Triage of Women with Low-Grade Cervical Lesions - HPV mRNA Testing versus Repeat Cytology

BACKGROUND: In Norway, women with low-grade squamous intraepithelial lesions (LSIL) are followed up after six months in order to decide whether they should undergo further follow-up or be referred back to the screening interval of three years. A high specificity and positive predictive value (PPV) of the triage test is important to avoid unnecessary diagnostic and therapeutic procedures. MATERIALS AND METHODS: At the University Hospital of North Norway, repeat cytology and the HPV mRNA test PreTect HPV-Proofer, detecting E6/E7 mRNA from HPV types 16, 18, 31, 33 and 45, are used in triage of women with ASC-US and LSIL. In this study, women with LSIL cytology in the period 2005-2008 were included (n = 522). Two triage methods were evaluated in two separate groups: repeat cytology only (n = 225) and HPV mRNA testing in addition to repeat cytology (n = 297). Histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) was used as the study endpoint. RESULTS: Of 522 women with LSIL, 207 had biopsies and 125 of them had CIN2+. The sensitivity and specificity of repeat cytology (ASC-US or worse) were 85.7% (95% confidence interval (CI): 72.1, 92.2) and 54.4 % (95% CI: 46.9, 61.9), respectively. The sensitivity and specificity of the HPV mRNA test were 94.2% (95% CI: 88.7, 99.7) and 86.0% (95% CI: 81.5, 90.5), respectively. The PPV of repeat cytology was 38.4% (95% CI: 29.9, 46.9) compared to 67.0% (95% CI: 57.7, 76.4) of the HPV mRNA test. CONCLUSION: HPV mRNA testing was more sensitive and specific than repeat cytology in triage of women with LSIL cytology. In addition, the HPV mRNA test showed higher PPV. These data indicate that the HPV mRNA test is a better triage test for women with LSIL than repeat cytology

Redegjør for HPV-resultater

Fire Tromsø-leger tilbakeviser kritikk fra Bergen-professor om at de har oversolgt resultater fra sin studie om HPV-testing. De redegjør for hvordan de har fulgt opp kvinner med usikre celleforandringer

HPV E6/E7 mRNA Testing Is More Specific than Cytology in Post-Colposcopy Follow-Up of Women with Negative Cervical Biopsy

BACKGROUND: In Norway, women with negative or low-grade cervical biopsies (normal/CIN1) are followed up after six months in order to decide on further follow-up or recall for screening at three-year intervals. A high specificity and positive predictive value (PPV) of the triage test is important to avoid unnecessary diagnostic and therapeutic procedures whereas a low risk of high-grade disease among triage negative women assures safety. MATERIALS AND METHODS: At the University Hospital of North Norway, cytology and the HPV mRNA test PreTect HPV-Proofer, detecting E6/E7 mRNA from HPV types 16, 18, 31, 33 and 45, are used in post-colposcopy follow-up of women with negative or low-grade biopsy. In this study, women with negative biopsy after high grade cytology (ASC-H/HSIL) and/or positive HPV mRNA test in the period 2005-2009 were included (n = 520). Histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) was used as study endpoint. RESULTS: Of 520 women with negative or low-grade biopsy, 124 women (23.8%) had CIN2+ in follow-up biopsy. The sensitivity and specificity of the HPV mRNA test were 89.1% (95% CI, 80.1-98.1) and 92.5% (95% CI, 88.2-96.7), respectively. The ratios of sensitivity, specificity and PPV of HPV mRNA testing compared to repeat cytology for finding CIN2+ was 1.05 (95% CI: 0.92-1.21), 1.21 (95% CI: 1.12-1.32), and 1.49 (95% CI: 1.20-1.86), respectively. The PPV of mRNA was 77.3% (95% CI, 59.8-94.8) in women aged 40 or older. CONCLUSION: Women with negative cervical biopsy require follow-up before resumption of routine screening. Post-colposcopy HPV mRNA testing was as sensitive but more specific than post-colposcopy cytology. In addition, the HPV mRNA test showed higher PPV. A positive mRNA test post-colposcopy could justify treatment in women above 40 years

Discordance, Disclosure and Normative Gender Roles: Barriers to Couple Testing Within a Community-Level HIV Self-Testing Intervention in Urban Blantyre, Malawi

A community-based HIV self-testing study in Blantyre, Malawi demonstrated that not all individuals living in couples tested with their partner. We describe factors dissuading individuals in couples from self-testing with their partner. Data were drawn from qualitative study exploring consequences of HIV self-testing within couples. In-depth interviews were conducted with 33 individuals living in couples who tested alone. Participants expressed fear of dealing with HIV-discordant relationships. Failure to self-test with a partner was correlated with gender, with more men than women overtly declining or unconsciously unable to have joint HIV self-test. Men feared exposure of infidelity and were often not available at home for economic reasons. Barriers to uptake of couple HIV self-testing seemed to be shaped by gendered dichotomies of social-relationships. To help achieve the first 90% of the UNAIDS 90:90:90 goals, it is important to overcome structural barriers to realise the full potential of HIV self-testing

Soluble biomarkers associated with chronic lung disease in older children and adolescents with perinatal HIV infection.

OBJECTIVE: HIV-associated chronic lung disease (HCLD) is a common comorbidity in children and adolescents in sub-Saharan Africa (SSA). The pathogenesis of HCLD is unclear and may be driven by underlying dysregulated systemic immune activation and inflammation. We investigated the association between 26 plasma soluble biomarkers and HCLD. DESIGN: Case--control analysis of baseline biomarker data from 336 children and adolescents (6-19 years old) with perinatal HIV infection (PHIV) and HCLD (cases) and 74 age-matched and sex-matched controls with PHIV but no CLD. HCLD was defined as having a forced expiratory volume in one second (FEV1) z score less than -1 with no reversibility. METHODS: Cryopreserved plasma collected at recruitment was used in a multiplex bead assay (Luminex) to measure baseline levels of soluble biomarkers. Logistic regression alongside data-reduction and techniques quantifying the interconnectedness of biomarkers were used to identify biomarkers associated with odds of HCLD. RESULTS: Biomarkers of general immune activation and inflammation (β2M, CRP, sCCL5, GCSF, IFN-γ, IP-10), T-cell activation (sCD25, sCD27), platelet activation (sCD40-L), monocyte activation (sCD14), coagulation (D-Dimer), cellular adhesion (E-selectin), and extracellular matrix degradation (MMP-1, MMP-7, MMP-10) were associated with increased odds of HCLD. Exploratory PCA and assessment of biomarker interconnectedness identified T-cell and platelet activation as centrally important to this association. CONCLUSION: HCLD was associated with a large number of soluble biomarkers representing a range of different pathways. Our findings suggest a prominent role for T-cell and platelet activation in HCLD

"The effect of 48-weeks azithromycin therapy on levels of soluble biomarkers associated with HIV-associated chronic lung disease".

OBJECTIVES: HIV-associated immune activation contributes to chronic lung disease (CLD) in children and adolescents living with HIV. Azithromycin has immunomodulatory and anti-microbial properties that may be useful for treating HIV-associated CLD (HCLD). This study describes the effect of azithromycin on expression of plasma soluble biomarkers in children and adolescents with HCLD. METHODS: This study was nested within a multi-site double-blind, placebo controlled, randomised controlled trial (RCT) of azithromycin in individuals aged 6-19 years with HCLD (defined as FEV1 z-score < -1) in Malawi and Zimbabwe (BREATHE (NCT02426112)). Participants were randomized 1:1 to once-weekly oral azithromycin with weight-based dosing, for 48 weeks, or placebo. Twenty-six plasma soluble biomarkers were measured on a MagPix Luminex instrument at enrolment, after 48-weeks of treatment and 24-weeks after treatment cessation. Mixed effects models were constructed to compare biomarker expression across treatment and placebo groups. RESULTS: Weekly azithromycin was associated with reduced levels of C-Reactive Protein (CRP), E-Selectin, Matrix metalloproteinase 10 (MMP-10). Treatment effects for all soluble biomarkers were not sustained 24-weeks after treatment cessation with biomarker expression returning to pre-treatment levels. CONCLUSIONS: We observed real-world effects of azithromycin on acute inflammation, neutrophil accumulation, and extracellular matrix degradation, that were not sustained after treatment cessation. These results are pertinent when using azithromycin for its immunomodulatory properties, or targeting pathways represented by the soluble biomarkers in this study

Ny generasjon HPV-tester på vent

Ny forskning viser at gentester for humant papillomvirus (HPV) siler ut de behandlingstrengende i langt større grad enn celleprøver. Samtidig er det grunn til å tro at mRNA-tester bør velges fremfor DNA-tester

HPV mRNA test in women with minor cervical lesions : experience of the University Hospital of North Norway

In the Norwegian Cervical Cancer Screening Programme tests for detection of human papillomavirus (HPV) are used to triage women with minor cytological cervical lesions. The material in this study comprises samples from 1798 women in the period 2006–2008. The HPV test was performed according to the guidelines of the Norwegian Cancer Registry. The HPV mRNA test (PreTect HPV-Proofer) detects and types 5 high-risk genotypes (16, 18, 31, 33 and 45). The HPV mRNA results were compared to cytology and then biopsy up to December 2009. Women with minor cytological cervical lesions and negative HPV test were followed with a new PAP smear after 12 months. A total of 327 women (18%) were HPV mRNA positive. Of the 1798 women with minor cytological lesions, 232 women (13%) had moderate dysplasia, severe dysplasia or cancer and 144 women (8%) had severe dysplasia or cancer in biopsy. 57% of the women with a positive HPV mRNA test had moderate dysplasia, severe dysplasia or cancer. 37% had severe dysplasia or cancer. The sensitivity of the HPV mRNA test to detect moderate dysplasia, severe dysplasia or cancer was 81%. The specificity for moderate dysplasia, severe dysplasia or cancer was 91%. The negative predictive value (NPV) of the HPV mRNA test for moderate dysplasia, severe dysplasia or cancer was 97%. Of 11 women with cervical cancer, 10 were positive for HPV type 16 or 18. The HPV mRNA test seems more suitable than HPV DNA tests to triage women with minor cytological cervical lesions due to its higher specificity

Triage of Women with Minor Cervical Lesions : Data Suggesting a "Test and Treat" Approach for HPV E6/E7 mRNA Testing

BACKGROUND: Human papillomavirus (HPV) testing is included in the cervical cancer screening program in the triage of women with equivocal (ASC-US) or low-grade (LSIL) cytological lesions. These women have an increased risk for developing high grade dysplasia and cancer (CIN2+) compared to women with normal cytology. However, in order to avoid unnecessary follow-up, as well as overtreatment, a high positive predictive value (PPV) of the triage test is important. METHODOLOGY/PRINCIPAL FINDINGS: The HPV test PreTect HPV-Proofer, detecting E6/E7 mRNA from the HPV types 16, 18, 31, 33 and 45, is used as triage test together with repeat cytology. PPV data for HPV E6/E7 mRNA testing during the period from January 2006 up to June 2009 are reported. In total, 406 of 2099 women (19.3%) had a positive HPV test result. Of the women with a positive test result and with a histological diagnosis (n = 347), 243 women had histological high-grade dysplasia or cancer (CIN2+), giving a PPV of 70.0% (95% confidence interval [CI], 65.2%–74.8%). For HPV 16 or HPV 33 positive women above 40 years of age, the PPV was 83.7% (95% CI, 73.3%–94.0%) and 84.6% (95% CI, 65.0%–100.0%) respectively. The PPV of test positive women with HSIL cytology was 94.2% (95% CI, 88.7%–99.7%). CONCLUSIONS: When the result in triage is HPV mRNA positive, our data suggest direct treatment for women above 40 years of age or for women with a concurrent cytological HSIL diagnosis, contributing to better clinical safety for these women. In addition, by decreasing the time to treatment, thereby reducing the number of recalls, the patient management algorithm will be considerably improved, in turn reducing follow-up costs as well as unnecessary psychological stress among patients

Triage of women with ASC-US/LSIL cytology: The added value of implementation of an HPV-test

This study has an historical prospective design by including in retrospect all screening- and follow-up tests for women aged 25 to 69 years old kept by the Department of Clinical Pathology, University Hospital of Northern Norway, Tromsø. All women with a first ASC-US/LSIL smear in 1996-98 and 2006-08 were identified and compared on outcomes such as proportion of cases resolved within 35 months of index smear and incidence of CIN2+. The Department of Clinical pathology has used an mRNA test (NorChip PreTect HPV-Proofer) since the autumn of 2005 in secondary cervical cancer screening. In triage of women with ASC-US/LSIL, the HPV mRNA test significantly reduced the time from the first abnormal cytology until biopsy and had predictive values comparable with those of repeat cytology