Clinical Review


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Guidance on HPV vaccination, cervical cancer screening, and colposcopically directed biopsy



Over the past year, we have gained further insight into the efficacy and safety of the human papillomavirus (HPV) vaccines; received new, practical cervical screening guidance from the Centers for Disease Control and Prevention (CDC); and gathered further evidence that colposcopy is not as sensitive at detecting high-grade cervical disease as we once thought.

In this article, I describe each of these developments in depth.

Both HPV vaccines are safe and effective—
and both offer cross-protection

Lu B, Kumar A, Castellsague X, Giuliano AR. Efficacy and safety of prophylactic vaccines against cervical HPV infection and diseases among women: a systematic review and meta-analysis. BMC Infect Dis. 2011;11(1):13.

HPV 16 accounts for about 55% of all cases of cervical cancer and HPV 18 for another 15%—and both HPV vaccines on the market provide coverage against these two types. Because vaccination stands to reduce the burden of cervical disease so dramatically, it behooves us to achieve the highest possible vaccination rate for girls and young women.

Regrettably, fewer than 40% of the eligible female population of the United States has received one or more injections of either the bivalent (HPV 16, 18) (Cervarix) or quadrivalent (HPV 6, 11, 16, 18) (Gardasil) vaccine—with the vaccination rate varying considerably by geographic location and socioeconomic status.1 Clearly, we have much work ahead of us to improve this rate.

What’s the big picture?

Each trial of the HPV vaccine to date has demonstrated high efficacy and safety. Drawing from the individual findings of these trials to develop a snapshot of overall efficacy

and safety has been difficult, however, owing to multiple clinical endpoints, differences in both the number of virus-like particle types and in the adjuvant used in each vaccine, variability of the populations, and different definitions of efficacy. These limitations have made it difficult for clinicians and patients to make an informed decision about which vaccine to choose.

To address these concerns, Lu and colleagues conducted a comprehensive systematic review and meta-analysis of seven unique randomized, controlled trials with a total enrollment of 44,141 females. Their goal: to assess the safety and efficacy of both vaccines against multiple virologic and clinical endpoints, including efficacy not only against the primary HPV vaccine types, but closely related types as well.

They focused on two groups of girls and women:

  • The per protocol population (PPP) included females who were both DNA- and sero-negative to the HPV types contained in the vaccine at the start and end of the vaccination period. The PPP group received all three injections of the vaccine, with no protocol violations.
  • The intention-to-treat cohort (ITT) included women and girls who had received one or more doses of the vaccine or placebo and who had follow-up data available, regardless of HPV status at enrollment.

The PPP more closely resembles the sexually naïve population that stands to benefit most from the full vaccination series, whereas the ITT is more similar to girls and women 18 to 26 years old who are seeking “catch-up” vaccination, most of them having initiated sexual activity or had less than perfect compliance with vaccination, or both.

In the ITT cohort, the pooled relative risk (RR) for HPV 16-related cervical intraepithelial neoplasia (CIN) grade 2 or worse was 0.47, corresponding to a pooled efficacy of 53%, a statistically significant benefit. In the PPP, the RR was 0.04, corresponding to a pooled efficacy of 96% for HPV 16-related CIN 2+. The RR was similar for HPV 18 (TABLE). The reduction in CIN 1 for women not previously infected with either of these high-risk HPV types was also high—95% for HPV 16 and 97% for HPV 18.

Effect of HPV vaccination on high-grade cervical disease

GroupRelative risk of CIN 2+Reduction in CIN 2+
HpV 16HpV 18HpV 16HpV 18
Intention to treat0.470.1653%84%
Per protocol0.040.1096%90%
CIN=cervical intraepithelial neoplasia
SOURCE: Lu B, et al. Efficacy and safety of prophylactic vaccines against cervical HPV infection and diseases among women: a systematic review and meta-analysis. BMC Infect Dis. 2011;11(1):13.

Vaccines offer cross-protection against 3 additional HPV types

The possibility that the HPV vaccines provide cross-protection against closely related HPV types has generated considerable interest. Lu and colleagues assessed cross-protection against 6-month persistent infection related to five HPV types:

  • HPV 31—relative risk (RR) of 0.47 and 0.30 in the ITT and PPP cohorts, respectively
  • HPV 45—RR of 0.50 and 0.42 in the ITT and PPP cohorts, respectively. There was significant heterogeneity between the trials in efficacy against persistent HPV 45 infection.
  • HPV 33—RR of 0.65 and 0.57 in the ITT and PPP cohorts, respectively
  • HPV 52 and 58—no statistically significant cross-protection.


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