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Combinations and conundrums: the challenges of hepatitis C treatment

Gus Cairns
Published: 01 July 2009

A multiplicity of new drugs for hepatitis C are being researched. As Gus Cairns discovers, though, they face an elusive enemy, a shape-shifter of a virus that won’t easily be tamed by a few pills.

In the April issue, HTU 185, we looked at how hepatitis C infections are rapidly increasing in gay men with HIV in Europe and parts of the USA. Since then, new studies have continued to document its spread and possible consequences to health.

More on the new epidemic in gay men

A recent study1 has found genetic evidence that the different outbreaks seen in European cities since 2000 are in fact one connected outbreak of hepatitis C - an outbreak that seems to be growing at a rate of about 20% a year in HIV-positive gay men.2 This study found that 86% of gay men co-infected with HIV and hepatitis C in Europe shared their virus in a ‘cluster’ with other men in the study. The study also found an apparently separate outbreak of hepatitis C among HIV-positive gay men in Australia. Only one case was found of infection by a European strain of hepatitis C and it also seems to feature different risk behaviours. Whereas few men affected by the European and US outbreaks of hepatitis C injected drugs, a large proportion of the Australian gay men did.  

Daniel Fierer, the HIV physician who first documented a rash of new hepatitis C cases among gay men in New York, told a hepatitis C and HIV workshop in Lisbon in June that the development of liver fibrosis (the scarring caused by hepatitis, which eventually leads to cirrhosis) appeared to be proceeding five times faster in his patients than in co-infected patients in previous studies, and the longer the interval was between hepatitis C diagnosis and liver biopsy, the more severe the fibrosis was.1 The liver is such a resilient organ it can do its job with this degree of scarring and people may have no symptoms; the concern is more about what may happen to these patients in the future.

So, to summarise, we are talking about an outbreak of a chronic and progressive liver disease among gay men. But they are not the people who need new treatments for hepatitis C most badly.

The global consequences of hepatitis C infection

While one in eleven HIV-infected people in the UK have hepatitis C,2 in the countries of southern and eastern Europe and elsewhere in the world where a significant proportion of HIV-positive people have acquired HIV through sharing injection equipment, hepatitis C infection is extremely common.  

In the USA about one-in-five people with HIV is co-infected with hepatitis C,3 in Italy and Spain one in two,4 and in Russia up to 80%.5  Some of these people may have had hepatitis C for decades and are starting to develop severe liver disease.

Hepatitis C is also one of the most significant causes of mortality and of poor health in people with HIV. A study from Denmark in 20066 estimated that a person diagnosed with HIV at the age of 25 and on HIV treatment could expect to enjoy 39 more years of life. In a person diagnosed with both HIV and hepatitis C that life expectancy was halved to 20 years. People with hepatitis C are more likely to be injecting drug users and have other health risks, but some of the higher death rate may be due to far higher rates of hepatitis-related liver disease.

Given that only about half of HIV and hepatitis C co-infected people respond positively to the current standard regimen of pegylated interferon and ribavirin, and fewer than a third of those infected with the harder-to-treat genotype 1 and 4 subtypes, there are a lot of people out there in urgent need of new approaches to hepatitis C treatment.

Luis Mendão, a Director of the European AIDS Treatment Group, is 51 and from Portugal. He suffers from the fluid accumulation, tiredness, diabetes and clotting disorders characteristic of cirrhosis – a condition in which the liver barely manages to keep performing its vital functions. He was diagnosed with HIV in 1996, with a low CD4 count, and with hepatitis C in 1998, though he had probably had both viruses for a long time.

“There was no record of my ever having had a hepatitis C test, but I kept having toxic hepatitis, so I insisted on one,” he says.

His experience of hepatitis C treatment was pretty disastrous. He had had an undetectable HIV viral load for seven years and a CD4 count of 950 when he decided to try pegylated interferon and ribavirin in 2003.

“I lasted three months. The hepatitis C treatment barely made an impression on the virus but my HIV viral load jumped to half a million and my CD4s crashed to 60 in two months.” He developed new AIDS-related illnesses and was only able to go back to full-time work this year.

New drugs

The good news is that there is a huge research programme underway looking at new treatments for hepatitis C and more than 50 candidate drugs are under study in human trials.

Firstly, companies are looking at new versions of interferon, like Albuferon, a slow-release formulation that may need only to be injected once a month. But though this may be more convenient for the patient it does not appear to achieve higher rates of sustained viral response (SVR). An SVR is the goal of hepatitis C treatment: it means there has been no reappearance of hepatitis C by the sixth month after the end of treatment, and is essentially a cure.

The challenge, therefore, is to develop hepatitis C drugs of new classes. Initially, and for the foreseeable future, these new drugs would not replace interferon. The reason is that most of the hepatitis C drugs in development work like HIV drugs: they prevent the virus replicating but do not clear it. This means that if they are stopped the virus will reappear, and if too few are taken they will cause resistance. In contrast interferon creates a stronger immune response to hepatitis C. So far there have been a couple of animal experiments in which an SVR was achieved without Interferon, using only oral drugs, but clinical application is probably ten to 15 years away.7

Like HIV therapy, the new hepatitis C drugs come in a number of classes. The two classes under the most scrutiny are the protease inhibitors and the polymerase inhibitors. The latter are the equivalent of reverse transcriptase inhibitors in HIV treatment. Many other classes are under investigation. Most of them are stop viral replication as described but some have different modes of action.8

The ones furthest along in development are the protease inhibitors. Positive results have come from clinical studies of two drugs, Schering-Plough’s boceprevir and Vertex Pharmaceuticals’ telaprevir. In several different trials, these drugs were added to pegylated interferon and ribavirin and given to HIV-negative patients with genotype 1 of hepatitis C. In both cases an increased proportion of patients (about 65% instead of 45%) achieved an SVR.9,10

Perhaps just as importantly, these rates of SVR were achieved in half the length of time of normal therapy – 24 weeks instead of 48, which is a significant improvement for anyone trying to put up with often taxing side-effects of interferon and ribavirin. Even more promisingly, one of the three telaprevir trials targeted patients who had failed previous pegylated interferon and ribavirin therapy and achieved SVR rates of 50%, compared with 14% in those taking a placebo - an unprecedented result in a population that has already experienced interferon therapy failure.11

Next in line are the nucleoside polymerase inhibitors (NPI). These appear to be very potent drugs, achieving large reductions in viral load, and active across a number of different varieties of hepatitis C. The first large phase 2 clinical trial of an NPI, Roche’s R7128, was announced in April.

Alongside these are the non-nucleoside polymerase inhibitors. These have a less potent effect on hepatitis C and are only active against specific subtypes, but they seem to cause fewer side-effects. The vanguard drug in this class is Gilead’s GS9190, currently in a phase 2 trial. (Phase 2 trials typically involve several hundred subjects and try to find out the optimum dose, establish the frequency of side-effects, and so on. They lead on to phase 3 trials, which may involve thousands of patients and establish the actual efficacy of a drug in a clinical population.)

A number of other antiviral classes are in early-stage development, including the NS5a inhibitors, which work against a component of the hepatitis C virus whose function is uncertain.

There are a number of non-antiviral drugs too. Some of these are improved formulations of interferon like Albuferon12 and Locteron13 that require less frequent dosing. Others are versions of ribavirin which aim to be less toxic, like taribavirin, though a trial of this drug last year found it had relatively few advantages.14

Many more classes of drugs are in development. Some, as interferon does, work on the machinery of the human cell which hepatitis C subverts in order to replicate itself, rather than the virus. These are potentially exciting drugs because they are less likely to cause resistance than antivirals and may be the best candidates eventually to replace interferon.

Results from early studies of two drugs from a class called cyclophilin inhibitors that stop cells making new hepatitis C viruses were presented this April. Importantly, one of the drugs, Debio 025, produced significant viral load drops when given to people with HIV and hepatitis C co-infection who had previously failed the standard pegylated interferon and ribavirin regimen,15 though it was still only effective when combined with these other two drugs.

Then there are a few wild cards like nitazoxanide. This is an antibiotic that was in trials for the AIDS-defining gut illness cryptosporidiosis. It was serendipitously found to have activity against hepatitis C infection – no one yet knows why. In one trial the efficacy of pegylated interferon and ribavirin therapy was increased from 50 to 80% in HIV-negative patients when they were given one to three months of nitazoxanide before starting therapy.16

This is by no means a complete list. Further off, in pre-clinical development, are drugs of many other classes: TLR agonists, Micro-RNA agents, A3AR agonists, anti-phospholipids, more thiazolide antibiotics like nitazoxanide, pancaspase inhibitors, glicosidase Inhibitors…whatever the challenges, it cannot be said that hepatitis C is not receiving enough attention from the scientific community.

When looking at the exciting new developments in hepatitis C treatment, however, we should be guided by caution. Two particular considerations come to mind.

The resistance problem

The first is that hepatitis C replicates furiously and makes numerous mistakes while doing so. This means it produces a viral load about100 times higher than HIV, has a much greater genetic variability than HIV and accordingly an even higher propensity to develop drug resistance.

This variability is a major stumbling block for hepatitis C drug development. It means that some of the new drugs only work against one genotype or even one sub-genotype of hepatitis C. It also means the new drugs absolutely cannot be taken alone17 – and they must be tested and developed together.

At the hepatitis C co-infection meeting in Lisbon, Alan Perelson of Los Alamos Laboratory in the USA said that in the billion viruses one would find in any untreated person with hepatitis C, one would expect to find not just every possible mutation (change) the virus is capable of producing in its genetic make-up, but every possible combination of two changes.18

That means, if you were relying on antiviral drugs alone you would need at least four drugs, if each of them stopped working after just one viral mutation. In the recent telaprevir study, 95% of the patients whose hepatitis C viral load became detectable again, either during or after therapy, developed drug resistance, and Perelson said that the time it takes for resistant virus to predominate in patients taking telaprevir as the only therapy - or any similar drug - would be two to three days.

If you need to study the effect of combining two experimental drugs, this poses problems. Firstly, pharmaceutical companies need to co-operate and share commercial secrets, which takes time and negotiation. And the regulatory authorities that license drugs do not like the idea of two experimental drugs being combined in one trial, both because it muddies the data (it’s difficult to establish the relative contribution of each drug), and because of the increased risk of side-effects.

Nonetheless, a number of double studies are underway or proposed. Furthest along is Roche, a company with several hepatitis C drugs in its portfolio, which is studying a combination of its nucleoside polymerase inhibitor R7128 with a protease inhibitor called R7227. Giving both these drugs for two weeks to 57 HIV-negative patients produced large drops in viral load and no acute side-effects.

Another solution to make the drug burden better for HIV and hepatitis C co-infected people would be a drug that works against both viruses. This has greatly simplified therapy for chronic hepatitis B co-infection, because the HIV drugs tenofovir, 3TC and FTC also work against hepatitis B. This year Roche and its biotech collaborators Rigel Pharmaceuticals and Medivir announced the discovery of two drugs called RO-0622 and RO-9187 that worked against both hepatitis C and HIV.19 These are very early test-tube studies but we now know that a single regimen for both infections is not inconceivable.

Drug interactions and side-effects

The second consideration especially concerns patients with HIV - drug interactions.

“HIV and hepatitis C protease drugs don’t work in the same way, so you’ll need to take two protease inhibitors,” says Dr Janice Main of St Mary’s Hospital in west London. “But they do affect the liver the same way. So drug developers are very nervous about co-infected people taking handfuls of drugs that may interact.”

The result is that studies in co-infected people have hardly begun. Anger and concern among activists led to the Sitges Declaration, an agreement signed in 2007 by companies, regulators and community representatives that urged that co-infected people be included in hepatitis C drug trials.

Spanish activist Joan Tallada was one of the architects of this resolution. “The first clinical trial in co-infected people is about to start,” he says. This will test if boceprevir strengthens the response to pegylated interferon and ribavirin.

There is some disagreement about who should enter trials, with some activists wanting patients who have run out of options entered into trials to save lives, while others urge that the less complex patients who are likely to do better should enter trials first because the results will be clearer.

Side-effects will certainly be a concern, as the new hepatitis C drugs are by no means free of them. Boceprevir, like ribavirin, may cause anaemia and in its phase 2 trial 50% of patients on both drugs developed anaemia despite discretionary use of the anti-anaemia drug erythropoietin.20 Telaprevir also causes mild anaemia but its main side-effect is a rash, which was sufficiently unpleasant to nearly double the proportion of patients who discontinued the trial compared with those taking a placebo.21

The dilemma of resistance was also exemplified in the boceprevir and telaprevir trials. Patients who fail to respond to treatment in such trials may develop resistance, and may therefore fail to benefit from better drugs of the same class in future. We have seen this before in HIV and need to avoid it again.

How can we avoid the problem of resistance? In the boceprevir trial patients were started on a ‘lead-in’ dose of pegylated interferon and ribavirin for four weeks before starting boceprevir. The idea is to suppress hepatitis C replication far enough to make the development of resistance less likely.

In the telaprevir trials, on the other hand, all three drugs were given from the start to maximise the suppression of hepatitis C, but in the second half of the study telaprevir was withdrawn. Various yardsticks – such as the proportion of patients with undetectable viral load at weeks four and twelve – are being used in trials to predict who will eventually achieve an SVR so that those unlikely to benefit from the new regimen under trial can be taken off before they develop resistance.

Conclusion

A few years ago it may have looked to both researchers and patients as if a new era of convenient, tolerable hepatitis C antiviral therapy was just round the corner. We know, however, from previous experiences such as the struggle to develop an HIV vaccine that such assumptions are often disappointed. Hepatitis C is a complex, slippery virus that may take a lot of pinning down. And unlike HIV, where the introduction of new drugs has led to far better health outcomes for patients who fail first-line regimens, no treatments will be available in the near future for people who have failed the current drugs, and who desperately need other options.

Nonetheless, it’s important to emphasise that hepatitis C, unlike HIV, is in some cases already curable. We just have to make the cure work for more people, with the more difficult-to-treat genotypes. Significant progress is already being made and we may only a year or two away from drugs that can strengthen, shorten and sweeten the course of hepatitis C therapy. Watch this space. 

References

1. Fierer D et al. Characterization of an epidemic of sexually-transmitted acute hepatitis C infection in HIV-infected men in New York City. Fifth International Workshop on HIV & Hepatitis Co-infection, Lisbon. Abstract O_15. 2009.

2. Amin J et al. HIV and hepatitis C coinfection within the CAESAR study. HIV Medicine, 5, 174–179. 2004.

3. Thomas DL. Hepatitis C and human immunodeficiency virus infection. Hepatology 36(S1): S201 - S209. 2006.

4. Amin, op. cit.

5. Twigg J. HIV/AIDS in Russia: Commitment, Resources, Momentum, Challenges. Report of the Task Force on HIV/AIDS Center for Strategic and International Studies, Octopber 2007.

6. Lohse N et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Annals of Internal Medicine 146: 87-95, 2007.

7. Pawlotsky J-M. Progress and Challenge in the Development of Small Molecule Inhibitors of HCV. 16th Conference on Retroviruses and Opportunistic Infections, Montreal. Presentation #63. 2009.

8.  Hazuda D. Evolving Paradigms for HIV/HCV Therapeutics. HIV Training and Resource Initiative Science and Innovation Lectures 2008. See www.hivtri.com/pdf/report_wellcome.pdf.

9. Kwo P et al. HCV SPRINT-1 Final Results: SVR 24 from a Phase 2 Study of Boceprevir Plus PegIntron (Peginterferon Alfa-2b)/Ribavirin in Treatment-Naive Subjects with Genotype-1 Chronic Hepatitis C. 44th Annual Meeting of the European Association for the Study of the Liver (EASL), Copenhagen. Abstract 4. 2009.

10. McHutchison JG et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. NEJM 360(18): 1827-1838. 2009. AND Hézode C et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. NEJM 360(18):1839-1850. 2009.

11. Manns M et al. Telaprevir in hepatitis c genotype-1-infected patients with prior non-response, viral breakthrough or relapse to peginterferon-alfa-2a/b and ribavirin therapy: SVR results of the PROVE 3 study. EASL Conference, Copenhagen. Abstract 1044. 2009.

12. Human Genome Sciences, Inc. Human Genome Sciences Announces Albuferon Meets Primary Endpoint in Phase 3 Trial in Chronic Hepatitis C. Press release, 8 December 2008.

13. Biolex Therapeutics., Inc. Biolex Therapeutics Researchers Present Locteron(R) U.S. Phase 2a Hepatitis C Trial Results At EASL Conference. Press release, 28 April 2009.

14. Poordad F et al. Treatment week 12 results of weight-based taribavirin versus weight-based ribavirin, both with peginterferon alfa-2b, in naive chronic hepatitis C, genotype 1 patients. 43rd annual meeting of the European Association for the Study of the Liver (EASL), Milan. 2008.

15. Nelson DR et al. Efficacy and Safety of the Cyclophilin Inhibitor Debio 025 in Combination with Pegylated Interferon Alpha-2a and Ribavirin in Previously Null-Responder Genotype 1 HCV Patients. 44th Annual Meeting of the European Association for the Study of the Liver (EASL), Copenhagen. 2009.

16. J Rossignol et al. Evaluation of a 4 Week Lead-In Phase with Nitazoxanide (NTZ) Prior to Peginterferon (PegIFN) Plus NTZ for Treatment of Chronic Hepatitis C: Final Report. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco, abstract 87/1848. 2008.

17. Perelson A New Insights into the Viral Dynamics of HCV Infection: Can Virologic Cure Be Achieved without Interferon and Ribavirin? 16th Conference on Retroviruses and Opportunistic Infections, Montreal. Presentation #62. 2009.

18. Perelson A. What modelling teaches about STAT-C. Invited lecture, Fifth International Workshop on HIV and Hepatitis Co-infection, Lisbon. 2009.

19. Klumpp K et al. 2′-deoxy-nucleoside analogs as potent dual inhibitors of HCV and HIV replication, with selectivity against other viral and human polymerases.  44th Annual Meeting of the European Association for the Study of the Liver (EASL), Copenhagen. 2009.

20. Kwo P et al. HCV SPRINT-1 Final Results: SVR 24 from a Phase 2 Study of Boceprevir Plus PegIntron (Peginterferon Alfa-2b)/Ribavirin in Treatment-Naive Subjects with Genotype-1 Chronic Hepatitis C. 44th Annual Meeting of the European Association for the Study of the Liver (EASL), Copenhagen. Abstract 4. 2009.

21. McHutchison, op. cit.

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