The beginning of the end of hepatitis C?

A convenient and tolerable cure for nearly all hepatitis C infections may be here by the end of this decade, as new drugs appear at a pretty astounding rate. Ingo van Thiel of Deutsche Leberhilfe (the German liver patients’ association) reports from the 2012 American Association for the Study of Liver Disease (AASLD) meeting. Edited by Gus Cairns. All the news stories reporting on studies referred to in this article can be seen in full at www.aidsmap.com/conferences.

About one-third of people with HIV also have hepatitis C, including a majority of injecting drug users and a growing minority of gay and bisexual men with HIV. Hepatitis C-related liver disease is a major cause of death for people with HIV in high-income and resource-limited countries.

The 2012 AASLD meeting (the ‘Liver Meeting’) in Boston showed that the noose around the hepatitis C virus is tightening further. New drug regimens with and without interferon are being developed, and we are seeing cure rates of well above 90% in people who only have hepatitis C (that is, without HIV co-infection).

We do not know yet how well the new hepatitis C treatments will work for people living with HIV, but such studies are ongoing. The Liver Meeting also showed improved hepatitis C cure rates with current interferon-containing regimens in people with HIV. 

In just a few years, hepatitis C treatment might be revolutionised.

Current treatment

At present, however, we’re still in a difficult transitional period where two or three drugs, each with significant side-effects, are needed to treat hepatitis C. Pegylated interferon and ribavirin (pIFN/RBV) are still the backbone of today’s approved treatments. These two medications are often enough to treat infections involving hepatitis C virus (HCV) genotypes 2 and 3, with up to 80% cure rates.

The most common variety of hepatitis C in the UK, western Europe and US, however, is genotype 1 (G1) - split into 1a and 1b - and here, cure rates with pIFN/RBV are only 40 to 50% and 30% respectively in people co-infected with HIV.

To combat this more stubborn virus we now have the new, HCV G1-specific protease inhibitors telaprevir (Incivo/Incivek) and boceprevir (Victrelis). One of them is now often added to a regimen, still combined with pegylated interferon and ribavirin. Neither is suitable nor approved for genotypes except G1.

The cure rates of current treatments are already much higher than those of five years ago. For the first time, people with G1 achieved 67 to 75% cure rates in approval studies.

However, the likelihood of cure depends on someone’s individual situation.

People who already have cirrhosis respond to treatment less often than people in earlier stages of liver disease. If previous treatment with pegylated interferon and ribavirin had little or no effect on the HCV viral load during treatment (null responders), the prospects are less good if the same medications are taken again with the addition of only one extra drug.

Only around one-in-three people who has previously taken hepatitis C treatment without viral response (null responders) eliminates the virus using current triple-drug treatment; the other two-thirds not only remain infected but usually develop drug-resistant virus. In studies to date, null responders with cirrhosis who took telaprevir-containing triple therapy only had 14% response rates (there were no such data for boceprevir at the Liver Meeting).

On the other hand, relapsers with genotype 1 have good prospects. In approval studies with boceprevir and telaprevir, 75 to 88% of relapsers became hepatitis C free.

Triple therapy in people with HIV co-infection

People who are concurrently infected with HIV and hepatitis C have a greater risk of developing late-stage liver disease such as cirrhosis and liver cancer. In addition, previous dual therapies with pegylated interferon and ribavirin were less successful for people in this situation. A new study¹ now reveals that triple therapy with telaprevir, pegylated interferon and ribavirin can cure hepatitis C in people with HIV co-infection just as often as in people with hepatitis C alone. In 74% of previously untreated people, hepatitis C was eliminated using triple therapy, whereas only 45% of trial subjects achieved this using two medications. As there can be many interactions with HIV drugs, it is important that this treatment is monitored by doctors who are experienced in treating both HIV and hepatitis C and who can customise the range of HIV medications. A second study by the same team² has found a 62.5% SVR12 response rate with boceprevir.

But, for the moment, the new drugs are mostly being studied in people who have hepatitis C only (monoinfection). This is the case for the rest of the reports in this article – research with people with HIV and hepatitis C co-infection will come later.

Additional side-effects

There is a drawback to the new triple therapies: an increased rate of side-effects, added to a regimen already notorious for them (interferon causes flu-like illness and depression, amongst other things, and ribavirin causes anaemia). In everyday clinical practice, more people seem to be stopping treatment than in the approval studies. For example, it was reported from three American clinics that up to 21% of people taking telaprevir stopped treatment early.

With boceprevir, changes in taste perception, in particular, were observed more frequently than with dual treatment. With telaprevir, skin rashes are very common, sometimes requiring treatment; in addition, pain or itching in the anal area is frequently reported.

The most significant side-effect of boceprevir and telaprevir is probably a raised rate of anaemia (lack of red cells, and therefore oxygen, in the blood). If boceprevir or telaprevir is added then ribavirin-related anaemia can intensify. On one hand, anaemia is a sign that treatment is working; people who experience anaemia as a side-effect are cured more often than people who do not. On the other hand, anaemia weakens people and increases the risk of them falling ill with other infections during treatment. The more severe the anaemia, the more medical intervention is required.

The dose of the HCV protease inhibitor cannot be reduced, as drug resistance can develop. However, the dose of ribavirin can be reduced with less concern about viral breakthrough than in the past – in fact, with triple treatment, taking a lower ribavirin dose barely diminishes the chances of cure at all. A study has found that cure rates remained as high regardless of whether doctors reduced the ribavirin due to anaemia, or whether the drug erythropoietin was given to treat the anaemia instead.³ (If you are on treatment, don’t reduce your ribavirin dose without medical advice.)

Not every person with genotype 1 requires three medications. One study⁴ suggests that some people, despite having G1, would have a good chance of eliminating their hepatitis C with two medications. This group is characterised as having had no previous treatment, no cirrhosis, low viral load (under 600,000 units before treatment) and a rapid response to pIFN/RBV, meaning viral undetectability after four weeks. If all these favourable factors come together, the chances of success in the study were just as high regardless of whether the trial participants added boceprevir or not after the fourth week (90 versus 89%). This applied to around a tenth of people with G1.

Telaprevir two or three times a day?

Until now, boceprevir capsules and telaprevir tablets have had to be taken three times a day and at eight-hour intervals, in order to avoid the emergence of drug-resistant virus. The drugs must also be taken with food, and while with boceprevir a snack is sufficient, with telaprevir 20g of fat must be consumed – three times a day. This is not easy for many people especially as hepatitis C treatment can cause nausea and loss of appetite.

Now a study shows that telaprevir tablets can also be taken twice a day: instead of three 750mg doses, two 1125mg doses resulted in the same cure rates.⁵ Even the side-effects were similar in both groups, regardless of whether people had cirrhosis or not, except that anaemia occurred slightly more often in the twice-daily dose. Twice-daily telaprevir has now been approved for use in Europe. This is seriously good news as it may turn a regimen that is almost impossible to fit into some people’s lifestyles into a practicable one.

Current triple treatment for people with cirrhosis

People with cirrhosis, who are already seriously ill, have less time to wait for future treatments but respond less often to current triple therapies and also have a significantly higher risk of complications.

In the French CUPIC study,⁶ half of the people with cirrhosis suffered complications such as infections, and more than 4% progressed to decompensated cirrhosis. In some cases, infections caused blood poisoning (sepsis). There were ten deaths. Severe complications usually occurred in people whose liver function was already impaired before treatment was started: warning signs were a low albumin level under 3.5g/dl and a blood platelet count under 100,000. As you might expect, the more diseased the liver, the greater the treatment-related risks.

Without treatment, however, people with cirrhosis are at risk of dying within a few years. The decision for or against starting current triple therapy is therefore not easy for those who have cirrhosis. Individual cases should be discussed in great detail with the doctor and treatment should be well supervised. The further advanced the cirrhosis, the more likely the possibility that a transplant will also be considered.

What the future might hold

Numerous new drugs are being explored. The first innovations we can expect will be more triple therapies, in which another drug with fewer side-effects is added to pegylated interferon and ribavirin, while for particularly stubborn infections, quadruple therapies will be tested. (See The new hepatitis drugs, below).

In addition, a novel version of interferon called pegylated interferon lambda is being explored. This produces fewer side-effects than pegylated interferon alfa (used in current standard treatment) but appears to be at least as effective.

The biggest focus of excitement at the Liver Meeting, however, was interferon-free regimens. It’s important to remember that the new drugs don't work equally well for everyone, and in particular, some only work, or work well, with certain HCV genotypes. In future, doctors and patients will have to consider the choice of medications very carefully.

The new hepatitis drugs

These new drugs are direct-acting antivirals, drugs that directly attack the ability of the hepatitis C virus to make copies of itself (replicate) – unlike interferon (which stimulates the immune system to attack HCV) and ribavirin.

HCV protease inhibitors

• Boceprevir (Victrelis, produced by Merck – already licensed)
• Telaprevir (Incivo/Incivek, Janssen/Vertex – already licensed)
• Asunaprevir (Bristol-Myers Squibb)
• Danoprevir (Roche/Genentech)
• Faldaprevir (Boehringer Ingelheim)
• Simeprevir (Janssen/Vertex)
• MK-5172 (Merck)
• ABT-450 (AbbVie, formerly Abbott)

Nucleotide/nucleoside polymerase inhibitors (similar to NRTIs in HIV therapy)

• Sofosbuvir (Gilead)
• Mericitabine (Roche)

Non-nucleoside polymerase inhibitors (similar to NNRTIs in HIV therapy)

• BI 207127 (Boehringer Ingelheim)
• BMS-791325 (Bristol-Myers Squibb)
• ABT-333 (AbbVie)

HCV NS5A inhibitors (no equivalent in HIV therapy)

• Daclatasvir (Bristol-Myers Squibb)
• Ledipasvir (Gilead)
• ABT-267 (AbbVie)

Danoprevir and mericitabine: better with interferon than without?

Roche studied results for mericitabine and ritonavir-boosted danoprevir⁷ taken in different combinations by people with G1 who were either null responders or relapsers. They devised a study involving people with G1a and G1b using the two drugs alongside IFN/RBV, and used them either with RBV alone or IFN alone in people with G1b.

There were a lot of relapses following interferon-free treatment, with only 39 to 55% achieving SVR12. The best results were achieved with quadruple therapy, with a 100% SVR12 rate in former relapsers or null responders with G1b, and 96% in relapsers with G1a. However, only 73% of previous null responders with G1a achieved SVR12 and thus a likely cure.

Interferon-free studies

Faldaprevir, BI 207127 and ribavirin

Boehringer Ingelheim studied the use of treatment which combined faldaprevir with BI 207127 and ribavirin in different doses over different periods of time.⁸ The combination that performed the best was in the group of participants who took faldaprevir once a day and BI 207127 and ribavirin twice a day over 28 weeks. People with G1b achieved a cure (SVR24) in 85% of cases but those with G1a only in 43% of cases. This was the first interferon-free hepatitis C study that also included people with cirrhosis – 9% of participants in this study had cirrhosis. As this was only 33 individuals, not many conclusions can be drawn yet as to how successful this treatment is in people with cirrhosis, but six out of nine people who had cirrhosis, with G1a or with G1b, were able to eliminate their hepatitis after 28 weeks of treatment. In the approval studies, this interferon-free treatment will only be examined in people with G1b; people with G1a will no longer be included, which may restrict this drug’s applicability.

Sofosbuvir and ribavirin

A year ago, ten out of ten previously untreated people with G2 or G3 were cured after taking Gilead’s protease inhibitor sofosbuvir with ribavirin for only twelve weeks. This caused quite a stir, but hepatitis C is generally easier to treat in people with G2 and G3 who have not taken treatment before.

The hope that this relatively simple treatment regimen could be effective for all other people with HCV such as people with G1, especially null responders, has been dashed. In people with G1 being treated for the first time with sofosbuvir and ribavirin, 84% were cured; in former null responders of genotype 1, however, nine out of the ten people suffered a relapse shortly after completing treatment.⁹ With difficult-to-treat virus, sofosbuvir obviously needs to be combined with something stronger than ribavirin alone – ideally another direct-acting antiviral substance.

Sofosbuvir and daclatasvir

A pioneering study was presented at the International Liver Congress, the annual meeting of the European Association for the Study of the Liver (EASL), in April 2012. Gilead’s sofosbuvir, then called GS-7977, was combined with Bristol-Myers Squibb’s daclatasvir, with and without ribavirin.¹⁰ After 24 weeks of treatment in previously untreated people with genotypes 1, 2 and 3, cure rates of over 93% were achieved. This was the first time cure rates like this had been achieved in an interferon-free regimen, and the study received wide publicity. However, co-operation between the two companies was only maintained for the period of this study, and combination treatments like this are now being followed up by both companies independently.

Indeed, what all companies are looking for is an equally potent and tolerable version of this combination, using their own drugs. Both sofosbuvir and daclatasvir have good chances of being approved independently of one another, and so using this combination is not completely out of the question if both drugs were available, could be combined ‘off-label' in everyday clinical practice, and were affordable.

Daclatasvir, asunaprevir and BMS-791325

Bristol-Myers Squibb has drugs of three classes in development and, at the AASLD meeting, reported on a study combining all three: daclatasvir (an NS5A inhibitor), asunaprevir (a protease inhibitor) and BMS-791325 (a non-nucleoside polymerase inhibitor), in a combination therapy without interferon or ribavirin.¹¹ The study treated 32 previously untreated people with genotype 1a or 1b and without cirrhosis for either 12 or 24 weeks. Excitingly, twelve weeks of treatment with these three drugs was sufficient to achieve a provisional cure (SVR12) in all 16 people. In the group treated for 24 weeks, only SVR4 data are available: all are (so far) virus negative, with one exception which may simply be missing data. Some people reported headaches, diarrhoea and general weakness but no-one discontinued the treatment. It is particularly encouraging that genotype 1a saw the same cure rates.

Sofosbuvir, ledipasvir and ribavirin

Meanwhile, Gilead is developing its own NS5A inhibitor, ledipasvir or GS-5885, and has started studies combining it with sofosbuvir. At AASLD, results of a phase II study of these two drugs plus ribavirin were presented,¹² with 25 people with G1 who had not previously taken treatment, and nine people who were former null responders. Everyone was still virus negative four weeks after the completion of treatment (SVR4), and at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) it was reported that all the participants had achieved a successful SVR12 response.

ABT-450r, ABT-267 and ABT-333 with ribavirin

AbbVie (formerly Abbott Laboratories) also has drugs of three different classes in development – a ritonavir-boosted protease inhibitor, a non-nucleoside polymerase inhibitor, and an NS5A inhibitor (see box). In a study called AVIATOR presented at AASLD, up to three of the new drugs, with or without ribavirin, were administered over different periods of time.¹³

Previously untreated people and null responders were both included in the study, all with G1 and the majority with the particularly stubborn G1a, though there were no people with cirrhosis in the study. The treatment duration varied in length depending on the patient group (8 to 24 weeks), and results were available for people treated for only eight to twelve weeks.

A lot of tablets, relatively short treatment duration – and impressive results. In 79 people given the three new drugs with ribavirin for twelve weeks, 77 people (97.5%) treated for the first time had an SVR12 response, as did 42 out of the 45 previous null responders (93.3%).

Just two of the 448 trial participants discontinued treatment due to side-effects but the virus was still cured despite the curtailment of the treatment. This combination will soon also be explored in licensing studies. AbbVie plans to reduce the number of tablets by combining ritonavir, ABT-450 and ABT-267 into one tablet.

Conclusion

In a few years’ time, the treatment of hepatitis C will probably be vastly different, when the first interferon-free treatments are generally available. This conference demonstrated once again that a lot of interferon-free treatments appear not only to have fewer side-effects but in some respects to be even more effective than the current standard treatment. Several combination therapies achieved cure rates of over 90%, even in people with difficult-to-treat genotypes. To what extent these outstanding results will prove to be true in large approval studies and then in everyday clinical life remains to be seen.

Thanks to Dr Bernd Kronenberger for medical advice.

Some definitions

• SVR SVR stands for ’sustained virologic response’.
• SVR24 means there is no hepatitis C virus evident in the blood 24 weeks after treatment has ended, currently the accepted definition of a cure. Subsequent relapses are very rare. If there is no virus evident twelve weeks after treatment has ended, in over 99% of cases this is still the case after 24 weeks. The European and American drug regulatory bodies, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), also recognise SVR12 as a cure.
• SVR4 Viral load data four weeks after treatment has ended, frequently presented at conferences. SVR4 results are somewhat provisional, and there may still be some relapses; results should be interpreted with caution and confirmed by 12- and 24-week results.
• Genotype (G1a, 1b, 2, 3, 4 etc.) Hepatitis C comes in many different genotypes (varieties), with very different rates of virulence and resistance to treatment. In general, G1 and G4 (especially G1a, which is the commonest genotype in the US and western Europe) are the hardest to treat – though now with new drugs G1b in particular is more treatable. G4 is common in the Middle East. G2 and G3 are more common in Asia and Australia.
• Null responder A person who has previously taken hepatitis C therapy but has shown no or little viral response to it, and has never achieved viral undetectability during their treatment.
• Relapse/Relapser People often achieve viral undetectability by the end of treatment, but their hepatitis C virus subsequently reappears after it ends. They therefore do not achieve an SVR and this is called relapse.
• Fibrosis Scarring to the liver (but the liver is still largely able to do its job). There are various grades of fibrosis.
• Cirrhosis Large portions of the liver are replaced with scar tissue; blood flow through the liver is restricted and the person will probably be suffering from symptoms caused by poor liver function.
• Decompensated cirrhosis Blood flow through the liver is almost completely blocked and the liver is unable to perform its vital functions. This is a life-threatening condition and can usually only be resolved with a liver transplant.