Centers for Disease Control and Prevention
MS E05, 1600 Clifton Road
Atlanta, GA 30333
email@example.comAugust 31, 2011
Dear Dr. Markowitz:
Thank you for your August 29, 2011 response to my letter requesting additional information about post licensure monitoring for Gardasil™ from the CDC. Before relaying your response to medical consumers, I would like to ask you to clarify the following two points.
1) Your letter stated: ‘In Australia…some decreases in HPV associated outcomes have been observed already.’ May I ask you to provide a published reference to support this statement? The only paper I have read from Australia on this issue is an article by Brotherton et al.  in which the authors stated ‘we recorded a decrease in the incidence of HGAs by 0.38%.’ According to the authors, HCAs were lesions coded as CIN2 or worse. Since CIN2 is not a true biologic entity  and 25-50% of the CIN2 lesions are self-resolving  a 0.38% decrease of CIN2 lesions with a self-resolving rate of up to 50% can hardly be used as convincing evidence for demonstrating the efficacy of a vaccine approved to prevent cervical cancer in the decades to come.
Furthermore, there appeared to be no HPV genotyping data in the Brotherton paper.  As a result, there were no HPV associated outcomes in their study. I assume you must have another Australian reference to support your statement. If you do, please provide the reference.
2) The HPV genotype distribution in the table attached to your letter seems to show highly contradictory results between the states. For example, the numbers of HPV-16 and HPV-18 infections in 2009 may well exceed the numbers infected by these two genotypes in 2008 in Oregon and Tennessee while the data in California, Connecticut and New York may show a decrease in HPV-16 and HPV-18 infections. I am wondering if the discrepancy in efficacy results in different states might be due to a lack of a common denominator or varying method being used for HPV genotyping.
According to a group of experts on HPV testing, ‘To meet currently achievable standards, the test should have a clinical sensitivity to detect at least 92% ± 3% of CIN 3+ …and the test should have clinical specificity of at least 85% such that adequate positive predictive value for CIN 3…’ 
Therefore, I would like to have elaboration on:
- Whether the CDC requires all states to use CIN3 lesions as the common denominator in tabulating the numbers of infections by various individual HPV genotypes?
- Does the CDC require all the methods used for HPV testing by these states to meet the clinical sensitivity to detect at least 92% of CIN3 lesions and the clinical specificity of at least 85% for CIN 3?
I am looking forward to receiving your kind clarification.
Norma Erickson, PresidentSANE Vax Inc.
154 Cecil Drive Troy Montana, 59935
 Brotherton JM, Fridman M, May CL, Chappell G, Saville AM, Gertig DM. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet. 2011; 377:2085-92.
 Castle PE, Stoler MH, Solomon D, Schiffman M. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol. 2007;127:805-815.
 Castle PE, Schiffman M, Wheeler CM, Wentzensen N, Gravitt PE. Impact of improved classification on the association of human papillomavirus with cervical precancer. Am J Epidemiol. 2010;171:155-63.
 Stoler MH, Castle PE, Solomon D, Schiffman M. The Expanded Use of HPV Testing in Gynecologic Practice per ASCCP-Guided Management Requires the Use of Well-Validated Assays. Am J Clin Pathol. 2007;127:1-3.
The following response was received from Dr. Lauri Markowitz via email on 21 Sept 2011:
Data from Australia on decreases in HPV-associated outcomes include mainly ecologic data on declines in genital warts. From Donovan et al. Lancet Infect Dis 2011: “After vaccination began, a decline in number of diagnoses of genital warts was noted for young female residents (59%, p(trend)<0·0001). No significant decline was noted in female non-residents, women older than 26 years in July, 2007, or in men who have sex with men. However, proportionally fewer heterosexual men were diagnosed with genital warts during the vaccine period (28%, p(trend)<0·0001).” The data on trends in cervical precancer lesions from Australia show minimal declines, as you stated, and there are no genotyping data.
Concerning the genotyping data we shared with you from the U.S, these are preliminary data. We do not have complete data from the states yet and it is not possible to compare between states. We eventually will be able to do so. All genotyping is done by the same method at CDC. The methods were shared with you in a previous letter.Sincerely, Lauri Markowitz, M.D.
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