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month visit ranged from 59.2% to 78.1%. There was no evidence that HPV vaccination significantly altered rates of viral clearance (VEVC estimates ranged from −7.6% to 7.6% at the 6-month visit and from −8.7% to 12.2% at the 12- month visit).


We evaluated the effect of HPV VLP- based vaccination on viral clearance among participants in our efficacy trial in Costa Rica with prevalent infection at the time of first vaccination. The trial has the advantage of being both com- munity-based (participants were iden- tified via a population census) and ran- domized. Our results show that rates of viral clearance over a 12-month period are not influenced by vaccination. Over- all, VEVC estimates obtained were close to 0%, and the 95% CIs (eg, −24.3% to 16.3% for HPV-16/18 at 12 months) sug- gest that even if vaccination provides some benefit, it is likely to be small. The post hoc power estimates are 82%, 98%, and 99% for testing the hypothesis that the vaccine efficacy for HPV-16/18 clear- ance at 12 months is 30%, 40%, or 50%, respectively.

These findings have important clini- cal implications. For example, in coun- tries where HPV DNA testing is incor- porated in cervical cancer screening and prevention efforts,19 adult women who have abnormal Papanicolaou test re- sults induced by HPV infection and/or who test positive for an oncogenic HPV type using the clinically available HC2 test might be interested in receiving the HPV vaccine to treat their existent in- fection. Our results indicate that clini- cians should discourage use of L1 VLP- based vaccines for this purpose.

Although VLP-based HPV vaccines are unlikely to provide benefit in the treatment of prevalent infections, women with established infections might benefit from vaccination in other ways at the individual level. From a population (or public health) perspec- tive, however, it is unclear whether, among women infected with HPV, the residual benefit of preventing infec- tion with HPV types contained in the

Species alpha-7 other than HPV-18

115/243 (47.0)

131/258 (50.8)

−7.6 (−27.9 to 9.5)

Species alpha-9 other than HPV-16

208/425 (48.8)

194/427 (44.6)

7.6 (−5.2 to 18.8)

Other oncogenic types

224/411 (54.5)

195/383 (50.9)

7.3 (−7.4 to 20.0)

Nononcogenic types

240/403 (59.4)

228/371 (61.1)

−4.5 (−24.6 to 12.4)


649/1337 (48.0)

651/1372 (47.2)

1.5 (−6.3 to 8.8)



for Viral Clearance,

Viral Type



% (95% CI)

Species alpha-7 other than HPV-18

119/178 (67.0)

133/209 (63.9)

8.4 (−21.0 to 30.7)

Species alpha-9 other than HPV-16

181/325 (55.7)

199/335 (59.2)

−8.7 (−30.1 to 9.1)

Other oncogenic types

236/322 (73.2)

216/299 (72.2)

3.5 (−25.2 to 25.7)

Nononcogenic types

264/327 (80.8)

254/326 (78.1)

12.2 (−18.3 to 34.8)


624/977 (63.7)

660/1037 (63.4)

0.8 (−12.0 to 12.1)

Table 4. Viral Clearance and Vaccine Efficacy for Viral Clearance for Other HPV Categories by Study Group at 6 Months and 12 Months of Follow-up

6-mo Follow-up

12-mo Follow-up

No. Cleared/Total Infections (%)


Vaccine Efficacy

Abbreviations: CI, confidence interval; HC2, Hybrid Capture 2 test; HPV, aPercentages calculated using generalized estimating equations method

human papillomavirus. and may therefore vary

from crude percentages.

vaccine to which the women have not yet been exposed would be sufficient to warrant vaccination. However, since HPVs are very common viruses to which women are typically exposed in the initial months or years following sexual debut,1 vaccination of women af- ter they have been exposed and in- fected (ie, after their peak period of ex- posure) is likely to be of less benefit than vaccination of women prior to initial exposure. This contrasts with other cervical cancer prevention ap- proaches (Papanicolaou screening and HPV DNA testing), whose benefits are highest when women older than the typical peak of HPV acquisition and clearance (eg, 30 years) are targeted for evaluation.27 Examination of the level of benefit provided by HPV vac- cination of women who are past their peak period of exposure is currently un- der evaluation in several ongoing clini- cal efficacy trials.

It is also not clear whether vaccina- tion would benefit women with preva- lent infection by increasing their immunologic resistance against reap- pearance (via reactivation or reinfec- tion) with the same viral type in the future. Because HPV-infected women who clear their infection have demon- strated immunocompetence to handle an established HPV infection, these women might be expected to be

capable of handling subsequent infec- tions without the need for vaccination. In particular, it is possible to hypoth- esize that T-cell responses developed following an initial HPV infection that successfully clears would be capable of adequately eradicating subsequent viral infections. This remains an open issue for future investigation.

In the present analysis, we avoided the evaluation of cytologic and/or his- tological data obtained after random- ization as potentially compromising the stated primary objective of our ran- domized trial to evaluate the efficacy of the HPV-16/18 cervical cancer vac- cine to protect women without HPV in- fection from the development of high- grade cervical precancers and cancer. We therefore cannot formally rule out the possibility that vaccination pre- vents progression to cytohistological outcomes. However, given that viral clearance rates did not differ by treat- ment group and that persistent viral in- fection is the best established predic- tor of risk of progression, it is unlikely that vaccination could have a signifi- cant beneficial impact on rate of le- sion progression.1,17

Since the trial is ongoing and inves- tigators and site personnel have no ac- cess to safety data by treatment group, we also did not evaluate the safety pro- file of the vaccine in this analysis. How-

©2007 American Medical Association. All rights reserved.

(Reprinted) JAMA, August 15, 2007—Vol 298, No. 7


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