Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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How efficient are these vaccines really?
- Ian N Miskin (23 July 2008)
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Dilemmas with HPV vaccination programme
- Tom J. Black (12 August 2008)
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A lost opportunity in HPV immunisation
- Peter D Bull (13 August 2008)
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HPV infection is more than Cervical Cancer and Genital Warts.
- Desmond A Nunez (13 August 2008)
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The choice of vaccine and exclusion of MSMs
- Ravindra Gokhale (13 August 2008)
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Ian N Miskin, Consultant in infectious diseases Clalit services, Jerusalem, Israel
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Dear Sir, The various articles published on the two current HPV vaccines stem from 3 major studies: FUTURE 1 & 2 which examined the effect of Merck gardasil quadrivalent vaccine and PATRICIA that of the bivalent vaccine cervarix (GSK). Both these studies were based on the rationale that HPV types 16 and 18 are the cause of over 70% of all cervical cancers worldwide. However, this does not seem to be the situation in Africa (JID 2008; 197: 555). In other countries such as Israel, the rates of the various HPV types are unknown. In all three studies a surrogate endpoint of premalignant cervical lesions was used, with the prior agreement of both the FDA and WHO. Both vaccines showed a 95% reduction in premalignant vaccine-type cervical lesions. However, even amongst those testing negative for HPV at the first vaccination, there was only a 27% reduction in premalignant cervical lesions caused by all HPV types. This is the equivalent of vaccinating prior to sexual activity and HPV exposure- the rationale for vaccinating at age 12. All data are from manufacture-sponsored studies. [The FUTURE 2 study NEJM 2007; 356: 1915] When those who tested positive for HPV at first vaccination were included, the reduction in premalignant lesions was even lower- 17%. This would appear to be the figure expected if the vaccination programme includes a catch-up group. The product insert for Gardasil on the Merck site contains the following statement: "GARDASIL reduced the overall rate of CIN 2/3 or AIS caused by vaccine or non-vaccine HPV types by 12.2% (95% CI: -3.2%, 25.3%), compared with placebo.” [http://www.merck.com/product/usa/pi_circulars/g/gardasil/gardasil_pi.pdf accessed 22/07/2008]. Thus it would appear that the manufacturer is aware of the limitations of the vaccine. Other questions have been raised by Mark Schiffman and others in their seminar "Human papillomavirus and cervical cancer" [Lancet 2007; 370: 890]. These address such issues as the effect of vaccination at an early age, later infection by HPV 16 and 18, the need for booster doses etc. These questions have yet to be answered due to the short duration (maximum 7 years) of these trials. Despite these limitations, many developed countries have started to introduce HPV vaccination both as primary vaccination at age 12 as well as offering it to those well past the age of HPV exposure. Most of these countries already have successful cervical cancer screening programmes, which are expected to further blunt the reduction in the rate of cervical cancer due to the vaccine. A 27% reduction in cervical cancer translates to a number needed to treat (NNT) of well over 1000. As stated, existing pap screening will attenuate this reduction and increase the NNT. It would appear that the cost per QALY gained will be higher than that quoted. Should we be looking for other ways of improving health? Ian Miskin MD, specialist in family practice and infectious diseases. Competing interests: None declared |
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Tom J. Black, Hon.Secretary Western LMC N.Ireland Abbey Medical Practice Derry BT48 9DN
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In negotiations last week to organise the HPV vaccination of 17 to 18 year olds in general practice in my area a number of ethical dilemmas quickly became evident.The government has decided to cover 12/13 year olds through a school vaccination programme and is asking GP practices to cover the more difficult to locate group of 17/18 yr olds.The bivalent vaccine Cervarix is preferred to the quadrivalent Gardasil for ''value for money'' reasons based on the logic of QALYs and opportunity costs(as outlined by Kim BMJ 2008;337).Assuming GPs agree we would expect to cover up to 90% of the population of 18/19 year old girls with a significant reduction in mortality and morbidity from cervical pathology in this cohort in the future. The dilemmas arise when we ask why we aren't using Gardasil,why we are delaying vaccinating the 13 to 17 year olds and why we have no plans to vaccinate the 18 to 26 year group.Of course since Gardasil is prescribable on an FP10 GPs could simply ignore the government plans and prescribe and vaccinate on an individual basis using clinical needs as our guide.The difficulty with this is that we would struggle to resource this work in terms of staff(nursing ,GP and receptionist) particularly since there would be no government support.We would be flying in the face of Department of Health guidance which would undermine confidence in the official programme and we would also struggle to achieve the high coverage levels of the official programme.The extra expense in prescribing Gardasil would have opportunity costs for the rest of the service. Is there a clear path through this for GPs trying to balance the needs of individual patients in a culture of population based health economics.Would any individual using their own money to purchase this vaccination have made the same choice as the NHS? I don't think so but is that a standard we can use in a universal health care system based on compulsory taxation? It would seem sensible to work with the Department of Health in the official programmes for 12/13 year olds and 17/18 year olds using the Cervarix vaccine.However if patients outside these age groups requested vaccination and this was clinically indicated a clear case could be made for using the quadrivalent vaccine Gardasil as this would give added protection against genital warts.It should be noted that individual prescription costs for Cervarix and Garasil are equivalent according to Mims.This would cause disquiet among the public as they compare the official programme to individual GP decisions. The overall impression is of a programme that has not been clearly thought through, where short term savings have been prioritised over longterm care and where individual needs have been subordinated to the needs of the population. Competing interests: GPs have been offered £7.51 per Cervarix vaccine |
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Peter D Bull, retired paediatric otolaryngologist Sheffield Children's Hospital, S10 2TH
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A rare but serious and occasionally fatal result of infection with HPV 6 or 11 is recurrent respiratory papillomatosis (RRP). This causes chronic illness and typically presents in infancy with loss of voice and airway impairment. In about half of the infants affected, the mother will have had genital warts during pregnancy. Adults are also affected by RRP, with adverse consequences on employment because of difficulty with the voice. Surgical treatment under general anaesthesia may be needed every few weeks to maintain an airway and the voice rarely recovers to normal. Immunisation with the quadrivalent vaccine, which is active against HPV6 and 11 as well as 16 and 18, held long-term the possibility of a reduction in the incidence of RRP, and the choice of the bivalent vaccine on what appear to be financial grounds has lost this opportunity. The cost of treating children with RRP, over many years in some cases, has been estimated in the USA at US$150million per annum (Derkay 1995)and this cost has been omitted completely from the UK analysis. Those of us who have spent a professional lifetime treating this awful disease will be very disappointed at this outcome. Peter Bull
Derkay CS, Task force on recurrent respiratory papillomas. A preliminary report. ArchOtolaryngol Head and Neck Surg 1995. 121:1386-1391. Competing interests: i have attended 2 meetings funded by SanofiPasteurMSD to explore the development of a European database for recurrent respiratory papillomatosis |
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Desmond A Nunez, ENT Director North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB
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Dear Sir or Madam: I am concerned that the 9th August issue of the BMJ gives the impression that HPV infection primarily affects females title page ‘protecting girls against HPV’ or is only of clinical importance because of a role in oncogenesis1 or genital warts2. Readers should be made aware that HPV types 6 and 11 cause recurrent respiratory papillomatosis a rare condition estimated to affect 3-4 per million in the European population3 associated with significant morbidity and risk of mortality. RRP presents with airway compromise or dysphonia. Juvenile onset disease is the more severe pattern affecting both males and females with a median age of onset between 3-5 years. Transmission is believed to be vertical from mother to child with an estimated 231 times increased risk of the disease in children born to mothers with genital tract condoylomata4. Surgery is the main stay of treatment but the condition is difficult to eradicate in many patients and multiple airway procedures under general anaesthesia are required per year over the course of several years5. As a result the economic costs of managing a single case of juvenile onset RRP in the USA is estimated at $201,724 USD6. HPV vaccination is likely to have an effect on the incidence of RRP and the subsequent clinical and economic costs associated with its management. It is unclear that a vaccine targeted against HPV16 and 18 alone will lead to a reduction in HPV6 and 11 related disease. More concerning would be an increase in HPV6 and 11 diseases secondary to targeting HPV16 and HPV18 with a bivalent vaccine. The foregone price may not simply be more cases of genital warts. Desmond A Nunez
1. Kim JJ. Human Papillomavirus vaccination in the UK. BMJ 2008;337:a482. 2. Jit M. Economic evaluation of human papillomavirus vaccination in the United Kingdom. BMJ 2008;337:a769. 3.Silverberg MJ, Thorsen P, Lindeberg H, Ahdieh-Grant L, Shah KV. Clinical course of recurrent respiratory papillomatosis in Danish children. Arch Otolaryngol Head Neck Surg. 2004 Jun; 130(6):711-6 4. Silverberg MJ, Thorsen P, Lindeberg H, Grant LA, Shah KV. Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory papillomatosis. Obstet.Gynecol. 2003;101(4):645-52. 5. Nunez DA. Recurrent Respiratory Papillomatosis: case report and literature review. Paediatriki 2008;71:162-164. 6. Bishai D, Kashima H, Shah K. The cost of juvenile-onset recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg. 2000 Aug;126(8):935-9. Competing interests: DAN has acted as a consultant for Sanofi Pasteur MSD and the European Recurrent Respiratory Papillomatosis Network of which he is chairman has received research funding from Sanofi Pasteur MSD, suppliers of Gardasil. |
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Ravindra Gokhale, Consultant Physician in Gento-Urinary Medicine Wirral University Teaching Hospital Foundation NHS Trust, Wirral CH49 5PE
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Dear Sir We are in a bit of dilemma. As a GUM (Genito-Urinary Medicine) and Sexual Health Physicians, we see majority of clinically obvious HPV infection in young sexually active men and women which remains the commonest sexually transmitted infection in the western world. Treatment of genital warts doesn't come cheap as it costs around £25 millions per year to the NHS, not to mention the psycho-social impact of persistent HPV infection. The chosen bi-valent vaccine Cervarix does not cover the common HPV types 6 and 11 and hence likely to have less impact on prevention of genital warts. I am also concerned with the exclusion of other at risk groups such as men who have sex with men (MSMs) in the national programme. HPV is extremely common in MSMs and has also been found to be asssociated with Anal and Penile Intra epithelial neoplasias (AIN and PIN). It is well documented that HIV positive gay men are at increased risk of invasive anal cancers and highly active anti retroviral therapy (HAART) does not reduce the risk. Presently we do not have studies in MSMs to support its use and it is not licensed for adults over 25 years of age. However one can easily extrapolate the current evidence to support its use for young men. In the mean time we have no options but to ask the patients to buy the quadruvalent Gardasil which I think would have also helped in preventing persistent HPV infection. Many thanks Dr Ravindra Gokhale
Competing interests: None declared |
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