers: p16 and Ki-67

Although HPV testing is sensitive, it has poor specificity and positive predictive value.^40,41 In a primary screening setting, women with normal cytology results who test positive for high-risk HPV may carry a risk of only 3% to 7% for high-grade CIN.^42,43

HPV 16/18 genotyping can be useful in this situation (see above). However, not everyone who carries HPV 16 or 18 goes on to develop CIN or cancer.⁴⁴

A novel biomarker, p16, has been shown to be overexpressed in cervical dysplasia and associated with high-risk HPV oncogenic transformation. Another novel marker, Ki-67, can be regarded as a surrogate marker of deregulated cell proliferation (Figure 1).³⁸

A recent study reported that a combined test for both of these markers (dual-stained cytology) had a sensitivity of 91.9% for detecting CIN2+ and 96.4% for CIN3+. This test was also highly specific: 82.1% for CIN2+ and 76.9% for CIN3+.³⁸

An Italian randomized trial reported that p16 immunostaining improved the specificity of HPV testing in detecting CIN2+.⁴⁵

In addition, the European Equivocal or Mildly Abnormal Papanicolaou Cytology Study⁴⁶ found that the dual-stained cytology test had excellent sensitivity for CIN2+ in women with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) cytology results (92.2% for ASCUS, 94.2% for LSIL). The specificity for CIN2+ in ASCUS and LSIL was 80.6% and 68%, respectively.

A US study also showed that the sensitivity and specificity to detect CIN3+ by using p16/Ki-67 were 97.2% and 60%, respectively, in women age 30 and older.⁴⁷

If confirmed in more studies, p16/Ki-67 dual staining could help us in deciding which women who have positive HPV but negative cytology results should be referred for colposcopy.

HPV oncogene E6/E7 mRNA testing

In October 2011, the FDA approved the clinical use of a new-generation HPV test, the Aptima HPV assay (Hologic Gen-Probe, San Diego, CA), which detects mRNA for the proteins E6 and E7 from high-risk HPV.³⁹

HPV E6/E7 mRNA expression has been found in virtually all HPV-positive cancer cases and demonstrates a stronger correlation with cervical disease than detection of HPV DNA.⁴⁸ High-risk HPV E6 and E7 proteins immortalize and malignantly transform infected cells by inhibiting two host cellular anticancer proteins, p53 and retinoblastoma protein (pRB).^44,49

The recent FDA approval was based on data from the CLEAR (Clinical Evaluation of Aptima HPV RNA) trial.³⁹ In this trial, in more than 11,000 women, the test was as sensitive for detecting CIN2+ as the HPV DNA-based test, and it was more specific. This advantage was statistically significant. The higher specificity may reduce the number of unnecessary colposcopies and allow for more effective management.^50,51

A promising future screening strategy: HPV testing first, then cytology

HPV testing is more sensitive than cytology, while cytology is more specific. Thus, it would be logical to test for HPV first, and then to perform cytologic testing in patients who have positive results on HPV testing.

In the past 5 years, several large randomized clinical trials within national screening programs in Italy, England, Sweden, and the Netherlands examined the value of a primary HPV-based screening strategy.^15–17,52 These studies confirmed the superior sensitivity of HPV testing for detection of CIN2+.

A large Canadian randomized trial⁵³ compared HPV testing and cytologic testing as screening tests in women age 30 to 69. HPV DNA testing was 94.6% sensitive in detecting CIN2 or CIN3, compared with 55.4% for cytology. The specificity of HPV testing was nearly as high as that of cytology, 94.1% vs 96.8%. Furthermore, HPV testing followed (in those positive for HPV) by cytology resulted in a lower referral rate for colposcopy than did either test alone (1.1% vs 2.9% with cytology alone or 6.1% with HPV testing alone).

More randomized trial data are needed to evaluate the validity of this promising new approach in varied populations. The HPV FOCAL trial is comparing HPV-then-cytology testing vs cytology-then (in women with ASCUS)-HPV testing.⁵⁴ In addition, the aforementioned novel biomarkers for HPV oncogenic activity may eventually play a greater role in primary screening.

With the latest evidence-based screening guidelines, we can implement a more sensitive and effective screening strategy for better prevention and early detection of cervical cancer. Newer cutting-edge molecular technologies appear promising; however, their cost-effectiveness needs to be further evaluated.

A MORAL AND ETHICAL RESPONSIBILITY

Our unscreened and underscreened populations carry a higher burden of cervical cancer and of death from cervical cancer. Identifying and reaching out to these women is our moral and ethical responsibility and yet poses the biggest challenge in screening. Arguably, this could have the most significant impact on rates of death from cervical cancer.

Innovative measures in overcoming healthcare barriers and in making testing cheaper will help to close the gap between well-screened and underscreened populations in the United States and globally. Examples would be a low-cost, point-of-care screening test for the general population, and a government-subsidized global vaccination program. It is entirely conceivable that women will no longer die from cervical cancer in the near future, thanks to global effective screening and preventive efforts through widespread HPV vaccination.

Advances in our understanding of the pathogenesis of cervical cancer, new tests for human papillomavirus (HPV), and the development of HPV vaccines in the last decade are transforming the way we screen for cervical cancer.

As a result, screening guidelines are evolving rapidly, requiring clinicians to keep up-to-date with the evidence and rationales supporting the latest guidelines to properly convey best practices to patients.^1–3

For example, we must understand why it is safe to extend the screening interval in women at low risk (as recommended in the new guidelines), and we need to be familiar with the options for women who test positive for HPV. Patients and providers may often find such new recommendations frustrating, and patients may feel that they are being denied something necessary by insurers rather than being treated according to scientific evidence.

This article will review the newest screening guidelines and the evidence supporting these recommendations for primary care providers. We will also review the potential role of novel biomarkers, newer HPV tests, and possible future strategies for cervical cancer screening.

WHAT’S NEW IN THE LATEST SCREENING GUIDELINES

Over the years, various organizations have issued separate screening guidelines, sometimes agreeing with each other, sometimes disagreeing.⁴ Now, for the first time, several of these organizations have developed guidelines collaboratively, and we have consensus in the screening recommendations.

Shortly after the American Congress of Obstetricians and Gynecologists (ACOG) issued its screening guidelines in December 2009,¹ the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP) convened an expert panel to review the available evidence and develop a new joint screening guideline. Concurrently, the US Preventive Services Task Force (USPSTF) commissioned a targeted systematic review of the latest evidence.

Both the ACS/ASCCP/ASCP group² and the USPSTF³ released their new guidelines on March 14, 2012. In November 2012, ACOG issued its latest recommendation on cervical cancer screening.⁴ The following discussion highlights the consensus recommendations from these organizations (Table 1).

These guidelines apply to the general population only. They do not apply to women at high risk who may require more intensive screening, such as those who have a history of cervical cancer, are immunocompromised (eg, positive for human immunodeficiency virus [HIV]), or were exposed in utero to diethylstilbestrol.

Start screening at age 21

According to the new guidelines, women younger than 21 years should not be screened, regardless of the age at which they start having sex.^1–3 This is a change from the 2002 and 2003 ACS recommendations, which said screening should begin 3 years after the onset of vaginal intercourse.^5,6

Evidence. The rationale for the recommendation not to screen before age 21 stems from two pieces of evidence:

• Invasive cervical cancer is rare in this age group.⁷
• Screening can cause harm. For example, unnecessary treatment of preinvasive lesions can lead to long-term complications such as cervical stenosis, preterm delivery, and preterm premature rupture of membranes.^8,9

Additionally, one study found that screening before age 21 has little or no impact on the incidence of invasive cervical cancer.¹⁰

Longer screening intervals

The 2012 ACS/ASCCP/ASCP guidelines² and the latest ACOG guidelines⁴ lengthen the interval between cytology (Papanicolaou) testing to every 3 years in women age 21 to 29. Previous recommendations from these groups were to screen every 2 years, and the USPSTF first recommended the 3-year interval in 2003.¹¹

For women age 30 to 65, the ACS/ASCCP/ASCP, ACOG, and the USPSTF now recommend screening every 5 years if the patient’s results on combined cytology and HPV testing are negative. However, cytologic testing alone every 3 years is also acceptable.^2–4

Evidence. The evidence supporting a 3-year screening interval in women age 21 to 29 is primarily from modeling studies—no randomized clinical trial has been done. These studies found no significant difference in outcomes with a 2-year vs a 3-year screening interval.^12,13 In particular, the predicted lifetime risk of cervical cancer in women screened every 3 years was 5 to 8 new cases of cancer per 1,000 women, compared with 4 to 6 cases per 1,000 women screened every 2 years.¹⁴

Similarly, screening women younger than age 30 at 2-year or 3-year intervals carried the same predicted lifetime risk of death from cervical cancer of 0.05 per 1,000 women, yet women screened every 2 years underwent 40% more colposcopies than those screened every 3 years.² Therefore, screening every 3 years offers the best balance of benefits and risks in this age group.

Adding HPV testing to cytologic testing increases the sensitivity of screening—thus the recommendation to lengthen the screening interval to every 5 years in women age 30 to 65 who are at low risk and who have negative results on both tests. (Previously, the interval was 3 years.)

Specifically, adding HPV testing improves the sensitivity of screening for cervical intraepithelial neoplasia grade 3 (CIN3), so that, in subsequent rounds of screening, fewer cases of CIN3 or worse (CIN3+) or cancer are detected.^15–17 The longer diagnostic lead time with combined testing is associated with a lower risk of CIN3+ or cancer following a double-negative test result than screening with cytology alone at shorter intervals. Combined testing at 5-year intervals is associated with a similar or lower cancer risk than cytology-alone screening at 3-year intervals.⁹

Moreover, modeling studies have shown that combined testing of women age 30 and older at 5-year intervals leads to fewer colposcopies and a similar or lower cancer risk than with cytology screening at 3-year intervals.^18,19

Combined cytologic and HPV testing has received its strongest endorsement to date from the ACS/ASCCP/ASCP, ACOG, and USPSTF in their latest guidelines.^2–4

In 2003, ACOG gave HPV and cytology combined testing an “optional” recommendation for women over age 30; in 2009, it upgraded its recommendation to the highest level of recommendation.¹ At that time, the USPSTF did not recommend for or against HPV testing, while the ACS did recommend HPV testing (with cytology testing alone every 2 to 3 years as an alternative screening strategy).⁵

Now, the ACS/ASCCP/ASCP and ACOG recommend HPV and cytology combined testing as the preferred strategy for screening women age 30 or over.^2,4 Similarly, the USPSTF gives combined testing for women age 30 to 65 a grade A (its highest) recommendation.³ (In 2003, it had given it a grade I—insufficient evidence to assess the balance of benefit and harm.)

Evidence. Several recent studies provide compelling evidence that HPV testing has high sensitivity and excellent negative predictive value, supporting the stronger endorsement of HPV testing and longer screening intervals.

The Joint European Cohort study,²⁰ in 24,295 women, conclusively showed that the 6-year risk of CIN3+ following a negative HPV test was significantly lower than that following a negative cytology result alone (0.27% vs 0.97%).

Katki et al,²¹ in another retrospective study, analyzed data from 330,000 women age 30 and older who underwent combined HPV and cytology testing. Looking at the tests separately, they found the risk of CIN3+ was comparable in the 3 years following a negative cytology test by itself and in the 5 years following negative combined HPV and cytology testing. In fact, combined testing at 5- or 6-year intervals offered better protection than cytology alone at 3-year intervals.

Furthermore, combined testing is also more sensitive for detecting cervical adenocarcinoma.²² (Most cancers of the cervix are squamous cell carcinomas, but approximately 10% are adenocarcinomas.)

Stop screening sooner

In 2002, the ACS recommended ending screening at age 70,¹¹ and in 2009 ACOG said to stop at age 65 to 70.¹ Now, the ACS/ASCCP/ASCP group² and ACOG⁴ recommend stopping screening sooner—at age 65—provided that:

• The patient has had adequate negative screening until then. (Adequate negative prior screening is defined as three consecutive negative cytology results or two consecutive negative combined HPV and cytologic testing results within the 10 years before ceasing screening, with the most recent test performed within the last 5 years.)
• The patient has no history of CIN2+ within the last 20 years.
• The patient is not at high risk of cervical cancer, eg, no history of a high-grade precancerous cervical lesion or cervical cancer, in utero exposure to diethylstilbestrol, or immunosuppression (eg, HIV infection).

The USPSTF had already adopted this position.

Evidence. In women over age 65 who have had good screening, cervical cancer is rare and CIN2+ is uncommon.^2,23,24 Kulasingam et al,⁹ in a modeling study performed for the USPSTF, calculated that continuing to screen until age 90 prevents only 1.6 cancer cases and 0.5 cancer deaths and extends life expectancy by only 1 year per 1,000 women.

Other studies also suggest that newly acquired high-risk HPV infection in women age 65 or older is associated with a very low absolute risk of HPV persistence and CIN3+ progression.^25,26

In addition, cervical cancer takes a median of 20 to 25 years to develop after infection with high-risk HPV.² Also, continuing to screen this older population will detect only a very small number of new cases of CIN2+ and may lead to harm from overtreatment.

Finally, postmenopausal women often have smaller and less accessible cervical transformation zones that may require more interventions to obtain adequate samples and to treat.

Stop screening after hysterectomy

The ACS/ASCCP/ASCP group, ACOG, and the USPSTF reaffirmed their recommendation against screening in women who have had a hysterectomy with removal of the cervix for a reason other than cancer and who have had no history of CIN2+ or cervical cancer.^2–4

Evidence. Several lines of evidence suggest stopping screening after a woman has a hysterectomy. The incidence of vaginal cancer is extremely low,²⁷ and the positive predictive value of cytologic testing of the vaginal cuff for vaginal cancer was zero in one study.²⁸ Also, a large cross-sectional study of 5,330 screening cytology tests in women who had a hysterectomy found only one case of dysplasia and no cancer.²⁹

Continue to screen after HPV vaccination

For the first time since HPV vaccines were introduced in 2006, the ACS/ASCCP/ASCP, ACOG, and the USPSTF have had to consider what to do for vaccinated women. All of their new guidelines say to keep screening them.

Evidence. The currently available HPV vaccines protect against cervical cancer,³⁰ but only against cervical cancer caused by HPV types 16 and 18. Other oncogenic types of HPV exist, and the current vaccines do not protect against them.

Furthermore, many women are vaccinated who are already infected. In addition, as of 2010, only about 32% of eligible girls and women in the United States had received all three recommended doses of the vaccine.³¹ And modeling studies predict that the impact of the HPV vaccine will not be apparent for at least another decade.³²

HPV 16/18 genotyping

The ACS/ASCCP/ASCP and ACOG now recommend HPV 16/18 genotyping as a triage option in women who have positive results on HPV testing but negative cytology results, and immediate referral for colposcopy if the genotyping test is positive.² The alternative option in this situation is to repeat combined HPV and cytologic testing in 12 months.^2,33

Evidence. The standard tests for HPV can detect DNA from about a dozen of the oncogenic types of HPV depending on the test, but they do not tell you which one the patient has. This information may be relevant, since not all “high-risk” HPV types are equally bad. HPV 16 and HPV 18 are the worst of all, together accounting for more than 70% of cases of cervical cancer.

Large cohort studies^34,35 have shown that the risk of CIN3 reaches 10% over 1 to 4 years in women who test positive for HPV 16, and over 2 to 5 years if they test positive for HPV 18. This clinically relevant short-term risk supports immediate referral for colposcopy.

In March 2009, the US Food and Drug Administration (FDA) approved a test for HPV 16 and HPV 18—Cervista HPV 16/18 (Hologic, Bedford, MA).³⁶

More recently, researchers from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) trial,³⁷ in 47,208 women, reported that they found CIN2+ in 11.4% of women who tested positive for either HPV 16 or HPV 18, and CIN3+ in 9.8%. Of those who were positive for HPV 16, 13.6% had CIN2+ and 11.7% had CIN3+.

WHAT’S COMING?

As we gain knowledge of the molecular oncogenesis of cervical cancer, we appreciate more the complex relation between HPV oncoproteins and cervical dysplasia. Recent studies demonstrated the clinical utility of detecting novel markers in women who have positive HPV results.^38,39

At present, however, there is insufficient evidence to integrate these strategies into our standard of care for cervical cancer screening.

Novel biomarkers: p16 and Ki-67

Although HPV testing is sensitive, it has poor specificity and positive predictive value.^40,41 In a primary screening setting, women with normal cytology results who test positive for high-risk HPV may carry a risk of only 3% to 7% for high-grade CIN.^42,43

HPV 16/18 genotyping can be useful in this situation (see above). However, not everyone who carries HPV 16 or 18 goes on to develop CIN or cancer.⁴⁴

A novel biomarker, p16, has been shown to be overexpressed in cervical dysplasia and associated with high-risk HPV oncogenic transformation. Another novel marker, Ki-67, can be regarded as a surrogate marker of deregulated cell proliferation (Figure 1).³⁸

A recent study reported that a combined test for both of these markers (dual-stained cytology) had a sensitivity of 91.9% for detecting CIN2+ and 96.4% for CIN3+. This test was also highly specific: 82.1% for CIN2+ and 76.9% for CIN3+.³⁸

An Italian randomized trial reported that p16 immunostaining improved the specificity of HPV testing in detecting CIN2+.⁴⁵

In addition, the European Equivocal or Mildly Abnormal Papanicolaou Cytology Study⁴⁶ found that the dual-stained cytology test had excellent sensitivity for CIN2+ in women with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) cytology results (92.2% for ASCUS, 94.2% for LSIL). The specificity for CIN2+ in ASCUS and LSIL was 80.6% and 68%, respectively.

A US study also showed that the sensitivity and specificity to detect CIN3+ by using p16/Ki-67 were 97.2% and 60%, respectively, in women age 30 and older.⁴⁷

If confirmed in more studies, p16/Ki-67 dual staining could help us in deciding which women who have positive HPV but negative cytology results should be referred for colposcopy.

HPV oncogene E6/E7 mRNA testing

In October 2011, the FDA approved the clinical use of a new-generation HPV test, the Aptima HPV assay (Hologic Gen-Probe, San Diego, CA), which detects mRNA for the proteins E6 and E7 from high-risk HPV.³⁹

HPV E6/E7 mRNA expression has been found in virtually all HPV-positive cancer cases and demonstrates a stronger correlation with cervical disease than detection of HPV DNA.⁴⁸ High-risk HPV E6 and E7 proteins immortalize and malignantly transform infected cells by inhibiting two host cellular anticancer proteins, p53 and retinoblastoma protein (pRB).^44,49

The recent FDA approval was based on data from the CLEAR (Clinical Evaluation of Aptima HPV RNA) trial.³⁹ In this trial, in more than 11,000 women, the test was as sensitive for detecting CIN2+ as the HPV DNA-based test, and it was more specific. This advantage was statistically significant. The higher specificity may reduce the number of unnecessary colposcopies and allow for more effective management.^50,51

A promising future screening strategy: HPV testing first, then cytology

HPV testing is more sensitive than cytology, while cytology is more specific. Thus, it would be logical to test for HPV first, and then to perform cytologic testing in patients who have positive results on HPV testing.

In the past 5 years, several large randomized clinical trials within national screening programs in Italy, England, Sweden, and the Netherlands examined the value of a primary HPV-based screening strategy.^15–17,52 These studies confirmed the superior sensitivity of HPV testing for detection of CIN2+.

A large Canadian randomized trial⁵³ compared HPV testing and cytologic testing as screening tests in women age 30 to 69. HPV DNA testing was 94.6% sensitive in detecting CIN2 or CIN3, compared with 55.4% for cytology. The specificity of HPV testing was nearly as high as that of cytology, 94.1% vs 96.8%. Furthermore, HPV testing followed (in those positive for HPV) by cytology resulted in a lower referral rate for colposcopy than did either test alone (1.1% vs 2.9% with cytology alone or 6.1% with HPV testing alone).

More randomized trial data are needed to evaluate the validity of this promising new approach in varied populations. The HPV FOCAL trial is comparing HPV-then-cytology testing vs cytology-then (in women with ASCUS)-HPV testing.⁵⁴ In addition, the aforementioned novel biomarkers for HPV oncogenic activity may eventually play a greater role in primary screening.

With the latest evidence-based screening guidelines, we can implement a more sensitive and effective screening strategy for better prevention and early detection of cervical cancer. Newer cutting-edge molecular technologies appear promising; however, their cost-effectiveness needs to be further evaluated.

A MORAL AND ETHICAL RESPONSIBILITY

Our unscreened and underscreened populations carry a higher burden of cervical cancer and of death from cervical cancer. Identifying and reaching out to these women is our moral and ethical responsibility and yet poses the biggest challenge in screening. Arguably, this could have the most significant impact on rates of death from cervical cancer.

Innovative measures in overcoming healthcare barriers and in making testing cheaper will help to close the gap between well-screened and underscreened populations in the United States and globally. Examples would be a low-cost, point-of-care screening test for the general population, and a government-subsidized global vaccination program. It is entirely conceivable that women will no longer die from cervical cancer in the near future, thanks to global effective screening and preventive efforts through widespread HPV vaccination.

The vaccines against human papillomavirus (HPV) are the only ones designed to prevent cancer caused by a virus^1,2—surely a good goal. But because HPV is sexually transmitted, HPV vaccination has met with public controversy.³ To counter the objections and better protect their patients’ health, primary care providers and other clinicians need a clear understanding of the benefits and the low risk of HPV vaccination—and the reasons so many people object to it.³

In this article, we will review:

• The impact of HPV-related diseases
• The basic biologic features of HPV vaccines
• The host immune response to natural HPV infection vs the response to HPV vaccines
• The clinical efficacy and safety of HPV vaccines
• The latest guidelines for HPV vaccination
• The challenges to vaccination implementation
• Frequently asked practical questions about HPV vaccination.

HPV-RELATED DISEASES: FROM BOTHERSOME TO DEADLY

Clinical sequelae of HPV infection include genital warts; cancers of the cervix, vulva, vagina, anus, penis, and oropharynx; and recurrent respiratory papillomatosis.^4–6

Genital warts

HPV types 6 and 11 are responsible for more than 90% of the 1 million new cases of genital warts diagnosed annually in the United States.^7–10

Bothersome and embarrassing, HPV-related genital warts can cause itching, burning, erythema, and pain, as well as epithelial erosions, ulcerations, depigmentation, and urethral and vaginal bleeding and discharge.^11,12 Although they are benign in the oncologic sense, they can cause a good deal of emotional and financial stress. Patients may feel anxiety, embarrassment,¹³ and vulnerability. Adolescents and adults who have or have had genital warts need to inform their current and future partners or else risk infecting them—and facing the consequences.

Direct health care costs of genital warts in the United States have been estimated to be at least $200 million per year.¹⁴

Cervical cancer

Cervical cancer cannot develop unless the cervical epithelium is infected with one of the oncogenic HPV types. Indeed, oncogenic HPV is present in as many as 99.8% of cervical cancer specimens.¹⁵ HPV 16 and 18 are the most oncogenic HPV genotypes and account for 75% of all cases of cervical cancer. Ten other HPV genotypes account for the remaining 25%.¹⁶

In 2012, there were an estimated 12,170 new cases of invasive cervical cancer in the United States and 4,220 related deaths.¹⁷ The cost associated with cervical cancer screening, managing abnormal findings, and treating invasive cervical cancer in the United States is estimated to be $3.3 billion per year.¹⁸

Although the incidence and the mortality rates of cervical cancer have decreased more than 50% in the United States over the past 3 decades thanks to screening,¹⁹ cervical cancer remains the second leading cause of death from cancer in women worldwide. Each year, an estimated 500,000 women contract the disease and 240,000 die of it.²⁰

Anal cancer

A recent study indicated that oncogenic HPV can also cause anal cancer, and the proportion of such cancers associated with HPV 16 or HPV 18 infection is as high as or higher than for cervical cancers, and estimated at 80%.²¹

The incidence of anal cancer is increasing by approximately 2% per year in both men and women in the general population,²² and rates are even higher in men who have sex with men and people infected with the human immunodeficiency virus.²³

Hu and Goldie²⁴ estimated that the lifetime costs of caring for all the people in the United States who in just 1 year (2003) acquired anal cancer attributable to HPV would total $92 million.

Oropharyngeal cancer

HPV types 16, 18, 31, 33, and 35 also cause oropharyngeal cancer. HPV 16 accounts for more than 90% of cases of HPV-related oropharyngeal cancer.²⁵

Chaturvedi et al⁶ tested tissue samples from three national cancer registries and found that the number of oropharyngeal cancers that were HPV-positive increased from 16.3% in 1984–1989 to 71.7% in 2000–2004, while the number of HPV-negative oropharyngeal cancers fell by 50%, paralleling the drop in cigarette smoking in the United States.

Hu and Goldie²⁴ estimated that the total lifetime cost for all new HPV-related oropharyngeal cancers that arose in 2003 would come to $38.1 million.²⁴

Vulvar and vaginal cancers

HPV 16 and 18 are also responsible for approximately 50% of vulvar cancers and 50% to 75% of vaginal cancers.^4,5

Recurrent respiratory papillomatosis

HPV 6 and 11 cause almost all cases of juvenile- and adult-onset recurrent respiratory papillomatosis.²⁶ The annual cost for surgical procedures for this condition in the United States has been estimated at $151 million.²⁷

HPV VACCINES ARE NONINFECTIOUS AND NONCARCINOGENIC

Currently, two HPV vaccines are available: a quadrivalent vaccine against types 6, 11, 16, and 18 (Gardasil; Merck) and a bivalent vaccine against types 16 and 18 (Cervarix; Glaxo-SmithKline). The quadrivalent vaccine was approved by the US Food and Drug Administration (FDA) in 2006, and the bivalent vaccine was approved in 2009.^28,29

Both vaccines contain virus-like particles, ie, viral capsids that contain no DNA. HPV has a circular DNA genome of 8,000 nucleotides divided into two regions: the early region, for viral replication, and the late region, for viral capsid production. The host produces neutralizing antibodies in response to the L1 capsid protein, which is different in different HPV types.

In manufacturing the vaccines, the viral L1 gene is incorporated into a yeast genome or an insect virus genome using recombinant DNA technology (Figure 1). Grown in culture, the yeast or the insect cells produce the HPV L1 major capsid protein, which has the intrinsic capacity to self-assemble into virus-like particles.^30–33 These particles are subsequently purified for use in the vaccines.³⁴

Recombinant virus-like particles are morphologically indistinguishable from authentic HPV virions and contain the same typespecific antigens present in authentic virions. Therefore, they are highly effective in inducing a host humoral immune response. And because they do not contain HPV DNA, the recombinant HPV vaccines are noninfectious and noncarcinogenic.³⁵

VACCINATION INDUCES A STRONGER IMMUNE RESPONSE THAN INFECTION

HPV infections trigger both a humoral and a cellular response in the host immune system.

The humoral immune response to HPV infection involves producing neutralizing antibody against the specific HPV type, specifically the specific L1 major capsid protein. This process is typically somewhat slow and weak, and only about 60% of women with a new HPV infection develop antibodies to it.^36,37

HPV has several ways to evade the host immune system. It does not infect or replicate within the antigen-presenting cells in the epithelium. In addition, HPV-infected keratinocytes are less susceptible to cytotoxic lymphocytic-mediated lysis. Moreover, HPV infection cause very little tissue destruction. And finally, natural cervical HPV infection does not result in viremia. As a result, antigen-presenting cells have no chance to engulf the virions and present virion-derived antigen to the host immune system. The immune system outside the epithelium has limited opportunity to detect the virus because HPV infection does not have a blood-borne phase.^38,39

The cell-mediated immune response to early HPV oncoproteins may help eliminate established HPV infection.⁴⁰ In contrast to antibodies, the T-cell response to HPV has not been shown to be specific to HPV type.⁴¹ Clinically, cervical HPV infection is common, but most lesions go into remission or resolve as a result of the cell-mediated immune response.^40,41

In contrast to the weak, somewhat ineffective immune response to natural HPV infection, the antibody response to HPV vaccines is rather robust. In randomized controlled trials, almost all vaccinated people have seroconverted. The peak antibody concentrations are 50 to 10,000 times greater than in natural infection. Furthermore, the neutralizing antibodies induced by HPV vaccines persist for as long as 7 to 9 years after immunization.⁴² However, the protection provided by HPV vaccines against HPV-related cervical intraepithelial neoplasia does not necessarily correlate with the antibody concentration.^43–47

Why does the vaccine work so well?

Why are vaccine-induced antibody responses so much stronger than those induced by natural HPV infection?

The first reason is that the vaccine, delivered intramuscularly, rapidly enters into blood vessels and the lymphatic system. In contrast, in natural intraepithelial infection, the virus is shed from mucosal surfaces and does not result in viremia.⁴⁸

In addition, the strong immunogenic nature of the virus-like particles induces a robust host antibody response even in the absence of adjuvant because of concentrated neutralizing epitopes and excellent induction of the T-helper cell response.^35,49,50

The neutralizing antibody to L1 prevents HPV infection by blocking HPV from binding to the basement membrane as well as to the epithelial cell receptor during epithelial microabrasion and viral entry. The subsequent micro-wound healing leads to serous exudation and rapid access of serum immunoglobulin G (IgG) to HPV virus particles and encounters with circulatory B memory cells.

Furthermore, emerging evidence suggests that even very low antibody concentrations are sufficient to prevent viral entry into cervical epithelial cells.^{46–48,51–53}

THE HPV VACCINES ARE HIGHLY EFFECTIVE AND SAFE

The efficacy and safety of the quadrivalent and the bivalent HPV vaccines have been evaluated in large randomized clinical trials.^{23,28,29,54,55} Table 1 summarizes the key findings.

The Females United to Unilaterally Reduce Endo/ectocervical Disease (FUTURE I)⁵⁴ and FUTURE II²⁸ trials showed conclusively that the quadrivalent HPV vaccine is 98% to 100% efficacious in preventing HPV 16- and 18-related cervical intraepithelial neoplasia, carcinoma in situ, and invasive cervical cancer in women who had not been infected with HPV before. Similarly, the Papilloma Trial against Cancer in Young Adults (PATRICIA) concluded that the bivalent HPV vaccine is 93% efficacious.²⁹

Giuliano et al⁵⁵ and Palefsky et al²³ conducted randomized clinical trials of the quadrivalent HPV vaccine for preventing genital disease and anal intraepithelial neoplasia in boys and men; the efficacy rates were 90.4%⁵⁵ and 77.5%.²³

A recent Finnish trial in boys age 10 to 18 found 100% seroconversion rates for HPV 16 and HPV 18 antibodies after they received bivalent HPV vaccine.⁵⁶ Similar efficacy has been demonstrated for the quadrivalent HPV vaccine in boys.⁵⁷

Adverse events after vaccination

After the FDA approved the quadrivalent HPV vaccine for girls in 2006, the US Centers for Disease Control and Prevention (CDC) conducted a thorough survey of adverse events after immunization from June 1, 2006 through December 31, 2008.⁵⁸ There were about 54 reports of adverse events per 100,000 distributed vaccine doses, similar to rates for other vaccines. However, the incidence rates of syncope and venous thrombosis were disproportionately higher, according to data from the US Vaccine Adverse Event Reporting System. The rate of syncope was 8.2 per 100,000 vaccine doses, and the rate of venous thrombotic events was 0.2 per 100,000 doses.⁵⁸

There were 32 reports of deaths after HPV vaccination, but these were without clear causation. Hence, this information must be interpreted with caution and should not be used to infer causal associations between HPV vaccines and adverse outcomes. The causes of death included diabetic ketoacidosis, pulmonary embolism, prescription drug abuse, amyotrophic lateral sclerosis, meningoencephalitis, influenza B viral sepsis, arrhythmia, myocarditis, and idiopathic seizure disorder.⁵⁸

Furthermore, it is important to note that vasovagal syncope and venous thromboembolic events are more common in young females in general.⁵⁹ For example, the background rates of venous thromboembolism in females age 14 to 29 using oral contraceptives is 21 to 31 per 100,000 woman-years.⁶⁰

Overall, the quadrivalent HPV vaccine is well tolerated and clinically safe. Postlicensure evaluation found that the quadrivalent and bivalent HPV vaccines had similar safety profiles.⁶¹

Vaccination is contraindicated in people with known hypersensitivity or prior severe allergic reactions to vaccine or yeast or who have bleeding disorders.

HPV VACCINATION DOES MORE THAN PREVENT CERVICAL CANCER IN FEMALES

The quadrivalent HPV vaccine was licensed by the FDA in 2006 for use in females age 9 to 26 to prevent cervical cancer, cervical cancer precursors, vaginal and vulval cancer precursors, and anogenital warts caused by HPV types 6, 11, 16, and 18. The CDC’s Advisory Committee on Immunization Practices (ACIP) issued its recommendation for initiating HPV vaccination for females age 11 to 12 in March 2007. The ACIP stated that the vaccine could be given to girls as early as age 9 and recommended catch-up vaccinations for those age 13 to 26.^62,63

The quadrivalent HPV vaccine was licensed by the FDA in 2009 for use in boys and men for the prevention of genital warts. In December 2010, the quadrivalent HPV vaccine received extended licensure from the FDA for use in males and females for the prevention of anal cancer. In October 2011, the ACIP voted to recommend routine use of the quadrivalent HPV vaccine for boys age 11 to 12; catch-up vaccination should occur for those age 13 to 22, with an option to vaccinate men age 23 to 26.

These recommendations replace the “permissive use” recommendations from the ACIP in October 2009 that said the quadrivalent HPV vaccine may be given to males age 9 to 26.⁶⁴ This shift from a permissive to an active recommendation connotes a positive change reflecting recognition of rising oropharyngeal cancer rates attributable to oncogenic, preventable HPV, rising HPV-related anal cancer incidence, and the burden of the disease in female partners of infected men, with associated rising health care costs.

The bivalent HPV vaccine received FDA licensure in October 2009 for use in females age 10 to 25 to prevent cervical cancer and precursor lesions. The ACIP included the bivalent HPV vaccine in its updated recommendations in May 2010 for use in girls age 11 to 12. Numerous national and international organizations have endorsed HPV vaccination.^65–71

Table 2 outlines the recommendations from these organizations.

HPV VACCINATION RATES ARE STILL LOW

HPV vaccine offers us the hope of eventually eradicating cervical cancer. However, the immunization program still faces many challenges, since HPV vaccination touches on issues related to adolescent sexuality, parental autonomy, and cost. As a result, HPV immunization rates remain relatively low in the United States according to several national surveys. Only 40% to 49% of girls eligible for the vaccine received even one dose, and of those who received even one dose, only 32% to 53.3% came back for all three doses.^72–75 Furthermore, indigent and minority teens were less likely to finish the three-dose HPV vaccine series.

Why are the vaccination rates so low?

Parental barriers. In one survey,⁷³ reasons that parents gave for not having their daughters vaccinated included:

• Lack of knowledge of the vaccine (19.4%)
• Lack of perceived need for the vaccine (18.8%)
• Belief that their daughter was not sexually active (18.3%)
• Clinician not recommending vaccination (13.1%).

In an effort to improve HPV vaccination rates,⁴¹ several states proposed legislation for mandatory HPV vaccination of schoolgirls shortly after licensure of the quadrivalent HPV vaccine.³ Since then, we have seen a wave of public opposition rooted in concerns and misinformation about safety, teenage sexuality, governmental coercion, and cost. Widespread media coverage has also highlighted unsubstantiated claims about side effects attributable to the vaccine that can raise parents’ mistrust of vaccines.⁷⁶ Concerns have also been raised about a threat to parental autonomy in how and when to educate their children about sex.⁷⁷

Moreover, the vaccine has raised ethical concerns in some parents and politicians that mandatory vaccination could undermine abstinence messages in sexual education and may alter sexual activity by condoning risky behavior.⁷⁸ However, a recent study indicated that there is no significant change in sexual behavior related to HPV vaccination in young girls.⁷⁹

In 2012, Mullins et al⁸⁰ also found that an urban population of adolescent girls (76.4% black, 57.5% sexually experienced) did not feel they could forgo safer sexual practices after first HPV vaccination, although the girls did perceive less risk from HPV than from other sexually transmitted infections after HPV vaccination (P < .001).⁸⁰ Inadequate knowledge about HPV-related disease and HPV vaccine correlated with less perceived risk from HPV after vaccination among the girls, and a lack of knowledge about HPV and less communication with their daughters about HPV correlated with less perceived risk from HPV in the mothers of the study population.⁸¹

Health-care-provider barriers. Physician endorsement of vaccines represents a key predictor of vaccine acceptance by patients, families, and other clinicians.^82–84 In 2008, a cross-sectional, Internet-based survey of 1,122 Texas pediatricians, family practice physicians, obstetricians, gynecologists, and internal medicine physicians providing direct patient care found that only 48.5% always recommended HPV vaccination to girls.⁷⁴ Of all respondents, 68.4% were likely to recommend the vaccine to boys, and 41.7% agreed with mandated vaccination. Thus, more than half of the physicians were not following the current recommendations for universal HPV vaccination for 11- to -12-year-olds.

In a survey of 1,013 physicians during the spring and summer of 2009, only 34.6% said they always recommend HPV vaccination to early adolescents, 52.7% to middle adolescents, and 50.2% to late adolescents and young adults.⁸⁵ Pediatricians were more likely than family physicians and obstetrician-gynecologists to always recommend HPV vaccine across all age groups (P < .001). Educational interventions targeting various specialties may help overcome physician-related barriers to immunization.⁸⁵

Financial barriers. HPV vaccine, which must be given in three doses, is more expensive than other vaccines, and this expense is yet another barrier, especially for the uninsured.⁸⁶ Australia launched a government-funded program of HPV vaccination (with the quadrivalent vaccine) in schools in 2007, and it has been very successful. Garland et al⁸⁷ reported that new cases of genital warts have decreased by 73% since the program began, and the rate of high-grade abnormalities on Papanicolaou testing has declined by a small but significant amount.

For HPV vaccination to have an impact on public health, vaccination rates in the general population need to be high. In order to achieve these rates, we need to educate our patients on vaccine safety and efficacy and counsel vaccine recipients about the prevention of sexually transmitted infections and the importance of regular cervical cancer screening after age 21. Clinicians can actively “myth-bust” with patients, who may not realize that the vaccine should be given despite a history of HPV infection or abnormal Pap smear.

FREQUENTLY ASKED QUESTIONS

What if the patient is late for a shot?

The current recommended vaccination schedule for the bivalent and quadrivalent HPV vaccines is a three-dose series administered at 0, 2, and 6 months, given as an intramuscular injection, preferably in the deltoid muscle. The minimal dosing interval is 4 weeks between the first and second doses and 12 weeks between the second and third doses.

The vaccines use different adjuncts with different specific mechanisms for immunogenicity; therefore, it is recommended that the same vaccine be used for the entire three-dose series. However, if circumstances preclude the completion of a series with the same vaccine, the other HPV vaccine may be used.⁶³ Starting the series over is not recommended.

Long-term studies demonstrated clinical efficacy 8.5 years after vaccination.⁴⁷ Amnestic response by virtue of activation of pools of memory B cells has been demonstrated, suggesting the vaccine may afford lifelong immunity.⁸⁸

Is a pregnancy test needed before HPV vaccination?

The ACIP states that pregnancy testing is not required before receiving either of the available HPV vaccines.

A recent retrospective review of phase III efficacy trials and pregnancy registry surveillance data for both vaccines revealed no increase in spontaneous abortions, fetal malformations, or adverse pregnancy outcomes.⁸⁹ Data are limited on bivalent and quadrivalent HPV vaccine given within 30 days of pregnancy and subsequent pregnancy and fetal outcomes. Both vaccines have been assigned a pregnancy rating of category B; however, the ACIP recommends that neither vaccine be given if the recipient is known to be pregnant. If pregnancy occurs, it is recommended that the remainder of the series be deferred until after delivery.⁶²

It is not known whether the vaccine is excreted in breast milk. The manufacturers of both the bivalent and quadrivalent HPV vaccines recommend caution when vaccinating lactating women.^30,31

Can HPV vaccine be given with other vaccines?

In randomized trials, giving the bivalent HPV vaccine with the combined hepatitis A, hepatitis B, meningococcal conjugate and the combined tetanus, diphtheria, and acellular pertussis vaccines did not interfere with the immunogenic response, was safe, and was well tolerated.^90,91 Coadministration of the quadrivalent HPV vaccine has been studied only with hepatitis B vaccine, with similar safety and efficacy noted.

The ACIP recommends giving HPV vaccine at the same visit with other age-appropriate immunizations to increase the likelihood of adherence to recommended vaccination schedules.⁶²

Is HPV vaccination cost-effective?

Kim and Goldie⁸⁶ performed a cost-effectiveness analysis of HPV vaccination of girls at age 12 and catch-up vaccination up to the ages of 18, 21, and 26. For their analysis, they considered prevention of cancers associated with HPV types 16 and 18, of genital warts associated with types 6 and 11, and of recurrent respiratory papillomatosis. They also assumed that immunity would be lifelong, and current screening practices would continue.

They calculated that routine vaccination of 12-year-old girls resulted in an incremental cost-effective ratio of $34,900 per quality-adjusted life-year (QALY) gained. A threshold of less than $50,000 per QALY gained is considered reasonably cost-effective, with an upper limit of $100,000 considered acceptable.⁹²

In the same analysis by Kim and Goldie,⁸⁶ catch-up vaccination of girls through age 18 resulted in a cost of $50,000 to $100,000 per QALY gained, and catch-up vaccination of females through age 26 was significantly less cost-effective at more then $130,000 per QALY gained. The vaccine was also significantly less cost-effective if 5% of the population was neither screened nor vaccinated, if a 10-year booster was required, and if frequent cervical cancer screening intervals were adopted.

This analysis did not include costs related to the evaluation and treatment of abnormal Pap smears and cross-protection against other HPV-related cancers.

The cost-effectiveness of HPV vaccination depends on reaching more girls at younger ages (ideally before sexual debut) and completing the three-dose schedule to optimize duration of immunity.⁹² Appropriate modification of the current recommendations for the intervals of cervical cancer screening for vaccinated individuals will further improve the cost-effectiveness of vaccination. The inclusion of male vaccination generally has more favorable cost per QALY in scenarios in which female coverage rates are less than 50%⁹³ and among men who have sex with men.⁹⁴

TO ERADICATE CERVICAL CANCER

Given the remarkable efficacy and expected long-term immunogenicity of HPV vaccines, we anticipate a decline in HPV-related cervical cancer and other related diseases in the years to come. However, modeling studies predicting the impact of HPV vaccination suggest that although substantial reductions in diseases can be expected, the benefit, assuming high vaccination rates, will not be apparent for at least another decade.⁹⁵ Furthermore, the current HPV vaccines contain only HPV 16 and 18 L1 protein for cancer protection and, therefore, do not provide optimal protection against all oncogenic HPV-related cancers.

The real hope of eradicating cervical cancer and all HPV-related disease relies on a successful global implementation of multivalent HPV vaccination, effective screening strategies, and successful treatment.

The vaccines against human papillomavirus (HPV) are the only ones designed to prevent cancer caused by a virus^1,2—surely a good goal. But because HPV is sexually transmitted, HPV vaccination has met with public controversy.³ To counter the objections and better protect their patients’ health, primary care providers and other clinicians need a clear understanding of the benefits and the low risk of HPV vaccination—and the reasons so many people object to it.³

In this article, we will review:

• The impact of HPV-related diseases
• The basic biologic features of HPV vaccines
• The host immune response to natural HPV infection vs the response to HPV vaccines
• The clinical efficacy and safety of HPV vaccines
• The latest guidelines for HPV vaccination
• The challenges to vaccination implementation
• Frequently asked practical questions about HPV vaccination.

HPV-RELATED DISEASES: FROM BOTHERSOME TO DEADLY

Clinical sequelae of HPV infection include genital warts; cancers of the cervix, vulva, vagina, anus, penis, and oropharynx; and recurrent respiratory papillomatosis.^4–6

Genital warts

HPV types 6 and 11 are responsible for more than 90% of the 1 million new cases of genital warts diagnosed annually in the United States.^7–10

Bothersome and embarrassing, HPV-related genital warts can cause itching, burning, erythema, and pain, as well as epithelial erosions, ulcerations, depigmentation, and urethral and vaginal bleeding and discharge.^11,12 Although they are benign in the oncologic sense, they can cause a good deal of emotional and financial stress. Patients may feel anxiety, embarrassment,¹³ and vulnerability. Adolescents and adults who have or have had genital warts need to inform their current and future partners or else risk infecting them—and facing the consequences.

Direct health care costs of genital warts in the United States have been estimated to be at least $200 million per year.¹⁴

Cervical cancer

Cervical cancer cannot develop unless the cervical epithelium is infected with one of the oncogenic HPV types. Indeed, oncogenic HPV is present in as many as 99.8% of cervical cancer specimens.¹⁵ HPV 16 and 18 are the most oncogenic HPV genotypes and account for 75% of all cases of cervical cancer. Ten other HPV genotypes account for the remaining 25%.¹⁶

In 2012, there were an estimated 12,170 new cases of invasive cervical cancer in the United States and 4,220 related deaths.¹⁷ The cost associated with cervical cancer screening, managing abnormal findings, and treating invasive cervical cancer in the United States is estimated to be $3.3 billion per year.¹⁸

Although the incidence and the mortality rates of cervical cancer have decreased more than 50% in the United States over the past 3 decades thanks to screening,¹⁹ cervical cancer remains the second leading cause of death from cancer in women worldwide. Each year, an estimated 500,000 women contract the disease and 240,000 die of it.²⁰

Anal cancer

A recent study indicated that oncogenic HPV can also cause anal cancer, and the proportion of such cancers associated with HPV 16 or HPV 18 infection is as high as or higher than for cervical cancers, and estimated at 80%.²¹

The incidence of anal cancer is increasing by approximately 2% per year in both men and women in the general population,²² and rates are even higher in men who have sex with men and people infected with the human immunodeficiency virus.²³

Hu and Goldie²⁴ estimated that the lifetime costs of caring for all the people in the United States who in just 1 year (2003) acquired anal cancer attributable to HPV would total $92 million.

Oropharyngeal cancer

HPV types 16, 18, 31, 33, and 35 also cause oropharyngeal cancer. HPV 16 accounts for more than 90% of cases of HPV-related oropharyngeal cancer.²⁵

Chaturvedi et al⁶ tested tissue samples from three national cancer registries and found that the number of oropharyngeal cancers that were HPV-positive increased from 16.3% in 1984–1989 to 71.7% in 2000–2004, while the number of HPV-negative oropharyngeal cancers fell by 50%, paralleling the drop in cigarette smoking in the United States.

Hu and Goldie²⁴ estimated that the total lifetime cost for all new HPV-related oropharyngeal cancers that arose in 2003 would come to $38.1 million.²⁴

Vulvar and vaginal cancers

HPV 16 and 18 are also responsible for approximately 50% of vulvar cancers and 50% to 75% of vaginal cancers.^4,5

Recurrent respiratory papillomatosis

HPV 6 and 11 cause almost all cases of juvenile- and adult-onset recurrent respiratory papillomatosis.²⁶ The annual cost for surgical procedures for this condition in the United States has been estimated at $151 million.²⁷

HPV VACCINES ARE NONINFECTIOUS AND NONCARCINOGENIC

Currently, two HPV vaccines are available: a quadrivalent vaccine against types 6, 11, 16, and 18 (Gardasil; Merck) and a bivalent vaccine against types 16 and 18 (Cervarix; Glaxo-SmithKline). The quadrivalent vaccine was approved by the US Food and Drug Administration (FDA) in 2006, and the bivalent vaccine was approved in 2009.^28,29

Both vaccines contain virus-like particles, ie, viral capsids that contain no DNA. HPV has a circular DNA genome of 8,000 nucleotides divided into two regions: the early region, for viral replication, and the late region, for viral capsid production. The host produces neutralizing antibodies in response to the L1 capsid protein, which is different in different HPV types.

In manufacturing the vaccines, the viral L1 gene is incorporated into a yeast genome or an insect virus genome using recombinant DNA technology (Figure 1). Grown in culture, the yeast or the insect cells produce the HPV L1 major capsid protein, which has the intrinsic capacity to self-assemble into virus-like particles.^30–33 These particles are subsequently purified for use in the vaccines.³⁴

Recombinant virus-like particles are morphologically indistinguishable from authentic HPV virions and contain the same typespecific antigens present in authentic virions. Therefore, they are highly effective in inducing a host humoral immune response. And because they do not contain HPV DNA, the recombinant HPV vaccines are noninfectious and noncarcinogenic.³⁵

VACCINATION INDUCES A STRONGER IMMUNE RESPONSE THAN INFECTION

HPV infections trigger both a humoral and a cellular response in the host immune system.

The humoral immune response to HPV infection involves producing neutralizing antibody against the specific HPV type, specifically the specific L1 major capsid protein. This process is typically somewhat slow and weak, and only about 60% of women with a new HPV infection develop antibodies to it.^36,37

HPV has several ways to evade the host immune system. It does not infect or replicate within the antigen-presenting cells in the epithelium. In addition, HPV-infected keratinocytes are less susceptible to cytotoxic lymphocytic-mediated lysis. Moreover, HPV infection cause very little tissue destruction. And finally, natural cervical HPV infection does not result in viremia. As a result, antigen-presenting cells have no chance to engulf the virions and present virion-derived antigen to the host immune system. The immune system outside the epithelium has limited opportunity to detect the virus because HPV infection does not have a blood-borne phase.^38,39

The cell-mediated immune response to early HPV oncoproteins may help eliminate established HPV infection.⁴⁰ In contrast to antibodies, the T-cell response to HPV has not been shown to be specific to HPV type.⁴¹ Clinically, cervical HPV infection is common, but most lesions go into remission or resolve as a result of the cell-mediated immune response.^40,41

In contrast to the weak, somewhat ineffective immune response to natural HPV infection, the antibody response to HPV vaccines is rather robust. In randomized controlled trials, almost all vaccinated people have seroconverted. The peak antibody concentrations are 50 to 10,000 times greater than in natural infection. Furthermore, the neutralizing antibodies induced by HPV vaccines persist for as long as 7 to 9 years after immunization.⁴² However, the protection provided by HPV vaccines against HPV-related cervical intraepithelial neoplasia does not necessarily correlate with the antibody concentration.^43–47

Why does the vaccine work so well?

Why are vaccine-induced antibody responses so much stronger than those induced by natural HPV infection?

The first reason is that the vaccine, delivered intramuscularly, rapidly enters into blood vessels and the lymphatic system. In contrast, in natural intraepithelial infection, the virus is shed from mucosal surfaces and does not result in viremia.⁴⁸

In addition, the strong immunogenic nature of the virus-like particles induces a robust host antibody response even in the absence of adjuvant because of concentrated neutralizing epitopes and excellent induction of the T-helper cell response.^35,49,50

The neutralizing antibody to L1 prevents HPV infection by blocking HPV from binding to the basement membrane as well as to the epithelial cell receptor during epithelial microabrasion and viral entry. The subsequent micro-wound healing leads to serous exudation and rapid access of serum immunoglobulin G (IgG) to HPV virus particles and encounters with circulatory B memory cells.

Furthermore, emerging evidence suggests that even very low antibody concentrations are sufficient to prevent viral entry into cervical epithelial cells.^{46–48,51–53}

THE HPV VACCINES ARE HIGHLY EFFECTIVE AND SAFE

The efficacy and safety of the quadrivalent and the bivalent HPV vaccines have been evaluated in large randomized clinical trials.^{23,28,29,54,55} Table 1 summarizes the key findings.

The Females United to Unilaterally Reduce Endo/ectocervical Disease (FUTURE I)⁵⁴ and FUTURE II²⁸ trials showed conclusively that the quadrivalent HPV vaccine is 98% to 100% efficacious in preventing HPV 16- and 18-related cervical intraepithelial neoplasia, carcinoma in situ, and invasive cervical cancer in women who had not been infected with HPV before. Similarly, the Papilloma Trial against Cancer in Young Adults (PATRICIA) concluded that the bivalent HPV vaccine is 93% efficacious.²⁹

Giuliano et al⁵⁵ and Palefsky et al²³ conducted randomized clinical trials of the quadrivalent HPV vaccine for preventing genital disease and anal intraepithelial neoplasia in boys and men; the efficacy rates were 90.4%⁵⁵ and 77.5%.²³

A recent Finnish trial in boys age 10 to 18 found 100% seroconversion rates for HPV 16 and HPV 18 antibodies after they received bivalent HPV vaccine.⁵⁶ Similar efficacy has been demonstrated for the quadrivalent HPV vaccine in boys.⁵⁷

Adverse events after vaccination

After the FDA approved the quadrivalent HPV vaccine for girls in 2006, the US Centers for Disease Control and Prevention (CDC) conducted a thorough survey of adverse events after immunization from June 1, 2006 through December 31, 2008.⁵⁸ There were about 54 reports of adverse events per 100,000 distributed vaccine doses, similar to rates for other vaccines. However, the incidence rates of syncope and venous thrombosis were disproportionately higher, according to data from the US Vaccine Adverse Event Reporting System. The rate of syncope was 8.2 per 100,000 vaccine doses, and the rate of venous thrombotic events was 0.2 per 100,000 doses.⁵⁸

There were 32 reports of deaths after HPV vaccination, but these were without clear causation. Hence, this information must be interpreted with caution and should not be used to infer causal associations between HPV vaccines and adverse outcomes. The causes of death included diabetic ketoacidosis, pulmonary embolism, prescription drug abuse, amyotrophic lateral sclerosis, meningoencephalitis, influenza B viral sepsis, arrhythmia, myocarditis, and idiopathic seizure disorder.⁵⁸

Furthermore, it is important to note that vasovagal syncope and venous thromboembolic events are more common in young females in general.⁵⁹ For example, the background rates of venous thromboembolism in females age 14 to 29 using oral contraceptives is 21 to 31 per 100,000 woman-years.⁶⁰

Overall, the quadrivalent HPV vaccine is well tolerated and clinically safe. Postlicensure evaluation found that the quadrivalent and bivalent HPV vaccines had similar safety profiles.⁶¹

Vaccination is contraindicated in people with known hypersensitivity or prior severe allergic reactions to vaccine or yeast or who have bleeding disorders.

HPV VACCINATION DOES MORE THAN PREVENT CERVICAL CANCER IN FEMALES

The quadrivalent HPV vaccine was licensed by the FDA in 2006 for use in females age 9 to 26 to prevent cervical cancer, cervical cancer precursors, vaginal and vulval cancer precursors, and anogenital warts caused by HPV types 6, 11, 16, and 18. The CDC’s Advisory Committee on Immunization Practices (ACIP) issued its recommendation for initiating HPV vaccination for females age 11 to 12 in March 2007. The ACIP stated that the vaccine could be given to girls as early as age 9 and recommended catch-up vaccinations for those age 13 to 26.^62,63

The quadrivalent HPV vaccine was licensed by the FDA in 2009 for use in boys and men for the prevention of genital warts. In December 2010, the quadrivalent HPV vaccine received extended licensure from the FDA for use in males and females for the prevention of anal cancer. In October 2011, the ACIP voted to recommend routine use of the quadrivalent HPV vaccine for boys age 11 to 12; catch-up vaccination should occur for those age 13 to 22, with an option to vaccinate men age 23 to 26.

These recommendations replace the “permissive use” recommendations from the ACIP in October 2009 that said the quadrivalent HPV vaccine may be given to males age 9 to 26.⁶⁴ This shift from a permissive to an active recommendation connotes a positive change reflecting recognition of rising oropharyngeal cancer rates attributable to oncogenic, preventable HPV, rising HPV-related anal cancer incidence, and the burden of the disease in female partners of infected men, with associated rising health care costs.

The bivalent HPV vaccine received FDA licensure in October 2009 for use in females age 10 to 25 to prevent cervical cancer and precursor lesions. The ACIP included the bivalent HPV vaccine in its updated recommendations in May 2010 for use in girls age 11 to 12. Numerous national and international organizations have endorsed HPV vaccination.^65–71

Table 2 outlines the recommendations from these organizations.

HPV VACCINATION RATES ARE STILL LOW

HPV vaccine offers us the hope of eventually eradicating cervical cancer. However, the immunization program still faces many challenges, since HPV vaccination touches on issues related to adolescent sexuality, parental autonomy, and cost. As a result, HPV immunization rates remain relatively low in the United States according to several national surveys. Only 40% to 49% of girls eligible for the vaccine received even one dose, and of those who received even one dose, only 32% to 53.3% came back for all three doses.^72–75 Furthermore, indigent and minority teens were less likely to finish the three-dose HPV vaccine series.

Why are the vaccination rates so low?

Parental barriers. In one survey,⁷³ reasons that parents gave for not having their daughters vaccinated included:

• Lack of knowledge of the vaccine (19.4%)
• Lack of perceived need for the vaccine (18.8%)
• Belief that their daughter was not sexually active (18.3%)
• Clinician not recommending vaccination (13.1%).

In an effort to improve HPV vaccination rates,⁴¹ several states proposed legislation for mandatory HPV vaccination of schoolgirls shortly after licensure of the quadrivalent HPV vaccine.³ Since then, we have seen a wave of public opposition rooted in concerns and misinformation about safety, teenage sexuality, governmental coercion, and cost. Widespread media coverage has also highlighted unsubstantiated claims about side effects attributable to the vaccine that can raise parents’ mistrust of vaccines.⁷⁶ Concerns have also been raised about a threat to parental autonomy in how and when to educate their children about sex.⁷⁷

Moreover, the vaccine has raised ethical concerns in some parents and politicians that mandatory vaccination could undermine abstinence messages in sexual education and may alter sexual activity by condoning risky behavior.⁷⁸ However, a recent study indicated that there is no significant change in sexual behavior related to HPV vaccination in young girls.⁷⁹

In 2012, Mullins et al⁸⁰ also found that an urban population of adolescent girls (76.4% black, 57.5% sexually experienced) did not feel they could forgo safer sexual practices after first HPV vaccination, although the girls did perceive less risk from HPV than from other sexually transmitted infections after HPV vaccination (P < .001).⁸⁰ Inadequate knowledge about HPV-related disease and HPV vaccine correlated with less perceived risk from HPV after vaccination among the girls, and a lack of knowledge about HPV and less communication with their daughters about HPV correlated with less perceived risk from HPV in the mothers of the study population.⁸¹

Health-care-provider barriers. Physician endorsement of vaccines represents a key predictor of vaccine acceptance by patients, families, and other clinicians.^82–84 In 2008, a cross-sectional, Internet-based survey of 1,122 Texas pediatricians, family practice physicians, obstetricians, gynecologists, and internal medicine physicians providing direct patient care found that only 48.5% always recommended HPV vaccination to girls.⁷⁴ Of all respondents, 68.4% were likely to recommend the vaccine to boys, and 41.7% agreed with mandated vaccination. Thus, more than half of the physicians were not following the current recommendations for universal HPV vaccination for 11- to -12-year-olds.

In a survey of 1,013 physicians during the spring and summer of 2009, only 34.6% said they always recommend HPV vaccination to early adolescents, 52.7% to middle adolescents, and 50.2% to late adolescents and young adults.⁸⁵ Pediatricians were more likely than family physicians and obstetrician-gynecologists to always recommend HPV vaccine across all age groups (P < .001). Educational interventions targeting various specialties may help overcome physician-related barriers to immunization.⁸⁵

Financial barriers. HPV vaccine, which must be given in three doses, is more expensive than other vaccines, and this expense is yet another barrier, especially for the uninsured.⁸⁶ Australia launched a government-funded program of HPV vaccination (with the quadrivalent vaccine) in schools in 2007, and it has been very successful. Garland et al⁸⁷ reported that new cases of genital warts have decreased by 73% since the program began, and the rate of high-grade abnormalities on Papanicolaou testing has declined by a small but significant amount.

For HPV vaccination to have an impact on public health, vaccination rates in the general population need to be high. In order to achieve these rates, we need to educate our patients on vaccine safety and efficacy and counsel vaccine recipients about the prevention of sexually transmitted infections and the importance of regular cervical cancer screening after age 21. Clinicians can actively “myth-bust” with patients, who may not realize that the vaccine should be given despite a history of HPV infection or abnormal Pap smear.

FREQUENTLY ASKED QUESTIONS

What if the patient is late for a shot?

The current recommended vaccination schedule for the bivalent and quadrivalent HPV vaccines is a three-dose series administered at 0, 2, and 6 months, given as an intramuscular injection, preferably in the deltoid muscle. The minimal dosing interval is 4 weeks between the first and second doses and 12 weeks between the second and third doses.

The vaccines use different adjuncts with different specific mechanisms for immunogenicity; therefore, it is recommended that the same vaccine be used for the entire three-dose series. However, if circumstances preclude the completion of a series with the same vaccine, the other HPV vaccine may be used.⁶³ Starting the series over is not recommended.

Long-term studies demonstrated clinical efficacy 8.5 years after vaccination.⁴⁷ Amnestic response by virtue of activation of pools of memory B cells has been demonstrated, suggesting the vaccine may afford lifelong immunity.⁸⁸

Is a pregnancy test needed before HPV vaccination?

The ACIP states that pregnancy testing is not required before receiving either of the available HPV vaccines.

A recent retrospective review of phase III efficacy trials and pregnancy registry surveillance data for both vaccines revealed no increase in spontaneous abortions, fetal malformations, or adverse pregnancy outcomes.⁸⁹ Data are limited on bivalent and quadrivalent HPV vaccine given within 30 days of pregnancy and subsequent pregnancy and fetal outcomes. Both vaccines have been assigned a pregnancy rating of category B; however, the ACIP recommends that neither vaccine be given if the recipient is known to be pregnant. If pregnancy occurs, it is recommended that the remainder of the series be deferred until after delivery.⁶²

It is not known whether the vaccine is excreted in breast milk. The manufacturers of both the bivalent and quadrivalent HPV vaccines recommend caution when vaccinating lactating women.^30,31

Can HPV vaccine be given with other vaccines?

In randomized trials, giving the bivalent HPV vaccine with the combined hepatitis A, hepatitis B, meningococcal conjugate and the combined tetanus, diphtheria, and acellular pertussis vaccines did not interfere with the immunogenic response, was safe, and was well tolerated.^90,91 Coadministration of the quadrivalent HPV vaccine has been studied only with hepatitis B vaccine, with similar safety and efficacy noted.

The ACIP recommends giving HPV vaccine at the same visit with other age-appropriate immunizations to increase the likelihood of adherence to recommended vaccination schedules.⁶²

Is HPV vaccination cost-effective?

Kim and Goldie⁸⁶ performed a cost-effectiveness analysis of HPV vaccination of girls at age 12 and catch-up vaccination up to the ages of 18, 21, and 26. For their analysis, they considered prevention of cancers associated with HPV types 16 and 18, of genital warts associated with types 6 and 11, and of recurrent respiratory papillomatosis. They also assumed that immunity would be lifelong, and current screening practices would continue.

They calculated that routine vaccination of 12-year-old girls resulted in an incremental cost-effective ratio of $34,900 per quality-adjusted life-year (QALY) gained. A threshold of less than $50,000 per QALY gained is considered reasonably cost-effective, with an upper limit of $100,000 considered acceptable.⁹²

In the same analysis by Kim and Goldie,⁸⁶ catch-up vaccination of girls through age 18 resulted in a cost of $50,000 to $100,000 per QALY gained, and catch-up vaccination of females through age 26 was significantly less cost-effective at more then $130,000 per QALY gained. The vaccine was also significantly less cost-effective if 5% of the population was neither screened nor vaccinated, if a 10-year booster was required, and if frequent cervical cancer screening intervals were adopted.

This analysis did not include costs related to the evaluation and treatment of abnormal Pap smears and cross-protection against other HPV-related cancers.

The cost-effectiveness of HPV vaccination depends on reaching more girls at younger ages (ideally before sexual debut) and completing the three-dose schedule to optimize duration of immunity.⁹² Appropriate modification of the current recommendations for the intervals of cervical cancer screening for vaccinated individuals will further improve the cost-effectiveness of vaccination. The inclusion of male vaccination generally has more favorable cost per QALY in scenarios in which female coverage rates are less than 50%⁹³ and among men who have sex with men.⁹⁴

TO ERADICATE CERVICAL CANCER

Given the remarkable efficacy and expected long-term immunogenicity of HPV vaccines, we anticipate a decline in HPV-related cervical cancer and other related diseases in the years to come. However, modeling studies predicting the impact of HPV vaccination suggest that although substantial reductions in diseases can be expected, the benefit, assuming high vaccination rates, will not be apparent for at least another decade.⁹⁵ Furthermore, the current HPV vaccines contain only HPV 16 and 18 L1 protein for cancer protection and, therefore, do not provide optimal protection against all oncogenic HPV-related cancers.

The real hope of eradicating cervical cancer and all HPV-related disease relies on a successful global implementation of multivalent HPV vaccination, effective screening strategies, and successful treatment.

The vaccines against human papillomavirus (HPV) are the only ones designed to prevent cancer caused by a virus^1,2—surely a good goal. But because HPV is sexually transmitted, HPV vaccination has met with public controversy.³ To counter the objections and better protect their patients’ health, primary care providers and other clinicians need a clear understanding of the benefits and the low risk of HPV vaccination—and the reasons so many people object to it.³

In this article, we will review:

• The impact of HPV-related diseases
• The basic biologic features of HPV vaccines
• The host immune response to natural HPV infection vs the response to HPV vaccines
• The clinical efficacy and safety of HPV vaccines
• The latest guidelines for HPV vaccination
• The challenges to vaccination implementation
• Frequently asked practical questions about HPV vaccination.

HPV-RELATED DISEASES: FROM BOTHERSOME TO DEADLY

Clinical sequelae of HPV infection include genital warts; cancers of the cervix, vulva, vagina, anus, penis, and oropharynx; and recurrent respiratory papillomatosis.^4–6

Genital warts

HPV types 6 and 11 are responsible for more than 90% of the 1 million new cases of genital warts diagnosed annually in the United States.^7–10

Bothersome and embarrassing, HPV-related genital warts can cause itching, burning, erythema, and pain, as well as epithelial erosions, ulcerations, depigmentation, and urethral and vaginal bleeding and discharge.^11,12 Although they are benign in the oncologic sense, they can cause a good deal of emotional and financial stress. Patients may feel anxiety, embarrassment,¹³ and vulnerability. Adolescents and adults who have or have had genital warts need to inform their current and future partners or else risk infecting them—and facing the consequences.

Direct health care costs of genital warts in the United States have been estimated to be at least $200 million per year.¹⁴

Cervical cancer

Cervical cancer cannot develop unless the cervical epithelium is infected with one of the oncogenic HPV types. Indeed, oncogenic HPV is present in as many as 99.8% of cervical cancer specimens.¹⁵ HPV 16 and 18 are the most oncogenic HPV genotypes and account for 75% of all cases of cervical cancer. Ten other HPV genotypes account for the remaining 25%.¹⁶

In 2012, there were an estimated 12,170 new cases of invasive cervical cancer in the United States and 4,220 related deaths.¹⁷ The cost associated with cervical cancer screening, managing abnormal findings, and treating invasive cervical cancer in the United States is estimated to be $3.3 billion per year.¹⁸

Although the incidence and the mortality rates of cervical cancer have decreased more than 50% in the United States over the past 3 decades thanks to screening,¹⁹ cervical cancer remains the second leading cause of death from cancer in women worldwide. Each year, an estimated 500,000 women contract the disease and 240,000 die of it.²⁰

Anal cancer

A recent study indicated that oncogenic HPV can also cause anal cancer, and the proportion of such cancers associated with HPV 16 or HPV 18 infection is as high as or higher than for cervical cancers, and estimated at 80%.²¹

The incidence of anal cancer is increasing by approximately 2% per year in both men and women in the general population,²² and rates are even higher in men who have sex with men and people infected with the human immunodeficiency virus.²³

Hu and Goldie²⁴ estimated that the lifetime costs of caring for all the people in the United States who in just 1 year (2003) acquired anal cancer attributable to HPV would total $92 million.

Oropharyngeal cancer

HPV types 16, 18, 31, 33, and 35 also cause oropharyngeal cancer. HPV 16 accounts for more than 90% of cases of HPV-related oropharyngeal cancer.²⁵

Chaturvedi et al⁶ tested tissue samples from three national cancer registries and found that the number of oropharyngeal cancers that were HPV-positive increased from 16.3% in 1984–1989 to 71.7% in 2000–2004, while the number of HPV-negative oropharyngeal cancers fell by 50%, paralleling the drop in cigarette smoking in the United States.

Hu and Goldie²⁴ estimated that the total lifetime cost for all new HPV-related oropharyngeal cancers that arose in 2003 would come to $38.1 million.²⁴

Vulvar and vaginal cancers

HPV 16 and 18 are also responsible for approximately 50% of vulvar cancers and 50% to 75% of vaginal cancers.^4,5

Recurrent respiratory papillomatosis

HPV 6 and 11 cause almost all cases of juvenile- and adult-onset recurrent respiratory papillomatosis.²⁶ The annual cost for surgical procedures for this condition in the United States has been estimated at $151 million.²⁷

HPV VACCINES ARE NONINFECTIOUS AND NONCARCINOGENIC

Currently, two HPV vaccines are available: a quadrivalent vaccine against types 6, 11, 16, and 18 (Gardasil; Merck) and a bivalent vaccine against types 16 and 18 (Cervarix; Glaxo-SmithKline). The quadrivalent vaccine was approved by the US Food and Drug Administration (FDA) in 2006, and the bivalent vaccine was approved in 2009.^28,29

Both vaccines contain virus-like particles, ie, viral capsids that contain no DNA. HPV has a circular DNA genome of 8,000 nucleotides divided into two regions: the early region, for viral replication, and the late region, for viral capsid production. The host produces neutralizing antibodies in response to the L1 capsid protein, which is different in different HPV types.

In manufacturing the vaccines, the viral L1 gene is incorporated into a yeast genome or an insect virus genome using recombinant DNA technology (Figure 1). Grown in culture, the yeast or the insect cells produce the HPV L1 major capsid protein, which has the intrinsic capacity to self-assemble into virus-like particles.^30–33 These particles are subsequently purified for use in the vaccines.³⁴

Recombinant virus-like particles are morphologically indistinguishable from authentic HPV virions and contain the same typespecific antigens present in authentic virions. Therefore, they are highly effective in inducing a host humoral immune response. And because they do not contain HPV DNA, the recombinant HPV vaccines are noninfectious and noncarcinogenic.³⁵

VACCINATION INDUCES A STRONGER IMMUNE RESPONSE THAN INFECTION

HPV infections trigger both a humoral and a cellular response in the host immune system.

The humoral immune response to HPV infection involves producing neutralizing antibody against the specific HPV type, specifically the specific L1 major capsid protein. This process is typically somewhat slow and weak, and only about 60% of women with a new HPV infection develop antibodies to it.^36,37

HPV has several ways to evade the host immune system. It does not infect or replicate within the antigen-presenting cells in the epithelium. In addition, HPV-infected keratinocytes are less susceptible to cytotoxic lymphocytic-mediated lysis. Moreover, HPV infection cause very little tissue destruction. And finally, natural cervical HPV infection does not result in viremia. As a result, antigen-presenting cells have no chance to engulf the virions and present virion-derived antigen to the host immune system. The immune system outside the epithelium has limited opportunity to detect the virus because HPV infection does not have a blood-borne phase.^38,39

The cell-mediated immune response to early HPV oncoproteins may help eliminate established HPV infection.⁴⁰ In contrast to antibodies, the T-cell response to HPV has not been shown to be specific to HPV type.⁴¹ Clinically, cervical HPV infection is common, but most lesions go into remission or resolve as a result of the cell-mediated immune response.^40,41

In contrast to the weak, somewhat ineffective immune response to natural HPV infection, the antibody response to HPV vaccines is rather robust. In randomized controlled trials, almost all vaccinated people have seroconverted. The peak antibody concentrations are 50 to 10,000 times greater than in natural infection. Furthermore, the neutralizing antibodies induced by HPV vaccines persist for as long as 7 to 9 years after immunization.⁴² However, the protection provided by HPV vaccines against HPV-related cervical intraepithelial neoplasia does not necessarily correlate with the antibody concentration.^43–47

Why does the vaccine work so well?

Why are vaccine-induced antibody responses so much stronger than those induced by natural HPV infection?

The first reason is that the vaccine, delivered intramuscularly, rapidly enters into blood vessels and the lymphatic system. In contrast, in natural intraepithelial infection, the virus is shed from mucosal surfaces and does not result in viremia.⁴⁸

In addition, the strong immunogenic nature of the virus-like particles induces a robust host antibody response even in the absence of adjuvant because of concentrated neutralizing epitopes and excellent induction of the T-helper cell response.^35,49,50

The neutralizing antibody to L1 prevents HPV infection by blocking HPV from binding to the basement membrane as well as to the epithelial cell receptor during epithelial microabrasion and viral entry. The subsequent micro-wound healing leads to serous exudation and rapid access of serum immunoglobulin G (IgG) to HPV virus particles and encounters with circulatory B memory cells.

Furthermore, emerging evidence suggests that even very low antibody concentrations are sufficient to prevent viral entry into cervical epithelial cells.^{46–48,51–53}

THE HPV VACCINES ARE HIGHLY EFFECTIVE AND SAFE

The efficacy and safety of the quadrivalent and the bivalent HPV vaccines have been evaluated in large randomized clinical trials.^{23,28,29,54,55} Table 1 summarizes the key findings.

The Females United to Unilaterally Reduce Endo/ectocervical Disease (FUTURE I)⁵⁴ and FUTURE II²⁸ trials showed conclusively that the quadrivalent HPV vaccine is 98% to 100% efficacious in preventing HPV 16- and 18-related cervical intraepithelial neoplasia, carcinoma in situ, and invasive cervical cancer in women who had not been infected with HPV before. Similarly, the Papilloma Trial against Cancer in Young Adults (PATRICIA) concluded that the bivalent HPV vaccine is 93% efficacious.²⁹

Giuliano et al⁵⁵ and Palefsky et al²³ conducted randomized clinical trials of the quadrivalent HPV vaccine for preventing genital disease and anal intraepithelial neoplasia in boys and men; the efficacy rates were 90.4%⁵⁵ and 77.5%.²³

A recent Finnish trial in boys age 10 to 18 found 100% seroconversion rates for HPV 16 and HPV 18 antibodies after they received bivalent HPV vaccine.⁵⁶ Similar efficacy has been demonstrated for the quadrivalent HPV vaccine in boys.⁵⁷

Adverse events after vaccination

After the FDA approved the quadrivalent HPV vaccine for girls in 2006, the US Centers for Disease Control and Prevention (CDC) conducted a thorough survey of adverse events after immunization from June 1, 2006 through December 31, 2008.⁵⁸ There were about 54 reports of adverse events per 100,000 distributed vaccine doses, similar to rates for other vaccines. However, the incidence rates of syncope and venous thrombosis were disproportionately higher, according to data from the US Vaccine Adverse Event Reporting System. The rate of syncope was 8.2 per 100,000 vaccine doses, and the rate of venous thrombotic events was 0.2 per 100,000 doses.⁵⁸

There were 32 reports of deaths after HPV vaccination, but these were without clear causation. Hence, this information must be interpreted with caution and should not be used to infer causal associations between HPV vaccines and adverse outcomes. The causes of death included diabetic ketoacidosis, pulmonary embolism, prescription drug abuse, amyotrophic lateral sclerosis, meningoencephalitis, influenza B viral sepsis, arrhythmia, myocarditis, and idiopathic seizure disorder.⁵⁸

Furthermore, it is important to note that vasovagal syncope and venous thromboembolic events are more common in young females in general.⁵⁹ For example, the background rates of venous thromboembolism in females age 14 to 29 using oral contraceptives is 21 to 31 per 100,000 woman-years.⁶⁰

Overall, the quadrivalent HPV vaccine is well tolerated and clinically safe. Postlicensure evaluation found that the quadrivalent and bivalent HPV vaccines had similar safety profiles.⁶¹

Vaccination is contraindicated in people with known hypersensitivity or prior severe allergic reactions to vaccine or yeast or who have bleeding disorders.

HPV VACCINATION DOES MORE THAN PREVENT CERVICAL CANCER IN FEMALES

The quadrivalent HPV vaccine was licensed by the FDA in 2006 for use in females age 9 to 26 to prevent cervical cancer, cervical cancer precursors, vaginal and vulval cancer precursors, and anogenital warts caused by HPV types 6, 11, 16, and 18. The CDC’s Advisory Committee on Immunization Practices (ACIP) issued its recommendation for initiating HPV vaccination for females age 11 to 12 in March 2007. The ACIP stated that the vaccine could be given to girls as early as age 9 and recommended catch-up vaccinations for those age 13 to 26.^62,63

The quadrivalent HPV vaccine was licensed by the FDA in 2009 for use in boys and men for the prevention of genital warts. In December 2010, the quadrivalent HPV vaccine received extended licensure from the FDA for use in males and females for the prevention of anal cancer. In October 2011, the ACIP voted to recommend routine use of the quadrivalent HPV vaccine for boys age 11 to 12; catch-up vaccination should occur for those age 13 to 22, with an option to vaccinate men age 23 to 26.

These recommendations replace the “permissive use” recommendations from the ACIP in October 2009 that said the quadrivalent HPV vaccine may be given to males age 9 to 26.⁶⁴ This shift from a permissive to an active recommendation connotes a positive change reflecting recognition of rising oropharyngeal cancer rates attributable to oncogenic, preventable HPV, rising HPV-related anal cancer incidence, and the burden of the disease in female partners of infected men, with associated rising health care costs.

The bivalent HPV vaccine received FDA licensure in October 2009 for use in females age 10 to 25 to prevent cervical cancer and precursor lesions. The ACIP included the bivalent HPV vaccine in its updated recommendations in May 2010 for use in girls age 11 to 12. Numerous national and international organizations have endorsed HPV vaccination.^65–71

Table 2 outlines the recommendations from these organizations.

HPV VACCINATION RATES ARE STILL LOW

HPV vaccine offers us the hope of eventually eradicating cervical cancer. However, the immunization program still faces many challenges, since HPV vaccination touches on issues related to adolescent sexuality, parental autonomy, and cost. As a result, HPV immunization rates remain relatively low in the United States according to several national surveys. Only 40% to 49% of girls eligible for the vaccine received even one dose, and of those who received even one dose, only 32% to 53.3% came back for all three doses.^72–75 Furthermore, indigent and minority teens were less likely to finish the three-dose HPV vaccine series.

Why are the vaccination rates so low?

Parental barriers. In one survey,⁷³ reasons that parents gave for not having their daughters vaccinated included:

• Lack of knowledge of the vaccine (19.4%)
• Lack of perceived need for the vaccine (18.8%)
• Belief that their daughter was not sexually active (18.3%)
• Clinician not recommending vaccination (13.1%).

In an effort to improve HPV vaccination rates,⁴¹ several states proposed legislation for mandatory HPV vaccination of schoolgirls shortly after licensure of the quadrivalent HPV vaccine.³ Since then, we have seen a wave of public opposition rooted in concerns and misinformation about safety, teenage sexuality, governmental coercion, and cost. Widespread media coverage has also highlighted unsubstantiated claims about side effects attributable to the vaccine that can raise parents’ mistrust of vaccines.⁷⁶ Concerns have also been raised about a threat to parental autonomy in how and when to educate their children about sex.⁷⁷

Moreover, the vaccine has raised ethical concerns in some parents and politicians that mandatory vaccination could undermine abstinence messages in sexual education and may alter sexual activity by condoning risky behavior.⁷⁸ However, a recent study indicated that there is no significant change in sexual behavior related to HPV vaccination in young girls.⁷⁹

In 2012, Mullins et al⁸⁰ also found that an urban population of adolescent girls (76.4% black, 57.5% sexually experienced) did not feel they could forgo safer sexual practices after first HPV vaccination, although the girls did perceive less risk from HPV than from other sexually transmitted infections after HPV vaccination (P < .001).⁸⁰ Inadequate knowledge about HPV-related disease and HPV vaccine correlated with less perceived risk from HPV after vaccination among the girls, and a lack of knowledge about HPV and less communication with their daughters about HPV correlated with less perceived risk from HPV in the mothers of the study population.⁸¹

Health-care-provider barriers. Physician endorsement of vaccines represents a key predictor of vaccine acceptance by patients, families, and other clinicians.^82–84 In 2008, a cross-sectional, Internet-based survey of 1,122 Texas pediatricians, family practice physicians, obstetricians, gynecologists, and internal medicine physicians providing direct patient care found that only 48.5% always recommended HPV vaccination to girls.⁷⁴ Of all respondents, 68.4% were likely to recommend the vaccine to boys, and 41.7% agreed with mandated vaccination. Thus, more than half of the physicians were not following the current recommendations for universal HPV vaccination for 11- to -12-year-olds.

In a survey of 1,013 physicians during the spring and summer of 2009, only 34.6% said they always recommend HPV vaccination to early adolescents, 52.7% to middle adolescents, and 50.2% to late adolescents and young adults.⁸⁵ Pediatricians were more likely than family physicians and obstetrician-gynecologists to always recommend HPV vaccine across all age groups (P < .001). Educational interventions targeting various specialties may help overcome physician-related barriers to immunization.⁸⁵

Financial barriers. HPV vaccine, which must be given in three doses, is more expensive than other vaccines, and this expense is yet another barrier, especially for the uninsured.⁸⁶ Australia launched a government-funded program of HPV vaccination (with the quadrivalent vaccine) in schools in 2007, and it has been very successful. Garland et al⁸⁷ reported that new cases of genital warts have decreased by 73% since the program began, and the rate of high-grade abnormalities on Papanicolaou testing has declined by a small but significant amount.

For HPV vaccination to have an impact on public health, vaccination rates in the general population need to be high. In order to achieve these rates, we need to educate our patients on vaccine safety and efficacy and counsel vaccine recipients about the prevention of sexually transmitted infections and the importance of regular cervical cancer screening after age 21. Clinicians can actively “myth-bust” with patients, who may not realize that the vaccine should be given despite a history of HPV infection or abnormal Pap smear.

FREQUENTLY ASKED QUESTIONS

What if the patient is late for a shot?

The current recommended vaccination schedule for the bivalent and quadrivalent HPV vaccines is a three-dose series administered at 0, 2, and 6 months, given as an intramuscular injection, preferably in the deltoid muscle. The minimal dosing interval is 4 weeks between the first and second doses and 12 weeks between the second and third doses.

The vaccines use different adjuncts with different specific mechanisms for immunogenicity; therefore, it is recommended that the same vaccine be used for the entire three-dose series. However, if circumstances preclude the completion of a series with the same vaccine, the other HPV vaccine may be used.⁶³ Starting the series over is not recommended.

Long-term studies demonstrated clinical efficacy 8.5 years after vaccination.⁴⁷ Amnestic response by virtue of activation of pools of memory B cells has been demonstrated, suggesting the vaccine may afford lifelong immunity.⁸⁸

Is a pregnancy test needed before HPV vaccination?

The ACIP states that pregnancy testing is not required before receiving either of the available HPV vaccines.

A recent retrospective review of phase III efficacy trials and pregnancy registry surveillance data for both vaccines revealed no increase in spontaneous abortions, fetal malformations, or adverse pregnancy outcomes.⁸⁹ Data are limited on bivalent and quadrivalent HPV vaccine given within 30 days of pregnancy and subsequent pregnancy and fetal outcomes. Both vaccines have been assigned a pregnancy rating of category B; however, the ACIP recommends that neither vaccine be given if the recipient is known to be pregnant. If pregnancy occurs, it is recommended that the remainder of the series be deferred until after delivery.⁶²

It is not known whether the vaccine is excreted in breast milk. The manufacturers of both the bivalent and quadrivalent HPV vaccines recommend caution when vaccinating lactating women.^30,31

Can HPV vaccine be given with other vaccines?

In randomized trials, giving the bivalent HPV vaccine with the combined hepatitis A, hepatitis B, meningococcal conjugate and the combined tetanus, diphtheria, and acellular pertussis vaccines did not interfere with the immunogenic response, was safe, and was well tolerated.^90,91 Coadministration of the quadrivalent HPV vaccine has been studied only with hepatitis B vaccine, with similar safety and efficacy noted.

The ACIP recommends giving HPV vaccine at the same visit with other age-appropriate immunizations to increase the likelihood of adherence to recommended vaccination schedules.⁶²

Is HPV vaccination cost-effective?

Kim and Goldie⁸⁶ performed a cost-effectiveness analysis of HPV vaccination of girls at age 12 and catch-up vaccination up to the ages of 18, 21, and 26. For their analysis, they considered prevention of cancers associated with HPV types 16 and 18, of genital warts associated with types 6 and 11, and of recurrent respiratory papillomatosis. They also assumed that immunity would be lifelong, and current screening practices would continue.

They calculated that routine vaccination of 12-year-old girls resulted in an incremental cost-effective ratio of $34,900 per quality-adjusted life-year (QALY) gained. A threshold of less than $50,000 per QALY gained is considered reasonably cost-effective, with an upper limit of $100,000 considered acceptable.⁹²

In the same analysis by Kim and Goldie,⁸⁶ catch-up vaccination of girls through age 18 resulted in a cost of $50,000 to $100,000 per QALY gained, and catch-up vaccination of females through age 26 was significantly less cost-effective at more then $130,000 per QALY gained. The vaccine was also significantly less cost-effective if 5% of the population was neither screened nor vaccinated, if a 10-year booster was required, and if frequent cervical cancer screening intervals were adopted.

This analysis did not include costs related to the evaluation and treatment of abnormal Pap smears and cross-protection against other HPV-related cancers.

The cost-effectiveness of HPV vaccination depends on reaching more girls at younger ages (ideally before sexual debut) and completing the three-dose schedule to optimize duration of immunity.⁹² Appropriate modification of the current recommendations for the intervals of cervical cancer screening for vaccinated individuals will further improve the cost-effectiveness of vaccination. The inclusion of male vaccination generally has more favorable cost per QALY in scenarios in which female coverage rates are less than 50%⁹³ and among men who have sex with men.⁹⁴

TO ERADICATE CERVICAL CANCER

Given the remarkable efficacy and expected long-term immunogenicity of HPV vaccines, we anticipate a decline in HPV-related cervical cancer and other related diseases in the years to come. However, modeling studies predicting the impact of HPV vaccination suggest that although substantial reductions in diseases can be expected, the benefit, assuming high vaccination rates, will not be apparent for at least another decade.⁹⁵ Furthermore, the current HPV vaccines contain only HPV 16 and 18 L1 protein for cancer protection and, therefore, do not provide optimal protection against all oncogenic HPV-related cancers.

The real hope of eradicating cervical cancer and all HPV-related disease relies on a successful global implementation of multivalent HPV vaccination, effective screening strategies, and successful treatment.

Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.

EVOLVING VACCINATION POLICY IN HEALTH CARE WORKERS

Starting in January 2013, the Centers for Medicare and Medicaid Services will require hospitals to report how many of their health care workers are vaccinated. These rates will be publicly reported as a measure of hospital quality. This has fueled the ongoing debate about mandating influenza vaccination for health care workers. Studies have shown that the most important factors in increasing influenza vaccination rates among health care workers are requiring vaccination as a condition for employment and making vaccination available on-site, for more than 1 day, at no cost to the worker.⁵⁸

As an alternative, some institutions have implemented a “shot-or-mask” policy whereby a health care worker who elects not to be vaccinated because of medical or religious reasons would be asked to wear a mask during all faceto-face encounters with patients.

NEW ANTIVIRAL DRUGS ON THE HORIZON

The emergence of oseltamivir-resistant strains in recent years caused a great deal of concern in public health regarding the potential for outbreaks of drug-resistant influenza.^{34,35,59–61}

A recent Asian randomized clinical trial reported the efficacy of a long-acting neuraminidase inhibitor, laninamivir octanoate, in the treatment of seasonal influenza.⁶² This study showed that a single inhalation of this drug is effective in treating seasonal influenza, including that caused by oseltamivir-resistant strains in adults. Laninamivir is currently approved in Japan.

CHALLENGES IN PREVENTING AND TREATING INFLUENZA

Despite the great advances that we have made in preventing and treating influenza in the last half-century, we still face many challenges. Each year in the United States, influenza infection results in an estimated 31 million outpatient visits, 226,000 hospital admissions, and 36,000 deaths.⁴²

Antigenic drift and shift. Influenza viruses circulating among animals and humans vary genetically from season to season and within seasons. As a result of this changing viral antigenicity, the virus can evade the human immune system, causing widespread outbreaks.

One of the unique and most remarkable features of influenza virus is the antigenic variation: antigenic drift and antigenic shift. Antigenic drift is the relatively minor antigenic changes that occur frequently within an influenza subtype, typically resulting from genetic mutation of viral RNA coding for hemagglutinin or neuraminidase. This causes annual regional epidemics. In contrast, antigenic shift is the result of genetic material reassortment: the emerging of new viral RNA from different strains of different species. This often leads to global pandemics.

Therefore, it is challenging to accurately predict the antigenic makeup of influenza viruses for each season and to include new emerging antigens in the vaccine production, as we are facing a moving target. We prepare influenza vaccines each season based on past experience.⁶³

Vaccination rates have hit a plateau of 60% to 70% in adults since the 1990s, in spite of greater vaccine supply and recommendations that all adults, regardless of underlying disease, be vaccinated annually.⁶⁴ Similarly, only 51% of children age 6 months to 17 years were vaccinated in the 2010–2011 season.⁶⁵ And vaccination rates are even lower in low-income populations.^66,67

The emergence of oseltamivir-resistant strains in recent years, not only in people exposed to oseltamivir but also in those who haven’t been exposed to this drug, with sustained transmission, certainly raises the possibility of a more difficult epidemic to control.³⁸

Global travel, global infection. Our last H1N1 pandemic in 2009 was an example of how easily the influenza virus can spread rapidly in today’s highly mobile global society.²²

What we must do

As primary health care providers, we must closely monitor the community outbreak and the emergence of drug-resistant strains and strongly recommend vaccination for all patients older than 6 months, since timely vaccination is the cornerstone of influenza prevention. Although many have questioned the efficacy of influenza vaccination, a recent meta-analysis showed a 59% pooled efficacy of the trivalent inactivated vaccine in adults age 18 to 65 years in preventing virologically confirmed influenza, and 83% pooled efficacy of the live-attenuated influenza vaccine in children age 6 months to 7 years.⁶⁸ Novel approaches for vaccination reminders, such as text messaging⁶⁹ in addition to traditional mail or telephone reminders, can improve vaccination compliance in today’s highly mobile world that is more than ever connected.

With the lessons learned from four pandemics in the last century, updated recommendations for prevention, and adequate vaccine supply, we should be ready to face the challenge of another flu season.

Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.