Sonntag, 13. Januar 2013

HPV Vaccination: Just Do It!

Why am I writing on this topic and why now? Already in 2012, I have briefly reviewed the evidence on HPV to be able to make evidence-based recommendations. While at the same time our national insurance was cementing its anti-intellectual reputation by opting out of covering even a fraction of the vaccine cost - against international recommendations (*). Now that I am taking a class on DNA viruses I decided to take up the topic again.The following article is both a response to Medizin-Transparent (German, quoted in blue) and also a Question & Answer session on HPV. Although, I quoted them in German, everything of importance for the international reader is in English.

* alternatively the issue may be political, several of our parties despise things like Sex Ed

Why does Austrian insurance (incl. their "experts") ignore expert consensus and why do well meaning skeptics promote the status quo?
There is now consensus in favour of a very broad vaccination program. In 2012, both the "Advisory Committee on Immunization Practices of the Centers for Disease Control " and "The American Academy of Pediatrics" agreed on as much, the latter recommends (2):

"All girls and women 13 through 26 years of age who have not been immunized previously or have not completed the full vaccine series should complete the series." [all quotes emphasis mine]

"All boys and men 13 through 21 years of age who have not been immunized previously or have not completed the full vaccine series should receive HPV4 vaccine."

Vaccinating older males is also effective, but cost-effectiveness is unclear:
"Men 22 through 26 years of age who have not been immunized previously or have not completed the full vaccine series may receive HPV4 vaccine. Cost-efficacy models do not justify a stronger recommendation in this age group."
(NB: cost-effectiveness considerations may differ, but efficacy will not be greatly different for Europe)

Even extremely conservative recommendations, like from the American Cancer Society (ACS), call for catch-up vaccinations in women up to 18-21yo. Importantly, these recommendations predate the CDC consensus and may be outdated, as per my ref. 7 the ACS published this in 2008, for instance.
The article I will critique (1) recommends vaccination starting age 12 and it "should" be done before having sex (technically this is not even wrong). Realistically, thinking like a layperson, I do not understand what it means. Do we have to guess an upper range? Also, their wording strongly emphasizes the "early" part, unintentionally poisoning the well.
"HPV-Impfung ab 12 Jahren empfohlen...Die HPV-Impfung wirkt allerdings nur dann, wenn es noch zu keiner Infektion mit dem Virus gekommen ist. Daher sollte die Impfung vor dem ersten sexuellen Kontakt stattfinden."

All in all, I have been disappointed to see that Medizin-Transparent did not second any of the recommendations. Normally, I enjoy their media-critical medicine articles a lot. Critics and even well-intentioned skeptics can be sloppy sometimes and I believe this is such a case.
I think the article is quite misleading but only slightly inaccurate - none of it deliberately, I hope.  Benefits are left out, or seem to be downplayed, expert consensus is not even mentioned, etc.

I. Which vaccine to chose?
II. Time frames: when will the vaccine work?
III. Does the vaccine prevent cancer or is the data limited to precancerous lesions?
IV. Efficacy: was it underestimated in the past?
V. Does the vaccine decrease morbidity? (esp. gardasil)
VI. Does vaccination prevent other cancers?
VII. Is there cross-resistance against non-vaccine strains?
VIII. Is there cross-protection of unvaccinated populations (herd immunity) and do we care?
IX. Durability, Safety and publication bias
X. How many lives will it save?  How many diseases prevent?
XI. Do we still need condoms and pap smears? Or: The vaccine paves the way for eradication (highly speculative) XII. Should boys and men also get the vaccine?

I. Which vaccine to chose?
I am not aware of a good reason not to chose the quadrivalent vaccine, Gardasil, which also protects against genital warts. Except price. Mostly I will focus on Gardasil, but some of the references I cite looked at both vaccines or pooled data.

II. Time frames: when will the vaccine work?
"Eine Modellrechnung des Wiener Ludwig Bolzmann-Instituts geht davon aus, dass die flächendeckende Einführung der HPV-Impfung für alle 12-jährigen Mädchen erste Erfolge in 20 Jahren zeigen würde"
Their summary says that reduced mortality from cervix carcinoma will (fully) manifest in 50 and begin after 20 years, but this seems extreme and the wording is misleading. Given the data on adenocarcinoma in situ (AIS) (see below) and what we know about the variability of cancer and its latency, some people will probably benefit after ~10 years.

More importantly benefits on genital warts and cervical intraepithelial neoplasia (CIN) will manifest within a few years as shown by randomized controlled trials (RCTs). These matter! The author(s) cannot hide behind the specifically worded question "will it reduce mortality?", since asking a half-question and giving half of a correct answer is still misleading to the public. This contradicts with the goal of informing the public. It is not enough to hyperlink to an accessible online FAQ, which also fails to mention established consensus.

III. Does the vaccine prevent cancer or is the data limited to precancerous lesions?
The authors find the clinical evidence convincing, as do other experts. These conclusions are based on studies of advanced precancerous lesions (CIN2 and higher). Nonetheless they say that no studies could demonstrate reduced cancer as of yet: "Da von der Infektion bis zur Ausbildung von Krebs Jahrzehnte vergehen können, konnte bis heute nur die Wirksamkeit gegen Krebs-Vorstufen gezeigt werden."

I am not aware of any meta-analysis that studied this endpoint. However, Ault et al. 2007 (n>20 000, ref. 4) did actually note a decrease in adenocarcinoma in situ (AIS) after pooling four studies, which was significant in PPP analysis and there was a numerical decrease in ITT (-50%). To be fair, cancer experts may consider AIS to be a precancerous lesion, although, Harrison's Principles of Internal Medicine does list it with the other carcinomas. So this is a minor quibble.

IV. Efficacy: was it underestimated in the past?
1. Is the vaccine effective in people who are sexually active? If so, until what age?
2. Is the vaccine effective in people who had been infected with HPV in the past? If so, does it prevent re-infection with the same strain or only strains never acquired before?
3. Or is it effective against an active infection? (so called therapeutic efficacy)
NB: 1 and 2 are slightly different questions, e.g. not all sexually active people have been infected

"The vaccine is inactive against HPV types previously acquired by the vaccine recipient [even this might be wrong, based on preliminary studies]" (2)
"Die HPV-Impfung wirkt allerdings nur dann, wenn es noch zu keiner Infektion mit dem Virus gekommen ist. Daher sollte die Impfung vor dem ersten sexuellen Kontakt stattfinden." (1)
I fear these statements may be easily misunderstood and the second quote seems misleading, as it basically and incorrectly replaces "HPV types" with "HPV virus infection".

The vaccine helps against types 6, 11, 16, 18 and offers some cross-protection against others, i.e. 31/33/45/52/58 with the latter two questionable (3). Unless you were infected by all of them, the vaccine should offer a degree of protection and maybe it does help against re-infection with the same type.
This is borne out by the very meta-analysis (3) the authors of (1) referenced: "lower [yet significant] efficacy [was] reported by the FUTURE trials [which] was likely due to inclusion of a larger proportion of trial participants already infected with vaccine HPV types at baseline in the ITT cohorts, some of whom may have progressed to cervical neoplasia during the follow-up period."
As well as other studies, as per (3):
While sexually naïve young women may derive greater public health benefit from HPV vaccination, vaccine appears to be of benefit to a broad age range of women many of whom may have acquired transient infections in the past or had active infection at the time of vaccination. Preliminary data from the quadrivalent vaccine trial of Muñoz and associates [18] enrolling 3819 24-45 year old women showed a 90% efficacy against combined incidence of vaccine HPV-related 6-month persistent infection, CIN 1-3 or external genital warts in PPP cohorts and a 31% efficacy in the ITT cohort. Recent studies further demonstrated that even among women who had detectable serological evidence of vaccine-HPV infection in the past and no DNA evidence of active infection at enrollment, prophylactic vaccination provides nearly 100 percent protection (95% CI: <0-100) against CIN2+ associated with a vaccine HPV type with which the women had been previously infected [22] [ie re-infection]. These data suggest that older reproductive-age women can still benefit from prophylactic vaccination.
Protection from new CIN lesions in women who had extant lesions at vaccination was confirmed in a recent analysis (6), actually, this was a useful sub-analysis of the FUTURE studies already reviewed in (3). I want to quote their lit. review for confirmation:
...suggest the benefits of vaccination are not limited to the primary target group of young, sexually naïve girls...Another study has shown the quadrivalent HPV vaccine generates an anamnestic response (renewed rapid production of an antibody on a subsequent encounter with the same antigen) in women aged 15–26 who are seropositive before vaccination,(35 36) and that the quadrivalent HPV vaccine prevents reinfection or reactivation of disease that is related to vaccine HPV types.(37)
For example, women who had cleared an HPV16 infection in the past were protected from developing subsequent HPV16 related disease. (37) A previous study has shown that women who are infected with one or more vaccine HPV types derive residual benefit by the quadrivalent HPV vaccine’s prevention of infection and disease from HPV type(s) to which the woman has not yet been exposed.(38) The vaccine is also effective in women up to the age of 45, whereby prophylactic vaccine efficacy against disease related to vaccine HPV types was 92.4% (49.6% to 99.8).(39)

On the other hand there seems to be zero therapeutic efficacy against ongoing infection and the vaccine does not treat existing precancerous lesions (e.g. ref. 21 in (3))

So the answers are:
1. yes, vaccination is effective until at least 26yo (official recommendation), perhaps up to age 45.
2. yes, vaccination will prevent a new infection, perhaps, even re-infection with the same type
3. no therapeutic efficacy

V. Does the vaccine decrease morbidity? (esp. gardasil)
Genital warts are at least ten times as common as cervical cancer, 12.4 times  as per (5), and lead to massive costs and morbidity. Since the vaccine also prevents CIN this will reduce associated morbidity (e.g. due to anxiety, ablation/excision, mis-diagnosis) and follow-up screening costs. CIN is more than ten times as common as cervical cancer (4). Another calculation: there are 10 to 15000 cases of cervical cancer each year in the US, but the number of cervical dysplasias is often given as 250'000 to >1000'000.  A ratio of 17-100, I'll work with 20.

The article (1) does mention protection from warts but not CIN or abnormal screening tests, calling warts a nuisance, "lästig und störend". Does this honestly not sound like downplaying vaccine benefits? Contrast the wording in a different publication:
"LSIL, HSIL [i.e. CIN or cervical dysplasias], and cervical cancer carry significant morbidity and/or mortality; genital warts and abnormal Pap test results are often significant sources of psychosocial distress...each episode of genital warts required an average of 3.1 doctor visits, with an average total cost of $436 for all visits...there [are no] comprehensive and effective treatments for the clinical consequences of infection...recurrence"

VI. Does vaccination prevent other cancers?
Yes, in all likelihood the vaccine also prevents other cancers which was corroborated by randomized controlled trials. HPV-related non-cervix carcinomas taken together are about 40-65% as common as cancer of the cervix, but probably not all of these are exclusively due to HPV (cdc fact sheet, ref. 5)
The authors of (1) describe them as comparatively rare, "vergleichsweise selten", which may be true, but I find this is misleading to a lay person, downplaying the importance of these cancers.

VII. Is there cross-resistance against non-vaccine strains?
Although HPV types 16 and 18 cause only approx. 70% of all cancers, there is evidence of cross-protection from types that cause another 18% (3). This means that in the best case the vaccine might grant close to 99% protection from HPV-induced cervix cancer, or from 88% of all cervical cancers - not just 75% as the authors say. This could be a minor error or a difference in source material, but why are all benefits systematically underestimated by the authors of (1)?

Efficacy against "CIN2 and 3 + AIS" from vaccine strains is indeed around 90 to 100% in the PPP analysis (3):
"The fixed-effect Relative Risk (RR) and 95% confidence intervals were 0.04 (0.01-0.11) and 0.10 (0.03-0.38) for HPV-16 and HPV 18-related CIN2+ in the per-protocol populations (PPP). The corresponding RR was 0.47 (0.36-0.61) and 0.16 (0.08-0.34) in the intention-to-treat populations (ITT)."

And in any case, it is inaccurate to claim that the vaccine does not protect against any of the other strains. It is possible the authors misread the abstract: "There was limited prophylactic effect against CIN2+ and 6-month persistent infections associated with non-vaccine oncogenic HPV types."
Limited is still meaningful and significant: "Our results demonstrated statistically significant but limited protection against CIN2+ associated with non-vaccine-type oncogenic HPV that are phylogenetically related to HPV 16 and 18 in both ITT and PPP cohorts (RR: 0.79 in ITT and 0.58 in PPP)."

VIII. Is there cross-protection of unvaccinated populations (herd immunity) and do we care?
The authors ignore that vaccinating women protects men and vulnerable unvaccinated partners as well: "once female vaccination coverage exceeds 50%, 'herd immunity' will eventually develop, and men who have sex only with women will be protected [obviously herd immunity will also apply to women]...In many developed countries, including those in western Europe, the burden of HPV-associated cancers in men is now comparable to that in women..."  (5)

IX. Durability, safety and publication bias
So far no bad surprises. Antibodies have been shown to persist for at least 9-10 years. (eg as mentioned in ref. 6, the latter two were confirmed in ref. 3) There was no evidence of publication bias and no significant safety concerns were seen (3).

X. How many lives will it save?  How many diseases prevent?
Let's use Austria as an example with a population size of about 8 million:
"...Angaben der Statistik Austria zufolge [sind] im Jahr 2010 nur 161 Frauen an Gebärmutterkrebs gestorben... [vgl. Übertreibungen in der Zeitung]"
In Austria there were 161 deaths from cervical cancer in 2010 but a Health technology assessment (HTA) published in 2007 estimates that only 33 deaths per year could be prevented with the vaccine. However, a study from 2007 must rely on outdated assumptions, given the pace of HPV research. Instead I will do a quick and dirty analysis based on up to date data, simply to show that the HTA is outdated and we need a new analysis. The calculations are rather long so you can skip to the "Summary" if you wish.

The authors estimated 33 deaths would be prevented, whereas my preliminary analysis showed that:

Approx. 70 deaths from cervix carcinoma will be prevented per year. Approx. 245 cervix carcinomas will be prevented per year. (Read: 245 cases of which 70 would have been deadly)
Approx. 4900 precancerous cervical lesions will be prevented per year.
Approx. 19 non-cervial cancer deaths will be prevented per year in women.
Approx. 66 non-cervial cancers will be prevented per year in women and >10 times as many precancerous changes.
Approx. 28 non-cervial cancer deaths will be prevented per year in men - due to herd immunity.
Approx. 99 non-cervial cancers will be prevented per year in men  and >10 times as many precancerous changes.
Approx. 3350 and 3000 genital warts will be prevented in women and men, respectively.

XI. Do we still need condoms and pap smears? Or: The vaccine paves the way for eradication (highly speculative)
Since the vaccine does not offer 100% protection condoms will still be required, indeed, more than ever. First of all, the so called "health halo" effect may offset some of the vaccine benefits if people engage in riskier behavior afterwards. (Do note that this also applies to other prevention measures like pap smears, for instance.)
Second, condoms will help eradication efforts. Humans are the only natural reservoir of HPV ( So it does not seem far fetched to believe that we may be able to eradicate the high-risk variants, even all cancer causing HPV types, some day. The sooner we get there, the sunnier the future.

XII. Should boys and men also get the vaccine?
As far as I know, and I may be off here, the argument against vaccinating boys is three-fold: the risk-benefit ratio is bad, it's uneconomic and it's unnecessary.
The risk-benefit ratio for males is obviously worse, but it's nonsense to say it's bad: men still get a lot of HPV-related cancers - 60% of the cervix carcinoma incidence - and more genital warts than women (VI, ref. 5).
"It's uneconomic" is not even an argument. This matters only from a public health perspective (insurance coverage) and much less on an individual level. Also, it has no bearing on efficacy.
It's unnecessary, because of herd immunity, remains the only good argument. If herd protection for men approaches 100%, the added vaccine benefit goes to zero and the risks remain. Herd immunity also explains why in certain models vaccinating males is too expensive.
This is still problematic, and a little cynical, since men would be disadvantaged until said herd immunity develops.
So for now I concur with the CDC (2): males until at least 21yo should get vaccinated and insurance should pay for it. I believe this course of action is prudent at least until herd immunity starts to develop.

(1) HPV-Impfung: nüchterne Fakten statt hitziger Diskussionen

(2) HPV vaccine recommendations.
Committee on Infectious Diseases.
Pediatrics. 2012 Mar;129(3):602-5. doi: 10.1542/peds.2011-3865. Epub 2012 Feb 27.

(3) Lu, B., A. Kumar, et al. (2011). “Efficacy and safety of prophylactic vaccines against cervical HPV infection and diseases among women: a systematic review & meta-analysis.” BMC Infect Dis 11: 13.

(4) Lancet. 2007 Jun 2;369(9576):1861-8.
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.
Ault KA; Future II Study Group.

(5) Nature. 2012 Aug 30;488(7413):S10. doi: 10.1038/488S10a.
Perspective: Vaccinate boys too.
Stanley M.

(6) BMJ. 2012 Mar 27;344:e1401. doi: 10.1136/bmj.e1401.
Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data.
Joura EA, Garland SM, Paavonen J, Ferris DG, Perez G, Ault KA, Huh WK, Sings HL, James MK, Haupt RM; FUTURE I and II Study Group.

(7) Saudi Med J. 2012 Dec;33(12):1270-7.
Human papillomavirus, vaccines, and protection from cervical cancer.
Altinbas SK, Tapisiz OL.

1 Kommentar:

  1. this post may undergo slight edits after it has been published