human papillomavirus ( hpv ) is a significant source of morbidity 
 and mortality in the united states and worldwide . high - risk , 
 oncogenic hpv types ( including hpv 16 and hpv 18 ) are associated 
 with 99.7% of all cervical cancers , as well as low - grade 
 squamous intraepithelial lesions ( lsil ) , high - grade squamous 
 intraepithelial lesions ( hsil ) , and abnormal papanicolaou ( pap ) 
 test results , which carry significant health care costs and 
 psychosocial morbidity . low - risk hpv types ( hpv 6 and hpv 11 ) are 
 responsible for additional abnormal pap test results , as well as 
 almost all cases of genital warts . hpv is so common that more than 
 half of all sexually active adults will be infected in their 
 lifetime , although young , sexually active women bear the brunt of 
 both infection and clinical complications . currently there are 
 neither effective hpv prevention strategies nor good treatments 
 for individuals with genital warts or cervical lesions ; available 
 treatments focus on removing the affected area , and recurrence is 
 common . prophylactic vaccines will soon become available , and 
 promise to significantly reduce the morbidity and mortality 
 associated with these infections . approximately 6.2 million new hpv infections occur every year in 
 the united states , and approximately 20 million individuals are 
 currently infected . hpv is spread by skin - to - skin sexual 
 contact and is prevalent in all sexually active populations . the 
 centers for disease control estimates that at least half of all 
 sexually active individuals will acquire hpv at some point in 
 their lives , whereas at least 80% of women will acquire an hpv 
 infection by age 50 . in the united states , it is 
 estimated that 10% of the population has an active hpv 
 infection , 4% has an infection that has caused cytological 
 abnormalities , and an additional 1% have infection causing 
 genital warts . although 1% of americans have 
 clinically visible genital warts , as many as 13% of those 
 attending std clinics have genital warts . the greatest 
 risk factors for infection are gender , youth , and sexual activity , 
 with the highest rates being consistently found in sexually active 
 women less than 25 years of age . winer et al followed 148 female 
 university students as they initiated sexual activity 
 ( figure 1 ) . hpv 16 was the most 
 common type , with a cumulative infection rate of 10.4% at 24 
 months ; the cumulative incidence of hpv 18 infection was 4.1% 
 for the same time period . brown et al studied a smaller cohort of 
 mid - adolescent women for two years . of the women studied , 82% 
 were infected with hpv during the 2-year study period 
 . dna from both low - risk and high - risk hpv types has even 
 been found in women who have sex with women , a population that 
 would be expected to have a low incidence of hpv infection 
 . it should be noted that prevalence estimates vary 
 depending on the technique used to assess viral load ; polymerase 
 chain reaction analysis is a more sensitive detection method and 
 yields higher rates of prevalence . hpv 16 alone is linked to more than 50% of all cervical cancers 
 ; thus , the prevalence of hpv 16 is of special interest . one study utilized an experimental serological test to determine 
 the presence of antibodies to hpv 16 , which signify prior exposure 
 to hpv , instead of the more commonly assessed viral dna which is 
 indicative of active infection . more than 7000 sera were tested 
 from a national sample from the united states . women were 
 more likely to be seropositive for hpv 16 ( 17.9% ) than were 
 men ( 7.9% ) . however , this methodology may in fact 
 underestimate the true prior exposure to hpv 16 , because < 60% 
 of women infected with hpv 16 develop type - specific antibodies 
 . sexual activity is the primary risk factor for hpv infection , but 
 condoms , although effective at preventing the spread of many other 
 sexually transmitted infections , may not prevent all hpv 
 infections . a meta - analysis of more than 20 trials investigating 
 the role of condoms in hpv transmission and the development of 
 clinical complications concluded that , although condoms do not 
 protect against cervical infection , they may offer some protection 
 against hpv - associated disease . specifically , although there is 
 conflicting evidence as to whether condom use protects against cin 
 2/3 , condoms may protect against cervical cancer . a 
 recent prospective study by hogewoning et al studied the effect 
 of condom use on the regression of cin lesions . women with 
 abnormal cervical smears or cin were randomized to use condoms 
 after the initial diagnosis . the 2-year cumulative 
 regression rate was 53% in the  condom  group and 35% in 
 the  noncondom  group . the 2-year cumulative rate of hpv 
 clearance was 23% in the condom group and 4% in the 
 noncondom group 
 . it is difficult to accurately assess the role of condoms 
 in preventing hpv infection and the development of clinical 
 complications of infections , not least because investigators rely 
 on patient self - report to assess condom use . the available 
 evidence does , however , suggest that condom use protects against 
 some clinical sequelae of hpv infection and aids clearance of 
 infection and clinical symptoms , even if it does not prevent 
 primary infection . hpv is a small dna virus with a genome of approximately 8000 base 
 pairs . hpv targets the basal cells in the stratified 
 squamous epithelium and the metaplastic cells at the 
 squamocolumnar junction of the cervix . additionally , hpv may 
 infect the glandular epithelium of the endocervix , resulting in 
 glandular neoplasms , such as adenocarcinoma in situ or invasive 
 adenocarcinoma . the two primary oncogenes of high - risk 
 hpv types are e6 and e7 . designation indicates that 
 these two genes are expressed early in the hpv life cycle . the 
 products of these two genes alter host - cell metabolism to favor 
 neoplastic development . an effect of this targeted degradation is to prevent 
 apoptosis of the infected host epithelial cells . the e7 
 protein has a similar effect on cell metabolism by binding to 
 retinoblastoma protein , inhibiting its function . in addition , e6 and e7 
 proteins may cause chromosomal destabilization , and inhibit 
 cyclin - dependent kinase inhibitors and host interferons . the degree of expression of hpv e6 and e7 is highly correlated 
 with the type of cervical lesion : in low - grade lesions , e6 and e7 
 are expressed at low levels in the basal cells and higher levels 
 in the upper layers of the epithelium , whereas in high - grade 
 lesions e6 and e7 are expressed at high levels throughout the 
 epithelium . in low - grade lesions , hpv is in episomal 
 form , whereas in higher grade lesions and cancer , the hpv dna is 
 more likely to have been integrated into the host - cell chromosome . the integration of hpv dna into the host dna increases cellular 
 proliferation and the chance of   malignancy . hpv infection , unlike many genitourinary infections , is not 
 usually associated with immediate symptoms such as itching , 
 burning , and vaginal discharge . rather , the majority of 
 those infected with hpv will not develop clinical disease or 
 symptoms because the host immune system resolves most infections . 
 in one study , only 24.8% of women infected with hpv 6 or 11 
 actually developed genital warts . a large , prospective 
 10-year cohort study of more than 20,000 women enrolled in a 
 health maintenance organization found that the incidence of cin 3 
 or cancer was approximately 7% in hpv - positive women for the 
 duration of the study . thus , only the minority of 
 patients with hpv infections develop serious clinical 
 complications . the exact mechanism by which hpv infection is 
 cleared by the host immune system is currently unknown . a number of factors are associated with an increased risk of 
 initial infection and/or clinical sequelae such as genital warts , 
 cin or invasive cancer . individuals who smoke are more likely to 
 develop cancer , and it is thought that smoking increases the 
 likelihood of developing sil . herpes simplex virus ( hsv ) 
 and c. trachomatis infection are also associated with 
 cervical cancer . smith et al performed a pooled analysis that 
 found prior exposure to hsv-2 was associated with 2-fold increased 
 risk of squamous cell carcinoma of the cervix in patients with hpv 
 ; c. trachomatis infection is associated with a similarly 
 increased risk of squamous cell carcinoma 
 . 
 c. trachomatis infection is also associated with more 
 persistent hpv infection , which may contribute to the increased 
 risk of clinical complications of hpv infection in individuals 
 coinfected with c. trachomatis . immunosuppressed and hiv positive individuals are at a high risk 
 of both hpv infection and hpv - associated disease . high hiv rna 
 levels and cd4 < 200 cells per mm counts are associated 
 with both incident and persistent hpv infection , although the 
 association with incident infection is stronger . among 
 women with oncogenic hpv , hiv - positive women with low cd4 cell 
 counts are more likely than either hiv - negative women or 
 hiv - positive women with high cd4 cell counts to develop sil . data concerning the effect of highly active anti - retroviral 
 therapy on the natural history of hpv infections and cervical 
 dysplasia are mixed and further investigation is needed in this 
 area . steps that occur from initial infection leading to the development 
 of cancer include overcoming host immune resistance , possible 
 integration of hpv dna into the host genome , and accumulation of 
 additional mutations within the infected host cell . hpv 
 must be persistent within the host epithelial cells as a 
 preliminary step toward advanced neoplastic changes . the 
 traditional view has been that this process takes years , if not 
 decades , to occur after initial hpv infection . recent studies 
 suggest that these changes may develop more quickly than 
 previously thought . winer et al followed women after initial hpv 
 infection for the development of cin 2/3 . as shown in 
 figure 3 , approximately 27% of women with an 
 initial hpv 16 or 18 infection progressed to cin 2/3 within 36 
 months . a second study of a large health maintenance 
 cohort found that approximately 20% of women 30 years of age or 
 older who were initially infected with hpv 16 developed cin 3 or 
 cervical cancer within 120 months . women who had an initial hpv 18 
 infection had approximately a 15% risk of developing cin 3 or 
 cervical cancer at 120 months . the strong correlation between infection with high - risk types of 
 hpv and lsil , hsil , and cervical cancer suggests that hpv dna 
 testing would be a useful tool for the management of women with 
 abnormal pap test results , especially in the case of those with 
 equivocal test results . in the case of an equivocal pap test result , hpv dna testing can help determine whether the individual 
 should be referred for colposcopic assessment . hpv is one of the most common infections of the female genital 
 tract , and it is also one of the most costly . hpv - associated 
 health care costs include routine pap tests , treatment of genital 
 warts , follow - up of cytological abnormalities , and management of 
 cervical malignancies . an observational study of the kaiser 
 permanente health plan found that the annual cost of screening and 
 treatment of hpv - related cervical neoplasia was $ 26,415 per 
 1000 women , with nearly 2/3 of that ( $ 16,746 ) attributable to 
 routine screening . another large study investigated the 
 incidence and costs associated with genital warts : each episode of 
 genital warts required an average of 3.1 doctor visits , with an 
 average total cost of $ 436 for all visits . incidence ranged 
 from 1.7 cases per 1000 patient - years overall to a peak of 6.2 
 cases of genital warts per 1000 person - years , in women aged 20 to 
 24 years , at a cost of $ 1692 per 1000 person - years , and 5 cases 
 per 1000 patient - years in men aged 25 to 29 at a cost of $ 1717 
 per 1000 patient - years 
 . currently there are no good methods for preventing hpv infection . 
 nor are there comprehensive and effective treatments for the 
 clinical consequences of infection : for both genital warts and 
 lesions , management entails removal of discrete lesions and 
 monitoring for recurrence . prophylactic hpv vaccines that confer 
 protection against both high- and low - risk hpv types are expected 
 to substantially reduce the burden of hpv - associated disease . a 
 bivalent vaccine formulated to protect against the two most 
 common high - risk hpv types , 16 and 18 , and a quadrivalent vaccine 
 that will protect against hpv 16 and 18 , and the two most common 
 low - risk types , hpv 6 and 11 , are in ongoing clinical testing . phase 2 data suggest that both vaccines are safe , are capable of 
 producing immune responses in orders of magnitude larger than 
 those produced in the wake of a natural infection , and are more 
 than 90% effective at preventing persistent hpv infection and 
 the clinical manifestations of hpv infection ; recent phase 3 data 
 suggest that the quadrivalent vaccine may be 100% effective at 
 preventing hpv 16/18-associated disease 
 [ 2527 ] . the vast majority of sexually active men and women will become 
 infected with hpv . although the host immune system successfully 
 clears most of these infections , some women will develop fulminant 
 disease such as genital warts , cervical dysplasia , and invasive 
 cervical cancer . current treatment options are not curative ; 
 therefore , preventative vaccines that lower the incidence of hpv 
 infection and its associated diseases may offer a promising 
 alternative to current therapies . cumulative rate of hpv infection among college - aged women 
 who were virgins at baseline . adapted from winer et al . . cumulative risk of cin 2/3 after infection with hpv 16 or 
 18 , or other types . adapted from winer et al 
 .
human papillomavirus ( hpv ) is the most common newly diagnosed 
 sexually transmitted infection in the united states . 
 although the 
 majority of sexually active adults will be infected with hpv at 
 least once in their lives , it is sexually active women less than 
 25 years of age who consistently have the highest rates of 
 infection . besides 
 youth and gender , common risk factors for hpv 
 infection and clinical sequelae of infection include high number 
 of sexual partners and coinfection with chlamydia 
 trachomatis or herpes simplex virus . 
 most hpv infections are 
 cleared by the immune system and do not result in clinical 
 complications . 
 clinical sequelae in cases of low - risk hpv 
 infection consist of genital warts , and clinical manifestations of 
 high - risk hpv infection include abnormal pap test results , 
 low - grade squamous intraepithelial lesions ( lsil ) , high - grade 
 squamous intraepithelial lesions ( hsil ) , and cervical cancer . 
 lsil , hsil , and cervical cancer carry significant morbidity and/or 
 mortality ; genital warts and abnormal pap test results are often 
 significant sources of psychosocial distress . 
 currently , there are 
 neither effective means of preventing hpv transmission nor cures 
 for clinical manifestations : infection can only be prevented via 
 complete sexual abstinence , while treatment for clinical sequelae 
 such as genital warts and cytologic abnormalities consists of 
 removing the problematic cells and watching for recurrence ; this 
 method consumes significant health care resources and is costly . 
 new prophylactic hpv vaccines promise to dramatically reduce the 
 incidence of hpv infection , genital warts , and cytologic 
 abnormalities .