Amanda Yu

Human Papillomavirus 16 (HPV 16) and HPV 18 Antibody Responses Measured by Pseudovirus Neutralization and Competitive Luminex Assays in a Two- versus Three-Dose HPV Vaccine Trial

ABSTRACT Human papillomavirus 16 (HPV 16) and HPV 18 antibody responses in a 2- versus 3-dose HPV vaccine (Gardasil) trial were measured by a pseudovirus neutralizing antibody (PsV NAb) assay and by the Merck competitive Luminex immunoassay (cLIA). Eight hundred twenty-four female subjects assigned to three dosing regimens (group 1, 9 to 13 years old; 2 doses, months 0 and 6 [n = 259]; group 2, 9 to 13 years old; 3 doses, months 0, 2, and 6 [n = 260]; group 3, 16 to 26 years old; 3 doses, months 0, 2, and 6 [n = 305]) had postvaccine responses assessed 1 month after the last dose. Of 791 subjects with baseline and 7-month sera, 15 (1.9%) and 9 (1.1%) were baseline seropositive for HPV 16 and HPV 18, respectively. All baseline-seronegative vaccinees seroconverted to both HPV 16 and HPV 18. Mean anti-HPV 16 levels were similar for groups 1 and 2 (for PsV NAb, P = 0.675; for cLIA, P = 0.874), and levels for both groups 1 and 2 were approximately 2-fold higher than that for group 3 (for PsV NAb and cLIA, P < 0.001). Mean anti-HPV 18 levels were approximately 1.4-fold lower in group 1 than in group 2 (for PsV, NAb P = 0.013; for cLIA, P = 0.001), and levels for both groups 1 and 2 were approximately 2.0- to 2.5-fold higher than that for group 3 (for PsV NAb and cLIA, P < 0.001). Pearson correlation coefficients for the assays were 0.672 for HPV 16 and 0.905 for HPV 18. Most of the discordant results were observed at lower cLIA signals. These results suggest that the PsV NAb assay could be a suitable alternative to cLIA for the measurement of postvaccine antibody responses.

GBV-C/hepatitis G virus infection and non-Hodgkin lymphoma: a case control study.

We investigated whether there was an association between GBV‐C viremia and the development of non‐Hodgkin lymphoma (NHL) in 553 NHL cases and 438 controls from British Columbia, Canada. Cases were aged 20–79, diagnosed between March 2000 and February 2004, and resident in Greater Vancouver or Victoria. Cases and controls were tested for GBV‐C RNA by RT‐PCR and positive samples were genotyped. Overall, GBV‐C RNA was detected in 4.5% of NHL cases vs. 1.8% of controls [adjusted odds ratio (OR) = 2.72, 95% confidence interval (CI) = 1.22–6.69]. The association between GBV‐C RNA detection and NHL remained even after individuals with a history of prior transfusion, injection drug use and hepatitis C virus sero‐positivity were excluded. GBV‐C viremia showed the strongest association with diffuse large B cell lymphoma (adjusted OR = 5.18, 95% CI = 2.06–13.71). Genotyping was performed on 29/33 GBV‐C RNA positive individuals; genotypes 2a (n = 22); 2b (n = 5) and 3 (n = 2) were identified, consistent with the distribution of genotypes found in North America. This is the largest case‐control study to date associating GBV‐C viremia and NHL risk. As GBV‐C is known to be transmitted through blood products this may have important implications for blood safety.

Genotype D amongst injection drug users with acute hepatitis B virus infection in British Columbia.

Summary.  The eight genotypes of hepatitis B virus (HBV) exhibit distinct geographical distributions. This study identified HBV genotypes and transmission modes associated with acute infection in British Columbia (BC), Canada, from 2001 to 2005. Seventy cases of acute HBV in BC were identified from laboratory reports using a standardized case definition. Interviews for risk factors and hepatitis history were conducted for each case. HBV genotypes were determined by BLAST comparison analysis of the surface (S) or preS gene sequence. To illustrate the distribution of genotypes identified amongst acute cases in BC, an annotated map was produced showing the global occurrence of HBV genotypes. The majority of acute HBV cases occurred in Caucasian, Canadian‐born males, with 30% of cases reporting injection drug use (IDU) and 21% reporting incarceration. The most common genotype observed was genotype D (62.9%), followed by genotypes A (18.6%), C (11.4%), B (4.3%), and E (1.4%). A significant association was observed between Genotype D and IDU (P = 0.0025) and previous incarceration (P = 0.0067). Phylogenetic analysis of the S gene sequence demonstrated identical or high genetic relatedness amongst genotype D viral strains (86% sub‐genotype D3), thus verifying transmission clustering amongst BC injection drug users. The association between acute HBV genotype and reported transmission modes has not been previously described in North America. Tracking of genotypes can help identify disease transmission patterns and target at‐risk populations for preventive immunization.

Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada

BACKGROUND & AIMS Evidence is limited on hepatocellular carcinoma (HCC) risk after sustained virological response (SVR) to interferon-based treatment of hepatitis C virus (HCV) infection. We evaluated the effect of SVR on the risk of HCC and estimated its incidence in post-SVR HCV patients from a large population-based Canadian cohort. METHODS The British Columbia Hepatitis Testers Cohort includes individuals tested for HCV between 1990-2013 linked with data on their medical visits, hospitalizations, cancers, prescription drugs and mortality. Patients receiving interferon-based HCV treatments were followed from the end of treatment to HCC diagnosis, death or December 31, 2012. We examined HCC risk among those who did and did not achieve SVR using multivariable proportional hazard models with the Fine and Gray modification for competing risks. RESULTS Of 8147 individuals who received HCV treatment and were eligible for analysis, 4663 (57%) achieved SVR and 3484 (43%) did not. Each group was followed for a median of 5.6years (range: 0.5-12.9) for an HCC incidence rate of 1.1/1000 person-years (PY) among the SVR and 7.2/1000 PY among the no SVR group. The HCC incidence rate was higher among those with cirrhosis (SVR: 6.4, no SVR: 21.0/1000 PY). In the multivariable model, SVR was associated with a lower HCC risk (subdistribution hazard ratio [SHR]=0.20, 95% CI: 0.13-0.3), while cirrhosis (SHR=2.61, 95% CI: 1.68-4.04), age ⩾50years, being male and genotype 3 infection were associated with a higher HCC risk. Among those who achieved SVR, cirrhosis, age ⩾50years and being male were associated with a higher HCC risk. CONCLUSION SVR after interferon-based treatment substantially reduces but does not eliminate HCC risk, which is markedly higher among those with cirrhosis and age ⩾50years at treatment initiation. Treatment of patients at an advanced fibrosis stage with new highly effective drugs will warrant continued surveillance for HCC post-SVR. LAY SUMMARY We assessed the effect of successful hepatitis C treatment with older interferon-based treatment on the occurrence of liver cancer (hepatocellular carcinoma) and found that successful treatment prevents liver cancer. However, more people with cirrhosis and older age continued to develop liver cancer after successful treatment. Thus, treatment with new drugs among those with cirrhosis will require continued monitoring for liver cancer.

HCV co-infection in HIV positive population in British Columbia, Canada

BackgroundAs HIV and hepatitis C (HCV) share some modes of transmission co-infection is not uncommon. This study used a population-based sample of HIV and HCV tested individuals to determine the prevalence of HIV/HCV co-infection, the sequence of virus diagnoses, and demographic and associated risk factors.MethodsPositive cases of HIV were linked to the combined laboratory database (of negative and positive HCV antibody results) and HCV reported cases in British Columbia (BC).ResultsOf 4,598 HIV cases with personal identifiers, 3,219 (70%) were linked to the combined HCV database, 1,700 (53%) of these were anti-HCV positive. HCV was diagnosed first in 52% of co-infected cases (median time to HIV identification 3 1/2 years). HIV and HCV was diagnosed within a two week window in 26% of cases. Among individuals who were diagnosed with HIV infection at baseline, subsequent diagnoses of HCV infection was independently associated with: i) intravenous drug use (IDU) in males and females, Hazard Ratio (HR) = 6.64 (95% CI: 4.86-9.07) and 9.76 (95% CI: 5.76-16.54) respectively; ii) reported Aboriginal ethnicity in females HR = 2.09 (95% CI: 1.34-3.27) and iii) males not identified as men-who-have-sex-with-men (MSM), HR = 2.99 (95% CI: 2.09-4.27).Identification of HCV first compared to HIV first was independently associated with IDU in males and females OR = 2.83 (95% CI: 1.84-4.37) and 2.25 (95% CI: 1.15-4.39) respectively, but not Aboriginal ethnicity or MSM. HIV was identified first in 22%, with median time to HCV identification of 15 months;ConclusionThe ability to link BC public health and laboratory HIV and HCV information provided a unique opportunity to explore demographic and risk factors associated with HIV/HCV co-infection. Over half of persons with HIV infection who were tested for HCV were anti-HCV positive; half of these had HCV diagnosed first with HIV identification a median 3.5 years later. This highlights the importance of public health follow-up and harm reduction measures for people identified with HCV to prevent subsequent HIV infection.

The Population Level Cascade of Care for Hepatitis C in British Columbia, Canada: The BC Hepatitis Testers Cohort (BC-HTC)

Background Population-level monitoring of hepatitis C virus (HCV) infected people across the cascade of care identifies gaps in access and engagement in care and treatment. We characterized a population-level cascade of care for HCV in British Columbia (BC), Canada and identified factors associated with leakage at each stage. Methods The BC Hepatitis Testers Cohort (BC-HTC) includes 1.5 million individuals tested for HCV, HIV, reported cases of hepatitis B, and active tuberculosis in BC from 1990 to 2013 linked to medical visits, hospitalizations, cancers, prescription drugs and mortality data. We defined six HCV cascade of care stages: 1) estimated population prevalence; 2) HCV diagnosed; 3) HCV RNA tested; 4) genotyped; 5) initiated treatment; and 6) achieved sustained virologic response (SVR). Results We estimated that 73,203 people were HCV antibody positive in BC in 2012 (undiagnosed: 18,301, 25%; diagnosed: 54,902, 75%). Of these, 56%(40,656) had HCV RNA testing; 34%(26,300) were genotyped; 12%( 8532 ) had received interferon-based therapy and 7%(5197) had SVR. Males, older birth cohorts, and HBV coinfected were less likely to undergo HCV RNA testing. Among those with chronic HCV infection, 32% had received liver-related care. Retention in liver care was more likely in those with HIV, cirrhosis, and drug/alcohol use and less likely in males and HBV coinfected. Conclusions Although there are gaps in HCV RNA testing and genotyping after HCV diagnosis, the major gap in the cascade of care was low treatment initiation. People with comorbidities progressed through the cascade of testing and care but few received treatment.

Assessment of HPV 16 and HPV 18 antibody responses by pseudovirus neutralization, Merck cLIA and Merck total IgG LIA immunoassays in a reduced dosage quadrivalent HPV vaccine trial

We assessed HPV 16 and 18 antibody responses of female subjects enrolled in a 2- vs. 3-dose quadrivalent HPV (Q-HPV) vaccine trial (ClinicalTrials.gov NCT00501137) using the Merck competitive Luminex (cLIA) and total IgG Luminex (TIgG) immunoassays, and a pseudovirus neutralizing antibody (PsV NAb) assay. Subjects were enrolled in one of three groups: (1) 9-13yr, 2 doses of Q-HPV at 0, 6 months (n=259); (2) 9-13yr, 3 doses at 0, 2, 6 months (n=260); and (3) 16-26yr, 3 doses at 0, 2, 6 months (n=305). Sera were collected from all subjects at baseline, months 7 and 24, and from half the subjects at months 18 and 36. High correlation was observed between all three assays. At month 36, HPV 16 antibodies remained detectable in all subjects by all assays, whereas 86.4%, 99.6% and 100% of subjects respectively were HPV 18 cLIA, TIgG and PsV NAb (partial neutralization endpoint) seropositive. The proportion seropositive for HPV 18 by cLIA at 36 months was not significantly different for 2-dose girls vs. 3-dose adults (85.9% vs. 79.4%; p=0.51), whereas the proportion for 3-dose girls was significantly higher than for 3-dose adults (95.3% vs. 79.4%; p<0.01). The HPV 18 seropositive proportions by the TIgG and PsV NAb (partial neutralization endpoint) assays were the same for all subjects. High baseline HPV 16 and HPV 18 seropositivity was observed for the TIgG assay and it is unclear if all the detected TIgG antibodies are type-specific and/or neutralizing. For the PsV NAb assay, 90% and partial neutralization geometric mean titres were consistently 2-8-fold higher than for 100% neutralization, which enabled detection of HPV 18 NAb in subjects who lost detectable cLIA antibodies over time. We conclude that the PsV NAb assay is more sensitive than the cLIA, and likely more specific than the TIgG assay.

Assessing Hepatitis C Burden and Treatment Effectiveness through the British Columbia Hepatitis Testers Cohort (BC-HTC): Design and Characteristics of Linked and Unlinked Participants

Background The British Columbia (BC) Hepatitis Testers Cohort (BC-HTC) was established to assess and monitor hepatitis C (HCV) epidemiology, cost of illness and treatment effectiveness in BC, Canada. In this paper, we describe the cohort construction, data linkage process, linkage yields, and comparison of the characteristics of linked and unlinked individuals. Methods The BC-HTC includes all individuals tested for HCV and/or HIV or reported as a case of HCV, hepatitis B (HBV), HIV or active tuberculosis (TB) in BC linked with the provincial health insurance client roster, medical visits, hospitalizations, drug prescriptions, the cancer registry and mortality data using unique personal health numbers. The cohort includes data since inception (1990/1992) of each database until 2012/2013 with plans for annual updates. We computed linkage rates by year and compared the characteristics of linked and unlinked individuals. Results Of 2,656,323 unique individuals available in the laboratory and surveillance data, 1,427,917(54%) were included in the final linked cohort, including about 1.15 million tested for HCV and about 1.02 million tested for HIV. The linkage rate was 86% for HCV tests, 89% for HCV cases, 95% for active TB cases, 48% for HIV tests and 36% for HIV cases. Linkage rates increased from 40% for HCV negatives and 70% for HCV positives in 1992 to ~90% after 2005. Linkage rates were lower for males, younger age at testing, and those with unknown residence location. Linkage rates for HCV testers co-infected with HIV, HBV or TB were very high (90–100%). Conclusion Linkage rates increased over time related to improvements in completeness of identifiers in laboratory, surveillance, and registry databases. Linkage rates were higher for HCV than HIV testers, those testing positive, older individuals, and females. Data from the cohort provide essential information to support the development of prevention, care and treatment initiatives for those infected with HCV.

Trends in mortality after diagnosis of hepatitis C virus infection: An international comparison and implications for monitoring the population impact of treatment

BACKGROUND & AIMS People living with hepatitis C virus (HCV) are at increased risk of all-cause and liver-related mortality, although successful treatment has been shown to reduce this risk. The aim of this study was to provide baseline data on trends in cause-specific mortality and to establish an international surveillance system for evaluating the population level impact of HCV treatments. METHODS Population level HCV diagnosis databases from Scotland (1997-2010), Australia (New South Wales [NSW]) (1997-2006), and Canada (British Columbia [BC]) (1997-2003) were linked to corresponding death registries using record linkage. For each region, age-adjusted cause-specific mortality rates were calculated, and trends in annual age-adjusted liver-related mortality were plotted. RESULTS Of 105,138 individuals diagnosed with HCV (21,810 in Scotland, 58,484 in NSW, and 24,844 in BC), there were 7275 deaths (2572 in Scotland, 2655 in NSW, and 2048 in BC). Liver-related deaths accounted for 26% of deaths in Scotland, 21% in NSW, and 22% in BC. Temporal trends in age-adjusted liver related mortality were stable in Scotland (males p=0.4; females p=0.2) and NSW (males p=0.9; females p=0.9), while there was an increase in BC (males p=0.002; females p=0.04). CONCLUSIONS The risk of liver-related mortality after a diagnosis of HCV has remained stable or increased over time across three regions with well-established diagnosis databases, highlighting that HCV treatment programmes to-date have had minimal impact on population level HCV-related liver disease. With more effective therapies on the horizon, and greater uptake of treatment anticipated, the potential of future therapeutic strategies to reduce HCV-related mortality is considerable.

Twin epidemics of new and prevalent hepatitis C infections in Canada: BC Hepatitis Testers Cohort

BackgroundWe characterized the twin epidemics of new and prevalent hepatitis C virus (HCV) infections in British Columbia, Canada to inform prevention, care and treatment programs.MethodsThe BC Hepatitis Testers Cohort (BC-HTC) includes individuals tested for HCV, HIV or reported as a case of HBV, HCV, HIV or active TB between 1990–2013 linked with data on their medical visits, hospitalizations, cancers, prescription drugs and mortality. Prevalent infection was defined as being anti-HCV positive at first test. Those with a negative test followed by a positive test were considered seroconverters or new infections.ResultsOf 1,132,855 individuals tested for HCV, 64,634 (5.8 %) were positive and an additional 3092 cases tested positive elsewhere for a total of 67,726. Of 55,781 HCV positive individuals alive at the end of 2013, 7064 were seroconverters while 48,717 had prevalent infection at diagnosis. The HCV positivity rate (11.2 %) was highest in birth cohort 1945–1964 which declined over time. New infections were more likely to be male, 15–34 years of age (born 1965-1984), HIV- or HBV-coinfected, socioeconomically disadvantaged, have problematic drug and alcohol use and a mental health illness. The profile was similar for individuals with prevalent infection, except for lower odds of HBV-coinfection, major mental health diagnoses and birth cohort >1975.ConclusionsThe HCV positivity rate is highest in birth cohort 1945–1964 which represents most prevalent infections. New infections occur in younger birth cohorts who are commonly coinfected with HIV and/or HBV, socioeconomically marginalized, and living with mental illness and addictions.