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A Step Forward in Therapy for Hepatitis C EDITORIAL - NEJM 4/2009
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NEJM April 30 2009
Jay H. Hoofnagle, M.D.
From the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
"An obvious question is why telaprevir was given for only 12 weeks and not continued with the peginterferon and ribavirin for a total of 24 or 48 weeks. The reason was the side effects. In both studies, telaprevir was associated with an increased rate of anemia, nausea, diarrhea, pruritus, and rash. The rashes tended to be severe, to arise after 8 weeks of treatment, and to increase in frequency thereafter. The nature and cause of the rashes were not elucidated....
...A second question is why the rate of sustained virologic response to the combination of telaprevir, peginterferon, and ribavirin was not higher. In preliminary studies, this combination led to decreases of the HCV RNA to undetectable levels within a few weeks in almost all patients.11,12,13 Nevertheless, at the end of the treatment period in these two trials, only 57% and 70% of patients had undetectable HCV RNA levels, end-of-treatment response rates that can be achieved with the use of peginterferon and ribavirin alone.5,6,7 Because the relapse rates were lower among patients receiving telaprevir than among those receiving standard therapy, the sustained virologic response rates were higher with telaprevir. Therefore, the enhanced response rates with telaprevir may be due to the prevention of viral breakthrough and relapse and may occur only in patients who have at least a partial response to peginterferon....
....Telaprevir appears to be a material advance in the therapy of hepatitis C, beginning a new era of treatment - an era of antiviral agents developed specifically to target this virus. Other HCV-specific agents, including other protease inhibitors,14 helicase and polymerase inhibitors, and molecular agents that interfere with viral replication,15 are likely to follow. Combinations of these new agents with drugs currently in use may ultimately provide effective therapy for all patients with hepatitis C, the promised goal of decades of research."
The therapy of hepatitis C began almost 25 years ago with a small trial of recombinant human interferon alfa.1 The rationale for using interferon was its broad antiviral effects and the suspicion that it might be active against the still-undiscovered agent of non-A, non-B hepatitis. Indeed, interferon had striking effects, lowering serum aminotransferase levels and, in a proportion of patients, inducing a lasting improvement in serum enzyme levels. Not until the discovery of the hepatitis C virus (HCV) were the effects of interferon understood; treatment resulted in a decrease in HCV RNA levels, which led to a sustained absence of virus in a proportion of patients.2 The difficulty was that interferon required parenteral injections, had multiple adverse effects, and resulted in a poor overall response rate. Nevertheless, interferon was approved for use for hepatitis C treatment in the United States in 1992.
The second important advance in hepatitis C therapy came with the use of ribavirin. Ribavirin is a nucleoside analogue known to have activity against several flaviviruses. When HCV was identified as a flavivirus, ribavirin was an obvious treatment choice. Ribavirin had little effect on serum HCV RNA levels but led to improvements in aminotransferase levels and histologic characteristics of the liver.3 More importantly, when combined with interferon, ribavirin increased the rate of sustained virologic response.4 Interferon and ribavirin given in combination for 48 weeks yielded rates of sustained virologic response of 40 to 50%, two to three times those obtained with interferon alone.3 Ribavirin was approved for use as an adjunct to interferon therapy of hepatitis C in 1998.
A third advance in therapy of hepatitis C came soon thereafter, with the introduction of pegylated forms of interferon that allowed for once-weekly (rather than thrice-weekly) injections. Peginterferon yielded higher rates of sustained virologic response than standard interferon: 45 to 55% after a 48-week course of peginterferon and ribavirin.5 The response rates varied according to HCV genotype. Among patients infected with genotypes 2 and 3 (approximately 25% of patients in the United States), rates of sustained virologic response were 70 to 80% and were achieved with a 24-week course and reduced doses of ribavirin.6 In contrast, rates of sustained virologic response among patients infected with genotype 1 (approximately 70% of patients in the United States) were less satisfactory, ranging from 40 to 50% and requiring 48 weeks of full doses of ribavirin. In some populations, response rates were even lower, with rates of approximately 25 to 30% among blacks.7 Higher doses and longer courses of therapy increased rates of sustained virologic response minimally and usually were associated with increased side effects.3 Peginterferon was approved in the United States in 2001.
Almost 10 years later, a fourth advance in hepatitis C therapy is still awaited but now may be close at hand. Two articles in this issue of the Journal describe results of phase 2 trials involving telaprevir (formerly known as VX-950).8,9 Telaprevir is a specific inhibitor of the HCV protease and is one of several molecules developed according to a rational drug design based on the molecular structure of HCV.10 Telaprevir is peptidomimetic, meaning that it resembles the HCV polypeptide that is cleaved by the viral protease, a necessary step in replication. However, telaprevir has an electrophilic "serine-trap warhead" that forms a covalent bond with the catalytic serine residue of the protease, blocking its activity. Telaprevir, an agent developed specifically to target HCV, represents a new era of therapy for hepatitis C.
Telaprevir has profound effects on HCV replication in cell culture and in animal models.10 In phase 1 studies of chronic hepatitis C, a 1-to-2-week course of telaprevir lowered HCV RNA levels by 2 to 5 log10 IU per milliliter.11 As expected, this short-term therapy was followed by a rebound in viral levels after the drug was stopped. Furthermore, telaprevir resistance appeared rapidly, and viral levels trended upward during the last days of treatment. The combination of telaprevir and peginterferon appeared to provide more profound viral suppression and less viral resistance.12,13 Some patients treated with peginterferon and ribavirin for a full 48 weeks after the short course of therapy with telaprevir, peginterferon, and ribavirin had a sustained virologic response.
These phase 1 studies led to the design of the two trials reported here, by McHutchison et al. in the United States (ClinicalTrials.gov number, NCT00336479 [ClinicalTrials.gov] )8 and Hˇzode et al. in Europe (NCT00372385 [ClinicalTrials.gov] ).9 The trial designs were somewhat complex. Telaprevir was given for 12 weeks only, in combination with peginterferon alfa-2a with or without ribavirin, which were given for either for the same 12 weeks or for a total of 24 or 48 weeks. The control group received the standard therapy of peginterferon and ribavirin for 48 weeks. Standard therapy yielded rates of sustained virologic response of 41% and 46%, respectively. In comparison, telaprevir given for 12 weeks combined with peginterferon and ribavirin given for 24 weeks yielded response rates of 61% and 69%, both significant increases over the responses to standard therapy.
The other regimens tested had less satisfactory results. The stopping of all therapy at 12 weeks yielded lower rates of sustained virologic response than seen with continuation of therapy through 24 weeks, and the use of peginterferon and telaprevir without ribavirin was associated with high rates of relapse. Finally, in the study by McHutchison et al., the continuation of peginterferon and ribavirin for a total of 48 weeks, including the initial 12-week course of all three agents, was no more effective than the 24-week regimen (rate of sustained virologic response, 67% and 61%, respectively). These phase 2 trials suggest that the addition of telaprevir to the combination of peginterferon and ribavirin will increase rates of sustained virologic response in patients with chronic hepatitis C due to infection with HCV genotype 1 from approximately 45% to as high as 65% and will permit therapy to be limited to 24 weeks, thus avoiding the expense and side effects of prolonged therapy.
An obvious question is why telaprevir was given for only 12 weeks and not continued with the peginterferon and ribavirin for a total of 24 or 48 weeks. The reason was the side effects. In both studies, telaprevir was associated with an increased rate of anemia, nausea, diarrhea, pruritus, and rash. The rashes tended to be severe, to arise after 8 weeks of treatment, and to increase in frequency thereafter. The nature and cause of the rashes were not elucidated.
A second question is why the rate of sustained virologic response to the combination of telaprevir, peginterferon, and ribavirin was not higher. In preliminary studies, this combination led to decreases of the HCV RNA to undetectable levels within a few weeks in almost all patients.11,12,13 Nevertheless, at the end of the treatment period in these two trials, only 57% and 70% of patients had undetectable HCV RNA levels, end-of-treatment response rates that can be achieved with the use of peginterferon and ribavirin alone.5,6,7 Because the relapse rates were lower among patients receiving telaprevir than among those receiving standard therapy, the sustained virologic response rates were higher with telaprevir. Therefore, the enhanced response rates with telaprevir may be due to the prevention of viral breakthrough and relapse and may occur only in patients who have at least a partial response to peginterferon.
Telaprevir appears to be a material advance in the therapy of hepatitis C, beginning a new era of treatment - an era of antiviral agents developed specifically to target this virus. Other HCV-specific agents, including other protease inhibitors,14 helicase and polymerase inhibitors, and molecular agents that interfere with viral replication,15 are likely to follow. Combinations of these new agents with drugs currently in use may ultimately provide effective therapy for all patients with hepatitis C, the promised goal of decades of research.
No potential conflict of interest relevant to this article was reported.
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