Staying Informed: Anticipating New Regimens with Direct Acting Antivirals for Hepatitis C

United States Department of Veterans Affairs

for Health Care Providers

The approval of two hepatitis C virus (HCV) protease inhibitors by the U. S. Food and Drug Administration in 2011--boceprevir and telaprevir--marked the start of a new chapter in hepatitis C treatment. These were the first new drugs approved in 10 years for hepatitis C treatment. With boceprevir and telaprevir, triple combination therapy for patients with genotype 1 HCV infection has become available, combining peginterferon and ribavirin with either of these two agents. This represents a huge advance in hepatitis C treatment, with improved sustained viral response (SVR) rates among patients who had never been treated before as well as among patients who had relapsed after treatment or did not fully respond to standard treatment.

But the story of hepatitis C treatment will not end here. Several new drugs are being developed for all strains of HCV, not just genotype 1. At this writing, no other new drugs are yet FDA approved or available for use, but several new agents may be approved in the next few years, making new treatment regimens available for patients.

All of these new drugs are called "DAAs"--direct acting antivirals. There are four major different HCV DAA classes:

1. HCV NS3/4 Protease Inhibitors
2. Nucleos(t)ide HCV NS5B Polymerase Inhibitors
3. Non-nucleos(t)ide HCV NS5B Polymerase Inhibitors
4. HCV NS5A Inhibitors

DAAs Under Development

HCV NS3/4 Protease Inhibitors	Nucleos(t)ide HCV NS5B Polymerase Inhibitors	Non-nucleos(t)ide HCV NS5B Polymerase Inhibitors	HCV NS5A Inhibitors
Telaprevir	Sofosbuvir	BI-207127	Daclatasvir
Boceprevir	Mericitabine	VX-222	Ledipasvir (GS-5885)
Danoprevir		ABT-333	ABT-267
Simeprevir		BMS-791325
ABT-450 (with ritonavir)		Tegobuvir
Faldaprevir		GS-9669
Asunaprevir
GS-9451

While boceprevir and telaprevir currently can only be used in combination with peginterferon and ribavirin, studies are currently exploring other new drug regimens using DAAs with and without interferon.

• Interferon-containing treatment: combining one of the new DAAs with peginterferon plus ribavirin.
• Interferon-free treatment: combining DAAs with each other and/or with ribavirin, for regimens which do not use interferon at all and are "interferon-free."

It is far too early to know which new drug combinations, if any, will receive FDA approval or when. But it is important to be aware that Phase 2 and Phase 3 current trials are showing increased SVR rates, shortened durations of treatment, and acceptable adverse event profiles, creating intriguing possibilities for patients who have not been candidates for hepatitis C treatment because of the toxicities caused by interferon. However, it is also important to know that these results have been obtained in carefully selected clinical trial populations and that effectiveness in the real-world is unlikely to be as high. In addition, the relatively small numbers of patients treated in these trials mean that these new drugs may show unexpected side effects.

Knowing that newer HCV treatment regimens with better efficacy and safety may be available in the next few years, you will likely consider for each of your HCV patients the question of whether it is best to treat them now with or whether to defer treatment and wait for more DAAs to become available.

Reasons to treat a patient now:

• Treatment earlier in the course of HCV infection is associated with higher SVR rates, an important consideration since SVR is associated with a greatly decreased risk of progression to advanced liver disease and death.
• Current SVR rates with triple therapy for genotype 1 patients are better than ever.
• The patient already has advanced fibrosis (stage 3 or 4) and deferring treatment could allow further disease progression and decompensation towards decompensation.
• There is no guarantee that drugs under development will be available in a reasonable period of time, nor that their efficacy and toxicity will be as favorable as in early studies.

Reasons to defer treatment until future drugs become available:

• Current regimens have are highly complex and impose significant pill burdens and other logistic issues on patients.
• Future regimens may have a significantly better benefit-risk profile than currently available therapies.
• A high rate of adverse events with current therapies.
• Some patients who may have contraindications to interferon may be candidates for an interferon-free regimen with potentially less toxicity.

Regardless of whether providers and patients decide to initiate treatment now or defer anti-viral therapy, the following principles are critical:

• All patients with HCV should be evaluated for candidacy for anti-viral treatment, including those with a history of depression, substance use disorders, alcohol use disorders, or other psychiatric comorbidities.
• Patients with psychiatric comorbidities that represent contraindications to anti-viral treatment should be offered effective, evidence-based treatments for such comorbid conditions.
• Patients who are not immediate candidates for anti-viral treatment should be periodically re-evaluated to determine whether they may benefit from such treatment.

Rena K. Fox, MD

May 30, 2013

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