REVIEW URRENT C OPINION
Current cervical cancer prevention strategies including cervical screening and prophylactic human papillomavirus vaccination: a review Klara Miriam Elfstro¨m, Eva Herweijer, Karin Sundstro¨m, and Lisen Arnheim-Dahlstro¨m
Purpose of review As screening methods evolve and human papillomavirus (HPV) vaccination efforts gain traction, knowledge of the current evidence on effectiveness of prevention methods is critical to support further development of programs. Recent findings Screening has dramatically reduced cervical cancer incidence and mortality; however, further progress could be made with implementing new screening techniques, such as HPV DNA testing. Continued focus has been given to methods such as visual inspection with acetic acid/Lugol’s iodine (VIA/VILI) and selftesting, which may provide an alternative in settings and populations wherein infrastructural challenges and logistical barriers pose challenges to achieving high screening coverage. Postlicensure studies of HPV vaccine show continued effectiveness against genital warts, the first outcome possible to measure. Of note, age-at-vaccination seems to play a pivotal role in effectiveness. Studies examining safety of the HPV vaccines could not confirm any increased risk associated with vaccination. Summary Existing cervical screening techniques are effective; however, programs should consider implementing HPV DNA testing where applicable and further process developments for alternative methods may result in improved results. The HPV vaccine is safe and effective and should be given before sexual debut to achieve maximum protection. Keywords adverse events, cervical cancer screening, effectiveness, human papillomavirus vaccination, prevention
INTRODUCTION Primary prevention of cervical cancer is now possible through the use of prophylactic vaccination against human papillomavirus (HPV) with two vaccines currently available (the bivalent Cervarix and the quadrivalent Gardasil), both of which offer protection against HPV types 16 and 18. The quadrivalent vaccine also includes HPV types 6 and 11. Secondary prevention of cervical cancer is best achieved through organized, population-based cervical screening. Countries with established cervical screening programs show significant reductions in prestages to cervical cancer (the detection and treatment of which is the main goal of such screening) and also of cervical cancer incidence and mortality [1,2]. Screening methods have evolved over the years as efforts to improve test sensitivity and specificity have continued, and programs have sought to www.co-oncology.com
provide the most efficient and definitive screening for participating women. Conventional cytology using the Papanicolaou stain, so-called Pap smears, is still the method of choice in many programs; however, some programs are now switching to liquid-based cytology (LBC) and are considering HPV DNA testing as a main screening option. Significant differences in screening method choice and recommended screening intervals exist between Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Correspondence to Lisen Arnheim Dahlstro¨m, Department of Medical Epidemiology and Biostatistics, Box 281, Karolinska Institutet, 171 77 Stockholm, Sweden. Tel: +46 8 5248 2364; fax: +46 8 31 11 01; e-mail: [email protected] Curr Opin Oncol 2014, 26:120–129 DOI:10.1097/CCO.0000000000000034 Volume 26 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Current cervical cancer prevention strategies Elfstro ¨ m et al.
KEY POINTS Screening using the conventional Pap smear has been effective, but new methods have now been thoroughly evaluated and promise further protection against cervical cancer.
&
HPV vaccination is effective at a population level and no elevated risks for serious adverse events have been confirmed.
&
countries. This review provides an overview of the current status of research on cervical cancer prevention strategies including methods for cervical screening (studies included listed in Table 1 [3 ,4 –7 , 8 ,9 ,10 ,11 ,12 ,13 ,14 ,15 ,16 ,17 ,18 ]) and HPV vaccination (Table 2 [19–21,22 ,23 ,24,25 , 26 ,27,28 ,29 ,30 ,31 ,32 ,33 ,34 – 38]). These two complementary aspects of cancer prevention have seen significant advances in recent years and hopefully herald continued gains in women’s health. &&
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CURRENT AND UPCOMING METHODS FOR CERVICAL SCREENING PROGRAMS Previous evidence from clinical trials comparing HPV testing to cytology has shown that HPV-based screening results in greater sensitivity (range 94.1– 95.4%) than cytology-based screening (range 55.4– 71.3%) with some loss in specificity for cervical intraepithelial neoplasia grade 2 or worse (CIN2þ; cytology specificity range 96.8–98.6% compared with HPV 94.1–94.2%) [39–42]. These early trials established HPV testing as a viable screening method and opened the discussion for including HPV testing in routine screening. The more recent focus has been determining recommended screening intervals and integrating HPV DNA testing into existing prevention efforts [43,44]. Questions remain regarding how to implement HPV testing most effectively: namely, whether HPV testing should be offered as a stand-alone test, how HPVpositive women should be managed clinically, and what ages would benefit the most from HPV-based screening [15 ]. Recent studies evaluating screening methods have, in general, continued along similar lines and compared methods with regard to test characteristics [sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)], detection rates, referral rates, acceptability among women, and feasibility for programs. A recent Japanese study compared LBC with conventional cytology and found that LBC had a lower sample inadequacy rate (1.4 compared with 11.5%) and a &
higher detection rate for high-grade squamous intraepithelial lesion than conventional cytology (0.6 compared to 0.3%), in accordance with much of the previous research on this topic [13 ]. Another study from Sweden compared LBC with HPV triage to conventional cytology and found similar detection rates in the two groups using outcomes CIN2þ and CIN3þ [18 ]. Regarding analysis method, a multicenter study from Europe compared the cobas HPV test with Hybrid Capture 2 and found that there was a high degree of concordance between the tests, but concluded that the ability of cobas to distinguish HPV16 and 18 may be of particular help in the clinical management of patients [11 ]. In this context, it should be noted that studies comparing HPV DNA testing with cytology have begun to diverge with regard to study design. Whereas some have followed a more traditional randomized controlled trial (RCT) format, others have been implemented through routine health services as randomized health services studies, or cohort studies [5 ,9 ,12 ,14 ,15 ]. Differences in triage sequences, comparison tests, and intervals exist between studies and highlight efforts to integrate studies into existing screening structures and address remaining evidence gaps in policy. For example, the early RCTs evaluating HPV testing used conventional cytology as the comparison test, whereas the FOCAL (HPV testing for cervical cancer screening) study in Canada has chosen to use LBC [5 ]. In either case, these studies confirm that HPV testing leads to an increased detection rate of CIN. However, they diverge somewhat with regard to whether this simply leads to overdiagnosis of potentially regressive lesions, as the Finnish randomized health services study concluded using CIN3þ as an outcome [8 ], or actual earlier detection of CIN2þ leading to a protection against CIN3þ lesions, as the final results of the Dutch POBASCAM trial concluded [14 ]. Visual inspection with acetic acid/Lugol’s iodine (VIA and VILI, a non-HPV-based screening approach) has been evaluated in low-resource settings where low-cost see-and-treat screening is an attractive approach, and evidence suggests increased detection rates of cervical cancer in some settings [45]. However, interobserver variability is a concern when evaluating VIA against the strictest endpoints [46]. Self-testing for cervicovaginal HPV has been proposed as a means to increase screening coverage and better include hard-to-reach populations, although the optimal screening tool and follow-up strategy are still under discussion [47]. A growing interest in testing for E6/E7 viral mRNA has been seen in recent years as screening programs consider HPV-based methods but aim to better risk-stratify
1040-8746 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
122
www.co-oncology.com Participants in the population-based cervical cancer screening program Randomized controlled trial
Ages 25–65 Ages 25–65 Ages 20–65 attending screening with private practice gynecologists Mean age 37 (range 16–82) Ages 25–64 Age 20
Ages 29–56
Finland [8 ]
Finland [9 ]
France – FASE study [10 ]
France, Italy, Spain [11 ]
Italy [12 ]
Japan [13 ]
The Netherlands – && POBASCAM study [14 ]
Ages 30–45 Ages 22–60
Peru – PERCAPS study [17 ]
Sweden [18 ]
Population-based cohort study
Community-based participatory research
Population-based project
Population-based cohort study
Population-based cohort study
Multicenter, convenience sample of routine screening participants
Multicenter trial
Prospective randomized trial
Randomized health services study
Population-based survey
Population-based survey
HPV, human papillomavirus; LBC, liquid-based cytology; VIA, Visual inspection with acetic acid.
&
&&
Ages 15–95
&&
Nigeria [16 ]
&&
Ages 29–61
&
&
The Netherlands – VUSA& Screen study [15 ]
&
&
&&
Ages 30–59
China [7 ]
&&
Ages 30–59
China [6 ]
&
Ages 25–65
Canada – FOCAL study [5 ]
Randomized controlled trial
Multisite, population-based cross-sectional
Ages 25–59
China – SHENCCAST II & study [4 ]
&
Cross-sectional and prospective cohort
Study design
Mean age 37.9 11.2 years
Study population
Argentina Brazil – LAMS && study [3 ]
Country
ThinPrep LBC Conventional cytology
HPV self-sampling, iFTA elute specimen cards
VIA, ThinPrep LBC, HR-HPV testing
Hybrid Capture 2, Conventional cytology
HR-HPV testing, Conventional cytology
SurePath LBC, Conventional cytology
Hybrid Capture 2, Conventional cytology
Hybrid Capture 2, cobas HPV test
Aptima, Hybrid Capture 2, ThinPrep LBC
Hybrid Capture 2, Traditional Pap-test
Hybrid Capture 2, Traditional Pap-test
VIA, VILI
VIA, VILI
Hybrid Capture 2, ThinPrep LBC
Pap test, VIA, VILI, HR-HPV testing, Cervicography, Colposcopy POI/NIH self-sampler, Conical-shaped brush, Endocervical samples
Test methods evaluated
Table 1. Screening methods studies published between 1 January 2012 and 31 July 2013
CIN2þ, CIN3þ
HR HPV test positivity, CIN2þ
Visibility of the squamocolumnar junction, Suspected cancer, Positive VIA
CIN2þ, CIN3þ
CIN2þ, CIN3þ
CIN2 CIN3, Squamous cell carcinoma
CIN2þ
HPV test positivity
CIN2þ, CIN3þ
CIN, Invasive cervical cancer
CIN3, Invasive cervical cancer
CIN1-3, Cancer
CIN1-3, Cancer
CIN2þ, CIN3þ
CIN3þ, Test positivity
CIN2þ
Outcome(s)
Detection rates, Test characteristics
Acceptability, Test turn-around time, Test results (counts)
Risk for cervical precancer, Test characteristics (sensitivity)
Cumulative risks, Test characteristics
Detection rates, Risk for cervical precancer and cancer
Detection rates, Sample adequacy
Detection rates, Referral rates, Test characteristics (PPV)
Test concordance
Absolute/relative risks, Test characteristics
Cumulative detection rates
Detection rates, Test characteristics (sensitivity), Overdiagnosis
Detection rates
Detection rates
Referral rates, Detection rates, Test characteristics (PPV)
Test characteristics
Referrals to colposcopy, Test characteristics
Effect measurements used
Cancer biology
Volume 26 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
GW
Ecological study design
Ecological study design
Ecological study design
Ecological study design
Nationwide registerbased cohort study
Nationwide registerbased cohort study
Australia [21]
Australia && [22 ]
Australia [23 ]
Australia [24]
Denmark [25 ]
1040-8746 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
Denmark && [26 ]
&
&
GW
Ecological study design
Australia [20]
GW
GW
Cervical abnormalities
GW
GW
GW
Ecological study design
Australia [19]
Outcome
Study design
Country
Table 2. Vaccine effectiveness studies
In/Outpatient hospital records
In/Outpatient hospital records
Victorian cervical cytology register
Private hospital inpatient treatments registered in Medicare; universal health insurance scheme of Australia
8 Sexual health services
Sexual health service of Melbourne
Sexual health service of Melbourne 8 Sexual health services
Data collection
Yes
No
No
No
No
No
No
No
Vaccination status
Birth cohort 1995–1996: HR¼0.12
Age 26–29; -13.1% AAPC
Age 22–25; -14.0% AAPC
Age 20–21; -14.7% AAPC
Age 18–19; -14.4% AAPC
Age 16–17; -45.3% AAPC
Age
Current cervical cancer prevention strategies including cervical screening and prophylactic human papillomavirus vaccination: a review Klara Miriam Elfstro¨m, Eva Herweijer, Karin Sundstro¨m, and Lisen Arnheim-Dahlstro¨m
Purpose of review As screening methods evolve and human papillomavirus (HPV) vaccination efforts gain traction, knowledge of the current evidence on effectiveness of prevention methods is critical to support further development of programs. Recent findings Screening has dramatically reduced cervical cancer incidence and mortality; however, further progress could be made with implementing new screening techniques, such as HPV DNA testing. Continued focus has been given to methods such as visual inspection with acetic acid/Lugol’s iodine (VIA/VILI) and selftesting, which may provide an alternative in settings and populations wherein infrastructural challenges and logistical barriers pose challenges to achieving high screening coverage. Postlicensure studies of HPV vaccine show continued effectiveness against genital warts, the first outcome possible to measure. Of note, age-at-vaccination seems to play a pivotal role in effectiveness. Studies examining safety of the HPV vaccines could not confirm any increased risk associated with vaccination. Summary Existing cervical screening techniques are effective; however, programs should consider implementing HPV DNA testing where applicable and further process developments for alternative methods may result in improved results. The HPV vaccine is safe and effective and should be given before sexual debut to achieve maximum protection. Keywords adverse events, cervical cancer screening, effectiveness, human papillomavirus vaccination, prevention
INTRODUCTION Primary prevention of cervical cancer is now possible through the use of prophylactic vaccination against human papillomavirus (HPV) with two vaccines currently available (the bivalent Cervarix and the quadrivalent Gardasil), both of which offer protection against HPV types 16 and 18. The quadrivalent vaccine also includes HPV types 6 and 11. Secondary prevention of cervical cancer is best achieved through organized, population-based cervical screening. Countries with established cervical screening programs show significant reductions in prestages to cervical cancer (the detection and treatment of which is the main goal of such screening) and also of cervical cancer incidence and mortality [1,2]. Screening methods have evolved over the years as efforts to improve test sensitivity and specificity have continued, and programs have sought to www.co-oncology.com
provide the most efficient and definitive screening for participating women. Conventional cytology using the Papanicolaou stain, so-called Pap smears, is still the method of choice in many programs; however, some programs are now switching to liquid-based cytology (LBC) and are considering HPV DNA testing as a main screening option. Significant differences in screening method choice and recommended screening intervals exist between Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Correspondence to Lisen Arnheim Dahlstro¨m, Department of Medical Epidemiology and Biostatistics, Box 281, Karolinska Institutet, 171 77 Stockholm, Sweden. Tel: +46 8 5248 2364; fax: +46 8 31 11 01; e-mail: [email protected] Curr Opin Oncol 2014, 26:120–129 DOI:10.1097/CCO.0000000000000034 Volume 26 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Current cervical cancer prevention strategies Elfstro ¨ m et al.
KEY POINTS Screening using the conventional Pap smear has been effective, but new methods have now been thoroughly evaluated and promise further protection against cervical cancer.
&
HPV vaccination is effective at a population level and no elevated risks for serious adverse events have been confirmed.
&
countries. This review provides an overview of the current status of research on cervical cancer prevention strategies including methods for cervical screening (studies included listed in Table 1 [3 ,4 –7 , 8 ,9 ,10 ,11 ,12 ,13 ,14 ,15 ,16 ,17 ,18 ]) and HPV vaccination (Table 2 [19–21,22 ,23 ,24,25 , 26 ,27,28 ,29 ,30 ,31 ,32 ,33 ,34 – 38]). These two complementary aspects of cancer prevention have seen significant advances in recent years and hopefully herald continued gains in women’s health. &&
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&&
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CURRENT AND UPCOMING METHODS FOR CERVICAL SCREENING PROGRAMS Previous evidence from clinical trials comparing HPV testing to cytology has shown that HPV-based screening results in greater sensitivity (range 94.1– 95.4%) than cytology-based screening (range 55.4– 71.3%) with some loss in specificity for cervical intraepithelial neoplasia grade 2 or worse (CIN2þ; cytology specificity range 96.8–98.6% compared with HPV 94.1–94.2%) [39–42]. These early trials established HPV testing as a viable screening method and opened the discussion for including HPV testing in routine screening. The more recent focus has been determining recommended screening intervals and integrating HPV DNA testing into existing prevention efforts [43,44]. Questions remain regarding how to implement HPV testing most effectively: namely, whether HPV testing should be offered as a stand-alone test, how HPVpositive women should be managed clinically, and what ages would benefit the most from HPV-based screening [15 ]. Recent studies evaluating screening methods have, in general, continued along similar lines and compared methods with regard to test characteristics [sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)], detection rates, referral rates, acceptability among women, and feasibility for programs. A recent Japanese study compared LBC with conventional cytology and found that LBC had a lower sample inadequacy rate (1.4 compared with 11.5%) and a &
higher detection rate for high-grade squamous intraepithelial lesion than conventional cytology (0.6 compared to 0.3%), in accordance with much of the previous research on this topic [13 ]. Another study from Sweden compared LBC with HPV triage to conventional cytology and found similar detection rates in the two groups using outcomes CIN2þ and CIN3þ [18 ]. Regarding analysis method, a multicenter study from Europe compared the cobas HPV test with Hybrid Capture 2 and found that there was a high degree of concordance between the tests, but concluded that the ability of cobas to distinguish HPV16 and 18 may be of particular help in the clinical management of patients [11 ]. In this context, it should be noted that studies comparing HPV DNA testing with cytology have begun to diverge with regard to study design. Whereas some have followed a more traditional randomized controlled trial (RCT) format, others have been implemented through routine health services as randomized health services studies, or cohort studies [5 ,9 ,12 ,14 ,15 ]. Differences in triage sequences, comparison tests, and intervals exist between studies and highlight efforts to integrate studies into existing screening structures and address remaining evidence gaps in policy. For example, the early RCTs evaluating HPV testing used conventional cytology as the comparison test, whereas the FOCAL (HPV testing for cervical cancer screening) study in Canada has chosen to use LBC [5 ]. In either case, these studies confirm that HPV testing leads to an increased detection rate of CIN. However, they diverge somewhat with regard to whether this simply leads to overdiagnosis of potentially regressive lesions, as the Finnish randomized health services study concluded using CIN3þ as an outcome [8 ], or actual earlier detection of CIN2þ leading to a protection against CIN3þ lesions, as the final results of the Dutch POBASCAM trial concluded [14 ]. Visual inspection with acetic acid/Lugol’s iodine (VIA and VILI, a non-HPV-based screening approach) has been evaluated in low-resource settings where low-cost see-and-treat screening is an attractive approach, and evidence suggests increased detection rates of cervical cancer in some settings [45]. However, interobserver variability is a concern when evaluating VIA against the strictest endpoints [46]. Self-testing for cervicovaginal HPV has been proposed as a means to increase screening coverage and better include hard-to-reach populations, although the optimal screening tool and follow-up strategy are still under discussion [47]. A growing interest in testing for E6/E7 viral mRNA has been seen in recent years as screening programs consider HPV-based methods but aim to better risk-stratify
1040-8746 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
122
www.co-oncology.com Participants in the population-based cervical cancer screening program Randomized controlled trial
Ages 25–65 Ages 25–65 Ages 20–65 attending screening with private practice gynecologists Mean age 37 (range 16–82) Ages 25–64 Age 20
Ages 29–56
Finland [8 ]
Finland [9 ]
France – FASE study [10 ]
France, Italy, Spain [11 ]
Italy [12 ]
Japan [13 ]
The Netherlands – && POBASCAM study [14 ]
Ages 30–45 Ages 22–60
Peru – PERCAPS study [17 ]
Sweden [18 ]
Population-based cohort study
Community-based participatory research
Population-based project
Population-based cohort study
Population-based cohort study
Multicenter, convenience sample of routine screening participants
Multicenter trial
Prospective randomized trial
Randomized health services study
Population-based survey
Population-based survey
HPV, human papillomavirus; LBC, liquid-based cytology; VIA, Visual inspection with acetic acid.
&
&&
Ages 15–95
&&
Nigeria [16 ]
&&
Ages 29–61
&
&
The Netherlands – VUSA& Screen study [15 ]
&
&
&&
Ages 30–59
China [7 ]
&&
Ages 30–59
China [6 ]
&
Ages 25–65
Canada – FOCAL study [5 ]
Randomized controlled trial
Multisite, population-based cross-sectional
Ages 25–59
China – SHENCCAST II & study [4 ]
&
Cross-sectional and prospective cohort
Study design
Mean age 37.9 11.2 years
Study population
Argentina Brazil – LAMS && study [3 ]
Country
ThinPrep LBC Conventional cytology
HPV self-sampling, iFTA elute specimen cards
VIA, ThinPrep LBC, HR-HPV testing
Hybrid Capture 2, Conventional cytology
HR-HPV testing, Conventional cytology
SurePath LBC, Conventional cytology
Hybrid Capture 2, Conventional cytology
Hybrid Capture 2, cobas HPV test
Aptima, Hybrid Capture 2, ThinPrep LBC
Hybrid Capture 2, Traditional Pap-test
Hybrid Capture 2, Traditional Pap-test
VIA, VILI
VIA, VILI
Hybrid Capture 2, ThinPrep LBC
Pap test, VIA, VILI, HR-HPV testing, Cervicography, Colposcopy POI/NIH self-sampler, Conical-shaped brush, Endocervical samples
Test methods evaluated
Table 1. Screening methods studies published between 1 January 2012 and 31 July 2013
CIN2þ, CIN3þ
HR HPV test positivity, CIN2þ
Visibility of the squamocolumnar junction, Suspected cancer, Positive VIA
CIN2þ, CIN3þ
CIN2þ, CIN3þ
CIN2 CIN3, Squamous cell carcinoma
CIN2þ
HPV test positivity
CIN2þ, CIN3þ
CIN, Invasive cervical cancer
CIN3, Invasive cervical cancer
CIN1-3, Cancer
CIN1-3, Cancer
CIN2þ, CIN3þ
CIN3þ, Test positivity
CIN2þ
Outcome(s)
Detection rates, Test characteristics
Acceptability, Test turn-around time, Test results (counts)
Risk for cervical precancer, Test characteristics (sensitivity)
Cumulative risks, Test characteristics
Detection rates, Risk for cervical precancer and cancer
Detection rates, Sample adequacy
Detection rates, Referral rates, Test characteristics (PPV)
Test concordance
Absolute/relative risks, Test characteristics
Cumulative detection rates
Detection rates, Test characteristics (sensitivity), Overdiagnosis
Detection rates
Detection rates
Referral rates, Detection rates, Test characteristics (PPV)
Test characteristics
Referrals to colposcopy, Test characteristics
Effect measurements used
Cancer biology
Volume 26 Number 1 January 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
GW
Ecological study design
Ecological study design
Ecological study design
Ecological study design
Nationwide registerbased cohort study
Nationwide registerbased cohort study
Australia [21]
Australia && [22 ]
Australia [23 ]
Australia [24]
Denmark [25 ]
1040-8746 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
Denmark && [26 ]
&
&
GW
Ecological study design
Australia [20]
GW
GW
Cervical abnormalities
GW
GW
GW
Ecological study design
Australia [19]
Outcome
Study design
Country
Table 2. Vaccine effectiveness studies
In/Outpatient hospital records
In/Outpatient hospital records
Victorian cervical cytology register
Private hospital inpatient treatments registered in Medicare; universal health insurance scheme of Australia
8 Sexual health services
Sexual health service of Melbourne
Sexual health service of Melbourne 8 Sexual health services
Data collection
Yes
No
No
No
No
No
No
No
Vaccination status
Birth cohort 1995–1996: HR¼0.12
Age 26–29; -13.1% AAPC
Age 22–25; -14.0% AAPC
Age 20–21; -14.7% AAPC
Age 18–19; -14.4% AAPC
Age 16–17; -45.3% AAPC
Age
