New antiviral treatment could significantly reduce global burden of hepatitis C - New Study
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- full text below....."advances indicate that a HCV treatment as prevention strategy among PWID may be feasible in the very near future....We project the potential impact of DAA therapy on HCV prevalence in three international settings with varied prevalence."
"Overall, the projections suggest IFN-free DAA HCV treatment as prevention is a feasible option for reducing the future burden of HCV-related disease, which is of critical public health importance given the lack of alternative effective HCV prevention strategies. HCV treatment is cost-effective, and in most settings treatment of PWID is highly cost effective(17) primarily because of the potential prevention benefit and reduction in secondary transmission"....."This modeling study explored the feasibility of HCV treatment as prevention in the era of IFN-free DAA-based HCV therapy. Current levels of HCV treatment among PWID are projected to only achieve modest or negligible reductions in HCV chronic prevalence among PWID. However, scaling-up treatment could lead to substantial reductions in HCV prevalence. In Edinburgh, a doubling of treatment rates (to 15 per 1000 PWID annually) could halve prevalence; a 3-fold increase could reduce chronic HCV prevalence to <7% within 15 years. Greater scale-up will be required in Melbourne and Vancouver where current treatment rates are lower and chronic prevalence higher, but prevalence could be halved in 15 years with treatment rates of 40 per 1000 PWID (13-fold increase from 3 per 1000 PWID annually) in Melbourne and 76 per 1000 PWID (a 15-fold increase from 5 per 1000 PWID annually) in Vancouver. A 20-fold increase from baseline treatment rates could reduce chronic prevalence to <15% and <20% in Melbourne and Vancouver, respectively, in 15 years.
Such scale-up, though considerable in Melbourne and Vancouver, has been achieved and exceeded for HIV treatment in both resource rich and poor settings"
Scientists show potential impact of therapy in reducing transmission in UK, Canada and Australia
Around 150 million people globally are chronically infected with the hepatitis C virus (HCV) - a major cause of liver disease and the fastest growing cause of liver transplantation and liver cancer.1 New prevention strategies are urgently required as people are continuing to be infected with HCV. Findings, published in Hepatology, reveal the impact of a new antiviral treatment that could potentially reduce HCV rates in some cities affected by chronic HCV prevalence by half over 15 years.
In Europe, the US and other developed countries the majority of HCV infections occur among people who inject drugs (PWID). Although current prevention strategies, which are based on needle and syringe programmes and opiate substitution therapy, can avert HCV infections and have reduced its prevalence in some cities from the very high levels that occurred in the 1980s, these interventions are unlikely alone to achieve further substantial reductions.
HCV treatment as prevention has been proposed as a possible solution. However, while current HCV antiviral treatment of pegylated-interferon and ribavirin can cure approximately 60 per cent of people treated, they are poorly tolerated, long in duration (five to 11 months), and have a low take-up among PWID.
Several new interferon free direct-active antivirals (DAAs) treatment are emerging with very promising results in trials suggesting that treatment is shorter (12 weeks) with fewer complications and side effects, and around a 90 per cent cure rate.
Using a mathematical model, researchers at the University of Bristol and London School of Hygiene and Tropical Medicine in collaboration with researchers and clinicians in the UK, Australia and Canada projected the potential impact of these new DAAs treatment among PWID in three cities with similar PWID prevalence (~1 per cent among adults) but very different levels of chronic HCV prevalence among PWID. The cities were Edinburgh, UK (25 per cent chronic HCV), Melbourne, Australia (50 per cent chronic HCV) and Vancouver, Canada (65 per cent chronic HCV).
In Melbourne and Vancouver, where current annual HCV treatment take-up rates and other interventions are around one per cent of PWID with chronic HCV, the findings show that switching to the new DAA treatment is likely to have very little impact on reducing HCV prevalence over the next 15 years. But in Edinburgh where chronic HCV prevalence is lower and current treatment rates already at three per cent of PWID with chronic HCV, then once the new DAA become available HCV prevalence is projected to reduce by 25 per cent over the next 15 years.
The researchers predict that chronic HCV prevalence among PWID could be halved in 15 years by doubling HCV treatment in Edinburgh to six per cent among PWID with chronic HCV and increasing HCV treatment by 13 to 15 fold in Melbourne and Vancouver respectively.
The findings strengthen the evidence that achievable levels of HCV antiviral treatment for PWID, particularly with the new emerging DAAs treatment, can substantially reduce prevalence across a range of global settings.
Clinicians, patient groups and policy-makers will be able to plan for large-scale population reductions in HCV and chronic liver disease. However, an important consideration will be how to make HCV treatment scale-up affordable - especially for lower and middle income settings but possibly also for developed countries that require very high treatment rates to achieve population goals.
The researchers estimate that if the cost of the new DAAs are equivalent to other new HCV antiviral drugs then treatment rates would require an annual treatment budget of US $3.2 million in Edinburgh and approximately $50 million in Melbourne and Vancouver.
Matthew Hickman, Professor in Public Health and Epidemiology at the University of Bristol's School of Social and Community Medicine and lead author of the study, said: "Scaling up HCV treatment is critical to the prevention of HCV in the population to support and enhance traditional harm reduction measures - opiate substitution treatment and needle exchange. The new direct-active antivirals treatment offer many sites the opportunity to achieve substantial reductions in HCV and future liver disease in the population, and the chance to demonstrate empirically that our model projections are right."
Professor David Goldberg, lead of the team implementing Scotland's hepatitis C Action Plan (2008-2011), said: "This study demonstrates that, in a country like Scotland which has a Government seriously committed to the improvement of hepatitis C services, increasing patient access to antiviral therapy could potentially have a major impact in the prevention of transmission of infection."
Professor Greg Dore, Head of the Viral Hepatitis Clinical Research Program, Kirby Institute for infection and immunity in society at the University of New South Wales Australia, said: "The development of highly effective simplified new HCV treatments has the potential to greatly enhance existing HCV prevention strategies. Access to affordable HCV direct acting antiviral regimens for people who inject drugs should be a major focus to harness this potential prevention capacity."
Professor Margaret Hellard from the Burnet Institute in Australia added: "This research suggests that with the advent of new direct-active antivirals treatment there is a real opportunity to achieve substantial reductions in HCV and future liver disease in the population. Although the cost of these treatments appear to be expensive, economic models by Martin et al in the UK and Burnet researchers in Australia suggests that scaling up HCV treatment in people who inject drugs is highly cost effective. It is also important that the scale up of HCV treatment occurs in combination with traditional harm reduction measures - opiate substitution treatment and needle exchange which have previously also been shown to be highly cost effective."
Hepatology March 2013
HCV treatment for prevention among people who inject drugs: Modeling treatment scale-up in the age of direct-acting antivirals
Authors: Natasha K Martin1,2, Peter Vickerman2, Jason Grebely3, Margaret Hellard4, Sharon J Hutchinson5,6, Viviane D Lima7, Graham R Foster8, John F Dillon9, David J Goldberg5, Gregory J Dore3, Matthew Hickman
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record
Substantial reductions in HCV prevalence among people who inject drugs (PWID) cannot be achieved by harm reduction interventions such as needle exchange and opiate substitution therapy (OST) alone. Current HCV treatment is arduous and uptake low, but new highly effective and tolerable interferon-free direct-acting antiviral (DAA) treatments could facilitate increased uptake. We projected the potential impact of DAA treatments on PWID HCV prevalence in three settings.
A dynamic HCV transmission model was parameterized to three chronic HCV prevalence settings: Edinburgh, UK (25%); Melbourne, Australia (50%); Vancouver, Canada (65%). Using realistic scenarios of future DAAs (90% sustained viral response, 12 weeks duration, available 2015), we projected the treatment rates required to reduce chronic HCV prevalence by half or three-quarters within 15 years.
Current HCV treatment rates may minimally impact prevalence in Melbourne and Vancouver (<2% relative reductions), but could reduce prevalence by 26% in 15 years in Edinburgh. Prevalence could halve within 15 years with treatment scale-up to 15, 40, or 76 per 1000 PWID annually in Edinburgh, Melbourne, or Vancouver, respectively (2, 13, 15-fold increases, respectively). Scale-up to 22, 54, or 98 per 1000 PWID annually could reduce prevalence by three-quarters within 15 years. Less impact occurs with delayed scale-up, higher baseline prevalence, or shorter average injecting duration. Results are insensitive to risk heterogeneity or restricting treatment to PWID on OST. At existing HCV drug costs, halving chronic prevalence would require annual treatment budgets of USD$3.2 million in Edinburgh and $50 million in Melbourne and Vancouver.
Interferon-free DAAs could enable increased HCV treatment uptake among PWID, which could have a major preventative impact. However, treatment costs may limit scale-up, and should be addressed.
The global burden of hepatitis C virus (HCV) infection continues to rise(1, 2). The core of the HCV epidemic in the developed world occurs among people who inject drugs (PWID), who comprise the majority of new (80%) and existing (60%) cases(1). Globally, HCV seroprevalence (>60% in most countries)(3) and incidence (5-40% per annum)(4, 5) remains high among PWID. Prevention strategies, such as needle and syringe programs (NSP) and opiate substitution therapy (OST), can reduce HCV transmission, and have maintained low levels of HIV infection in many settings, but are insufficient to achieve
substantial reductions in HCV prevalence(6-9). This is partly because high HCV prevalence and long injecting duration among PWID in many settings combine so the intervention coverage required for major prevalence reductions is unobtainable and unsustainable(9). Given there is no HCV vaccine, alternative strategies for HCV prevention are urgently needed.
In HIV, the demonstration that antiretroviral therapy given to HIV-infected people can prevent secondary transmission has generated considerable excitement(10) and suggestions we may have reached a tipping point for preventing HIV transmission(11). In contrast to HIV, HCV is curable and therapy is finite. Therefore, HCV treatment as prevention may provide even greater opportunity for preventing onward HCV transmission and directly reducing HCV chronic prevalence.
Mathematical modeling studies have suggested HCV treatment for PWID could be an effective(12-16) and cost-effective(17) intervention to prevent HCV transmission.
However, these studies only considered treatment with pegylated interferon and ribavirin (PEG-IFN+RBV). The feasibility of expanding this treatment regimen as a strategy for treatment as prevention is limited, given the poor tolerability and limited uptake of PEGIFN+RBV therapy, particularly among PWID(18, 19). However, therapeutic options for HCV are evolving rapidly. Preliminary data from IFN-free direct-acting antiviral (DAA) therapy phase II trials indicates that in the near future regimens will be available with markedly reduced toxicity, high efficacy (>90% cure), improved dosing schedules (once or twice-daily) and shortened treatment duration (6-24 weeks)(20-22). Such advances indicate that a HCV treatment as prevention strategy among PWID may be feasible in the very near future.
We project the potential impact of DAA therapy on HCV prevalence in three international settings with varied prevalence.
Without any treatment scale-up, low chronic HCV prevalence in Edinburgh (25%) combined with switching to new DAAs and moderate baseline levels of treatment (8/1000 PWID annually) could lead to a 26% [13-45%, 95% credibility interval (CrI)] relative reduction in prevalence within 15 years. However, in Melbourne and Vancouver, higher chronic HCV prevalence (50% and 65%, respectively) combined with low current levels of treatment (<5 per 1000 PWID annually) produce little impact (<2%) on prevalence over 15 years. Figure 3 shows HCV chronic prevalence reductions over time, and figure 4 shows relative prevalence reductions at year 15 (10 years after full scaleup).
Minimal and achievable levels of treatment scale-up result in substantial impact in Edinburgh and Melbourne. Scaling-up treatment to 20 per 1000 PWID annually could result in relative prevalence reductions within 15 years of 69% [54-83% CrI] and 23% [17-32% CrI] in Edinburgh and Melbourne, respectively, but only 9% [7-15% CrI] in Vancouver. Higher treatment rates (>40 per 1000 PWID annually) are required to reduce prevalence by over >20% in Vancouver within 15 years. A scale-up to treating 80 per 1000 PWID annually could reduce HCV chronic prevalence to below 5% in Edinburgh and Melbourne, and to 30% in Vancouver, within 15 years.
Figure 5 shows the levels of treatment necessary to reduce prevalence by 1/4, 1/2, and 3/4 within 15 years (10 years after full scale-up) in all settings. Halving current prevalence could be achieved through scaled-up treatment rates of 15 [12-19 CrI], 40 [30-50 CrI], and 76 [56-102 CrI] per 1000 PWID annually in Edinburgh, Melbourne, and Vancouver, respectively. This would require doubling treatment rates in Edinburgh (currently 32 PWID [8 per 1000] PWID annually). However, in Melbourne it would require a 13-fold scale-up (currently 75 PWID [3 per 1000 PWID] annually), and in Vancouver would
require a 15-fold scale-up (currently 68 PWID [5 per 1000 PWID] annually). Reducing prevalence by 3/4 would require a scale-up by: 3-fold in Edinburgh to 22 [18-27 CrI] per 1000 PWID annually, 18-fold in Melbourne to 54 [43-67 CrI] per 1000 PWID annually, and 20-fold in Vancouver to 98 [74-127 CrI] per 1000 PWID annually. This would result in HCV chronic prevalences of <10% in Edinburgh, <15% in Melbourne and <20% in Vancouver, respectively.
ANCOVA analyses indicated that uncertainty in average injecting duration contributed to the majority of variation (59%-78%) in impact at 15 years with a treatment scale-up to 10 per 1000 PWID annually. The remaining variation was due to uncertainty in baseline treatment rate in Edinburgh, baseline prevalence in Melbourne, and baseline prevalence and death rate in Vancouver.
One-way sensitivity analyses showed baseline prevalence, injecting duration, and time to scale-up initiation had the most effect on model projections at 15 years with treatment scale-up to 10 per 1000 PWID annually (figure 6, shown for Melbourne). Across the sites, if baseline chronic HCV prevalences were 5% lower, the impact of treatment scaleup increased by 24-37%, whereas if baseline prevalences were 5% higher, impact decreased by 20-27%. If the average injecting career was 20 rather than 11 years then potential impact increased by 16-53% (with greater impact at higher chronic prevalence); whereas if average injecting duration was shorter at six years impact was reduced by 29-43%. Delaying the initiation of scale-up by four years (2019 versus 2015) resulted in 7-18% less impact. Decreasing/increasing IFN-free DAA SVR rates (to 80%/100% versus 90%) correspondingly decreased/increased impact by 12 to 15%. If acute infection was associated with a 5-fold increase in transmissibility as compared to chronic infection (equal for base-case), impact was reduced by 11-16%.
Changing other assumptions regarding treatment duration or population heterogeneity (e.g. average time in OST/high risk, proportion high-risk, relative transmission risk when in OST or high-risk, mixing assumptions between low and high-risk, restricting treatment to only those on OST or low-risk) had <10% impact on projections for a scaled-up treatment rate of 10/1000 PWID annually. However, at higher treatment rates (such as 80 per 1000 PWID for Melbourne), sustaining treatment at this level would require treating the non-OST population or expanding OST coverage.
Previous cost-effectiveness analyses estimated the drug-only cost of triple therapy with protease inhibitors in the US at approximately USD$50,000 per course(40). The cost of future IFN-free DAA regimens is unknown, but if they cost USD$50,000 [$25,000-75,000], then the scaled-up treatment rates necessary to halve prevalence within 15 years (15, 40, and 76 per 1000 PWID annually in Edinburgh, Melbourne, and Vancouver, respectively) would require an annual HCV treatment budget for PWID of $3.2 million [$1.6-4.7 million] in Edinburgh, $50.0 million [$25.0-75.0 million] in Melbourne, and $51.3 million [$25.7-77.0 million] in Vancouver.
This modeling study explored the feasibility of HCV treatment as prevention in the era of IFN-free DAA-based HCV therapy. Current levels of HCV treatment among PWID are projected to only achieve modest or negligible reductions in HCV chronic prevalence among PWID. However, scaling-up treatment could lead to substantial reductions in HCV prevalence. In Edinburgh, a doubling of treatment rates (to 15 per 1000 PWID annually) could halve prevalence; a 3-fold increase could reduce chronic HCV prevalence to <7% within 15 years. Greater scale-up will be required in Melbourne and Vancouver where current treatment rates are lower and chronic prevalence higher, but prevalence could be halved in 15 years with treatment rates of 40 per 1000 PWID (13-fold increase from 3 per 1000 PWID annually) in Melbourne and 76 per 1000 PWID (a 15-fold increase from 5 per 1000 PWID annually) in Vancouver. A 20-fold increase from baseline treatment rates could reduce chronic prevalence to <15% and <20% in Melbourne and Vancouver, respectively, in 15 years.
Such scale-up, though considerable in Melbourne and Vancouver, has been achieved and exceeded for HIV treatment in both resource rich and poor settings(41), and even amongst PWID in some settings(42, 43). In addition, programs designed to address barriers to care among PWID have achieved yearly HCV treatment rates of 40-80 per 1000 PWID with PEG-IFN+RBV in Australia, Canada, Europe, and the United States(44-47). Moreover, scale-up of IFN-free DAA in theory will be easier to implement and have greater impact than current treatment regimes. IFN-free DAA regimens will require shorter duration and less complex monitoring(22) which in combination with higher SVR and reduced toxicity will markedly accelerate the current expansion of HCV treatment into the community, including integration with drug treatment, such as OST.
These projections are based on a theoretical mathematical model, with several limitations. First, there is uncertainty in a number of parameters. These projections are predicated on assumptions of the effectiveness of IFN-free DAAs (based on phase II studies as evidence from large-scale evaluations are not yet available). Outcomes among PWID are unknown, but systematic reviews report similar response rates among PWID and non-PWID for IFN+RBV regimens(48, 49). Additionally, active PWID are generally younger (a meta-analysis(48) found a lower median age (38 years) for studies with HCV treatment among PWID compared to registration trials for PEG-IFN+RBV (43-45 years)) and have less advanced liver disease than the broader HCV population. We do not explicitly model HIV/HCV coinfection, as two of our settings have marginal (<1%) coinfection prevalences. However, in settings where a greater proportion of PWID are HIV/HCV coinfected, lower SVR rates may be achieved. Sensitivity analyses showed a lower SVR of 80% would still achieve substantial impact, although slightly higher treatment rates would be required to achieve specific reductions in HCV prevalence.
Furthermore, better information on average injecting duration could substantially reduce uncertainty in the projections. The average age (and injecting duration) of people in drug treatment and serological surveys in the three sites suggest injecting durations between 11 and 27 years(19, 28, 35), but unbiased estimates are unavailable. An 11 year average injecting duration was assumed(34), but if it were longer then greater impact would be achieved. Also, HCV risk and treatment uptake will vary between PWID sub-groups, relating to injecting patterns or other factors such as homelessness. However, we considered scenarios where HCV treatment is delivered only in OST or when PWID are at "low risk" and show there is little impact on the outcome given movement between low and high risk states over an injecting career.
Second, complexities involved in treatment scale-up are not modeled. Treatment scale-up will likely be delivered in the community alongside OST, but additional interventions may be required to increase the case-finding among PWID, including health-care workforce training and interventions addressing stigma surrounding testing and treatment. Importantly, in our model a fixed number of PWID are treated annually, so as prevalence falls an increasing proportion of infected PWID are treated. This will have implications for diagnosis and treatment retention, particularly among harder to reach PWID. However, treatment recruitment may become easier as more PWID are treated.
Third, the model assumes a stable injecting population size, which although true in the settings examined may not be applicable to all settings. For example, data from Amsterdam(50) suggests a decline in the number of injectors. In these settings, as PWID prevalence falls we would expect HCV prevalence to increase as the cohort ages, and detailed models of these settings would require age-specific information on prevalence of PWID and injecting duration to determine intervention impact.
Finally, the model incorporates current levels of OST, but did not consider the impact of scaling-up of or targeting interventions such as OST and NSP-which may additionally contribute towards reducing HCV transmission(9). As our aim was to explore the scaleup of antiviral treatment, we did not stratify the population by drug-type or explore OST eligibility criteria. Additionally, we do not explicitly model NSP, but account for existing levels of coverage in modeling the epidemic in each setting.
Implications and Comparison with other studies
This is the first analysis to explore the potential of new and future direct-acting HCV antiviral therapy as prevention in a range of global prevalence settings, and supports previous modeling studies indicating HCV antiviral treatment could reduce transmission and HCV prevalence among PWID(12-16). In contrast, mathematical models have shown scale-up of OST/NSP could have considerable impact in areas with historically low levels of OST/NSP, but in many developed countries where coverage is already high (such as our sites) the scale-up required (e.g. 80% PWID on OST or high coverage NSP for 15 years) would be unachievable and unsustainable, and would achieve less impact than modest levels of HCV treatment(9).
Overall, the projections suggest IFN-free DAA HCV treatment as prevention is a feasible option for reducing the future burden of HCV-related disease, which is of critical public health importance given the lack of alternative effective HCV prevention strategies. HCV treatment is cost-effective, and in most settings treatment of PWID is highly cost effective(17) primarily because of the potential prevention benefit and reduction in secondary transmission.
A question still remains, though, as to whether scaling-up is affordable - especially if the drugs are marketed at similar cost to existing therapy. Expansion will be costly, and so any future scale-up of HCV treatment for prevention will require drug-price reform, especially for lower and middle income settings, but possibly also for developed countries that require high treatment rates.