HPV Virus Medical Research - Screening

Behbakht K, Friedman J, Heimler I, Aroutcheva A, Simoes J, Faro S. Department of Obstetrics and Gynecology, Rush Medical College, Chicago, IL, USA. kian.behbakht@uchsc.edu

OBJECTIVE: To identify alterations in the cytokine profile and microbial ecosystem of the vagina in association with cervical dysplasia. METHODS: Demographics, lifestyle variables and Papanicolau (Pap) smear results of subjects presenting to the same site for gynecologic complaints, obstetric visits or colposcopy were prospectively recorded. Vaginal smear for Gram stain, aerobic and anaerobic culture, pH, and wet mount and KOH examination for Trichomonas vaginalis, Gardnerella vaginalis and yeast organisms were performed. Vaginal lavage specimens were centrifuged, and the pellets and supernatants were assayed for human papillomavirus (HPV) by polymerase chain reaction and for cytokines interleukin (IL)-1beta IL-6, IL-10 and IL-12 by enzyme-linked immunosorbent assay (ELISA) respectively. Subjects with abnormal Pap smears underwent colposcopy and biopsy as indicated. RESULTS: Of 51 patients, 32 were referred for colposcopy, 12 presented with gynecologic needs, and seven presented for obstetric visits. Median age was 24 years. Demographics did not differ significantly between the dysplasia and control groups except for a trend towards more sexual partners in the dysplasia group. Biopsies were performed in 81% (26/32) of patients presenting for colposcopy and 17 revealed cervical intraepithelial neoplasia. IL-1beta, IL-6, IL-10, and IL-12 levels were elevated in 63% (20/32), 38% (15/39), 4% (2/49), and 0% of samples respectively. Elevated vaginal lavage IL-1beta was associated with a 6.1 odds ratio (95% confidence interval 1.06-35) of cervical dysplasia. Alterations in other variables studied were not associated with cervical dysplasia. CONCLUSIONS: Elevated IL-1beta, possibly representing a complex host inflammatory response to multiple pathogens, was demonstrated in patients with cervical dysplasia.

Int J Gynaecol Obstet. 2003 Jan;80(1):41-7.

Risk factors as the basis for triage in low-resource cervical cancer screening programs.

Gaffikin L, Ahmed S, Chen YQ, McGrath JM, Blumenthal PD. The JHPIEGO Corporation, Baltimore, MD, USA.

OBJECTIVES: Several studies have shown impressive sensitivity and specificity of visual inspection using acetic acid wash (VIA) in detecting cervical dysplasia. This study examines how risk-factor based triage, using clinical history-taking to limit the testing to those at highest risk of disease, improves the clinical utility of VIA. METHODS: The study population included 2206 woman aged 25-56 from peri-urban primary care clinics in Zimbabwe. Three risk factors variables [age, lifetime number of sexual partners and history of a sexually transmitted infection (STI)] were selected as the basis for computer-simulated patient triage. Criteria for selecting risk factors were biological relevance, programmatic feasibility, historical evidence in the scientific literature as a risk factor for cervical cancer and a significant (P<0.05) predictor of dysplasia in this study population. Predictive values for VIA were calculated on subgroups of women with combinations of the three risk factors and then compared with the predictive value of VIA calculated on the full study population. RESULTS: The positive predictive value (PPV) among women with all three risk factors (30.2%) was 1.6 times higher than that of all study women and 4.5 times higher than women with none of the three risk factors (4.1%). Additionally, the PPV was slightly (30%) higher than that obtained from computer-simulated serial testing using VIA as the primary test followed by HPV testing (27.4%). CONCLUSION: Clinical history-taking could provide the basis for patient triage to increase the clinical utility of VIA. Such an approach could also serve to prioritize who gets tested first in low-resource countries with high disease prevalence that are struggling to strengthen national cervical cancer prevention programs.

Publication Types:
• Evaluation Studies

Reesink-Peters N, Helder MN, Wisman GB, Knol AJ, Koopmans S, Boezen HM, Schuuring E, Hollema H, de Vries EG, de Jong S, van der Zee AG. Department of Gynaecological Oncology, University Hospital Groningen, 9700 RB, Groningen, The Netherlands.

AIM: To examine whether the detection of either telomerase and its components or high risk human papillomavirus (HPV) are of value in predicting the presence of cervical intraepithelial neoplasia (CIN) grade II/III in women referred because of cervical cytology reports showing at most moderate dyskaryosis. METHODS: Cervical scrapings of 50 women referred with cytological borderline, mild, or moderate dyskaryosis were analysed. Telomerase activity was assessed by a commercially available telomere repeat amplification protocol assay and its components human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) were assessed by reverse transcriptase polymerase chain reaction (PCR). HPV was detected by GP5+/6+ PCR enzyme immunosassay. Histological findings on colposcopy guided biopsies or excised cervical tissue were regarded as the final pathological diagnosis. The sensitivity and specificity for detecting CIN II/III were calculated. RESULTS: Twenty eight women were diagnosed with CIN II/III. Telomerase activity was detected in none, hTR in 88%, hTERT in 23%, and high risk HPV was detected in 79% of these women. As a diagnostic test none of the described analyses combined a sensitivity of at least 90% with a specificity >or= 90%. Despite the small numbers, calculation of the 95% confidence intervals excluded a combined sensitivity and specificity of at least 90% for all of the evaluated parameters. CONCLUSIONS: Neither detection of telomerase or its components, nor detection of high risk HPV seem suitable for the triage of women with borderline, mild, and moderate cytological dyskaryosis.

Publication Types:
• Evaluation Studies

J Clin Epidemiol. 2002 Oct;55(10):1025-32.

Human papillomavirus testing for triage of women referred because of abnormal smears. a decision analysis considering outcomes and costs.

Meerding WJ, van Ballegooijen M, Burger MP, van den Akker-van Marle ME, Quint WG, Habbema JD. Department of Public Health, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. meerding@mgz.fgg.eur.nl

The objective of this article was to evaluate the utility of high-risk human papillomavirus (HR-HPV) testing for triage of women referred for colposcopy because of abnormal smears. We considered women with persistent mild or moderate dyskaryosis and women with severe dyskaryosis who were referred for colposcopy. For both patient groups we evaluated three alternative management policies: (1) conventional management based on histological assessment; (2) HR-HPV-triage with direct treatment without prior histologic assessment for HR-HPV-positive women and conventional management for HR-HPV-negative women; and (3) direct treatment without histologic assessment for all referred women. For each policy the average number of medical procedures, doctor visits, and the costs per referred woman were calculated. Based on a literature review, the results were tested and translated to other patient groups. Per woman with persistent mild or moderate dyskaryosis and compared with conventional policy, HR-HPV-triage will avoid 0.51 colposcopically directed biopsies, but adds 0.05 local treatments of the cervix (i.e., loop excision of the transformation zone) and 0.09 outpatient visits, and will cost US dollars extra. HPV triage is less efficient in women with borderline or mildly dyskaryotic cytology. In women with severe dyskaryosis, direct treatment is more efficient as conventional management or HPV triage. The decision to introduce HPV testing or direct treatment in women with persistent mild or moderate dyskaryosis strongly depends on the relative burden attributed to a colposcopically directed biopsy and an outpatient visit compared to loop excision of the transformation zone treatment of the cervix. For women with severe dyskaryosis, direct treatment should be seriously considered.

Publication Types:
• Evaluation Studies

Kulasingam SL, Hughes JP, Kiviat NB, Mao C, Weiss NS, Kuypers JM, Koutsky LA. Department of Epidemiology, University of Washington, Seattle, WA, USA.

CONTEXT: Human papillomavirus (HPV) DNA testing of women having Papanicolaou (Pap) smears showing atypical squamous cells of undetermined significance (ASCUS) has clinical usefulness. Whether HPV DNA testing alone is useful in primary screening remains to be determined. OBJECTIVE: To determine the accuracy of HPV DNA testing for detecting cervical intraepithelial neoplasia (CIN) grade 3 or cancer (the criterion standard). DESIGN, SETTING, AND PARTICIPANTS: Between December 1997 and October 2000, 4075 women who attended Planned Parenthood clinics in Washington State were screened simultaneously using thin-layer Pap and HPV DNA testing by a polymerase chain reaction (PCR)-based method and by a liquid-based RNA-DNA hybridization capture with signal amplification assay (signal amplification). Women who were positive for high-risk HPV types, or had Pap results of ASCUS or higher, were considered to have positive screening test results and were referred for colposcopy and biopsy. Additionally, a random sample of women with negative screening test results was referred for colposcopy. Based on individual and combined thin-layer Pap, HPV PCR, and HPV signal amplification test results from the screening and the colposcopy visits, 7 colposcopy triage strategies were defined and evaluated. MAIN OUTCOME MEASURE: Sensitivity and specificity for detecting cervical lesions graded CIN 3 or higher for each of the 7 triage strategies. RESULTS: The estimated prevalence of CIN 3 or higher was 3.2%. The sensitivity (95% confidence interval) of thin-layer Pap (with a result of > or = ASCUS) for identifying women with CIN 3 or higher was only 61.3% (48.5%-70.9%) compared with 88.2% (78.9%-93.8%) for HPV testing by PCR and 90.8% (83.1%-95.8%) by signal amplification. Differences in specificities were also observed: 82.4% (81.8%-83.1%) for thin-layer Pap (with a result of > or = ASCUS), 78.8% (77.9%-79.7%) for PCR, and 72.6% (69.4%-75.0%) for signal amplification. Compared with referral for colposcopy of all women with ASCUS or higher, signal amplification testing of women with ASCUS and referral of those with a positive result was about as sensitive (61.3% vs 60.3%, respectively) and significantly more specific (82.4% vs 88.9%, respectively). The strategy requiring repeat positive PCR tests on 2 visits had a sensitivity of 84.2% (75.3%-91.0%) and a specificity of 86.2% (85.1%-87.3%). All tests were more specific and less sensitive in older (> or = 30 years) vs younger women. CONCLUSIONS: Testing for HPV has higher sensitivity but lower specificity than thin-layer Pap screening. In some settings, particularly where screening intervals are long or haphazard, screening for HPV DNA may be a reasonable alternative to cytology-based screening of reproductive-age women.

Publication Types:
• Evaluation Studies

HPV Virus Medical Research - Screening for HPV Links

HPV 1995 - An article on screening for human papillomavirus infection in asymptomatic women.

JAMA -- HPV Screening - An article for Benefits and Costs of Using HPV Testing to Screen for Cervical Cancer.