It’s been just two years since the protease-inhibitors boceprevir (Victrelis) and telaprevir (Incivek), the first in what was described as a “disease-changing” class of drugs for the treatment of hepatitis C (HCV), were approved. Yet many clinicians already consider the original directly acting antivirals (DAAs) obsolete.
Although clinical trials showed they increase the cure rate from the 50% seen with the standard of care peginterferon-alpha (PEG-IFN) and ribavirin (RBV), to about 75% in patients chronically infected with HCV-1, their high rate of adverse effects, high pill burden, drug-drug interactions, low response in certain populations, and the need to administer them in conjunction with PEG-IFN and RBV has significantly limited their use.1 The reality is that clinicians are abandoning the drugs as they wait for the first in a new wave of HCV therapies expected to hit the market in late 2013 and 2014.
A recent French study found rates of serious adverse events between 38% and 49% in clinical practice, compared to rates seen in the clinical trials.
“Yes, there are more side effects (with boceprevir and telaprevir) observed in the clinical setting than what we saw in the clinical trials,” said Michael Sagg, MD, who directs the Division of Infectious Disease at the University of Alabama-Birmingham and who is a member of the Infectious Disease Society of America’s Hepatitis Task Force. “But in my mind, it’s all moot, because in a year there are going to be so many more agents released with much fewer side effects that don’t require administration with PEG-IFN or RBV.”
“I wouldn’t treat anyone with HCV right now unless they were cirrhotic or had some other manifestation of HCV,” he said, a process called “warehousing.” Instead, he’s waiting for the new agents to become available.
Most of the novel medications, which include second-generation protease inhibitors, are given orally once a day, without PEG-IFN or, in some cases, reviparin, and with 90% to 100% success rates, depending on the viral genotype. “They result in a cure in 12 weeks,” Dr. Sagg said. “So why use these other drugs?”
The reason for his optimism is a “revolution” in the development of HCV antivirals that he compares to the HIV drug explosion in the 1990s, “only three or four times bigger.”
Indeed, this year at the European Association for the Study of the Liver (EASL) in Amsterdam investigators presented what one expert called an “astounding number” of phase III results, writing in a summary of the meeting.1
What’s happening in the HCV world today, said Dr. Saag, is “HIV all over again,” albeit with one important difference: “You can cure the infection in about 12 weeks of therapy.”
This explosion in HCV drug development is driven by two factors: the development of an in vitro model of the virus in 1999 that allowed investigators to screen large numbers of potentially therapeutic compounds, and a greater understanding of the virus’ infection and replication process, which provides numerous targets for treatment.2
The first drugs developed with this newfound knowledge were telaprevir and boceprevir. Second-generation protease inhibitors are designed to overcome some their limitations, with studies showing fewer side effects. Most are also taken once daily, making them easier to integrate into treatment which will, most likely, improve adherence.3
The nucleoside inhibitors (NI) are potent compounds that appear active against all HCV genotypes and demonstrate low rates of resistance. Some under investigation do, however, require co-administration with PEG-IFN and/or RBV.3
A study presented at the EASL (European Association for the Study of the Liver) meeting found that 24 weeks of treatment with the NS5A inhibitor daclatsivir in combination with the polymerase inhibitor sofosbuvir with or without ribavirin cured 100% of 41 HCV-1 patients who had failed IFN-based therapy with boceprevir or telaprevir.
The non-nucleoside inhibitors, however, however, appear less potent, with high rates of resistance, although they may play a role in combination therapy.3
Other direct-acting antivirals under investigation include cyclophilin inhibitors, antagomirs, and immunomodulators. Also under development are indirectly acting antivirals, which do not induce resistance but may play an important role in combination therapy, and analogues of interferon and ribavirin.3
Several articles about emerging therapies highlight some unanswered questions and potential challenges that need to addressed. These include:4
• The continued role of pegylated interferon plus ribavirin
• Deferring treatment until the “ideal” combination is available
• Stratifying patients for treatment based on genomic and other markers
• Optimum duration of treatment
• Availability of clinicians and necessary infrastructure to treat and follow the higher number of patients who will be candidates for the new therapies
• The economic burden that will occur when large numbers of HCV-infected patients begin highly-active anti-HCV therapy, and the attendant reimbursement issues
As the author of one review wrote: “The introduction of DAA and creation of highly active anti-HCV therapeutic drug regimens has the potential to produce a dramatic improvement in outcomes in patients with chronic hepatitis C. However, the future also has the potential to challenge the healthcare system’s ability to deliver the promise of these new medications.”2
1. Rockstroh J. Summary from EASL 2013 for Hepatitis C - New HCV DAAs on their way soon: what do the phase III studies tell us? . Paper presented at: European Association for the Study of the Liver 48th annual meeting 2013; Amsterdam.
2. Poordad F, Dieterich D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents. J Viral Hepat. (2012) 19(7):449-464.
3. Doyle JS, Aspinall E, Liew D et al. Current and emerging antiviral treatments for hepatitis C infection. Br J Clin Pharmacol. (2013) 75(4):931-943.
4. Jesudian AB, de Jong YP, Jacobson IM. Emerging therapeutic targets for hepatitis C virus infection. Clinical Gastroenterology and Hepatology (2013) 11(6):612-619 e611.