Clinical usefulness of BK virus plasma quantitative PCR to prevent BK virus associated nephropathy.

The present study investigated the clinical usefulness of plasma real-time polymerase chain reaction (PCR) (plasma-PCR) in the prevention of BK virus-associated nephropathy (BKVAN). First, we investigated the diagnostic value of plasma BK-PCR, urine BK-PCR, and urine cytology for the prediction of BKVAN retrospectively. Then we designed a prospective study of regular plasma-PCR monitoring and pre-emptive immunosuppression (IS) reduction based on the result. In the retrospective cohort, the prevalence of BKVAN was 3.7% (14/379) and the positive rate of decoy cells, urine-PCR (>1 × 10(10) copies/ml), and plasma-PCR (>1 × 10(4) copies/ml) was 18.6%, 11.1%, and 5.5%, respectively. Plasma-PCR was superior to urine-PCR or urine cytology in specificity and positive predictive value for detection of BKVAN. In prospective study, regular monitoring of plasma-PCR detected significant BKV viremia in 8.3% (12/145) and BKVAN in 1 patient (0.6%). After IS reduction, BKV viremia was eliminated in 91.6% (11/12) within 103 days (25-254). In patients with viremia, the frequency of acute rejection did not increase and allograft function did not differ significantly compared with those in patients without viremia during the first year post-transplant (P > 0.05, in both). Plasma-PCR is useful to predict an increased risk for BKVAN, and regular monitoring is effective to prevent the development of BKVAN.

The need for anal dysplasia screening and treatment programs for HIV-infected men who have sex with men: a review of the literature.

Anal cancer rates, which were higher for men who have sex with men (MSM) compared to the general population before HIV, increased dramatically after the HIV epidemic began and continue to increase in HIV-infected MSM despite the advent of antiretroviral therapy and associated immune reconstitution. Because of the similarity to cervical cancer and an established link to human papillomavirus infection, many experts have called for widespread implementation of anal cytological screening and treatment programs, especially for HIV-infected MSM. However, other experts argue that it is too early for widespread implementation of such programs for reasons including lack of clear evidence that anal dysplasia is a precursor to anal cancer, or that detecting and treating anal dysplasia reduces the risk for developing anal cancer; lack of effective treatments for anal dysplasia when it is discovered; and lack of resources. This paper reviews current literature regarding these issues.

Detection of polyomavirus BK reactivation after renal transplantation using an intensive decoy cell surveillance program is cost-effective.

BACKGROUND: Reactivation of polyomavirus BK (BKV) after renal transplantation can lead to allograft dysfunction or loss with early detection improving outcomes. Current guidelines recommend quantitative polymerase chain reaction for surveillance; however, urinary decoy cell detection is a potentially cost-effective alternative. We present the outcomes from an early intensive BKV surveillance program using decoy cell detection for initial screening starting 2 weeks after transplantation. METHODS: Records for all recipients of kidney (n=211) or simultaneous kidney and pancreas (n=102) transplants performed over 2 years in a single center were reviewed. Follow-up was for a minimum of 1 year. Urine cytology screening was performed fortnightly from 0 to 3 months after transplantation, monthly from 3 to 6 months then every 2 months from 6 to 12 months. RESULTS: Decoy cell positivity occurred in 56 of 313 patients (17.9%) with sustained decoy cell positivity (≥2 positive urine samples >2 weeks apart) present in 32 patients (10.2%). Twenty-four patients (7.6%) became viremic and three patients (1%) developed polyoma virus nephropathy. The median time after transplantation until decoy cell positivity was 78 days, decreasing to 67 days for patients with sustained positivity and 57 days for patients who developed polyoma virus nephropathy. No grafts were lost due to BKV during the study period. Decoy cell screening resulted in savings of approximately £135,000 over 2 years, when compared with routine surveillance by quantitative polymerase chain reaction. CONCLUSIONS: Clinically significant BKV reactivation occurs early after transplantation and can be reliably detected by decoy cell screening. A surveillance strategy for detecting BKV reactivation based on urine cytology is cost-effective.

Assessment of human papillomavirus in lung tumor tissue.

BACKGROUND: Lung cancer kills more than 1 million people worldwide each year. Whereas several human papillomavirus (HPV)-associated cancers have been identified, the role of HPV in lung carcinogenesis remains controversial. METHODS: We selected 450 lung cancer patients from an Italian population-based case-control study, the Environment and Genetics in Lung Cancer Etiology. These patients were selected from those with an adequate number of unstained tissue sections and included all those who had never smoked and a random sample of the remaining patients. We used real-time polymerase chain reaction (PCR) to test specimens from these patients for HPV DNA, specifically for E6 gene sequences from HPV16 and E7 gene sequences from HPV18. We also tested a subset of 92 specimens from all never-smokers and a random selection of smokers for additional HPV types by a PCR-based test for at least 54 mucosal HPV genotypes. DNA was extracted from ethanol- or formalin-fixed paraffin-embedded tumor tissue under strict PCR clean conditions. The prevalence of HPV in tumor tissue was investigated. RESULTS: Specimens from 399 of 450 patients had adequate DNA for analysis. Most patients were current (220 patients or 48.9%) smokers, and 92 patients (20.4%) were women. When HPV16 and HPV18 type-specific primers were used, two specimens were positive for HPV16 at low copy number but were negative on additional type-specific HPV16 testing. Neither these specimens nor the others examined for a broad range of HPV types were positive for any HPV type. CONCLUSIONS: When DNA contamination was avoided and state-of-the-art highly sensitive HPV DNA detection assays were used, we found no evidence that HPV was associated with lung cancer in a representative Western population. Our results provide the strongest evidence to date to rule out a role for HPV in lung carcinogenesis in Western populations.

Cost-effectiveness analysis of human papillomavirus vaccination in the Netherlands.

BACKGROUND: In the Netherlands, low cervical cancer incidence and mortality rates might limit the cost-effectiveness of vaccination against the human papillomavirus (HPV). We examined the effect on cervical cancer incidence and mortality of adding HPV vaccination to the current Dutch cervical cancer screening situation and calculated the cost-effectiveness. METHODS: Costs and effects were estimated under favorable assumptions (ie, that HPV vaccination provides lifelong protection against 70% of all cervical cancers, has no side effects, and is administered to all women regardless of their risk of cervical cancer) by using the microsimulation screening analysis (MISCAN) model. The impact of changes in the price of vaccination, number of booster vaccinations, vaccination attendance rate, vaccination efficacy, cervical cancer incidence level, and quality-of-life assumptions was investigated in sensitivity analyses. RESULTS: Using the current price of euro118 per vaccine dose and with discounting of costs and effects at an annual rate of 3%, adding HPV vaccination to the current Dutch screening situation had a cost-effectiveness ratio of euro53 500 per quality-adjusted life-year (QALY) gained. The threshold price per vaccine dose at which the cost-effectiveness of vaccination would correspond to an acceptability threshold of euro20 000 per QALY gained was euro40. With the addition of one or more (up to four) booster vaccinations during a lifetime, this threshold price decreased to euro33 for one booster (to euro16 for four boosters). With a doubling of the cervical cancer incidence level, the cost-effectiveness ratio was euro24 400 per QALY gained and the maximum price per dose at threshold of euro20 000 was euro97. All threshold prices were lower under less favorable effectiveness assumptions. CONCLUSIONS: In the Netherlands, HPV vaccination is not cost-effective even under favorable assumptions. To become cost-effective, the vaccine price would have to be decreased considerably, depending on the effectiveness of the vaccine.

Vaccine-related HPV genotypes in women with and without cervical cancer in Mozambique: burden and potential for prevention.

Knowledge about the burden of Human Papillomavirus (HPV) infections in Sub-Saharan Africa is very limited. We collected cervical samples from 262 women from the general population and 241 tumor samples from women with invasive cervical cancer in Mozambique and tested them for HPV genotyping by the SPF(10)-LiPA(25) PCR system. Among the 195 women without cervical abnormalities by cytology HPV prevalence was 75.9%. In this group of women, the most frequently identified HPV types among HPV-positive women were in descending order of frequency: HPV51 (23.6%), HPV35 (19.6%), HPV18 (14.2%), HPV31 (13.5%) and HPV52 (12.8%). In women with cervical cancer HPV DNA detection was 100%. The type-specific distribution of the most frequent types in descending order of frequency was: HPV16 (47.0%), HPV18 (31.3%), HPV51 (14.8%), HPV52 (14.3%), HPV45 (12.6%), HPV35 (10.4%), HPV33 (4.8%) and HPV31 (2.6%). HPVs 16/18 and HPVs 16/18/31/45 were detected in 71.7% and 80.9% of cervical cancer tissue, respectively. While HPVs 51 and 35 were the two most common types in cytologically normal women in Mozambique, HPVs 16 and 18 remained the two most frequently identified types in cervical cancer. The introduction of an efficacious HPV 16/18 vaccine could potentially prevent the occurrence of 72% of cervical cancer cases and up to 81% of the cases if full cross-protection against HPVs 31 and 45 is assumed.

Assessment of JC polyoma virus in colon neoplasms.

PURPOSE: Research data have recently emphasized an intriguing association of JC polyoma virus with colon carcinogenesis. Tumorigenicity of JC virus is attributed to the T-antigen of its Mad-1 variant. Controversy arose when another research group did not confirm this association. The purpose of this study was to detect JC virus in a series of colon neoplasms from Greek patients. METHODS: A nested polymerase chain reaction assay was used to detect JC virus in 80 cancerous, 25 adenomatous specimens of large bowel, and 20 colonoscopic biopsy samples from normal patients without colorectal neoplasia. Quantitation of JC virus DNA was performed by real-time polymerase chain reaction. RESULTS: JC polyoma virus nucleotide sequence was detected in 61 percent of colon adenocarcinomas and in 60 percent of adenomas, at a viral load of 9 x 10(3) to 20 x 10(3) copies/microg DNA. Adjacent normal mucosa in 35 positive colon adenocarcinoma specimens, and normal mucosa from six patients of the control group, had low viral loads (50-450 copies/microg DNA). CONCLUSIONS: JC polyoma virus genome is present in colon neoplasms. JC virus detection in adenomas at comparable viral loads to malignant tumors suggests its implication at early steps of colonic carcinogenesis. Taking into consideration other published data, infection of colonic epithelium with JC virus might be a prime candidate for a role in chromosomal and genomic instability.

Projected clinical benefits and cost-effectiveness of a human papillomavirus 16/18 vaccine.

BACKGROUND: Human papillomavirus (HPV) vaccine may be commercially available in a few years. We explored the clinical benefits and cost-effectiveness of introducing an HPV16/18 vaccine in a population with an organized cervical cancer screening program. METHODS: A computer-based model of the natural history of HPV and cervical cancer was used to project cancer incidence and mortality, life expectancy (adjusted and unadjusted for quality of life), lifetime costs, and incremental cost-effectiveness ratios (i.e., the additional cost of a strategy divided by its additional clinical benefit compared with the next most expensive strategy) associated with different cancer prevention policies, including vaccination (initiated at age 12 years), cytologic screening (initiated at 18, 21, 25, 30, or 35 years), and combined vaccination and screening strategies. We assumed that vaccination was 90% effective in reducing the risk of persistent HPV16/18 infections and evaluated alternative assumptions about vaccine efficacy, waning immunity, and risk of replacement with non-16/18 HPV types. RESULTS: Our model showed that the most effective strategy with an incremental cost-effectiveness ratio of less than 60 dollars-000 per quality-adjusted life year is one combining vaccination at age 12 years with triennial conventional cytologic screening beginning at age 25 years, compared with the next best strategy of vaccination and cytologic screening every 5 years beginning at age 21 years. This triennial strategy would reduce the absolute lifetime risk of cervical cancer by 94% compared with no intervention. These results were sensitive to alternative assumptions about the underlying patterns of cervical cancer screening, duration of vaccine efficacy, and natural history of HPV infection in older women. CONCLUSIONS: Our model predicts that a vaccine that prevents persistent HPV16/18 infection will reduce the incidence of HPV16/18-associated cervical cancer, even in a setting of cytologic screening. A program of vaccination that permits a later age of screening initiation and a less frequent screening interval is likely to be a cost-effective use of health care resources.

Atypical squamous cells of undetermined significance in liquid-based cytologic specimens: results of reflex human papillomavirus testing and histologic follow-up in routine practice with comparison of interpretive and probabilistic reporting methods.

BACKGROUND: Human papillomavirus (HPV) DNA testing for high-risk types after Papanicolaou (Pap) smear interpretations of atypical squamous cells of undetermined significance (ASCUS) is a sensitive method for identifying women who harbor underlying high-grade squamous intraepithelial lesions (HSIL). To the authors' knowledge, the application of HPV testing to ASCUS smears in routine practice with comparison of probabilistic and interpretive models of cytologic reporting has not been reported. METHODS: HPV DNA testing was performed reflexively on 216 liquid-based Pap smears that initially were interpreted as ASCUS. According to the interpretive model, ASCUS interpretations were modified and reported as either low-grade squamous intraepithelial lesions (LSIL) or squamous intraepithelial lesions (SIL) when HPV positive and as reactive when HPV negative. Using the probabilistic model, ASCUS interpretations were maintained and simply reported with the HPV test result. Histologic follow-up data were obtained. RESULTS: Of the 216 women with ASCUS cytology, 142 (65.7%) were positive for high-risk HPV types. Of the 142 HPV-positive ASCUS smears, 101 (71.1%) were modified to an interpretation of LSIL (96 cases) or SIL (5 cases). Histologic follow-up of 55 of the 101 HPV-positive smears in the interpretive group and 26 of the 41 HPV-positive smears in the probabilistic group yielded similar percentages of lesions (18 lesions [32.7%] and 9 lesions [34.6%], respectively). However, there was a preponderance of low-grade lesions in the interpretive group (89%) but a nearly equal distribution of low-grade and high-grade lesions in the probabilistic group (56% and 44%, respectively); overall, 22% of the lesions were high-grade. Of the 74 HPV-negative ASCUS smears, 71 (96%) were modified to reactive and all 5 with histologic follow-up were judged as negative. CONCLUSIONS: Colposcopy with tissue studies was virtually restricted to HPV-positive cases, regardless of the reporting model used, suggesting that clinicians are basing colposcopy triage on the HPV test result rather than the definitiveness of the cytologic interpretation. This observation, the similar yield of lesions in both groups, and the significant risk of high-grade lesions argue against application of the interpretive model to HPV-tested ASCUS cases.

Chapter 1: Human papillomavirus and cervical cancer--burden and assessment of causality.

Cervical cancer remains the second most common cancer in women worldwide and the most frequent in developing countries. Pre-neoplasic cervical lesions represent an additional burden in countries where screening is widespread. The human papillomavirus (HPV) prevalence and type distribution in normal smears and in cancer specimens are being described and show relatively small international variation. State-of-the-art detection techniques have unequivocally shown that HPV-DNA can be detected in 95% to 100% of adequate specimens of cervical cancer, supporting the claim that HPV is the necessary cause. The odds ratios for cervical cancer related to a cross sectional detection of HPV-DNA range from 50 to several hundred in all studies. The risk for any of 15 high-risk types is not statistically different from the risk reported for HPV16. The estimates of the attributable fraction range from 90% to 98%. Additional work should be done in providing information on incidence of cervical cancer and on HPV infection in areas where the disease is common. Theoretical work including modeling of the incidence could be of potential use in the evaluation of the existing and novel preventive strategies. Research is currently being conducted on the mechanisms of HPV carcinogenesis. These include the determinants of the systemic and cellular immune response to the viral infection, the interaction between the host and the virus and the relevance of the different strains and variants of the HPV viral types. Technology developments in this area suitable for epidemiological studies are needed.

Chapter 15: Public health policy and cost-effectiveness analysis.

Recent scientific advances are providing an opportunity to revisit strategies for cervical cancer prevention. How to invest health resources wisely, such that public health benefits are maximized-and opportunity costs are minimized-is a critical question in the setting of enhanced cytologic screening methods, human papillomavirus DNA testing, and vaccine development. Developing sound clinical guidelines and public health policy will require careful consideration of the incremental benefits, harms, and costs associated with new interventions compared with existing interventions, at both an individual and a population level. In addition to an intervention's effectiveness, public health decision making requires the consideration of its feasibility, sustainability, and affordability. No clinical trial or single cohort study will be able to simultaneously consider all of these components. Cost-effectiveness analysis and disease-simulation modeling, capitalizing on data from multiple sources, can serve as a valuable tool to extend the time horizon of clinical trials, to evaluate more strategies than possible in a single clinical trial, and to assess the relative costs and benefits of alternative policies to reduce mortality from cervical cancer.

[High and low risk human papilloma virus infection in women with CIN. Differential characteristics]. / Infección por virus del papiloma humano de alto y bajo riesgo en mujeres con NIC. Características diferenciales.

UNLABELLED: The objective of this study was to determine high risk human papillomavirus infection (HPV-RH) and factors with cervical intraepithelial neoplasia appears (CIN). MATERIAL AND METHOD: From October 1998 to January 2000, a case-control study, was made; women with benefit package from Mexican Institute of Social Security. The cases were of the colposcopic clinic of the department of the Hospital Obstetrics and Gynecology Luis Castelazo Ayala, women histologically diagnosed with colposcopy and CIN cervical biopsy, and controls patients with negative cervical uterine cytologic study of the Preventive Medicine Department, Unit of Familiar Medicine No. 8, of Mexico City. Trained personnel obtained information about socioeconomic and reproductive factors did the interview. A cytobrush was used to take the cervical sample for HPV-RH to determine HPV-RH utilizing Hybrid Capture II test. Both bivariate analysis and logistic regression analysis were used for the adjustment of variables. RESULTS: We analyzed 102 cases and 192 controls, 79% (44/56) of the cases with CIN I and 89% (37/42) of CIN II-III as 21% of controls, respectively, were positive for HPV-RH. Global risk for HPV-RH association to CIN was OR = 40.6 (95% CI, = 17-96.8). Women age was determinative for HPV-RH association to CIN. We observed a high correlation between HPV positive magnitude and CIN degree. CONCLUSIONS: Frequency of RH-HPV in controls and CIN I is higher than other reports in the literature. HPV was identified as the most important agent associated with this neoplasia, other factors involved and age is an important modifier in HPV-RH and CIN.

Infección por virus del papiloma humano de alto y bajo riesgo en mujeres con NIC. Características diferenciales / High and low risk human papilloma virus infection in women with CIN. Differential characteristics

The objective of this study was to determine high risk human papillomavirus infection (HPV-RH) and factors with cervical intraepithelial neoplasia appears (CIN). MATERIAL AND METHOD: From October 1998 to January 2000, a case-control study, was made; women with benefit package from Mexican Institute of Social Security. The cases were of the colposcopic clinic of the department of the Hospital Obstetrics and Gynecology Luis Castelazo Ayala, women histologically diagnosed with colposcopy and CIN cervical biopsy, and controls patients with negative cervical uterine cytologic study of the Preventive Medicine Department, Unit of Familiar Medicine No. 8, of Mexico City. Trained personnel obtained information about socioeconomic and reproductive factors did the interview. A cytobrush was used to take the cervical sample for HPV-RH to determine HPV-RH utilizing Hybrid Capture II test. Both bivariate analysis and logistic regression analysis were used for the adjustment of variables. RESULTS: We analyzed 102 cases and 192 controls, 79 (44/56) of the cases with CIN I and 89 (37/42) of CIN II-III as 21 of controls, respectively, were positive for HPV-RH. Global risk for HPV-RH association to CIN was OR = 40.6 (95 CI, = 17-96.8). Women age was determinative for HPV-RH association to CIN. We observed a high correlation between HPV positive magnitude and CIN degree. CONCLUSIONS: Frequency of RH-HPV in controls and CIN I is higher than other reports in the literature. HPV was identified as the most important agent associated with this neoplasia, other factors involved and age is an important modifier in HPV-RH and CIN.

Human papillomavirus as a form of risk assessment.

There is a huge amount of interest in the use of human papillomavirus testing to improve both the sensitivity and specificity of cervical screening. Although oncogenic human papillomavirus subtypes are recognized to be the most important factor in the development of cervical disease, only a minority of such infections results in invasive cancer. Given our current, albeit limited, knowledge of the natural history of human papillomavirus infection and the development of cervical intra-epithelial neoplasia, it may be possible to identify well-defined high-risk groups of women. Such groups may benefit from intensive surveillance, or indeed new developments in immunoprophylaxis, while allowing low-risk women less screening intervention. Known high-risk groups include those with chronic immunosuppression and previous treatment for high-grade cervical intra-epithelial neoplasia. Lowering the upper age limit for cervical screening is already under consideration because of the low incidence of both human papillomavirus infection and cervical intra-epithelial neoplasia in older women, and human papillomavirus testing could rationalize the screening programme.