- Email: [email protected]
18 AS04-adjuvanted vaccine – Author's reply
Correspondence
The 4-year end-of-study analysis of the PATRICIA trial published in The Lancet Oncology1 adds to findings of previous interim analyses.2,3 In this trial, Lehtinen and colleagues assessed the efficacy of a bivalent human papillomavirus (HPV) vaccine, administered to 18 644 healthy women aged 15–25 years, for reduction of high-grade cervical intraepithelial neoplasia (CIN3+). We question the interpretation that the total vaccinated cohort (TVC)-naive population (women who received at least one vaccine dose and completed follow-up, who at baseline had normal cytological findings, were DNA-negative for the 14 oncogenic HPV types investigated, and were seronegative for HPV16/18) is similar to the target population of the immunisation campaign (young adolescent before sexual debut). On the basis of available data, vaccine efficacy (VE) measured in this subset is significantly better than the one measured in the TVC; the assumption made by Lehtinen and colleagues, that efficacy in the naive group is the same that will be reached when vaccinating girls aged 12 years, is doubtful. As shown in table 1 of the webappendix (which contains a mistake of inversion in the two categories of women having “less than” and “at least” three sexual partners), naive girls are sexually active: 95% had at least one sexual partner the year before enrolment, 55% used hormonal contraceptive, and 5% used an intrauterine device. Moreover, in a previous report, 35% of this population was also regular condom users.3 Thus, it is difficult to accept the equivalence made: naive girls equal girls not exposed to HPV equal girls before sexual debut. More probably, naive girls, although exposed to HPV, did not become infected with www.thelancet.com/oncology Vol 13 February 2012
HPV. These girls probably represent a selection of the population engaging in healthier behaviour and possibly have a higher socioeconomic status than the rest of the population: they are not promiscuous (only 5% had three or more sexual partners in the year before enrolment) and are less frequent smokers than the non-naive girls (25% and 36%, respectively, were smokers). In view of the weakness of the assumption made, the efficacy of HPV vaccine used in real life could be lower than that suggested by Lehtinen and colleagues. Post-marketing effectiveness studies will prove useful to clarify these doubts. We declare that we have no conflicts of interest.
*Simona Di Mario, Vittorio Basevi, Silvana Borsari, Sara Balduzzi, Nicola Magrini [email protected] NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-based Research Synthesis and Guideline Development in Reproductive Health, Modena, Italy (SDM, VB, NM); Programme on Women’s Health, Modena, Italy (SBo); and Faculty of Medical Statistics at the University of Modena and Reggio Emilia, Modena, Italy (SBa) 1
2
3
Lehtinen M, Paavonen J, Wheeler CM, et al, for the HPV PATRICIA Study Group. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2012; 13: 89–99. Paavonen J, Jenkins D, Bosch FX, et al, for the HPV PATRICIA study group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-likeparticle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 2007; 369: 2161–70. Paavonen J, Naud P, Salmerón J, et al, for the HPV PATRICIA study group. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009; 374: 301–14.
Author’s reply Di Mario and colleagues raise a point about our interpretation of TVC-naive VE results in our recent publication.1 About half the TVC-naive group were adolescent Finnish girls (aged 16–17 years) in the population-based recruitment, for whom no sexual
behaviour exclusion criteria were used,2 indicating that the TVC-naive population was probably not selected materially for healthier behaviour or being less promiscuous. The other half of the TVC-naive group had had up to six lifetime sexual partners, which was considered in our discussion of the paper’s limitations. Moreover, data we have on file3 show that smoking does not affect the vaccine-induced immune response. On the contrary, past HPV infections might have gone undetected at baseline, which would lower the VE, as was shown in the TVC population, yet different age-strata of the TVC-naive group showed similar high VEs. Thus, VE in the TVC-naive group is a reasonable approximation for those in the target population (girls aged 12–15 years). We see no reason to revise our cautious conclusion that, in view of the vaccine’s high efficacy against CIN3+ (irrespective of HPV type) in HPV-naive women, the target population might receive substantial protection against cervical cancer. Finally, we doubt whether postmarketing studies, which are mostly uncontrolled or non-randomised, on efficacy (not effectiveness studies, which assess differences in vaccination strategies—eg, in our community randomised phase 4 trial4) will be helpful.
A J Photo/Science Photo Library
Overall efficacy of HPV-16/18 AS04adjuvanted vaccine
ML has received funding through his institution to do HPV vaccine studies for GlaxoSmithKline Biologicals or Merck Sharp & Dohme (Sanofi Pasteur MSD).
Matti Lehtinen matti.lehtinen@uta.fi University of Tampere, School of Public Health, Tampere, Finland 1
2
3
4
Lehtinen M, Paavonen J, Wheeler CM, et al, for the HPV PATRICIA Study Group. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2012; 13: 89–99. Lehtinen M, Herrero R, Mayaud P, et al. Studies to assess long-term efficacy and effectiveness of HPV vaccination in developed and developing countries. Vaccine 2006; S24: 233–41. Simen-Kapeu A. Epidemiological study of tobacco use and human papillomavirus. PhD thesis, University of Tampere, Finland, 2009. Lehtinen M, M, French K, Dillner J, Paavonen J, Garnett G. Sound implementation of HPV vaccination. Future Med 2008; 5: 289–94.
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The 4-year end-of-study analysis of the PATRICIA trial published in The Lancet Oncology1 adds to findings of previous interim analyses.2,3 In this trial, Lehtinen and colleagues assessed the efficacy of a bivalent human papillomavirus (HPV) vaccine, administered to 18 644 healthy women aged 15–25 years, for reduction of high-grade cervical intraepithelial neoplasia (CIN3+). We question the interpretation that the total vaccinated cohort (TVC)-naive population (women who received at least one vaccine dose and completed follow-up, who at baseline had normal cytological findings, were DNA-negative for the 14 oncogenic HPV types investigated, and were seronegative for HPV16/18) is similar to the target population of the immunisation campaign (young adolescent before sexual debut). On the basis of available data, vaccine efficacy (VE) measured in this subset is significantly better than the one measured in the TVC; the assumption made by Lehtinen and colleagues, that efficacy in the naive group is the same that will be reached when vaccinating girls aged 12 years, is doubtful. As shown in table 1 of the webappendix (which contains a mistake of inversion in the two categories of women having “less than” and “at least” three sexual partners), naive girls are sexually active: 95% had at least one sexual partner the year before enrolment, 55% used hormonal contraceptive, and 5% used an intrauterine device. Moreover, in a previous report, 35% of this population was also regular condom users.3 Thus, it is difficult to accept the equivalence made: naive girls equal girls not exposed to HPV equal girls before sexual debut. More probably, naive girls, although exposed to HPV, did not become infected with www.thelancet.com/oncology Vol 13 February 2012
HPV. These girls probably represent a selection of the population engaging in healthier behaviour and possibly have a higher socioeconomic status than the rest of the population: they are not promiscuous (only 5% had three or more sexual partners in the year before enrolment) and are less frequent smokers than the non-naive girls (25% and 36%, respectively, were smokers). In view of the weakness of the assumption made, the efficacy of HPV vaccine used in real life could be lower than that suggested by Lehtinen and colleagues. Post-marketing effectiveness studies will prove useful to clarify these doubts. We declare that we have no conflicts of interest.
*Simona Di Mario, Vittorio Basevi, Silvana Borsari, Sara Balduzzi, Nicola Magrini [email protected] NHS Centre for the Evaluation of the Effectiveness of Health Care, WHO Collaborating Centre for Evidence-based Research Synthesis and Guideline Development in Reproductive Health, Modena, Italy (SDM, VB, NM); Programme on Women’s Health, Modena, Italy (SBo); and Faculty of Medical Statistics at the University of Modena and Reggio Emilia, Modena, Italy (SBa) 1
2
3
Lehtinen M, Paavonen J, Wheeler CM, et al, for the HPV PATRICIA Study Group. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2012; 13: 89–99. Paavonen J, Jenkins D, Bosch FX, et al, for the HPV PATRICIA study group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-likeparticle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 2007; 369: 2161–70. Paavonen J, Naud P, Salmerón J, et al, for the HPV PATRICIA study group. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 2009; 374: 301–14.
Author’s reply Di Mario and colleagues raise a point about our interpretation of TVC-naive VE results in our recent publication.1 About half the TVC-naive group were adolescent Finnish girls (aged 16–17 years) in the population-based recruitment, for whom no sexual
behaviour exclusion criteria were used,2 indicating that the TVC-naive population was probably not selected materially for healthier behaviour or being less promiscuous. The other half of the TVC-naive group had had up to six lifetime sexual partners, which was considered in our discussion of the paper’s limitations. Moreover, data we have on file3 show that smoking does not affect the vaccine-induced immune response. On the contrary, past HPV infections might have gone undetected at baseline, which would lower the VE, as was shown in the TVC population, yet different age-strata of the TVC-naive group showed similar high VEs. Thus, VE in the TVC-naive group is a reasonable approximation for those in the target population (girls aged 12–15 years). We see no reason to revise our cautious conclusion that, in view of the vaccine’s high efficacy against CIN3+ (irrespective of HPV type) in HPV-naive women, the target population might receive substantial protection against cervical cancer. Finally, we doubt whether postmarketing studies, which are mostly uncontrolled or non-randomised, on efficacy (not effectiveness studies, which assess differences in vaccination strategies—eg, in our community randomised phase 4 trial4) will be helpful.
A J Photo/Science Photo Library
Overall efficacy of HPV-16/18 AS04adjuvanted vaccine
ML has received funding through his institution to do HPV vaccine studies for GlaxoSmithKline Biologicals or Merck Sharp & Dohme (Sanofi Pasteur MSD).
Matti Lehtinen matti.lehtinen@uta.fi University of Tampere, School of Public Health, Tampere, Finland 1
2
3
4
Lehtinen M, Paavonen J, Wheeler CM, et al, for the HPV PATRICIA Study Group. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2012; 13: 89–99. Lehtinen M, Herrero R, Mayaud P, et al. Studies to assess long-term efficacy and effectiveness of HPV vaccination in developed and developing countries. Vaccine 2006; S24: 233–41. Simen-Kapeu A. Epidemiological study of tobacco use and human papillomavirus. PhD thesis, University of Tampere, Finland, 2009. Lehtinen M, M, French K, Dillner J, Paavonen J, Garnett G. Sound implementation of HPV vaccination. Future Med 2008; 5: 289–94.
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