Abstract
Background:
Human papillomavirus (HPV) vaccination coverage continues to be at low to moderate levels throughout the United States. HPV infection is linked to multiple types of cancers resulting in high economic and health burden. We aimed to estimate the excess number of cancer cases and associated medical costs due to current human papillomavirus (HPV) vaccination coverage for a 20 year old birth cohort in California.
Methods:
We estimated the lifetime number of cancer cases caused by vaccine-preventable strains of HPV for a cohort of 20 year olds in California. We then estimated the excess number of cancer cases in that cohort which would occur due to 2017 HPV vaccination coverage compared to an optimal coverage of 99.5%. By multiplying those excess cases by the average cost of treatment, we determined the excess cost due to current HPV vaccination coverage.
Results:
With current vaccination coverage in California, the 20 year old cohort is at risk for an excess 1352 cancer cases that could be prevented with a projected optimal vaccination coverage of 99.5%. The excess cost of treatment for those cancer cases would be $52.2 million. Male oropharyngeal cancer accounts for the greatest projected cost burden $21.3 million followed by cervical cancer $16.1 million.
Conclusion:
Increased HPV vaccination coverage in California is needed to reduce economic and health burdens associated with cancers caused by HPV infection.
Keywords: human papillomavirus, vaccine, sexually transmitted infection, public health, cost savings
Short summary: Suboptimal human papillomavirus vaccination coverage in California contributes to a significant economic and health burden from cancer, which could be avoided with increased vaccination coverage.
Introduction
Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States, affecting approximately 79 million individuals at any given time (1). There are over 150 types of HPV, some of which can cause genital warts or cancer. It is estimated that more than 80–90% of sexually active men and women will be infected with at least one type of HPV in their lifetime, about one half of which will be a high risk cancer-causing type (1). The majority of the focus of HPV-related illness has been on cervical cancer, but HPV also causes cancers of the anus, penis, oropharynx (middle part of the throat, including the soft palate, base of the tongue and tonsils), vulva, and vagina (2). Each year over 33,000 cancer diagnoses are attributed to HPV infection (3).
In 2006, the first vaccine to prevent HPV infection was approved by the Food and Drug Administration (FDA) and recommended by the Advisory Committee on Immunization Practices (ACIP) for use among females. The vaccine was later recommended for males aged 9 through 26 years in 2011. After the initial quadrivalent HPV vaccine, bivalent and 9-valent vaccines have since been developed (4). The current 9-valent HPV vaccine has a gender-neutral immunization policy and protects against 9 types of HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58), seven of which can cause HPV-related cancer (4). The ACIP currently recommends routine vaccination for both boys and girls at age 11 or 12 years, with catch-up vaccination of females through age 26 years and males through age 21 years. If vaccinated before age 15 years, only two doses are required. Recently, the FDA expanded approval of the vaccine to include catch-up vaccination for adults up to age 45 years (5). Despite its proven safety and efficacy, up-to-date HPV vaccination coverage among adolescents aged 13–17 years remains modest at only 43.4% nationally, leading to unnecessary and preventable morbidity and mortality caused by HPV infections (6).
Previous studies have evaluated the cost-effectiveness of the HPV vaccine and costs associated with treatment of HPV-related cancers. A study conducted in Sweden estimated the societal cost of HPV related pre-cancers and cancers to be nearly $110 million annually and reported a high loss in productivity among males with HPV-associated oropharyngeal cancer (7). Additional studies conducted in the United States have explored the associated costs of the HPV vaccines, including comparisons that found the 9-valent vaccination to be the most cost-effective compared to the 2- or 4-valent vaccine (8,9,10).
Although vaccination coverage has increased since HPV vaccination was recommended by the ACIP in 2006, many adolescents remain unvaccinated and consequently vulnerable to preventable HPV-associated cancers. Federal funding is available so that eligible youth under age 19 years can get the vaccine through the Centers for Disease Control and Prevention (CDC) funded Vaccines for Children Program (11), yet coverage continues to remain lower than that of other vaccines recommended for adolescents (6). Those vaccines may have higher coverage due to their requirements for school entry. Currently, only Rhode Island, Washington D.C., Virginia, and Puerto Rico require HPV vaccination for public school entry. In California, the completed HPV vaccination coverage was moderate at 61% among female and 46% among male adolescents in 2017 (12). The federal government’s Healthy People 2020 initiative set a goal to increase vaccination coverage of HPV vaccination to 80% for both males and females aged 13 to 17 years, a goal California is still far from reaching (13).
The current study aimed to evaluate a California birth cohort’s lifetime risk for HPV associated cancer using current up-to-date HPV vaccination coverage and a projected optimal vaccination coverage of 99.5%.
Materials and Methods
For each type of cancer that could be caused by HPV infection, we used secondary data to determine the HPV-related cancer incidence in California, the estimated percent attributable to HPV infection and the direct medical cost of treatment (14,15,16). The types of cancer included in the analyses were cervical, vaginal, vulvar, penile, anal, rectal, and oropharyngeal.
Cohort
We used a population cohort of 20 year olds to estimate the benefits of increased vaccination. The entire cohort was assumed to live greater than 80 years. We determined the cohort size by using California census data for the number of people age 20 years old in California in 2017 (17). We chose that group because the number of cancer cases caused by HPV in people under 20 years old was negligible. The census data provided a breakdown of the population by age within a ten year range. Therefore, we assumed the number of 20 year olds was one tenth of the population of people age 20–29 years. We then used the cohort to estimate the number of excess cancer cases and medical costs due to moderate vaccination.
Total prevalence of vaccine-preventable cancer cases within the cohort
For each of the seven types of cancer, we retrieved data on annual incidence rates of cancer cases recorded in California from the CDC (15). The data also included national rates of cancer cases by age group within a ten year range. Assuming the age distribution of cancer cases in California was similar to that at the national level, we estimated incidence rate by age group in California for each cancer type. We applied the incidence rates to the size of cohort to derive the number of type-specific new cancer cases that would arise within our cohort per type of cancer and within each age group.
To estimate the number of those cancer cases that were caused by HPV and vaccine-preventable, we multiplied the number of new cases by the proportion of cases caused by any of the nine types of HPV included in the 9-valent HPV vaccine (15, 16). Assuming 100% vaccination efficacy and coverage, that calculation yielded the number of vaccine-preventable cancer cases by cancer type in the cohort over time.
Adjusting the model for vaccine efficacy
We modified the number of vaccine-preventable cancer cases to account for vaccine efficacy. We multiplied the prevalence of vaccine-preventable cancers by 90%, which is an approximation for vaccine efficacy of cancer prevention (18). We also performed a sensitivity analysis using vaccine efficacy of 85% and 95% to establish a range or uncertainty interval.
Adjusting the model for sub-optimal vaccination coverage
Next, we multiplied the modified number of vaccine-preventable cancer cases by current and projected maximum HPV vaccination coverage in California. Vaccination coverage in 2017 in California was 60.9% (95% uncertainty interval, 50.3%−71.5%) for adolescent girls and 46.3% (95% uncertainty interval, 36.9%−55.7%) for adolescent boys (6). Cohort vaccination was assumed to be completed by age 12 years. We used vaccination coverage in 2017 for our hypothetical model to represent the most current vaccination rate. Projected optimal HPV vaccination coverage is 99.5%, assuming a 0.5% medical exemption rate (19). These series of calculations determined the number of vaccine-preventable cancer cases avoided through vaccination in either scenario. Subtracting the number of cases avoided from the total number vaccine-preventable cancer cases in the cohort yielded the number of cases remaining under current vaccination and under projected maximum vaccination.
Excess number of cases due to moderate HPV vaccination coverage
The number of cases that would still remain after optimal vaccination coverage was subtracted from the number of cases remaining after vaccination with the current coverage to yield the excess number of cancer cases due to moderate HPV vaccination. The values for each cancer type and age group were added together to get the total number of excess cancer cases over the lifetime of the cohort.
Excess cost of cancer treatment from excess cases due to moderate HPV vaccination
We multiplied the excess number of cancer cases for each cancer type by the average cost of cancer treatment by cancer type to determine the excess cost of cancer treatment due to moderate HPV vaccination among the cohort. We used the cost per case from data in Chesson, et al that reflected the direct medical cost of treatment by cancer type (14).
Results
Cohort
The size of our cohort was 296,525, the approximate number of 20 year olds in California in 2017.
Total prevalence of HPV vaccine-preventable cancer
Of the approximately 4,552 cancer cases that would result in the lifetime of the cohort, 3,643 (80%) were caused by HPV. Of the cases caused by HPV, 3,366 (92%) were caused by an HPV type included in the 9-valent HPV vaccine (Table 1).
Table 1.
Total number of 9-valent human papillomavirus (HPV) vaccine-preventable cancers within the cohort of 20 year olds in California, 2017.
| Type of Cancer | Number of cancer cases within the cohort | % of cancer cases caused by a 9-valent HPV vaccine strain* | Number of 9-valent HPV vaccine-preventable cancer cases within the cohort |
|---|---|---|---|
| Cervical | 1474 | 81% | 1192 |
| Vaginal | 93 | 73% | 68 |
| Vulvar | 286 | 63% | 179 |
| Penile | 166 | 57% | 94 |
| Rectal (female) | 60 | 90% | 54 |
| Rectal (male) | 33 | 83% | 27 |
| Anal (female) | 370 | 90% | 334 |
| Anal (male) | 261 | 83% | 214 |
| Oropharyngeal (female) | 289 | 60% | 174 |
| Oropharyngeal (male) | 1520 | 68% | 1029 |
| Total | 4552 | 3366 |
Source: Saraiya M, Unger ER, Thompson TD, et al. US Assessment of HPV Types in Cancers: Implications for Current and 9-Valent HPV Vaccines. JNCI 2015; 107(6): 1–12
Excess number of cases due to moderate HPV vaccination coverage
Figure 1 shows the total HPV related cancer cases throughout the lifetime of the birth cohort with current vaccination coverage and projected maximum vaccination coverage. With current vaccination coverage, the number of future vaccine-preventable cancer cases over the cohort’s lifetime was determined to be 1704 cases, with 32% (n=539) due to cervical cancer and 35% (n=601) due to male oropharyngeal cancer (Table 2). With a projected vaccination coverage of 99.5%, the estimated number of HPV-related cancer cases that would remain would be 352 cases (Table 2).
Figure 1.
Total human papillomavirus related cancer cases throughout the lifetime of a 20 year old birth cohort in California, 2017.
Table 2.
Number of cancer cases remaining in the cohort of 20 year olds in California under current (2017) vaccination coverage and under projected 99.5% vaccination coverage.
| Type of Cancer | Number of 9-valent HPV vaccine preventable cancers within the cohort | Cases avoided with current 2017 vaccination coverage* | Cases remaining with current 2017 vaccination coverage* | Cases avoided with projected maximum vaccination coverage** | Cases remaining with projected maximum vaccination coverage** |
|---|---|---|---|---|---|
| Cervical | 1192 | 653 | 539 | 1068 | 124 |
| Vaginal | 68 | 37 | 31 | 61 | 7 |
| Vulvar | 179 | 98 | 81 | 160 | 19 |
| Penile | 94 | 39 | 55 | 85 | 10 |
| Rectal (female) | 54 | 30 | 25 | 49 | 6 |
| Rectal (male) | 27 | 11 | 16 | 24 | 3 |
| Anal (female) | 334 | 183 | 151 | 300 | 35 |
| Anal (male) | 214 | 90 | 126 | 192 | 23 |
| Oropharyngeal (female) | 174 | 95 | 79 | 156 | 18 |
| Oropharyngeal (male) | 1029 | 429 | 601 | 922 | 107 |
| Total | 3366 | 1665 | 1704 | 3017 | 352 |
Current (2017) HPV-9 vaccination coverage was 60.9% for girls and 46.3% for boys. Coverage was adjusted for 90% vaccine efficacy.
Projected maximum HPV-9 vaccination coverage is 99.5%. Coverage was adjusted for 90% vaccine efficacy.
The difference between the number of vaccine-preventable cancer cases based on 99.5% coverage and current vaccination coverage was 1352 cases (uncertainty range: 1276–1426 cases). That is the excess number of cases due to the current moderate HPV vaccination coverage and therefore considered avoidable if vaccination coverage were to reach 99.5% (Table 3).
Table 3.
Excess number of human papillomavirus (HPV) cancer cases with current HPV-vaccination coverage, excess costs, and distribution of burden for a birth cohort of 20 year olds in California, 2017.
| Type of Cancer | Excess vaccine-preventable cancer cases due to moderate vaccination* | Distribution of excess cases | Cost per case | Excess cost of vaccine-preventable cancer cases due to moderate vaccination* | Distribution of cost |
|---|---|---|---|---|---|
| Cervical | 415 | 31% | $38,800 | $16,092,158 | 31% |
| Vaginal | 24 | 2% | $27,100 | $641,597 | 1% |
| Vulvar | 62 | 5% | $23,600 | $1,465,529 | 3% |
| Penile | 45 | 3% | $19,800 | $896,673 | 2% |
| Rectal (female) | 19 | 1% | $36,200 | $683,430 | 1% |
| Rectal (male) | 13 | 1% | $36,200 | $469,164 | 1% |
| Anal (female) | 116 | 9% | $36,200 | $4,242,615 | 8% |
| Anal (male) | 104 | 8% | $36,200 | $3,759,950 | 7% |
| Oropharyngeal (female) | 61 | 4% | $43,200 | $2,615,483 | 5% |
| Oropharyngeal (male) | 494 | 37% | $43,200 | $21,339,932 | 41% |
| Total | 1352 | 100% | N/A | $52,176,531 | 100% |
| Female | 696 | 51% | N/A | $25,710,812 | 49% |
| Male | 656 | 49% | N/A | $26,465,719 | 51% |
Moderate vaccination refers to current (2017) coverage, which was 60.9% for girls and 46.3% for boys. Coverage was adjusted for 90% vaccine efficacy.
Excess cost of cancer treatment
Figure 2 shows the excess estimated direct medical cost of treatment for HPV related cancers throughout the lifetime of the cohort. Applying the treatment cost for each excess case of cancer by type yielded a total excess cost of $52.2 million (uncertainty range: $49.2-$55.0 million). Of the excess cost, $16.1 million (31%) was due to cervical cancer and $21.3 million (41%) was due to male oropharyngeal cancer (Table 3).
Figure 2.
Excess direct medical cost of treatment for human papillomavirus related cancers throughout the lifetime of a 20 year old birth cohort in California, 2017.
Discussion
We conducted a modeling study examining the incidence of HPV-related cancers to estimate the number of excess cancer cases and associated medical costs due to current HPV vaccination coverage among a birth cohort in California. Our results reveal that with current HPV vaccination coverage, the birth cohort is at risk for excess cancer cases which would likely be preventable with increased vaccination. The benefits of increased vaccination coverage would grow with time, as HPV-related cancers often take 10 to 30 years to develop.
California urgently needs new strategies to increase vaccination coverage, in particular for adolescent males. We found that male oropharyngeal cancer would have a slightly smaller impact on the number of cancer cases among the cohort, yet would have the greatest impact on cost of treatment among the cohort. HPV oropharyngeal infections among males account for 37% of the excess estimated cancer cases and 41% of the cost burden. Cervical cancer accounts for 31% of both the excess estimated cancer cases and the cost burden.
Previous studies have predicted that rates of male oropharyngeal cancer will continue to rise, and may surpass those of cervical cancers by the year 2020 (20). In a recent study, only 14.3% of men indicated that they believed the HPV vaccine would be effective at preventing oropharyngeal cancer (21). Lack of knowledge of the HPV vaccine’s preventative benefits may lower confidence in the effectiveness of the vaccine, thus lowering the vaccination coverage among boys. Without interventions that can increase uptake of the vaccine, the low vaccination among boys, coupled with the increasing trend of new oropharyngeal cancers may add substantially to the economic and health burden of cancer in California.
The benefits of increased HPV vaccination coverage determined in our study are consistent with other studies which show a high vaccine effectiveness and large favorable impact. Markowitz et al. found a decrease in the prevalence of HPV types 6, 11, 16, and 18 among adolescents six years after the introduction of HPV vaccination (22). Others have reported a reduction in HPV 16/18-associated high grade cervical lesions following HPV vaccine introduction in the United States from 2008–2012 (23). While our model did not include the cost of the HPV vaccine, prior studies have found the vaccine cost-effective, providing substantial health and economic benefits that extend beyond state borders (7).
Our study used modeling methods that could be widely applied, an important consideration as national HPV vaccination remains suboptimal. Modeling at the population level can be complex and dynamic, therefore we restricted our model to a specific birth cohort in California for improved accuracy.
While the predicted future excess cancer cases and cost of treatment from our study are substantial, there may be sources of underestimation. The estimation of direct medical cost was reported in 2010 USD, and we did not account for inflation. We only evaluated direct medical costs from the treatment of HPV related cancers, however research suggests there are numerous additional costs associated with HPV-related cancers and precancers such as loss of productivity due to sick leave days and early retirement, with highest rates of costs among females with cervical cancer (7). Other consequences that were unaccounted for include cancer deaths, pre-cancer lesions, genital warts and quality of life. Furthermore, we only used CDC-reported cases of HPV related cancers, which likely do not capture all cases of HPV related cancers in California.
Since the efficacy of the vaccine on each HPV-related cancer type is not well studied, we estimated the efficacy of the HPV vaccine using a weighted average of reported values. Therefore, our estimated value might vary from the true efficacy of the vaccine. We also based projected maximum vaccination coverage with the 2016 medical exemption rate, which may contain sources of error or be subject to future change (19). Our model further assumed the same cost for both anal and rectal cancer which was determined from the estimated cost of treatment for anorectal cancer from Chesson et al. (14).
Additionally, we did not consider factors that could have decreased HPV rates within our cohort. For instance, although we used the vaccination rates for up-to-date HPV vaccine series as a proxy for HPV prevention, there may be potential benefits associated with receiving less than complete dosage of the vaccine. A recent study found that a single dose of quadrivalent HPV vaccine can provide a sustained immune response against HPV 16 and 18, but this immune response is inferior to that of receiving two or three doses of the vaccine (24). Besides vaccination, there are other preventative measures against HPV (e.g., condom use and cervical cancer screening) that our model did not account for. Unvaccinated individuals may also be protected from HPV-related cancers indirectly through herd immunity, which can provide significant protection (25). Therefore, the benefits from current HPV vaccination coverage may be greater than our model predicts.
While our analyses were limited to California, we would expect similar health and financial benefits for increased vaccination coverage in other states. Our findings may be used to support further analyses of the socioeconomic burden of HPV-related cancers and inform policy efforts to increase HPV vaccination coverage. One such effort might be policy changes that would require HPV vaccination for school entry.
Acknowledgements:
This study was supported in part by Team Klausner Saving Lives and National Institutes of Health: Center for AIDS Research 5P30AI028697.
Footnotes
Conflict of interest statement: The authors do not have a commercial or other association that might pose a conflict of interest.
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