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Human virus (HPV) Vaccine Policy and Evidence-based Medicine at Odds

Human virus (HPV) Vaccine Policy and Evidence-based Medicine at Odds

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Human papillomavirus (HPV) vaccine policy and evidence-basedmedicine: Are they at odds?
Lucija Tomljenovic
& Christopher A. Shaw
Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia, 828 W. 10th Ave,Vancouver, BC, V5Z 1L8, Canada and 
 Program in Experimental Medicine and the Graduate Program in Neuroscience, University of BritishColumbia, Vancouver, BC, Canada
In  the US Food and Drug Administration (FDA) stated that vaccines represent a special category o drugs aimed mostly athealthy individuals and or prophylaxis against diseases to whichan individual may never be exposed (). Tis, according to theFDA,places signifcant emphasis on vaccine saety (). In otherwords, contrary to conventional drug treatments aimed at man-agement o existing, oentimes severe and/or advanced diseaseconditions, in preventative vaccination a compromise in e cacy or the beneft o saety should not be seen as an unreasonableexpectation. Furthermore, physicians are ethically obliged toprovide an accurate explanation o vaccine risks and benefts to theirpatients and, where applicable, a description o alternative courseso treatment. Tis in turn enables patients to make a ully inormeddecision with regard to vaccination. For example, the Australianguidelines or vaccination emphasize that or a consent to belegally valid, the ollowing element
be satisfed: ‘it [consent]can
be given aer the relevant vaccine (s) and their potentialrisks and benefts have been explained to the individual’ (empha-sis added) (). Likewise, the United Kingdom (UK) guidelinespertaining to vaccination practices state that subjects must be given
 Annals of Medicine
, 2011; Early Online,
© 2011 Informa UK, Ltd.ISSN 0785-3890 print/ISSN 1365-2060 onlineDOI: 10.3109/07853890.2011.645353
Key messages
o date, the e cacy o HPV vaccines in preventing
cervical cancer has not been demonstrated, while vaccine risks remain to be ully evaluated.Current worldwide HPV immunization practices with
either o the two HPV vaccines appear to be neither justifed by long-term health benefts nor economicall viable, nor is there any evidence that HPV vaccination(even
proven eective against cervical cancer) wouldreduce the rate o cervical cancer beyond what Papscreening has already achieved.Cumulatively, the list o serious adverse reactions
related to HPV vaccination worldwide includes deaths,convulsions, paraesthesia, paralysis, Guillain–Barrésyndrome (GBS), transverse myelitis, acial palsy,chronic atigue syndrome, anaphylaxis, autoimmunedisorders, deep vein thrombosis, pulmonary embolisms,and cervical cancers.Because the HPV vaccination programme has global
coverage, the long-term health o many women may beat risk against still unknown vaccine benefts.Physicians should adopt a more rigorous evidence-based
medicine approach, in order to provide a balanced andobjective evaluation o vaccine risks and benefts to theirpatients.
 All drugs are associated with some risks o adverse reactions. Be-cause vaccines represent a special category o drugs, generallygiven to healthy individuals, uncertain benefts mean that onlya small level o risk or adverse reactions is acceptable. Further-more, medical ethics demand that vaccination should be carriedout with the participants ull and inormed consent. This neces-sitates an objective disclosure o the known or oreseeable vac-cination benefts and risks. The way in which HPV vaccines areoten promoted to women indicates that such disclosure is notalways given rom the basis o the best available knowledge. Forexample, while the worlds leading medical authorities state thatHPV vaccines are an important cervical cancer prevention tool,clinical trials show no evidence that HPV vaccination can protectagainst cervical cancer. Similarly, contrary to claims that cervicalcancer is the second most common cancer in women worldwide,existing data show that this only applies to developing countries.In the Western world cervical cancer is a rare disease with mor-tality rates that are several times lower than the rate o reportedserious adverse reactions (including deaths) rom HPV vaccina-tion. Future vaccination policies should adhere more rigorouslyto evidence-based medicine and ethical guidelines or inormedconsent.Key words:
Cervarix, cervical cancer, Gardasil, HPV vaccines, informed consent, vaccine adverse reactions
Lucija omljenovic, Neural Dynamics Research Group, Department o Ophthalmology and Visual Sciences, University o British Columbia,828 W. 10th Ave, Vancouver, BC, V5Z 1L8, Canada. E-mail: lucijat77@gmail.com
(Received 24 May 2011; accepted 31 October 2011)
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L. Tomljenovic & C. A. Shaw 
adequate inormation on which to base their decision on whetherto accept or reuse a vaccine (). Tis includes having a clearexplanation on vaccine risks and side-eects ().Surprisingly, in the United States (US), there are no governmen-tal requirements or inormed consent or vaccination (). Suchan omission leaves the door open to a ailure to obtain inormedconsent. Nonetheless, there are regulatory agencies such as theUS FDA which are empowered to assure that only demonstrably sae and eective vaccines reach the market.In addition, healthauthorities (i.e. US Centers or Disease Control and Prevention(CDC)) are expected to provide expert advice concerning thebenefts and risks related to particular drugs, including vaccines.When these o cial bodies are not able to provide their normalregulatory oversight and/or i fnancial interests take precedenceover public health, signifcant problems in true inormed consentguidelines can occur.What is known about the currently licensed human papillo-mavirus (HPV) vaccines? What are their benefts, and what aretheir risks? While medical authorities in a number o countries,including the US, strongly advocate their use, some members o the public have become increasingly sceptical or a variety o rea-sons. Te key question posed by such sceptics is this: Is it possiblethat HPV vaccines have been promoted to women based on inac-curate inormation? Te present article examines the evidence inorder to answer this critical question.
Can the currently licensed HPV vaccines preventcervical cancer?
Gardasils manuacturer, Merck, states on their website thatGardasil does more than help prevent cervical cancer, it pro-tects against other HPV diseases, too.’ Merck urther claimsthat ‘Gardasil does not prevent all types o cervical cancer’ ().Similarly, the US CDC and the FDA claim that ‘his [Garda-sil] vaccine is an important cervical cancer prevention toolthat will potentially beneit the health o millions o women() and ‘Based on all o the inormation we have today, CDCrecommends HPV vaccination or the prevention o mosttypes o cervical cancer’ (). All our o these statements are atsigniicant variance with the available evidence as they imply that Gardasil can indeed protect against some types o cervicalcancer.At present there are no signifcant data showing that eitherGardasil or Cervarix (GlaxoSmithKline) can prevent any type o cervical cancer since the testing period employed was too shortto evaluate long-term benefts o HPV vaccination. Te longestollow-up data rom phase II trials or Gardasil and Cervarix are and . years, respectively (), while invasive cervical cancertakes up to  years to develop rom the time o acquisition o HPV inection (). Both vaccines, however, are highly eec-tive in preventing HPV-/ persistent inections and the associ-ated cervical intraepithelial neoplasia (CIN) / lesions in youngwomen who had no HPV inection at the time o frst vaccination(). Nonetheless, although cervical cancer may be causedby persistent exposure to  out o  extant HPVs throughsexual contact (), even persistent HPV inections caused by high-risk ’ HPVs will usually not lead to immediate precursor le-sions, let alone in the longer term to cervical cancer.Te reasonor this is that as much as % HPV inections resolve spontane-ously within  years and, o those that do not resolve, only a smallproportion may progress to cancer over the subsequent years (,,). Moreover, research data show that evenhigher degrees o atypia (such as CIN /) can either resolveor stabilize over time (). Tus, in the absence o long-termollow-up data, it is impossible to know whether HPV vaccinescan indeed prevent
cervical cancers or merely postponethem. In addition, neither o the two vaccines is able to clear exist-ing HPV-/ inections, nor can they prevent their progressionto CIN / lesions (,). According to the FDA, ‘It is
 that prevention o cervical precancerous lesions is highly 
 to result in the prevention o those cancers’ (emphasis added)(). It would thus appear that even the FDA acknowledges thatthe long-term benefts o HPV vaccination rest on assumptionsrather than solid research data.
Gardasil and Cervarix: do the benefits of vaccinationoutweigh the risks?
Currently, governmental health agencies worldwide state thatHPV vaccines are ‘sae and eective’ and that the beneitso HPV vaccination outweigh the risks (,,). Moreover,the US CDC maintains that Gardasil is ‘an important cervi-cal cancer prevention tool’ and thereore ‘recommends HPV vaccination or the prevention o most types o cervical can-cer’ (,). However, the rationale behind these statements isunclear given that the primary claim that HPV vaccinationprevents cervical cancer remains unproven. Furthermore, inthe US, the current age-standardized death rate rom cervi-cal cancer according to World Health Organization (WHO)data (./,) (able I), is . times lower than the rateo serious adverse reactions (ADRs) rom Gardasil reportedto the Vaccine Adverse Event Reporting System (VAERS)(./, doses distributed) (able II). In the Netherlands,the reported rate o serious ADRs rom Cervarix per ,doses administered (.) (able II) is nearly -old higherthan the age-standardized death rate rom cervical cancer(./,) (able I).Although it may not be entirely appropriate to comparedeaths alone rom cervical cancer to serious ADRs rom HPV vaccines, it should be re-emphasized that (in accordance withFDA guidelines) the margin o tolerance or serious ADRs ora vaccine with uncertain benefts needs to be very narrow, es-pecially when such vaccine is administered to otherwise healthy individuals ().HPV vaccination, even
proven eective asclaimed, is targeting  year old girls to prevent approximately % o cervical cancers, some o which may cause death at a rateo ../, women in developed countries with eectivePap smear screening programmes (able I). For a vaccine de-signed to prevent a disease with such a low death rate, the risk to those vaccinated should be minimal. Further, according tosome estimates, HPV vaccination would do little to decrease thealready low rate o cervical cancer in countries with regular Papscreening (). Tus, any expected beneft rom HPV vaccina-tion will notably drop in the setting o routine Pap screening.Accordingly, the risk-to-beneft balance associated with HPV vaccination will then also become less avourable. On the otherhand, in developing countries where cervical cancer deaths aremuch higher and Pap screening coverage low (able I), the po-tential benefts o HPV vaccination are signifcantly hampered by high vaccine costs ().It should be noted that or any vaccine the number o dosesthat are eventually administered is lower than the number o doses that are distributed. Tus, calculations based on the lattertend to under-estimate the rate o vaccine-associated ADRs (Fig-ure ). Supporting this interpretation, we show in able II andFigure  that or any o the two HPV vaccines, the reported rate o ADRs per , doses administered is very similar across di-erent countries and approximately seven times higher than that
   A  n  n   M  e   d   D  o  w  n   l  o  a   d  e   d   f  r  o  m   i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m   b  y   U  n   i  v  e  r  s   i   t  y  o   f   B  r   i   t   i  s   h   C  o   l  u  m   b   i  a  o  n   1   2   /   2   2   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .
HPV vaccines and evidence-based medicine
3calculated rom the number o distributed doses. Te latter calcu-lations also show a comparable range across several countries (Fig-ure ). Given that government-o cial vaccine surveillance pro-grammes routinely rely on passive reporting (), the rate o ADRsrom HPV and other vaccines may be urther under-estimated.According to some estimates, only –% o the ADRs in the USare reported to VAERS ().Te lack o data on serious ADRs in countries where routineHPV vaccination or young women is recommended and strongly promoted (able II) greatly hampers our understanding about the
able I. Key data on cervical cancer, HPV-/ prevalence, and cervical cancer prevention strategies in  countries. Data sourced rom the World HealthOrganization (WHO)/Institut Catala dOncologia (ICO) Inormation Centre on HPV and cervical cancer ().Country Incidence per, women(age-standardized)Mortality per, women(age-standardized)Mortality rankingamong all cancers(all ages)Pap screening coverage (%)HPV-/prevalence inwomen with low-/high-grade lesions/cervical cancer (%)HPV vaccineintroducedAustralia..th.(All women aged  y screened every  y)././.YesNetherlands..th. (All women aged
 y screened every  y)././.YesUS..th. (All women aged
 y screened every  y).//.YesFrance..th.(All women aged  y screened every  y ././.YesCanada..th.(All women aged  y screened every  y; Annual i athigh risk)././.YesSpain..th.(All women aged  y screened every  y ././.YesUK and Ireland.th(All women aged  y screened every  y)././.YesIsrael..th.(All women aged  y screened every  y)././.YesGermany..th.(Women aged  y screened every  y)././.YesChina..th.(All women aged  y screened every  y)././NoViet Nam..th.(All women aged  y screened every  y)././.YesRussia..th.(All women aged  y screened every y).//YesBrazil..nd.(All women aged  y screened every  y).//.YesTailand..nd.(All women aged  y ever screened././.YesPakistan..nd.(All women aged  y screened every  y)/./.YesSouth Arica..nd.(All women aged  y screened every  y ././.YesIndia.st.(All women aged  y screened every  y)//.YesCambodia..stNone././.YesNepal..st.(All women aged y screened every  y /./.NoNigeria.ndNone././YesGhana..st.(All women aged  y screened every  y)././YesUganda..stNone././.Yes able II. Summary o adverse reactions (ADRs) rom HPV vaccines Gardasil and Cervarix. Note that the US FDA Code o Federal Regulation defnes a seriousadverse drug event as ‘any adverse drug experience occurring at any dose that results in any o the ollowing outcomes: death, a lie-threatening adverse drugexperience, inpatient hospitalization or prolongation o existing hospitalization, a persistent or signifcant disability/incapacity, or a congenital anomaly/birthdeect’ ().VaccineCountryotal
seriousADRs/, dosesGardasilUS,(),,
not available.
 Doses distributed.
 Doses administered.
 Excluding  data(unavailable at the time o writing o this report).
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