Comparable strategies needed to evaluate human papillomavirus vaccine efficiency across Europe.
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Adolescent↗
Biomedical subjects
J Dillner
Publications and source records attributed to J Dillner.
Detection of adeno-associated virus type 2 genome in cervical carcinoma.
Adeno-associated virus (AAV) can impair the replication of other viruses. Adeno-associated virus seroprevalences have been reported to be lower among women with cervical cancer. In-vitro, AAV can interfere with the production of human papillomavirus virions. Adeno-associated virus-2 DNA has also been detected in cervical cancer tissue, although not consistently. To evaluate the role of AAV infection in relation to invasive cervical cancer, we performed a nested case-control study within a retrospectively followed population-based cohort. A total of 104 women who developed invasive cervical cancer on average 5.6 years of follow-up (range: 0.5 months-26.2 years) and 104 matched control-women who did not develop cervical cancer during the same follow-up time were tested for AAV and human papillomavirus by polymerase chain reaction. At baseline, two (2%) case-women and three (3%) control-women were positive for AAV-2 DNA. At the time of cancer diagnosis, 12 (12%) case-women and 3 (3%) matched control-women were positive for AAV-2 DNA. Persisting AAV infection was not evident. In conclusion, AAV-2 DNA was present in a low proportion of cervical cancers and we found no evidence that the presence of AAV in cervical smears of healthy women would be associated with reduced risk of cervical cancer.
Adult↗
Joint Nordic prospective study on human herpesvirus 8 and multiple myeloma risk.
An association between human herpesvirus 8 (HHV8) and multiple myeloma (MM) has been reported, though most studies have not confirmed such association. To follow-up on a previous prospective seroepidemiological study, where HHV8 tended to associate with MM risk, we linked five large serum banks in the Nordic countries with the Nordic cancer registries and 329 prospectively occurring cases of MM were identified, together with 1631 control subjects matched by age and gender. The HHV8 seroprevalences among cases and controls were similar (12 and 15%, respectively) and HHV8 seropositivity did not associate with the risk of MM, neither when considering positivity for lytic antibodies (relative risk (RR) = 0.8, 95% confidence interval (CI) = 0.5-1.1) nor for latent antibodies (RR = 0.6, 95% CI = 0.1-2.7). Similar risks were seen when analysis was restricted to case-control sets with at least 2 years lag before diagnosis (RR = 0.8, 95% CI = 0.5-1.2 and RR = 0.9, 95% CI = 0.1-4.2). In conclusion, the data indicate that HHV8 infection is not associated with MM.
Antibodies, Viral↗
Clinical utility of HPV-DNA detection: triage of minor cervical lesions, follow-up of women treated for high-grade CIN: an update of pooled evidence.
OBJECTIVE: Human papilloma virus (HPV) testing and repeat cytology are both proposed as methods to triage women with minor cytological cervical lesions. By triage, those women can be identified who need referral for diagnostic exploration with colposcopy and/or biopsy. METHODS: We conducted meta-analyses of reported studies on the accuracy to detect high-grade cervical intra-epithelial neoplasia or worse disease (CIN2+) in women with ASCUS or LSIL. We also performed meta-analyses to examine the best predictor of recurrence of CIN after treatment for CIN2 or CIN3. RESULTS: We found that HPV testing using the Hybrid Capture II test is more effective (more sensitive, equally specific) than cytology for the triage of patients with ASCUS Pap smears. Because of the high rate of HPV positivity, this is not the case for patients with LSIL. Studies concerning post-treatment follow-up were heterogeneous. In general, HPV testing performed better than follow-up cytology to predict success or failure of treatment (significantly higher sensitivity, not significantly lower specificity). CONCLUSIONS: Overall, in comparison with follow-up cytology, HPV DNA testing is more sensitive and equally specific for triage of ASCUS cases and for predicting recurrence of CIN in women treated for high-grade CIN.
Carcinoma, Squamous Cell↗
A population-based cohort study of KIR genes and genotypes in relation to cervical intraepithelial neoplasia.
Natural killer (NK) cells are involved both in control of virus infections and in elimination of tumor cells. Killer immunoglobulin-like receptors (KIRs) either activate or inhibit NK cell-mediated cytolysis, protecting healthy cells from destruction while enabling killing of abnormal cells. To investigate whether KIR genes or genotypes are associated with cervical carcinogenesis, a nested case-control study of 65 case women with cervical intraepithelial neoplasia (CIN) diagnosed during a 6-year follow-up of 15,234 women and 150 control women from the same cohort that remained healthy was performed. More than 70 different genotypes were observed, and 33 of which had not been described previously. An A-genotype including KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR3DL1, KIR3DL2, KIR3DL3, and KIR2DS4 was associated with increased risk of CIN (OR 6.7; 95% CI 1.7-26.3), and KIR2DL5B*002 appeared to have an inverse association with disease (OR 0.5; 95% CI 0.5-2.9). There was no association of CIN with the number of activating KIR genes. There was also no association between KIR genes and type of human papilloma virus or with other CIN-related immune response genes. It was concluded that certain KIR genes and genotypes may associate with cervical neoplasia.
Adult↗
An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study.
OBJECTIVE: To investigate the association between human herpesviruses and multiple sclerosis (MS), as well as between measles virus and MS. METHODS: The authors identified prospectively collected serum samples from 73 MS cases and retrospective sera from 161 MS cases in two population-based serum bank registers. Analyses of IgG antibody responses in cases and matched referents were performed for Epstein-Barr virus (EBV [EBNA-1 and VCA]), human herpesvirus 6 (HHV-6), herpes simplex virus (HSV), varicella zoster virus (VZV), and measles. RESULTS: All cases showed signs of past EBV infection. High activity to EBNA-1 and HHV-6 significantly (borderline significance for HHV-6) increased the risk for MS in prospective sera. A discrepancy between activities to EBNA-1 and VCA was striking in MS samples collected less than 5 years before relapsing-remitting MS onset, where high activity to EBNA-1 significantly increased, and high VCA activity significantly decreased the risk for MS. There was no support for major causal roles for HSV, VZV, or measles. CONCLUSION: Individuals who will develop MS exhibit an altered immune response against the EBV virus characterized by a high IgG activity to EBNA-1 in the absence of high activity to VCA, this being most pronounced in the 5-year period preceding MS onset.
Adolescent↗
Joint effects of different human papillomaviruses and Chlamydia trachomatis infections on risk of squamous cell carcinoma of the cervix uteri.
This case-control study based in Nordic serum banks evaluated the joint effects of infections with genital human papillomavirus (HPV) types, and Chlamydia trachomatis in the aetiology of cervical squamous cell carcinoma. Through a linkage with the cancer registries, 144 cases were identified and 420 controls matched to them. Exposure to past infections was defined by the presence of specific IgG antibodies. The odds ratio (OR) for the second-order interaction of HPV16, HPV6/11 and C. trachomatis was small (1.0) compared to the expected multiplicative OR, 57, and the additive OR, 11. The interactions were not materially different among HPV16 DNA-positive squamous cell carcinomas. When HPV16 was replaced with HPV18/33 in the analysis of second-order interactions with HPV6/11 and C. trachomatis, there was no evidence of interaction, the joint effect being close to the expected additive OR. Possible explanations for the observed antagonism include misclassification, selection bias or a true biological phenomenon with HPV6/11 and C. trachomatis exposures antagonizing the carcinogenic effects of HPV16.
Adult↗
Reactivity to human papillomavirus type 16 L1 virus-like particles in sera from patients with genital cancer and patients with carcinomas at five different extragenital sites.
A retrospective seroepidemiologic study was performed to examine the association between human papillomaviruses (HPV) 16 infection and carcinomas of the oropharynx, the oesophagus, penis and vagina. Sera were selected from the serum bank from the Antoni van Leeuwenhoek Hospital (Netherlands Cancer Institute) and the Slotervaart Hospital in Amsterdam, the Netherlands. Presence of HPV 16 specific antibody was assessed using HPV 16 L1 capsids. Sera positive for HPV 16 capsid antibody were further tested for antibody against HPV 16 E7 peptides. Prevalence of antibody against HPV 16 L1 capsids among both the negative control group without cancer and the negative control group with gastric cancer was 18%, while seroprevalence among the control group of patients with HPV-associated cervical squamous cell carcinoma was 47% (P<0.001). Among the patients with penile squamous cell carcinoma seroprevalence was 38% (P<0.001), among patients with oropharyngeal carcinoma 33% (P=0.04) and among patients with oesophageal squamous cell carcinoma 14% (P=0.7). The serological evidence for association between HPV 16 infection and both oropharyngeal carcinoma and penile carcinoma was established. The conclusion that no association was found between the presence of antibody against HPV 16 L1 capsids and oesophageal squamous cell carcinoma was in accordance with results of other studies carried out in the Netherlands using HPV DNA technology. In the subjects with HPV 16 L1 capsid antibody, no association was found between the antibody against HPV 16 E7 and clinical outcome.
Aged↗
Laboratory diagnosis of human herpesvirus 8 infection in humans.
Human herpesvirus 8 (HHV-8) is causally associated with Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. Serological and molecular biology assays are used to investigate the biology of this virus in different populations and diseases. Serological assays are mainly used to study the prevalence of the viral infection and to predict the diagnosis of Kaposi's sarcoma and other HHV-8-associated cancers. The appearance of antibodies against lytic antigens precedes the appearance of antibodies against latent antigens, probably explaining the lower sensitivity of assays based on latent HHV-8 antigens. The lack of international reference serum panels is presently the major bottleneck for further progress in the field of HHV-8 serology. Molecular biological assays are an absolute requirement for both the diagnosis and the follow-up of HHV-8 infection. Qualitative methods have been particularly useful to elucidate the mode of transmission and the causal association between HHV-8 and HHV-8-associated diseases. Quantitative methods have become an essential tool to monitor the progression of the infection and the effects of antiviral therapies. This review analyzes the performance of the different serological and molecular biological assays available at present. The main conclusion is that more research is needed to define the most useful laboratory tests for the diagnosis of HHV-8 infection and to establish the clinical role of such tests.
Herpesviridae Infections↗
A prospective study of the relationship between prediagnostic human papillomavirus seropositivity and HPV DNA in subsequent cervical carcinomas.
Several prospective studies with invasive carcinoma as endpoint have supported Human Papillomavirus as a cause of cervical carcinoma. However, the largest study used seroepidemiology and did not analyse presence of Human Papillomavirus DNA in the subsequent tumour. Linkage of serum bank registries and cancer registries had identified 196 women with a registered cervical carcinoma after donation of a serum sample. For the present study, biopsies for 127 cases could be located, verified to contain invasive carcinoma and be amplified by PCR. Three control women who had remained alive and without cervical carcinoma during an equal length of follow-up had been matched to each of the case women and tested for HPV antibodies. Presence of Human Papillomavirus DNA in the tumours was analysed by general primer and type specific PCR. HPV16-seropositive women had a relative risk of 4.4 (95% CI: 2.2-8.8) to develop cervical carcinoma carrying HPV16 DNA. By contrast, there was no excess risk for Human Papillomavirus 16-seropositive women to develop cervical carcinoma devoid of HPV16 DNA. Prediagnostic HPV16 seropositivity was strongly correlated with later HPV16 DNA positivity of the tumour (P<0.001) and prediagnostic HPV18 seropositivity correlated with HPV18 DNA in the tumour (P<0.03). The link between prediagnostic seropositivity and type of viral DNA in the cancer implies that the carcinogenic effect of infection with these viruses is dependent on persistent presence of type-specific viral DNA.
Adult↗
Human papillomavirus infection as a risk factor for anal and perianal skin cancer in a prospective study.
Human papillomavirus has emerged as the leading infectious cause of cervical and other anogenital cancers. We have studied the relation between human papillomavirus infection and the subsequent risk of anal and perianal skin cancer. A case-cohort study within two large Nordic serum banks to which about 760 000 individuals had donated serum samples was performed. Subjects who developed anal and perianal skin cancer during follow up (median time of 10 years) were identified by registry linkage with the nationwide cancer registries in Finland and Norway. Twenty-eight cases and 1500 controls were analysed for the presence of IgG antibodies to HPV 16, 18, 33 or 73, and odds ratios of developing anal and perianal skin cancer were calculated. There was an increased risk of developing anal and perianal skin cancer among subjects seropositive for HPV 16 (OR=3.0; 95%CI=1.1-8.2) and HPV 18 (OR=4.4; 95%CI=1.1-17). The highest risks were seen for HPV 16 seropositive patients above the age of 45 years at serum sampling and for patients with a lag time of less than 10 years. This study provides prospective epidemiological evidence of an association between infection with HPV 16 and 18 and anal and perianal skin cancer.
Adult↗
Preventive human papillomavirus vaccination.
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Female↗
[How to handle biological material? New legislation concerning biobanks in Finland].
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Finland↗
Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck.
BACKGROUND: Oncogenic human papillomaviruses (HPVs), especially HPV type 16 (HPV-16), cause anogenital epithelial cancers and are suspected of causing epithelial cancers of the head and neck. METHODS: To examine the relation between head and neck cancers and HPVs, we performed a nested case-control study within a joint Nordic cohort in which serum samples were collected from almost 900,000 subjects. Samples collected at enrollment from 292 persons in whom squamous-cell carcinoma of the head and neck developed, on average, 9.4 years after enrollment and from 1568 matched controls were analyzed for antibodies against HPV-16, HPV-18, HPV-33, and HPV-73 and for cotinine levels as a marker of smoking habits. Polymerase-chain-reaction (PCR) analyses for HPV DNA were performed in tumor tissue from 160 of the study patients with cancer. RESULTS: After adjustment for cotinine levels, the odds ratio for squamous-cell carcinoma of the head and neck in subjects who were seropositive for HPV-16 was 2.2 (95 percent confidence interval, 1.4 to 3.4). No increased risk was observed for other HPV types. Fifty percent of oropharyngeal and 14 percent of tongue cancers contained HPV-16 DNA, according to PCR analysis. CONCLUSIONS: HPV-16 infection may be a risk factor for squamous-cell carcinoma of the head and neck.
Adult↗
Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine.
BACKGROUND: Studies in animal models have shown that systemic immunization with a papillomavirus virus-like particle (VLP) vaccine composed of L1, a major structural viral protein, can confer protection against subsequent experimental challenge with the homologous virus. Here we report results of a double-blind, placebo-controlled, dose-escalation trial to evaluate the safety and immunogenicity of a human papillomavirus (HPV) type 16 (HPV16) L1 VLP vaccine in healthy adults. METHODS: Volunteers were given intramuscular injections with placebo or with 10- or 50-microg doses of HPV16 L1 VLP vaccine given without adjuvant or with alum or MF59 as adjuvants at 0, 1, and 4 months. All vaccine recipients were monitored for clinical signs and symptoms for 7 days after each inoculation. Immune responses were measured by an HPV16 L1 VLP-based enzyme-linked immunosorbent assay (ELISA) and by an HPV16 pseudovirion neutralization assay. The antibody titers were given as the reciprocals of the highest dilution showing positive reactivity in each assay. All statistical tests were two-sided. RESULTS: The prevaccination geometric mean ELISA titer for six seropositive individuals was 202 (range, 40--640). All vaccine formulations were well tolerated, and all subjects receiving vaccine seroconverted. Serum antibody responses at 1 month after the third injection were dose dependent in recipients of vaccine without adjuvant or with MF59 but were similar at both doses when alum was the adjuvant. With the higher dose, the geometric means of serum ELISA antibody titers (95% confidence intervals) to purified VLP 1 month after the third injection were as follows: 10,240 (1499 to 69 938) without adjuvant, 10,240 (1114 to 94 145) with MF59, and 2190 (838 to 5723) with alum. Responses of subjects within each group were similar. Neutralizing and ELISA antibody titers were highly correlated (Spearman correlation =.85), confirming that ELISA titers are valid proxies for neutralizing antibodies. CONCLUSIONS: The HPV16 L1 VLP vaccine is well tolerated and is highly immunogenic even without adjuvant, with the majority of the recipients achieving serum antibody titers that were approximately 40-fold higher than what is observed in natural infection.
Adjuvants, Immunologic↗
Vaccinating women against premature death: summary of an International Workshop, Helsinki, Finland, 10.01.2000.
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Clinical Trials as Topic↗
A prospective seroepidemiological study of human herpesvirus-8 infection and the risk of multiple myeloma.
Presence of the Human Herpesvirus 8 (HHV8) genome has been reported in the bone marrow of multiple myeloma (MM) patients. So far, serological studies of HHV8 and MM have been inconsistent but have not included prospective epidemiological studies. We evaluated whether HHV8 infection is associated with increased risk for MM in a prospective population-based study of 39 000 Finnish subjects who donated serum samples in the period 1968-72. Serum samples from 47 subjects who developed MM during a 23-year follow-up and 224 age, area of residence and sex-matched subjects who remained healthy over a similar follow-up period were evaluated for HHV8 antibodies at enrollment, as assayed both with an immunofluorescence assay (IFA) for lytic and latent HHV8 antigens and by Western blot (WB) with three recombinant HHV8 proteins (ORFs 65, 73 and K8.1A). HHV8 seropositivity for at least one HHV8 protein on WB was found in 7% of the Finnish population and was not associated with the risk of developing MM (Relative Risk (RR) = 0.89, Confidence Interval (CI): 0.25-3.25). HHV8 seropositivity for lytic and latent antigens in the IFA was found in 16% and 0.4% of the Finnish population and tended to associate with risk of MM (RR = 2.02, CI: 0.94-4.33 and RR = 10.00, CI: 0.91-110.29, respectively). In conclusion, no statistically significant evidence for an association between HHV8 infection and the risk of future MM was found.
Antigens, Viral↗
Serotypes of Chlamydia trachomatis and risk for development of cervical squamous cell carcinoma.
CONTEXT: Human papillomavirus (HPV) infection has been established as a cause of cervical cancer. Epidemiologic studies suggest that Chlamydia trachomatis infection also confers increased risk for cervical squamous cell carcinoma (SCC). Whether this risk is serotype-specific is unknown. OBJECTIVE: To study the association between exposure to different C trachomatis serotypes and subsequent development of cervical SCC. DESIGN AND SETTING: Longitudinal, nested case-control study within a cohort of 530 000 women who provided samples to serum banks in Finland, Norway, and Sweden. The data files were linked to respective national cancer registries. SUBJECTS: One hundred twenty-eight women who had developed invasive cervical SCC at least 12 months following serum donation. Each case had 3 matched controls. MAIN OUTCOME MEASURE: Risk for the development of cervical SCC by IgG antibodies to 10 different C trachomatis serotypes, adjusted for antibodies to HPV types 16, 18, and 33 and for serum cotinine levels. RESULTS: Of specific C trachomatis serotypes, serotype G was most strongly associated with SCC (adjusted odds ratio [OR], 6.6; 95% confidence interval [CI], 1. 6-27.0). Other serotypes associated with SCC were I (OR, 3.8; 95% CI, 1.3-11.0) and D (OR, 2.7; 95% CI, 1.3-5.6). Presence of serum IgG antibodies to more than 1 serotype increased the adjusted ORs for SCC (P<.001 for trend). CONCLUSIONS: Chlamydia trachomatis serotype G is most strongly associated with subsequent development of cervical SCC. Increasing numbers of exposures to different C trachomatis serotypes also increases risk. Our results strengthen the evidence that there is a link between past C trachomatis infection and cervical SCC.
Antibodies, Bacterial↗