Hepatitis C: the cure?

Dr Ed Gane, hepatologist and transplant specialist

As usual, hepatitis C was nowhere near the main stage. The elders of the American Association for the Study of Liver Diseases – the AASLD – had put the disease in its accustomed place: the upper floors and smaller meeting rooms of its enormous, annual research conference.

“The Liver Meeting”, or AASLD 2011, was taking place at the great, glass-fronted Moscone West Convention Center in downtown San Francisco. Almost 9,000 people were there – family doctors, hepatologists, gastroenterologists, academics, drug salesmen, public health officials – all networking, trudging the escalators, wandering the beige exhibit halls, trying to stay on top of an avalanche of medical information. Across five days in early November, no fewer than 2,200 liver-related scientific abstracts were being presented, at sessions that ran from 6.30am until 9pm. Specialists in hepatitis C, an awkward, under-recognised health problem, were used to finding their way to the back rooms, the less-glamorous receptions.

Many felt it was time the disease moved up the agenda. Since it was identified in 1989, “Hep C” or “HCV” to those who work on it, has only confounded those who underestimate it. Transmitted through blood, the virus is now thought to infect around 2.5 per cent of the world’s population, or 170 million people. Of those, around a quarter will develop liver cirrhosis, or cancer, within a decade or two. In the UK, deaths from hepatitis C have trebled since 1996 and more than 200,000 people are infected. No one knows what to do about the coming demand for liver transplants. For the past decade at least, scientists have used phrases such as “gathering storm” and “silent epidemic” to try to bring attention to the subject.

There has also been a torrent of new data to keep up with. Despite its orphan status, the sheer numbers of people infected with hepatitis C have made it the subject of hundreds of millions of dollars of medical research – particularly by pharmaceutical companies, working on a new generation of drugs. And AASLD, as the world’s premier liver event, has become the occasion when information on those drugs – known as “direct-acting antivirals” – is often shared for the first time. In recent years, hepatitis C delegates had got used to turning up to must-see presentations that were filled way beyond capacity.

One look at the 2011 programme told conference-goers that a session on the Sunday afternoon – “HCV: Refining the Use of Direct-Acting Antivirals” – was going to be mobbed. Room 2001, on the second floor of the convention centre, only held about 400 people. Dr Ed Gane, a 51-year-old hepatologist and transplant specialist from New Zealand, who was to give the fourth of six presentations in the session, arrived about 10 minutes before it was due to begin. “It was packed to the gunwales,” he told me. Conference staff began setting up a video link to adjoining rooms to cope with the spillover.

The cognoscenti were there to hear Gane. An unshowy, respected doctor, he had been working on hepatitis C since the early 1990s, and for the past year, had been carrying out a clinical trial of a particularly promising new drug developed by a small American pharmaceutical company called Pharmasset. The drug was known by its laboratory name, “PSI-7977”, and today, Gane was to give an update on the trial, called ELECTRON.

Although Gane had tested the drug on just 40 patients, and although it was a phase two trial (all new drugs are tested over three, increasingly rigorous phases before they are approved), ELECTRON represented something big in the world of hepatitis C. Since they began treating the disease in the early 1990s, doctors have had to rely on a crude, antiviral drug called interferon. Interferon occurs naturally in the human body, and when extra quantities are injected, the immune system is stimulated to fight off hepatitis C, a tricky infection which stays in the liver for decades. Unfortunately, interferon does this at a cost: patients feel depressed and weak, and suffer flu-like symptoms. They cough and ache and itch. By tweaking the chemical structure of interferon, and adding a second, similar agent, called ribavirin, in 1998, clinicians managed to improve the treatment somewhat, but the standard regimen for hepatitis C has long been an ugly proposition. “They are both just dirty drugs,” one doctor told me. Patients take three ribavirin pills a day and have one interferon injection a week for anything up to a year. They get better about 60 per cent of the time.

As a result, the holy grail for hepatitis C researchers has been to discover new drugs that work better and that work without negative side effects. Dozens of drug companies and hundreds of research scientists have been working on this for more than a decade, and by late 2011, PSI-7977 was one of about 60 prototype drugs in the race. At a conference in Berlin earlier in the year, Gane had shown that the drug could noticeably improve the treatment of hepatitis C when used in combination with the standard drugs – interferon and ribavirin. Now he was about to show what happened when you took interferon out of the equation.

At about 4.30pm, Gane stood up to present his data. Like the other speakers, he had a 15-minute slot. By this time, three adjoining conference rooms had been filled, so he had a total audience of about 2,000 scientists – almost a quarter of the entire attendance at AASLD – but he could only see the few hundred standing and sitting in front of him. Among them was Professor Graham Foster, a leading British expert on hepatitis C and one of a handful of people in the world who knew what Gane was going to say next. A member of Pharmasset’s advisory board, Foster, who had also worked on hepatitis C for more than 20 years, had seen the results a few weeks earlier. “It really was a jaw-dropper,” he said. “Just ... Blimey.”

Gane began to click through the slides. The acoustics in Room 2001 were difficult, so he did not really have a sense of how the information was going over. He trotted through the design of the trial. The 40 patients on ELECTRON had been divided into four groups. Three groups of 10 patients had taken PSI-7977 in various combinations with the standard treatment of interferon and ribavirin. A fourth group had taken PSI-7977 and ribavirin alone.

After just three months of treatment – as opposed to six months, or a year – all 10 patients in this group were cleared of hepatitis C. In medical language, their “sustained virologic response”, or SVR, was 100 per cent. Gane clicked through to the next screen. At six months, long after their treatment had stopped, their SVR (scientists call this measurement at 24 weeks, “the cure rate”) was the same: 100 per cent. No one had relapsed. The drug had worked. There were no reported side effects. “There was a hush,” said Gane. “Yes, that’s right. I kind of noted that.”

“You could hear a pin drop in the auditorium,” Greg Dore, another hepatitis C doctor, from Sydney, told me. Dore was standing against a wall. “People were just absolutely amazed by what they were seeing.” Gane finished his presentation by thanking his patients. His final slide showed damage from the recent earthquake in Christchurch, where part of the trial was carried out. The room broke into applause.

Even now, more than a year later, people from the field of hepatitis C find it hard to know exactly what happened in San Francisco that afternoon – still less, its precise consequences for their patients, and their own work. “And now, without interferon,” intoned Foster, able to remember Gane’s exact words, as he recreated the big moment for me in his office in Whitechapel a few weeks ago. In that crowded room, tough, methodical research scientists, many of whom had spent their entire careers on hepatitis C, watching novel treatments flatter and deceive, felt their scepticism quiver before the columns of 100 per cents arrayed across the screen.

The shock showed on the faces of the delegates as they drifted out into the hallways. “Everyone knew – this is a cliché – but everyone knew this was a new dawn,” said Dore, the Australian doctor. Clinicians were delighted, but conscious that many things could still go wrong. Drug developers from rival companies were frankly panicked. Everybody’s world shifted a little on its axis. Jason Grebely, a colleague of Dore’s, who arrived after the presentation, remembers wandering into a quiet, stunned crowd. “Everybody was dumbfounded,” he said. “We spoke to pharma people ... and they were just, ‘Oh, whoah. What just happened?’”

Some decided that they had just witnessed the cure to hepatitis C. On November 21, 15 days after Ed Gane’s presentation, Gilead Sciences, a US pharmaceuticals company, agreed to buy Pharmasset – effectively the PSI-7977 molecule – for $11.1bn. The founder of Pharmasset, an Italian-Egyptian chemist called Raymond Schinazi, who oversaw the drug’s development, made $440m personally from the sale.

Others less intimately involved entered a longer, more private process of revelation. They waited first for bad news, corrective data, that did not come, and then they found themselves thinking that if this wasn’t the cure itself, then it had certainly shown them the shape of the answer they had been seeking. “The fundamental problem has gone,” Foster decided. “We know how to do this.” Along with the thrill for patients, this knowledge brought with it a secondary, much more subtle feeling, of being part of a huge, collective, intellectual enterprise that was now, rather suddenly, going to end. “There are moments when there is a final grain of sand on the pile and the pile collapses,” the professor said. “I advise youngsters to look around. Hepatitis C is not a disease for a career any more.”

The cure. The breakthrough. Eureka. These are the moments that science, certainly the Hollywood version of it, craves more than any other, and yet they are elusive, many-sided things. While there is no doubt about the reality of PSI-7977 – it is now in phase 3 trials in the US and Britain, under the name “Sofosbuvir”, and is expected to be available to treat patients in the next two years – to live through this kind of ruction is often a rather fraught, complicated affair.

Like other occasions of extreme achievement, science often manages to combine very bright and very dark sides of the human character (and plenty of shades in between) often in the same people, even at the same time. Think of Isaac Newton. Not content to reshape humanity’s understanding of the universe, he pursued his competitors relentlessly, deleting their names from successive editions of the Principia Mathematica and taking pleasure in their deaths. When Gottfried Leibniz, who had the misfortune of inventing calculus independently from Newton in the 1670s, died in 1716, Newton boasted of breaking his heart. “Second inventors,” he wrote, “count for nothing.”

Even such marvels as the polio vaccine – one of the great medical success stories of the 20th century – barely managed to conceal the human emotions that went into making them. The race to inoculate the world’s children against a crippling disease was driven partly by a pathological, 40-year rivalry between Jonas Salk and Albert Sabin, two virologists, who continued to disagree on almost everything until their deaths in the 1990s.

In the end, there was enough polio in the world for both Salk and Sabin, but the two men handled their triumphs in very different ways. One of the unspoken hazards of making a breakthrough is having to figure out what to do next. Sabin went back to his lab and got to work on other viruses; whereas Salk, who won a far greater share of the popular adulation, quit his job, set up a grand, self-named institute overlooking the Pacific and got divorced. “Salk did not cope with it particularly well,” said David Oshinsky, who wrote a Pulitzer Prize-winning history of the polio vaccine. “Sometimes when a huge project is done, there is more than a sense of relief, there is sort of a sense of depression: that it’s over, that all this time and effort you’ve put into it, that nothing will ever be quite like this again.”

This century, at a time when scientific problems require huge, interdisciplinary teams, often collaborating on the other sides of the world – or staggering pieces of equipment, like Cern’s Large Hadron Collider – it can be difficult to even identify when breakthroughs occur. “I would just like to say this: there is never a moment of apotheosis,” an American virologist called Dr Paul Offit told me. “There is never that one clear, definitive moment when you say, ‘This is it. We’ve got it.’”

Offit is one of three inventors of a vaccine for rotavirus, an infection that causes diarrhoea in young children. Since it was licensed in 2006, the vaccine has saved hundreds of thousands of lives. But when Offit described his quest to develop it, he spoke mostly about the overwhelming feeling of responsibility as his team’s vaccine began to make its way into the world – with the always unknowable risk of rare side effects. “You know, it was given to hundreds of thousands and then millions and then tens of millions of people,” Offit said. “And then finally you can breathe a sigh of relief. But that was it. After 25 years, I would say it was more like a large exhale, rather than a moment of exhilaration.”

The thrill became visible in retrospect. Offit knows now that his delight was in the years buried inside the problem he was trying to solve. “You would come into that room, into that laboratory and it was like a room with a purpose. It was like a church.” He never thought he would actually be part of the team to crack the vaccine. It was almost too much to take in. “It was sort of like winning the lottery,” he said. Ed Gane used a similar phrase when telling me about his work testing PSI-7977. “It’s like a dream being realised,” he said. “It’s a privilege for me.”

From the beginning, hepatitis C has been a contrary disease. No one knows how the virus got its start: maybe in dogs, or bats. Different variations, known as genotypes, exist in different parts of the world. It has certainly existed for thousands of years, but because the virus travels in the blood, for centuries it never moved very far. It was only, paradoxically, with improvements in public health in the 20th century – particularly vaccination programmes and blood transfusions – that hepatitis C really got going. Worldwide, infections were probably at their peak in the 1970s and 1980s, when poorly sterilised needles in the developing world, and intravenous drug use in the west, gave the virus a million pathways to spread.

When doctors first noticed the new disease, they were not sure what to do with it. They called it a type of hepatitis, which means inflammation of the liver, but for more than 20 years, it was just “non-A, non-B hepatitis”. Hepatitis C resisted definition because it didn’t look like other hepatitises – it is more closely related to diseases such as West Nile virus and yellow fever than either Hepatitis A or B – and also because of its variability. Even by virus standards, hepatitis C mutates constantly and haphazardly: it has six genotypes, and more than 50 “subtypes”. Even after it was formally identified, and cloned, in 1989, it took teams of researchers in the UK, Germany and Japan another 12, immensely frustrating, years to manage to grow hepatitis C in cell culture – a critical step towards finding a cure.

Most cruelly, work on hepatitis C was also held back by its manifestation both in patients’ bodies, and in society. Around a quarter of people infected with the disease manage to shrug it off within six months. For the vast majority, however, hepatitis C is a silent, asymptomatic passenger for several decades. When Charles Gore, the chief executive of the Hepatitis C Trust, was diagnosed in 1995, doctors simply didn’t know what to tell him. “‘Try not to drink too much,’” was the advice he got. “That was it, absolutely it.” Clinicians argued about whether it was even a serious infection.

Instead, one of the only solid things that people knew about hepatitis C was that it was a disease of drug users and, sometimes, immigrants: groups poorly positioned to lobby for medical research. Even now, hepatitis C remains woefully under-publicised, in large part because people are reluctant to admit having it, or even to be tested for it, because of the associated stigma. Conversations about hepatitis C almost always involve a comparison with the very different, vigorous world of Aids campaigns. Part of the comparison is about timing. In many countries, hepatitis C suffered greatly from being the next, frightening virus to come after HIV. “There was, if you like, a horror fatigue,” said Graham Foster. “People couldn’t believe there was yet another disease wreaking havoc.”

Raymond Schinazi, chemist and founder of Pharmasset

Still, for all its trickiness, hepatitis C has always tantalised scientists. Since they have been able to study it properly, they have come to realise that, unlike other viruses, such as HIV, or hepatitis B, hepatitis C does not inveigle itself particularly well inside the body. It doesn’t get tangled up in the immune system, or create hidden reservoirs of itself: it replicates only in the cytoplasm of liver cells, making it open, relatively speaking, to attack.

What’s more, through knowledge chiefly gained from the study of HIV, drug developers and virologists have had a good sense of where the virus’s likely weak points might be. In a sense, it has all added up to a jackpot, waiting to be won. As Foster put it: “There are half a dozen possible targets on the hepatitis C virus, so you don’t have many things to test. There are hundreds of millions of people infected; the current cure rate is 60 per cent; and the drugs are virtually intolerable ... You’d want to play wouldn’t you?”

Raymond Schinazi decided to play in 1995. The son of Italian Jews, born in Alexandria, Schinazi’s family was forced to leave Egypt as refugees in the early 1960s. He studied chemistry first at the University of Bath, before moving to Yale in the late 1970s to study under William Prusoff, the father of a new branch of pharmacology, called antivirals. By constructing his own nucleosides – a type of nucleic acid, very closely related to the building blocks of DNA and RNA, from which viruses are also made – Prusoff had created Idoxuridine, a chemical compound that stopped the herpes virus from replicating itself and became the world’s first effective antiviral drug, in 1959.

Schinazi was a staggeringly successful pupil. By the late 1990s, he had used nucleosides himself to help develop two of the most widely-used HIV antivirals, Lamivudine and Emtricitabine, better known as 3TC and FTC. Emory University, outside Atlanta, Georgia, where his lab was based, boasted that 94 per cent of people in the world being treated for HIV took drugs that were designed by Schinazi. As researchers began to strip away some of hepatitis C’s secrets, Schinazi, who is now 62 and known for his direct, rather bold manner, recognised his next target. “I thought to myself, this is a virus that wants to get cured,” he told me.

In 1998, Schinazi set up two separate companies as vehicles for his hepatitis C research: Idenix and Pharmasset. Both were small – with teams of a dozen chemists or fewer – and they focused, in keeping with Schinazi’s expertise, on trying to design nucleoside-type drugs that would interrupt the life cycle of hepatitis C inside the liver. Alongside another class of drugs, known as protease inhibitors, nucleoside and nucleotide analogues had been found to be effective against HIV because they managed – a bit like a plug in plughole – to block up “active sites” on the virus that enabled its replication. In 2002, a young chemist at Pharmasset, called Jeremy Clark, came up with a compound, called PSI-6130, that would bind, very unusually, with the hepatitis C virus in two places at once. Despite PSI-6130 having been licensed to Roche the following year, the much larger company failed to derive a working drug from the molecule, which, several years later, under Schinazi’s guidance at Pharmasset, turned out to be PSI-7977.

“Lo and behold this compound,” said Schinazi. “The hot compound which will blow everybody out of the water.” Unlike his modest tester, Ed Gane, the drugmaker is something of a showman. (He is fond of saying “Lo and behold”.) As well as his financial gain, Schinazi has already begun to experience the more poignant rewards of his work on hepatitis C. Last year, on a business trip to New York, he found himself shaking the hand of a young man who had undergone a clinical trial for Sofosbuvir. “He almost wanted to kiss my hand ... He is free from hepatitis C for life. This person, I hardly know him,” said the chemist. “This is the ultimate. This is so gratifying. You have no idea.”

But Schinazi has been around the block enough times – seen enough drugs fall over, more elegant solutions found – to know that he cannot do anything like declare victory. As well as the enormous social complexities around treating hepatitis C, there are also considerable financial obstacles – Sofosbuvir is likely to cost tens of thousands of dollars per treatment course – and even legal ones, still in the way. Both Jeremy Clark, the original inventor of PSI-6130, and Idenix are now involved in patent litigation cases.

And, of course, there remains the danger that the drug could be superceded by another, better cure. Because of the slippery nature of the hepatitis C virus, Sofosbuvir is always likely to be used with other drugs and, as of now, the perfect cocktail is yet to be found. The very latest trials have shown mixed – some brilliant, some merely good – results, and rival drugs are in the pipeline, ready to take over as the next great hope. But as Schinazi said: “We’re not finished by the way.” The torment does not stop. The search never ends.

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