A. No. In the FUTURE I trial, among women who were naïve to all strains of the human papillomavirus (HPV) vaccine at the time of inoculation, the vaccine was 100% effective in preventing anogenital lesions, cervical intraepithelial neoplasia (CIN) 2,3, adenocarcinoma in situ, and cervical cancer. In FUTURE II, among the same population, it was 98% effective in preventing all cervical lesions.
However, in FUTURE I, when the groups comprising HPV-naïve and HPV-positive subjects and those with and without preexisting neoplasia were combined, the vaccine was 20% effective in preventing CIN 2,3, adenocarcinoma in situ, and cervical cancer, and 34% effective in preventing genital warts and vulvar and vaginal intraepithelial neoplasia and cancer due to vaccine and nonvaccine HPV types. In FUTURE II, when the same groups were included, the vaccine was 17% effective in preventing all cervical lesions (regardless of the causal HPV type).
The women involved in these trials fell within the target age range for prophylactic vaccination, with ages from 15 to 26 years.
Even females in the target population for HPV vaccination (ages 9 to 26) present with different histories and risk status. An individual may be a candidate for:
- true primary prevention (no evidence of any HPV subtype or neoplasia)
- primary prevention for the vaccine subtypes (ie, negative for HPV type 6, 11, 16, or 18)
- prevention despite the presence of HPV type 6, 11, 16, or 18
- prevention despite the presence of a subtype not covered in the vaccine
- vaccination despite existing vulvar, vaginal, or cervical neoplasia.
The effect of the vaccine on this last group would be considered both prophylactic and therapeutic, defined as secondary prevention of cervical cancer. Secondary prevention (reversal of HPV effect in CIN lesions, leading to regression) has not been demonstrated with the quadrivalent HPV vaccine (Gardasil).
Trials followed women over 3 years
In these randomized trials, both vaccine efficacy (lesions prevented) and safety (side effects) were evaluated.
FUTURE I enrolled nearly 5,500 young women within the advised age range for prophylaxis who were randomized to the quadrivalent HPV vaccine or placebo. Cervical screening and colposcopic biopsy (if indicated) were conducted at baseline, and HPV status was determined. Investigators studied the effect of prophylactic vaccination in women naïve to the four viral subtypes targeted by the vaccine (6, 11, 16, and 18), as well as women in each of the other groups listed above.
The principal aim of FUTURE I was to provide an “ideal” frequent visit schedule with broader referral to colposcopy and determine whether the vaccine would reduce the combined incidence of anogenital warts, vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), CIN 1,2,3, and cancer related to HPV subtypes 6, 11, 16, and 18.
FUTURE II involved 12,167 women and a wider visit interval more consistent with clinical practice than FUTURE I. The aim was to determine whether the quadrivalent vaccine would reduce the incidence of CIN 2,3, adenocarcinoma in situ, or invasive carcinoma of the cervix related to HPV subtypes 16 and 18.
In both trials, polymerase chain reaction was used to identify the HPV subtype associated with any CIN, adenocarcinoma in situ, or anogenital lesion that was biopsy-proven, and this information was correlated with the patient’s HPV status before and after vaccination. The baseline and postvaccination serological status against HPV subtypes was also measured.
Safety is not a concern thus far
There were no adverse events that caused death or withdrawal from the studies. The most common side effect was pain at the injection site, which occurred more frequently among vaccinated women.
Bottom line: Keep screening
The quadrivalent vaccine is not equally effective among all female candidates. I recommend the following:
- Encourage vaccination in very young girls and virgins. The vaccine is most effective in females who have not been exposed to any of the four subtypes targeted.
- A lack of type-specific, clinically available serology or lower genital tract screening in a woman who is already sexually active leaves the clinician in the dark about how to counsel her. Because most women I counsel do not harbor all four subtypes covered by the vaccine and lack anogenital disease, I offer the vaccine to all women in the age range that is indicated.
- Counsel women who are already sexually active and who harbor HPV before vaccination, as well as those who acquire the virus during the vaccination period, that even with inoculation they are susceptible to infection and neoplastic transformation, unlike those naïve to the vaccine-specific subtypes. Efficacy is still substantial, however—near 90% overall.
- If type-specific HPV testing becomes commercially available, counsel women who test positive for one of the four HPV subtypes targeted by the vaccine, as well as those with other HPV subtypes, that they are susceptible to neoplastic transformation even with the vaccine.
- Advise women who already have CIN, adenocarcinoma in situ, VIN, VAIN, or benign anogenital disease that the vaccine is not therapeutic and will not prevent the natural progression of these lesions toward cancer.
- Remember that few women harbor all four subtypes targeted by the vaccine. The vaccine may provide some marginal benefit to women already being treated for intraepithelial neoplasia, but each patient should be counseled about the potential lack of benefit.
- Be aware that there is clear benefit in the prevention of anogenital disease independent of the oncogenic risks associated with the virus.
- Don’t forget the other 13 known oncogenic HPV subtypes and the many more nononcogenic types identified so far. The effect of the vaccine is modestly reduced in women who harbor one or more of those subtypes when compared with its efficacy in uninfected recipients and virgins. Therefore, screening for cervical cancer and lower genital tract lesions should continue despite vaccination.
- In an editorial accompanying the FUTURE I and II trials, Sawaya and Smith-McCune observed that oncogenic HPV strains not targeted by the vaccine were responsible for a large number of CIN 2,3 and adenocarcinoma lesions in the FUTURE II trial.1 Although there are no concrete data, the editorialists suggest that, as we vaccinate for known strains, existing strains that are not included or new strains that evolve may “fill the niche” and continue to cause incident cases of neoplasia despite vaccination. This is another reason to screen women cytologically or by direct visual or other in-vivo methods to detect neoplasia.