A WORLDWIDE SILENT KILLER

by André Picard


Worldwide, an estimated 550 million people have been infected with viral hepatitis, a family of viruses that can cause debilitating liver diseases like cirrhosis and liver cancer.

Between them, hepatitis B and C kill almost 1.5 million people annually – more than any of the « big three » infectious diseases : HIV-AIDS (1.4 million), tuberculosis (1.4 million) and malaria (700,0000)– that capture most of the public attention and research dollars, and mobilize political action.

Through determined global public health campaigns, the infection rates and mortality rates of AIDS, TB and malaria are all falling. But hepatitis cases and mortality are still rising sharply : Consider that the number of hepatitis C deaths has quadrupled in the last decade.

Viral hepatitis is one of the most common and deadly infections on the planet, but, for a variety of reasons, the scourge is well down the list of public health and political priorities and, as a result, gets a negligible amount of media coverage.

Why do we hear so little about the scourge of hepatitis ?

There are a variety of reasons.

First and foremost, hepatitis kills slowly and silently. The virus can damage the liver over a period of decades before a person has visible signs of cancer or cirrhosis. But the virus can be merciless. About one in five people infected with viral hepatitis will develop cirrhosis (scarring of the liver) that can necessitate a transplant, and 1-5 per cent will die of liver cancer.

Due to the stealth nature of the infection, a large number of sufferers – up to 40 per cent by some estimates – are unaware of their infection. Patterns of infection vary markedly between countries, meaning there is no single global pandemic, but hundreds of overlapping but seemingly unrelated epidemics.

There is also a significant disconnect between the cause and the effect of the infection. Few people make the link between getting a blood transfusion as a child, risky sexual behaviour as an experimenting teenager, or one-time needle-sharing, and contracting liver disease later in life.

There is also a lot of stigma attached to hepatitis. The chronic fatigue often associated with infection means that sufferers can be pegged as lazy and unproductive.

Because hepatitis viruses can be transmitted sexually and by injection drug use, there are oftentimes negative stereotypes perpetuated about carriers of the disease. Yet, while many cases of hepatitis are preventable, the reality is that the source of infection is often unknown.

The lack of profile of viral hepatitis means few countries undertake systemic screening and data collection is poor which, in turn, creates a vicious cycle of indifference and inaction.

Journalists and other science communicators can help break that cycle by understanding the reality of hepatitis, including the breadth of the problem, and the challenges of prevention and treatment, as well as the opportunities for change on the horizon.


LIVER DISEASE

Liver disease is caused by alcohol abuse : That is an ingrained belief around the world. But there are, in fact, a number of causes, the most common of which is hepatitis (hepa is the Greek word for liver ; -itis means inflammation.).

There are several types of hepatitis – A, B, C, D, E, G – all of which have a common origin. The illness hepatitis has been known for centuries – there are reports of epidemic outbreaks of liver disease dating back to 2000 B.C. This long history robs hepatitis of the cache of newness that propels other infectious diseases like AIDS, SARS and MERS into the headlines.

Yet, hepatitis is, in many ways, a relatively new story. It was not until World War II that scientists realized that hepatitis was caused by viruses and could be blood-borne as well as water-borne. This breakthrough occurred after a large number of soldiers immunized against yellow fever developed hepatitis due to the re-use of needles, not from contaminated water, as was usually the case.

Hepatitis B was identified in 1963, hepatitis A in 1973 and hepatitis C (long known as non-A-non-B) not until 1989.

While they share a common name, the viruses are quite different, and even have different routes of transmission. To complicate matters further, there are different genotypes of the viruses in various parts of the world ; there are already seven hepatitis C genotypes that have been identified.

Hepatitis A is spread through the fecal-oral route, meaning it is generally food-borne and water-borne, but can also be spread by some sexual practices. Hepatitis A also tends to be an acute illness, much like food poisoning, and is deadly only in rare cases.

Hepatitis B is spread by contact with bodily fluids such as blood, semen and saliva. The virus can be transmitted sexually, during the birth of a child, or by blood transfusion or contact with a contaminated needle.

Because it is spread easily, hepatitis B is the most common form of liver disease. Some people become acutely ill after infection, but most cases are chronic, eventually causing liver cancer or cirrhosis.

Globally, hepatitis B kills about 700,000 people annually. This, even though it is vaccine-preventable. The vaccine, which has been available since 1973, is given to babies and, again, before young people become sexually active.

Hepatitis C is not as easily spread. It is almost exclusively blood-borne, though it is sometimes sexually transmitted.

It is, however, quite deadly, also killing about 700,000 people a year. There is no vaccine. There are, however, medications that can cure hepatitis C.
For all intents and purposes, hepatitis C should be considered principally a healthcare-acquired infection. Most sufferers contract it through exposure to unsafe blood – for example, untested (or inadequately tested) blood used for transfusions, re-used and inadequately sterilized needles and other surgical/medical equipment, and via tattooing and piercing.

While hepatitis C is often described as a disease of intravenous drug users, only about 10 per cent of the overall number of cases are believed to be caused by shared needles.
It is important to bear in mind too that much remains to be learned, particularly about hepatitis C. For example, in about 25 per cent of cases, the route of transmission is unknown.

What we do know is that a significant number of people who are infected with viral hepatitis – perhaps as many as one in four – clear the virus on their own and that many others, because the viruses take so long to damage the liver and cause conditions like cancer and cirrhosis, die of other causes. The lengthy period between infection and illness helps create complacency.


THE GLOBAL PUZZLE

Globally, 3-5 per cent of the population is infected with viral hepatitis. But the prevalence varies tremendously by region, by country and even within countries.

In Western countries, where immunization against hepatitis B, screening of blood for hepatitis C antibodies, and universal precautions in healthcare settings are the norm, the infection rate is low – less than two per cent.

In many middle- and low income countries, where vaccination may come late or be incomplete, and where healthcare safety norms are not always followed to the letter because of the cost, the infection rate tends to hover around 5-8 per cent.

And in some parts of Africa and Asia, where the healthcare infrastructure is severely lacking, and unsafe healthcare practices are commonplace, the rate can be as high as 10-15 per cent.

This distribution of cases is a reminder that, like most infectious diseases, the greatest burden of hepatitis is borne by the poorest countries – those that have the fewest resources to undertake prevention programs and to offer adequate care to those who are sick with hepatic disease – and especially by marginalized populations within every country, such as drug users and sex workers.

One has to bear in mind, however, that a lot of the figures cited are guesswork, estimates extrapolated from small samples.

The data are weak because there is little effort and few resources dedicated to collecting it. Few countries conduct universal screening for hepatitis, and many do not even screen pregnant women or those in high risk groups (as is now the norm with HIV) to cut the chain of transmission.

That leads a number of researchers to believe that despite the shockingly high estimates of the prevalence of viral hepatitis – 350 million carriers of HBV, 185 million HCV and 15 million other chronic carriers – that those numbers may actually be an under-estimate.
For example, India reports a hepatitis C infection rate of only one per cent, which beggars belief given the crude health infrastructure in large parts of the populous country, not to mention significant levels of injection drug use. Currently, however, there is little incentive for countries to seek out data, as was the case in the early days of the AIDS pandemic. It was only when efforts (and money) were put into research, prevention and treatment that the true extent of HIV infection became clear, but there is no such effort related to viral hepatitis.

What is unquestionable, regardless of the precise numbers, is that they are going in the wrong direction – ever upwards. There is a large and growing gulf between the burden of hepatitis and the awareness and ability to respond to the challenges.

It is also clear that, beyond the regional differences, within countries (even those with good screening and treatment) there are some clearly identifiable risk groups that need to be singled out for particular attention.

Intravenous drug users, particularly those who live on the streets or other low-income settings, are the most obvious risk group because there tends to be a fair bit of needle-sharing and high-risk sex work, and harm reduction programs like needle exchanges are not always in place. In some countries, fully half of IV drug users are infected with hepatitis C, and they can also be co-infected with HIV (which has similar means of transmission), acting as carriers of disease.

In some cultures, there are also high-risk practices like tattooing, piercing, scarification, ritual circumcision and female genital mutilation that put people at increased risk of HCV infection. In Pakistan, a study showed that barbers – who use straight razors to shave customers and often nick them – are a major source of the spread of HCV infection.

In some countries with poor health infrastructure, the use of « traditional » healers is also commonplace and they don’t follow safety practices ; neither do merchants who, in public markets, sell concoctions like vitamin and iron shots.

But, again, the greatest risk still comes in the healthcare setting.

That reality has also left a legacy. A significant number of people get surgery at some point in their lives, and that often involves a transfusion. As a result, in Western countries such as the U.S and Europe, there are a large number of seniors – notably Baby Boomers – who are now being struck by the ravages of hepatitis. Because exposure to blood is so widespread and many received transfusions before testing was implemented, more people die of hepatitis C than AIDS in North America.

Screening of blood for hepatitis B did not begin until the mid-1970s, blood products were not heat-treated to kill viruses like hepatitis until the mid-1980s, and a test for hepatitis C was not developed and implemented until the early-1990s.

The notion that needles and other medical equipment should not be re-used because of the risks of spreading infection is also relatively recent, and disposable « sharps » are still not the norm in many countries.

Practically, that means a lot of people were exposed to potentially contaminated blood – and may only learn of their exposure decades later when they are diagnosed with liver disease in the form of cancer or cirrhosis.

A striking example of this is in Egypt, which has one of the highest incidences of hepatitis C in the world with about one in every seven adults infected. In the early 1980s, Egypt set out to deal with the epidemic of schistosomiasis, a common parasitic disease along the Nile River. The treatment, an injection of tartar emetic, was broadly offered, but needles were re-used and not sterilized. The result was to get rid of schistosmiasis, but to infect hundreds of thousands with HCV.

Hepatitis B vaccine has been available since 1982. It is highly effective, but must be given quickly – preferably within 24 hours of birth – if it is going to be effective.

That is particularly important in parts of the world where there is a high prevalence of HBV, like East Asia, where mother-to-child transmission is a significant risk factor.

The earlier in life someone is infected, the greater the likelihood they will develop liver cancer or cirrhosis. But, in parts of the world where births tend to be at home, and there is not always ready access to healthcare providers who provide services like neonatal vaccination, many children do not get vaccinated adequately, even if they get their childhood hepatitis B shots later on.

There is no vaccine that protects against hepatitis C, and there is unlikely to be. There are at least six genetically distinct forms (genotypes) of HCV and more than 50 subtypes have been identified, so it is unlikely that a global vaccine could protect against all the variants.
The genotypes tend to vary by geographic region. Type 1 HCV is most common in the U.S. and Europe ; type 3 dominates in India, the Far East and Australia and ; type 4 is found most frequently in Africa and the Middle East.

The other main reason vaccine development is on the back burner is that there are effective treatments for hepatitis C. In fact, new drugs are so effective they are being called a cure. But, of course, the word « cure » should be used carefully, because there are some provisos notably that the treatment doesn’t always work, and they do not leave people immune to being infected anew.

Treatment for hepatitis C has been around for a long time. Well before the virus was actually identified, severe liver disease was treated with inteferon, and that was, until recently, the standard treatment for patients beginning to feel the effects of chronic infection with viral hepatitis.

Interferon, however, is a long, demanding treatment that has a lot of nasty side effects, and works less than half the time.

Interferon boosts the immune system, while the new drugs work by attacking the virus itself ; they keep HCV from replicating and kill off the existing virus in the body.
Cure rates are in the neighborhood of 95-97 per cent in well-controlled trials and about 85-90 per cent in the real world – and, as an added bonus, the drugs have far fewer side effects.

There are, to date, two principal products on the market : A combination of ledipasvir and sofosbuvir (brand name SOVALDI) and a four drug combo – ombitasvir, paritaprevir, ritonavir, and dasabuvir (known as VIEKIRAX + EXVIERA).

These drugs have made headlines largely because of the cost – in the U.S. about $1,000 a pill, or up to $95,000 for a full course of treatment. In India, however, the price is as little as $1,000 in total.

But should not forget that the drugs work differently on various genotypes. They are highly effective on HCV 1 genotype (the one that is predominant in North America and Europe) but quite ineffective on HCV type 3 genotype (which we see in India and Africa).

prevalence_map_1

 Map taken from Messina et al., 2015

Relative prevalence of each HCV genotype by Global Burden of Disease region. Size of pie charts are proportional to the number of estimated HCV cases estimated by Hanafiah et al., 2013

prevalence map_genotypes

Map Taken from Messina et al., 2015 – Distribution of most common HCV genotypes.

Again, the gap in care is growing between rich and poor countries: The issue is not only cost but the fact that the new drugs are most effective in treating HCV genotypes most prevalent in the developed world. Thankfully, there are new drugs in the pipeline that will address this problem, though whether they will be affordable is another matter.

The other bit of good news is that, because the new HCV drugs work on different parts of the virus, it is unlikely that resistance will develop, as has been the case with AIDS drugs.
Studies show these new hepatitis drugs are cost-effective at least on an individual basis, because treating the diseases that HCV causes, with liver transplants and cancer treatment, is extremely costly.

The larger issue, given the high number of people with hepatitis C, is that the cash outlay to treat everyone would be prohibitive, even if drug costs come down considerably. It is often said that the new treatments will bankrupt drug plans, which is a bit of rhetorical overkill. As with all new expensive drugs, choices will have to be made, and prices should come down over time.

What it means, practically, is that not everyone infected with HCV will get treated immediately ; there will have to be a prioritization and selection process. Guidelines are already being developed, and they are based on severity of illness, genotype, co-morbidities and drug interactions with treatments for other disease.

Given the effectiveness of these new treatments, there have been moves to step-up screening, which raises a host of practical and ethical issues.

The debate about the cost of treating and curing hepatitis C has focused too narrowly on drugs, which are only a portion of the overall cost.

As with HIV-AIDS drugs, there are discussions about the need to bring down prices, especially in resource-poor settings. Pharmaceutical companies will have an important role to play in these negotiations, and having patent pools and deals with generic makers will likely be solutions.

But having cheaper drugs is only one part of the equation, and the cost.

If you are going to treat, you first have to test. Screening tests are relatively inexpensive, but genotype testing is not. You also have to test liver function to help determine who is sickest, and to judge effectiveness of the treatment. All of this requires hi-tech laboratories and well-trained personnel. Not to mention a decent healthcare system.

Most important of all is that, even if you cure someone of their HCV infection, their liver disease does not magically disappear. Damage to the organ has occurred over decades, and can still result in liver cancer or cirrhosis, so the promised savings are likely to not be as great as assumed.

Cure is not the same as a vaccine either. People can be re-infected, even after expensive treatment. Given that reality, do you deny treatment to those with high-risk behaviors?
Even the idea of universal screening – and, in many countries, liver disease support groups advocate that all people born prior to 1975 be tested – raises some thorny ethical dilemmas.

If you test everyone do you have an obligation to treat everyone? Is it ethical – and responsible – to tell someone they are infected with a cancer-causing agent and then turn around and say treatment costs are prohibitive so they are ineligible ? If you test, will the infected be stigmatized and discriminated against, for example putting their jobs in peril?

These new treatments may be a medical miracle, but they are also a nightmare for policy-makers, especially those whose job it is to contain health budgets.


THE END GAME

There is not a single country on Earth that is free of hepatitis C. Yet, the promising medical developments that make it possible – at least in theory – to cure most sufferers have some public health advocates dreaming big after years of being relegated to the shadows.

There is now open and hopeful talk of hepatitis C « elimination » by 2030. That does not mean eradicating the disease (although that is theoretically possible because there is no insect vector or animal reservoir for HCV). Rather, the ambitious goal is to have 90 per cent of people who are infected with HBV or HCV to be screened and diagnosed, and for 90 per cent of those eligible for treatment have their condition suppressed or cured. This approach mirrors the 90-90-90 strategy for eliminating HIV-AIDS by 2030.

It is estimated that meeting those targets would reduce the number of people infected with viral hepatitis by 70 per cent and cut the mortality rate by half within the next generation.

Treatment is only part of the solution. There is not an effective treatment or cure for hepatitis B but there is a vaccine and, after 20 years on the market, it is finally starting to have a significant impact on infection rates.

Because viral hepatitis is principally acquired in the healthcare setting, it is also important to cut infection at the source. Campaigns like Safer Healthcare Now are helping educate and inform the public and health care providers about the importance of hand hygiene, the appropriate use of antibiotics, and monitoring surgical sites to reduce the risk of infections. Public policies that also inadvertently undermine prevention of hepatitis, like the so-called War on Drugs, also have to be abandoned in favor of evidence-based harm reduction initiatives like supervised injection sites, or needle exchanges to decrease the risk of disease spread.

The only way to to rein in the ever-worsening and ever-more deadly epidemic of viral hepatitis is with a concerted global effort, similar to the response to AIDS, tuberculosis and malaria – and it has to be said that the « big three » infectious diseases have a considerable head start. Research is particularly lacking and underfunded; if you want to eliminate a disease, you have to have a solid grasp on how it is transmitted, and on the barriers to prevention and treatment.

Viral hepatitis was long taken for granted, even by global public health agencies like the World Health Organization.

In 2006, when the Millenium Development Goals were drafted, viral hepatitis was notably absent. It had no champions. At the WHO, an organization with 8,000 employees, there was not a single person with responsibility for hepatitis in their title. Meanwhile there were entire agencies and divisions for AIDS, TB and malaria.

The impetus for change came from the grassroots, from patients. In 2007, hepatitis support groups in a number of countries joined forces to create the World Hepatitis Alliance, and one of their first initiatives was to create World Hepatitis Day, which occurred for the first time on May 19, 2008.

Two years later, the WHO created a global hepatitis program and, in 2014, it published the first guidelines for the screening, care and treatment of HBV and HCV. That same year, the World Health Assembly called on every country to adopt national strategies for dealing with viral hepatitis.

The desire – and need – to draft and implement such strategies was given a considerable boost by the arrival of new drugs. The message being driven home by groups like the World Hepatitis Alliance is that countries simply cannot sit on the sidelines anymore; they have to be part of the conversation.

The advent of new treatments, combined with the empowerment of patients, has helped break the silence surrounding this age-old killer.

There is now a rare opportunity to significantly prevent and treat millions of cases of cancer and other deadly liver diseases. There is, in essence, a solution – or, more accurately, solutions – to a millenium old problem.

There is also a story – no, stories – to be told. But those stories need to be factual, nuanced and evidence-informed.