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The end of hepatitis C?

Next-gen hep C therapies may see the disease's global elimination - but treament access must be stepped up dramatically
Hep C blue

2014 will do down as a pivotal year in the fight against hepatitis C virus (HCV), a blood-borne infection that is thought to infect around 2.5% of the world's population - some 170 million people.

The availability of new, more effective therapies for hepatitis C virus have raised the tantalising prospect of being able to eliminate the infection on a global basis,  although there are still significant obstacles to overcome.

Viral hepatitis - which generally means hepatitis B and C - “kills more people every year than HIV, malaria and tuberculosis combined, but has not had the same level of resources committed to it,” according to Charles Gore, who is chief executive of the Hepatitis C Trust in the UK and president of the World Hepatitis Alliance (WHA).

A resolution passed at the Assembly last year called on the World Health Organization (WHO) to draw up a strategy with targets for the elimination of viral hepatitis, and with milestones on the path to elimination likely to be set for 2020 and 2030.

While the availability of a vaccine for hepatitis B has made elimination of that form of viral hepatitis feasible, for HCV that would have been unthinkable before the development of new directly-acting antivirals - across three drug classes - that have simplified treatment and improved sustained virologic response (SVR) rates, which in HCV can be considered an effective cure.

The launch of drugs such as Gilead's Sovaldi (sofosbuvir) and Harvoni (sofosbuvir and ledipasvir), AbbVie's Viekirax (ombitasvir/paritaprevir/ritonavir) and Exviera (dasabuvir), J&J's Olysio (simeprevir) and Bristol-Myers Squibb's Daklinza (daclatasvir) means that doctors finally have an alternative to lengthy, cumbersome and hard-to-tolerate regimens based on immune-stimulating pegylated interferons.

Interferon regimens required months of therapy, saddled patients with debilitating side effects including fatigue, depression and flu-like symptoms and - even with the addition of an oral antiviral called ribavirin - only cleared the virus in around 60% of recipients.

The launch a few years ago of first-generation protease inhibitors to the pharmaco-therapeutic arsenal - Vertex' Incivek (telaprevir) and Merck & Co's Victrelis (boceprevir) - drastically improved success rates in some patients. However, the development of resistance, increases in adverse effects and a lack of activity in some HCV genotypes reduced their impact and initial blockbuster sales fell off dramatically once the new generation of treatments (see figure 1) approached the market.

Treatment numbers are declining when an increase is urgently needed

In fact, the Hepatitis C Trust has made a commitment to shutting down no later than 2030, says Gore, “on the ground that HCV will be eliminated as a public health concern and our organisation will no longer be needed”.

“There are not very many conditions you can cure in just 12 weeks,” he points out.

While there is every reason to be optimistic about the prospects for HCV elimination, there are still massive problems to overcome before that can become a reality.
At the moment, low rates of diagnosis and a sizeable population of carriers of the virus who do not know they are infected means that only around 3% of patients are treated, even in developed countries. Given that  around a quarter of people infected with the virus will go onto develop liver cancer or cirrhosis without treatment, its unsurprising that there are deep concerns that the disease could eventually become a public health timebomb.

Public Health England's 2014 report Hepatitis C in the UK last year reveals the scale of the problem, even for a country with a sophisticated healthcare system. Hospital admissions from hepatitis C-related end-stage liver disease quadrupled between 1998 and 2012 to reach around 2,400, with deaths rising by the same margin to 428, and that pattern is repeated in many other developed countries around the world. 

The latest official data put the number of HCV patients in the UK at around 214,000, with around 11,000 having serious complications such as liver cancer or cirrhosis.

Figure 1: Late-stage HCV pipeline
NS3/4A protease inhibitors
CompoundCompanyPhase
simeprevirJ&J/Medivirmarketed
bocepravirMerck & Codiscontinued
asunepravirBMSIII
vaniprevirMerck & CoIII
paritaprevirAbbviemarketed
grazoprevirMerck & CoIII
telaprevirVertex Pharmadiscontinued
 
NS5B polymerase inhibitors
CompoundCompanyPhase
sofosbuvirGilead Sciencesmarketed
dasabuvirAbbViemarketed
mericitabineRocheIII
beclabuvirBMSIII
ABT-072AbbVieII
 
NS5A inhibitors
CompoundCompanyPhase
daclatasvirBMSmarketed
ledipasvirGilead Sciencesmarketed
ombitasvirAbbViemarketed
GS-5816Gilead SciencesIII
elbasvirMerck & CoIII

“There is evidence that the number of people being treated each year is levelling off or starting to decline when an increase in the numbers treated is urgently needed,” notes the author of the report - hepatitis specialist Dr Helen Harris of Public Health England.

“Part of the problem may be that many of those who are willing and 'easy' to treat have already been treated,” she added, whilst acknowledging that another factor may be people waiting for improved treatments rather than undergoing more difficult-to-tolerate regimens with lower rates of sustained viral response (SVR).

People with HCV generally fall into three categories - those who have injected drugs at some point in their lives, those who are exposed to the virus in healthcare settings from contaminated blood or unsanitary equipment, and migrants who are born or brought up in countries with a high prevalence of HCV.

As a result the infection “is concentrated in populations who are marginalised and underserved and therefore have poorer healthcare access and health outcomes,” says Harris.

“Because new therapies are easier to administer, are of shorter duration, with improved side effect profiles and higher efficacy, they have the potential to be more easily rolled out in community settings, including drug services, prisons, and primary care.”

Pricing and access
Of course, the benefits of the new HCV therapies have come at a price, and Sovaldi has become a focal point for the debate about the cost of innovative medicines and how healthcare systems around the world can pay for them.

It is clear that the new generation of drugs are cost-effective - despite the high list price of around $84,0000 per 12-week course in the US and €60,000 in some EU countries. France and Germany have negotiated discounts to around €41,000 per course, which can be weighed against other healthcare costs, such as the management of end-stage liver disease and liver transplant.

The picture is somewhat complicated by the fact that not all patients with HCV go on to develop these complications, points out Gore, though there is some evidence of a cumulative increase in risk over the length of infection which could drive the complication rate higher as the current infected population ages.

“In England, we are currently facing the prospect of an ageing population of HCV-infected individuals in increasingly advanced disease stages, and current treatments are insufficient to prevent this mounting health problem,” notes Harris.

That will change when funding for the new drugs is made available to NHS patients in England and Wales in the coming months. The National Institute for Health and Care Excellence (NICE) ruled in January that Sovaldi was cost-effective but delayed access to the drug due to an extension to the deadline that requires NHS England to have services and funding in place to meet the treatment recommendations for patients.

That decision has raised eyebrows, not least at the Hep C Trust. Gore believes that in contrast to other diseases there is a lack of political will to tackle HCV, and people with the virus - already marginalised and stigmatised - are being sacrificed in favour of funding therapies for diseases with a higher profile such as cancer.
The only grounds for a delay is that the infrastructure to deliver therapy is not in place, but that is not the case here - patients have been treated with drugs for HCV for years - so it appears other factors are at play.

“If you step back from immediate budget pressures, surely you want to invest in therapies that work, are cost-effective and can make a difference?” asks Gore.

“The costs of inaction can be high too,” agrees Harris, pointing out that improved reach to marginalised patient populations “will also help reduce health inequalities and the excess premature mortality from liver disease in these groups”.

Concerns about the cost of the new drugs are also bubbling away across the Atlantic, with a Congressional investigation launched last year look into the pricing of Sovaldi and the Obama administration now looking to ways to use the purchasing power of Medicare Part D to negotiate drug prices downwards.

Meanwhile, a somewhat unforeseen consequence of the high-price of the new directly-acting antivirals in the US is that a form of horse-trading has emerged in the US market, with pharmacy benefit managers (PBMs) agreeing discounted rates with manufacturers in return for an exclusive for their products in formularies.

Many physicians are uncomfortable with this scenario as they believe this limits their freedom to prescribe HCV therapies on the basis of clinical criteria, with some arguing that the available interferon-free regimens are not interchangeable in terms of tolerability, ease of administration and efficacy.

That is particularly significant given that around 150m people in the US are thought to be insured in plans that now offer only one option, according to a recent poll of US physicians by First Word.

Of course, the bulk of HCV cases worldwide are in low-income countries, and Gilead has taken the step of introducing reduced pricing as well as licensing rights to produce its HCV drugs to generic drugmakers.

Finding the undiagnosed is very important

While the company was immediately criticised for not making provisions for middle-income countries, it is reported to be negotiating tiered pricing contracts with countries such as Brazil which has a sizeable HCV population but would struggle to pay the full price offered to developed economies.

The availability of additional HCV drugs should help drive prices down, but the sheer numbers of patients makes this a massively expensive problem to treat. Recognising that, HCV groups are already exploring new ways to finance treatment and several met in London in February to discuss options.

One model on the table was a variant of the social impact bonds (Sibs) - pioneered in the UK as a means of unlocking private investment for social initiatives - that have been deployed to try to reduce re-offending rates among short-sentence prisoners, according to Gore.

In a nutshell, these involve private service providers and investors fronting cash for projects - rather than the taxpayer - on the promise of a return on the investment provided the programme is successful. The approach allowed government to only pay for successful outcomes, rather than simply allocate funds with the hope of meeting the objectives.

Sibs “haven't completely taken off yet”, notes Gore, but are an example of an alternative funding vehicles that could warrant consideration in healthcare.

Drugs are not enough
Of course, to achieve HCV elimination, prevention activity, including oral substitution therapy and needle and syringe programmes for people who inject drugs, will also be crucial. Reaching people who inject drugs is vitally important because modelling work has shown that actively treating this group can result in reductions in prevalence, and that reducing transmission via oral substitution therapy and needle exchange alone is not sufficient.

“Finding the undiagnosed is also very important,” says Harris. “The undiagnosed cannot benefit from hepatitis treatments, or from other 'non-treatment' prevention measures[…]such as moderation of alcohol consumption and vaccination against other hepatitis viruses.”

Without a diagnosis, individuals' ability to take practical steps to limit the spread of the virus to others is limited.

“In theory, when the right tools are available, all infectious diseases can be eliminated,” according to Harris. “In reality there are distinct biological features of organisms, and technical factors of dealing with them, that make their potential for elimination more or less likely.”

Several factors, including the lack of an effective vaccine, the asymptomatic nature of the infection, the high cost of therapies in economically challenging times, and the need to restructure treatment services to improve their accessibility, all make tackling HCV a challenge.

That said, new therapies offer the potential to improve outcomes, reduce hospitalisations and deaths, reduce the prevalence of infection and stem transmission of the virus. So whilst elimination of the virus is currently not possible, it is possible to eliminate hepatitis C-related liver disease as a serious public health concern. 

Article by
Phil Taylor

is a freelance journalist specialising in the pharmaceutical industry

24th March 2015

From: Sales

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