Male Circumcision and Papillomavirus Studies Reviewed by Infection Stage and Virus Type

Cathryn J. Rehmeyer, PhD

The unkeratinized epithelium of the inner human foreskin is thought to be more susceptible to human papillomavirus (HPV) entry than the rest of the penis. However, studies exploring a potential association between male circumcision and HPV infection have produced conflicting results. The present review stratifies the evidence based on methods of sampling and detection of HPV infection, HPV type, and the stage of infection. This approach reveals that circumcision reduces the risk of HPV infection in a stage- and type-specific manner. There is no consistent associa - tion of HPV acquisition with circumcision status, indicating that circumcised men may be no more protected from initial HPV infec - tion than their uncircumcised peers. Circumcision is not protective against nononcogenic types of HPV, but is associated with a reduced prevalence and persistence of oncogenic HPV infections. Circumcised men are also less susceptible to multiple infections. These findings indicate that circumcision modulates HPV persis - tence rather than acquisition. Through promoting HPV infection clearance, male circumcision could be an important adjunct to edu - cation, condom use, and vaccination in reducing the global burden of HPV morbidity and mortality. J Am Osteopathy Assoc . 2011;111(3 suppl 2):S11-S18

ecent randomized controlled trials detection method, and the stage of infec - First, I evaluate the research methods R(RCTs) 1,2 conducted in Africa have tion under study, making them used in studies published to date. Second, confirmed the efficacy of male circum - extremely challenging to review. Indeed, strengths identified in these methods are cision in preventing female-to-male a meta-analysis 3 determined that there used as article selection criteria for a more transmission of human immunodefi - is no relationship between male cir - focused analysis of male circumcision as ciency virus (HIV) in high-risk popula - cumcision and HPV infection risk, but it relates to stage of HPV infection and tions. Does this benefit extend to other other investigators reached the oppo - HPV type. Finally, I evaluate the current sexually transmitted infections as well, site conclusion in 2 subsequent reanal - model for the relationship between cir - and in particular to human papillo - yses of the data. 4,5 Further obfuscating cumcision and HPV infection risk and mavirus (HPV) infection? Most of the any conclusions, to my knowledge, no propose future directions for research. research about HPV and male circum - reviews published to date have orga - cision has been observational in nature nized the studies by the HPV infection Overview of HPV and Circumcision and was conducted in the past 10 years. stage they are designed to investigate Identification of Studies These investigations are extremely (eg, acquisition vs clearance) or consid - Studies were identified via PubMed varied in sampling technique, HPV ered that the association might be influ - using the search term circumcision HPV , enced by HPV type. and the search was further expanded by In the present review, I establish a examining each publication’s reference baseline of knowledge about HPV infec - list. Articles were limited to those that Financial Disclosures: None reported. tion as it relates to circumcision status. explored HPV infection as it could be Address correspondence to Cathryn J. Rehmeyer, PhD, Assistant Professor of Pathology, Pikeville College School of Osteopathic Medicine, This supplement is supported by an independent educational grant from Merck & Co, Inc. 147 Sycamore St, Pikeville, KY 41501-9118. E-mail: [email protected]

Rehmeyer • Male Circumcision and HPV Studies Reviewed by Infection Stage and Virus Type JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S11 related to circumcision status of the par - by default, nononcogenic (ie, low risk). its low specificity in differentiating ticipants. A total of 31 original studies Later studies used peniscopy to detect between LR-HPV and HR-HPV types were identified and selected for the pre - lesions for biopsy and Southern blot anal - and its inability to distinguish specific sent review. 6-36 ysis, 8,9 significantly improving the quality types within these groupings. 39 There is of evidence by allowing confirmation of currently no clinical indication for the Study Design HPV infection and virus typing. use of these tests in men. Most investigations of HPV infection as Polymerase chain reaction (PCR)– Much of the perceived discordance it relates to circumcision status are obser - based methods are the current standard in the HPV and circumcision literature vational and cross-sectional. Although for investigations of HPV and circumci - has arisen from superficial tallies of cohort studies are available, such as the sion. Because a biopsy of anogenital tis - studies without regard to the types of HPV Infection in Men studies, 24,25 most of sues is not required for PCR, an addi - HPV under study. Stratifying the evi - the reported data as they apply to cir - tional advantage of PCR-based methods dence by HPV type resolves some of cumcision status are derived from base - is that they allow the detection of sub - this conflict. For example, of 9 studies line analyses rather than follow-up of clinical lesions. This aspect is important, that identified HPV infection by self- participants over time to identify new because most subclinical lesions are due report or clinical diagnosis of genital HPV infections. Four RCTs 6,7,31,34 have to infection with oncogenic (ie, high-risk) warts, 12 -14,16,20,21,23,26,27 which are exclu - explored male circumcision and HPV HPV types, which are the most important sively caused by LR-HPV infections, infection in men, all of which were con - HPV types with respect to anogenital only 2 studies 23,26 found a protective ducted in Africa and published within cancer risk. 38 However, HPV detection effect of circumcision on HPV infection. the past 2 years. Most studies have been by PCR only implies HPV infection; In contrast, 15 of 21 studies using molec - limited to reporting HPV prevalence because of the extreme sensitivity of these ular methods of HPV detection, which data. Because disease prevalence is a tests for detecting HPV DNA, the tests can also identify HR-HPV types, found product of both the incidence and dura - may also detect shed cells from an a protective effect of circumcision. 6-11,17- tion of infection, it does not demonstrate infected partner or low-copy infections 19,22,24,25,28-34,36 Among studies that whether circumcision is influencing the that will soon abort and become irrele - included LR-HPV types in the analysis, acquisition of HPV, the ability of the host vant. 38 Serology has been used in one the vast majority reported no signifi - to clear the infection, or both. study 15 and does overcome these limi - cant difference in the prevalence of LR- Longitudinal studies are the pre - tations, but it is generally considered an HPV infection among circumcised ferred method for identifying factors that inferior method because it cannot dis - men. 6,18,22,24,25,30,32,34,35 It is therefore more modify HPV infection risk, because they tinguish the location of infection (eg, gen - appropriate to consider that the efficacy can identify incident cases. These types of ital vs oral) and not every infected person of circumcision varies with respect to studies also allow detection of stage-spe - generates an antibody response to HPV HPV type and to review LR- and HR- cific factors that influence HPV infection, infection. 38 HPV studies independently. because they have the potential to follow Although HPV genotyping with An additional caution is warranted a given individual and identify when Southern blot analysis was performed when studies that assay different HPV HPV is acquired and how long the infec - as early as 1994 among circumcision and types are considered together, because tion lasts. Unfortunately, longitudinal HPV infection studies, analyses could bias may be interjected into analyses of studies of men are underrepresented in not be performed efficiently until the prevalence data. High-risk HPV infec - the literature on HPV and circumcision. introduction of PCR-based methods in tions are generally more persistent than The effective design of these studies is 2002. 11 Type-specific explorations into LR-HPV infections. 37 A difference in hampered by a lack of knowledge about the subject are therefore relatively new. HPV infection prevalence would be the natural history of HPV infection in Various primer sets are available for the observed if a particular group was pre - men. For example, there is no consistent detection of HPV by , but more disposed to HR-HPV infection, even if between-test interval that defines per - commonly a portion of the HPV L1 gene incident infection rates did not differ sistent HPV infection in men, 37 which is amplified and genotyped via reverse between groups ( Figure ). Original can lead to conflicting results when line blot analysis. The Digene HPV research and meta-analyses may there - studies use different intervals between Hybrid Capture 2 test is a more recent fore overstate or understate disease risk HPV detection points. introduction to genotyping that has not when they use prevalence data for HPV been used in any of the circumcision infections, particularly when they do not Detection of HPV Infection studies published to date. This method distinguish between LR- and HR-HPV Until the advent of molecular methods to uses a signal amplification system to infections. study HPV infection, studies were lim - detect low-risk HPV (LR-HPV) and high- ited to clinical diagnosis of HPV lesions, risk HPV (HR-HPV), primarily in com - Tissue Collection most commonly genital warts. The most bination with Papanicolaou tests in for PCR-Based Methods common HPV assayed were, women. Limitations of the test include Detection of HPV by means of PCR

S12 • JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 Rehmeyer • Male Circumcision and HPV Studies Reviewed by Infection Stage and Virus Type explained earlier in this review and reaf - Sample firmed here, there is no consistent asso - ciation of circumcision with LR-HPV infection. Only 2 studies 17,31 found a sta - Patient A tistically significant association of cir - cumcision status with the prevalence of LR-HPV infection. By contrast, among 9 Patient B Persistence studies that reported prevalence data by HPV type, 7,17,18,24,25,30-32,35 5 demonstrated Acquisition that circumcision is associated with a decreased prevalence of HR-HPV infec - Time tions, including the 2 RCTs that explored this outcome. 7,17,18,30,31 These results indi - Figure. Effect of persistence on estimates of human papillomavirus (HPV) prevalence. The cate that male circumcision does not influ - acquisition and persistence of HPV infection is modeled over time for 2 hypothetical patients ence the prevalence of LR-HPV infection with identical numbers of acquired infections. Random sampling will indicate greater HPV preva - but may be associated with a reduced lence in populations with infection patterns similar to Patient B due to prolonged infection prevalence of HR-HPV infection. 42 persistence. HPV Incidence and Acquisition Male circumcision is thought to prevent requires a small sample of cells from go so far as to analyze semen and urine HPV infection by limiting virus access which to extract DNA for analysis. In samples. Such extensive sampling is gen - to basal keratinocytes in the more corni - contrast to cell collection from the cervix, erally unnecessary, however, because fied epithelium of the circumcised adequate cell collection from the kera - more than 95% of HPV in asymptomatic penis. 11,18,22,31 Although there is probably tinized epithelium of the male genitalia men may be detected in the penile shaft, no difference between the keratinization is challenging. Cells are usually collected coronal sulcus and glans penis, prepuce of the glans penis in circumcised and by rubbing with a wet cotton or Dacron (in uncircumcised men), and scrotum. 41 uncircumcised men, 43 the mucosal swab. Preparation of the collection site epithelium of the inner prepuce is unker - with emery paper increases cell removal Analysis of Select HPV atinized, which is thought to make it sus - and reduces the incidence of incomplete and Circumcision Studies ceptible to injury during intercourse. 18,42 specimens, as measured by internal β- With the above limitations in mind, the The relatively larger surface area pro - globin controls. 33 articles identified in this review were vided by the foreskin could also provide In circumcised men, HPV infections parsed further. Articles were limited to more opportunity for infection. 11 If this are most commonly detected on the those that distinguished HPV infections model is correct, one would expect a penile shaft, whereas the foreskin—par - based on type and location, which nec - decreased incidence of HPV infection in ticularly on the inner mucosal surface 40 — essarily restricted inclusion to those circumcised men, which would reflect is the most common site in uncircum - studies employing PCR-based methods reduced acquisition of the virus. Very cised men. 33 Some studies have been of detection. To minimize the influence of few studies have deliberately explored criticized as introducing sampling bias sampling bias, articles were also restricted the effect of circumcision on virus acqui - by sampling only specific penile sites to those that sampled multiple anogen - sition, but this model could be tested in that predispose to HPV detection in ital sites. Exceptions to these criteria were the longitudinal studies and several of either circumcised or uncircumcised made, however, and articles were the RCTs of male circumcision that are men. 3 For example, in a 2004 study, 33 included in the analysis if they described available. 6,19,21,22,28,31,34,36 sampling only the coronal sulcus and longitudinal studies or RCTs; such Acquisition of HPV infection in glans penis showed a protective effect studies are underrepresented in the HPV these longitudinal studies is usually of circumcision on HPV detection, but and circumcision literature but may be defined as the detection of HPV in no significant difference in prevalence the most informative with regard to virus someone who was previously HPV neg - was detectable when all sites were com - acquisition and persistence. A total of ative or the detection of a different type bined. To avoid this bias, more recent 16 articles were identified and are out - of HPV in someone who was previously studies 17,19,29,30,33 typically sample the lined in Table 1 . infected. The interval between detection entire penis and scrotum, with many points in these studies ranged from studies 17,19,30,32,35 pooling samples rather Prevalence of HPV Infection 2 months to 2 years, and acquisition of than conducting a site-by-site analysis. As shown in Table 2 , HPV type influences HPV infection was inferred from inci - Some studies 18,24,25,28 also include the peri - the association between circumcision and dence data. As shown in Table 3 , these anal region, anal canal, or urethra or even the prevalence of HPV infection. As studies found that circumcision status

Rehmeyer • Male Circumcision and HPV Studies Reviewed by Infection Stage and Virus Type JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S13 Table 1. Selected Studies Exploring the Association Between Male Circumcision and Human Papillomavirus Infection

Sites Sampled No. of Participants Study (Collection/Detection Method) Location (Population) (% Circumcised)

■ Randomized Controlled Trial □ Auvert et al, 2009 7 Urethra (swab/PCR) Orange Farm, South Africa 1264 (50) (males aged 18-24 years) □ Gray et al, 2010 34 Coronal sulcus and glans penis Rakai, Uganda (males aged 15-49 years) 780 (43) (swab/PCR) □ Serwadda et al, 2010 6 Coronal sulcus and glans penis Rakai, Uganda (HIV-positive males 210 (49) (swab/PCR) aged 15-49 years) □ Tobian et al, 2009 31 Coronal sulcus and preputial space Rakai, Uganda (males aged 15-49 years) 3393 (50) (swab/PCR) ■ Longitudinal □ Hernandez et al, 2010 36 Coronal sulcus and glans penis, University of Hawaii ( у18-year-old 357 (81) shaft, scrotum male university students) (textured paper, swab/PCR) □ Lajous et al, 2005 19 Scrotum, shaft, coronal sulcus, Mexico City, Mexico (male soldiers 336 (13.1) urethral meatus* (swab/PCR) aged 16-40 years) □ Lavreys et al, 1999 21 Clinical diagnosis of genital warts Mombasa, Kenya (HIV-seronegative 746 (87) (not applicable) trucking company employees) □ Lu et al, 2009 22 Coronal sulcus and glans penis, Southern Arizona (male residents aged 285 (88) shaft, scrotum † (swab/PCR) 18-44 years with no current or prior diagnosis of any STI) □ Partridge et al, 2007 28 Glans, shaft, scrotum, urine, University of Washington in Seattle 240 (76.7) fingernails † (emery paper, swab, (male university students aged or cytobrush/PCR) 18-20 years) ■ Cross-Sectional □ Giuliano et al, 2009 17 Coronal sulcus and glans penis, Sao Paulo, Brazil; Morelos, Mexico; 988 (40.3) shaft, scrotum* (swab/PCR) University of Florida (male residents aged 18-70 years with no current or prior diagnosis of any STI) □ Hernandez et al, 2008 18 Coronal sulcus and glans penis, University of Hawaii ( у18-year-old male 351 (79) shaft, scrotum, semen, urine university students) (textured paper, swab/PCR) □ Muller et al, 2010 35 Coronal sulcus and glans penis, Johannesburg, South Africa 214 (26) shaft, perianal region if warts (у18-year-old men attending a sexual present* (swab/PCR) health clinic) □ Nielson et al, 2007 24 Coronal sulcus and glans penis, Tucson, AZ, and Tampa, FL (men aged 463 (84) shaft, scrotum, perianal region, 18-40 years with no previous genital urethra, anal canal, semen † warts, anogenital cancer diagnosis, (swab/PCR) or current STI) □ Nielson et al, 2009 25 Coronal sulcus and glans penis, Tucson, AZ, and Tampa, FL (men aged 463 (84) shaft, scrotum, semen, urethra, 18-40 years with no previous genital perianal region, anal canal warts, anogenital cancer diagnosis, (swab/PCR) or current STI) □ Svare et al, 2002 30 Coronal sulcus and glans penis, Copenhagen, Denmark (STD clinic 216 (12) shaft, scrotum, perianal region* male patients) (swab/PCR) □ Vaccarella et al, 2006 32 Coronal sulcus and glans penis, 14 states in Mexico (men requesting 779 (31.7) shaft, scrotum* (cytobrush/PCR) vasectomy in public clinics)

* The study pooled samples rather than analyzing each site independently. † The study pooled sample data for analysis of circumcision (no site-specific statistics were reported).

Abbreviations: PCR, polymerase chain reaction; STI, sexually transmitted infection; STD, sexually transmitted disease.

S14 • JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 Rehmeyer • Male Circumcision and HPV Studies Reviewed by Infection Stage and Virus Type Table 2. Selected Studies Exploring the Association Between Male Circumcision and Prevalence of HPV Infection

Reported Statistics for Association of Circumcision With HPV Infection Type (95% Confidence Interval)* Study Low-Risk HPV High-Risk HPV Multiple Type Any ■ Randomized Controlled Trial □ Auvert et al, 2009 7 NA APRR, 0.62 (0.47-0.80) PRR, 0.43 (0.28-0.66) NA □ Tobian et al, 2009 31 RR, 0.66 (0.49-0.91) ARR, 0.65 (0.46-0.90) RR, 0.35 (0.17-0.71) RR, 0.70 (0.53-0.91) ■ Longitudinal □ Lajous et al, 2005 19 NA NA NA OR, 0.48 (0.30-0.77) □ Giuliano et al, 2009 17 OR, 0.63 (0.42-0.93) OR, 0.7 (0.50-0.97) NA OR, 0.7 (0.52-0.94) ■ Cross-Sectional □ Hernandez et al, 2008 18 AOR, 1.92 (0.93-4.00) †,§ AOR, 2.51 (1.11-5.69 )†,§ AOR, 3.56 (1.50-8.50) †,§ AOR, 1.97 (1.03-3.77) †,§ □ Muller et al, 2010 35 Not significant ‡,|| OR, 0.69 (0.37-1.28) AOR, 0.63 (0.24-1.69) ‡ AOR, 0.51 (0.21-1.25) ‡ □ Nielson et al, 2007 24 OR, 1.0 (0.6-1.9) OR, 0.9 (0.5-1.8) NA NA □ Nielson et al, 2009 25 AOR, 0.84 (0.43-1.67) AOR, 0.47 (0.22-0.99) § AOR, 0.54 (0.30-0.98) AOR, 0.53 (0.28-0.99) □ Svare et al, 2002 30 AOR, 0.8 (0.1-4.1) AOR, 0.4 (0.08-1.7) NA AOR, 0.2 (0.06-0.6) □ Vaccarella et al, 2006 32 Not significant || Not significant || NA OR, 0.2 (0.1-0.4)

* Statistically significant reductions in human papillomavirus (HPV) infection prevalence are underlined . † Statistic reflects increased prevalence of HPV infection for uncircumcised participants. ‡ Association was statistically significant until adjustment for human immunodeficiency virus (HIV) serostatus. § Statistic reported for the coronal sulcus and glans penis; other sites were not statistically significant. || Data not shown.

Abbreviations: AHR, adjusted hazard ratio; AOR, adjusted odds ratio; APRR, adjusted prevalence rate ratio; ARR, incidence rate ratio; NA, not available (HPV type was not investigated or statistic was not reported); OR, odds ratio; PRR, prevalence rate ratio; RR, risk ratio.

had no effect on the acquisition of single If circumcision modulates the immune sistence of infection by HPV type, finding HPV infection. The absence of an asso - response to HPV infection, the mecha - 70% and 85% reductions in persistence ciation holds true both for investigations nism is unclear. for general and HR-HPV types, respec - that studied HPV acquisition generally tively. 22 The demonstration of increased and for those that conducted type-specific Persistence of HPV Infection persistence of HPV infection in uncir - analyses. These observations indicate that In contrast to its effects on virus acquisi - cumcised men is extremely important men are equally susceptible to virus tion, circumcision seems to be protective given that the rate of HPV acquisition acquisition regardless of circumcision against persistent HPV infection. Five seems to be uninfluenced by circumci - status. studies, including 2 RCTs, have exam - sion status. These results could explain Circumcision seems to protect ined the persistence of HPV infection as why the prevalence of HR-HPV infec - against infection with multiple HPV influenced by male circumcision. 6,19,22,34,36 tion is increased among uncircumcised types, however. With one exception, 35 The time between HPV detection points men in the absence of any increase in all studies exploring this association varied from 2 months to 2 years. As incidence: it results from a prolonged found decreased prevalence and inci - shown in Table 4 , almost all studies found duration of infection. dence of multiple infections among cir - a profound and statistically significant cumcised men. 6,7,18,25,31,34 Although the reduction in the persistence of HPV infec - Implications and Future Directions significance of multiple infections in men tion among circumcised men; the excep - The current model for the biologic plau - is unknown, multiple infections predis - tion 6 studied HIV-infected men—a pop - sibility of circumcision in reducing HPV pose to persistence of cervical HPV infec - ulation that would be predisposed to infection risk is focused on virus acqui - tions, which is believed to result from a persistent infections. In one study of Mex - sition. If circumcision status influences less efficient immune response to HPV in ican military men, the reduction in odds viral accessibility to basal keratinocytes, some women. 44 Paradoxically, the fore - for persistence of HPV infection was 90% a statistically significant difference in skin contains the highest density of in circumcised men compared with HPV incidence between circumcised and Langerhans cells, CD4+ T cells, and uncircumcised men. 19 Another study uncircumcised men would be antici - macrophages in the penis, 45,46 yet it is conducted in Arizona as part of the HPV pated—an effect that is not observed. more susceptible to multiple infections. 47 Infection in Men study addressed per - Rather, the key mechanism by which cir -

Rehmeyer • Male Circumcision and HPV Studies Reviewed by Infection Stage and Virus Type JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 • S15 Table 3. Selected Studies Exploring the Association Between Male Circumcision and Incidence of HPV Infection

Reported Statistics for Association of Circumcision With HPV Infection Type (95% Confidence Interval)* Study Low-Risk HPV High-Risk HPV Multiple Type Any

■ Randomized Controlled Trial □ Gray et al, 2010 34 IRR, 1.09 (0.78-1.52) IRR, 0.89 (0.60-1.30) IRR, 0.45 (0.28-0.73) † IRR, 0.67 (0.50-0.90) IRR, 0.61 (0.41-0.91) ‡ □ Serwadda et al, 2010 6 NA IRR, 1.00 (0.65-1.53) IRR, 0.40 (0.19-0.84) IRR, 0.74 (0.54-1.01) ■ Longitudinal □ Hernandez et al, 2010 36 NA NA NA Not significant § □ Lajous et al, 2005 19 NA NA NA AOR, 1.12 (0.45-2.80) □ Lavreys et al, 1999 21 HRR, 1.3 (0.4-4.4) || NA NA NA □ Lu et al, 2009 22 HR, 1.0 (0.4-2.5) || AHR, 1.7 (0.6-4.9) || NA HR, 1.1 (0.5-2.3) || □ Partridge et al, 2007 28 NA NA NA HR 1.1 (0.6-2.0)

* Statistically significant reductions in human papillomavirus (HPV) infection incidence are underlined . † High-risk multiple-type HPV infections ‡ Low-risk multiple-type HPV infections § Data not shown. || Statistic reflects incidence of HPV infection for uncircumcised participants.

Abbreviations: AHR, adjusted hazard ratio; AOR, adjusted odds ratio; HR, hazard ratio; HRR, hazard rate ratio; IRR, incidence rate ratio; NA, not available (HPV type was not investigated or statistic was not reported).

cumcision seems to influence the preva - frenulum, and coronal sulcus. 10,11,18,25,31,33,38 pling to the coronal sulcus and glans lence of HPV infection is through pro - In addition, HR-HPV–positive penile penis. Although it has been argued that moting the clearance of infection (ie, intraepithelial neoplasia occurs “almost sampling only the coronal sulcus and reducing persistence). exclusively” on the inner foreskin, glans penis introduces sampling bias, 3 it How might circumcision status frenulum, and coronal sulcus. 38 These may be prudent to consider that these modulate viral persistence? One possi - observations indicate that persistence is sites may be biologically biased to harbor bility is that the intimate association of influenced by anatomic site and is the persistent HPV infections. The almost the prepuce and glans penis promotes most important factor influencing HPV exclusive occurrence of HPV-positive autoinfection. 42 In uncircumcised men, infection prevalence in comparisons of penile intraepithelial neoplasia in these there is frequent concordance between circumcised and uncircumcised men. sites 38 certainly supports this possibility. HPV types in the glans penis and pre - Strategies for controlling the spread Rather than introducing sampling bias, it puce, 18 suggesting that infection could of HPV infection are primarily targeted could be argued that sampling of the occur in one location and then spread at virus acquisition, but the findings sum - coronal sulcus and glans penis yields sequentially, thereby prolonging HPV marized here indicate that promoting information that is more biologically or detection. An alternative possibility is clearance in infected individuals may clinically relevant. that the uncircumcised penis has an also be a worthwhile goal. To better Given that circumcision reduces the increased susceptibility to establishment quantify the potential role of circumci - persistence and thereby the prevalence of of HR-HPV infections, which generally sion in limiting the persistence of infec - HR-HPV infections, it could be an impor - persist longer than LR-HPV types. 37 How - tion, future studies of HPV and circum - tant adjunct to condom use, vaccination, ever, studies indicate that incidence rates cision should report disease incidence and education in the worldwide pre - of HPV infection are equal across penile rather than prevalence data. To be most vention of HPV-associated malignancy. sites, 28 and all sites seem equally suscep - informative, longitudinal studies with An RCT published earlier this year 50 has tible to acquisition of LR- and HR-HPV, frequent detection points will be demonstrated reduced prevalence, inci - as reflected by equivalent incidence data required. Given the availability of molec - dence, and persistence of HPV infection from samples collected at these loca - ular HPV typing, studies should also in the female partners of circumcised tions. 28,48 Despite this, there is an estab - separate infections by virus type in anal - men, supporting the clinical relevance lished difference in HPV infection preva - yses. To keep research costs reasonable of male circumcision and HPV research lence by penile site, 33,40,47 and HR-HPV and simplify analyses, it may be appro - findings. It is important to avoid using is more common on the inner foreskin, priate in many situations to limit sam - descriptors that exaggerate the actual

S16 • JAOA • Supplement 2 • Vol 111 • No 3 • March 2011 Rehmeyer • Male Circumcision and HPV Studies Reviewed by Infection Stage and Virus Type Table 4. Selected Studies Exploring the Association Between Male Circumcision and Persistence of HPV Infection

Reported Statistics for Association of Circumcision With HPV Infection Type (95% Confidence Interval)* Study Low-Risk HPV High-Risk HPV Multiple Type Any

■ Randomized Controlled Trial □ Gray et al, 2010 34 NA ARR, 1.39 (1.17-1.64) † NA NA □ Serwadda et al, 2010 6 NA RR, 1.09 (0.94-1.27) † NA NA ■ Longitudinal □ Hernandez et al, 2010 36 AHR, 0.50 (0.25-0.98) ‡ AHR, 0.36 (0.14-0.91) ‡ NA AHR, 0.59 (0.36-0.98) ‡ □ Lajous et al, 2005 19 NA NA NA OR, 0.1 (0.00-0.87) □ Lu et al, 2009 22 HR, 1.6 (0.7-3.7) † AHR, 6.5 (2.1-19.7) † NA AHR, 3.1 (1.2-8.2) †

* Statistically significant reductions in human papillomavirus (HPV) infection persistence are underlined . † Statistic reflects increased clearance (ie, reduced persistence) of HPV infection for circumcised participants. ‡ Statistic reported for the coronal sulcus and glans penis; other sites were not statistically significant.

Abbreviations: AHR, adjusted hazard ratio; ARR, adjusted risk ratio; NA, not available (HPV type was not investigated or was not reported); OR, odds ratio; RR, risk ratio.

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