With new data presented at the International Liver Congress, practicing physicians now have the power to make informed recommendations for patients who were not included in original pivotal trials of direct-acting antiviral regimens, such as those in renal failure and with decompensated cirrhosis.

Ira M. Jacobson

For myself and other clinicians, the data that came out of EASL are transformative in terms of what we can now bring to the table with our patients with renal failure. Before the meeting, we really didn’t know what to do. We had no database on which to predicate our results and now we do.

As Michael R. Charlton, MD, FRCP, explains in his Take Home from the ILC, the RUBY-1 study showed that the combination of ombitasvir, paritaprevir and ritonavir plus dasabuvir (Viekira Pak, AbbVie) had a positive response among their 14 patients with renal failure, with further data to follow. Now we have a regimen that seems to bear out the prediction, based on previous pharmacokinetic studies, that these drugs should not cause any particular problems for renal failure patients. There were no new or unique side effects that hadn’t been seen before, though dose interruptions related to hemoglobin declines from the ribavirin were fairly frequent. Even more impressive results, based on a much larger number of patients, were seen in C-SURFER (cited in the Patient Profile from Catherine T. Frenette, MD, for the not-yet-approved regimen of grazoprevir/elbasvir (Merck).

This shows us that the agents can be used in a fairly routine way to treat these patients with this previously extraordinarily unmet need. The question of the hour is whether these drugs are ready to be put into patients without label amendments for any of the existing regimens. For now, it’s up to individual clinicians and their patients to determine if these data are sufficient to proceed.

For me, the question was answered when I saw a patient with genotype 4 the day I returned from Vienna. The patient has bridging fibrosis and he’s desperate to receive antiviral therapy because his nephrologist won’t give him a new kidney without being cured.

We know that from earlier studies that the 3D regimen is very effective in genotype 4 (even the regimen of ombitasvir/paritaprevir/ritonavir works well, especially with ribavirin), so I felt comfortable making a recommendation for this patient, who keenly desired treatment without further delay, that from my perspective there was enough data from the RUBY-1 study to give this regimen.

Given that there are variable levels of urgency in treating patients with renal failure, including the question of whether, as in my patient, their progression toward getting a kidney transplant is being delayed by ongoing viremia in the setting of advanced fibrosis, there’s room for individualization.

Thus, depending on one’s perspective, EASL was a turning point in conferring on us the ability to make decisions to treat some of these renal failure patients proactively without waiting for additional data. There have also been encouraging small case reports of patients receiving sofosbuvir in the setting of renal failure, but sofosbuvir is renally excreted and no dose has yet been established for, nor can a dosing recommendation be made in, patients with renal failure at the present time. The issue is being studied.

Additionally, the presentation of SOLAR-2 data reaffirmed the groundshaking paradigm shift initiated by the SOLAR-1 results in decompensated cirrhotics presented at AASLD 2014.

One came home from that earlier meeting with a radically different perspective to the management of patients with decompensated cirrhosis than one likely had going into the meeting. In Vienna, we saw nearly duplicate results in the SOLAR-2 study, affirming rates of SVR of 85% to 90% with ledipasvir/sofosbuvir combined with ribavirin, with 12 weeks of treatment appearing (much to my surprise) as effective as 24 weeks. Even if the cure rates are not quite at the 95% or higher levels to which we have become accustomed in less advanced liver disease, it is near miraculous that we can cure our sickest patients at a rate close to 90% with 12 weeks of therapy. For now, we don’t know whether we can avoid ribavirin in this population because all the treatment arms in both studies contained it.

But this data poses a new dilemma, brought up by Mitchell L. Shiffman, MD, in his Take Home, which is whether our capacity to cure decompensated cirrhotics necessarily means you should treat all them.

That may seem like a foolish question, but it’s really a profound dilemma, particularly with regards to the decompensated cirrhotics who are very advanced, such as Child Pugh C patients with very high MELD scores, eg, above 20 (most of the patients in the SOLAR studies had MELD scores less than 20). This is because patients may reach a “point of no return” at which it’s too late to salvage a patient’s quality of life or even their very life by curing them virologically and you may actually delay their ability to get a transplant by reducing the MELD score sufficiently to deprioritize the patient on the transplant list.

The potential to harm patients by delaying their ability to get a transplant even has the potential to come with medico-legal consequences. We are going to have to work very hard in the next couple of years in a rigorous systematic fashion to identify this point of no return beyond which, although counterintuitive, we should not institute this curative therapy even though we’re capable of curing the disease. Some patients may simply be better off if we defer antiviral therapy until after transplantation, especially since recent data have been extraordinarily encouraging with regard to outcomes of antiviral therapy in the post-transplant setting.

— Ira M. Jacobson, MD

Co-Chief Medical Editor

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