Mass Human Papilloma Virus (HPV) vaccination of women in the general population

Guest post by Dr. Lee Say Fatt (the article also appeared in Berita MMA December 2011 Vol 41 No 12 )

Mass Human Papilloma Virus (HPV) vaccination of women in the general population – a re-look at the real efficacy in preventing pre-cancerous and cancerous lesions of the cervix.

This article was written in response to the recent announcement by the Government of Malaysia regarding the allocation of RM 50 million for the HPV immunization program in 2012. It was subsequently reported in the Sunday Star (9 October 2012) headlines “Shot in the arm”. The headlines mentioned that at least 350,000 unmarried women aged 18 and above are expected to benefit from the free HPV immunization program to protect women against cervical cancer. Women, Family and Community Development Minister Datuk Seri Shahrizat Abdul Jalil further mentioned that no age limit has been set for the HPV vaccination and those who would qualify would be determined later.

Introduction
Cervical cancer is the second most common malignant disease in women worldwide. Similarly, in Malaysia, it is also the second most common female cancer, constituting 12.9% of all female cancers The Malaysian National Cancer Registry reported an average of 2,000-3,000 hospital admissions of cervical cancer per year in Malaysia, with the majority presenting at late stages of the disease.

It is now well established that human papillomaviruses (HPV) is the etiologic agent of almost all cervical cancers. Persistent viral infection with oncogenic types of HPV can lead to cancer of the cervix, anus, vagina, vulva, penis, mouth, and sinuses. In a study by the International Agency for Research on Cancer, HPV was detected in 99.7% of invasive cervical cancers from 22 countries. Although 15 high-risk HPV types have been shown to be associated with cancer, types 16 and 18 are responsible for two thirds to three quarters of cervical cancers worldwide.

The prevalence of genital HPV infection in the world is around 440 million. Epidemiological studies in the USA have reported that 75% of the 15–50 year-old population is infected with genital HPV over their lifetime. These are grouped into “high-risk” and “low-risk” types according to the degree of risk of development of cancer after infection with each genotype. Genital HPV infection is extremely common and most often causes no symptoms. A proportion of individuals infected with low-risk HPV types such as HPV-6 or HPV-11 will develop genital warts, whereas a subset of women infected with high-risk HPV such as HPV-16 or HPV-18 may develop cervical intraepithelial neoplasia (CIN), which can later leads to cervical cancer.

Types of HPV Vaccine
There are currently two HPV vaccines available in Malaysia, the quadrivalent vaccine (Gardasil, from Merck) against types 6, 11, 16 and 18 and the bivalent vaccine (Cervarix, from GlaxoSmithKline), which protects against HPV types 16 and 18. The HPV vaccines consist of a recombinant HPV major capsid protein L1, which generate virus-like particles (VLP) resembling HPV virions, but which are non-infectious, immunogenic and subtype specific. The vaccine is able to stimulate a high antibody response that has been shown to persist for at least 5 years. The vaccine is generally safe and well tolerated

Vaccine Efficacy and target groups

The HPV vaccine has been proven effective in almost all the clinical trials done so far. All the landmark studies showing such excellent results were done mainly in young women up to the age of 26. The excellent efficacy only applies to young women who are negative for HPV 16 and 18 (naïve group) at entry points at the trials. In this group of women, the efficacy in preventing CIN caused by the HPV 16 and 18 was more than 90%. It is important to note that the vaccine protect against only two (maybe a few more strains due to the cross protection) of the 15 other oncogenic HPV strains. It is not surprising therefore to find that the oncogenic HPV strains not targeted by the vaccine were responsible for a large number of CIN 2,3 and adenocarcinoma lesions in one of the trials. This explained the reduced efficacy of the vaccine against the reduction of CIN caused by any of the oncogenic HPV types.

The efficacy is even lower when analyzing the intention to treat population which will include women even if they were already infected with HPV-6/11/16/18 at baseline, may acquire the infection before completion of the vaccination schedule, had HPV-associated disease, or violated the study protocol. The efficacy of the vaccine in reducing CIN caused by any strains of oncogenic HPV in this intention to treat population was only 17% to 33%. This group represents the general population of young women, including those that are sexually active and may have already been infected with the HPV at first vaccination

In other words, the HPV vaccine is most effective in females who have not been exposed to any of the vaccine subtypes targeted. In the one of the quadrivalent trial (FUTURE I) involving 5455 young women who reported a lifetime history of four or fewer sexual partners, 27% of them already had either serological or molecular evidence of infection with either HPV 16 or 18. Similarly, about a third of women (33.2%) were positive to HPV 6, 11, 16 and 18 at baseline by serological or DNA testing (via PCR). Therefore, these data proved that one third of women who are sexually active are already infected with vaccine type HPV. All these underscores the importance of vaccinating women before they become infected, which, in most cases, means before the onset of sexual activity.

At the present moment, HPV testing before initiating vaccination, however, is not recommended because there are no good measures of past exposure; additionally current clinically available testing reflects only current viral shedding. This makes it difficult to counsel a sexually active woman regarding the need to be given the vaccine. In contrast to the Center for Disease Control (CDC) guidelines which recommends vaccination of women up to 26 years old, the American Cancer Society (ACS) stated that there is currently insufficient data to recommend for or against universal vaccination of females aged 19 to 26 years in the general population. Furthermore, the ACS guidelines stated that the HPV vaccination for women over age 26 years is not currently recommended. A decision about whether a woman aged 19 to 26 years should receive the vaccine should be based on an informed discussion between the woman and her health care provider regarding her risk of previous HPV exposure and potential benefit from vaccination. This is especially so if the woman has been sexually active. They should be told that the efficacy is significantly reduced and the vaccine may not alter the natural course of the disease (still at risk of cervical cancer) if they are already infected with any of the oncogenic HPV strain. Therefore, women must continue to be screened for cervical lesions after being vaccinated. Efficacy would still be high in females aged 19 years and older who have not yet engaged in sexual intercourse and these women would still derive full benefit from HPV vaccination.

Conclusion

From a number of excellent trials, both vaccines have been shown to be highly successful in reducing the incidence of pre-cancerous cervical lesions (CIN) caused by HPV-16 and HPV-18, particularly in those who are HPV negative at the beginning. However, it is apparent that the vaccine may have much lower levels of efficacy in a “real world” setting, particularly in women above aged of 18 and already sexually active. One third of them may have already been infected with the oncogenic HPV strain that the vaccine is intended to protect against. The efficacy is only 17 to 33% for prevention of CIN caused by any of the oncogenic HPV strain. Therefore, proper counseling should be given to sexually active women above aged 18 seeking advise on vaccination. All these issues regarding reduced efficacy and the need to continue regular cervical cytology smear should be discussed to allow them to make an informed choice. So far, the cost effectiveness of mass vaccination in this group of women has not been proven. The criteria of being 18 years old and single do not mean that the woman has not been infected with the HPV. Mass vaccination like this may give them a false sense of security and yet may not provide any benefit in terms of the natural progression of the disease in those already infected. There is concern that vaccinated women may feel protected from cervical cancer and may be less likely than unvaccinated women to pursue screening. Vaccination of secondary target populations of older adolescent females or young women is recommended only if this is feasible, affordable, cost effective, does not divert resources from vaccinating the primary target population or effective cervical cancer screening programs, and if a significant proportion of the secondary target population is likely to be naive to vaccine-related HPV types. With so many essential questions still unanswered, there is good reason to be cautious about introducing large-scale vaccination programs. Instead, we should be more selective and focus on the groups where the benefit is maximal. In view of this, the Government of Malaysia and the relevant Ministries should re-look again into this program of mass vaccination and evaluate whether the RM 50 million is worth it.

Dr Lee Say Fatt
Consultant Obstetrician and Gynaecologist
Sime Darby Medical Centre
Subang Jaya