San Francisco—Soon after the FDA approved two direct-acting antiviral agents (DAAs) last spring for treating infection with hepatitis C virus (HCV), a 57-year-old black man came to see gastroenterologist Andrew Muir, MD.

The man had been diagnosed with hepatitis C in 2001. A liver biopsy one year later revealed he had stage II fibrosis. At the time, the patient declined treatment, saying the duration was too long and offered too few benefits.

But recently, he came back to Dr. Muir wanting to try a new protease inhibitor. Based on his reading, the man believed he could avoid interferon (IFN) and ribavirin (RBV), take a protease inhibitor as monotherapy for 24 weeks and expect a 75% chance of achieving a sustained virologic response (SVR).

Unfortunately, the patient’s expectations were unrealistic on all counts. The new protease inhibitor can only be given in conjunction with IFN and RBV, and the treatment duration varies. For blacks, therapy usually lasts a full 48 weeks, and in clinical trials, only 30% of black patients achieved an SVR with 28 weeks of therapy. Moreover, among black patients in the Phase III trials, SVR rates fell short of the 75% that the patient expected, and in treatment-naive blacks, only 62% receiving telaprevir and 53% on boceprevir achieved an SVR.

Educate To Encourage Adherence
Unrealistic expectations are common among patients with HCV infection who, after years of waiting for better therapies, are eager to try treatment with the new DAAs, said Dr. Muir. The DAAs on the market today are complex, with varied stoppage rules, monitoring points and some serious adverse events and drug–drug interactions.

“This is a real problem for clinicians. There’s tremendous excitement about these new therapies, but oftentimes, patients’ expectations are not in line with what these drugs can deliver,” said Dr. Muir, clinical director of hepatology at Duke University Medical Center, Durham, N.C.
In a presentation at The Liver Meeting 2011, Dr. Muir stressed that clinicians need to take time to carefully prepare patients for DAA therapy. Physicians must have clear, detailed discussions with their patients before and throughout treatment to optimize the benefits of DAA therapy, he said.
“The major challenges are preparing patients for the rigors of therapy, checking in frequently to make decisions about the duration of treatment and managing any issues as the patient goes along,” said Dr. Muir.

When patients come into the office considering treatment with DAAs, the first step is to clarify their expectations, said Dr. Muir. Patients need to learn the reality about DAAs if they want treatment to succeed.

Dr. Muir outlines for patients the complex prescribing rules, the contraindications, the lifestyle changes and duration of treatment with DAAs. The lifestyle changes can be significant, he cautions patients. Both telaprevir and boceprevir must be taken three times a day, or once every eight hours, and always with a meal. Dr. Muir then asks if the patient still wants treatment when these things are taken into account.

“That’s no small feat. Patients must adhere to that regimen because lapses in the concentration of telaprevir and boceprevir have historically been the risk period for breakthrough variants on therapy,” said Raymond Chung, MD, chief of hepatology and vice-chief of gastroenterology at Massachusetts General Hospital, Boston. Many of Dr. Chung’s patients limit or reschedule their work hours while on DAA therapy to help with adherence.

The key to getting patients through DAA treatment successfully is to select patients carefully and prepare them assiduously, said Gary L. Davis, MD, director of general and transplant hepatology at Baylor University Medical Center, Dallas. “This means that any issues that might impact compliance, tolerance and drug access should be dealt with before treatment starts. Educating the patient is essential. Patients and their support person need to clearly understand the importance of dosing compliance, lab monitoring and treatment stopping rules/end points.”

The treatment care team then needs to remain in close contact with the patient throughout treatment to reinforce adherence and offer feedback on their process, he added. At Dr. Chung’s office at Massachusetts General Hospital, one nurse practitioner has been assigned full-time to managing patients on DAAs. She works with them on everything from managing possible reactions like rash and anemia to helping them set up a daily schedule for taking the medications.

“We have 50 to 100 patients in varying stages of DAA treatment,” said Dr. Chung. “Every one of these patients is coming in for frequent visits—weekly in the beginning—and they are very much in need of monitoring, not just for adverse events like rash but also for fatigue and their ability to carry out work.”

Begin With a Thorough History
Before patients start the new therapies, gastroenterologists and hepatologists should consider getting a liver biopsy to help guide treatment, said Dr. Muir. Physicians also should confirm a patient’s history of treatment for HCV. If patients were previously on antiviral therapies, physicians need to find out as much as they can about that experience.

“You must ask whether we can improve upon previous treatment,” said Dr. Muir. “Were there adverse events with treatments? Were there dose reductions? If so, were they appropriate? How was patient adherence to medications? Did they use alcohol?”

Based on that information, physicians should outline the likelihood of each individual patient achieving an SVR, he said. The key predictors of SVR are whether patients are treatment-naive or treatment-experienced, whether they have cirrhosis and their race. Another important issue for patients is treatment duration. Duration will vary depending on each patient’s characteristics. “It’s important to speak with every patient about their likelihood of a shorter duration of treatment,” said Dr. Muir.
The American Association for the Study of Liver Diseases recommends 48 weeks of treatment for all patients with cirrhosis, as fewer patients with cirrhosis were included in the clinical trials that led to approval of the new drugs. Among those included, virologic response levels were lower than for patients without cirrhosis. For treatment-naive patients, 46% of non-black and 29% of black patients in the boceprevir SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial achieved undetectable levels of HCV by 28 weeks, making them eligible for the shortened course of treatment (Poordad F et al. N Engl J Med 2011;364:1195-1206). In the telaprevir trial, 58% of patients had an early rapid virologic response (Jacobson IM et al. N Engl J Med 2011;364:2405-2416).

Patients’ interleukin-28B (IL28B) genotype also affects the expected duration of treatment. For both boceprevir and telaprevir, patients with the IL28B CC genotype are most likely to attain an early virologic response, more likely to receive a shortened course of therapy and more likely to have an SVR, according to studies presented at last year’s annual meeting of the European Association for the Study of the Liver.

Follow Through: Monitor for Response, Resistance, Reactions, Interactions
When the new HCV drugs were first approved, physicians’ offices reported some trouble getting approval from third-party payers for the full course of treatment, said Dr. Chung. His office had to provide documentation of successful early virologic response to get the go-ahead from payers to approve continuation of treatment with a protease inhibitor.

“You can imagine that if any gaps occur in the virologic tests or their reporting, this could lead to interruption of protease inhibitor therapy. It’s been a real challenge,” he said.

Experts recommend following patients very carefully over the course of treatment, monitoring any virologic breakthroughs or adverse reactions to the medications, particularly rash and anemia. Dr. Chung sees patients after the first, second and fourth week of therapy, and every four weeks thereafter if patients are having an uneventful course. Treatment monitoring is essential to prevent unwarranted continuation of treatment in patients when a breakthrough has occurred, he said.
“That would signal the emergence of resistant variants. Upon discovery, it would be paramount to discontinue the entire regimen to prevent selection of additional resistance mutations,” he said.
Equally important is the need to monitor patients closely for adverse reactions and drug–drug interactions. As IFN and RBV remain the backbone of this HCV regimen, the same contraindications exist as with standard dual therapy: decompensated cirrhosis, renal insufficiency, advanced cardiac/pulmonary disease, active depression, severe mental illness, anemia/neutropenia/thrombocytopenia and noncompliance.

Additionally, there are important drug–drug interactions with boceprevir and telaprevir. Both DAAs inhibit the CYP3A4/5 enzyme. Drugs metabolized by CYP3A4/5 may have increased effect in the presence of boceprevir or telaprevir. The DAAs themselves are metabolized by this cytochrome. As a result, other drugs that induce or inhibit CYP3A4/5 could affect HCV levels.
“Planning is key to deal with drug–drug interactions,” said Dr. Muir. It’s very important to do a risk–benefit analysis of treatment with boceprevir and telaprevir, taking into account patients’ comorbidities, he added.

It is important to review all drugs that the patient is taking, including over-the-counter and herbal medications. Check with the patient’s primary care provider, cardiologist and psychiatrist about medication use, Dr. Muir said. “It’s a good time to revisit the need for all medications. Ask if the antidepressant can be changed, the blood pressure medicines. Can the patient hold their statin for 12 weeks?” he said.

Women taking oral contraceptives should be advised to try other methods of contraception, such as an intrauterine device or barrier methods. Additionally, pregnant women should not take either drug, as both are considered pregnancy category X, meaning the risks “clearly outweigh potential benefits,” according to the FDA.

Anemia and rashes are the two most common adverse events associated with the new therapies. Experts suggest physicians be proactive about managing both.
Before a patient starts therapy, do a pretreatment evaluation for anemia and consider the impact on comorbidities, such as cardiac and pulmonary disorders. Weigh the benefits of reducing the dose versus increasing or starting erythropoietin.

For rashes, patients should be proactive by moisturizing twice a day, limiting sun exposure and wearing loose-fitting clothing. Dr. Chung recommends including a dermatologist on the treatment team.

Keep an Eye on the ‘Holy Grail of Therapy’
One other important element that needs to be taken into account when considering patients for DAA therapy is whether patients should wait for something else to be approved, said Dr. Chung. Recent results from Phase II studies of second-generation DAAs suggest that some combination of these could be approved in the next three years (see “New Polymerase Inhibitor Could Become Cornerstone of Interferon-free HCV Treatment Regimen,” by Christina Frangou. Gastroenterology & Endoscopy News 2012;63[2]:16 and “Second Study of New Hep C Drug Is Promising for Difficult-to-Treat HCV Genotype 1 Patients,” by Christina Frangou. Gastroenterology & Endoscopy News 2012;63[2]:17-19). These therapies omit IFN from the treatment regimen and can generally be taken orally once a day, with or without food.

“That’s something critical to consider. With all the complexities of therapy—the issues of tolerability, adherence, drug–drug interactions, quality of life—there’s another equally important set of events going on, and that’s the emerging data on all-oral, interferon-free treatments,” said Dr. Chung. “It’s clear that the promise of interferon-sparing therapy is very real. For all of us, that would be the holy grail of therapy.”

Dr. Chung currently recommends that all patients with HCV infection who have advanced-stage disease, regardless of whether they are treatment-naive or experienced, should be considered for boceprevir or telaprevir, provided the benefits outweigh the risks. Patients who can reasonably defer treatment because of early-stage disease or who cannot tolerate IFN may be able to wait for investigational therapies to be approved. These patients also may be eligible for investigational studies, which are ongoing.

Dr. Muir disclosed that he is on advisory committees or review panels for Merck & Co., and Vertex Pharmaceuticals; is a consultant for Inhibitex, Merck & Co., and Vertex Pharmaceuticals; and receives grant/research support from Abbott Laboratories, Anadys, Bristol-Myers Squibb, Gilead, Medtronic, Merck & Co., Pfizer, Roche, Santaris, Scynexis and Vertex Pharmaceuticals. Dr. Chung receives grant/research support from Gilead, Merck & Co., Pfizer and Romark. Dr. Davis is a consultant for Vertex Pharmaceuticals and receives grant/research support from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Novartis, Pharmasset, Tibotec and Vertex Pharmaceuticals.