Treatment as prevention for hepatitis C virus in Pakistan: mathematical modelling projections.
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ABSTRACT: Objective
Direct-acting antivirals have opened an opportunity for controlling hepatitis C virus (HCV) infection in Pakistan, where 10% of the global infection burden is found. We aimed to evaluate the implications of five treatment programme scenarios for HCV treatment as prevention (HCV-TasP) in Pakistan.Design
An age-structured mathematical model was used to evaluate programme impact using epidemiological and programme indicators.Setting
Total Pakistan population.Participants
Total Pakistan HCV-infected population.Interventions
HCV treatment programme scenarios from 2018 up to 2030.Results
By 2030 across the five HCV-TasP scenarios, 0.6-7.3 million treatments were administered, treatment coverage reached between 3.7% and 98.7%, prevalence of chronic infection reached 2.4%-0.03%, incidence reduction ranged between 41% and 99%, program-attributed reduction in incidence rate ranged between 7.2% and 98.5% and number of averted infections ranged between 126 221 and 750 547. Annual incidence rate reduction in the first decade of the programme was around 6%-18%. Number of treatments needed to prevent one new infection ranged between 4.7-9.8, at a drug cost of about US$900. Cost of the programme by 2030, in the most ambitious elimination scenario, reached US$708 million. Stipulated WHO target for 2030 cannot be accomplished without scaling up treatment to 490 000 per year, and maintaining it for a decade.Conclusion
HCV-TasP is a highly impactful and potent approach to control Pakistan's HCV epidemic and achieve elimination by 2030.
SUBMITTER: Ayoub HH
PROVIDER: S-EPMC6537971 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:The World Health Organization (WHO) has developed a global health strategy to eliminate viral hepatitis. We project the treatment and prevention requirements to achieve the WHO HCV elimination target of reducing HCV incidence by 80% and HCV-related mortality by 65% by 2030 in Pakistan, which has the second largest HCV burden worldwide. Methods:We developed an HCV transmission model for Pakistan, and calibrated it to epidemiological data from a national survey (2007), surveys among people who inject drugs (PWID), and blood donor data. Current treatment coverage data came from expert opinion and published reports. The model projected the HCV burden, including incidence, prevalence and deaths through 2030, and estimated the impact of varying prevention and direct-acting antiviral (DAA) treatment interventions necessary for achieving the WHO HCV elimination targets. Results:With no further treatment (currently ?150 000 treated annually) during 2016-30, chronic HCV prevalence will increase from 3.9% to 5.1%, estimated annual incident infections will increase from 700 000 to 1 100 000, and 1 400 000 HCV-associated deaths will occur. To reach the WHO HCV elimination targets by 2030, 880 000 annual DAA treatments are required if prevention is not scaled up and no treatment prioritization occurs. By targeting treatment toward persons with cirrhosis (80% treated annually) and PWIDs (double the treatment rate of non-PWIDs), the required annual treatment number decreases to 750 000. If prevention activities also halve transmission risk, this treatment number reduces to 525 000 annually. Conclusions:Substantial HCV prevention and treatment interventions are required to reach the WHO HCV elimination targets in Pakistan, without which Pakistan's HCV burden will increase markedly.
| S-EPMC5913612 | biostudies-literature
Project description:The standard of care for HCV genotype 1 is a protease inhibitor (telaprevir or boceprevir) combined with pegylated interferon (PEG-IFN) and ribavirin (RBV). A lead-in phase of PEG-IFN/RBV therapy before addition of the protease inhibitor has been used, with the aim of improving response rates by reducing the development of protease inhibitor resistance. However, whether such a strategy can bring benefit to patients is unclear.A viral dynamic model was used to compare in silico HCV dynamics in patients treated with a period of PEG-IFN/RBV lead-in therapy followed by the addition of a protease inhibitor versus immediate triple therapy without lead-in.The model predicts that both regimens result in a similar end-of-treatment viral load change (viral decline or breakthrough). Thus, the current lead-in strategy may not decrease the rate of viral breakthrough/relapse or increase the rate of sustained virological response. This agrees with available data from clinical trials of several HCV protease inhibitors, such as telaprevir, boceprevir and faldaprevir.These results suggest that current PEG-IFN/RBV lead-in strategies may not improve treatment outcomes. However, viral kinetics during a period of PEG-IFN/RBV therapy, combined with other factors, such as the IL28B polymorphism and baseline viral load, can identify IFN-sensitive patients and help develop response-guided therapies.
| S-EPMC4101064 | biostudies-literature
Project description:BackgroundThe revolution in hepatitis C virus (HCV) treatment through the development of direct-acting antivirals (DAAs) has generated international interest in the global elimination of the disease as a public health threat. In 2017, this led WHO to establish elimination targets for 2030. We evaluated the impact of public health interventions on the global HCV epidemic and investigated whether WHO's elimination targets could be met.MethodsWe developed a dynamic transmission model of the global HCV epidemic, calibrated to 190 countries, which incorporates data on demography, people who inject drugs (PWID), current coverage of treatment and prevention programmes, natural history of the disease, HCV prevalence, and HCV-attributable mortality. We estimated the worldwide impact of scaling up interventions that reduce risk of transmission, improve access to treatment, and increase screening for HCV infection by considering six scenarios: no change made to existing levels of diagnosis or treatment; sequentially adding the following interventions: blood safety and infection control, PWID harm reduction, offering of DAAs at diagnosis, and outreach screening to increase the number diagnosed; and a scenario in which DAAs are not introduced (ie, treatment is only with pegylated interferon and oral ribavirin) to investigate the effect of DAA use. We explored the effect of varying the coverage or impact of these interventions in sensitivity analyses and also assessed the impact on the global epidemic of removing certain key countries from the package of interventions.FindingsBy 2030, interventions that reduce risk of transmission in the non-PWID population by 80% and increase coverage of harm reduction services to 40% of PWID could avert 14·1 million (95% credible interval 13·0-15·2) new infections. Offering DAAs at time of diagnosis in all countries could prevent 640 000 deaths (620 000-670 000) from cirrhosis and liver cancer. A comprehensive package of prevention, screening, and treatment interventions could avert 15·1 million (13·8-16·1) new infections and 1·5 million (1·4-1·6) cirrhosis and liver cancer deaths, corresponding to an 81% (78-82) reduction in incidence and a 61% (60-62) reduction in mortality compared with 2015 baseline. This reaches the WHO HCV incidence reduction target of 80% but is just short of the mortality reduction target of 65%, which could be reached by 2032. Reducing global burden depends upon success of prevention interventions, implemention of outreach screening, and progress made in key high-burden countries including China, India, and Pakistan.InterpretationFurther improvements in blood safety and infection control, expansion or creation of PWID harm reduction services, and extensive screening for HCV with concomitant treatment for all are necessary to reduce the burden of HCV. These findings should inform the ongoing global action to eliminate the HCV epidemic.FundingWellcome Trust.
| S-EPMC6484702 | biostudies-literature
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.
| S-EPMC7295205 | biostudies-literature
Project description:BACKGROUND:Chronic infections with hepatitis C virus (HCV) and HIV are highly prevalent in the USA and concentrated in people who inject drugs. Treatment as prevention with highly effective new direct-acting antivirals is a prospective HCV elimination strategy. We used network-based modelling to analyse the effect of this strategy in HCV-infected people who inject drugs in a US city. METHODS:Five graph models were fit using data from 1574 people who inject drugs in Hartford, CT, USA. We used a degree-corrected stochastic block model, based on goodness-of-fit, to model networks of injection drug users. We simulated transmission of HCV and HIV through this network with varying levels of HCV treatment coverage (0%, 3%, 6%, 12%, or 24%) and varying baseline HCV prevalence in people who inject drugs (30%, 60%, 75%, or 85%). We compared the effectiveness of seven treatment-as-prevention strategies on reducing HCV prevalence over 10 years and 20 years versus no treatment. The strategies consisted of treatment assigned to either a randomly chosen individual who injects drugs or to an individual with the highest number of injection partners. Additional strategies explored the effects of treating either none, half, or all of the injection partners of the selected individual, as well as a strategy based on respondent-driven recruitment into treatment. FINDINGS:Our model estimates show that at the highest baseline HCV prevalence in people who inject drugs (85%), expansion of treatment coverage does not substantially reduce HCV prevalence for any treatment-as-prevention strategy. However, when baseline HCV prevalence is 60% or lower, treating more than 120 (12%) individuals per 1000 people who inject drugs per year would probably eliminate HCV within 10 years. On average, assigning treatment randomly to individuals who inject drugs is better than targeting individuals with the most injection partners. Treatment-as-prevention strategies that treat additional network members are among the best performing strategies and can enhance less effective strategies that target the degree (ie, the highest number of injection partners) within the network. INTERPRETATION:Successful HCV treatment as prevention should incorporate the baseline HCV prevalence and will achieve the greatest benefit when coverage is sufficiently expanded. FUNDING:National Institute on Drug Abuse.
| S-EPMC5860640 | biostudies-literature
Project description:BACKGROUND:The introduction of oral direct-acting antivirals (DAAs) has dramatically changed the landscape of HCV treatment. However, a small percentage of patients fail to achieve sustained virologic response (SVR). Understanding the number of people who fail on DAAs and require re-treatment is important for budget impact and disease burden projections. AIM:To quantify the number of HCV patients who fail to achieve SVR on oral DAAs (NS5A vs. non-NS5A) and require re-treatment. METHODS:We used a mathematical model to simulate clinical management of HCV in the USA, which included the implementation of HCV screening, treatment, and disease progression. We simulated different waves of DAA treatment and used real-world data to extract SVR rates and market shares of available therapies. RESULTS:Our model projected that the number of people living without viraemia (i.e. cured) would increase from 0.70 million in 2014 to 1.78 million by 2020. Between 2014 and 2020, 1.50 million people would receive treatment with DAAs, of whom 124 000 (8.3%) are projected to fail to achieve SVR. Among those treatment failures, 66 600 (53.7%) patients would fail treatment with NS5A inhibitors and 69 600 (56.1%) would have cirrhosis. During the same period, 34 200 people would progress to decompensated cirrhosis and 27 300 would develop hepatocellular carcinoma after failing to achieve SVR. CONCLUSIONS:Even in the era of highly effective DAAs, a significant number of patients will fail to achieve SVR and will require re-treatment options. Timely and effective re-treatment is essential to prevent the long-term sequelae of HCV.
| S-EPMC5842132 | biostudies-literature
Project description:BackgroundWith one in every 20 Pakistanis already infected, Pakistan has the second largest number of hepatitis C virus (HCV) infections globally. The aim of this study was to present a quantitative and analytical characterization of the HCV epidemic in Pakistan.MethodsA standardized database of HCV antibody incidence and prevalence and HCV genotypes in all subpopulations was systematically assembled. Random-effects meta-analyses and random-effects meta-regressions were performed. Shannon Diversity Index was calculated to determine genotype diversity.ResultsThe database included two incidence, 309 prevalence, and 48 genotype measures. Pooled mean HCV prevalence ranged between 7.0% (95% confidence interval (CI): 5.8-8.3%) in Sindh and 0.9% (95% CI: 0.1-2.4%) in Federally Administered Tribal Areas (F.A.T.A). Estimated number of chronically-infected persons ranged between 4.2 million in Punjab and 0.03 million in F.A.T.A. HCV prevalence was stable over time [adjusted odds ratio (AOR) of 1.0 (95% CI: 1.0-1.0)]. Population classification was the strongest predictor of HCV prevalence, explaining 51.8% of prevalence variation. Relative to the general population, HCV prevalence was higher in people who inject drugs [AOR of 23.8 (95% CI: 13.0-43.6)], populations with liver-related conditions [AOR of 22.3 (95% CI: 15.7-31.6)], and high-risk clinical populations [AOR of 7.8 (95% CI: 4.8-12.7)]. Low genotype diversity was observed (Shannon diversity index of 0.67 out of 1.95; 34.5%). There were only minor differences in genotype diversity by province, with genotype 3 being most common in all provinces.ConclusionPakistan's HCV epidemic shows homogeneity across the provinces, and over time. HCV prevalence is strikingly persistent at high level, with no evidence for a decline over the last three decades. Scale up of HCV treatment and prevention is urgently needed.
| S-EPMC6744714 | biostudies-literature
Project description:Direct-acting antiviral agents (DAAs) for hepatitis C treatment tend to fare better in individuals who are also likely to respond well to interferon-alpha (IFN), a surprising correlation given that DAAs target specific viral proteins whereas IFN triggers a generic antiviral immune response. Here, we posit a causal relationship between IFN-responsiveness and DAA treatment outcome. IFN-responsiveness restricts viral replication, which would prevent the growth of viral variants resistant to DAAs and improve treatment outcome. To test this hypothesis, we developed a multiscale mathematical model integrating IFN-responsiveness at the cellular level, viral kinetics and evolution leading to drug resistance at the individual level, and treatment outcome at the population level. Model predictions quantitatively captured data from over 50 clinical trials demonstrating poorer response to DAAs in previous non-responders to IFN than treatment-naïve individuals, presenting strong evidence supporting the hypothesis. Model predictions additionally described several unexplained clinical observations, viz., the percentages of infected individuals who 1) spontaneously clear HCV, 2) get chronically infected but respond to IFN-based therapy, and 3) fail IFN-based therapy but respond to DAA-based therapy, resulting in a comprehensive understanding of HCV infection and treatment. An implication of the causal relationship is that failure of DAA-based treatments may be averted by adding IFN, a strategy of potential use in settings with limited access to DAAs. A second, wider implication is that individuals with greater IFN-responsiveness would require shorter DAA-based treatment durations, presenting a basis and a promising population for response-guided therapy.
| S-EPMC6057683 | biostudies-literature
Project description:BACKGROUND:Avian hepatitis E virus (aHEV) has been associated with hepatitis-splenomegaly syndrome (HSS) in chickens along with asymptomatic subclinical infection in many cases. So far, four genotypes have been described, which cause infection in chickens, specifically in broiler breeders and layer chickens. In the present study, we isolated and identified two novel aHEV strains from the bile of layer chickens in Pakistan evincing clinical symptoms related to HSS. METHODOLOGY:Histology of liver and spleen tissues was carried out to observe histopathological changes in these tissues. Bile fluid and fecal suspensions were used for viral RNA isolation through MegNA pure and Trizol method which was further used for viral genome detection and characterization by cDNA synthesis and amplification of partial open reading frame (ORF) 1, ORF2 and complete ORF3. The bioinformatics tools; Molecular Evolutionary Genetics Analysis version 6.0 (MEGA 6), Mfold and ProtScale were used for phylogenic analysis, RNA secondary structure prediction and protein hydropathy analysis, respectively. RESULTS:Sequencing and phylogenetic analysis on the basis of partial methyltranferase (MeT), helicase (Hel) domain, ORF2 and complete ORF3 sequence suggests these Pakistani aHEV (Pak aHEV) isolates may belong to a Pakistani specific clade. The overall sequence similarity between the Pak aHEV sequences was 98-100%. The ORF1/ORF3 intergenic region contains a conserved cis-reactive element (CRE) and stem-loop structure (SLS). Analysis of the amino acid sequence of ORF3 indicated two hydrophobic domains (HD) and single conserved proline-rich domain (PRD) PREPSAPP (PXXPXXPP) with a single PSAP motif found in C-terminal. Amino acid changes S15 T, A31T, Q35H and G46D unique to the Pak aHEV sequences were found in the N-terminal region of ORF3. CONCLUSIONS:Our data suggests that Pak aHEV isolates may represent a novel Pakistani clade and high sequence homology to each other support the supposition they may belong to a monophyletic clade circulating in the region around Pakistan. The data presented in this study provide further information for aHEV genetic diversity, genotype mapping, global distribution and epidemiology.
| S-EPMC6868781 | biostudies-literature
Project description:We utilized a disease progression model to predict the number of viraemic infections, cirrhotic cases, and liver-related deaths in the state of Rhode Island (RI) under four treatment scenarios: (1) current HCV treatment paradigm (about 215 patients treated annually, Medicaid reimbursement criteria fibrosis stage ?F3); (2) immediate scale-up of treatment (to 430 annually) and less restrictive Medicaid reimbursement criteria (fibrosis stage ?F2); (3) immediate treatment scale-up and no fibrosis stage-specific Medicaid reimbursement criteria (?F0); (4) an 'elimination' scenario (i.e. a continued treatment scale-up needed to achieve >90% reduction in viraemic cases by 2030). Under current treatment models, the number of cirrhotic cases and liver-related deaths will plateau and peak by 2030, respectively. Treatment scale-up with ?F2 and ?F0 fibrosis stage treatment criteria could reduce the number of cirrhotic cases by 21·7% and 10·0%, and the number of liver-related deaths by 19·3% and 7·4%, respectively by 2030. To achieve a >90% reduction in viraemic cases by 2030, over 2000 persons will need to be treated annually by 2020. This strategy could reduce cirrhosis cases and liver-related deaths by 78·9% and 72·4%, respectively by 2030. Increased HCV treatment uptake is needed to substantially reduce the burden of HCV by 2030 in Rhode Island.
| S-EPMC5562531 | biostudies-literature