It is difficult to be anything other than dazzled by astounding cure rates of up to 100% from a multitude of interferon-free hepatitis C virus (HCV) clinical trials presented at the American Association for the Study of Liver Diseases (AASLD) meeting in November of 2012.
Proof-of-concept has been established: hepatitis C, a disease that claims more than 350,000 lives annually, can be cured with three months of oral antiviral drugs.
These incredible advances bear scrutiny, since most of these interferon-free trials enrolled people with minimal liver disease -- many of whom were being treated for the first time. Information about safety, efficacy and tolerability of interferon-free regimens is needed in other groups, including people coinfected with HIV, liver transplant candidates and recipients, and people with cirrhosis (especially those who are treatment-experienced). These are also the people with the greatest immediate need of a safe and effective cure.
Cure rates for interferon-containing and interferon-free regimens have skyrocketed in HCV genotype 1, although in treatment-naive people certain factors such as HCV subtype (1a versus 1b), IL-28B genotype (CC versus non-CC), and extent of liver damage (advanced versus mild-to-moderate) may impair response to treatment (see Table 2. Update: Interferon-free regimens in HCV genotype 1, treatment-naive).
The term sustained virologic response (SVR) is used when the hepatitis C viral load (also called HCV RNA) remains undetectable after completing HCV treatment; it indicates that hepatitis C has been cured. SVR has been proven to lower the risk for liver-related illness and death, although people with pre-treatment cirrhosis should be monitored regularly, since they are still at risk for liver cancer.
With pegylated interferon and ribavirin, a person was considered cured when HCV RNA became undetectable during treatment and remained undetectable for 24 weeks after completing therapy (known as SVR-24). Recently, the U.S. Food and Drug Administration (FDA) regulators revised this time point from SVR-24 to SVR-12, since most post-treatment relapses (when HCV RNA becomes detectable after treatment completion) occur within 12 weeks. Thus, SVR-12 became the new primary outcome for clinical trials studying peginterferon-based regimens.
The hunger for information about cure rates from interferon-free regimens has led to earlier reporting of results; SVR-4 (undetectable HCV RNA four weeks after finishing treatment) is now commonly used. But with interferon-free regimens, SVR-4 does not always predict SVR-12, and SVR-12 does not always predict SVR-24. In fact, there have been two late relapses, between 24 and 48 weeks after treatment with an interferon-free regimen: one in Abbott's PILOT trial1 and one in Boehringer Ingelheim's SOUND-C2 trial.2 In both cases, treatment consisted of an HCV protease inhibitor, a non-nucleoside polymerase inhibitor and ribavirin. Although SVR-12 and SVR-24 are primary outcomes for interferon-free trials, monitoring for late relapse will continue.
Results from trials in both treatment-naive and treatment experienced people with HCV genotypes 2 and 3 were presented at AASLD (see Table 5. Update: HCV genotypes 2 and 3, treatment-naive and treatment-experienced).
In late November 2012, Gilead Sciences issued the somewhat disappointing top-line results from POSITRON, a 278-person, interferon-free phase III trial in HCV genotypes 2 and 3. POSITRON compared 12 weeks of sofosbuvir (a nucleotide polymerase inhibitor) and ribavirin to placebo in treatment-naive, interferon ineligible, intolerant or unwilling participants.3 In HCV genotype 2, SVR-12 was close to 100%, but in HCV genotype 3, SVR-12 was only 61% (see Table 1. SVR in genotypes 2 and 3 by population and regimen).
In treatment naive people with HCV genotypes 2 and 3, interferon-free regimens offer the advantage of improved tolerability and ease of administration. But high prices will make these drugs unappealing to payers without a clear demonstration of improved efficacy, and the potential to fill unmet therapeutic needs.
In genotypes 2 and 3, a retreatment regimen -- especially for people with HCV genotype 3 who do not have any options -- should be prioritised by pharmaceutical companies. Sponsors need to develop safe, effective, tolerable and affordable regimens when no alternatives exist, in addition to improving the existing standard of care.
AASLD also brought good news for treatment-experienced people with HCV genotype 1 (see Table 3. Update: Interferon-free regimens in HCV genotype 1, treatment-experienced). Phase 3 trials of DAA combinations, in both treatment-naive and treatment-experienced people, with and without peginterferon and/or ribavirin are ongoing or soon to be launched.
Although people with hepatitis C and their medical providers want to dispense with interferon and ribavirin, some people -- especially null responders with HCV genotype 1a and IL28B non-CC genotypes -- may require one or both drugs plus a combination of direct-acting antivirals (DAAs) for a cure. Therefore, regimens that shorten duration of pegylated interferon and/or ribavirin or substitute peginterferon lambda (a potentially more tolerable type of interferon) for peginterferon alfa, are moving forward (see Table 4. Update on interferon-based regimens in HCV genotype 1, treatment-naive and treatment-experienced).
AASLD brought good news for treatment-experienced people with HCV genotypes 2 and 3, since there is currently no recommended retreatment option when peginterferon and ribavirin are unsuccessful.
For treatment-naive people with HCV genotypes 2 and 3, interferon-free regimens combining sofosbuvir (a nucleotide polymerase inhibitor) and ribavirin yielded cure rates similar to those achieved with the current standard of care (which is 24 weeks of peginterferon and ribavirin), but duration was shortened to 8 weeks. When daclatasvir (an NS5a inhibitor) was added, SVR increased but duration doubled from 12 to 24 weeks (see Table 5. Update: HCV Genotypes 2 and 3, Treatment-Naive and Treatment-Experienced).
|Table 1. SVR in Genotypes 2 and 3 by Population and Regimen|
|Current standard of care: 24 weeks of peginterferon/ ribavirin.*||HCV genotype 2, treatment naive||74% (SVR-24)|
|Current standard of care: 24 weeks of peginterferon/ribavirin.*||HCV genotype 3, treatment naive||69% (SVR-24)|
|ELECTRON trial: 12 weeks of sofosbuvir/ribavirin.||HCV genotypes 2 and 3, treatment naive,(N=10).||100% (SVR-24)||Gane et al.4|
|POSITRON trial: 12 weeks of sofosbuvir/ribavirin.||HCV genotype 2 treatment naive plus interferon ineligible, intolerant and unwilling, (N=120).||93% (SVR-12)||Gilead PR.3|
* European Society for the Study of Liver Diseases (EASL). EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. June 2011.
For people with HCV genotypes 4 and 6, big news came in a small group of treatment naive, non-cirrhotic people in the ATOMIC study, treated with 24 weeks of sofosbuvir, peginterferon and ribavirin. Of the 11 people with HCV genotype 4, 82% had an SVR-12 (two participants, who were responding to treatment, did not return for follow-up visits). In genotype 6, 100% of 5 people had an SVR-12. No relapses were reported between weeks 12 and 24.19
Adding an HCV protease inhibitor to peginterferon and ribavirin boosted SVR and shortened treatment duration for 30 non-cirrhotic, treatment-naive people with HCV genotype 4. The DAUPHINE trial studied 50, 100 or 200 mg of danoprevir/r (a boosted protease inhibitor) plus peginterferon and ribavirin for 24 weeks (with the exception of one arm, where treatment was response-guided; early responders stopped treatment at 12 weeks). Regardless of the danoprevir/r dose, or treatment duration, 97% achieved SVR-24 (one person was lost to follow up). In the response-guided arm, all seven participants were eligible for 12 week of treatment, and SVR-24 was 100%.20
Peginterferon lambda may be a good option for people with HCV genotype 4, if phase III trials confirm the favourable side effect profile seen in phase 2. The EMERGE trial (which compared safety, efficacy and tolerability of peginterferon alfa and ribavirin versus peginterferon lambda and ribavirin) included a small group of people with HCV genotype 4 (approximately 18; 12 received peginterferon lambda).21 Although overall efficacy was comparable, lambda was significantly less likely to cause flulike symptoms and laboratory abnormalities such as anemia and neutropenia than peginterferon alfa-2a.16