HPV Vaccination and Testing

Sustained Efficacy and Immunogenicity of the Human Papillomavirus (HPV)-16/18 ASO4-Adjuvanted Vaccine: Analysis of a Randomized Placebo-Controlled Trial Up to 6.4 Years

The GlaxoSmithKline Vaccine HPV-007 Study Group Lancet 2009;374:1975–1985.

Cervical Cancer: Problem Solved? Vaccinating Girls Against Human Papillomavirus

Crosbie EJ, Brabin L. BJOG 2010;117:137–142.

Human papillomavirus (HPV) vaccinations hold a commanding position in the prevention of cervical cancer. There is accumulating evidence that the protection offered by the vaccines is enduring, which is encouraging if extensive programs are rolled out in developing countries where booster doses would increase the complexity of delivery.

The latest data show that Cervarix^® (human papillomavirus bivalent [types 16 and 18] vaccine, GlaxoSmithKline, Research Triangle Park, NC) is effective in preventing recurrent HPV infections in HPV-naive young women who were vaccinated 6 years previously. In a trial by the GlaxoSmithKline Vaccine HPV-007 Study Group, the vaccine prevented any cervical neoplasia associated with types 16 and 18 as well as most other lesions independent of HPV DNA type.

Possibly more significant were the levels of neutralizing antibodies that were sustained in the study population. Naturally occurring infections are superficial and do not provoke strong antibody responses, unlike the injected vaccines which result in high levels of circulating antibodies. The vaccine antibodies peak at 7 months then taper off but it appears as if they are maintained-at least from 3 to 6 years-suggesting long-term immunity with models of 20 years being quoted.

These encouraging data should galvanize international efforts such as the GAVI Alliance (Global Alliance for Vaccines and Immunisation) to provide vaccines for the poorest countries. Approximately 80% of cervical cancers occur in developing countries and if the vaccine price could be reduced to $10 then cost-effective worldwide protection is possible.¹

The situation in developed countries is eloquently summarized in an article by Crosbie and Brabin that opens the question of future screening by cytology and HPV DNA testing.

The present consensus is that cytology screening prior to age 21 years is not recommended. Sawaya² described the evidence in favor of this age restriction as “compelling”and that earlier testing simply leads to unnecessary and harmful interference. The updated American guidelines from the American Congress of Obstetricians and Gynecologists are summarized as follows³:

• Age < 21 years

• Age 21 to 29 years

• Age 30 to 65 years

• Age 65 to 70 years

• Avoid screening

• Screen every 2 years

• May screen every 3 years

• May stop screening

The “may” refers to low-risk women with 3 consecutive negative smears.

These pronouncements are sure to put question marks with regard to the American tradition of annual pelvic examination but the motivation is as it should be-to balance benefits and harms to the patient and not financial or political considerations.

The situation in terms of HPV DNA testing is far more complicated. Because HPV infections are common and selflimiting in young women, HPV testing is contraindicated. Our state of knowledge is evolving for ≥ 35-year-olds and it may be that HPV testing followed by cytologic triaging will prove the most cost-effective strategy.

It is too early to change policies for HPV testing and cytology itself will change as vaccinated women may only be required to start screening after age 21 years because the “non-16 and 18 type” neoplasms occur at a later age. Cytology may improve as well because molecular markers or cell-cycle detection may make the prediction of progression likelihood more accurate.

Screening is rightly being reviewed as the evidence accumulates. The sadness is that those most at risk-the poor, the disadvantaged, and those in developing countries-are least likely to be vaccinated and least likely to present for screening. The screening net needs to be widened as well as refined.