Note Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Jeffrey J. VanWormer,1 Allen C. Bateman,2,3 Stephanie A. Irving,4 Burney A. Kieke,1 David K. Shay,5 and Edward A. Belongia1 1
Marshfield Clinic Research Foundation, Marshfield, Wisconsin; 2Centre for Infectious Disease Research, Lusaka, Zambia; 3University of North Carolina, Chapel Hill; 4Kaiser Permanente Center for Health Research, Portland, Oregon; and 5Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia
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References 1. Bateman AC, Kieke BA, Irving SA, Meece JK, Shay DK, Belongia EA. Effectiveness of monovalent 2009 pandemic influenza A virus subtype H1N1 and 2010–2011 trivalent inactivated influenza vaccines in Wisconsin during the 2010–2011 influenza season. J Infect Dis 2013; 207:1262–9. 2. Fedson DS. Vaccination effectiveness, unmeasured confounding, and immunomodulatory treatment. J Infect Dis 2014; 209:1300–1. 3. Irving SA, Donahue JG, Shay DK, Ellis-Coyle TLBelongia EA. Evaluation of self-reported and registry-based influenza vaccination status in a Wisconsin cohort. Vaccine 2009; 27: 6546–9. 4. Belongia EA, Kieke BA, Donahue JG, et al. Effectiveness of inactivated influenza vaccines varied substantially with antigenic match from the 2004–2005 season to the 2006– 2007 season. J Infect Dis 2009; 199:159–167. 5. Belongia EA, Irving SA, Waring SC, et al. Clinical characteristics and 30-day outcomes for influenza A 2009 (H1N1), 2008–2009 (H1N1), and 2007–2008 (H3N2) infections. JAMA 2010; 304:1091–8. 6. Belongia EA, Kieke BA, Donahue JG, et al. Influenza vaccine effectiveness in Wisconsin during the 2007–08 season: comparison of interim and final results. Vaccine 2011; 29: 6558–63. 7. Fleming DM, Verlander NQ, Elliot AJ, et al. An assessment of the effect of statin use on the incidence of acute respiratory infections in England during winters 1998–1999 to 2005– 2006. Epidemiol Infect 2010; 138:1281–8. 8. Smeeth L, Douglas I, Hall AJ, Hubbard R, Evans S. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br J Clin Pharmacol 2009; 67:99–109. 9. Foppa IM, Haber M, Ferdinands JM, Shay DK. The case test-negative design for studies of the effectiveness of influenza vaccine. Vaccine 2013; 31:3104–9. 10. Jackson ML, Nelson JC. The test-negative design for estimating influenza vaccine effectiveness. Vaccine 2013; 31:2165–8. 11. De Serres G, Skowronski D, Wu X, Ambrose C. The test-negative design: validity, accuracy and precision of vaccine efficacy estimates compared to the gold standard of randomised placebo-controlled clinical trials. Euro Surveill 2013 Sep 12;18(37). pii: 20585. PubMed PMID: 24079398. Received 22 November 2013; accepted 26 November 2013; electronically published 15 December 2013. Correspondence: Edward A. Belongia, MD, Epidemiology Research Center (ML2), Marshfield Clinic Research Foundation, 1000 N Oak Ave, Marshfield, WI 54449 (belongia. edward@marshfieldclinic.org). The Journal of Infectious Diseases 2014;209:1301–2 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit810
CORRESPONDENCE
Reduction in HPV Prevalence— No Evidence to Support HPV Vaccination reduces HPV Prevalence TO THE EDITOR—The recent Centers for Disease Control and Prevention (CDC) study by Markowitz et al [1] provides limited and inconclusive data on 111 sexually active females between 14 and 19 years of age who received at least 1 dose of quadrivalent human papillomavirus vaccine (HPV4). The broad ranging conclusions are inconsistent with current knowledge about risk factors for HPV infection and HPV prevalence among US adolescents, herd immunity, and vaccine efficacy evaluation with fewer than 3 doses. The single most important risk factor for HPV infection, after human immunodeficiency virus (HIV) infection, is number of lifetime sexual partners [2]. Markowitz’s study aligns with this knowledge by showing for the 2007– 2010 ( postvaccination) time frame, a 4fold increase in HPV prevalence among sexually active 14–19-year olds who have 3 or more lifetime sexual partners compared to those with fewer than 3 partners. However, the study reports an adolescent cohort composed of twice as many adolescents who are both unvaccinated and minimally sexually active (hence, likely to have a low prevalence of HPV infection) as are vaccinated and highly sexually active. Combining these 2 groups lowers the overall reported postvaccination HPV prevalence leading to the false conclusion that vaccination lowered the HPV prevalence rates. Reducing sexual activity is a potent prevention strategy for reducing HPV prevalence. Another recent CDC report indicates that 73% of 15–17 year-old females in the postvaccination era have not initiated sexual activity [3]. Indeed, condom use is also proven to reduce HPV infection rates. Other significant successes reported by the CDC among adolescents in this same postvaccination time frame include an increased use of condoms, a decrease in the overall number of
Downloaded from http://jid.oxfordjournals.org/ at Bibliothekssystem der Universitaet Giessen on June 11, 2015
vaccine effectiveness under most realworld assumptions [9–11]. In particular, a re-analysis of data from 4 randomized clinical trials (RCTs) found that efficacy estimates and confidence intervals for the gold standard RCT analysis and the alternative TND analysis were virtually identical [11]. Other than age, confounding variables have been notably absent in most vaccine effectiveness studies using the TND. Medication confounding may be more plausible in older age groups, but only 10% of participants in the study by Bateman et al [1] were elderly. Our vaccine effectiveness studies adjusted for age, high-risk conditions, and calendar time of illness onset, and the unadjusted and adjusted vaccine effectiveness estimates are often quite similar. This does not rule out unmeasured confounding, but it does suggest that the TND has lower potential for confounding, compared with studies using nonspecific end points. We support Fedson’s suggestion that further research is needed regarding the potential impact of statins on the severity of respiratory infections, including those caused by influenza virus, other viruses, and bacteria. However, it is important to recognize that statin use is unlikely to affect the validity of influenza vaccine effectiveness estimates using the TND. We plan to specifically examine the relationship between statin use and influenza among patients who have been enrolled in prior vaccine effectiveness studies at Marshfield Clinic.
Table 1.
HPV Prevalence Reported in Two CDC Studies
HPV Prevalence Among Sexually Active 14–19 y Olds (%, 95% Confidence Interval)
Any HPV
HPV Prevalence Among All 14–19 y Olds Including Those not Reporting any Sexual Activity (%, 95% Confidence Interval)
Prevaccine [8]
Prevaccine [1]
Postvaccine [1]
Prevaccine [8]
Prevaccine [1]
Postvaccine [1]
2003–2004 N < 652
2003–2006 N = 736
2007–2010 N = 358
2003–2004 N = 652
2003–2006 N = 1363
2007–2010 N = 740
39.6 (32.9, 47.8)
53.1 (48.9, 57.2)
42.9 (36.2, 49.9)
24.5 (19.6, 30.5)
32.9 (29.5, 36.4)
26.1 (22.4, 30.2)
Abbreviations: CDC, Centers for Disease Control and Prevention; HPV, human papillomavirus.
4-year prevaccination cohort has a significantly higher prevalence of any HPV among both sexually active adolescents (53.1% vs. 39.6%) and among all adolescents regardless of sexual activity (32.9% vs. 24.5%). These data inconsistencies indicate that the reported decrease in HPV prevalence is suspect at best. In addition, to celebrate HPV4 efficacy with fewer than 3 doses is premature and unsupported in this study. Although there are efficacy data for only 1 dose of HPV2, there are no HPV4 efficacy studies of 5 years or longer with fewer than 3 doses. The HPV4 published studies to date use antibody titers as the surrogate endpoint for efficacy [9], an unsupported endpoint as there is no immunologic surrogate of protection yet identified. The antibody studies indicate that over 5 years, 32% of females having received 3 doses will no longer have detectable HPV 18 antibodies [10]. The supplementary table of Markowitz’s study indeed shows that there is no difference in HPV 18 prevalence rates between the pre- and postvaccination time frames, supporting the lack of long-term efficacy for HPV 18 protection. Finally, the self-sampling methodology is a point for further exploration, as it is well documented that vulvar swabbing will result in a significantly lower prevalence of HPV than vaginal swabbing [11]. How well these adolescents were able to self-swab must be quality controlled for future studies. The only supportable conclusion from this work is that the many sexually active adolescents are receiving at least 1 dose of HPV4.
Note Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed
Jennifer A. Groner,1 George D. Harris,2 and Diane M. Harper3,4,5 1
Assistant Professor of Medicine, Department of Community and Family Medicine, UMKC School of Medicine, 2Professor of Medicine, Assistant Dean, Department of Community and Family Medicine, UMKC School of Medicine, 3Professor of Medicine, Department of Community and Family Medicine, 4 Department of Obstetrics and Gynecology and 5 Department of Biomedical and Health Informatics, UMKC School of Medicine
References 1. Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, national health and nutrition examination surveys, 2003–2010. J Infect Dis 2013; 208: 385–93. 2. Burchell AN, Tellier PP, Hanley J, Coutlée F, Franco EL. Influence of partner’s infection status on prevalent human papillomavirus among persons with a new sex partner. Sex Transm Dis 2010; 37:34–40. 3. Centers for Disease Control and Prevention. Sexual experience and contraceptive use among female teens—United States, 1995, 2002, and 2006–2010. MMWR 2012; 61:297–301. 4. Centers for Disease Control and Prevention (CDC). Trends in HIV-related risk behaviors among high school students—United States, 1991–2011. MMWR 2012; 61:556–60. 5. Hamilton BE, Hoyert DL, Martin JA, Strobino DM, Guyer B. Annual summary of vital statistics: 2010–2011. Pediatrics 2013; 131: 548–58. 6. Harper DM, Groner JA, Griffith RS, Harper WH. RE: Annual report to the nation on the status of cancer, 1975–2009, featuring the
CORRESPONDENCE
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sexual partners during adolescence, and a large decrease in the number of teenage pregnancies [4, 5]. In addition, adolescent sexual mating has been defined as an assortative mixing pattern, where males are twice as likely to be cutpoints as females [6]. This means that vaccination of males, not females, is more likely to interrupt HPV transmission (and provide herd immunity) among females in the short term. Herd immunity is an unlikely scenario as the proportion of males receiving 3 HPV4 doses in the United States is reported to be only 6% [7]. Therefore, the decrease in HPV prevalence reported in the Markowitz study is less likely due to HPV vaccination than due to adolescent sexual behavioral changes. Similarly there are inconsistencies in the prevaccination HPV prevalence reported by Markowitz. Prevalence of any HPV type during the prevaccination time frame 2003–2004 among 14–19-year-old adolescents is reported by the same group of researchers [8] and does not differ from the postvaccination rates contrary to what was reported in Markowitz’s study (Table 1). The 2003–2004 prevaccination cohort includes 652 adolescents 14–19 years old. The prevalence of any HPV among those sexually active was 39.6%; this rate significantly falls to 24.5% when adolescents who report no sexual activity are included. The Markowitz study adds 2 years to the prevaccination cohort (2003–2006), reporting on a total of 736 adolescents, 84 more subjects than in the 2003–2004 cohort. Compared with the 2003–2004 cohort, the
7.
8.
9.
11.
Received 2 July 2013; accepted 16 December 2013; electronically published 23 December 2013. This work has not been presented at a conference. Correspondence: Diane M Harper, MD, MPH, MS, Professor and Chair, University of Louisville School of Medicine, 501 East Broadway, Louisville, KY 40202 (diane.harper@louisville. edu). The Journal of Infectious Diseases 2014;209:1302–4 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit836
Previous History and Cigarette Smoking as Interfering Factors for the Effect of Vaccine on Human Papillomavirus Infection TO THE EDITOR—We have read with great interest the news and views in the article “Reduction in Human Papillomavirus (HPV) Prevalence Among Young Women Following HPV Vaccine Introduction in the United States, National Health and Nutrition Examination Surveys, 2003– 2010” [1]. This article pointed out a remarkable reduction in the prevalence of human papillomavirus (HPV) due to HPV vaccine introduction. However, it is unclear why the vaccine only protected female subjects aged 14–19 years but failed to bring benefit to subjects with older ages. As is stated in the article, most Americans are infected with HPV in their 1304
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late teens and early twenties. Unfortunately, the HPV infection status of each interviewed subject was not screened before the vaccine introduction; thus we cannot exclude the possibility that the nonsignificant protection in females more than 20 years old results from a preexisting history of HPV infection. Furthermore, it is well known that nicotine (a major component of cigarette smoking) exerts strong suppressive effects on the immune system and increases the risk of various virus infections [2]. Substantial evidences have demonstrated the ability of nicotine to increase virus infection rate via enhancing the proliferation of cancer cells or stem cells [3, 4]. In addition, cigarette smoking has been linked to increased HPV DNA load [5], a strong indicator of higher risk of cervical cancer [6]. Therefore, it is important to investigate whether the observed discrepancy in vaccine efficacy among groups with different ages is associated with specific behaviors, such as cigarette smoking. Though the report of HPV vaccine has revealed encouraging result for teenagers, to confirm the conclusion and more importantly to guarantee a better protection, the previous history of HPV infection and cigarette smoking, as well as other interfering factors, should be included into the interview questionnaire and statistical analysis. Notes Financial support. This work was supported by the National Basic Research Program (973 Program; grant 9732013CB531200) and Chinese National Science Funds (grants 81070676 and 81170186). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Haifeng Pei,1 Qiujun Yu,1 Qiang Xue,1 Feipeng Wei,2 and Ling Tao1 1
Department of Cardiology, Xijing Hospital, and 2 Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
CORRESPONDENCE
References 1. Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003–2010. J Infect Dis 2013; 208:385–93. 2. Sopori M. Effects of cigarette smoke on the immune system. Nat Rev Immunol 2002; 2: 372–7. 3. Roman J, Koval M. Control of lung epithelial growth by a nicotinic acetylcholine receptor: the other side of the coin. Am J Pathol 2009; 175:1799–801. 4. Yu J, Huang NF, Wilson KD, et al. nAChRs mediate human embryonic stem cell-derived endothelial cells: proliferation, apoptosis, and angiogenesis. PLoS One 2009; 4:e7040. 5. Xi LF, Koutsky LA, Castle PE, et al. Relationship between cigarette smoking and human papilloma virus types 16 and 18 DNA load. Cancer Epidemiol Biomarkers Prev 2009; 18: 3490–6. 6. Cigarette smoking linked to increased human papillomavirus DNA load. CA Cancer J Clin 2010; 60:137–8. Received 13 November 2013; accepted 16 December 2013; electronically published 23 December 2013. Correspondence: Ling Tao, MD, PhD, Professor and Vice Chief, Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Rd, Xi’an 710032, China ([email protected]) The Journal of Infectious Diseases 2014;209:1304 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit837
Reply to Groner et al and Pei et al TO THE EDITOR—The comments from Groner and colleagues relating to human papillomavirus (HPV) DNA prevalence among 14–19 year olds in the prevaccine and vaccine eras [1] reflect their profound misunderstanding of the data that we would like to correct. Prevaccine era HPV data from the National Health and Nutrition Examination Surveys (NHANES) 2003–2004 were first published based on a less sensitive HPV assay than the one we currently use [2]. We subsequently documented the impact of an assay change [3] and published updated data on HPV prevalence from NHANES 2003– 2006 in order to be able to monitor HPV prevalence trends [4]. The data in our recent article, showing a decline in vaccine type HPV prevalence after vaccine
Downloaded from http://jid.oxfordjournals.org/ at Bibliothekssystem der Universitaet Giessen on June 11, 2015
10.
burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels and RE: inequalities in human papillomavirus (HPV)-associated cancers: implications for the success of HPV vaccination. J Natl Cancer Inst 2013; 105:749–50. Centers for Disease Control and Prevention (CDC). National and state vaccination coverage among adolescents aged 13–17 years— United States. 2011. MMWR 2012; 34:671–7. Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA 2007; 297:813–9. Dobson SR, McNeil S, Dionne M, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA 2013; 309:1793–802. Harper DM, Vierthaler SL, Santee JA. Review of gardasil. J Vaccines Vaccin 2010; 1. doi:pii: 1000107. Forman D, de Martel C, Lacey CJ, et al. Global burden of human papillomavirus and related diseases. Vaccine 2012; 30(Suppl 5): F12–23.
Marshfield Clinic Research Foundation, Marshfield, Wisconsin; 2Centre for Infectious Disease Research, Lusaka, Zambia; 3University of North Carolina, Chapel Hill; 4Kaiser Permanente Center for Health Research, Portland, Oregon; and 5Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia
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References 1. Bateman AC, Kieke BA, Irving SA, Meece JK, Shay DK, Belongia EA. Effectiveness of monovalent 2009 pandemic influenza A virus subtype H1N1 and 2010–2011 trivalent inactivated influenza vaccines in Wisconsin during the 2010–2011 influenza season. J Infect Dis 2013; 207:1262–9. 2. Fedson DS. Vaccination effectiveness, unmeasured confounding, and immunomodulatory treatment. J Infect Dis 2014; 209:1300–1. 3. Irving SA, Donahue JG, Shay DK, Ellis-Coyle TLBelongia EA. Evaluation of self-reported and registry-based influenza vaccination status in a Wisconsin cohort. Vaccine 2009; 27: 6546–9. 4. Belongia EA, Kieke BA, Donahue JG, et al. Effectiveness of inactivated influenza vaccines varied substantially with antigenic match from the 2004–2005 season to the 2006– 2007 season. J Infect Dis 2009; 199:159–167. 5. Belongia EA, Irving SA, Waring SC, et al. Clinical characteristics and 30-day outcomes for influenza A 2009 (H1N1), 2008–2009 (H1N1), and 2007–2008 (H3N2) infections. JAMA 2010; 304:1091–8. 6. Belongia EA, Kieke BA, Donahue JG, et al. Influenza vaccine effectiveness in Wisconsin during the 2007–08 season: comparison of interim and final results. Vaccine 2011; 29: 6558–63. 7. Fleming DM, Verlander NQ, Elliot AJ, et al. An assessment of the effect of statin use on the incidence of acute respiratory infections in England during winters 1998–1999 to 2005– 2006. Epidemiol Infect 2010; 138:1281–8. 8. Smeeth L, Douglas I, Hall AJ, Hubbard R, Evans S. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br J Clin Pharmacol 2009; 67:99–109. 9. Foppa IM, Haber M, Ferdinands JM, Shay DK. The case test-negative design for studies of the effectiveness of influenza vaccine. Vaccine 2013; 31:3104–9. 10. Jackson ML, Nelson JC. The test-negative design for estimating influenza vaccine effectiveness. Vaccine 2013; 31:2165–8. 11. De Serres G, Skowronski D, Wu X, Ambrose C. The test-negative design: validity, accuracy and precision of vaccine efficacy estimates compared to the gold standard of randomised placebo-controlled clinical trials. Euro Surveill 2013 Sep 12;18(37). pii: 20585. PubMed PMID: 24079398. Received 22 November 2013; accepted 26 November 2013; electronically published 15 December 2013. Correspondence: Edward A. Belongia, MD, Epidemiology Research Center (ML2), Marshfield Clinic Research Foundation, 1000 N Oak Ave, Marshfield, WI 54449 (belongia. edward@marshfieldclinic.org). The Journal of Infectious Diseases 2014;209:1301–2 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit810
CORRESPONDENCE
Reduction in HPV Prevalence— No Evidence to Support HPV Vaccination reduces HPV Prevalence TO THE EDITOR—The recent Centers for Disease Control and Prevention (CDC) study by Markowitz et al [1] provides limited and inconclusive data on 111 sexually active females between 14 and 19 years of age who received at least 1 dose of quadrivalent human papillomavirus vaccine (HPV4). The broad ranging conclusions are inconsistent with current knowledge about risk factors for HPV infection and HPV prevalence among US adolescents, herd immunity, and vaccine efficacy evaluation with fewer than 3 doses. The single most important risk factor for HPV infection, after human immunodeficiency virus (HIV) infection, is number of lifetime sexual partners [2]. Markowitz’s study aligns with this knowledge by showing for the 2007– 2010 ( postvaccination) time frame, a 4fold increase in HPV prevalence among sexually active 14–19-year olds who have 3 or more lifetime sexual partners compared to those with fewer than 3 partners. However, the study reports an adolescent cohort composed of twice as many adolescents who are both unvaccinated and minimally sexually active (hence, likely to have a low prevalence of HPV infection) as are vaccinated and highly sexually active. Combining these 2 groups lowers the overall reported postvaccination HPV prevalence leading to the false conclusion that vaccination lowered the HPV prevalence rates. Reducing sexual activity is a potent prevention strategy for reducing HPV prevalence. Another recent CDC report indicates that 73% of 15–17 year-old females in the postvaccination era have not initiated sexual activity [3]. Indeed, condom use is also proven to reduce HPV infection rates. Other significant successes reported by the CDC among adolescents in this same postvaccination time frame include an increased use of condoms, a decrease in the overall number of
Downloaded from http://jid.oxfordjournals.org/ at Bibliothekssystem der Universitaet Giessen on June 11, 2015
vaccine effectiveness under most realworld assumptions [9–11]. In particular, a re-analysis of data from 4 randomized clinical trials (RCTs) found that efficacy estimates and confidence intervals for the gold standard RCT analysis and the alternative TND analysis were virtually identical [11]. Other than age, confounding variables have been notably absent in most vaccine effectiveness studies using the TND. Medication confounding may be more plausible in older age groups, but only 10% of participants in the study by Bateman et al [1] were elderly. Our vaccine effectiveness studies adjusted for age, high-risk conditions, and calendar time of illness onset, and the unadjusted and adjusted vaccine effectiveness estimates are often quite similar. This does not rule out unmeasured confounding, but it does suggest that the TND has lower potential for confounding, compared with studies using nonspecific end points. We support Fedson’s suggestion that further research is needed regarding the potential impact of statins on the severity of respiratory infections, including those caused by influenza virus, other viruses, and bacteria. However, it is important to recognize that statin use is unlikely to affect the validity of influenza vaccine effectiveness estimates using the TND. We plan to specifically examine the relationship between statin use and influenza among patients who have been enrolled in prior vaccine effectiveness studies at Marshfield Clinic.
Table 1.
HPV Prevalence Reported in Two CDC Studies
HPV Prevalence Among Sexually Active 14–19 y Olds (%, 95% Confidence Interval)
Any HPV
HPV Prevalence Among All 14–19 y Olds Including Those not Reporting any Sexual Activity (%, 95% Confidence Interval)
Prevaccine [8]
Prevaccine [1]
Postvaccine [1]
Prevaccine [8]
Prevaccine [1]
Postvaccine [1]
2003–2004 N < 652
2003–2006 N = 736
2007–2010 N = 358
2003–2004 N = 652
2003–2006 N = 1363
2007–2010 N = 740
39.6 (32.9, 47.8)
53.1 (48.9, 57.2)
42.9 (36.2, 49.9)
24.5 (19.6, 30.5)
32.9 (29.5, 36.4)
26.1 (22.4, 30.2)
Abbreviations: CDC, Centers for Disease Control and Prevention; HPV, human papillomavirus.
4-year prevaccination cohort has a significantly higher prevalence of any HPV among both sexually active adolescents (53.1% vs. 39.6%) and among all adolescents regardless of sexual activity (32.9% vs. 24.5%). These data inconsistencies indicate that the reported decrease in HPV prevalence is suspect at best. In addition, to celebrate HPV4 efficacy with fewer than 3 doses is premature and unsupported in this study. Although there are efficacy data for only 1 dose of HPV2, there are no HPV4 efficacy studies of 5 years or longer with fewer than 3 doses. The HPV4 published studies to date use antibody titers as the surrogate endpoint for efficacy [9], an unsupported endpoint as there is no immunologic surrogate of protection yet identified. The antibody studies indicate that over 5 years, 32% of females having received 3 doses will no longer have detectable HPV 18 antibodies [10]. The supplementary table of Markowitz’s study indeed shows that there is no difference in HPV 18 prevalence rates between the pre- and postvaccination time frames, supporting the lack of long-term efficacy for HPV 18 protection. Finally, the self-sampling methodology is a point for further exploration, as it is well documented that vulvar swabbing will result in a significantly lower prevalence of HPV than vaginal swabbing [11]. How well these adolescents were able to self-swab must be quality controlled for future studies. The only supportable conclusion from this work is that the many sexually active adolescents are receiving at least 1 dose of HPV4.
Note Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed
Jennifer A. Groner,1 George D. Harris,2 and Diane M. Harper3,4,5 1
Assistant Professor of Medicine, Department of Community and Family Medicine, UMKC School of Medicine, 2Professor of Medicine, Assistant Dean, Department of Community and Family Medicine, UMKC School of Medicine, 3Professor of Medicine, Department of Community and Family Medicine, 4 Department of Obstetrics and Gynecology and 5 Department of Biomedical and Health Informatics, UMKC School of Medicine
References 1. Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, national health and nutrition examination surveys, 2003–2010. J Infect Dis 2013; 208: 385–93. 2. Burchell AN, Tellier PP, Hanley J, Coutlée F, Franco EL. Influence of partner’s infection status on prevalent human papillomavirus among persons with a new sex partner. Sex Transm Dis 2010; 37:34–40. 3. Centers for Disease Control and Prevention. Sexual experience and contraceptive use among female teens—United States, 1995, 2002, and 2006–2010. MMWR 2012; 61:297–301. 4. Centers for Disease Control and Prevention (CDC). Trends in HIV-related risk behaviors among high school students—United States, 1991–2011. MMWR 2012; 61:556–60. 5. Hamilton BE, Hoyert DL, Martin JA, Strobino DM, Guyer B. Annual summary of vital statistics: 2010–2011. Pediatrics 2013; 131: 548–58. 6. Harper DM, Groner JA, Griffith RS, Harper WH. RE: Annual report to the nation on the status of cancer, 1975–2009, featuring the
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Downloaded from http://jid.oxfordjournals.org/ at Bibliothekssystem der Universitaet Giessen on June 11, 2015
sexual partners during adolescence, and a large decrease in the number of teenage pregnancies [4, 5]. In addition, adolescent sexual mating has been defined as an assortative mixing pattern, where males are twice as likely to be cutpoints as females [6]. This means that vaccination of males, not females, is more likely to interrupt HPV transmission (and provide herd immunity) among females in the short term. Herd immunity is an unlikely scenario as the proportion of males receiving 3 HPV4 doses in the United States is reported to be only 6% [7]. Therefore, the decrease in HPV prevalence reported in the Markowitz study is less likely due to HPV vaccination than due to adolescent sexual behavioral changes. Similarly there are inconsistencies in the prevaccination HPV prevalence reported by Markowitz. Prevalence of any HPV type during the prevaccination time frame 2003–2004 among 14–19-year-old adolescents is reported by the same group of researchers [8] and does not differ from the postvaccination rates contrary to what was reported in Markowitz’s study (Table 1). The 2003–2004 prevaccination cohort includes 652 adolescents 14–19 years old. The prevalence of any HPV among those sexually active was 39.6%; this rate significantly falls to 24.5% when adolescents who report no sexual activity are included. The Markowitz study adds 2 years to the prevaccination cohort (2003–2006), reporting on a total of 736 adolescents, 84 more subjects than in the 2003–2004 cohort. Compared with the 2003–2004 cohort, the
7.
8.
9.
11.
Received 2 July 2013; accepted 16 December 2013; electronically published 23 December 2013. This work has not been presented at a conference. Correspondence: Diane M Harper, MD, MPH, MS, Professor and Chair, University of Louisville School of Medicine, 501 East Broadway, Louisville, KY 40202 (diane.harper@louisville. edu). The Journal of Infectious Diseases 2014;209:1302–4 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit836
Previous History and Cigarette Smoking as Interfering Factors for the Effect of Vaccine on Human Papillomavirus Infection TO THE EDITOR—We have read with great interest the news and views in the article “Reduction in Human Papillomavirus (HPV) Prevalence Among Young Women Following HPV Vaccine Introduction in the United States, National Health and Nutrition Examination Surveys, 2003– 2010” [1]. This article pointed out a remarkable reduction in the prevalence of human papillomavirus (HPV) due to HPV vaccine introduction. However, it is unclear why the vaccine only protected female subjects aged 14–19 years but failed to bring benefit to subjects with older ages. As is stated in the article, most Americans are infected with HPV in their 1304
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late teens and early twenties. Unfortunately, the HPV infection status of each interviewed subject was not screened before the vaccine introduction; thus we cannot exclude the possibility that the nonsignificant protection in females more than 20 years old results from a preexisting history of HPV infection. Furthermore, it is well known that nicotine (a major component of cigarette smoking) exerts strong suppressive effects on the immune system and increases the risk of various virus infections [2]. Substantial evidences have demonstrated the ability of nicotine to increase virus infection rate via enhancing the proliferation of cancer cells or stem cells [3, 4]. In addition, cigarette smoking has been linked to increased HPV DNA load [5], a strong indicator of higher risk of cervical cancer [6]. Therefore, it is important to investigate whether the observed discrepancy in vaccine efficacy among groups with different ages is associated with specific behaviors, such as cigarette smoking. Though the report of HPV vaccine has revealed encouraging result for teenagers, to confirm the conclusion and more importantly to guarantee a better protection, the previous history of HPV infection and cigarette smoking, as well as other interfering factors, should be included into the interview questionnaire and statistical analysis. Notes Financial support. This work was supported by the National Basic Research Program (973 Program; grant 9732013CB531200) and Chinese National Science Funds (grants 81070676 and 81170186). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Haifeng Pei,1 Qiujun Yu,1 Qiang Xue,1 Feipeng Wei,2 and Ling Tao1 1
Department of Cardiology, Xijing Hospital, and 2 Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
CORRESPONDENCE
References 1. Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003–2010. J Infect Dis 2013; 208:385–93. 2. Sopori M. Effects of cigarette smoke on the immune system. Nat Rev Immunol 2002; 2: 372–7. 3. Roman J, Koval M. Control of lung epithelial growth by a nicotinic acetylcholine receptor: the other side of the coin. Am J Pathol 2009; 175:1799–801. 4. Yu J, Huang NF, Wilson KD, et al. nAChRs mediate human embryonic stem cell-derived endothelial cells: proliferation, apoptosis, and angiogenesis. PLoS One 2009; 4:e7040. 5. Xi LF, Koutsky LA, Castle PE, et al. Relationship between cigarette smoking and human papilloma virus types 16 and 18 DNA load. Cancer Epidemiol Biomarkers Prev 2009; 18: 3490–6. 6. Cigarette smoking linked to increased human papillomavirus DNA load. CA Cancer J Clin 2010; 60:137–8. Received 13 November 2013; accepted 16 December 2013; electronically published 23 December 2013. Correspondence: Ling Tao, MD, PhD, Professor and Vice Chief, Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Rd, Xi’an 710032, China ([email protected]) The Journal of Infectious Diseases 2014;209:1304 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jit837
Reply to Groner et al and Pei et al TO THE EDITOR—The comments from Groner and colleagues relating to human papillomavirus (HPV) DNA prevalence among 14–19 year olds in the prevaccine and vaccine eras [1] reflect their profound misunderstanding of the data that we would like to correct. Prevaccine era HPV data from the National Health and Nutrition Examination Surveys (NHANES) 2003–2004 were first published based on a less sensitive HPV assay than the one we currently use [2]. We subsequently documented the impact of an assay change [3] and published updated data on HPV prevalence from NHANES 2003– 2006 in order to be able to monitor HPV prevalence trends [4]. The data in our recent article, showing a decline in vaccine type HPV prevalence after vaccine
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burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels and RE: inequalities in human papillomavirus (HPV)-associated cancers: implications for the success of HPV vaccination. J Natl Cancer Inst 2013; 105:749–50. Centers for Disease Control and Prevention (CDC). National and state vaccination coverage among adolescents aged 13–17 years— United States. 2011. MMWR 2012; 34:671–7. Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA 2007; 297:813–9. Dobson SR, McNeil S, Dionne M, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA 2013; 309:1793–802. Harper DM, Vierthaler SL, Santee JA. Review of gardasil. J Vaccines Vaccin 2010; 1. doi:pii: 1000107. Forman D, de Martel C, Lacey CJ, et al. Global burden of human papillomavirus and related diseases. Vaccine 2012; 30(Suppl 5): F12–23.
