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Modeling of randomized hepatitis C vaccine trials: Bridging the gap between controlled human infection models and real-word testing
Abstract
Global elimination of chronic hepatitis C (CHC) remains difficult without an effective vaccine. Since injection drug use is the leading cause of hepatitis C virus (HCV) transmission in Western Europe and North America, people who inject drugs (PWID) are an important population for testing HCV vaccine effectiveness in randomized-clinical trials (RCTs). However, RCTs in PWID are inherently challenging. To accelerate vaccine development, controlled human infection (CHI) models have been suggested as a means to identify effective vaccines. To bridge the gap between CHI models and real-world testing, we developed an agent-based model simulating a two-dose vaccine to prevent CHC in PWID, representing 32,000 PWID in metropolitan Chicago and accounting for networks and HCV infections. We ran 500 trial simulations under 50% and 75% assumed-vaccine efficacy (aVE) and sampled HCV infection status of recruited in silico PWID. The mean estimated vaccine efficacy (eVE) for 50% and 75% aVE was 48% (standard deviation (SD ±12) and 72% (SD±11), respectively. For both conditions, the majority of trials (∼71%) resulted in eVEs within 1SD of the mean, demonstrating a robust trial design. Trials that resulted in eVEs >1SD from the mean (lowest eVEs of 3% and 35% for 50% and 75% aVE, respectively), were more likely to have imbalances in acute infection rates across trial arms. Modeling indicates robust trial design and high success rates of finding vaccines to be effective in real-life trials in PWID. However, with less effective vaccines (aVEs∼50%) there remains a higher risk of concluding poor vaccine efficacy due to post-randomization imbalances.
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Elimination of hepatitis C virus (HCV) without the need for medical intervention, known as spontaneous clearance (SC), occurs at a significantly lower rate than in the case of hepatitis B virus infection and only in selected individuals, such as reportedly in Keith Richards, a guitarist of The Rolling Stones. The present paper provides an updated narrative review of the research devoted to the phenomenon in order to identify and discuss the demographic, lifestyle-related, clinical, viral genotype-related, and host genetic factors underpinning the SC occurrence. The body of evidence indicates that the likelihood of SC is decreased in older individuals, men, Black people, HIV-coinfected subjects, and intravenous drug and alcohol users. In turn, HBV coinfection and specific polymorphism of the genes encoding interferon lambda 3 (particularly at rs8099917) and interferon lambda 4 (particularly at rs12979860) and HLA genes increase the odds of SC. Numerous other host-specific genetic factors could be implicated in SC, but the evidence is limited only to certain ethnic groups and often does not account for confounding variables. SC of HCV infection is a complex process arising from a combination of various factors, though a genetic component may play a leading role in some cases. Understanding factors influencing the likelihood of this phenomenon justifies better surveillance of high-risk groups, decreasing health inequities in particular ethnic groups, and may guide the development of a prophylactic vaccine, which at present is not available, or novel therapeutic strategies. Further research is needed to elucidate the exact mechanisms underlying SC and to explore potential interventions that could enhance this natural antiviral response.
Egypt has long been overwhelmed by the hepatitis C virus (HCV) infection, and it used to be the country with the world’s highest prevalence rates. The disease had been a significant public health problem, affecting millions of Egyptians and posing severe economic and social challenges. By the early 2000s, it was estimated that around 10% of the Egyptian population was infected with HCV. However, in recent years, with the availability of direct-acting antiviral therapies, the country has made enormous steps in combating this public health threat. The combination of innovative health strategies and political will enabled Egypt to establish a successful model of care for HCV management and to be the first country to eliminate hepatitis C, setting a model for the rest of the world. In 2023, Egypt became the first country to fulfill the World Health Organization’s set programmatic criteria of reduction of hepatitis C incidence and mortalities to levels close to elimination of disease or achieve the “gold tier” status on the path to disease elimination.
Hepatitis C virus (HCV) was discovered more than two decades ago, but progress towards a vaccine has been slow. HCV infection will spontaneously clear in about 25% of people. Studies of spontaneous HCV clearance in chimpanzees and human beings have identified host and viral factors that could be important in the control of HCV infection and the design of HCV vaccines. Although data from studies of chimpanzees suggest that protection against reinfection is possible after spontaneous clearance, HCV is a human disease. Results from studies of reinfection risk after spontaneous clearance in injecting drug users are conflicting, but some people seem to have protection against HCV persistence. To guide future vaccine development, we assess data from studies of HCV reinfection after spontaneous clearance, discuss flaws in the methods of previous human studies, and suggest essential components for future investigations of control of HCV infection.
Background:
The 69th World Health Assembly endorsed the global health sector strategy on viral hepatitis to eliminate viral hepatitis as a public health threat by 2030. Achieving and measuring the 2030 targets requires a substantial increase in the capacity to test and treat viral hepatitis infections and a mechanism to monitor the progress of hepatitis elimination. This study aimed to identify the gaps in data availability or quality and create a new mechanism to monitor the progress of hepatitis elimination.
Methods:
In 2020, using a questionnaire, we collected empirical, systematic, modelled, or surveyed data-reported by WHO country and WHO regional offices-on indicators of progress towards elimination of viral hepatitis, including burden of infection, incidence, mortality, and the cascade of care, and validated these data.
Findings:
WHO received officially validated country-provided data from 130 countries or territories, and used partner-provided data for 70 countries or territories. We estimated that in 2019, globally, 295·9 million (3·8%) people were living with chronic hepatitis B virus (HBV) infection and 57·8 million (0·8%) people were living with chronic hepatitis C virus (HCV) infection. Globally, there were more than 3·0 million new infections with HBV and HCV and more than 1·1 million deaths due to the viruses in 2019. In 2019, 30·4 million (95% CI 24·3-38·0) individuals living with hepatitis B knew their infection status and 6·6 million (5·3-8·3) people diagnosed with hepatitis B received treatment. Among people with HCV infection, 15·2 million (95% CI 12·1-19·0) had been diagnosed between 2015 and 2019, and 9·4 million (7·5-11·7) people diagnosed with hepatitis C infection were treated with direct-acting antiviral drugs between 2015 and 2019.
Interpretation:
There has been notable global progress towards hepatitis elimination. In 2019, 30·4 million (10·3%) people living with hepatitis B knew their infection status, which was slightly higher than in 2015 (22·0 million; 9·0%), and 6·6 million (22·7%) of those diagnosed with hepatitis B received treatment, compared with 1·7 million (8·0%) in 2015. Mortality from hepatitis C has declined since 2019, driven by an increase in HCV treatment ten times that of the strategy baseline. However, an estimated 89·7% of HBV infections and 78·6% of HCV infections remain undiagnosed. A new global strategy for 2022-30, based on these new estimates, should be implemented urgently to scale up the screening and treatment of viral hepatitis.
Funding:
World Health Organization.
Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and mortality worldwide. Direct-acting antiviral (DAA) therapy leads to high cure rates. However, persons who inject drugs (PWID) are at risk for reinfection after cure and may require multiple DAA treatments to reach the World Health Organization’s (WHO) goal of HCV elimination by 2030. Using an agent-based model (ABM) that accounts for the complex interplay of demographic factors, risk behaviors, social networks, and geographic location for HCV transmission among PWID, we examined the combination(s) of DAA enrollment (2.5%, 5%, 7.5%, 10%), adherence (60%, 70%, 80%, 90%) and frequency of DAA treatment courses needed to achieve the WHO’s goal of reducing incident chronic infections by 90% by 2030 among a large population of PWID from Chicago, IL and surrounding suburbs. We also estimated the economic DAA costs associated with each scenario. Our results indicate that a DAA treatment rate of >7.5% per year with 90% adherence results in 75% of enrolled PWID requiring only a single DAA course; however 19% would require 2 courses, 5%, 3 courses and <2%, 4 courses, with an overall DAA cost of $325 million to achieve the WHO goal in metropolitan Chicago. We estimate a 28% increase in the overall DAA cost under low adherence (70%) compared to high adherence (90%). Our modeling results have important public health implications for HCV elimination among U.S. PWID. Using a range of feasible treatment enrollment and adherence rates, we report robust findings supporting the need to address re-exposure and reinfection among PWID to reduce HCV incidence.
Background
Direct acting antiviral (DAA) therapy is highly effective for hepatitis C virus (HCV) infection, but reinfection following treatment may compromise benefits of cure. This study assessed the real-world effectiveness of treatment for reinfection.
Methods
Real-world effectiveness of antiviral therapy in chronic hepatitis C (REACH-C) is an observational study evaluating treatment outcomes following sequential DAA initiations across 33 health services in Australia between March 2016-June 2019. Reinfection was defined by post-treatment genotype switch or HCV viraemia after sustained virologic response (SVR12).
Results
Of the 10,843 individuals initiating DAA therapy post-treatment viraemia was reported in 526 of whom 99 were reinfections. Treatment for reinfection occurred in 88 individuals. In those with available treatment outcomes, SVR12 was similar to initial treatment in the overall REACH-C cohort (95% vs 95%; p = 0.745) and comparable across primary, tertiary, and prison settings. Classifying unknown treatment outcomes as failures, SVR12 for treatment of reinfection was lower than initial treatment in REACH-C (67% vs 81%; p = 0.002), due to higher lost to follow-up.
Conclusions
Treatment of reinfection is highly effective and can be delivered in non-specialist settings. Access to treatment for reinfection in high-risk populations is crucial to HCV elimination.
Background
A safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease.
Methods
In this phase 1–2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months.
Results
A total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, −53%; 95% CI, −255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, −66%; 95% CI, −250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×10³ IU per milliliter and 1804.93×10³ IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups.
Conclusions
In this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.)
With political will, modest financial investment and effective technical assistance, public sector hepatitis C virus (HCV) programmes can be established in low- and middle-income countries as a first step towards elimination. Seven countries, with support from the Clinton Health Access Initiative (CHAI) and partners, have expanded access to HCV treatment by combining programme simplification with market shaping to reduce commodity prices. CHAI has supported a multipronged approach to HCV programme launch in Cambodia, India, Indonesia, Myanmar, Nigeria, Rwanda and Vietnam including pricing negotiations with suppliers, policy development, fast-track registrations of quality-assured generics, financing advocacy and strengthened service delivery. Governments are leading programme implementation, leveraging HIV programme infrastructure/financing and focusing on higher-HCV prevalence populations like people living with HIV, people who inject drugs and prisoners. This manuscript aims to describe programme structure and strategies, highlight current commodity costs and outline testing and treatment volumes across these countries. Across countries, commodity costs have fallen from >US750–US80 per-cure commodity package, including WHO-prequalified generic drugs (sofosbuvir + daclatasvir). As of December 2019, 5900+ healthcare workers were trained, 2 209 209 patients were screened, and 120 522 patients initiated treatment. The cure (SVR12) rate was >90%, including at lower-tier facilities. Programmes are successfully implementing simplified, decentralised public health approaches. Combined with political will and affordable pricing, these efforts can translate into commitments to achieve global targets. However, to achieve elimination, additional investment in scale-up is required.
Background & aims:
Egypt has a major treatment programme, with an ambitious goal of HCV elimination by 2021. Our aim was to assess the impact on incidence of new HCV infections in nine villages in rural Egypt following implementation of a comprehensive HCV prevention, test and treat programme.
Methods:
An HCV "educate, test and treat" project was implemented in 73 villages across 7 governorates in Egypt between 06/2015 and 06/2018. In 2018, in 9 of the villages we re-tested persons who originally tested HCV antibody (HCV-Ab) and HBsAg negative using rapid diagnostic tests (RDTs) with HCV RNA confirmation of positive cases. Incidence rate per 1000 person-years (py) was calculated, and risk factors for incident HCV infections assessed through an interviewer administered questionnaire in 1:3 age and gender matched cases and controls.
Results:
19816 (96.7%) of 20490 individuals who originally tested HCV-Ab negative in the 9 villages during the 2015-2016 implementation of the "educate, test and treat" programme were re-tested in 2018. Over a median of 2.4 years (IQR 2.1-2.7), there were 19 new HCV infections and all were HCV RNA positive (incidence rate 0.37/1000 py) (95%CI 0.24-0.59). Compared to a previous estimate of incidence in Nile Delta region (2.4/1000 py) from 2006, there was a substantial reduction in overall incidence of new HCV infections. Exposures through surgery (OR 51 95%CI 3.5-740.1) and dental procedures (OR 23.8, 95%CI 2.9-194.9) were significant independent predictors of incident infections.
Conclusions:
This is the first study to show a substantial reduction in incidence of new HCV infections in the general population in Egypt following high coverage of testing and treatment - based on re-testing of those previously tested antibody negative.
Hepatitis C (HCV) is a leading cause of chronic liver disease and mortality worldwide and persons who inject drugs (PWID) are at the highest risk for acquiring and transmitting HCV infection. We developed an agent-based model (ABM) to identify and optimize direct-acting antiviral (DAA) therapy scale-up and treatment strategies for achieving the World Health Organization (WHO) goals of HCV elimination by the year 2030. While DAA is highly efficacious, it is also expensive, and therefore intervention strategies should balance the goals of elimination and the cost of the intervention. Here we present and compare two methods for finding PWID treatment enrollment strategies by conducting a standard model parameter sweep and compare the results to an evolutionary multi-objective optimization algorithm. The evolutionary approach provides a pareto-optimal set of solutions that minimizes treatment costs and incidence rates.
Background and aims
Persons who inject drugs (PWID) are at highest risk for acquiring and transmitting hepatitis C (HCV) infection. The recent availability of oral direct-acting antiviral (DAA) therapy with reported cure rates >90% can prevent HCV transmission, making HCV elimination an attainable goal among PWID. The World Health Organization (WHO) recently proposed a 90% reduction in HCV incidence as a key objective. However, given barriers to the use of DAAs in PWID, including cost, restricted access to DAAs, and risk of reinfection, combination strategies including the availability of effective vaccines are needed to eradicate HCV as a public health threat. This study aims to model the cost and efficacy of a dual modality approach using HCV vaccines combined with DAAs to reduce HCV incidence by 90% and prevalence by 50% in PWID populations.
Methods
We developed a mathematical model that represents the HCV epidemic among PWID and calibrated it to empirical data from metropolitan Chicago, Illinois. Four medical interventions were considered: vaccination of HCV naive PWID, DAA treatment, DAA treatment followed by vaccination, and, a combination of vaccination and DAA treatment.
Results
The combination of vaccination and DAAs is the lowest cost-expensive intervention for achieving the WHO target of 90% incidence reduction. The use of DAAs without a vaccine is much less cost-effective with the additional risk of reinfection after treatment. Vaccination of naïve PWID alone, even when scaled-up to all reachable PWID, cannot achieve 90% reduction of incidence in high-prevalence populations due to infections occurring before vaccination. Similarly, the lowest cost-expensive way to halve prevalence in 15 years is through the combination of vaccination and DAAs.
Conclusions
The modeling results underscore the importance of developing an effective HCV vaccine and augmenting DAAs with vaccines in HCV intervention strategies in order to achieve efficient reductions in incidence and prevalence.
Background:
Previous estimates of the burden of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) among people who inject drugs have not included estimates of the burden attributable to the consequences of past injecting. We aimed to provide these estimates as part of the Global Burden of Disease (GBD) Study 2013.
Methods:
We modelled the burden of HBV and HCV (including cirrhosis and liver cancer burden) and HIV at the country, regional, and global level. We extracted United Nations data on the proportion of notified HIV cases by transmission route, and estimated the contribution of injecting drug use (IDU) to HBV and HCV disease burden by use of a cohort method that recalibrated individuals' history of IDU, and accumulated risk of HBV and HCV due to IDU. We estimated data on current IDU from a meta-analysis of HBV and HCV incidence among injecting drug users and country-level data on the incidence of HBV and HCV between 1990 and 2013. We calculated estimates of burden of disease through years of life lost (YLL), years of life lived with disability (YLD), deaths, and disability-adjusted life-years (DALYs), with 95% uncertainty intervals (UIs) calculated for each metric.
Findings:
In 2013, an estimated 10·08 million DALYs were attributable to previous exposure to HIV, HBV, and HCV via IDU, a four-times increase since 1990. In total in 2013, IDU was estimated to cause 4·0% (2·82 million DALYs, 95% UI 2·4 million to 3·8 million) of DALYs due to HIV, 1·1% (216 000, 101 000-338 000) of DALYs due to HBV, and 39·1% (7·05 million, 5·88 million to 8·15 million) of DALYs due to HCV. IDU-attributable HIV burden was highest in low-to-middle-income countries, and IDU-attributable HCV burden was highest in high-income countries.
Interpretation:
IDU is a major contributor to the global burden of disease. Effective interventions to prevent and treat these important causes of health burden need to be scaled up.
Funding:
Bill & Melinda Gates Foundation and Australian National Health and Medical Research Council.
Background and Aims
The advent of highly effective hepatitis C (HCV) treatments has questioned the need for a vaccine to control HCV amongst people who inject drugs (PWID). However, high treatment costs and ongoing reinfection risk suggest it could still play a role. We compared the impact of HCV vaccination amongst PWID against providing HCV treatment.
Methods
Dynamic HCV vaccination and treatment models among PWID were used to determine the vaccination and treatment rates required to reduce chronic HCV prevalence or incidence in the UK over 20 or 40 years. Projections considered a low (50% protection for 5 years), moderate (70% protection for 10 years) or high (90% protection for 20 years) efficacy vaccine. Sensitivities to various parameters were examined.
Results
To halve chronic HCV prevalence over 40 years, the low, moderate and high efficacy vaccines required annual vaccination rates (coverage after 20 years) of 162 (72%), 77 (56%) and 44 (38%) per 1000 PWID, respectively. These vaccination rates were 16, 7.6 and 4.4 times greater than corresponding treatment rates. To halve prevalence over 20 years nearly doubled these vaccination rates (moderate and high efficacy vaccines only) and the vaccination-to-treatment ratio increased by 20%. For all scenarios considered, required annual vaccination rates and vaccination-to-treatment ratios were at least a third lower to reduce incidence than prevalence. Baseline HCV prevalence had little effect on the vaccine’s impact on prevalence or incidence, but substantially affected the vaccination-to-treatment ratios. Behavioural risk heterogeneity only had an effect if we assumed no transitions between high and low risk states and vaccinations were targeted or if PWID were high risk for their first year.
Conclusions
Achievable coverage levels of a low efficacy prophylactic HCV vaccine could greatly reduce HCV transmission amongst PWID. Current high treatment costs ensure vaccination could still be an important intervention option.
A licensed malaria vaccine would provide a valuable new tool for malaria control and elimination efforts. Several candidate vaccines targeting different stages of the malaria parasite's lifecycle are currently under development, with one candidate, RTS,S/AS01 for the prevention of Plasmodium falciparum infection, having recently completed Phase III trials. Predicting the public health impact of a candidate malaria vaccine requires using clinical trial data to estimate the vaccine's efficacy profile-the initial efficacy following vaccination and the pattern of waning of efficacy over time. With an estimated vaccine efficacy profile, the effects of vaccination on malaria transmission can be simulated with the aid of mathematical models. Here, we provide an overview of methods for estimating the vaccine efficacy profiles of pre-erythrocytic vaccines and transmission-blocking vaccines from clinical trial data. In the case of RTS,S/AS01, model estimates from Phase II clinical trial data indicate a bi-phasic exponential profile of efficacy against infection, with efficacy waning rapidly in the first 6 months after vaccination followed by a slower rate of waning over the next 4 years. Transmission-blocking vaccines have yet to be tested in large-scale Phase II or Phase III clinical trials so we review ongoing work investigating how a clinical trial might be designed to ensure that vaccine efficacy can be estimated with sufficient statistical power. Finally, we demonstrate how parameters estimated from clinical trials can be used to predict the impact of vaccination campaigns on malaria using a mathematical model of malaria transmission.
People who inject drugs (PWID) are at high risk for blood-borne pathogens transmitted during the sharing of contaminated injection equipment, particularly hepatitis C virus (HCV). HCV prevalence is influenced by a complex interplay of drug-use behaviors, social networks, and geography, as well as the availability of interventions, such as needle exchange programs. To adequately address this complexity in HCV epidemic forecasting, we have developed a computational model, the Agent-based Pathogen Kinetics model (APK). APK simulates the PWID population in metropolitan Chicago, including the social interactions that result in HCV infection. We used multiple empirical data sources on Chicago PWID to build a spatial distribution of an in silico PWID population and modeled networks among the PWID by considering the geography of the city and its suburbs. APK was validated against 2012 empirical data (the latest available) and shown to agree with network and epidemiological surveys to within 1%. For the period 2010–2020, APK forecasts a decline in HCV prevalence of 0.8% per year from 44(±2)% to 36(±5)%, although some sub-populations would continue to have relatively high prevalence, including Non-Hispanic Blacks, 48(±5)%. The rate of decline will be lowest in Non-Hispanic Whites and we find, in a reversal of historical trends, that incidence among non-Hispanic Whites would exceed incidence among Non-Hispanic Blacks (0.66 per 100 per years vs 0.17 per 100 person years). APK also forecasts an increase in PWID mean age from 35(±1) to 40(±2) with a corresponding increase from 59(±2)% to 80(±6)% in the proportion of the population >30 years old. Our studies highlight the importance of analyzing subpopulations in disease predictions, the utility of computer simulation for analyzing demographic and health trends among PWID and serve as a tool for guiding intervention and prevention strategies in Chicago, and other major cities.
Background:
We aimed to characterize the natural history of hepatitis C virus (HCV) reinfection and spontaneous clearance following reinfection (reclearance), including predictors of HCV reclearance.
Methods:
Data were synthesized from the 9 prospective cohorts of the International Collaboration of Incident Human Immunodeficiency Virus and HCV in Injecting Cohorts study, which evaluated HCV infection outcomes among people who inject drugs. Participants with primary HCV infection were classified as having achieved viral suppression if they had negative results of at least 1 subsequent HCV RNA test. Those with positive results of an HCV RNA test following viral suppression were investigated for reinfection. Viral sequence analysis was used to identify reinfection (defined as detection of heterologous virus with no subsequent detection of the original viral strain).
Results:
Among 591 participants with acute primary HCV infection, 118 were investigated for reinfection. Twenty-eight participants were reinfected (12.3 cases/100 person-years; 95% confidence interval [CI], 8.5-17.8). Peak HCV RNA level was lower during reinfection than primary infection (P = .011). The proportion of individuals with reclearance 6 months after reinfection was 52% (95% CI, 33%-73%). After adjustment for study site, females with the IFNL4 (formerly IFNL3 and IL28B) rs12979860 CC genotype detected were more likely to have reclearance (hazard ratio, 4.16; 95% CI, 1.24-13.94; P = .021).
Conclusions:
Sex and IFNL4 genotype are associated with spontaneous clearance after reinfection.
Hepatitis C virus (HCV) causes significant morbidity and mortality in injecting drug users (IDU) worldwide. HCV vaccine candidates have shown promise for reducing the infectivity of acute infection and averting chronic infection, yet the impact of varying levels of vaccine efficacy and vaccine delivery strategies on the HCV epidemic in IDU have not been explored.
We utilized extensive data on injecting behavior collected in the UFO Study of young IDU in San Francisco to construct a stochastic individual-based model that reflects heterogeneous injecting risk behavior, historical HCV trends, and existing information on viral dynamics and vaccine characteristics.
Our modeled HCV rate closely paralleled observed HCV incidence in San Francisco, with estimated incidence of 59% per person year (ppy) early in the epidemic, and 27% ppy after risk reduction was introduced. Chronic HCV infection, the clinically relevant state of HCV infection that leads to liver disease and hepatocellular cancer, was estimated at 22% ppy (± 3%) early in the epidemic and 14% ppy (± 2%) after risk reduction was introduced. We considered several scenarios, and highlight that a vaccine with 50% to 80% efficacy targeted to high-risk or sero-negative IDU at a high vaccination rate could further reduce chronic HCV incidence in IDU to 2-7% ppy 30 years after its introduction.
Our results underscore the importance of further efforts to develop both HCV vaccines and optimal systems of delivery to IDU populations.
Hepatitis C virus (HCV) is predominantly transmitted through parenteral exposures to infectious blood or body fluids. In 2019, approximately 58 million people worldwide were still infected with HCV, and 290,000 deaths occurred due to hepatitis C–related conditions, despite hepatitis C being curable. There are substantial barriers to elimination, including the lack of widespread point-of-care diagnostics, cost of treatment, stigma associated with hepatitis C, and challenges in reaching marginalized populations, such as people who inject drugs. The World Health Organization (WHO) has set goals to eliminate hepatitis C by 2030. Several countries, including Australia, Egypt, Georgia, and Rwanda, have made remarkable progress toward hepatitis C elimination. In the United States, the Biden–Harris administration recently issued a plan for the national elimination of hepatitis C. Global progress has been uneven, however, and will need to accelerate considerably to reach the WHO's 2030 goals. Nevertheless, the global elimination of hepatitis C is within reach and should remain a high public health priority.
Vaccination is a key intervention for the elimination of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections to fulfil the WHO’s 2030 global elimination goal. Innovations in 2021 promise to curb HBV transmission by reducing mother-to-child transmission and enhancing vaccine immunogenicity in at-risk adult groups. Additionally, an HCV vaccination trial was conducted, and there were also advances in our understanding of the immunology underpinning the lack of protection against HCV reinfection.
The moratorium on experimentation with chimpanzees has impeded the progress of research on a vaccine against hepatitis C virus. Given the availability of highly effective, direct-acting antiviral therapy for HCV, the authors argue for the use of a controlled human infection model, or CHIM, to accelerate HCV vaccine research.
Evidence for the existence of another hepatitis-causing pathogen, other than the known hepatitis A and B viruses, emerged in the mid-1970s. A frustrating search of 15 years was ended by the identification of the hepatitis C virus in 1989 using a recombinant DNA immunoscreening method. This discovery quickly led to blood tests that eliminated posttransfusion hepatitis C and could show the partial efficacy of type 1 interferon-based therapies. Subsequent knowledge of the viral replication cycle then led to the development of effective direct-acting antivirals targeting its serine protease, polymerase, and nonstructural protein 5A that resulted in the approval of orally available drug combinations that can cure patients within a few months with few side effects. Meanwhile, vaccine strategies have been shown to be feasible, and they are still required to effectively control this global epidemic.
Chronic hepatitis is a major public health challenge that can be eliminated. There has already been progress toward this goal, especially with the prevention of chronic hepatitis B by vaccination and reductions in the transmission of hepatitis C from transfusions and unsafe injections. There are also potentially potent interventions to detect and treat HCV and HBV infections. However, for the elimination targets to be reached by 2030, substantially more resources and additional innovations are needed to make these interventions widely available. The degree to which elimination of hepatitis is global or focused on select subpopulations will be directly related to the vigor of the international response.
The hepatitis C virus is responsible for more deaths in the United States than any other infectious disease, and hepatitis C infections have been rising at an alarming rate since 2010. We evaluated the role of the opioid epidemic and, in particular, the 2010 introduction of an abuse-deterrent version of OxyContin. The OxyContin reformulation led some users of the drug to switch to heroin, which could have exposed them to the hepatitis C virus. We used difference-in-differences methods, using data for the period 2004-15, to assess whether states with higher rates of OxyContin misuse prior to reformulation-states where the reformulation had more impact-experienced faster growth in infections after the reformulation. States with above-median OxyContin misuse before the reformulation experienced a 222 percent increase in hepatitis C infection rates in the post-reformulation period, while states with below-median misuse experienced only a 75 percent increase. These results suggest that interventions to deter opioid misuse can have unintended long-term public health consequences.
The major route of hepatitis C virus (HCV) transmission in the United States is injection drug use. We hypothesized that if an HCV vaccine were available, vaccination could affect HCV transmission among people who inject drugs by reducing HCV titers after viral exposure without necessarily achieving sterilizing immunity. To investigate this possibility, we developed a mathematical model to determine transmission probabilities relative to the HCV RNA titers of needle/syringe-sharing donors. We simulated sharing of two types of syringes fitted with needles that retain either large or small amounts of fluid after expulsion. Using previously published viral kinetics data from both naïve subjects infected with HCV and reinfected individuals who had previously cleared an HCV infection, we estimated transmission risk between pairs of serodiscordant injecting drug users, accounting for syringe type, rinsing, and sharing frequency. We calculated that the risk of HCV transmission through syringe sharing increased ~10-fold as viral titers (log10 IU/ml) increased ~25-fold. Cumulative analyses showed that, assuming sharing episodes every 7 days, the mean transmission risk over the first 6 months was >90% between two people sharing syringes when one had an HCV RNA titer >5 log10 IU/ml. For those with preexisting immunity that rapidly controlled HCV, the cumulative risk decreased to 1 to 25% depending on HCV titer and syringe type. Our modeling approach demonstrates that, even with transient viral replication after exposure during injection drug use, HCV transmission among people sharing syringes could be reduced through vaccination if an HCV vaccine were available.
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.
Direct acting antivirals can cure chronic hepatitis C virus (HCV) infection but whether they will reduce global liver disease burden is uncertain. Most chronic infections are undiagnosed and transmission has increased in recent years. The first trial of a preventive vaccine is now underway in humans at risk for HCV infection. It will test the novel hypothesis that T cell-mediated immunity alone can prevent persistent HCV infection. Another vaccine that elicits neutralizing antibodies is at an advanced stage of development. Attention is turning to the understudied question of whether direct acting antiviral (DAA) cure of chronic infection restores HCV immunity. If not, it will be important to determine if preventive vaccines can also act therapeutically to reverse immune dysfunction and protect from re-infection.
Malaria is one of the most frequently occurring infectious diseases worldwide, with almost 1 million deaths and an estimated 243 million clinical cases annually. Several candidate malaria vaccines have reached Phase IIb clinical trials, but results have often been disappointing. As an alternative to these Phase IIb field trials, the efficacy of candidate malaria vaccines can first be assessed through the deliberate exposure of participants to the bites of infectious mosquitoes (sporozoite challenge) or to an inoculum of blood-stage parasites (blood-stage challenge). With an increasing number of malaria vaccine candidates being developed, should human malaria challenge models be more widely used to reduce cost and time investments? This article reviews previous experience with both the sporozoite and blood-stage human malaria challenge models and provides future perspectives for these models in malaria vaccine development.
Studies in patients and chimpanzees that spontaneously cleared hepatitis C virus (HCV) infections demonstrated that natural immunity to the virus is induced during primary infections and that this immunity can be cross protective. These discoveries led to optimism about prophylactic HCV vaccines, and several studies were performed in chimpanzees, although most included fewer than 6 animals. To draw meaningful conclusions about the efficacy of HCV vaccines in chimpanzees, we performed statistical analyses of data from previously published studies from different groups.
We performed a meta-analysis that compared parameters among naïve (n = 63), vaccinated (n = 53), and rechallenged (n = 36) animals, including peak RNA titer postchallenge, time points of peak RNA titer, duration of viremia, and proportion of persistent infections.
Each vaccination study induced immune responses that were effective in rapidly controlling HCV replication. Levels of induced T-cell responses did not indicate vaccine success. There was no reduction in the rate of HCV persistence in vaccinated animals, compared with naïve animals, when nonstructural proteins were included in the vaccine. Vaccines that contained only structural proteins had clearance rates that were significantly higher than vaccines that contained nonstructural components (P = .015).
The inclusion of nonstructural proteins in HCV vaccines might be detrimental to protective immune responses, and/or structural proteins might activate T-cell responses that mediate viral clearance.
We followed patients with ongoing hepatitis C virus (HCV) exposure following control of an initial HCV infection to determine whether primary control conferred protection against future persistent infections.
Twenty-two active injection drug users (IDU) who had cleared a primary hepatitis C viremia for at least 60 days were monitored monthly. Reinfection was defined as the detection of a new HCV infection. Protection was assessed based on the magnitude and duration of viremia following reinfection and generation of T-cell and neutralizing antibody (nAb) responses.
Reinfection occurred in 11 IDU (50%) who previously spontaneously controlled primary HCV infection. Although viral clearance occurs in approximately 25% of patients with primary infections, spontaneous viral clearance was observed in 83% of reinfected patients. The duration and maximum level of viremia during subsequent episodes of reinfection were significantly decreased compared with those of the primary infection in the same subjects. In contrast to chronic infection, reinfection was associated with a significant increase in the breadth of T-cell responses. During acute infection, nAbs against heterologous viral pseudoparticles were detected in 60% of reinfected subjects; cross-reactive nAbs are rarely detected in patients who progress to chronic infection.
HCV reinfection is associated with a reduction in the magnitude and duration of viremia (compared with the initial infection), broadened cellular immune responses, and generation of cross-reactive humoral responses. These findings are consistent with development of adaptive immunity that is not sterilizing but protects against chronic disease.
A large number of studies have reported on spontaneous viral clearance rates in acute hepatitis C infection, however most have been small, and reported rates have varied quite widely. To improve the precision of the estimated rate of spontaneous viral clearance, a systematic review was conducted of longitudinal studies. Factors associated with viral clearance were also examined. Inclusion criteria for studies were: longitudinal assessment from time of acute hepatitis C; hepatitis C virus RNA analysis as determinant of viral clearance; untreated for acute hepatitis C. Information on study population, and factors that may influence viral clearance were extracted from each study. Viral clearance was defined among individuals with at least 6 months follow-up following acute hepatitis C. The number of subjects with viral clearance was expressed as a proportion for each study and a weighted mean for proportion was calculated. A total of 31 studies were examined. Study populations included nine studies of post-transfusion hepatitis, 19 of acute clinical hepatitis, and three of sero-incident cases. In total, data was available for 675 subjects and the mean study population was 22 (range 4-67). The proportion with viral clearance ranged from 0.0 to 0.8, with a weighted mean of 0.26 (95% CI 0.22-0.29). Factors associated with viral clearance were female gender and acute clinical hepatitis C study population. Further studies are required to more clearly define predictors of clearance and guide therapeutic intervention strategies.