Evidence of Decreased Long-term Risk of Cervical Precancer after Negative Primary HPV Screens Compared with Negative Cytology Screens in a Longitudinal Cohort Study.

BACKGROUND: The growing use of primary human papillomavirus (HPV) cervical cancer screening requires determining appropriate screening intervals to avoid overtreatment of transient disease. This study examined the long-term risk of cervical precancer after HPV screening to inform screening interval recommendations. METHODS: This longitudinal cohort study (British Columbia, Canada, 2008 to 2022) recruited women and individuals with a cervix who received 1 to 2 negative HPV screens (HPV1 cohort, N = 5,546; HPV2 cohort, N = 6,624) during a randomized trial and women and individuals with a cervix with 1 to 2 normal cytology results (BCS1 cohort, N = 782,297; BCS2 cohort, N = 673,778) extracted from the provincial screening registry. All participants were followed through the registry for 14 years. Long-term risk of cervical precancer or worse [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)] was compared between HPV and cytology cohorts. RESULTS: Cumulative risks of CIN2+ were 3.2/1,000 [95% confidence interval (CI), 1.6-4.7] in HPV1 and 2.7/1,000 (95% CI, 1.2-4.2) in HPV2 after 8 years. This was comparable with the risk in the cytology cohorts after 3 years [BCS1: 3.3/1,000 (95% CI, 3.1-3.4); BCS2: 2.5/1,000 (95% CI, 2.4-2.6)]. The cumulative risk of CIN2+ after 10 years was low in the HPV cohorts [HPV1: 4.7/1,000 (95% CI, 2.6-6.7); HPV2: 3.9 (95% CI, 1.1-6.6)]. CONCLUSIONS: Risk of CIN2+ 8 years after a negative screen in the HPV cohorts was comparable with risk after 3 years in the cytology cohorts (the benchmark for acceptable risk). IMPACT: These findings suggest that primary HPV screening intervals could be extended beyond the current 5-year recommendation, potentially reducing barriers to screening.

Colposcopy referral rates post-introduction of primary screening with human papillomavirus testing: evidence from a large British Columbia cohort study.

Background: Shifting from cytology to human papillomavirus (HPV)-based cervical cancer screening will initially increase colposcopy referrals. The anticipated impact on health systems has been raised as a concern for implementation. It is unclear if the higher rate of colposcopy referrals is sustained after initial HPV-based screens or reverts to new lower baselines due to earlier detection and treatment of precancer. This study aimed to investigate long-term rates of colposcopy referrals after participation in HPV-based screening. Methods: Participants of HPV for Cervical Cancer Screening trial (HPV FOCAL) received one (HPV1, N = 6204) or two (HPV2, N = 9540) HPV-based screens. After exit, they returned to British Columbia's (BC) cytology screening program. A comparison cohort from the BC screening population (BCS, N = 1,140,745) was identified, mirroring trial inclusion criteria. All participants were followed for 10-14 years through the provincial screening registry. Colposcopy referral rates per 1000 screens were calculated for each group. Trial colposcopy referrals for HPV1 and HPV2 were calculated under two referral scenarios: (1) all HPV positive referred to colposcopy; (2) cytology triage with ASCUS or greater referred to colposcopy. Colposcopy referrals from post-trial screens in HPV1 an HPV2 and all screens in BCS were based on actual recommendations from the screening program. A multivariable flexible survival regression model compared hazard ratios (HR) throughout follow-up. Findings: Scenario 2 referral rates were higher during initial HPV screen(s) vs cytology screen (HPV1: 28 per 1000 screens (95% CI: 24, 33), HPV2: 32 per 1000 screens (95% CI: 29, 36), BCS: 8 per 1000 screens (95% CI: 8.9)). However, post-trial rates in HPV1 and HPV2 were significantly lower than in BCS. Cumulative rates in HPV1 and HPV2 approached the cumulative rate in BCS 11-12 years after HPV-based screening (HPV1: 11 per 1000 screens (95% CI: 10, 12), HPV2: 16 per 1000 screens (95% CI: 15-17), BCS: 11 per 1000 screens (95% CI: 10, 11)). Adjusted models demonstrated reductions in referral rates in HPV1 (HR = 0.6, 95% CI: 0.5, 0.7) and HPV2 (HR = 0.7, 95% CI: 0.6, 0.8) relative to BCS by 54 and 72 months post-final HPV screen respectively. Interpretation: Reduced colposcopy referral rates were observed after initial rounds of HPV-based screening. After initial HPV screening, referral rates to colposcopy after cytology triage were below the current rates seen in a centralized cytology program after approximately four years. Any expected increase in referrals at initiation of HPV-based screening could be countered by staged program implementation. Funding: This work was supported by the National Institutes of Health (R01 CA221918), Michael Smith Health Research BC (RT-2021-1595), and the Canadian Institutes of Health Research (MCT82072).

British Columbia's Experience after Implementation of the Treponema pallidum Reverse Algorithm and PCR Detection, 2015 to 2020.

British Columbia (BC) implemented the syphilis reverse screening algorithm and Treponema pallidum PCR testing in 2014. We summarize the performance characteristics of the algorithm, together with PCR direct detection, and report on syphilis cases identified from 2015 to 2020. Prior to 2015, samples for syphilis diagnosis were first screened by rapid plasma reagin (RPR). As of 2015, sera were screened by the Siemens Advia Centaur syphilis assay (enzyme immunoassay [EIA]). Positive and equivocal samples were reflex tested by a T. pallidum passive particle agglutination assay (TPPA) and RPR. We used T. pallidum DNA PCR on clinical samples and restriction fragment length polymorphism analysis to identify azithromycin resistance mutations. Case/epidemiological data were obtained from the BC surveillance system. Of 1,631,519 samples screened by the EIA, 72,492 (4.4%) were positive and 187 (<0.1%) were equivocal. Of EIA-positive/equivocal samples, 10.6% were false positive, and false positivity was higher at lower EIA indices. The reverse algorithm detected 4,693 late latent syphilis cases that likely would have been missed by RPR screening. PCR had a very high sensitivity of 100% versus 52.9% and 52.4% for dark-field (DF) and immunofluorescence (IF) microscopy, respectively. The azithromycin resistance mutation A2058G was identified in 96% of PCR-positive samples, and A2059G was identified in 4%. Annually, there were 944 to 1,467 syphilis cases, with 62% in men who reported male sexual partners. The reverse algorithm had a low false-positive rate and very few equivocal screening results but did identify previously undiagnosed late latent syphilis cases. PCR was more sensitive than both DF and IF microscopy for direct diagnosis and enabled monitoring for azithromycin resistance. IMPORTANCE In this study, we summarize the performance characteristics of the algorithm, together with PCR direct detection and epidemiological analysis, and report on syphilis cases identified from 2015 to 2020. This allowed us to paint a complete picture of the outcome of the utilization of the reverse algorithm for diagnosing syphilis cases. The study clearly showed that the reverse algorithm had a low false-positive rate and very few equivocal screening results but did identify previously undiagnosed late latent syphilis cases. PCR was more sensitive than both DF and IF microscopy for direct diagnosis and enabled monitoring for azithromycin resistance.

Human papillomavirus-based screening at extended intervals missed fewer cervical precancers than cytology in the HPV For Cervical Cancer (HPV FOCAL) trial.

While cervix screening using cytology is recommended at 2- to 3-year intervals, given the increased sensitivity of human papillomavirus (HPV)-based screening to detect precancer, HPV-based screening is recommended every 4- to 5-years. As organized cervix screening programs transition from cytology to HPV-based screening with extended intervals, there is some concern that cancers will be missed between screens. Participants in HPV FOr CervicAL Cancer (HPV FOCAL) trial received cytology (Cytology Arm) at 24-month intervals or HPV-based screening (HPV Arm) at 48-month intervals; both arms received co-testing (cytology and HPV testing) at exit. We investigated the results of the co-test to identify participants with cervical intraepithelial neoplasia grade 2 or higher (CIN2+) who would not have had their precancer detected if they had only their arm's respective primary screen. In the Cytology Arm, 25/62 (40.3%) identified CIN2+s were missed by primary screen (ie, normal cytology/positive HPV test) and all 25 had normal cytology at the prior 24-month screen. In the HPV arm, three CIN2+s (3/49, 6.1%) were missed by primary screen (ie, negative HPV test/abnormal cytology). One of these three misses had low-grade cytology findings and would also not have been referred to colposcopy outside of the trial. Multiple rounds of cytology did not detect some precancerous lesions detected with one round of HPV-based screening. In our population, cytology missed more CIN2+, even at shorter screening intervals, than HPV-based screening. This assuages concerns about missed detection postimplementation of an extended interval HPV-based screening program. We recommend that policymakers consider a shift from cytology to HPV-based cervix screening.

High-risk HPV prevalence among women undergoing cervical cancer screening: Findings a decade after HPV vaccine implementation in British Columbia, Canada.

BACKGROUND: British Columbia (BC) introduced a publicly funded, school-based human papillomavirus (HPV) immunization program in 2008 with the quadrivalent vaccine. In 2010/2011, a baseline evaluation of HPV prevalence was conducted among women undergoing cervical cancer screening. After 10 years of publicly funded HPV vaccination, HPV-type prevalence was re-evaluated. METHODS: From August 2017 to March 2018, 1107 physicians were invited to return cytobrushes used during routine Pap screening to the Cervical Cancer Screening Laboratory for HPV testing. Only age or year of birth was collected. Specimens were screened for high-risk HPV (hrHPV) and positive samples were genotyped. HPV type prevalence was compared for females 15-22 yrs (those eligible for the school-based vaccination) and 23+ yrs (ineligible for school-based vaccination) for the 2010/2011 and the 2017/2018 data. RESULTS: There were 3309 valid samples received for testing; of these, 3107 were included in the analysis. The overall hrHPV prevalence was 12.2% (95% CI 11.3-13.3) in 2010/11, and 12.0% (95% CI 10.9-13.2) in 2017/18. For the 15-22 age group, the prevalence for any hrHPV was 26.8% (95% CI 23.1-30.8) in 2010/11 and 25.4% (95% CI 15.3-37.9) in 2017/18. For those aged 15-22, HPV16 prevalence in 2010/11 was 8.8% (95% CI 6.5-11.5) and in 2017/18 was 6.3% (95% CI 1.8-15.5), with corresponding figures for HPV18 3.7% (95% CI 2.3-5.7) and 0% (95% CI 0.0-5.7), respectively. For all hrHPV types, there were no statistically significant differences between the 2010/11 and 2017/18 periods. CONCLUSIONS: This study illustrates the prevalence of hrHPV in BC over time in women undergoing cervical cancer screening, where an indication of a decline in HPV16/18 is seen in vaccine eligible women.

SARS-CoV-2 serology: Validation of high-throughput chemiluminescent immunoassay (CLIA) platforms and a field study in British Columbia.

BACKGROUND: SARS-CoV-2 antibody testing is required for estimating population seroprevalence and vaccine response studies. It may also increase case identification when used as an adjunct to routine molecular testing. We performed a validation study and evaluated the use of automated high-throughput assays in a field study of COVID-19-affected care facilities. METHODS: Six automated assays were assessed: 1) DiaSorin LIAISONTM SARS-CoV-2 S1/S2 IgG; 2) Abbott ARCHITECTTM SARS-CoV-2 IgG; 3) Ortho VITROSTM Anti-SARS-CoV-2 Total; 4) VITROSTM Anti-SARS-CoV-2 IgG; 5) Siemens SARS-CoV-2 Total Assay; and 6) Roche ElecsysTM Anti-SARS-CoV-2. The validation study included 107 samples (42 known positive; 65 presumed negative). The field study included 296 samples (92 PCR positive; 204 PCR negative or not PCR tested). All samples were tested by the six assays. RESULTS: All assays had sensitivities >90% in the field study, while in the validation study, 5/6 assays were >90% sensitive and DiaSorin was 79% sensitive. Specificities and negative predictive values were >95% for all assays. Field study estimated positive predictive values at 1-10% disease prevalence were 100% for Siemens, Abbott and Roche, while DiaSorin and Ortho assays had lower PPVs at 1% prevalence, but PPVs increased at 5-10% prevalence. In the field study, addition of serology increased diagnoses by 16% compared to PCR testing alone. CONCLUSIONS: All assays evaluated in this study demonstrated high sensitivity and specificity for samples collected at least 14 days post-symptom onset, while sensitivity was variable 0-14 days after infection. The addition of serology to the outbreak investigations increased case detection by 16%.

Long-term cervical precancer outcomes after a negative DNA- or RNA-based human papillomavirus test result.

BACKGROUND: Cervical cancer, a preventable disease associated with the human papillomavirus, is responsible for significant morbidity and mortality globally. Primary human papillomavirus testing is more sensitive in detecting precancerous cervical lesions than cytologic screening and can be conducted using either DNA- or RNA-based assays. Screening programs must select the most appropriate assay from several available assays for their population. It is not yet known whether these assays perform equivalently in the long term, particularly among women with a negative human papillomavirus test result. This study aims to compare long-term safety after a negative human papillomavirus test result across both DNA- and RNA-based testing assays. OBJECTIVE: This study aimed to compare long-term high-grade cervical intraepithelial neoplasia (grade 2 or higher and grade 3 or higher) outcomes of 2 DNA-based assays (Digene Hybrid Capture 2 High-Risk HPV DNA Test and cobas 4800 HPV Test) and 1 messenger RNA-based assay (Aptima HPV Assay) using data from the Human Papillomavirus For Cervical Cancer Trial-DECADEl (FOCAL-DECADE) cohort, by first comparing the positive and negative rates between the assays and then investigating the cumulative incidence of cervical intraepithelial neoplasia grade 2 and higher and grade 3 or higher detection among participants in the FOCAL DECADE cohort over follow-up according to human papillomavirus testing assays. STUDY DESIGN: The FOCAL Trial was a randomized controlled trial that evaluated human papillomavirus testing for primary cervical cancer screening. The FOCAL-DECADE cohort subsequently followed FOCAL Trial participants passively through the British Columbia Cervix Screening Program Database for approximately 10 years after the FOCAL Trial study exit to examine the rates of cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher. For this study, eligible participants had baseline human papillomavirus-negative results from at least 1 assay and had 1 or more cytologic screens after baseline (9509 participants for DNA-based and 3473 participants for DNA- vs RNA-based assay comparisons). We constructed cumulative incidence curves and compared the hazard ratios for cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher detection according to the assays. RESULTS: Over 10 years of follow-up, the cumulative incidence of cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher did not significantly differ between the DNA-based assays (hazard ratio, 0.95; 95% confidence interval, 0.84-1.06; P=.35 and hazard ratio, 0.82; 95% confidence interval, 0.66-1.01; P=.06 for cervical intraepithelial neoplasia grade 2 or higher and cervical intraepithelial neoplasia grade 3 or higher, respectively) or between the DNA- and RNA-based assays (hazard ratio, 0.97; 95% confidence interval, 0.87-1.06; P=.48 and hazard ratio, 0.94; 95% confidence interval, 0.79-1.13; P=.52 for cervical intraepithelial neoplasia grade 2 or higher and cervical intraepithelial neoplasia grade 3 or higher, respectively). CONCLUSION: Among participants who tested negative for human papillomavirus at baseline, the long-term risk of cervical intraepithelial neoplasia grade 2 or higher and grade 3 or higher did not significantly differ regardless of whether DNA- or RNA-based human papillomavirus testing assays were used. Screening program decision makers can be confident that for women who test negative for human papillomavirus, DNA- and RNA-based assays exhibit similar cervical intraepithelial neoplasia grade 2 or higher outcomes over several years.

Cost-effectiveness analysis of primary human papillomavirus testing in cervical cancer screening: Results from the HPV FOCAL Trial.

The Human Papillomavirus FOr CervicAL cancer (HPV FOCAL) trial is a large randomized controlled trial comparing the efficacy of primary HPV testing to cytology among women in the population-based Cervix Screening Program in British Columbia, Canada. We conducted a cost-effectiveness analysis based on the HPV FOCAL trial to estimate the incremental cost per detected high-grade cervical intraepithelial neoplasia of grade 2 or worse lesions (CIN2+). A total of 19,009 women aged 25 to 65 were randomized to one of two study groups. Women in the intervention group received primary HPV testing with reflex liquid-based cytology (LBC) upon a positive finding with a screening interval of 48 months. Women in the control group received primary LBC testing, and those negative returned at 24 months for LBC and again at 48 months for exit screening. Both groups received HPV and LBC co-testing at the 48-month exit. Incremental costs during the course of the trial were comparable between the intervention and control groups. The intervention group had lower overall costs and detected a larger number of CIN2+ lesions, resulting in a lower mean cost per CIN2+ detected ($7551) than the control group ($8325), a difference of -$773 [all costs in 2018 USD]. Cost per detected lesion was sensitive to the costs of sample collection, HPV testing, and LBC testing. The HPV FOCAL Trial results suggest that primary HPV testing every 4 years produces similar outcomes to LBC-based testing every 2 years for cervical cancer screening at a lower cost.

Differences in risk factors for hepatitis B, hepatitis C, and human immunodeficiency virus infection by ethnicity: A large population-based cohort study in British Columbia, Canada.

OBJECTIVES: Addressing the needs of ethnic minorities will be key to finding undiagnosed individuals living with hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV). To inform screening initiatives in British Columbia (BC), Canada, the factors associated with HBV and/or HCV and/or HIV infection among different ethnic groups within a large population-based cohort were assessed. METHODS: Persons diagnosed with HBV, HCV, or HIV in BC between 1990 and 2015 were grouped as East Asian, South Asian, Other Visible Minority (African, Central Asian, Latin American, Pacific Islander, West Asian, unknown ethnicity), and Not a Visible Minority, using a validated name-recognition software. Factors associated with infection within each ethnic group were assessed with multivariable multinomial logistic regression models. RESULTS: Participants included 202 521 East Asians, 126 070 South Asians, 65 210 Other Visible Minorities, and 1 291 561 people who were Not a Visible Minority, 14.4%, 3.3%, 4.5%, and 6.3% of whom had HBV and/or HCV and/or HIV infections, respectively. Injection drug use was most prevalent among infection-positive people who were Not a Visible Minority (22.1%), and was strongly associated with HCV monoinfection, HBV/HCV coinfection, and HCV/HIV coinfection, but not with HBV monoinfection among visible ethnic minorities. Extreme material deprivation and social deprivation were more prevalent than injection drug use or problematic alcohol use among visible ethnic minorities. CONCLUSIONS: Risk factor distributions varied among persons diagnosed with HBV and/or HCV and/or HIV of differing ethnic backgrounds, with lower substance use prevalence among visible minority populations. This highlights the need for tailored approaches to infection screening among different ethnic groups.

Elevated risk of colorectal, liver, and pancreatic cancers among HCV, HBV and/or HIV (co)infected individuals in a population based cohort in Canada.

INTRODUCTION: Studies of the impact of hepatitis C virus (HCV), hepatitis B virus (HBV) and HIV mono and co-infections on the risk of cancer, particularly extra-hepatic cancer, have been limited and inconsistent in their findings. METHODS: In the British Columbia Hepatitis Testers Cohort, we assessed the risk of colorectal, liver, and pancreatic cancers in association with HCV, HBV and HIV infection status. Using Fine and Gray adjusted proportional subdistribution hazards models, we assessed the impact of infection status on each cancer, accounting for competing mortality risk. Cancer occurrence was ascertained from the BC Cancer Registry. RESULTS: Among 658,697 individuals tested for the occurrence of all three infections, 1407 colorectal, 1294 liver, and 489 pancreatic cancers were identified. Compared to uninfected individuals, the risk of colorectal cancer was significantly elevated among those with HCV (Hazard ration [HR] 2.99; 95% confidence interval [CI] 2.55-3.51), HBV (HR 2.47; 95% CI 1.85-3.28), and HIV mono-infection (HR 2.30; 95% CI 1.47-3.59), and HCV/HIV co-infection. The risk of liver cancer was significantly elevated among HCV and HBV mono-infected and all co-infected individuals. The risk of pancreatic cancer was significantly elevated among individuals with HCV (HR 2.79; 95% CI 2.01-3.70) and HIV mono-infection (HR 2.82; 95% CI 1.39-5.71), and HCV/HBV co-infection. DISCUSSION/CONCLUSION: Compared to uninfected individuals, the risk of colorectal, pancreatic and liver cancers was elevated among those with HCV, HBV and/or HIV infection. These findings highlight the need for targeted cancer prevention and diligent clinical monitoring for hepatic and extrahepatic cancers in infected populations.

Assessing 10-Year Safety of a Single Negative HPV Test for Cervical Cancer Screening: Evidence from FOCAL-DECADE Cohort.

BACKGROUND: Long-term safety of a single negative human papillomavirus (HPV) test for cervical cancer screening is unclear. The HPV FOr cerviCAL Cancer Trial (FOCAL) was a randomized trial comparing HPV testing with cytology. The FOCAL-DECADE cohort tracked women who received one HPV test during FOCAL, and were HPV negative, for up to 10 years to identify cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) detected through a provincial screening program. METHODS: FOCAL participants who received one HPV test, were negative, and had at least one post-FOCAL cervix screen were included (N = 5,537). We constructed cumulative incidence curves of CIN2+/CIN3+ detection, analyzed cumulative risk of detection at intervals post-HPV test, calculated average incidence rates for detection, and compared hazard across ages. RESULTS: Ten years after one negative HPV test, the probability of CIN2+ detection was lower than 1%, with most lesions detected 7 years or later. Average incidence rates of CIN2+/CIN3+ lesions over follow-up were 0.50 [95% confidence interval (CI), 0.31-0.78] and 0.18 (95% CI, 0.07-0.36) per 1,000 person-years, respectively. Hazards were higher for younger ages (nonsignificant trend). CONCLUSIONS: Among women with a single negative HPV test, long-term risk of CIN2+ detection was low, particularly through 7 years of follow-up; thus, one negative HPV test appears to confer long-term protection from precancerous lesions. Even 10-year risk is sufficiently low to support extended testing intervals in average-risk populations. IMPACT: Our findings support the safety of screening policies using HPV testing alone at 5-year or longer intervals.

Real-world Effectiveness of Sofosbuvir/Velpatasvir for Treatment of Chronic Hepatitis C in British Columbia, Canada: A Population-Based Cohort Study.

BACKGROUND: Clinical trials show high efficacy of sofosbuvir/velpatasvir (SOF/VEL), but there are limited data from "real-world" settings. We aimed to evaluate SOF/VEL effectiveness for all hepatitis C virus (HCV) genotypes (GTs) in British Columbia (BC), Canada. METHODS: We used the BC Hepatitis Testers Cohort, which includes all HCV cases in the province (1990-2015) linked to administrative databases, including prescriptions to end of 2018. We measured sustained virologic response (SVR; negative RNA ≥10 weeks after treatment end) and identified characteristics associated with non-SVR. Conservatively, we excluded individuals with no assessment for SVR if their last RNA test after treatment initiation was negative (but included if positive). RESULTS: Of 2821 eligible participants, most were infected with GT1 (1076, 38.1%) or GT3 (1072, 38.0%), and a minority (278, 9.9%) were treated with RBV. SVR was 94.6% (2670/2821) overall and 94.5% (1017/1076) for GT1, 96.4% (512/531) for GT2, and 93.7% (1004/1072) for GT3. When disaggregated by GT, treatment regimen, and cirrhosis/treatment experience, SVR was lowest (30/40, 75.0%) among treatment-experienced GT3 individuals treated with RBV. Characteristics associated with non-SVR in multivariable analysis included younger age, RBV addition, and being a person with HIV (PWH) or who injects/injected drugs (PWID). When treatment regimen (±RBV) was removed from multivariable model, treatment experience was associated with non-SVR for GT3. Of 151 non-SVR individuals, 56.3% were nonvirological failures (treatment incomplete/no assessment for SVR) and 43.7% were virological failures (nonresponse/relapse). A disproportionately high percentage of non-SVR among PWID was due to nonvirological failure. CONCLUSIONS: SOF/VEL was highly effective in this "real-world" population-based cohort. Additional support is required for PWID/PWH to reach SVR.

Loss to follow-up: A significant barrier in the treatment cascade with direct-acting therapies.

Effectiveness of direct-acting antiviral (DAA) therapies could be influenced by patient characteristics such as comorbid conditions, which could lead to premature treatment discontinuation and/or irregular medical follow-ups. Here, we evaluate loss to follow-up and treatment effectiveness of sofosbuvir/ledipasvir ± ribavirin (SOF/LDV ± RBV), ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (OBV/PTV/r + DSV ± RBV) for hepatitis C virus (HCV) genotype 1 (GT1) and sofosbuvir + ribavirin (SOF + RBV) for genotype 3 (GT3) in British Columbia Canada: The British Columbia Hepatitis Testers Cohort includes data on individuals tested for HCV since 1992, integrated with medical visit, hospitalization and prescription drug data. HCV-positive individuals who initiated DAA regimens, irrespective of treatment completion, for GT1 and GT3 until 31 December, 2017 were included. Factors associated with sustained virological response (SVR) and loss to follow-up were assessed by using multivariable logistic regression models. In total 4477 individuals initiated DAAs. The most common prescribed DAA was SOF/LDV ± RBV with SVR of 95%. The highest SVR of 99.5% was observed among OBV/PTV/r + DSV-treated patients. Overall, 453 (10.1%) individuals were lost to follow-up. Higher loss to follow-up was observed among GT1 patients treated with OBV (17.8%) and GT3 patients (15.7%). The loss to follow-up rate was significantly higher among individuals aged <60 years, those with a history of injection drug use (IDU), on opioid substitution therapy and with cirrhosis. Our findings indicate that loss to follow-up exceeds viral failure in HCV DAA therapy and its rate varies significantly by genotype and treatment regimen. Depending on the aetiology of lost to follow-up, personalized case management for those with medical complications and supporting services among IDU are needed to achieve the full benefits of effective treatments.

Disease detection at the 48-month exit round of the HPV FOCAL cervical cancer screening trial in women per-protocol eligible for routine screening.

HPV FOCAL is a randomized control trial of cervical cancer screening. The intervention arm received baseline screening for high-risk human papillomavirus (HPV) and the control arm received liquid-based cytology (LBC) at baseline and 24 months. Both arms received 48-month exit HPV and LBC cotesting. Exit results are presented for per-protocol eligible (PPE) screened women. Participants were PPE at exit if they had completed all screening and recommended follow-up and had not been diagnosed with cervical intraepithelial neoplasia Grade 2 or worse (CIN2+) earlier in the trial. Subgroups were identified based upon results at earlier trial screening. There were 9,457 and 9,552 and women aged 25-65 randomized to control and intervention and 7,448 (77.8%) and 8,281 (86.7%), respectively, were PPE and screened. Exit cotest results were similar (p = 0.11) by arm for PPE and the relative rate (RR) of CIN2+ for intervention vs. control was RR = 0.83 (95% CI: 0.56-1.23). The RR for CIN2+ comparing intervention women baseline HPV negative to control women with negative cytology at baseline and at 24 months, was 0.68 (95% CI: 0.43-1.06). PPE women who had a negative or CIN1 colposcopy in earlier rounds had elevated rates (per 1,000) of CIN2+ at exit, control 31 (95% CI: 14-65) and intervention 43 (95% CI: 25-73). Among PPE women HPV negative at exit LBC cotesting identified little CIN2+, Rate = 0.3 (95% CI: 0.1-0.7). This per-protocol analysis found that screening with HPV using a 4-year interval is as safe as LBC with a 2-year screening interval. LBC screening in HPV negative women at exit identified few additional lesions.

Immunogenicity of 2 and 3 Doses of the Quadrivalent Human Papillomavirus Vaccine up to 120 Months Postvaccination: Follow-up of a Randomized Clinical Trial.

BACKGROUND: Several countries have implemented a 2-dose (2D) human papillomavirus (HPV) vaccination schedule for adolescents based on immunobridging studies. We compared immunogenicity of 2D vs 3-dose (3D) schedules of the quadrivalent vaccine (4vHPV) up to 10 years after the first dose. METHODS: Girls aged 9-13 years were randomized to receive 2D or 3D and were compared with women aged 16-26 receiving 3D at day 1 and months 7, 24, and 120 after the first dose. Antibody levels for HPV6/11/16/18 were evaluated using the competitive Luminex immunoassay (cLIA) and total immunoglobulin G assay. Geometric mean titers (GMTs) and seropositivity rates were compared between the different groups at different time points. Noninferiority of GMT ratios was defined as the lower bound of the 2-sided 95% confidence interval (CI) being greater than 0.5. Kinetics of antibody titers over time among study groups were examined. RESULTS: At 120 months, data from 35 2D girls, 38 3D girls, and 30 3D women were used for analyses. cLIA seropositivity rates were above 95% for all HPV vaccine types and all schedules, except HPV18, with the lowest seropositivity observed among 3D women (60.0%; 95% CI, 40.6%-77.3%). GMT ratios (cLIA) for both 2D and 3D girls were noninferior to 3 doses in women for HPV6/11/16/18. Trends were comparable between assays. CONCLUSIONS: GMTs for HPV6/11/16/18 after 2D or 3D of 4vHPV in girls were noninferior to 3D in adult women up to 120 months postvaccination. This study demonstrates long-term immunogenicity of the 2D HPV vaccine schedule.

What is killing people with hepatitis C virus infection? Analysis of a population-based cohort in Canada.

BACKGROUND: Persons with hepatitis C virus (HCV) infection are at risk of mortality from both chronic liver disease and HCV acquisition risk activities. We compared causes of death among HCV positive and negative individuals to characterize contributions of acquisition risks and viral sequelae. METHODS: The British Columbia (BC) Hepatitis Testers Cohort (BC-HTC) includes all individuals tested for HCV or reported as a HCV case since 1992, linked to health administrative data. ICD-10 codes were used to classify deaths as: 1) liver-related (LR); 2) HCV acquisition risk-related (AR); and 3) other causes. Mortality proportions and trends were assessed among HCV positive and negative individuals overall and by birth cohort (born <1945, 1945-64 and ≥1965). RESULTS: As of December 31, 2018, of 1,300,204 HCV-tested individuals, 20,049 (27.5%) HCV positive and 132,999 (10.2%) HCV negative individuals had died (median age at death: 56.4 vs. 74.5 years, respectively). HCV positive individuals were more likely than negatives to die from both AR (24.7%/4.2%) and LR (23.4%/6.2%) causes. Deaths among older HCV positive individuals were more likely to be LR while younger individuals were more likely AR: 1) birth cohort <1945 (25.3%/2.7%); 2) 1945-64 (26.5%/23.7%) and ≥1965 (7.7%/59.9%). Among HCV positives, LR mortality increased from 1992 to 2014, then declined sharply, coinciding with the introduction and uptake of direct-acting antiviral drugs. AR mortality increased from 1992 to 2000, declined slowly until 2013, then rapidly increased, coinciding with the recent surge in opioid overdose deaths. CONCLUSIONS: Curative HCV treatments reduce LR mortality, but typically will not impact AR mortality. This will need to be addressed if the World Health Organization 2030 HCV mortality reduction goals are to be achieved.

Effectiveness of Ledipasvir/Sofosbuvir and Sofosbuvir/Velpatasvir in People Who Inject Drugs and/or Those in Opioid Agonist Therapy.

We evaluated the effectiveness of ledipasvir/sofosbuvir (LDV/SOF) in treating hepatitis C virus (HCV) genotype 1 and SOF/velpatasvir (SOF/VEL) for all genotypes among people who inject drugs (PWID) and those not injecting drugs and who were on or off opioid agonist therapy (OAT). Study participants comprised a population-based cohort in British Columbia, Canada. The British Columbia Hepatitis Testers Cohort includes data on individuals tested for HCV from 1990 to 2016 that are integrated with medical visits, hospitalization, and prescription drug data. We classified study participants as off OAT/recent injection drug use (off-OAT/RIDU), off OAT/past IDU (off-OAT/PIDU), off OAT/no IDU (off-OAT/NIDU), on OAT/IDU (on-OAT/IDU), and on OAT/no IDU (on-OAT/NIDU). We assessed sustained virologic response (SVR) 10 weeks after HCV treatment among study groups treated with LDV/SOF or SOF/VEL until January 13, 2018. Analysis included 5,283 eligible participants: 390 off-OAT/RIDU, 598 off-OAT/PIDU, 3,515 off-OAT/NIDU, 609 on-OAT/IDU, and 171 on-OAT/NIDU. The majority were male patients (64%-74%) and aged ≥50 years (58%-85%). The SVRs for off-OAT/RIDU, off-OAT/PIDU, off-OAT/NIDU, on-OAT/IDU, and on-OAT/NIDU were 91% (355/390), 95% (570/598), 96% (3,360/3,515), 93% (567/609), and 95% (163/171), respectively. Among those with no SVR, 14 individuals died while on treatment or before SVR assessment, including 4 from illicit drug overdose. In the overall multivariable model, off-OAT/RIDU, on-OAT/IDU, male sex, cirrhosis, treatment duration <8 weeks, treatment duration 8 weeks, and treatment with SOF/VEL were associated with not achieving SVR. Conclusion: In this large real-world cohort, PWID and/or those on OAT achieved high SVRs, although slightly lower than people not injecting drugs. This finding also highlights the need for additional measures to prevent loss to follow-up and overdose-related deaths among PWID.

Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial.

Human papillomavirus (HPV)-based cervical cancer screening requires triage of HPV positive women to identify those at risk of cervical intraepithelial neoplasia grade 2 (CIN2) or worse. We conducted a blinded case-control study within the HPV FOCAL randomized cervical cancer screening trial of women aged 25-65 to examine whether baseline methylation testing using the S5 classifier provided triage performance similar to an algorithm relying on cytology and HPV genotyping. Groups were randomly selected from women with known HPV/cytology results and pathology outcomes. Group 1: 104 HPV positive (HPV+), abnormal cytology (54 CIN2/3; 50

Comparative performance of human papillomavirus messenger RNA versus DNA screening tests at baseline and 48 months in the HPV FOCAL trial.

BACKGROUND: HPV FOCAL is a randomized trial comparing high-risk HPV [Hybrid Capture 2 (HC2)] vs. liquid-based cytology (LBC) for primary cervical screening. OBJECTIVE: The present study objective was to compare Aptima HPV (AHPV) and HC2 assay performance at the intervention arm baseline and 48 mo. screens in relation to the rates of cervical intraepithelial neoplasia (CIN) grade 2 or worse (CIN2+). STUDY DESIGN: Women enrolled after December 2010 (n = 3475) were screened at baseline with both AHPV and HC2 (AHPV was blinded). Women with CIN2+ exited the trial; HC2 negative (-) women and those HC2 positive (+) with

Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High-grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV FOCAL Randomized Clinical Trial.

Importance: There is limited information about the relative effectiveness of cervical cancer screening with primary human papillomavirus (HPV) testing alone compared with cytology in North American populations. Objective: To evaluate histologically confirmed cumulative incident cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) detected up to and including 48 months by primary HPV testing alone (intervention) or liquid-based cytology (control). Design, Setting, and Participants: Randomized clinical trial conducted in an organized Cervical Cancer Screening Program in Canada. Participants were recruited through 224 collaborating clinicians from January 2008 to May 2012, with follow-up through December 2016. Women aged 25 to 65 years with no history of CIN2+ in the past 5 years, no history of invasive cervical cancer, or no history of hysterectomy; who have not received a Papanicolaou test within the past 12 months; and who were not receiving immunosuppressive therapy were eligible. Interventions: A total of 19 009 women were randomized to the intervention (n = 9552) and control (n = 9457) groups. Women in the intervention group received HPV testing; those whose results were negative returned at 48 months. Women in the control group received liquid-based cytology (LBC) testing; those whose results were negative returned at 24 months for LBC. Women in the control group who were negative at 24 months returned at 48 months. At 48-month exit, both groups received HPV and LBC co-testing. Main Outcomes and Measures: The primary outcome was the cumulative incidence of CIN3+ 48 months following randomization. The cumulative incidence of CIN2+ was a secondary outcome. Results: Among 19 009 women who were randomized (mean age, 45 years [10th-90th percentile, 30-59]), 16 374 (8296 [86.9%] in the intervention group and 8078 [85.4%] in the control group) completed the study. At 48 months, significantly fewer CIN3+ and CIN2+ were detected in the intervention vs control group. The CIN3+ incidence rate was 2.3/1000 (95% CI, 1.5-3.5) in the intervention group and 5.5/1000 (95% CI, 4.2-7.2) in the control group. The CIN3+ risk ratio was 0.42 (95% CI, 0.25-0.69). The CIN2+ incidence rate at 48 months was 5.0/1000 (95% CI, 3.8-6.7) in the intervention group and 10.6/1000 (95% CI, 8.7-12.9) in the control group. The CIN2+ risk ratio was 0.47 (95% CI, 0.34-0.67). Baseline HPV-negative women had a significantly lower cumulative incidence of CIN3+ at 48 months than cytology-negative women (CIN3+ incidence rate, 1.4/1000 [95% CI, 0.8-2.4]; CIN3+ risk ratio, 0.25 [95% CI, 0.13-0.48]). Conclusions and Relevance: Among women undergoing cervical cancer screening, the use of primary HPV testing compared with cytology testing resulted in a significantly lower likelihood of CIN3+ at 48 months. Further research is needed to understand long-term clinical outcomes as well as cost-effectiveness. Trial Registration: isrctn.org Identifier: ISRCTN79347302.