Expert Opinion - HPV immunisation policy needs to be clarified

If the DoH introduces an HPV vaccination programme, who should be vaccinated? By Dr Sarah Gray

HPV has many types, the oncogenic types 16 and 18 being implicated in the development of 70 per cent of cases of invasive cervical cancer (ICC). The public health burden of this condition is significant. Worldwide, ICC is the second most common cancer in women, with approximately 500,000 diagnoses and more than 250,000 deaths from the condition each year - 80 per cent of these occur in developing countries.

Although early surgery can be curative, and radiotherapy and chemotherapy have been shown to delay disease progression, there is little to offer in late-stage disease.

Screening, rather than prevention, has been the main strategy to date, although this is difficult to achieve in developing countries, which are doubly penalised because treatment may be unaffordable.

In the UK, the NHS Cervical Screening Programme has significantly reduced deaths from ICC. However, incidence of HPV infection and CIN 3 has risen in the past decade.

HPV has been implicated in 80 per cent of vaginal and vulval intraepithelial cancers. If the disease burden from genital warts and other anogenital malignancies in men and women is added to the equation, the potential individual and public health benefits to be gained from prevention are magnified.

Considerable effort has been expended to develop an effective vaccine against oncogenic HPV serotypes. Two vaccines have been extensively trialled, with the first (Gardasil) gaining approval from the European Medicines Agency in September 2006. UK approval followed shortly after, but NHS use is yet to be clarified. A second vaccine (Cervarix) has evidence of high efficacy and tolerability, and its EU approval is expected soon.

Implementing a vaccination programme
Gardasil is a quadrivalent vaccine, active against HPV types 6, 11, 16 and 18, which together are responsible for 90 per cent of genital warts. Cervarix is bivalent (16 and 18). Both vaccines have shown cross-immunity against HPV types 31 and 45.

A recent analysis of four randomised trials found the HPV vaccines used had 99 per cent efficacy against HPV-related CIN 2/3, adenocarcinoma in situ and cervical cancer.1 One of the trials used anti-HPV 16 vaccine only; the others had used the quadrivalent vaccine. The quadrivalent vaccine has been shown to provide similar levels of protection against vulval and vaginal intraepithelial neoplasia. Vaccination was less efficient where the regimen was not completed.1

The problem for clinicians is translating the science into practice. What do we tell patients? Are there cautionary notes or should vaccination be offered to all? Best protection is achieved from pre-exposure prophylaxis. How should we achieve this?

There are many reasons for reticence, particularly because it is not yet known how long immunity will last. Current evidence indicates anti-HPV antibodies persist for four to five years, but with potential sexual activity for more than 60 years, that leaves a long period of uncertainty.

Lack of long-term efficacy would undermine the programme's cost-effectiveness and be a major problem in developing countries, where booster doses would be impractical. Lack of long-term safety data adds to this dilemma.

The best age for vaccination is unknown. Efficacy evidence for licensing has been provided to age nine and it would appear desirable to immunise before the onset of sexual activity. While immune response may be greatest between the ages of nine and 11, does the response last long enough and is this the best time for the vaccine to be offered from a social perspective?

What about women and girls older than 12? Should they be offered a catch-up programme and will previous HPV exposure need to be excluded first? What about boys? No major trials have yet reported. Men can suffer the effect of HPV infection, with genital warts and anal carcinoma; should they not also be offered protection? News reports suggest that some men are actively seeking vaccination to protect themselves and their partners of either sex, despite the lack of evidence of efficacy.

Cost is likely to be a major barrier to general acceptance. The DoH estimate is £300 per full course of three injections over six months if delivered to 12- to 13-year-old girls at school. Such costs will cause particular difficulty in the developing world.

Issues of enforcement have also been raised. Mandatory vaccination is being considered by a number of US states and this has initiated a fierce debate.

Problems in primary care
Nearly a year after licensing in the UK, we still have no answers for our patients. This is causing problems in primary care. The Joint Committee on Vaccination and Immunisation has considered the scientific evidence, cost-effectiveness models and social issues and recommended to the DoH that girls of 12-13 should be offered the quadrivalent vaccine. This would be in the first year after secondary school entry and would allow the associated issues to be incorporated into the curriculum.

A robust recording system has been recommended, with the screening programme to continue to monitor effect. We are told this would cost less than the suggested revised NHS threshold of £20,000 per QALY. The politicians must now decide whether the UK can afford to proceed. Clinicians urgently need to know where the NHS stands on this issue.

- Dr Sarah Gray is a GPSI in women's health in Truro, Cornwall

Reference
1. Ault KA, Future II Study Group. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 2007; 369: 1861-8.

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