By Rebecca H. Allen, MD, MPH

Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI

Dr. Allen reports she is a Nexplanon trainer for Merck, and is on the advisory boards for Bayer and Pharmanest.

SYNOPSIS: In this randomized, controlled trial, the human papillomavirus (HPV) 16/18 vaccine did not hasten resolution of existing oncogenic HPV infections nor prevent persistent HPV 16/18 associated infection and cervical dysplasia recurrence after loop electrosurgical excisional procedure treatment.

SOURCE: Hildesheim A, Gonzalez P, Kreimer AR, et al. Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment. Am J Obstet Gynecol 2016;215:212.e1-15.

This is a re-analysis of a randomized, controlled trial conducted in Costa Rica among 7,466 women 18-25 years of age that evaluated the efficacy of the human papilloma virus (HPV) 16/18 vaccine (Cervarix). Women were randomized to either the HPV 16/18 vaccine or the hepatitis A vaccine and were followed annually with referral to colposcopy for high-grade dysplasia and/or persistent low-grade dysplasia, and treatment by loop electrosurgical excisional procedure (LEEP) when indicated. This reanalysis included two groups of women: 1) 1,711 participants who, at entry, were infected with one or more of 12 oncogenic HPV types and who were randomized, vaccinated, and followed for a median of 56.7 months; and 2) 311 participants who were randomized, vaccinated, and at some point during follow-up received a LEEP, and followed for a median of 27.3 months. HPV infection was chosen as the unit of analysis, and 31.4% of women had more than one HPV type at enrollment. HPV infection was divided into the following categories: 1) HPV 16 and/or 18; 2) HPV 31 and/or 33 and/or 45, which are HPV types for which evidence of cross-protection with the HPV 16/18 vaccine has been documented; and 3) other oncogenic HPV types. The outcomes for the evaluation of women with prevalent infections at enrollment included type-specific viral clearance and development of cervical lesions. The outcomes for the evaluation of women treated by LEEP were HPV infection, persistent HPV infection (detecting a specific type at two or more consecutive visits after treatment), and development of cervical lesions. Vaccine efficacy was reported as a percent reduction or increase in the outcome rates observed when the HPV vaccine arm was compared to the control hepatitis A vaccine arm.

Among women with oncogenic HPV infection at enrollment, there was no evidence that the HPV vaccine compared to control altered resolution of existing HPV infections. For example, among infected women without existing cervical dysplasia, the efficacy of the vaccine was -5.4% (95% confidence interval [CI], -19 to 10) for clearance, -15.5% (95% CI, -86 to 28) for progression to CIN 1+, and 0.3% (95% CI, -69 to 41) for progression to CIN 2. Among women who underwent LEEP procedures, it was found that, after treatment, 34.1% of the 311 women had one or more oncogenic HPV infections detected and 1.6% had CIN 2+ detected. Among these women, approximately 70% of infections were new HPV infections and 20% of the CIN 2+ lesions were the result of new HPV infections that were absent before treatment. There was no effect of vaccination on persistent HPV 16/18 infections or HPV 16/18 associated cytologic/histologic lesions after LEEP.

COMMENTARY

The HPV vaccine is highly effective in preventing new HPV infection in girls and women naïve to the virus and, thus, preventing HPV-related dysplasia. The HPV vaccines available in the United States include Gardasil-4 (6, 11, 16, 18), Cervarix-2 (16, 18), and Gardasil-9 (6, 11, 18, 31, 33, 45, 52, 28). The HPV vaccine is recommended for females between the ages of 11 and 26 and males between the ages of 11 and 21 by the Centers for Disease Control and Prevention.1 The mechanism of action of the various HPV vaccines is to induce antibodies against the L1 protein in HPV that then neutralize the ability of HPV to infect cells. Whether there is a secondary vaccine effect on existing infected cells whereby the antibodies reduce spread of virus to new cells or the development of a cell-mediated immunity against L1, which promotes clearance of virus in infected cells, is controversial. The authors of this study previously had reported shorter-term results on a smaller number of women that the HPV 16/18 vaccine did not have any effect of clearing existing infections.2 Now they have expanded that analysis in a larger study with longer follow-up, adding an evaluation of the effect of vaccination on the progression of prevalent infections and after LEEP treatment.

This well-done study falls short only in the evaluation of the women who underwent LEEP, as some of the categories had very small numbers and, thus, large confidence intervals. Nevertheless, in the main analysis, the data are convincing that the HPV vaccine does not hasten resolution of existing infections or prevent progression to cervical dysplasia. Furthermore, the vaccine does not reduce post-LEEP infections or dysplasia. On a positive note, there was some suggestion that the vaccine may protect against new infections post-LEEP.

So what are the implications of this study? Current recommendations allow for HPV vaccination in women who have known HPV infections in the hopes that they may be protected from strains they have not been exposed to yet.3 This makes more sense to me now that Gardasil-9 is available. Nevertheless, this study further reinforces the fact that we should be vaccinating young men and women before the onset of sexual activity to reap the full benefits of vaccination. By the time the patient presents for colposcopy, the benefit of vaccination is small, as this study shows. Unfortunately, current vaccination rates in the United States are low, with the latest estimates being 50% of males have started the vaccine series with 28% completing three doses and 63% of females have started the vaccine series with 42% completing three doses.4 This is compared to approximately 87% of adolescents having received at least one Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) vaccine. Although obstetrician-gynecologists usually do not see females in the preteen age group, we can work to support HPV vaccination efforts in the patients we do see, speaking to mothers about the importance of vaccination for their daughters and sons, as well as supporting efforts to confront misconceptions regarding the vaccine in our schools and communities.

REFERENCES

  1. Markowitz LE, Dunne EF, Saraiya M, et al. Human papillomavirus vaccination: Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2014;63:1-30.
  2. Hildesheim A, Herrero R, Wacholder S, et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: A randomized trial. JAMA 2007;298;743-753.
  3. ACOG Committee Opinion Number 641. Human papillomavirus vaccination. September 2015.
  4. Reagan-Steiner S, Yankey D, Jeyarajah J, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years — United States, 2015. MMWR Morb Mortal Wkly Rep 2016;65;850-858.