Blockbuster drugs that singularly transform management of a disease are rare, but two new protease inhibitors designed to treat hepatitis C virus (HCV) have the potential to do just that. The medications, boceprevir and telaprevir, both approved by the Food and Drug Administration (FDA) in May 2011, are the first direct acting agents for treatment of HCV to receive a nod from the agency. In clinical trials leading to their approval, both demonstrated sustained virologic response rates of 65–70% in the most common but difficult-to-treat HCV genotype 1, which compares with 40–45% in established therapies. Experts say these landmark drugs are merely the opening salvo in a new offensive against HCV, one that could radically change treatment of the disease, as well as the type and volume of lab tests needed.

"These new drugs absolutely changed the landscape. In the past, the gold standard was dual peginterferon-ribovarin therapy, but the response rates were less-than-stellar and the side-effects somewhat difficult. When you combine that with a significant duration of therapy, it hasn't been a perfect environment for treatment, although that was all we had," observed Rick Pesano, MD, PhD, medical director of infectious diseases at Quest Diagnostics. "Now, with the direct acting agents, we've not only significantly upped the cure rate, but also shortened the duration of therapy. These drugs have absolutely changed the topography of therapy, and it's not over. They're the wave of the future."

An Imperfect Standard of Care

The standard of care for HCV treatment since the early 1990s has been interferon, aimed at boosting the immune system rather than attacking the virus outright. By the late 1990s, ribavirin was added to the mix, increasing sustained virologic response rates and decreasing relapse rates. A few years later, long-acting pegylated forms of interferon came along, but the peginterferon/ribavirin combination maxed out at about a 45% overall sustained response rate.

Yet the need to find better treatments is great. HCV accounts for about 45% of all liver disease and is the leading cause of cirrhosis, liver failure, and liver transplantation. An estimated 3.9 million people—more than 1% of the U.S. population—carry the virus, but perhaps as many as 80% are unaware of it. The virus simmers in the background for years, eventually causing significant liver damage. Even so, most patients either opt not to pursue therapy at all, or drop-out after starting due to its rigor: weekly injections for nearly a year and a plethora of some annoying, and other potentially serious, side-effects.

Strict New Regimens

Enter boceprevir and telaprevir. Both compounds inhibit the HCV NS3/4A serine protease, effectively preventing cleavage of the HCV polyprotein chain and curtailing replication of the virus. The drugs were approved for treatment-naïve patients, or those with unsuccessful prior treatment, including failed or relapsed responses. In Phase 3 clinical trials, sustained virologic response rates were as high as 96% for certain subjects on boceprevir, and 89% for telaprevir, with overall response rates of 70–75%.

Based on these findings, FDA approved both drugs to be taken in combination with peginterferon/ribavirin, according to strict drug dosage and viral load testing schedules under a response-guided approach to therapy that determines duration of treatment (See Table). Findings from clinical trials suggest that about half of patients will need only 28 weeks of therapy, whereas others whose previous treatment failed or who have slower virologic responses will stay on regimen for a full 48 weeks. The bottom line with either drug is that monitoring virologic response via nucleic acid testing is essential.

"HCV rapidly mutates and virtually all our patients will develop resistance to the current protease inhibitors, if those protease inhibitors are used as monotherapy. This is why we use them in combination with peginterferon/ribavirin. The protease inhibitor rapidly brings down HCV RNA and then the effects of peginterferon/ribavirin eradicate the virus in a high percentage of patients, leading to sustained virologic response and cure," said Mitchell Shiffman, MD, medical director of the Liver Institute of Virginia at Bon Secours Virginia Health System in Newport News. "Breakthrough primarily occurs due to resistance to interferon. If the interferon isn't working and can't eradicate HCV, resistance to the protease inhibitor can emerge. So measuring HCV RNA during treatment is critical." Shiffman recently participated in an AACC webinar involving current issues in hepatitis testing.

Boceprevir requires a 4-week lead-in with dual peginterferon/ribavirin therapy, followed by 24 weeks of triple boceprevir/peginterferon/ribavirin treatment. The package insert and American Association for the Study of Liver Diseases (AASLD) practice guidelines recommend HCV RNA viral load testing at weeks 8 and 24. Patients who have not been treated before and who have undetectable HCV RNA levels at these two junctures may be considered for a shortened 28-week course of therapy. However, those who either had treatment before or detectable viral levels ≥100 IU/mL at week 8 but undetectable levels at week 24 would need a full 36 weeks of triple therapy, followed by combination peginterferon/ribavirin for 12 weeks, for a total 48 weeks' treatment.

In contrast, patients taking telaprevir do not have a 4-week lead-in with peginterferon/ribavirin. Instead, they immediately start 12 weeks of triple telaprevir/peginterferon/ribavirin therapy, with HCV-RNA viral testing at weeks 4 and 12, followed by at least 24 weeks of dual peginterferon/ribavirin therapy, for a total of 28 weeks' treatment. Those with undetectable viral loads at both weeks 4 and 12 would be eligible for the shortened 28-week regimen. However, those with detectable levels <1,000 IU/mL at both time points would stay on dual therapy for an additional 36 weeks, for a total 48 weeks' therapy. Patients treated previously with only partial or no response also would stay on dual therapy for an additional 36 weeks, for 48 weeks in total.

With either drug, therapy must be stopped anytime viral loads exceed recommended thresholds, >100 IU/mL in the case of boceprevir and >1,000 IU/mL for telaprevir. "We have to be vigilant about adhering to these rules because the continuation of a failing regimen has negative implications for the selection of further resistance and consequences that may be unfavorable for future courses of therapy," noted Raymond Chung, MD, chief of hepatology and vice chief of gastroenterology at Massachusetts General Hospital in Boston.

Implementing HCV Nucleic Acid Testing

Given the importance of nucleic acid testing in assessing the success of the new regimens and both providers' and patients' renewed interest in pursuing HCV treatment, labs that have not yet invested in HCV RNA PCR assays might consider doing so, according to Chong-Gee Teo, MD, PhD, chief of the Centers for Disease Control and Prevention's viral hepatitis lab. "With the promise of faster and more accepted therapy with the protease inhibitors, there's a drive to go beyond antibody-based screening of HCV to identify patients who are actively infected," he explained. "Most labs right now test for antibodies to HCV and will stop there unless a physician requests confirmation that a patient's actively infected. So labs might now expect more demand for HCV RNA testing." Teo also pointed out that since nucleic acid testing requires specimen preparation and testing platforms different than those used in conventional antibody testing, labs that pursue the technology will need special expertise, equipment, and reagents to support the move.

Experts urged labs that either already offer or expect to implement HCV nucleic acid testing to review the telaprevir and boceprevir package inserts to ensure that their technologies are sufficiently robust. "The requirements are very similar with some minor differences. The assay should have a lower limit of HCV RNA quantitation ≤25 IU/mL. But it also has to have a limit of HCV RNA detection of 10–15 IU/mL. That's a change," observed Pesano. "In the past, we've had some technologies for detecting HCV RNA that were not that sensitive. But the new required levels of quantitation and detection are needed in order for physicians to be comfortable taking patients off therapy and making sure they've succeeded in care. The lab technologies have moved in combination with those requirements."

Shiffman recommended that labs "use a very good, reliable PCR assay. The ones that are FDA-approved will reliably measure down to a level of 40 or 60 IU/mL, which is sufficient for the 100 IU/mL cutoff utilized for boceprevir treatment and clearly lower than the 1,000 IU/mL for telaprevir. What is unacceptable is to measure HCV RNA levels with a cutoff level of 650 IU/mL or higher in our current treatment paradigms."

Pesano also advised laboratorians to be prepared to discuss virologic response in the context of HCV RNA testing. "A question I get on a regular basis is around clinicians' understanding of when patients' viral loads are adequately low for the physicians to be confident in moving to the next stage in therapy. Many people are learning the thresholds now, and depending on the test that's used, it can be confusing sometimes to clinicians between limit of detection and limit of quantitation. But these data points are imperative in monitoring HCV patients appropriately."

The Importance of Timely Turnaround

Hepatologists emphasized the importance of providing timely HCV RNA results so clinicians can adjust treatment regimens as necessary. "Our greatest need for the future is rapid virologic testing. Having these tests sent out with seven-to-14 day turnaround times challenges our ability to make decisions around therapy," said David Nelson, professor of medicine and associate dean for clinical research in the division of gastroenterology, hepatology, and nutrition at the University of Florida College of Medicine in Gainesville. "We're looking for resistance, and if you see a rapid increase in virus, you know that's resistance." AASLD guidelines define virologic breakthrough as >1 log increase in serum HCV RNA above nadir.

Echoing this sentiment, Chung relayed lessons he learned about the need for fast turnaround times. "We ran into a very practical issue, which was that the third-party payer wanted to see evidence that we were not violating the week four stop rule for telaprevir, meaning they needed to know that the HCV RNA level was below 1,000 IU/mL before approving a prescription renewal. So in some cases we were sweating it out to make sure they got that information. It's a multi-step process, and if not done in a timely way, the patient runs the risk of missing renewal of their medications, and jeopardizing the success of therapy. That's a highly practical consequence of slow turnaround times."

Those circumstances aside, Chung indicated that a few days' processing time is about the norm for most labs. "This is not a test that's run 18 hours per day every day. It's a batch decision on the part of molecular diagnostic labs as to when they have enough for the next run. Depending on the volume, that may be two or three times a week. Our turnaround time has been two or three days, and for most purposes, that's been acceptable."

Still, Nelson is pushing the envelope for speedier turnaround times. "In the future I'd like to have it so that a patient gives a blood sample and within half-an-hour I'd have a good idea of what their viral response has been and what their CBC is. Then I can be very efficient and appropriately change the course of therapy as needed without having to wait three days to a week. If we can get to the technology to point-of-service efficiency, I think we'll really improve care in this arena."

IL28B Testing: A Flash in the Pan?

Availability of boceprevir, telaprevir, and other protease and polymerase inhibitors in the pipeline is not only changing demand for HCV RNA testing but also other molecular diagnostic tests. The landmark discovery in 2009 that IL28B modulated interferon response prompted an immediate interest in testing for haplotypes of this gene, an interest that will soon fade, said experts. "It's becoming less important in clinical algorithms or clinical decision-making with introduction of the new direct acting agents. With the next wave of treatments that are on the horizon, IL28B status is probably not going to be a factor at all in determining response," predicted Nelson.

By the same token, at least for now hepatologists report being more interested than ever before in HCV subtyping. "There's a consistent efficacy difference between genotype IA and IB with the new direct acting agents. Depending on the regimen used, IB appears to experience higher sustained response rates in comparison to IA. As such, knowledge of the subtype will factor into, at least in the early going, our prognostication about future sustained response rates," observed Chung. "As we get better with pan-genotypic coverage, those distinctions will start to dissipate. We're in a unique period right now when, with the current generation of protease inhibitors, we're seeing this discordance between IA and IB. It's not dramatic, but it's noteworthy." In Nelson's view, the difference between IA-IB response rates is substantial enough that he suggested labs unable to offer robust subtype analysis will be left in the dust.

Other Treatment Challenges

Aside from molecular diagnostic considerations, hepatologists emphasized that triple protease inhibitor/peginterferon/ribavirin therapy also is picking up demand for other lab tests, such as CBCs. Anemia, a well-known side-effect of peginterferon/ribavirin treatment, can be accentuated with either boceprevir or telaprevir. "It's proving to be very challenging and unusually severe in some cases," said Chung. "Not only have we had to dose-reduce ribavirin, but we've also employed erythropoietin-stimulating agents, and even needed to transfuse some patients. Unfortunately, despite assiduous monitoring, we've had to admit some patients for severe anemia."

Drug-drug interactions between boceprevir, telaprevir, and a host of other drugs is another consideration for managing patients on triple HCV therapy. The extent to which any lab testing will be beneficial in this realm remains to be seen, according to Nelson. "There are extensive drug-drug interactions around the CYP450/CYP3A4 pathways, but currently we don't have data to say which SNP would be predictive of significant adverse events. Clearly there's a role for research in looking at pharmacogenomic associations, and hopefully that type of data is on the way."

Absent further guidance or evidence, extreme vigilance in this area will be the order of the day, according to Anna Lok, MD, Alice Lohrman Andrews research professor in hepatology, director of clinical hepatology, and professor of internal medicine at the University of Michigan Health System in Ann Arbor. "Very important, the physician needs to review all of the patient's medications prior to start of triple therapy, and some meds might need to be stopped or switched to others. It's also imperative that patients inform physicians if they are started on new meds during the course of treatment."

As enthusiastic as the hepatology community is about the availability of the new protease inhibitors, managing these treatments is so challenging that some providers might back away from the regimens, according to Chung. "The complexity of the therapy has intensified manpower utilization, and in some ways, despite the promise, has narrowed the spectrum of providers who are equipped to be in the business of treating these patients," he said. "It's actually made many of us think that for most patients whose disease can afford to wait two, three, or four years until the next generation of direct acting agents are available, deferral may be the most rational step."

The Road Ahead

Even if therapy with boceprevir and telaprevir has some bumps and curves, experts see a much smoother course just down the road. For example, findings about a new polymerase inhibitor presented as an abstract at a recent AASLD meeting have taken the field by storm. The agent, PSI-7977, showed 100% virologic response rates when taken only with ribavirin or with three different peginterferon regimens. "This presentation left the group quiet without a comment for virtually a minute as everybody pondered these results," recalled Shiffman. "This leaves the door open for the first time now that we think we can cure HCV without peginterferon/ribavirin. We look forward to Phase III clinical trials starting some time in 2012."