Monday April 14 2014
Hepatitis C is a virus that can infect and damage the liver
"A new treatment for hepatitis C 'cured' 90% of patients with the infection in 12 weeks, scientists said," BBC News reports after a new drug protocol designed to target the protein that assists the spread of the virus through the body has shown promising results.
The study the BBC reports on involved 394 people with hepatitis C who had not responded to previous standard treatment, or who had responded but later relapsed.
They were randomised to either an active five-drug combination or a matching placebo for 12 weeks. The five drugs were ABT-450, ritonavir and ombitasvir, dasabuvir and ribavirin. At the end of the 12-week treatment period, the active treatment group stopped treatment, while all people in the placebo group switched to receiving 12 weeks' active treatment.
The people in the original active treatment group were only assessed 12 weeks after they had stopped taking their treatment, at which time the majority of them (96%) did demonstrate a response.
However, because of their unusual RCT design, by this time there was no comparison group as the placebo group had just then completed the same 12-week course of treatment. In this sense, the research was essentially a cohort study that has reported the outcomes for a group of people tested with a particular treatment.
Overall, the results suggest that this drug combination may be effective for people with the hepatitis C virus who have not responded to previous treatment. But whether this is more effective or more tolerable than other standard treatment options for such people remains to be proven. Side effects remain a big issue in terms of drug treatments for hepatitis C.
Where did the story come from?
The study was carried out by researchers from Johann Wolfgang Goethe University and Hannover Medical School in Germany and other institutions in Europe, the US, Canada and Australia. It was funded by the pharmaceutical company, AbbVie.
It is unclear whether there were any conflicts of interest, as relevant information was not provided in the study.
The study was published in the peer-reviewed medical journal, the New England Journal of Medicine, on an open access basis, so the study is free to read online.
BBC News is perhaps a little premature in hailing this treatment a breakthrough considering the limitations of the study's design. A randomised controlled trial comparing this combination with standard treatment is needed first. There were also some inaccuracies in the BBC's reporting, as the participants in the study did not have liver cirrhosis, as reported.
What kind of research was this?
This was a randomised controlled trial that aimed to examine the effectiveness and safety of a combination of drugs compared with inactive placebo in people with hepatitis C infection. It is reported to be a phase 3 randomised controlled trial, though arguably the study design does not meet the standards of a phase 3 RCT as there is no comparison with another treatment.
The study involved patients who had previously been treated with the standard treatment option for hepatitis C (specifically, genotype hepatitis C 1, which is the most common type of the virus), but who had not got better with this treatment.
This treatment is the combination of pegylated interferon and ribavirin, which is licensed for the treatment of hepatitis C. Previous research has shown that up to 50% of people with hepatitis C respond to this combination (as demonstrated by the virus being no longer detected in the blood).
An additional two drugs (telaprevir and boceprevir) have also been recommended as treatment options for use in combination with peginterferon–ribavirin in people who have the type 1 hepatitis C virus. Response rates have been shown to increase to up to around three-quarters in people who receive first-line treatment with one of these triple therapy combinations.
However, response rates to triple therapy can be lower in people who have previously been treated with peginterferon–ribavirin. There are many reports of patients not responding, or responding but later relapsing.
The peginterferon–ribavirin combination and the newer drugs telaprevir and boceprevir are also associated with side effects such as anaemia. There is therefore still a need for new, more effective and better-tolerated drug treatments to be developed.
This phase 3 randomised controlled trial investigated the use of non-interferon-based combination treatment with the drugs ABT-450, ritonavir and ombitasvir (in one formulation), dasabuvir and ribavirin. This combination was compared with matching placebo for 12 weeks.
Earlier phase studies demonstrated that the majority of people with type 1 hepatitis C infection who had previously not responded to peginterferon–ribavirin did respond to this five-drug combination.
This trial therefore aimed to further investigate the safety and effectiveness of this treatment combination in people with genotype 1 hepatitis C who had previously not got better with peginterferon–ribavirin.
These drugs can also all be taken by mouth, while peginterferon has to be given by injection under the skin.
What did the research involve?
The researchers included adults with genotype 1 hepatitis C (virus RNA level more than 10,000 international units per millilitre) who did not have liver cirrhosis.
The participants had also not responded to previous dual combination treatment with peginterferon–ribavirin.
Non-response to previous treatment included those with:
- initial response and later relapse (undetectable viral RNA at treatment end but detectable levels within one year)
- partial response (viral RNA levels decrease by a certain amount at week 12 of treatment, but detectable again by treatment end)
- no response
The researchers did not include people who had previously not responded to triple therapy, or who had HIV infection or a recent history of drug or alcohol abuse.
People were recruited across 76 sites in North America, Europe and Australia. They were randomised to receive either inactive placebos or the active drug combination for 12 weeks, which included:
- the co-formulation of ABT-450/r–ombitasvir (a once-daily dose of 150mg of ABT-450, 100mg ritonavir, and 25mg of ombitasvir)
- dasabuvir (250mg twice daily)
- ribavirin (1000mg daily if body weight was less than 75kg or 1200mg daily if body weight was equal to or greater than 75kg
People in the placebo group received matching placebo pills for these three sets of tablets. The study was double blind, meaning that neither participants nor researchers knew which treatment was being given.
The main outcome examined was the rate of a sustained virologic response (SVR) 12 weeks after the end of the study treatment. This is a term used to describe when the person has undetectable levels of the viral RNA in their blood. SVR for hepatitis C is defined as having an RNA level of less than 25 international units per millilitre.
Other outcomes examined included normalisation of liver enzyme levels, treatment response according to whether the genotype was 1a or 1b, and relapse after treatment.
Side effects of treatment were monitored throughout treatment and up to 30 days after the last drug dose.
All analyses were by intention to treat on the basis that all people who received at least one dose of the study drug were included in the analyses, regardless of whether they completed treatment.
Of note, the research describes that after the 12-week double-blind treatment period, people in the placebo group received the active treatment regimen on an open-label basis for 12 weeks.
As the outcomes were assessed 12 weeks after treatment end, this suggests that at the time of assessment people assigned to the placebo group had been receiving the active treatment for the past 12 weeks, while those assigned to the active treatment had completed 12 weeks of active treatment 12 weeks ago. A case could therefore be made that this was more of a cohort study than a textbook RCT.
What were the basic results?
Of 562 eligible people, 395 were randomised and 394 received at least one dose of their assigned treatment and were included in the analyses.
Twelve weeks after treatment was completed, 286 of 297 people in the active treatment group (96.3%) had a sustained virologic response. Looking by specific genotype, there was little difference in SVR rates between those with hepatitis C virus type 1a (96%) and 1b (96.7%).
According to previous response to peginterferon–ribavirin, SVR rates were 95.3% among those with initial response then relapse, 100% among those with previous partial response, and 95.2% among those with previous null response. Only 7 of 293 people (2.4%) who completed treatment had a post-treatment relapse.
SVR rates for those receiving placebo are not reported. However, at the time of outcome assessment, people in the placebo group had been receiving the active treatment for the past 12 weeks.
During the 12-week double-blind treatment period, side effects were reported by 91% of the active treatment group and 83% of the placebo group. Headache was the most common side effect in both groups, occurring in just over a third of people. Itching occurred significantly more often in the active treatment group (13.8% versus 5.2% in people taking placebo).
Three people in the active regimen group (1.0%) discontinued the study drugs because of side effects. Anaemia also occurred significantly more commonly in the active treatment group, with a decrease in haemoglobin below 10g per decilitre affecting about 5%.
How did the researchers interpret the results?
The researchers concluded that, "Rates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response."
Although designed as an RCT, the study had an analysis of drug effectiveness that becomes more like a single cohort of people receiving an active treatment, with no comparison arm.
People were assigned to the five-drug combination or matching placebos for 12 weeks. During this time, the side effects in both treatment groups were monitored and these could be compared, with itching and anaemia occurring more commonly in the active treatment group.
However, the double-blind drug treatment period was completed at 12 weeks and response outcomes were then assessed 12 weeks later. Twelve weeks later, the active treatment group demonstrated high response rates, with sustained virological response present in almost all (96%) of those who had been treated.
Problematically, however, there is no comparison group for these people. At the end of the 12-week double-blind treatment period, all people in the placebo group went on to receive 12 weeks' active treatment with the five-drug combination.
This means that at the time the outcomes were assessed in the active treatment group, the placebo group had also just completed 12 weeks of active treatment. The response rates for the placebo group are not reported.
Overall, the results suggest that the oral combination of ABT-450, ritonavir and ombitasvir (in one formulation) and dasabuvir and ribavirin may have potential in the treatment of hepatitis C.
However, the safety and effectiveness of this combination now need to be compared with other standard treatment options for this group of people – including repeat treatment with the peginterferon–ribavirin combination, and triple therapy with peginterferon–ribavirin and either telaprevir and boceprevir.
Only then will we know whether this five-drug combination may one day be licensed for this condition, and for which specific groups of people.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.