A vaccine against cancer-causing strains of human papilloma virus (HPV) has no therapeutic effect, according to the results of a large randomised trial published in the August 15th edition of the Journal of the American Medical Association. The study’s investigators conclude that HPV vaccination has no therapeutic effect and that women already infected with potentially cancer-causing HPV strains should be managed according to existing guidelines.
It is now well-established that cervical (and anal) cancer is linked to certain strains of HPV, the virus that causes genital warts. Recently, two vaccines have been developed that provide near-total protection against the two strains of HPV with the greatest risk of cancerous or pre-cancerous cervical cell changes – HPV16 and HPV-18 - for women as yet unexposed to the virus.
In clinical trials, the vaccines, Gardasil and Cervarix, had the highest levels of efficacy in women who were not yet sexually active or who had not been exposed to HPV. Much lower levels of effectiveness were seen in the Gardasil study in women with pre-existing HPV infection.
Both HPV vaccines are virus-like particle-based, and have been shown to generate both protective antibodies against certain strains of HPV and to induce a cell-mediated immune response, which is usually associated with eradication of viruses. Some researchers have therefore suggested that providing HPV vaccination to women with pre-existing HPV-16 and/or HPV-18 infection could have some therapeutic effect and encourage clearance of the virus.
To test this hypothesis, investigators compared rates of HPV-16/18 clearance amongst women who received the Cervarix vaccine (which provides protection against HPV-16/18) and a comparable control population in an ongoing community-based randomised controlled trial in Costa Rica. None of the women were HIV-positive.
A total of 7,466 women aged between 18 and 25 have been recruited to the study, but the investigators restricted their analysis to 2,189 women with positive HPV DNA test results. Recruitment took place between June 2004 and December 2005. Women were randomised to receive three doses of Cervarix (1,101 individuals) over six months or a control hepatitis A vaccine (1,088 individuals). The investigators then compared rates of HPV clearance in the two groups of women at six-monthly and twelve-monthly follow-up visits.
At the six months follow-up visit, there was no difference in the number of women in the vaccine and control arms who had cleared infection with HPV-16/18. Of the women infected with HPV-16, 27% of those who received the vaccine cleared the infection, compared to 28% of those in the control arm.
Similar results were observed for women infected with HPV-18, with 46% of the vaccinated women clearing the infection compared to 45% of those in the control arm. For women with both HPV-16 and HPV-18 infection, 33% of vaccinated women cleared the infection compared to 32% of those in the control population.
At twelve months, rates of clearance remained comparable in the vaccination and control arms, with clearance of HPV-16 observed in 44% of the vaccinated women and 46% of control; clearance of HPV-18 in 59% of the vaccine arm and 61% of the control arm, and clearance of HPV-16 and HPV-18 in 49% of those who received the vaccine and 50% of those in the control arm.
Nor did the investigators observe any significant effect of vaccination when the investigators restricted their analysis to women who received all the doses of the vaccination, or who were only infected with single HPV types (including strains not associated with cancer). Furthermore, when the investigators modified their analysis to include factors such as time since sexual debut, use of oral contraceptives, or concomitant infection with gonorrhoea or chlamydia, rates of clearance remained comparable in the vaccination and control arms.
The investigators comment, “the trial has the advantage of being both community-based…and randomized. Our results show that rates of viral clearance over a 12-month period are not influenced by vaccination.” They add that doctors should “discourage” the use of the currently available HPV vaccines by women with existing HPV-16/18 infection hoping for a therapeutic benefit.
They conclude, “our results demonstrate that in women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used for purposes of treating prevalent infections.”
An accompanying editorial notes that the findings of this study further support current US guidelines for the use of the Gardasil HPV vaccine (Cervarix has been approved in Australia and is being considered by regulatory authorities in several other countries).
US guidelines state that Gardasil should be provided to girls before they become sexually active – between the ages of eleven and twelve (in the UK, vaccination has been recommended for girls aged twelve and 13). Catch-up vaccination for women aged 13 – 26 is warranted, provided that they are not yet sexually active, or if they are, have not yet acquired HPV infection. The author of the editorial adds, “women with abnormal Pap test results or those with positive DNA results should be managed according to current guidelines [surgical and non-invasive procedures] and that HPV vaccine does not have a role in treatment.”
Studies into the safety and efficacy of HPV vaccination in men are ongoing, and there are currently no data on the use of such vaccines in individuals who are HIV-positive.
Hildesheim A et al. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomised controlled trial. JAMA 298: 743 – 753, 2007.
Markowitz LE. HPV vaccines – prophylactic not therapeutic. JAMA 298: 805 – 806, 2007.