Dataset Information

Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus.

ABSTRACT: Cell-free virus is a well-recognized and efficient mechanism for the spread of hepatitis B virus (HBV) infection in the liver. Cell-to-cell transmission (CCT) can be a more efficient means of virus propagation. Despite experimental evidence implying CCT occurs in HBV, its relative impact is uncertain. We develop a 3-D agent-based model where each hepatocyte changes its viral state according to a dynamical process driven by cell-free virus infection, CCT and intracellular replication. We determine the relative importance of CCT in the development and resolution of acute HBV infection in the presence of cytolytic (CTL) and non-CTL mechanisms. T cell clearance number is defined as the minimum number of infected cells needed to be killed by each T cell at peak infection that results in infection clearance within 12 weeks with hepatocyte turnover (HT, number of equivalent livers) ?3. We find that CCT has very little impact on the establishment of infection as the mean cccDNA copies/cell remains between 15 to 20 at the peak of the infection regardless of CCT strength. In contrast, CCT inhibit immune-mediated clearance of acute HBV infection as higher CCT strength requires higher T cell clearance number and increases the probability of T cell exhaustion. An effective non-CTL inhibition can counter these negative effects of higher strengths of CCT by supporting rapid, efficient viral clearance and with little liver destruction. This is evident as the T cell clearance number drops by approximately 50% when non-CTL inhibition is increased from 10% to 80%. Higher CCT strength also increases the probability of the incidence of fulminant hepatitis with this phenomenon being unlikely to arise for no CCT. In conclusion, we report the possibility of CCT impacting HBV clearance and its contribution to fulminant hepatitis.

SUBMITTER: Goyal A

PROVIDER: S-EPMC4999077 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus.

Goyal Ashish A Murray John M JM

PloS one 20160825 8

Cell-free virus is a well-recognized and efficient mechanism for the spread of hepatitis B virus (HBV) infection in the liver. Cell-to-cell transmission (CCT) can be a more efficient means of virus propagation. Despite experimental evidence implying CCT occurs in HBV, its relative impact is uncertain. We develop a 3-D agent-based model where each hepatocyte changes its viral state according to a dynamical process driven by cell-free virus infection, CCT and intracellular replication. We determin ...[more]

PMID: 27560827

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Project description:Background and aimsTo reduce hepatitis C virus (HCV) transmission among people who inject drugs (PWID), Scottish Government-funded national strategies, launched in 2008, promoted scaling-up opioid substitution therapy (OST) and needle and syringe provision (NSP), with some increases in HCV treatment. We test whether observed decreases in HCV incidence post-2008 can be attributed to this intervention scale-up.DesignA dynamic HCV transmission model among PWID incorporating intervention scale-up and observed decreases in behavioural risk, calibrated to Scottish HCV prevalence and incidence data for 2008/09.SettingScotland, UK.ParticipantsPWID.MeasurementsModel projections from 2008 to 2015 were compared with data to test whether they were consistent with observed decreases in HCV incidence among PWID while incorporating the observed intervention scale-up, and to determine the impact of scaling-up interventions on incidence.FindingsWithout fitting to epidemiological data post-2008/09, the model incorporating observed intervention scale-up agreed with observed decreases in HCV incidence among PWID between 2008 and 2015, suggesting that HCV incidence decreased by 61.3% [95% credibility interval (CrI) = 45.1-75.3%] from 14.2/100 person-years (py) (9.0-20.7) to 5.5/100 py (2.9-9.2). On average, each model fit lay within 84% (10.1/12) of the confidence bounds for the 12 incidence data points against which the model was compared. We estimate that scale-up of interventions (OST + NSP + HCV treatment) and decreases in high-risk behaviour from 2008 to 2015 resulted in a 33.9% (23.8-44.6%) decrease in incidence, with the remainder [27.4% (17.6-37.0%)] explained by historical changes in OST + NSP coverage and risk pre-2008. Projections suggest that scaling-up of all interventions post-2008 averted 1492 (657-2646) infections over 7 years, with 1016 (308-1996), 404 (150-836) and 72 (27-137) due to scale-up of OST + NSP, decreases in high-risk behaviour and HCV treatment, respectively.ConclusionsMost of the decline in hepatitis C virus (HCV) incidence in Scotland between 2008 and 2015 appears to be attributable to intervention scale-up (opioid substitution therapy and needle and syringe provision) due to government strategies on HCV and drugs.

Project description:Background and aimsPeople who inject drugs (PWID) experience high incarceration rates, and previous incarceration is associated with elevated hepatitis C virus (HCV) transmission risk. In Scotland, national survey data indicate lower HCV incidence in prison than the community (4.3 versus 7.3 per 100 person-years), but a 2.3-fold elevated transmission risk among recently released (< 6 months) PWID. We evaluated the contribution of incarceration to HCV transmission among PWID and the impact of prison-related prevention interventions, including scaling-up direct-acting antivirals (DAAs) in prison.DesignDynamic mathematical modelling of incarceration and HCV transmission, using approximate Bayesian computation for model calibration.SettingScotland, UK.ParticipantsA simulated population of PWID.MeasurementsPopulation-attributable fraction (PAF) of incarceration to HCV transmission among PWID. Decrease in HCV incidence and chronic prevalence due to current levels of prison opiate substitution therapy (OST; 57% coverage) and HCV treatment, as well as scaling-up DAAs in prison and/or preventing the elevated risk associated with prison release.FindingsIncarceration contributes 27.7% [PAF; 95% credible interval (CrI) -3.1 to 51.1%] of HCV transmission among PWID in Scotland. During the next 15 years, current HCV treatment rates (10.4/6.8 per 1000 incarcerated/community PWID annually), with existing prison OST, could reduce incidence and chronic prevalence among all PWID by a relative 10.7% (95% CrI = 8.4-13.3%) and 9.7% (95% CrI = 7.7-12.1%), respectively. Conversely, without prison OST, HCV incidence and chronic prevalence would decrease by 3.1% (95% CrI = -28.5 to 18.0%) and 4.7% (95% CrI = -11.3 to 14.5%). Additionally, preventing the heightened risk among recently released PWID could reduce incidence and chronic prevalence by 45.0% (95% CrI = 19.7-57.5%) and 33.3% (95% CrI = 15.6-43.6%) or scaling-up prison HCV treatments to 80% of chronic PWID prison entrants with sufficient sentences (>16 weeks) could reduce incidence and prevalence by 45.6% (95% CrI = 38.0-51.3%) and 45.5% (95% CrI = 39.3-51.0%), respectively.ConclusionsIncarceration and the elevated transmission risk following prison release can contribute significantly to hepatitis C virus transmission among people who inject drugs. Scaling-up hepatitis C virus treatment in prison can provide important prevention benefits.

Project description:BACKGROUND:The WHO elimination strategy for hepatitis C virus advocates scaling up screening and treatment to reduce global hepatitis C incidence by 80% by 2030, but little is known about how this reduction could be achieved and the costs of doing so. We aimed to evaluate the effects and cost of different strategies to scale up screening and treatment of hepatitis C in Pakistan and determine what is required to meet WHO elimination targets for incidence. METHODS:We adapted a previous model of hepatitis C virus transmission, treatment, and disease progression for Pakistan, calibrating using available data to incorporate a detailed cascade of care for hepatitis C with cost data on diagnostics and hepatitis C treatment. We modelled the effect on various outcomes and costs of alternative scenarios for scaling up screening and hepatitis C treatment in 2018-30. We calibrated the model to country-level demographic data for 1960-2015 (including population growth) and to hepatitis C seroprevalence data from a national survey in 2007-08, surveys among people who inject drugs (PWID), and hepatitis C seroprevalence trends among blood donors. The cascade of care in our model begins with diagnosis of hepatitis C infection through antibody screening and RNA confirmation. Diagnosed individuals are then referred to care and started on treatment, which can result in a sustained virological response (effective cure). We report the median and 95% uncertainty interval (UI) from 1151 modelled runs. FINDINGS:One-time screening of 90% of the 2018 population by 2030, with 80% referral to treatment, was projected to lead to 13·8 million (95% UI 13·4-14·1) individuals being screened and 350?000 (315?000-385?000) treatments started annually, decreasing hepatitis C incidence by 26·5% (22·5-30·7) over 2018-30. Prioritised screening of high prevalence groups (PWID and adults aged ?30 years) and rescreening (annually for PWID, otherwise every 10 years) are likely to increase the number screened and treated by 46·8% and decrease incidence by 50·8% (95% UI 46·1-55·0). Decreasing hepatitis C incidence by 80% is estimated to require a doubling of the primary screening rate, increasing referral to 90%, rescreening the general population every 5 years, and re-engaging those lost to follow-up every 5 years. This approach could cost US$8·1 billion, reducing to $3·9 billion with lowest costs for diagnostic tests and drugs, including health-care savings, and implementing a simplified treatment algorithm. INTERPRETATION:Pakistan will need to invest about 9·0% of its yearly health expenditure to enable sufficient scale up in screening and treatment to achieve the WHO hepatitis C elimination target of an 80% reduction in incidence by 2030. FUNDING:UNITAID.

Dataset Information

Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus.

Publications

Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus.

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