Some people have taken issue with the conclusion and analysis in my previous post, "Should Boys Be Given the HPV Vaccine? The Science Is Weaker Than the Marketing," including epidemiologist Tara Smith in her blog, Aetiology, at ScienceBlogs. Here’s a clarification of some of the points in my post, and a response to some of hers. First I’ll reiterate the key point of my post: There are many, many instances in which researchers have promised cures and interventions that were expected to work based on eminently reasonable logic, but did not pan out. Take one recent recent example: bypass a clogged artery and you will prevent strokes (see Sharon Begley’s excellent blog post on “When Biology Refuses to Listen to Medical Logic”). And now comes one more eminently logical assumption: prevent cervical lesions from some strains of HPV in some people for some period of time, and you will save lives from cervical cancer overall. Unfortunately, while the two HPV vaccines on the market may decrease the serious illness and death from cervical cancer, no study has proved that at this point, since no study has been conducted long enough to observe the development of cervical cancer or cervical cancer deaths. Conclusive studies with the most important, clinically relevant end points should precede wide uptake of any intervention. The data currently rely on surrogate end points (markers of possible cancer) and are simply not conclusive. So we can’t truly say how effective the vaccine is. Wake Forest medical researcher Curt Furberg, a former FDA advisor and co-author of the textbook Fundamentals of Clinical Trials, told me, “Getting data from markers is a first step. But we have burned our fingers too many times with surrogate markers. You should try to determine the real health benefit. Everything will be up in the air until we have the answer to the question: Will it prevent cancer? And until we have that answer, we should limit its use to girls enrolled in studies of the vaccine.” Here are some other reasons why the HPV vaccines may not be as effective as advertised: Duration of Protection:An important issue raised by Diane Harper, an HPV researcher, is how long the vaccine will remain effective. She says the antibody titers in women who receive the vaccine fall off over time—i.e., the vaccine loses effectiveness. “One third of women lose antibody titers and hence protection from HPV by 5 years,” and “at 8.5 years, 15 percent have lost all detectable antibody titers to HPV-16, which leaves them completely unprotected from HPV-16 and -18, the only two cancer-causing strains that Gardasil was supposed to protect against.” Harper says because of the vaccine’s limited duration, it likely won’t decrease the cervical cancer rate significantly below where it is with the routine Pap screening currently in use, although it may postpone cancer until later in life. Booster shots could presumably extend the effectiveness of the vaccine, she says, but we don’t yet have data on that. (Harper has received funding from Merck and GlaxoSmithKline for research on their HPV vaccines.) HPV Rates in Pre-Sexual-Activity Girls:Smith dismisses my concern that many girls and women were excluded from the FUTURE I and II analyses, which I said prevented a real-world analysis and inflated the value of the vaccine. She said those test subjects should be excluded from the analysis because, as she and a number of readers have suggested, the subjects in the trials were older than the 9- and 11- year old girls the vaccine targets. And because they were older (15 to 26 years of age), many were sexually active and already had HPV. Smith says excluding these girls is reasonable since they did not represent the ideal vaccine candidate. What makes an ideal candidate? Nine- to 11-year-old girls are allegedly ideal since they presumably won’t be sexually active and won’t have HPV---i.e., they will be “susceptible” to the virus and vaccine. The problem with that logic is that while sexual contact is taken to be the primary transmission mechanism for HPV, some studies have found that the HPV infection rate is far from negligible among girls who are not yet sexually active. One small study found that 15 percent of all newborns had genital HPV at birth, rising to 18 percent at six months. Another set of researchers detected HPV in nearly one in five girls (18 percent) ages 4 to 15 years (median age 9.5 years) who were virgins (girls who were victims of verified or suspected abuse, and girls that became sexually active during the trial, were excluded from the study). That percentage could be higher in the real-world cohort of vaccine recipients, since abused girls would not be excluded from vaccination. Another, much larger study found that among females aged 14-19 who said they’d never had sex (vaginal, anal, or oral), 9.8 percent were HPV positive. (Among all 14-19-year-olds, the rate of high-risk HPV was 25 percent, which is relevant for the teenagers who are vaccinated along with the pre-teens.) Furberg says that before deciding that 9- and 11-year-old girls are good candidates for the vaccine, manufacturers need to answer the question: “Can you extrapolate benefit from a subgroup of tested subjects [those who were not HPV infected] to the girls you want to vaccinate? You should at least find out first whether the proportion [of HPV-infected girls] is high. I don’t think you need to do another study---but you need to answer the question." Although the HPV rates are probably higher in the study's population (who were mostly sexual active) than in the pre-teens the vaccine is aimed at, we don't have data on what the HPV infection rate is among the target population---though we have good evidence it's not negligible---so we can't truly say what the vaccine effectiveness will be. Effects on Pap Screening Rates:Doctors and researchers are clear about the fact that the HPV vaccine will not reduce the need for Pap smears, as the vaccine only works against some cancer-causing strains of HPV. It’s less clear that all the women who receive the shot will know that as well. If Pap screening rates go down because some women assume they’re immune to all HPV strains for life, “there is a real risk that cervical cancer will increase in the U.S.” says Harper. Only time will tell how HPV vaccinations will affect screening rates---an experiment that’s now being run on a pool of many millions of women. Overall Vaccine Effectiveness in FUTURES Studies:While Smith is right that 44 percent I mentioned in my post (effectiveness in preventing high-grade lesions due to the vaccine strains, in the intent-to-treat population) isn't a perfect measure, she doesn't get any closer to showing how the vaccine fares on its most important test: how much it decreases cervical cancer in the real world. A later study after the end of the FUTURES trials found that the vaccine was 30 percent effective in preventing cervical lesions for all carcinogenic strains of HPV---43 percent against high-grade lesions---among females who tested negative for all of those strains at the beginning of the study. That rate probably overestimates effectiveness because some of the vaccinated girls are most likely HPV positive. Indeed, in the final tally, the vaccine was 19 percent effective at preventing high-grade lesions in the intent-to-treat population. And again, there are also questions about the duration of the vaccine’s potency, and the possibility that Pap screening rates may go down, plus the fundamental problem that the trials measure lesions rather than cases of cancer. We can’t say with certainty how HPV vaccination will affect cancer rates, but we can certainly say the effectiveness won’t come near the 98 percent cited as the primary end point in the FUTURES II study. Testing for Actual Efficacy vs. Cancer:In the FUTURES II report, the authors say there’s no feasible alternative to using cervical lesions as an end point to stand in for actual invasive cancer:
Although prevention of invasive cervical cancer is the main goal of prophylactic HPV vaccination, it is ethically unacceptable to use invasive cancer as the end point in efficacy trials. Cervical intraepithelial neoplasia grade 3 and adenocarcinoma in situ, which the International Federation of Obstetrics and Gynecology classifies as stage 0 noninvasive cervical cancers, are clinically important outcomes because they are likely to persist and may become invasive without treatment.
But Otis Brawley, chief medical and scientific officer of the American Cancer Society, says it is indeed possible, though costly and lengthy, to do such a test.
I would love to see a public health initiative to see this out [several decades]. You need to follow girls who get the vaccine at age 10 and then look at them and compare them at ages 40 and 50 to a cohort of girls who didn’t get the vaccine, and you should assess not just cervical cancer outcomes but the amount of testing and treatment that is necessary for both groups.
Of course, women in the study would be encouraged to get Pap smears and have any dangerous cervical lesions treated. But just as some women in the general female population get cervical cancer even under the current Pap screening regime, so too will some women in a long-term study. Comparing the placebo and vaccine groups will show the true long-term effectiveness of the vaccine. And a trial that looked at women vaccinated as adults, like the older subjects in the FUTURES studies, could provide some real-world results faster than Brawley’s example. Gardasil for Prevention of Head and Neck Cancer:Smith correctly points out that HPV-caused head and neck cancers are much more common in men than anal cancer (and seem to be on the rise), and she says Gardasil would be a good way to prevent those cancers. But on what evidence? Researchers at the National Cancer Institute and the CDC told the Wall Street Journal
that there’s no clinical-trial data showing the vaccine prevents cancer in males, andMerck said it “has no plans to study the potential of Gardasil to prevent these cancers.” Again, it’s biologically plausible that the vaccine will prevent oral cancers, but there’s no clinical evidence of that. What’s more, the evidence we do have suggests antibody titers may decrease faster in men than in women; Harper says the vaccine loses effectiveness against HPV-18
in 40 percent of men after two years, as opposed to five years in women. Other Researchers’ Questions About Vaccine Effectiveness: Many other experts have voiced concerns about the effectiveness, costliness, or potential side effects of the HPV vaccines, in public and in private. Here are a couple more examples:
A huge publicity & PR campaign (not counterbalanced by independent experts, scholars and the medical profession) has obscured the fact that millions of healthy teenage girls are being vaccinated under a promise: that vaccination programs will prevent cervical cancer---just a reasonable hypothesis, untested, which could easily be refuted. It is a huge mistake to vaccinate healthy persons under a promise. As a physician, I believe systematic, universal vaccination programs have a crucial role in our societies. And, hence, I deplore that the credibility of such programs is jeopardized by unbalanced commercial influences.
---Cancer epidemiologist and physician Miquel Porta, in email interview
Despite great expectations and promising results of clinical trials, we still lack sufficient evidence of an effective vaccine against cervical cancer. Several strains of human papillomavirus (HPV) can cause cervical cancer, and two vaccines directed against the currently most important oncogenic strains (i.e., the HPV-16 and HPV-18 serotypes) have been developed. That is the good news. The bad news is that the overall effect of the vaccines on cervical cancer remains unknown. As Kim and Goldie point out in this issue of the Journal, the real impact of HPV vaccination on cervical cancer will not be observable for decades….
With so many essential questions still unanswered, there is good reason to be cautious about introducing large-scale vaccination programs. Instead, we should concentrate on finding more solid answers through research rather than base consequential and costly decisions on yet unproven assumptions.
---Charlotte J. Haug, editor-in-chief of the The Journal of the Norwegian Medical Association, in the New England Journal of Medicine
The burden of proof regarding any new intervention should be on “them that sells their wares.” Right now, the data from the manufacturer-sponsored studies are far from conclusive, which brings us back to the problem neatly summed up by Steven Nissen, a Cleveland Clinic researcher and FDA advisor who's seen many logical interventions that failed: “The road to hell is paved with biological plausibility
.” Let’s see the evidence first. Jeanne Lenzer (A side note on terminology: Smith says I called high-grade lesions “innocent cellular abnormalities,” which is incorrect. I used “innocent cellular abnormalities” to refer to low-grade lesions: grade 1 cervical intraepithelial neoplasia, or CIN1. The issue is that in the 2007 NEJM papers on the FUTURES trials, the vaccine seemed to disproportionately prevent those low-grade lesions and had a smaller effect on the high-grade lesions (CIN2 and CIN3 and adenocarcinoma in situ), as pointed out in a New England Journal of Medicine editorial
that accompanied the study. ("No efficacy was demonstrable for higher-grade disease, but the trial may have lacked adequate power to detect a difference [in FUTURES I]…the efficacy appears to be significant only for grade 2 cervical intraepithelial neoplasia; no efficacy was demonstrable for grade 3 cervical intraepithelial neoplasia or adenocarcinoma in situ [in FUTURES II].” But this disproportionate effect seemed to disappear in the later paper
that included the end-of-study FUTURES data, so it's not as big a concern as the points previously mentioned. [Ed note: Due to a production error, the original post linked to the wrong skeptical editorial in the NEJM. These quotes are from the right one.])
Jeanne Lenzer is a medical investigative journalist and frequent contributor to the British medical journal BMJ. Her work has been published in The Atlantic, The New York Times Magazine, Newsweek Japan, and many other outlets.