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We’re getting there: towards a comprehensive hepatitis C cure

Gus Cairns
Published: 01 April 2011

Research on new cures for hepatitis C has made rapid progress, Gus Cairns reports.

The first hepatitis C protease inhibitors, Merck’s boceprevir and Vertex’s telaprevir, are being reviewed by the US Food and Drug Administration and may be licensed for treating hepatitis C patients (those without HIV) by September. These drugs double to triple the likelihood of a cure in previously untreated people when taken with standard therapy (pegylated interferon and ribavirin) – and may halve the duration of treatment.

For people co-infected with hepatitis C and HIV, early results from a trial of telaprevir were unveiled recently, showing that their early viral suppression rates were just as good as in patients without HIV.

In results announced in October, interferon-free regimens comprising two new drugs achieved large reductions in hepatitis C viral load in mono-infected people. Although these results were often not sustained, due to rapid development of resistance, they suggest that in the future combination therapies that dispense with interferon injections may be possible.

A host of other drugs are being developed for hepatitis C. We may, in a few years’ time, have a cure for 90% of cases.

The problem up to now

Hepatitis C is already curable in some patients. The definition of a cure is that, six months after therapy is stopped, viral load tests can find no trace of hepatitis C virus (HCV). This is called a sustained viral response (SVR).

Until now, therapy has consisted of weekly injections of a long-lasting ‘pegylated’ formulation of interferon-alfa, a naturally occurring virus-fighting protein, which can be made artificially. This is combined with ribavirin, an antiviral drug.

Both drugs can have severe side-effects. Interferon causes aches and pains, chills, exhaustion and depression, which can be intense. Ribavirin causes potentially debilitating anaemia.

At most, two-thirds of patients are cured, after up to a year of therapy, and no more than half of those with genotype 1, the most common and aggressive form of HCV. Cure rates for co-infected patients are worse: about 40% generally and about 30% for genotype 1. If hepatitis C is diagnosed and treated early, over two-thirds even of the co-infected can expect a cure: but for many people whose hepatitis was not detected early, or whose first course of therapy fails, a cure is not possible.

The latest results: co-infected people

Perhaps of most interest is a co-infection study presented in February:1 a small study – 59 people –that hasn’t gone on long enough to assess SVR rates yet, but with promising interim results.

Patients with no prior experience of hepatitis C treatment took telaprevir or placebo plus pegylated interferon/ribavirin (I/R) for twelve weeks. After this they continue taking I/R for another 36 weeks.

The biggest stumbling block in treating co-infection has been interactions between HIV and hepatitis C drugs. Studies indicate that combining telaprevir with the HIV protease inhibitors darunavir, fosamprenavir and lopinavir will be problematic, as levels of both the PIs and telaprevir were halved. Because of this, the patients on HIV therapy had to be either on efavirenz or atazanavir, plus tenofovir and FTC.   

After twelve weeks, the results were impressive: 68% of patients taking telaprevir had an undetectable hepatitis C viral load, compared with 14% on placebo.

The viral response rate at twelve weeks is a good guide to whether patients will achieve an SVR. One exciting aspect of the new treatments is that they work fast. After just four weeks of treatment, 70% of patients on telaprevir already had undetectable hepatitis C viral loads, compared with 5% on placebo. In mono-infection trials, this has meant that treatment could be reduced to 24 weeks.

While these results are encouraging, it will be important to learn more about response rates in people who failed to clear hepatitis C with a previous course of pegylated interferon and ribavirin, who are likely to be among the first to be offered the new drugs.

Trials in people without HIV

Results from the trials for telaprevir and boceprevir are especially impressive in patients who have previouslyexperienced a relapse of hepatitis C after an initial response. In the case of boceprevir, there was no difference in the SVR rate in treatment-experienced and treatment-naive patients.

In two trials – SPRINT (drug-naive patients)2 and RESPOND (drug-experienced)3 – 67% of boceprevir recipients achieved SVR, compared with 38% of treatment-naive patients on a placebo and 21% of the drug-experienced. All these patients had genotype 1.

With telaprevir, in the studies ADVANCE4 and REALIZE,5 75% of drug-naive and 65% of drug-experienced patients with genotype 1 achieved SVR, compared with 44% and 17% on placebo.

Patients took 24 weeks of boceprevir (which could be extended to 48 weeks), but in telaprevir trials patients only took the drug for up to twelve weeks, and any treatment for 24 weeks.

However, in all these studies people who did not respond to prior treatment with pegylated interferon and ribavirin had a lower likelihood of SVR when re-treated with a combination including one of the new drugs.

In the boceprevir trials, patients took a ‘lead-in’ of four weeks of interferon/ribavirin, to bring down the hepatitis C viral load and minimise the chance of resistance to the new drugs developing.

Resistance has not been a big concern in hepatitis C treatment, because interferon and ribavirin don’t work in a way that facilitates it. But the new drugs work much more like HIV drugs, and hepatitis C has a ferocious replication and mutation rate, so could develop resistance.

There is a particular concern that people who fail to respond to boceprevir or telaprevir will develop resistance to most of the other protease inhibitors now being developed to treat HCV, which could be an argument for what doctors call `watchful waiting`. This means waiting until more is known about how best to use the new drugs, or until newer drugs come along, and only treating if hepatitis C is causing rapid liver damage.

Trials without interferon

There were several reports, at last October’s American Association for the Study of Liver Disease (AASLD) meeting, of studies using two new drugs of two new classes, without interferon or ribavirin.

Bristol-Myers Squibb has combined a hepatitis C protease inhibitor (BMS650032) with a drug (BMS790052) that inhibits a component of HCV called NS5A, which HCV needs to replicate.6 It compared patients on dual therapy alone to patients on dual therapy plus I/R. All patients had failed to respond to I/R therapy before.

The two-drug combination reduced hepatitis C viral load to undetectable within four weeks in a majority of patients, whether or not they were also on standard treatment: 60% became undetectable on I/R plus the new drugs and 64% on the new drugs alone. After this, however, the balance swung towards standard treatment. By week twelve, the percentage of patients undetectable in the dual therapy group had reduced to 45%, while in the dual therapy-plus I/R group it had gone up to 90%.

Results of a study of two Gilead drugs, an HCV protease inhibitor (GS9256) and a polymerase inhibitor (GS9190), in drug-naive patients, showed that some might be able to take a combination of two new drugs plus ribavirin, leaving out the interferon.7 The mean viral load decrease on the two new drugs plus ribavirin was ten times larger than on the two drugs alone, and adding interferon made it 50 times larger.

Lots more to come

This selection of results only scratches the surface. A large number of different classes of drugs are in development, including a new drug called alisporivir (Debio 025), a cyclophylline inhibitor – a completely new class with a high barrier to resistance.8

There are even hints of a vaccine. One therapeutic vaccine has effected a change in some people’s genetic response to interferon,9 which enabled them to use this drug for the first time, and another produced a modest but long-lasting reduction in hepatitis C viral load.10 

The advice of many doctors, for chronically infected patients who don’t already have severe liver problems, has been to wait for new drugs – advice that the co-infected will need to consider for a few years yet.

Mark Nelson, HIV consultant at London’s Chelsea and Westminster Hospital, comments: “I think next time one of my hepatitis C patients hears me say ‘Hang on for the new drugs’ they’re going to hit me. I may have to keep on saying this for a while longer – but can now tell them that day is nearer.”

The bad news, however, is the cost. The price set by Vertex, the company pegging its hopes on telaprevir, is rumoured to be £18,000 for 24 weeks’ treatment. Add £10,000 for interferon and ribavirin and treatment becomes an expensive proposition.

A UK liver specialist, Professor Mark Thursz, of Imperial College, has said that if the drugs are priced at this level in the UK, their use may be restricted to people who have failed to respond to the current standard of care.

So, while we are getting closer to a more effective and tolerable cure for hepatitis C, we haven’t quite got there yet.  

References

  1. Sulkowski M et al. Interim analysis of a phase 2a double-blind study of TVR in combination with pegIFNα2a and RBV in HIV/HCV co-infected patients. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 146LB, 2011.
  2. Sulkowski M et al. BOC combined with P/R for treatment-naive patients with HCV genotype-1: SPRINT-2 final results. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 115, 2011.
  3. Gordon S et al. HCV RESPOND-2 final results: high sustained virologic response among genotype-1 previous non-responders and relapsers to pegIFN/RBV when re-treated with BOC + Pegintron/RBV. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 116, 2011.
  4. Jacobson IM et al. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naive patients: final results of phase 3 ADVANCE study. AASLD Conference, Boston, abstract 211, 2010.
  5. Zeuzem S et al. REALIZE Trial Final Results: Telaprevir-Based Regimen in Genotype 1 Hepatitis C Virus Infection in Patients with Prior Null Response, Partial Response or Relapse to Peginterferon/Ribavirin. 46th Annual Meeting of the European Association for the Study of the Liver (EASL), Berlin, abstract 2371, 2011.
  6. Lok A et al. Combination therapy with BMS-790053 and BMS-650032 alone or with pegylated interferon and ribavirin (pegIFN/RBV) results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders. 61st AASLD conference, Boston, abstract LB-8, 2010.
  7. Zeuzem S et al. dual, triple and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or pegFN/RBV for up to 28 days in treatment naive, genotype 1 HCV subjects. 61st AASLD conference, Boston, abstract LB-1, 2010.
  8. Siddall R 'Fantastic' data on Novartis' first-in-class hep C antiviral. Novartis press release, 1 April 2011.
  9. Pockros PC et al. GI-5005 therapeutic vaccine plus pegIFN/ribavirin improved sustained virologic response versus pegIFN/ribavirin in prior non-responders with genotype 1 chronic HCV infection. 61st AASLD conference, Boston, abstract LB-6, 2010.
  10. Klade CS et al. Significant continuous viral load decline in treatment-naïve HCV genotype 1 patients after therapeutic peptide vaccination with IC41. 60th AASLD conference, Boston, abstract 1558, 2009.  

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