Symposium addresses difficult-to-treat HCV cases, drug-drug interactions

BOSTON — A panel of experts gave presentations on the use of triple therapy in patients with hepatitis C during a symposium held at The Liver Meeting.

The panel focused on difficult-to-treat patients with HCV, specifically cirrhotic null responders, HCV/HIV coinfected patients and liver transplant recipients; as well as drug-drug interactions related to triple therapy.

Ira M. Jacobson, MD, chief of the gastroenterology and hepatology division and professor of medicine at The Joan Sanford I. Weill Medical College of Cornell University, addressed the issue of cirrhotic patients who had been nonresponsive to prior treatment. These patients, he said, have the lowest sustained virological response (SVR) rates with protease inhibitors, and treatment in these cases should be highly individualized. Factors such as stability and access to trials should be considered.

“I have been more proactive about treating my null responders who have steadily deteriorating liver function, as manifested by lowering platelet counts or albumin levels,” Jacobson said. “However, if you take that approach, you have to acknowledge that the risks in the patient who’s on the way to decompensation … are probably greater than in a stable cirrhotic patient.” He added that failure to achieve SVR in a null responder is likely to result in resistant variants, affecting future treatability with protease inhibitors, but that these resistant variants often clear over time.

Jacobson also suggested that a null responder scheduled for a 48-week triple therapy regimen may benefit from a 4-week lead-in with pegylated interferon/ribavirin. This allows for early dose adjustment or termination and avoids potential side effects and the risk for emergent resistant variants prior to initiation of protease inhibitors. In turn, it maintains a patient’s eligibility for future trials.

Quadruple therapy has proven effective in this population, he added, but interferon-free regimens are of particular interest. “Novel [direct-acting antiviral agent, DAA] regimens must be explored … because hitherto we have no data on DAA regimens without interferon in the null-responder cirrhotic population.”

Monitor drug-drug interactions carefully in HCV patients

Greg Everson, MD, professor of medicine and director of the hepatology division at the University of Colorado, Denver, addressed drug-drug interactions (DDIs) related to HCV treatments, particularly boceprevir and telaprevir.

“One of the big issues in the management of our patients in the emerging new pharmacopeia of direct-acting antivirals is understanding the management of DDIs,” he said. “We have to dose-adjust these drugs, we may have to alter duration of drugs, and importantly, we have to monitor drug levels and laboratory parameters, and clinically assess these patients carefully.”

Everson outlined the interactions between boceprevir and telaprevir and medications such as calcium blockers, antidepressants, sleep aids and certain statins. He also discussed the effect of other drugs on boceprevir and telaprevir concentrations. Both medications inhibit CYP3A4 and P-glycoprotein; any drug administered simultaneously that induces CYP3A4 or P-glycoprotein will lower systemic concentrations of boceprevir or telaprevir, reducing treatment efficacy and promoting drug-resistant variants.

“If patients are being evaluated for direct-acting antiviral therapy, the first step is: Check the med list,” he said. “If you need some help, [consult] a clinical pharmacy, Web sites, [and] your pharmaceutical liaisons. If you identify no drug interactions, treat. If you have DDIs, you have to have a strategy: Do you hold the drug, or explore alternative drugs? You implement your strategy to avoid DDIs, but monitor the patient, and you treat … And don’t forget: Our patients can sometimes take things we don’t know about.”

HIV/HCV coinfections hasten liver disease

Mark Sulkowski, MD, professor of medicine and medical director of the Viral Hepatitis Center at Johns Hopkins University School of Medicine, discussed patients coinfected with HIV and HCV. These patients experience a more rapid progression of liver disease and fibrosis, and liver disease is one of the top causes of death among patients with HIV, he said.

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“In my view, liver disease staging is the first step, followed by the decision to initiate treatment or not,” Sulkowski said. “If you’re going to treat, I believe a protease inhibitor is justified. … The data do support the cautious use of telaprevir or boceprevir, in carefully selected patients on the appropriate antiretroviral regimens, based on their ability to tolerate therapy.”

As of 2011, he noted, the AASLD indicated that boceprevir or telaprevir can be administered to HIV coinfected patients, but cautiously and under close monitoring, as significant pharmacokinetic interactions have been observed between these therapies and HIV medications. Sulkowski also acknowledged the potential benefits of interferon-free treatment in this population. “Like any human being with HCV, they really don’t want to take interferon,” he said.

He added that antiretrovirals may reduce the risk for serious liver outcomes in coinfected patients: “While we were at one point concerned about liver toxicity from antiretroviral drugs, these therapies appear to decrease progression of liver disease, including among cirrhotic patients. Therefore, this may be the first line in controlling HCV in the treatment of HIV.”

Concerns abound for treating liver transplant patients with HCV

Jacqueline O’Leary, MD, MPH, medical director of the Inpatient Liver & Transplant Unit at Baylor University Medical Center in Dallas, addressed the treatment of liver transplant recipients with HCV.

“Triple drug therapy in the post-liver transplant patient is being utilized in highly selected liver transplant recipients by experienced treaters,” she said. “ … however, safety concerns are significant.”

O’Leary noted a lack of published results from randomized, controlled trials evaluating HCV in this patient population, and presented an analysis of eight related abstracts submitted for The Liver Meeting and one published paper involving 204 post-transplant patients treated with off-label triple drug therapy.

Her pooled analysis revealed that 39% of patients achieved HCV RNA negativity after 4 weeks and 70% after 12 weeks. Thirty percent of patients, however, required treatment cessation because of futility or adverse events, and a 3% risk for death was observed in a cohort selected for their tolerance to therapy.

“SVR is well-documented to improve survival. However, SVR remains somewhat elusive in our transplant patient population,” she said. “… Is ‘SVR or no SVR’ really the most important question to be asked, when in fact the elephant in the room is whether or not this can be accomplished safely?”

O’Leary said the first question to ask regarding a post-transplant patient with HCV is whether they can wait for the emergence of future, interferon-free therapies without DDIs. She acknowledged two “exciting” treatments on the horizon, including sofosbuvir (formerly GS-7977), a once-daily medication that has no indicated DDIs or significant side effects, and daclatasvir, a once-daily NS5A inhibitor that shows no DDIs with transplant medications and no major side effects.

“Fortunately, we are experiencing an HCV treatment revolution, whereby an army of pharmaceutical companies is lined up with HCV planted firmly in their crosshairs,” she said.