Hepatitis C virus reinfection after successful treatment with direct-acting antiviral therapy in a large population-based cohort.

BACKGROUND & AIMS: Direct-acting antiviral therapies (DAA) are an important tool for hepatitis C virus (HCV) elimination. However, reinfection among people who inject drugs (PWID) may hamper elimination targets. Therefore, we estimated HCV reinfection rates among DAA-treated individuals, including PWID. METHODS: We analyzed data from the British Columbia Hepatitis Testers Cohort which included ∼1.7 million individuals screened for HCV in British Columbia, Canada. We followed HCV-infected individuals treated with DAAs who achieved a sustained virologic response (SVR) and had ≥1 subsequent HCV RNA measurement to April 22nd, 2018. Reinfection was defined as a positive RNA measurement after SVR. PWID were identified using a validated algorithm and classified based on recent (<3 years) or former (≥3 years before SVR) use. Crude reinfection rates per 100 person-years (PYs) were calculated. Poisson regression was used to model adjusted incidence rate ratios (IRRs) and 95% CIs. RESULTS: Of 4,114 individuals who met the inclusion criteria, most were male (n = 2,692, 65%), born before 1965 (n = 3,411, 83%) and were either recent (n = 875, 21%) or former PWID (n = 1,793, 44%). Opioid-agonist therapy (OAT) was received by 19% of PWID. We identified 40 reinfections during 2,767 PYs. Reinfection rates were higher among recent (3.1/100 PYs; IRR 6.7; 95% CI 1.9-23.5) and former PWID (1.4/100 PYs; IRR 3.7; 95% CI 1.1-12.9) than non-PWID (0.3/100 PYs). Among recent PWID, reinfection rates were higher among individuals born after 1975 (10.2/100 PYs) and those co-infected with HIV (5.7/100 PYs). Only one PWID receiving daily OAT developed reinfection. CONCLUSIONS: Population-level reinfection rates remain elevated after DAA therapy among PWID because of ongoing exposure risk. Engagement of PWID in harm-reduction and support services is needed to prevent reinfections. LAY SUMMARY: Direct-acting antivirals are an effective tool for the treatment of hepatitis C virus, enabling the elimination of the virus. However, some patients who have been successfully treated with direct-acting antivirals are at risk of reinfection. Our findings showed that the risk of reinfection was highest among people with recent injection drug use. Among people who inject drugs, daily use of opioid-agonist therapy was associated with a lower risk of reinfection

Differential spatial distribution of hepatitis B virus by ethnicity in British Columbia, Canada: Expanded role of a large administrative cohort

Introduction Most chronic hepatitis B virus (HBV) infections in Canada are diagnosed among immigrants from endemic countries and lack traditional risk factors while most acute infections are usually diagnosed in Caucasian population with co-occurring risk factors. Thus, understanding geographical distribution of HBV infection by ethnicity could inform screening and care strategies. Objectives and Approach We identified geographic clusters of HBV infection in British Columbia by ethnicity during the years 1990-2015 using the BC Hepatitis Testers Cohort (BC-HTC). The BC-HTC includes ~1.7 million individuals tested for HCV or HIV at the BC Public Health Laboratory or reported as a case of HCV, HIV, or HBV linked to healthcare administrative databases. We plotted maps of HBV diagnoses (acute and chronic) rate at the Dissemination Area level between 1990-2015 stratified by ethnicity and compared this distribution with injection drug use (IDU) distribution in BC. Results The distribution of HBV varied considerably by ethnicity. From 1990 to 2015, a higher rate of HBV infection was found among East Asians and Caucasians followed by South Asians and other ethnicities. East Asians with highest rates were mainly concentrated in Vancouver city, Burnaby and Richmond (Metro Vancouver) while South Asians with highest rates were mostly concentrated in urban areas in Surrey and Abbotsford. Caucasians with higher rates were clustered in Downtown Eastside in Vancouver, Surrey and Abbotsford (Metro Vancouver) and urban areas in Greater Victoria (Vancouver Island), Prince George (Northern BC) and Kamloops (Interior BC). The distribution of IDU closely followed the distribution of HBV among Caucasians but did not align with other ethnic groups. Conclusion/Implications Results highlight distinct areas of HBV infection clustering by ethnicity, which differ from areas with high IDU distribution except in Caucasians. Findings support ethnicity-based HBV screening/prevention and care services to areas with immigrants from HBV-endemic countries and integrated HBV and harm reduction services for early diagnosis and treatment in Caucasians

Mortality rates among patients successfully treated for hepatitis C in the era of interferon-free antivirals: population based cohort study

Objectives To quantify mortality rates for patients successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals and compare these rates with those of the general population.Design Population based cohort study.Setting British Columbia, Scotland, and England (England cohort consists of patients with cirrhosis only).Participants 21 790 people who were successfully treated for hepatitis C in the era of interferon-free antivirals (2014-19). Participants were divided into three liver disease severity groups: people without cirrhosis (pre-cirrhosis), those with compensated cirrhosis, and those with end stage liver disease. Follow-up started 12 weeks after antiviral treatment completion and ended on date of death or 31 December 2019.Main outcome measures Crude and age-sex standardised mortality rates, and standardised mortality ratio comparing the number of deaths with that of the general population, adjusting for age, sex, and year. Poisson regression was used to identify factors associated with all cause mortality rates.Results 1572 (7%) participants died during follow-up. The leading causes of death were drug related mortality (n=383, 24%), liver failure (n=286, 18%), and liver cancer (n=250, 16%). Crude all cause mortality rates (deaths per 1000 person years) were 31.4 (95% confidence interval 29.3 to 33.7), 22.7 (20.7 to 25.0), and 39.6 (35.4 to 44.3) for cohorts from British Columbia, Scotland, and England, respectively. All cause mortality was considerably higher than the rate for the general population across all disease severity groups and settings; for example, all cause mortality was three times higher among people without cirrhosis in British Columbia (standardised mortality ratio 2.96, 95% confidence interval 2.71 to 3.23; P<0.001) and more than 10 times higher for patients with end stage liver disease in British Columbia (13.61, 11.94 to 15.49; P<0.001). In regression analyses, older age, recent substance misuse, alcohol misuse, and comorbidities were associated with higher mortality rates.Conclusion Mortality rates among people successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals are high compared with the general population. Drug and liver related causes of death were the main drivers of excess mortality. These findings highlight the need for continued support and follow-up after successful treatment for hepatitis C to maximise the impact of direct acting antivirals

Cohort profile: the British Columbia COVID-19 Cohort (BCC19C)—a dynamic, linked population-based cohort

PurposeThe British Columbia COVID-19 Cohort (BCC19C) was developed from an innovative, dynamic surveillance platform and is accessed/analyzed through a cloud-based environment. The platform integrates recently developed provincial COVID-19 datasets (refreshed daily) with existing administrative holdings and provincial registries (refreshed weekly/monthly). The platform/cohort were established to inform the COVID-19 response in near “real-time” and to answer more in-depth epidemiologic questions.ParticipantsThe surveillance platform facilitates the creation of large, up-to-date analytic cohorts of people accessing COVID-19 related services and their linked medical histories. The program of work focused on creating/analyzing these cohorts is referred to as the BCC19C. The administrative/registry datasets integrated within the platform are not specific to COVID-19 and allow for selection of “control” individuals who have not accessed COVID-19 services.Findings to dateThe platform has vastly broadened the range of COVID-19 analyses possible, and outputs from BCC19C analyses have been used to create dashboards, support routine reporting and contribute to the peer-reviewed literature. Published manuscripts (total of 15 as of July, 2023) have appeared in high-profile publications, generated significant media attention and informed policy and programming. In this paper, we conducted an analysis to identify sociodemographic and health characteristics associated with receiving SARS-CoV-2 laboratory testing, testing positive, and being fully vaccinated. Other published analyses have compared the relative clinical severity of different variants of concern; quantified the high “real-world” effectiveness of vaccines in addition to the higher risk of myocarditis among younger males following a 2nd dose of an mRNA vaccine; developed and validated an algorithm for identifying long-COVID patients in administrative data; identified a higher rate of diabetes and healthcare utilization among people with long-COVID; and measured the impact of the pandemic on mental health, among other analyses.Future plansWhile the global COVID-19 health emergency has ended, our program of work remains robust. We plan to integrate additional datasets into the surveillance platform to further improve and expand covariate measurement and scope of analyses. Our analyses continue to focus on retrospective studies of various aspects of the COVID-19 pandemic, as well as prospective assessment of post-acute COVID-19 conditions and other impacts of the pandemic

The resistance of human APOBEC3H to HIV-1 NL4-3 molecular clone is determined by a single amino acid in Vif.

Some human APOBEC3 cytidine deaminases have antiviral activity against HIV-1 and other retroviruses. The single deaminase domain APOBEC3H (A3H) enzyme is highly polymorphic and multiple A3H haplotypes have been identified. A3H haplotype II (A3H-hapII) possesses the strongest activity against HIV-1. There remains, however, uncertainty regarding the extent to which A3H-hapII is sensitive to HIV-1 Vif mediated degradation. We tested, therefore, the two different reference Vif proteins widely used in previous studies. We show that A3H-hapII is resistant to NL4-3 Vif while it is efficiently degraded by LAI Vif. Co-immunoprecipitation assays demonstrate that LAI Vif, but not NL4-3 Vif associates with A3H-hapII. Chimeras between NL4-3 and LAI Vif identify the amino acid responsible for the differential degradation activity: A histidine at position 48 in Vif confers activity against A3H-hapII, while an asparagine abolishes its anti-A3H activity. Furthermore, the amino acid identity at position 48 only affects the degradation of A3H-hapII, whereas recognition of and activity against human A3D, A3F and A3G are only minimally affected. NL4-3 encoding 48H replicates better than NL4-3 WT (48N) in T cell-lines stably expressing A3H hapII, whereas there is no fitness difference in the absence of APOBEC3. These studies provide an explanation for the conflicting reports regarding A3H resistance to Vif mediated degradation

NL4-3 Vif 48H replicates more efficiently on SupT1 cells expressing A3H-hapII.

<p>NL4-3 WT (closed circles) and NL4-3 Vif N48H (open circles) were used to infect SupT1 T-cell lines expressing untagged APOBEC3H hapII (A3H hapII, <b>A</b>), HA-tagged APOBEC3G (A3G, <b>B</b>), and the empty vector (<b>C</b>). Clarified supernatants were harvested each day and infectivity was determined on TZM-bl reporter cells. Representative infections of each cell lines are shown. Error bars represent standard deviations of triplicate TZM-bl infections.</p

APOBEC3H sensitivity to NL4-3 and LAI Vif.

<p>(<b>A</b>) Increasing amounts of NL4-3 or LAI Vif expression plasmids (0, 2.5, 5, 10, 25 and 50 ng) were cotransfected with 100 ng of FLAG-tagged A3H-hapII or A3G in 293T cells. Two days post transfection cells were lysed and analyzed by western blot. (<b>B</b>) A3H-hapII and A3G expression from (A) were quantified by measuring non-saturated signals using the Fujifilm Intelligent Lightbox LAS-3000 instrument and Image Reader LAS-3000 software. Signals were normalized by setting both A3H-hapII and A3G expression levels without Vif at 100%. Error bars represent standard deviation from three independent experiments.</p

A3H-hapII and A3G restriction of Vif proficient and Vif deficient HIV-1 NL4-3 and LAI molecular clones.

<p>Increasing amounts of A3H-hapII or A3G (0, 25, 50 and 100 ng) were cotransfected with the different HIV molecular clones (500 ng) in 293T cells. Two days post transfection cleared supernatants were used to infect TZM-bl reporter cells and β-Galactosidase was measured two days later. One representative experiment of three consisting of triplicate transfections is shown. Error bars represent standard deviations from triplicate transfections.</p