New hepatitis C drugs pose many questions

Keith Alcorn
Published: 08 April 2011

Even before new hepatitis C drugs come to market later this year, the vast array of hepatitis C antivirals currently in clinical trials is opening up new horizons for treatment of hepatitis C, in a situation strongly reminiscent of the explosion of HIV drugs research in the mid-1990s.

At last week’s International Liver Congress (EASL) in Berlin, agents from four new classes of drugs, as well as potential improvements to current therapy, were presented.

But the issue at the top of every liver specialist's agenda is how to use the new hepatitis C protease inhibitors that will come to market in the United States and Europe later this year – and who can afford to use them.

Telaprevir (being developed by Vertex and Tibotec, a Johnson & Johnson company) and boceprevir (Victrelis, being developed by Merck) are due for review by the US Food and Drug Administration in late April, with Europe to follow later in the year. Both drugs have demonstrated improved rates of sustained virological response (SVR, an outcome that is considered a cure) in patients with hepatitis C, when added to the current standard of care, 24 to 48 weeks of treatment with pegylated interferon and ribavirin.

Current SVR rates range from 15 to 40% and tend to be lower in African-Americans, people with cirrhosis, transplant recipients and older people. People with HCV genotype 1 have less favourable outcomes on current treatment, as do people with HIV/HCV coinfection.

In comparison studies combining a protease inhibitor with standard of care have shown SVR rates of 60-70% in previously untreated patients. A study of telaprevir in coinfected patients indicates that the early response to treatment is just as good as in monoinfected patients, but longer follow-up is needed to confirm this.

For patients with previously untreated hepatitis C infection the new drugs will offer a substantially higher prospect of cure, with the potential for a shorter course of therapy. Unsurprisingly, the imminent availability of telaprevir and boceprevir is raising hopes among people with hepatitis C and those coinfected with HIV and hepatitis C, and among liver specialists.

Questions about how to use new drugs

However the headline outcomes of these trials conceal a number of caveats, notes Tracy Swan of New York’s Treatment Action Group

In the Hepatitis C Treatment Pipeline Report published last month, she highlighted a host of unanswered questions that should give clinicians pause for thought when considering how to treat patients with hepatitis C using the new drugs. These issues are likely to be just as relevant in HIV/HCV coinfected people as in the much larger HCV-monoinfected population.

In particular she points to the lower rate of response in patients who failed to respond to first-line treatment with pegylated interferon. These patients were much less likely to achieve a sustained virological response in trials of telaprevir and boceprevir, although the responses were still better than those seen in the control groups receiving standard treatment.

In the case of the REALIZE study of telaprevir, for example, just 31% of prior null responders had a successful response to telaprevir, compared to 83% of those who experienced a virological relapse after completing treatment successfully. Among those null responders with cirrhosis – the people with a more urgent need for successful treatment – the cure rate was just 14% in the telaprevir group.

Cure rates were similarly lower among patients with cirrhosis who had a partial response to prior therapy (defined as a reduction in HCV viral load of at least 2 log at week 12 without achieving undetectable viral load before therapy was completed). 34% of this group achieved a sustained virological response compared to 59% of non-responders in the study as a whole.

These findings suggest that patients with advanced liver disease will need to weigh up carefully the risks and benefits of attempting another course of pegylated interferon and ribavirin in combination with a new HCV protease inhibitor. Would it be better to wait for further drugs, or is the severity of liver disease such that a further attempt at a cure would be advisable now?

These issues may be more pressing for patients with HIV/HCV coinfection, where liver disease may be more rapidly progressive, particularly if HIV is uncontrolled by treatment.

There is also uncertainty about just how long patients need to take the new drugs, a question that has a crucial bearing on the cost of new hepatitis C treatments – and the convenience and tolerability of these drugs.

On the up side, trials of both protease inhibitors reinforced the concept of 'response-guided therapy' to hepatitis C treatment, by establishing a series of time points at which protease inhibitor treatment or all treatment could be stopped if HCV was undetectable.

In the case of telaprevir, there is evidence to suggest that treatment with pegylated interferon and ribavirin can be shortened to 24 weeks if HCV is undetectable after 12 weeks of telaprevir treatment. With boceprevir, treatment should carry on until week 24, but hepatitis C treatment can stop completely at this point if HCV RNA was undetectable at weeks 8 and 24.

However, a further complexity of boceprevir treatment is the four-week lead-in phase of pegylated interferon and ribavirin, designed to reduce viral load and so minimise the risk of resistance to boceprevir. What should happen if a patient fails to show some signs of virological response after this four-week lead-in phase? Is the patient fundamentally unresponsive to interferon, and thus likely to fail treatment completely?

The REALIZE study of telaprevir in treatment-experienced patients showed that a four-week lead-in phase did not improve response rates.

In a possible re-run of history from the HIV field, some experts are concerned that premature use of new agents in patients with a poor chance of response could leave them with resistance to new agents that may affect their response to subsequent innovations in hepatitis C treatment.

Professor Heiner Wedemeyer, Secretary General of the European Association for the Study of the Liver, told a press conference at last week’s Congress: “Studies show that care must be taken in the prescription and use of the new compounds. What we want to avoid is a rapid spread of HCV resistance within the patient population, which could drastically lower the effectiveness of the new drugs.”

Evidence from the SPRINT-2 study of boceprevir showed that patients in the poor-responder category had a high risk of developing drug resistance. This in turn could compromise their response to future experimental treatment. (See Clinical Care Options summary of this study – registration required.)

However there is also evidence that resistance mutations to telaprevir may fade over time, possibly allowing that drug or other HCV protease inhibitors to be used again. A lot more evidence will be needed on this question to convince liver experts that re-use or sequencing of HCV protease inhibitors would be possible in the case of treatment failure.

Other protease inhibitors are being developed. Tibotec presented preliminary results from a phase IIb study of TMC-435, studied in combination with pegylated interferon and ribavirin. Week 24 virological response data showed a much less marked gap in response rates between relapsers, prior partial responders and null responders. At week 24, 92 to 96% of protease inhibitor recipients in the prior relapser group had undetectable HCV RNA, as did 70 to 87% of null responders, according to dosing and treatment schedule.

To make a meaningful comparison with boceprevir or telaprevir a further 24 weeks of follow-up data will be needed in order to assess whether these patients achieve a sustained virological response.

Roche’s HCV protease inhibitor also showed strong preliminary results in a study of previous null responders, at least in patients infected with HCV genotype 1b. Danoprevir is boosted with ritonavir in the same way as HIV protease inhibitors, and administered alongside pegylated interferon and ribavirin. By week 12 88% of those with genotype 1b receiving danoprevir had achieved a rapid virologic response (undetectable HCV RNA by week 4). In comparison a high rate of viral breakthrough occurred within weeks of viral suppression in the genotype 1a group. (See Clinical Care Options summary of this study – registration required.)

Moving towards interferon-free combination therapy

The news that caused the biggest stir at the Congress came from a study conducted by Bristol-Myers Squibb which showed that, in a small number of patients, it is possible to cure hepatitis C infection in 24 weeks without pegylated interferon, using two new drugs – an HCV protease inhibitor and an HCV NS5A inhibitor. Not only were these patients cured without interferon, but they were patients who had previously failed to respond to interferon – the hardest-to-treat group.

Furthermore, in those also treated with pegylated interferon and ribavirin the cure rate was 90%.

These results come from a phase IIa study, which means that optimal dosing still needs to be defined before large trials can take place to achieve licensing of the drugs.

Similarly, two drugs developed by Pharmasset – a nucleotide analogue and an inhibitor of HCV’s NS5A protein – produced undetectable HCV viral load after 14 days of treatment without pegylated interferon or ribavirin in 15 out of 16 previously untreated patients without cirrhosis.

These results also come from a phase Ib study and longer studies will be needed to determine whether this very rapid response is sustained without interferon.

Better interferon?

Improving responses to interferon, or tolerability of interferon, was also an important focus of research presented at the conference.

A study conducted in Romania showed that adding the cholesterol-lowering statin fluvastatin to pegylated interferon and ribavirin resulted in a significantly higher rate of sustained virological response (63 vs 49%) in monoinfected patients treated for 48 weeks. These patients continued to receive fluvastatin for a further 24 weeks.

Bristol Myers Squibb presented results from a phase IIb trial of pegylated interferon lamda, a type of interferon which has interactions with fewer human cell types. This means it should be better tolerated. The randomised study, conducted in patients with all HCV genotypes, showed a higher rate of sustained virological response in patients treated with pegylated interferon lamda, coupled with fewer flu-like symptoms and less musculoskeletal pain. In HCV genotypes 2 and 3 better responses were achieved only at higher doses of the new product.

 

Further information on studies presented at EASL

Reports from HIVandhepatitis.com

Capsule summaries of studies from Clinical Care Options (registration required).

Further information on hepatitis C drug developments

Treatment Action Group: The Hepatitis C Treatment Pipeline Report

Hepatitis C treatment news at aidsmap.com from global sources, selected by aidsmap editors.

Hepatitis information

For more information on hepatitis visit infohep.org.

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