VIENNA — An investigational drug combination had high efficacy among patients with cirrhosis associated with hepatitis C (HCV) or recurrence of the disease after a transplant, researchers said here.
But the very success of the combination of daclatasvir and sofosbuvir (Sovaldi) in an open-label phase III trial raises difficult ethical and practical issues, according toFred Poordad, MD, of The University of Texas Health Science Center at San Antonio, and colleagues.
In some cases, successfully treating HCV might be exactly the wrong course of action, Poordad said in a late-breaker session at the European Association for the Study of the Liver (EASL) annual meeting.
The so-called ALLY-1 study was testing the combination, given with ribavirin for 12 weeks, in a population with what Poordad called “unmet needs” — those with cirrhosis or whose disease has recurred after transplant.
In those patients, data on treatment outcomes is limited, he said, so his group enrolled 60 patients with advanced cirrhosis and 53 with HCV post-transplant.
Although patients with all genotypes were permitted in the study, the primary endpoint was a sustained virologic response 12 weeks after the end of therapy (SVR12), which is regarded as a cure, among the 86 patients with genotype 1 disease.
The drugs had shown great promise, but they belonged to different companies that had decided to stop collaborating.
The ALLY-1 trial was sponsored by Bristol-Myers Squibb, which is developing daclatasvir, an NS5A complex inhibitor that is approved in Europe but has not yet been given the nod in the U.S.
The maker of sofosbuvir, Gilead Sciences, was not involved in the study.
The advantage of pairing daclatasvir with sofosbuvir — rather than using, for instance, a fixed-dose single pill combination — is that the drugs are not co-formulated, allowing clinicians to modulate dosing to work around drug-drug interactions, experts have said.
Poordad reported that SVR rates were high overall. Among all patients, SVR12 rates were 83% among cirrhotics and 94% among post-transplant patients, while rates among genotype 1 patients were almost the same: 82% and 95%, respectively.
SVR12 rates among Child-Pugh A and B patients were 92 and 94% respectively, but only 56% among those in class C, he reported. On the other hand, among most class C patients, Model For End-Stage Liver Disease (MELD) scores used to determine transplant eligibility improved, potentially taking patients off the list.
If such a patient is cured of HCV — but thereby loses the chance for a liver transplant — “have you done this patient any favor?” asked Stefan Zeuzem, MD, of Goethe University Hospital in Frankfurt, Germany, who was not part of the study but who co-moderated the EASL session.
The issue is that curing the disease does not restore the cirrhotic liver to normal function, and so the patient remains “still very ill,” Zeuzem told MedPage Today.
“My takeaway message is that if this is a patient on a transplant list who has very good chances of receiving an organ, I may be more inclined to let him go towards a transplant and take care of the viral elimination after the transplant,” he said.
On the other hand, treating the HCV might be the right choice for Child-Pugh C patients not likely to get a transplant for some reason, he added.
For patients with untreated HCV, a liver transplant does not eliminate the disease; the virus inevitably recurs. But several studies — including this one — have shown that it is possible to treat HCV successfully after transplant.
Zeuzem noted that among the 53 patients treated after recurrence, 50 reached an SVR12. Importantly, there were no drug-drug interactions with medications used to suppress the immune system and no need to adjust dosing to compensate for other drugs either before or after transplant.
Patients were allowed to continue in the study if they went to transplant and four did so, Poordad said. All reached an SVR12 after extending the post-transplant treatment for 12 weeks.
The four included one patient who received a liver from a genotype 1-infected donor, he said.