As compared with Pap testing, HPV testing has greater sensitivity for the detection of cervical intraepithelial neoplasia. (Current Controlled Trials number, ISRCTN57612064 [controlled-trials.com].).

Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread-optimally universal-implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters.

Background: Besides an established role for certain human papillomavirus (HPV) genotypes in the etiology of cervical cancer, little is known about the influence of multiple-type HPV infections on cervical lesion risk. We studied the association between multiple HPV types and cervical lesions among 2,462 Brazilian women participating in the LudwigMcGill study group investigation of the natural history of HPVs and cervical neoplasia. Methods: Cervical specimens were typed by a PCR protocol. The cohort's repeated-measurement design permitted the assessment of the relation between the cumulative and concurrent number of HPV types and any-grade squamous intraepithelial lesions (SIL) and high-grade SIL (HSIL). Result: At individual visits, 1.9% to 3.2% of the women were infected with multiple HPVs. Cumulatively during the first year and the first 4 years of follow-up, 12.3% and 22.3%

The intratypic variability of HPVs 16 and 18 has been extensively studied and has been used as an important tool in epidemiological studies of viral transmission, persistence and progression to clinically relevant cervical lesions. Infections by non-European variants of HPVs 16 and 18 are associated with an increased risk for the development of high grade squamous intraepithelial lesions (HSIL). Our aim was to correlate the intratypic molecular variability of both HPV types and risk of persistent infection and lesion outcome in a cohort study conducted in Brazil. We characterized molecular variants of HPV types 16 and 18 by sequencing a fragment of the LCR, and of the E6 and L1 genes, for HPV-16 variants only. For both types, European variants composed the most prevalent and diverse group. Persistent infections with HPV-18 were associated with continuous detection of European variants. However, risk for simultaneous detection of HSIL and HPV DNA was higher in women harboring non-European variants of HPV-16. The same trend was observed with HSIL detected during follow-up. Our study confirms the association between non-European variants and risk of cervical neoplasia, and highlights the importance of their geographic distribution for cervical cancer risk assessment. ' 2007 Wiley-Liss, Inc.Key words: human papillomavirus; molecular variants; oncogenic potential; cohort study; cervical neoplasia More than 120 different human papillomavirus (HPV) genotypes associated with infections in humans have been described, of which approximately 40 infect the anogenital area. Nearly 20 of these are classified as high-risk HPV types (HR-HPV) due to their association with cancer. In particular, HPVs 16 and 18 are the most common high-risk types in cancer biopsies, worldwide. 1 Their oncogenic potential has been demonstrated both in vitro and in vivo. 2 Nevertheless, only a minority of women infected with HPVs 16 and 18 develop neoplastic lesions. 3,4 Intratypic molecular variants of HPVs are characterized by differences in nucleotide sequence from the prototypic L1 gene of less than 2%. 5 Recently, full genome analysis of HPV-16 isolates revealed that 4% of the sequence is variable. 6 Moreover, these authors described a 9.9% amino acid variability within the eight HPV genes of the different HPV-16 molecular variants studied. The nucleotide variability of HPVs 16 and 18 has been extensively studied, and several molecular variants have been described on the basis of their geographical distribution. 7-9 Studies conducted in multiethnic populations have shown the association between Asian-American or other non-European variants of HPVs 16 and 18 and increased risk of persistent infection and development of cervical lesion. 4,10-13 Specific variants of HPVs 16 and 18 seem to be associated also with certain histopathological features of cervical neoplastic lesions. 10,14,15 In one study, Asian-American variants of both HPVs 16 and 18 were associated with squamous cell carcinomas and adenocarcinomas, while European variants were assoc...

HPV infections are believed to be a necessary cause of cervical cancer. Viral burden, as a surrogate indicator for persistence, may help predict risk of subsequent SIL. We used results of HPV test and cytology data repeated every 4 -6 months in 2,081 women participating in a longitudinal study of the natural history of HPV infection and cervical neoplasia in São Paulo, Brazil. Using the MY09/11 PCR protocol, 473 women were positive for HPV DNA during the first 2 visits. We retested all positive specimens by a quantitative, low-stringency PCR method to measure viral burden in cervical cells. Mean viral loads and 95% CIs were calculated using log-transformed data. RRs and 95% CIs of incident SIL were calculated by proportional hazards models, adjusting for age and HPV oncogenicity. The risk of incident lesions increased with viral load at enrollment. The mean number of viral copies/cell at enrollment was 2.6 for women with no incident lesions and increased (trend p ‫؍‬ 0.003) to 15.1 for women developing 3 or more SIL events over 6 years of follow-up. Compared to those with <1 copy per cell in specimens tested during the first 2 visits, RRs for incident SIL increased from 1.9 (95% CI 0.8 -4.2) for those with 1-10 copies/cell to 4.5 (95% CI 1.9 -10.7) for those with >1,000 copies/cell. The equivalent RR of HSIL for >1,000 copies/cell was 2.6 (95% CI 0.5-13.2). Viral burden appears to have an independent effect on SIL incidence. Measurement of viral load, as a surrogate for HPV persistence, may identify women at risk of developing cervical cancer precursors. © 2002 Wiley-Liss, Inc. Key words: human papillomavirus; cervical neoplasia; cohort study; longitudinal analysis; viral loadEstablishment of productive infections by oncogenic types of HPV is a key early event in the natural history of cervical cancer. Given the positive relationship between viral load and the likelihood of persistent HPV infection 1 and the strong relationship between the latter and risk of cervical neoplasia, 2 a single measurement of viral load in cervical specimens may be a suitable biomarker of either a transient infection, or the likelihood that an instance of HPV DNA positivity may represent a persistent infection or one that may become persistent over time and lead to the development of cervical SIL. In the latter case, little is known, however, about the relationship between level of viral burden and lesion incidence or lesion grade severity in the natural history of CIN. HPV DNA viral load has been identified as a biomarker for cervical lesions in women, 3,4 primarily with minor-grade cytologic atypia. 5 However, only a few studies have evaluated the predictive effect of viral load on the incidence of cervical cancer precursors. 3,4,6 -8 A few methods of viral load estimation have been evaluated in epidemiologic studies. Although several cross-sectional studies have examined the association between HPV load measured by HC and the presence of SIL, 9 -13 HC cannot accurately quantify HPV DNA in cervical specimens because of the variabl...

Needle exchange programs (NEPs) are designed to prevent human immunodeficiency virus (HIV) transmission among injection drug users. Although most studies report beneficial effects in terms of behavior modification, a direct assessment of the effectiveness of NEPs in preventing HIV infection has been lacking. A cohort study was conducted to assess the association between risk behaviors and HIV seroprevalence and seroincidence among injection drug users in Montreal, Canada. The association between NEP use and HIV infection was examined in three risk assessment scenarios using intensive covariate adjustment for empirical confounders: a cross-sectional analysis of NEP use at entry as a determinant of seroprevalence, a cohort analysis of NEP use at entry as a predictor of subsequent seroconversion, and a nested case-control analysis of NEP participation during follow-up as a predictor of seroconversion. From September 1988 to January 1995, 1,599 subjects were enrolled with a baseline seroprevalence of 10.7%. The mean follow-up period was 21.7 months. The adjusted odds ratio for HIV seroprevalence in injection drug users reporting recent NEP use was 2.2 (95% confidence interval 1.5-3.2). In the cohort study, there were 89 incident cases of HIV infection with a cumulative probability of HIV seroconversion of 33% for NEP users and 13% for nonusers (p < 0.0001). In the nested case-control study, consistent NEP use was associated with HIV seroconversion during follow-up (odds ratio = 10.5, 95% confidence interval 2.7-41.0). Risk elevations for HIV infection associated with NEP attendance were substantial and consistent in all three risk assessment scenarios in our cohort of injection drug users, despite extensive adjustment for confounders. In summary, in Montreal, NEP users appear to have higher seroconversion rates then NEP nonusers.

The authors investigated the joint effects of tobacco and alcohol consumption on the risk of squamous cell carcinomas of the upper aero-digestive tract (UADT) using data from a hospital-based case-control study conducted in southern Brazil, 1986-1989. A total of 784 cases of cancers of the mouth, pharynx, and larynx and 1,578 non-cancer controls matched on age, sex, hospital catchment area, and period of admission were interviewed about their smoking and drinking habits and other characteristics. Using logistic regression, evidence was found for interaction between the cumulative exposures for smoking and alcohol on UADT cancer risk. The joint effects for pharyngeal cancers exceeded the levels expected under a multiplicative model for moderate smokers (p = 0.007). There was little statistical evidence, however, for interaction on cancers of the mouth (p = 0.28) or larynx (p = 0.95). Among never smokers, heavy drinkers had 9.2 times (95% confidence interval 1.7, 48.5) greater risk of cancers of mouth, pharynx, and supraglottis than never drinkers, with a dose-response trend (p = 0.013) with cumulative consumption. The authors conclude that the interaction occurring in the pharynx between smoking and alcohol on UADT cancers is not uniform, with varying effects depending on the level of smoking exposure. Alcohol may act as both a promoter for tobacco and as an independent risk factor.

review reminds us that simple vaginal hysterectomy is often curative in women with endometrial cancer. In this series of 128 women over age 70 with endometrial cancer, the 5-year survival rate was 89.2% for stage I disease and a very respectable 67.4% for 33 women with stage II or III disease. All patients had a bilateral salpingo-oophorectomy, but only 8.6% of these women had a pelvic lymphadenectomy through an extraperitoneal approach. Others, including Chan et al from the University of California at Irvine, have also reported excellent results with minimal morbidity in a series of 51 medically compromised women with endometrial cancer (Obstet Gynecol 2001;97: 707). Most of these women were morbidly obese and many had 3 or more risk factors. Morbidity was minimal and 5-year survival was 88%.Although radiation therapy alone has been used to treat women with endometrial adenocarcinoma, older reports have indicated a worse outcome than when hysterectomy is part of the treatment, and there are no recent studies that have examined this question. In a study of 34 women over age 75 with endometrial cancer, Citron et al found minimal morbidity when pelvic radiation was added to surgery for high-risk disease (Int J Radiat Biol Phys 2004;59:1432). The 5-year disease-free survival was actually better in the women treated with radiation for deep myometrial invasion, cervical involvement, or poorly differentiated adenocarcinoma.Laparoscopically assisted hysterectomy has also been used for older women with endometrial cancer with good results (Scribner et al. Gynecol Oncol 2001;83:563). However, operative time and surgical morbidity are usually greater than with abdominal hysterectomy and staging. Once again, the value of lymphadenectomy in the survival of women with endometrial cancer is very much in question.-HWJ)