Norah Terrault, MPH, MD: Managing DAA Failures When Treating Hepatitis C Virus Infections

Patient nonadherence to treatment is an ongoing issue that physicians from all specialties face. It is particularly prevalent among patients who are infected with hepatitis C virus. Gaps in treatment of any infection or condition can have deleterious effects on patient outcomes; however, new research has revealed that gaps in treatment for hepatitis C virus is no longer a deal-breaker in terms of achieving sustained viral response (SVR), including in patients who abuse drugs.

We sat down with Norah Terrault, MPH, MD, director of the Viral Hepatitis Center at University of California, San Francisco, at the 2018 American Association for the Study of Liver Diseases (AASLD) Liver Meeting, November 9-13, 2018, in San Francisco, California, to discuss gaps in treatment in people who are infected with hepatitis C virus and what steps clinicians should take when treating these patients.

[Editor’s note: Transcript is slightly modified for readability.]

MD Magazine®: How long is ‘too long’ in terms of nonadherence to DAA treatment?

Terrault: We presented a case of a patient who took 4 weeks of treatment, and then his prescription did not get refilled, and he was off treatment for 6 days [before] he got his next supply. The question I received was, ‘Would you continue treatment, or would you stop because they missed too many doses?’

One of the reasons for treatment failure might be because somebody is nonadherent. We [have to make] a decision around the concept of treatment failure as it relates to nonadherence (ie, how many doses can patient miss before you say, ‘My chance of getting SVR [sustained virologic response] now is so low that I should stop,’ versus continuing on).

There is hard data to inform this. Studies have shown that patients missing even 1 to 2 doses per week still have SVR rates that are equivalent to people who take every dose, and there’s data being presented at this meeting in the population of persons who have used drugs where they documented how many days they may have missed. [The investigators showed] that even when patients missed several days in a row, it resulted in very high rates of SVR. That is very reassuring to us.

Of course, we should still advocate for high adherence and reinforce the importance of [taking their medication every day] to patients, but if patients are missing doses, we are still seeing very high rates of adherence. As clinicians, we should not stop treatment in that setting—we should continue on, complete the treatment course as was planned. They may have a few pills at the end that you should just complete—and we would anticipate that the SVR rates would be high.

As we move to shorter duration treatment—an 8-week course versus a 12- or 24-week course—perhaps missing a whole week of treatment may have more impact. Again, [we need to] reinforce adherence.

[In our Meet-the-Professors session at AALSD,] we talked a lot about how clinicians ensure adherence. We talked about the importance of phone follow-ups as a way to connect with patients and make sure that they are taking their medications, getting their refills appropriately, confirming if they’ve missed doses, and again reinforcing that it is important for [them to take their medication]. Overall though, we have very effective drugs and so a few missed doses do not seem to really have an impact on SVR rates.

I think that is reassuring information because it comes up pretty often [where clinicians ask], ‘My patient missed a few doses this month/week, what should I do?’ The answer is: keep going. Reinforce the importance of not missing doses, but keep going, complete the treatment course.

MD Magazine®: How do you treat patients with hepatitis C virus infection who are highly treatment experienced and notoriously nonadherent?

Terrault: We are moving into treating patients who are less engaged with health care. As we move into treating individuals who are newly identified and may not be as linked with health care, we are certainly finding ourselves being challenged by individuals [with whom] adherence is more difficult—for the patients and for us, too. They are not coming to the clinic regularly, [and] they do not show up to do their lab tests.

I think the consensus among the experts is that when they receive a newly-diagnosed patient with hepatitis C virus infection or they have somebody who has been referred to them who failed a prior treatment course, it is important to have a good understanding of what happened the last time, and what are the things that they could do to ensure that the second course is successful.

That means not only looking at whether they were adherent, but also looking at whether they were on any medications that might have interfered or reduced their likelihood of getting an SVR. The key area might be whether they were on antacids, [or] PPIs [proton pump inhibitors] because we know that high-dose PPIs can interfere with some of the drugs in terms of their efficacy, and so [it is important to review] what medications they were on.

We should ensure that the patient, had a regimen that was appropriate, and that they had the appropriate dose. [Furthermore, we need to] think through why the patient failed, and try to see if there is anything we would do differently the second time around.

Those are the practical things, and then, of course, choosing a regimen that has a high chance of success based on data about DAA [direct-acting antiviral] failures. The good news is that we do have very good options for people who failed a prior DAA therapy. We don’t have 6 different options, but we do have 2 or 3 that are very good. We have something to go on, and every DAA failure has an option in terms of re-treatment.

I would say the [cases] that are more challenging are patients who have more advanced liver disease. We have less options when patients are decompensated. In general, if we have compensated patients, there are very good options to re-treat [such as] sofosbuvir, velpatasvir, and voxilaprevir. That triplet is frequently recommended. It differs by genotypes, and by prior DAAs, but it is 1 of the more frequently prescribed re-treatment options.

Glecaprevir/pibrentasvir can be a very good option for specific groups of previously treated patients, as can sofosbuvir/velpatasvir. Sometimes we have to consider adding ribavirin—that’s an old drug—but we still use it occasionally in that more-difficult-to-treat population, and sometimes we look at extending duration.

For the re-treatment of a DAA-experienced patient, sometimes we have to consider adding ribavirin-extending treatment if we think they are a particularly difficult group to treat. That’s where you have to look at the patient pretty carefully. It’s not just [asking what] their prior DAA treatment regimen was, but [it is important to ask] if you are dealing with a patient who has cirrhosis because cirrhosis is a little more challenging.

[We also need to ask,] ‘Do they have other conditions?’ We know that patients who have appendiceal carcinoma [are] group in which we sometimes see lower rates of SVR. We have to carefully think how we are going to re-treat that group. [Again] the particularly challenging group is the decompensated patient because in that group, we can’t use protease inhibitors. That narrows your treatment options. In that group, ribavirin becomes much more important to include and where we have to think about extended duration more frequently.

MD Magazine®: Are there any considerations you think are important to keep in mind when treating these patients?

Terrault: When you have a patient who appears to have relapsed after treatment, [it is important] to always remember that they may have been re-infected. That’s because we are increasingly treating patients who are potentially at risk for re-infections. When somebody comes back with a virus at week 12 after their treatment, you should repeat the genotype and the viral load and of course get resistance testing, and also query the patient about whether they were engaged in any behaviors that might have put them at risk for getting re-infected. We want to protect against another re-infection.

[We need to] reinforce [the fact that] achieving SVR does not protect against getting hepatitis C virus re-infection, and ensure that we are giving good counseling messages around re-infection. Sometimes you will see patients and you are not sure [if they are re-infected]. Obviously if the genotype is different, you know it’s a re-infection, but sometimes the genotype is the same, and that could still be a re- infection.

[We need to] as our patients about [their behaviors], and make sure we are getting our counseling messages across to protect against re-infection.