1 Peer Review Comments and CDC Responses for Information for Providers to Share with Male Patients and Parents Regarding Male Circumcision and the Prevention of HIV infection, Sexually Transmitted Infections, and other Health Outcomes* and Background, Methods, and Synthesis of Scientific Information Used to Inform “Information for Providers to Share with Male Patients and Parents Regarding Male Circumcision and the Prevention of HIV Infection, Sexually Transmitted Infections, and other Health Outcomes”** *Formerly titled: Recommendations for Providers Counseling Male Patients and Parents Regarding Male Circumcision and the Prevention of HIV Infection, Sexually Transmitted Infections, and other Health Outcomes **Formerly titled: Background, Methods, and Synthesis of Scientific Information Used to Inform the “Recommendations for Providers Counseling Male Patients and Parents Regarding Male Circumcision and the Prevention of HIV Infection, Sexually Transmitted Infections, and other Health Outcomes.” GENERAL RESPONSE: We thank the peer reviewers for taking the time to review and provide comments regarding the “Recommendations for Providers Counseling Male Patients and Parents Regarding Male Circumcision and the Prevention of HIV Infection, STIs, and other Health Outcomes” and the “Background, Methods, and Synthesis of Scientific Information Used to Inform the ‘Recommendations for Providers Counseling Male Patients and Parents Regarding Male Circumcision and the Prevention of HIV infection, STIs, and other Health Outcomes.” Citations corresponding to reviewer comments are located on pages 154-226. Citations corresponding to CDC responses are located on pages 227-230. The three peer reviewers were professors of internal medicine and pediatrics with expertise in HIV, sexually transmitted infections, and male circumcision. Reviewer No. 1: COMMENT: I have reviewed both documents and agree with the recommendations. I don’t have substantive changes to suggest. Please see the attached for a suggestion about removing two comma splices. RESPONSE: Thanks for taking the time to review the documents. The suggested edits were made to the policy document. Reviewer No. 2: COMMENT: I've reviewed the documents and recommendations, and I find them to be fair, well crafted, and appropriately extensive. I support them in their current form and in their entirety, and I do not have edits to recommend. From the perspective of a practicing urologist, I would say that great benefit will be derived from such a clear statement indicating efficacy not only in potentially preventing HIV but also of other STDs and health conditions likely related to STDs in a care environment that is 2 increasingly limiting. Another great potential benefit to be derived will be in increasing acceptance of male circumcision in a historical era of increasing opposition. RESPONSE: Thanks for taking the time to review the documents and provide comments. Reviewer No. 3: Note from CDC: Reviewer No. 3 has provided three sections of commentary: (1) general comments regarding the CDC recommendations, (2) comments pertaining to specific text of the CDC recommendations, and (3) summary comments about each section of the CDC background document. A response has been provided to each main point in the general comments on the CDC recommendations (1) and to each comment about specific text in the draft recommendations (2). A summary response has been provided at the beginning commentary on the CDC background document (3). Citations pertaining to comments from peer reviewer No. 3 are located on pages 140 – 208. Citations pertaining to responses from CDC are located on pages 209-212. CDC thanks the reviewer for taking the time to review the documents and providing extensive comments. General Comments Regarding CDC Draft Recommendations and Background Documents COMMENT: This peer-review of the Centers for Disease Control and Prevention’s (CDC’s) Draft Recommendations and Background Documents was generated after December 2, 2014 when the documents first became available. Because of the limited time in which to review and comment on these documents, there may be some topics that could have been addressed more completely, some topics that were addressed more than once, and some citations that may be missing. In the interest of time, the citations given in the review may not be sequenced properly, but each citation should be properly identified. There may be some grammatical and typographical errors because there was insufficient time to identify and correct them. The comments addressing the Recommendations draft are made in direct response to the statements in that draft and appear in italics. The evaluation of the Background draft does not use the statement-by- statement format. This is a peer-review of draft documents and the comments are directed at these documents. It may be helpful for the reader to have copies of the drafts available. 3 Several things are remarkable about this draft. First, is the obvious lack of scientific and scholarly rigor that went into preparing this draft. While it is stated that the writers of the draft performed a search of the medical literature, the evidence (in the form of the draft itself) indicates that their search was far from complete. Instead of collecting and analyzing data, they relied on review articles to do the work for them. One review article was published in 1983 — a bit dated to say the least. In some sections, the draft relied on opinion pieces as their sources of information. In areas where review articles were not available, the information provided was far from complete. For example, in reviewing the medical literature on the impact of male circumcision in North America, which is a major thrust of the draft, only two of the eight available studies are mentioned. Similarly, no serious attempt was made to review the harms, risks, complications, or pain associated with male circumcision. The draft has only 255 references, some of which are redundant, which are only a small sampling of the material available in the literature. A PUBMED search using the search word “circumcision” on January 12, 2015 identified 6338 publications. RESPONSE 1: The CDC background document summarizes findings from a systematic literature review that was conducted in order to assess evidence on the association of male circumcision with medical benefits and adverse effects. Systematic reviews were conducted for the following outcomes related to medically attended male circumcision: HIV acquisition and transmission (female-to-male, male-to-female, and male-to-male); other STIs; penile cancer; cervical cancer; infant UTIs; risks and adverse events; sexual function and penile sensation. All studies of outcomes of male circumcision up to the end of November 2012 in Medline, Embase and Cochrane Library, as well as citation lists were included in the draft recommendations for public comment and peer review. More recent data through March 2013 were included in updating data related to the HIV epidemic in the United States. Studies were restricted to those published in English after 1950, presenting original data, including RCTs, cohort studies, case-control studies, cross-sectional studies, case series and case reports. Study design was classified according to guidelines used for collecting scientific data in reports published in the Guide to Community Preventive Services (the Guide). The evidence was assessed according to strength of association, consistency of findings across studies and the methodologic rigor of study designs. Because they minimize considerably the risk of spurious causality and bias, randomized controlled trails (RCTs) are considered the most rigorous method for determining whether a cause-effect relationship exists between a treatment and an outcome. Our literature review through November 2012 also included a broad, non-systematic narrative review for the section “Considerations related to male circumcision in the United States,” because this section did not evaluate clinical outcomes. Since the time of the initial review, an updated literature review was conducted through October 2015 which added more evidence to the already strong field of evidence indicating that male circumcision is associated not only with a reduction in transmission of HIV, HSV-2, and oncogenic forms of HPV, but also decreased transmission of other STDs including genital ulcer disease, syphilis, m. genitalium, t. vaginalis, bacterial vaginosis, and trichomoniasis. 4 COMMENT: The draft also ignores basic epidemiological principles. It fails to apply the standards that are needed to identify when an intervention should be applied. Throughout the draft, it is assumed that male circumcision will be successful as a primary prevention for HIV, when the data clearly demonstrate that it is ineffective as primary prevention. RESPONSE 2: Male circumcision is an effective primary prevention strategy, preventing transmission of HIV infections to men during penile-vaginal intercourse. Three large, well-designed RCTs have demonstrated that men who were circumcised are 50-60% less likely to acquire HIV through heterosexual intercourse than men who were not circumcised. The findings from the RCTs are also consistent with many other observational studies of the effect of male circumcision on HIV transmission. In 2007, a panel of consultants convened by CDC concluded that conducting a trial in the United States to evaluate efficacy of male circumcision for HIV prevention would not satisfy the criteria