PEG-IFN or Nucleos(t)ide Analogues? Personalize Treatment is the Best

Harry L.A. Janssen University Medical Center, Rotterdam, The Netherlands

Hepatology Digest: One of your lectures at APASL is about the selection between PEG-IFN and nucleos(t) ide analogues. Could you give some suggestions on the use of those two types of drugs?

Prof. Janssen: They are clearly very different drugs for hepatitis B. PEG-IFN is a drug that has at leasibility oft a poss an off-treatment sustaine dresponse. This means that you give for a certain amount of time and then you hope for a response, which occurs in about 30% of the patients, both in epositive and e-negative disease. When that occurs you can stop the drug and there is a continued response afterwards. In other words, there is an immune control of the virus. The downside of interferon is that it has major side effects and it is not an easy drug to use. You have to inject it and the side effects are rather nasty sometimes so you have to really counsel the patient and guide them through the therapy. If the patient is very young and is willing to take the treatment and is a responder, he does not need to be treated anymore during his life and remains in remission.

On the other side, you have the nucleos(t)ide analogues, which are a different category of drugs obviously, which are drugs that are not inducing immunological control over the virus, but rather virological control. You could compare this type of treatment to the treatment of HIV. You give the drug, which is an easy pill to take without any side effects, you suppress the viral load vigorously, and the HBV DNA becomes negative. The problem, however, is that if you discontinue this type of drug, you usually get a relapse very quickly. In other words, you have to continue treatment for most patients probably lifelong. You suppress the virus, which also is good, because it does reduce the complications of this disease, which are cirrhosis, liver failure, and liver cancer. However, a risk of longterm treatment is resistance of these agents. If you give these drugs for a long time you may have the problem that resistant strains of the virus are not sensi-tive for the drug. This happens a lot with lamivudine , which is the first generation of these nucleos(t)ide analogues, and also with adefovir. The latest generation of these drugs, in particular entecavir and tenofovir are very strong drugs, which so far have not shown any resistance, particularly not in treatment naive patients. The major question is if you can individualize treatment in such a way that you can pick out the right patients for PEG-IFN treatment, which is a treatment with a lot of side effects and is not cheap. I think you can. We did extensive studies, particularly in HBeAg positive disease, where we collected all patients from the pivotal trials who have been treated with PEG-IFN and we analyzed the most important factors that predicted response in patients. We tried to make an easy algorithm and a more sophisticated algorithm. The easy algorithm says that you have to determine the genotype of the virus. Patients with genotype A are always good candidates for interferon treatment because they have a high response rate, roughly approaching 50%. Then you have genotype B and C, which are the genotypes prevalent in China and East Asia. In particular the genotype B and C patients with high ALT values of twice the upper limit of normal and low HBV DNA (<109 copies/ml) are good candidates for interferon treatment. Genotype D patients, in general, don’t react well to the drug so I am very reluctant to treat these patients. In fact, all genotype A, genotype B, and genotype C only with high transaminase and low HBV DNA are good candidates and not genotype D patients. In my view, that would be the best way to personalize treatment in chronic hepatitis B.

Hepatology Digest: Do you think that we could combine PEG-IFN and nucleos(t)ide analogues to treat hepatitis B?

Prof. Janssen: I think you can, but the trials that have been conducted so far do show any additional benefit of the combination. The problem with the trials that have been dos a rather week antiviral agent with a high rate of resistance. Therefore, we need to do studies combining PEG-IFN with the strongest nucleos(t)ide analogues with the highest genetic barrier, which means using tenofovir and entecavir. The other point is that we might have to combine the drugs in ne, of which I coordinated one, is that lamivudine was used, which ia smarter way than we have done so far because what we have done so far is just start the drugs at the same time and end at the same time, but we might have to start with one drug and then come in with the other. We really have to do more research on that. I think there is a plea for combination of nucleos (t)ide analogues and PEG-IFN.

Hepatology Digest: Today, with more and more nucleos(t)ide analogues coming out, do you think that sometimes doctors ignore that interferon may still have a role in the treatment of chronic hepatitis B?

Prof. Janssen: The problem with interferon is that it is not an easy drug for the patient, but it is often not prescribed because it isn’t an easy drug for the doctor.Many doctors have to see their patients within 5~10 minutes at most and you really have to explain to the patient how it works, otherwise it doesn’t fly. In that respect, nucleos(t)ide analogues are a much easier because you just prescribe it. You tell the patient to take one pill a day and it doesn’t have side effects and the patient leaves.

Another problem is that we haven’t had the instruments to pick the right patients and my studies helps to pick out the best patients for interfeicity. At the moment, I am working on getting better stopping rules for interferonron before the start of treatment. Still, we need good stopping rules as well because the treatment is expensive and there is tox treatment. Because then you could start treatment for three months or six months and if the viral load hasn’t declined by 1~2 log then you could stop the drug because the chances of response would be very slim. That will make it much easier to convince patients to undergo this treatment than if everyone has to be treated for a year.

I think there is still a place for interferon and interferon might even come back into the arena of antiviral treatment because it is a drug that definitely creates immune control and offtreatment sustained response. The market has largely been taken over by nucleos(t)ide analogues, and that is fine, but to get the final steps and become HBsAg negative we might need interferon. We have made huge improvements with nucleos(t)ide analogues and I am very happy with them, but we still might need interferon as well.