we used the terms  hpv  and  urine  to search the pubmed database in august 2012 for relevant literature . the identified studies were then individually evaluated to ascertain whether results on hpv prevalence in adolescents were reported . studies in hiv - positive populations and renal allograft recipients were excluded as these patient groups have a reported increased risk of hpv infection . studies that included paired urine and cervical samples were sought as they would allow for comparison of the presence of hpv in both samples . we therefore excluded female studies in which hpv dna was detected in urine samples only , with the exception of the four studies including adolescents as they shed some light on the expected urinary hpv prevalence rates in this group . as few studies in asymptomatic male populations were found , we included the male populations of four studies despite the fact that they may be at greater risk of hpv infection : two studies on male partners of hpv - positive women , one on male partners of women with cervical cancer , and one on males with urethritis . whenever possible we extracted information on country , recruitment setting , age ( range and mean ) , urine sampling procedure , total sample size , percentage of samples containing human genomic dna , hpv assay used , proportion and type of cervical lesions , and availability of cervical sample . as a main result we report hpv prevalence in urine samples and cervical samples in female study populations . we also report sensitivity , ie , the probability of an hpv - positive urine sample given an hpv - positive cervical sample , and specificity , ie , the probability an hpv - negative urine sample given an hpv - negative cervical sample . concordance for any hpv type and for hpv16 ( and/or hpv18 ) was measured as the percentage of paired urine and cervical samples that yielded the same hpv result , ie , either both positive or both negative . in contrast , type - specific concordance ( combined concordance for a group of hpv types ) was measured only in the set of paired urine and cervical samples that were both positive for any hpv type . within this smaller set of samples , type - specific concordance was calculated as the percent of paired urine and cervical samples that were positive for the same hpv type . results from 21 female study populations from 17 publications that reported hpv prevalence in urine samples are summarized in table 1 . prusty et al22 and manhart et al23 included females 1825 years of age , while only two studies , one from scotland by oleary et al24 and one from india by hussain et al,25 included females less than 18 years of age ( figure 1 and table 1 ) . the hpv prevalence ( any type ) varied from 1.1% in the age group 1114 years in the oleary et al24 study to 29.6% in the age group 2021 years in the manhart et al23 study . oleary et al24 reported the lowest percentage of samples ( 83.6% ) containing amplifable human genomic dna ; prusty et al22 reported the highest percentage ( 100% ) . we identified 14 studies that measured hpv positivity in paired urine and cervical samples from symptomatic females;18,22,2637 of these studies , nine reported the age range and nine the mean age of the study population . these studies included women with symptoms that led to various gynecological complaints and women diagnosed with invasive cervical cancer . urine and cervical samples were collected at gynecological , colposcopy , genitourinary , sexually transmitted disease , and adolescent clinics . in general , hpv prevalence increased with the severity of cytological or pathological findings , and this was observed both in urine samples and cervical samples . all studies that reported age - specific hpv prevalence showed lower prevalence in urine samples than paired cervical samples , with the majority of the studies reporting a 10%20% lower hpv prevalence , save the studies by rymark et al33 and cuschieri et al18 ( figure 2 ) . with the exception of studies by rymark et al33 and jacobson et al,31 which covered narrow age ranges ( 1621 years and 1120 years , respectively ) , the studies in this review generally reported hpv prevalence in a broad age range . populations presenting cytological or histological pathology generally had a higher hpv prevalence compared to those with normal cytology ( figures 1 and 2 ) . the studies showed a 75%100% concordance for any hpv type in paired urine and cervical samples ( or 41%93% by kappa agreement ) . type - specific concordance was reported in five studies , showing 100% , 90.5% , 71.0% , 70.8% , and 40.0% concordance . the latter estimates were calculated by including hpv - negative samples from either ( not both ) site , thereby reducing the type - specific concordance . eight of the eleven studies published after 2000 also reported either type - specific concordance for hpv16 or hpv18 , or concordance for the two types in combination . hpv16-specific concordance or concordance for any hpv type by severity of cervical lesion was reported in three studies . in contrast alameda et al26 reported a higher concordance for any hpv type in low grade squamous intraepithelial lesion ( lsil ) than in high grade squamous intraepithelial lesion ( hsil ) . forslund et al29 showed neither an increase nor a decrease in concordance for any hpv type with increasing severity . the only study that estimated sensitivity and specificity for hpv dna detection in urine samples compared to cervical samples in a presumably asymptomatic , drop - in , sexual health service clinic population was published by cuschieri et al18 who reported a sensitivity of 90.6% ( 95% confidence interval [ ci ] 79.3%96.9% ) and a specificity of 67.6% ( 95% ci 50.2%82.0% ) . in the studies with symptomatic populations , the sensitivity varied from 52.9% to 100% . we identified 14 male study populations from 13 publications that reported hpv positivity in urine samples and at least one other urogenital site ( table 2 ) . only the studies by lazcano - ponce et al38 and cuschieri et al18 included males less than 18-years old . the 117 males aged 1625 years in the cuschieri et al18 study showed a 36.7% hpv prevalence in urine samples versus 29.1% in samples taken from the shaft of the penis . the study by lazcano - ponce et al38 included 120 healthy males aged 1455 years in mexico ( 43 males in the range 1420 years ) and reported a 6.9% and 42.7% hpv prevalence in urine samples and urethra samples , respectively . similarly , hpv prevalence in the other studies listed in table 2 was generally lower in urine samples than in other urogenital samples . for example , weaver et al39 recruited 317 sexually active university students , aged 1825 years , and measured hpv prevalence in urine samples as well as in samples from the glans , penile shaft , scrotum , and foreskin . samples taken from the foreskin showed the highest prevalence ( 28.1% ) , while urine samples showed the lowest prevalence ( 5.8% ) . the percentage of urine samples in which human genomic dna could be detected varied substantially between the studies . while weaver et al39 detected human genomic dna in 99.7% of urine samples and 94.0%98.3% of samples from other sites , giuliano et al only detected human genomic dna in 51.3% of urine samples and 84.0%98.0% of samples from other sites , with semen samples having the highest human genomic dna detection rate . in the study by hernandez et al,40 semen samples and urine samples had the lowest human genomic dna detection rate , with 56.1% and 57.0% , respectively , compared to 78.8%95.1% from other urogenital sites . to illustrate some of the technical variability in these studies , we have listed the urine sampling procedure and the dna detection method used ( tables 1 and 2 ) . the most common urine sampling procedure in both female and male populations was first - void urine in contrast to mid - stream urine , which vorsters et al17 suggested would be preferable if the goal were to analyze a maximum number of exfoliated cells . the order of urine and cervical sampling may also affect the hpv dna detection rate in urine , and some studies have suggested that it is preferable to collect the urine sample first ( reviewed in sehgal et al).21 in the female populations listed in table 1 , urine sampling was not always carried out prior to cervical sampling and was sometimes done after washing the genitals . for hpv dna detection , variants of the my09/my11 primer were most commonly used , but other primers , such as general primer gp5/6 , in - house primers , e6-primers , hybrid capture ii , and dna chip assays were also used . in summary , the technical variability may contribute substantially to hpv dna detection rates . results from 21 female study populations from 17 publications that reported hpv prevalence in urine samples are summarized in table 1 . prusty et al22 and manhart et al23 included females 1825 years of age , while only two studies , one from scotland by oleary et al24 and one from india by hussain et al,25 included females less than 18 years of age ( figure 1 and table 1 ) . the hpv prevalence ( any type ) varied from 1.1% in the age group 1114 years in the oleary et al24 study to 29.6% in the age group 2021 years in the manhart et al23 study . oleary et al24 reported the lowest percentage of samples ( 83.6% ) containing amplifable human genomic dna ; prusty et al22 reported the highest percentage ( 100% ) . we identified 14 studies that measured hpv positivity in paired urine and cervical samples from symptomatic females;18,22,2637 of these studies , nine reported the age range and nine the mean age of the study population . these studies included women with symptoms that led to various gynecological complaints and women diagnosed with invasive cervical cancer . urine and cervical samples were collected at gynecological , colposcopy , genitourinary , sexually transmitted disease , and adolescent clinics . in general , hpv prevalence increased with the severity of cytological or pathological findings , and this was observed both in urine samples and cervical samples . all studies that reported age - specific hpv prevalence showed lower prevalence in urine samples than paired cervical samples , with the majority of the studies reporting a 10%20% lower hpv prevalence , save the studies by rymark et al33 and cuschieri et al18 ( figure 2 ) . with the exception of studies by rymark et al33 and jacobson et al,31 which covered narrow age ranges ( 1621 years and 1120 years , respectively ) , the studies in this review generally reported hpv prevalence in a broad age range . populations presenting cytological or histological pathology generally had a higher hpv prevalence compared to those with normal cytology ( figures 1 and 2 ) . the studies showed a 75%100% concordance for any hpv type in paired urine and cervical samples ( or 41%93% by kappa agreement ) . type - specific concordance was reported in five studies , showing 100% , 90.5% , 71.0% , 70.8% , and 40.0% concordance . the latter estimates were calculated by including hpv - negative samples from either ( not both ) site , thereby reducing the type - specific concordance . eight of the eleven studies published after 2000 also reported either type - specific concordance for hpv16 or hpv18 , or concordance for the two types in combination . hpv16-specific concordance or concordance for any hpv type by severity of cervical lesion was reported in three studies . in contrast alameda et al26 reported a higher concordance for any hpv type in low grade squamous intraepithelial lesion ( lsil ) than in high grade squamous intraepithelial lesion ( hsil ) . forslund et al29 showed neither an increase nor a decrease in concordance for any hpv type with increasing severity . the only study that estimated sensitivity and specificity for hpv dna detection in urine samples compared to cervical samples in a presumably asymptomatic , drop - in , sexual health service clinic population was published by cuschieri et al18 who reported a sensitivity of 90.6% ( 95% confidence interval [ ci ] 79.3%96.9% ) and a specificity of 67.6% ( 95% ci 50.2%82.0% ) . in the studies with symptomatic populations , the sensitivity varied from 52.9% to 100% . we identified 14 male study populations from 13 publications that reported hpv positivity in urine samples and at least one other urogenital site ( table 2 ) . only the studies by lazcano - ponce et al38 and cuschieri et al18 included males less than 18-years old . the 117 males aged 1625 years in the cuschieri et al18 study showed a 36.7% hpv prevalence in urine samples versus 29.1% in samples taken from the shaft of the penis . the study by lazcano - ponce et al38 included 120 healthy males aged 1455 years in mexico ( 43 males in the range 1420 years ) and reported a 6.9% and 42.7% hpv prevalence in urine samples and urethra samples , respectively . similarly , hpv prevalence in the other studies listed in table 2 was generally lower in urine samples than in other urogenital samples . for example , weaver et al39 recruited 317 sexually active university students , aged 1825 years , and measured hpv prevalence in urine samples as well as in samples from the glans , penile shaft , scrotum , and foreskin . samples taken from the foreskin showed the highest prevalence ( 28.1% ) , while urine samples showed the lowest prevalence ( 5.8% ) . the percentage of urine samples in which human genomic dna could be detected varied substantially between the studies . while weaver et al39 detected human genomic dna in 99.7% of urine samples and 94.0%98.3% of samples from other sites , giuliano et al only detected human genomic dna in 51.3% of urine samples and 84.0%98.0% of samples from other sites , with semen samples having the highest human genomic dna detection rate . in the study by hernandez et al,40 semen samples and urine samples had the lowest human genomic dna detection rate , with 56.1% and 57.0% , respectively , compared to 78.8%95.1% from other urogenital sites . to illustrate some of the technical variability in these studies , we have listed the urine sampling procedure and the dna detection method used ( tables 1 and 2 ) . the most common urine sampling procedure in both female and male populations was first - void urine in contrast to mid - stream urine , which vorsters et al17 suggested would be preferable if the goal were to analyze a maximum number of exfoliated cells . the order of urine and cervical sampling may also affect the hpv dna detection rate in urine , and some studies have suggested that it is preferable to collect the urine sample first ( reviewed in sehgal et al).21 in the female populations listed in table 1 , urine sampling was not always carried out prior to cervical sampling and was sometimes done after washing the genitals . for hpv dna detection , variants of the my09/my11 primer were most commonly used , but other primers , such as general primer gp5/6 , in - house primers , e6-primers , hybrid capture ii , and dna chip assays were also used . in summary , the technical variability may contribute substantially to hpv dna detection rates . according to the world health organization ( who ) , 33 countries have implemented hpv vaccination as part of their national immunization program.41 generally , vaccination is provided to girls , and it is therefore recommended to monitor the impact of vaccination on hpv prevalence among female adolescents.15 in august 2012 , we identified four publications that reported hpv prevalence in urine samples from asymptomatic female adolescents . hpv prevalence has been strongly associated with age , being nearly nonexistent in preadolescents , gradually increasing with sexual activity among adolescents , and generally peaking around 25 years of age.42 however , regional differences in hpv prevalence do exist.43 therefore , the first step when monitoring hpv prevalence is to establish the baseline hpv prevalence in the relevant age groups . to date , only hussain et al and oleary et al reported baseline hpv prevalence based on urine samples from a large unvaccinated adolescent population.24,25 the hussain et al25 study from india used self - collected urine of the cervix and that care should be taken when samples from healthy children attending public school and achieved a 57.3% participation rate . oleary et al24 analyzed urine samples from 1118-year - old school and college males ( 1121 ) and females ( 1341 ) in scotland 4 months before vaccination was introduced in the national immunization schedule in 2008 . a limitation of the study was that the estimated response rate for providing a urine sample was as low as 14% . while the low response rate can introduce bias and lead to erroneous estimates of the overall hpv prevalence , it was not directly related to the sampling method and probably refects a general challenge to achieve high response rates in this age group . this , in turn , could partially explain why only few studies measuring hpv prevalence in urine samples from female adolescents in the general population have been performed and published . the five studies that reported hpv prevalence by lesion severity showed a similar association for paired urine and cervical samples , with higher hpv prevalence in the most severe lesions . this is to some degree related to regional differences in hpv prevalence,43 the age distribution of the different study populations,43 and the setting in which the women were recruited . there were also differences in sampling procedures and hpv detection methods , including the number of types detected by a given assay . it is therefore not possible , as vorsters et al17 pointed out , to perform a meta - analysis on the present urine - based hpv prevalence studies . detection of human genomic dna is commonly used to control for the adequacy of samples for hpv detection . studies including female populations showed a high detection rate of human genomic dna in urine samples ( 83%100% ) , while male populations showed a larger range of detection rates ( 30%100% ) . in an hpv monitoring setting , a low human genomic dna detection rate would lead to reduced coverage and create a concern of bias in hpv estimates . in general , studies on female populations in this review indicated that high detection rates of human genomic dna are feasible . in cervical screening the main focus is to detect hpv or cervical abnormalities at the individual level , while population - based hpv prevalence is used more in a monitoring or epidemiological setting . therefore , although prevalence in urine samples was lower than in cervical samples in the studies included in this review , monitoring by regular urine measurements over time may still be a useful way of identifying shifts in hpv prevalence due to imparted immunity against vaccine hpv types . however , the differences in hpv concordance of paired urine and cervical samples illustrates that hpv positivity in urine should be interpreted independently of the cervix and that care should be taken when inferring that a similar change is taking place in the cervix . on the other hand hpv detection in urine samples could be considered an independent measurement of the impact of hpv vaccination but it would have only limited public health interest . furthermore , we observed that hpv negativity in the cervix commonly predicted an hpv - negative result in the urine as well , while hpv positivity in the cervix less commonly predicted hpv positivity in the urine . although daponte et al showed an increased concordance with increased lesion severity for any hpv type , other studies like alameda et al,26 rymark et al,33 and gupta et al30 showed a relatively high concordance , even in populations where hpv prevalence is low . the variability of hpv16/18-specific concordance , the types included in both of the available hpv vaccines , further exemplifies the uncertainty of using urine samples to estimate future changes in the incidence of cervical lesions . the most comprehensive monitoring of changes in hpv prevalence would be carried out by establishing baseline hpv prevalence before measuring any impact of vaccination as well as regular measurements of hpv prevalence in both vaccinated and unvaccinated females and males . the age group ( or groups ) and sample size to include in hpv monitoring should be carefully selected to assure there is enough statistical power to identify changes in overall hpv prevalence as well as hpv type - specific changes . models suggest that there will be a significant reduction in the prevalence of vaccine hpv types in males in the future because after vaccination , fewer girls will transmit hpv to their male partners.44 monitoring hpv prevalence in males could therefore be a near - term end point that could also help to estimate the effect of herd immunity . the differences in hpv prevalence across different urogenital sites illustrates that no single site repeatedly shows the highest hpv dna detection rate and that urine in particular has a relatively low hpv dna detection rate compared to other sites . in addition , male urine generally has a lower detection rate for human genomic dna than samples from other urogenital sites . with lower detection rates for human genomic dna , a larger sample size would be needed to detect changes with the same power as other urogenital sites . a protocol with sufficient detail on technical and practical issues that influence hpv detection is therefore necessary to ensure comparability between these measurements . this includes , among other issues , urine sampling procedure , handling of samples , extraction of dna , and assay used for hpv genotyping.17 in addition it might be useful to store an extra aliquot of extracted dna from each regular measurement to be able to perform hpv genotyping on all dna collected from urine samples over many years . this would also allow for using any novel genotyping technology that may have developed during the monitoring period . information on more aspects of hpv monitoring can also be found in the human papillomavirus laboratory manual issued in 2009 by the who hpv laboratory network ( who hpv labnet).45 this manual covers guidance on specimen collection and handling for hpv testing , with the aim to assist in establishing the laboratory support required for implementation and monitoring of hpv vaccination programs . several of the who hpv labnet members are actively undertaking studies of hpv detection in urine , and a leading role for the who hpv labnet in further standardizing and optimizing the technology for hpv detection in urine seems appropriate.18,45,46 this is the first review that focuses solely on the use of urine to monitor changes in hpv prevalence in an asymptomatic population . the major shortcoming of this review is that , to date , there are few studies on the topic . we have therefore included studies from symptomatic populations and older populations that used urine for purposes other than monitoring , although these are not comparable to asymptomatic adolescents in all aspects . in addition , the studies highlighted in the present review as well as in the reviews of vorsters et al17 and seghal et al,21 showed that the large variability in sampling and genotyping methodology make direct comparisons of data , like concordance , inaccurate.17,21 assuming a future reduction in overall hpv prevalence and vaccine hpv type - specific prevalence and using urine testing as a monitoring method , care should be taken when interpreting the data . indeed the data may not necessarily mimic the true hpv distribution in the cervix nor estimate the expected reductions in cervical cancer and high - grade lesions , as indicated by variable vaccine hpv type - specific ( hpv16/18 ) concordance between paired urine and cervical samples . there is great scientific and political interest in monitoring the early effects of hpv vaccination in the general population . however , monitoring hpv prevalence as an early measurement of vaccine impact is only possible in a few countries as substantial financial and human resources are needed as well as a 510-year commitment in order to demonstrate results.16 urine is an adequate alternative biospecimen for monitoring hpv prevalence in female adolescents to determine the early effect of hpv vaccination on a population level . strategies for recruitment should be optimized to avoid low response rates , sampling and hpv detection protocols should be detailed and standardized to ensure comparability , and importantly , care should be taken when extrapolating findings to the cervix . in males , urine samples do not seem to be optimal for monitoring hpv prevalence due to a low human genomic dna content compared to other urogenital sites . although urine sampling has some advantages and is the only relevant option for sampling the general population in the youngest age groups , it also has several disadvantages , most importantly the fact that hpv prevalence in urine is only a distant measure of the main end point of vaccine impact , cervical cancer . in each situation the costs and benefits of hpv dna detection in urine , compared to alternative monitoring options , should be carefully considered.16,47
human papillomavirus ( hpv ) is the main cause of cervical cancer , and many countries now offer vaccination against hpv to girls by way of government - funded national immunization programs . 
 monitoring hpv prevalence in adolescents could offer a near - term biological measure of vaccine impact , and urine sampling may be an attractive large - scale method that could be used for this purpose . 
 our objective was to provide an overview of the literature on hpv dna detection in urine samples , with an emphasis on adolescents . 
 we searched the pubmed database using the terms  hpv  and  urine  and identified 21 female and 14 male study populations in which hpv prevalence in urine samples was reported , four of which included only asymptomatic female adolescents . 
 we provide herein an overview of the recruitment setting , age , urine sampling procedure , lesion type , hpv assay , and hpv prevalence in urine samples and other urogenital samples for the studies included in this review . in female study populations , concordance for any hpv type and type - specific concordance in paired urine and cervical samples are provided in addition to sensitivity and specificity . 
 we concluded that few studies on hpv prevalence in urine samples have been performed in asymptomatic female adolescent populations but that urine samples may be a useful alternative to cervical samples to monitor changes in hpv prevalence in females in the post - hpv vaccination era . 
 however , care should be taken when extrapolating hpv findings from urine samples to the cervix . in males 
 , urine samples do not seem to be optimal for monitoring hpv prevalence due to a low human genomic dna content and hpv dna detection rate compared to other urogenital sites . 
 in each situation the costs and benefits of hpv dna detection in urine compared to alternative monitoring options should be carefully considered .