Tuesday, August 16, 2011

Use of New HCV Protease Inhibitors ‘Not That Simple’


Use of New HCV Protease Inhibitors ‘Not That Simple’
by Christina Frangou

On May 13, patients began phoning Donald Jensen, MD, at his office at the University of Chicago’s Center for Liver Diseases, as soon as the FDA announced its approval of boceprevir. The call frequency increased when the FDA gave the go-ahead for telaprevir several days later.
Within two weeks, more than 115 patients had phoned the office asking about the much-anticipated, direct-acting antivirals. Patients wanted to know if they were candidates for one of the new agents and if they could trade their pegylated interferon and ribavirin regimen for one of the new therapies. And, most often, they wanted to know when they could start.
But it’s not that simple, said Dr. Jensen, professor of medicine and director of the center. “It’s not like giving pills to someone and saying, ‘Here, go home, take this for 10 days and let me know how you’re doing.’ These are much, much more difficult therapies.”

The therapies, which are approved only for patients infected with hepatitis C virus (HCV) genotype 1, can only be given in combination with pegylated interferon and ribavirin so there’s no trading one regimen for the other. Both direct-acting antivirals for the treatment of HCV infection were approved with a complex treatment algorithm that outlines highly specific rules for stopping the treatment as well as a response-guided delivery plan. Each therapy comes with a long list of contraindicated drugs and conditions, and each is linked to more side effects than the previous standards of care. Most notably, patients taking boceprevir are prone to anemia, and patients on telaprevir report more cases of rashes.

Extra time will be required to educate and monitor patients as they go on the new therapies, said Dr. Jensen. He estimates that “on average, a health care provider can reasonably initiate therapy on only three patients each week before exceeding their work capacity,” he wrote in a recent editorial in Hepatology (2011;53:1789-1791).

Health care centers that treat patients with HCV will likely have to increase staffing to meet the demands of patients requesting treatment, Dr. Jensen said. Physicians and health care staff also will need additional education in the new therapies.

“These therapies are game changers in terms of how they work and the improvements in response rates,” said Dr. Jensen. “There are also a lot of differences that, as gastroenterologists, we are not used to dealing with.”

Several liver specialists who are experienced with the new drugs are urging physicians, nurses and other health care providers to sign up for courses on the new therapies and slowly introduce the new drugs—both HCV protease inhibitors (PIs)—into their practice.

“We’re now starting the process of training gastroenterologists who are in practice, those who were not involved in trials. It’s important that physicians know the drug interactions, the treatment algorithm, the stopping and futility information,” said Paul Pockros, MD, division head of gastroenterology/hepatology and director of the Center for Liver Diseases at Scripps Clinic in La Jolla, Calif.

Several universities have launched courses to educate health care providers about telaprevir and boceprevir. The Scripps Clinic recently kicked off a series of hepatitis B and C meetings, with special focus on the new therapies, to be held in cities across the country between now and October. And the University of Chicago has also launched a series of educational seminars. The new therapies are expected to be key topics at the 18th International Symposium on Hepatitis C Virus and Related Viruses, to be held in Seattle, Sept. 8-12, and the American Association for the Study of Liver Diseases (AASLD) meeting, to be held in San Francisco in November. Finally, both Merck & Co., manufacturer of boceprevir, and Vertex Pharmaceuticals Inc., maker of telaprevir, offer courses and training seminars.

Treatment Complexity: Pros and Cons

The two direct-acting antivirals work in a similar fashion, by directly inhibiting the replication of HCV. They are far better treatments than anything in the past, but are also significantly more complicated, a trend that’s likely to continue as more direct-acting antivirals come to market, said Dr. Jensen.

Both of the new drugs significantly interact with other drugs, much more so than pegylated interferon and ribavirin alone. Boceprevir and telaprevir interact through the cytochrome P450 3A4/5 enzyme system in the liver, thereby influencing the metabolism of other drugs. Other drugs, in turn, influence the metabolism of these direct-acting antivirals, which can have sometimes devastating consequences if people aren’t aware.

In particular, the American Gastroenterological Association (AGA) cautioned in a statement (www.gastro.org/mobiletools/news-item/832) that endoscopists should be aware that oral midazolam is contraindicated with these therapies. These drugs may enhance the effect of the IV form, they caution. “It is important that all treating and nontreating physicians be familiar with these drugs and be aware of potential drug interactions.”

Cholesterol-lowering medication is also contraindicated. “If you are unaware that a patient is on simvastatin and you give either boceprevir or telaprevir, the simvastatin level in the blood can go high and patients can develop muscle breakdown,” said Dr. Jensen.

Physicians and patients must be aware of these drug–drug interactions, Dr. Jensen said. Even asking about herbal supplements will be important to ensure proper metabolism of boceprevir and telaprevir, because St. John’s wort can be problematic with the new therapies.
At press time, no widely accepted treatment algorithms were available for boceprevir and telaprevir other than the FDA prescribing information. However, the AASLD plans to issue a detailed treatment guideline for HCV that outlines the use of each of these drugs. A release date has not been set but committee members expect to release the document sometime this fall.
In the meantime, the AASLD has issued a summary statement
(http://publish.aasld.org/aboutus/publicpolicy/Pages/newhepctreatments.aspx ) reminding physicians that neither drug can be used as a single agent but only in combination with pegylated interferon and ribavirin. Used alone, these drugs are not effective and can cause antiviral-resistant mutants that may be more difficult to treat. The AASLD also reminds physicians that the new therapies are only approved for use in patients with HCV genotype 1 and are not approved for use in post-transplant patients with recurrent HCV, patients coinfected with HIV/HCV or children.

The prescribing information for both drugs stresses that the therapies should be stopped if patients do not experience a sustained virologic response (SVR) or a breakthrough. Patients with inadequate viral response are unlikely to achieve SVR, and may develop treatment-emergent resistance substitutions. For boceprevir, discontinuation due to likely treatment futility is recommended for patients who still have an HCV viral load of at least 100 IU/mL at week 12 or detectable HCV RNA at week 24. The futility rules differ for telaprevir; discontinuation is recommended in all patients with HCV RNA levels of at least 1,000 IU/mL at week 4 or 12, or with confirmed detectable HCV RNA levels at week 24.

“It’s essential to adhere to the futility rules,” said Dr. Jensen.
The resistance variants that patients develop from both drugs are the same v36M or R155K variants. If a patient develops a resistance to one drug, “it’s not likely that crossing over to another would be effective,” said Dr. Pockros.
However, patients who were taken off one drug early in trials due to severe adverse events may be considered for therapy with the other.

Boceprevir or Telaprevir?

At this year’s Digestive Disease Week (DDW) meeting, prior to the FDA approval of boceprevir and telaprevir, many gastroenterologists and hepatologists were already discussing which patients should receive which drug. At this point, neither drug has been proven superior—it comes down to patient preference and risk factors, said experts.
“There’s been no head-to-head trials of these drugs, so one has not been proven significantly better than the other,” said Marcelo Kugelmas, MD, a gastroenterologist at South Denver Gastroenterology in Colorado.

The treatment regimens studied with boceprevir and telaprevir are different and the studies were not done head to head, added Dr. Kugelmas. The data for both drugs, published recently in The New England Journal of Medicine, cannot be compared (2011;364:2417-2428; 2011;364:2405-2416; 2011;364:1207-1217; and 2011;364:1195-1206).
The reported SVR rates with boceprevir are 63% on the label, whereas telaprevir has an SVR rate of 79% in treatment-naive patients. That difference has many patients asking why they wouldn’t be put on telaprevir, said Sue Simon, director of the Hepatitis C Association, a national patient advocacy and educational organization.

Experts say patients need to be told that the studies were not head-to-head trials.
“You can’t compare the results that way, although that’s sometimes difficult for patients, who aren’t aware of the nuances of clinical trials, to understand,” said Dr. Pockros.
Physicians should be familiar with both therapies and with prescribing both, said Dr. Kugelmas. “I honestly don’t think that we should be pushing one more than the other or that anyone should prescribe 100% one or the other.”

Although both agents act similarly, there are some key differences in lead-in times and side-effect profiles. The treatment period is longer with boceprevir. Boceprevir requires a four-week lead-in with pegylated interferon and ribavirin, which lowers the virus level modestly before boceprevir is added for 24 or 32 weeks. Telaprevir therapy is started at the same time as the pegylated interferon and ribavirin and given for 12 weeks as triple therapy. The pegylated interferon and ribavirin are continued for either 12 or 26 weeks thereafter.
The inclusion of pegylated interferon and ribavirin is, at this point in time, necessary to suppress any mutants that emerge over the course of treatment, explained Adrian M. Di Bisceglie, MD, co-director of the liver center and professor of internal medicine at the Saint Louis University School of Medicine, during a presentation at the DDW meeting when physicians questioned why pegylated interferon and ribavirin are needed with the new therapies.

There are differences, too, in the side-effect profiles. Boceprevir causes anemia and a metallic taste; telaprevir also causes anemia, as well as skin rash and mild to moderate anorectal disorders.

In the case of boceprevir, less than 2% of patients discontinued therapy because of anemia. However, anemia was a significant factor in predicting SVR in Phase III trials of patients taking boceprevir. In the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial, 72% of patients with hemoglobin below 10 dL/g attained SVR compared with 58% of patients without anemia (Sulkowski MS et al. Presented at the 46th annual meeting of the European Association for the Study of the Liver. Abstract 476).

In patients taking boceprevir, anemia can be managed most often by reducing ribavirin and, at times, with the addition of erythropoietin, said Dr. Pockros. “Successful management of rash and anemia will allow high SVR rates,” he observed.
In the telaprevir trials, 56% of patients receiving the telaprevir combination reported rash and skin problems, 22% more than in the control arm. Of these, 4% had severe rashes and less than 1% had drug rash with eosinophilia and systemic symptoms and Stevens-Johnson syndrome. Patients with these severe symptoms should have their drug therapy stopped immediately, according to the prescribing label.

“There are some differences between these drugs that make one preferable for some patients over others. I think mostly it’s going to be a matter of individual preference and side-effect comparisons as much as anything,” said Dr. Kugelmas.

The costs of the two therapies are similar, provided patients remain on the drugs as long as permitted. The price of telaprevir is $49,200 for the course of treatment, and boceprevir costs between $26,400 and $48,400 for the full course. Those prices do not include the cost of pegylated interferon and ribavirin.

Both Merck and Vertex have established patient and co-pay assistance programs, and physicians who have started patients on the therapies say that most insurance companies are covering the therapy now that the agents have been approved by the FDA.
Experienced liver specialists are urging physicians to set up allocation systems within their practices so that the sickest patients have first access to direct-acting antiviral therapy.
In his editorial in Hepatology, Dr. Jensen proposed a “needs-based allocation system,” similar to the Model for End-Stage Liver Disease (2011;53:1789-1791). As part of the system, all patients will need to be educated about the natural history of the disease to help them understand why some patients warrant earlier treatment.

Dr. Jensen suggests that physicians host educational symposia for their patients and families in which they stress the importance of expediting treatment to the sickest patients.
“Then, patients who have previously deferred therapy and new patients will be prioritized on the basis of need, with patients with cirrhosis at one end of the spectrum and asymptomatic patients with FO-F2 fibrosis at the other end of the spectrum,” said Dr. Jensen. “This system satisfies the principle of justice while placing appropriate emphasis on medical need.”

With the two therapies now on the market, research efforts are shifting to focus on other drugs and other combinations and on patients who do not fare well with triple therapy. Some studies are looking at quadruple therapies, whereas others are looking at interferon- or ribavirin-free regimens. Many trials are also exploring other classes of drugs such as polymerase inhibitors or nonstructural protein 5A inhibitors. “Those will be the next classes of drugs and they are under investigation now,” said Dr. Pockros.

Dr. Jensen reported no relevant disclosures. He is currently treasurer of the AASLD. Dr. Pockros consults, speaks and does research for Vertex; he also consults and receives independent research and CME grants from Merck.



  1. Thank you for this article. It helped me to understand why my doctor has delayed the start of my treatment. Good information also as to the decisions that are made in using one new drug over the other.

  2. Hopefully inf/riba -free therapy trials produce better tolerated drugs.will not Tx again unless therapy does not involve interferon.