Entecavir + Interferon combo

[cyrus131]

Dear all,

     I have been on Entecavir 0.5mg for over 6 years and my HBV DNA is nearly undetectable.  I will see my doctor tomorrow and what tests should I perform so as to assess whether I will benefit from the Entecavir + Interferon combo treatment (i.e. higher chance to achieve Hbsag seroconversion.)  Many thanks.

Regards,

Cyrus

[imdrew]

6 years of usage but not Undetectable? I thought you have to be undetected in 6 months. Do you mind sharing your latest lab result starting with HbsAg (iu/ml), HbeAg -/+, HBV DNA and Fibroscan?

[cyrus131]

Yes still detectable, last HBV DNA was about 180 copies /ml.  I am HbeAg+ and have not tested for HbsAg quantity.  Fibroscan done a month ago and will see my result tomorrow.

[stef2011]

detactable hbvdna after 6-12 months is failure of the antviral and add on of tenofovir or tenofovir switch is needed.i hope hbsag lowered even if hbvdna was detactable

if you add intf you can keep etv and see results of this combo, please let us know after 6years intf should work on hbsag

[cyrus131]

Should I do some tests e.g. hbsag quantity, hbv genotype etc. to assess my successful rate before I start etv + intf combo?

[cyrus131]

Yes, I also thought etv is not effective for me but my doctor (as my previous post mentioned) advised me to use entecavir 1mg instead of adding on tdf.  I will see him again tomorrow and don't know what to do.

[stef2011]

no increasing etv dose is useless, 1mg has even less potency than 0.5mg on latest reports and doesn t work to prevent resistance, it really makes no sense
best option is 6months of combo etv+tdf, if hbvdna becomes totally und etv can be discontinued

unless your doctor has benefits from the drug maker to prescribe etv what he says makes no sense, tdf is more potent, no resistance, cheaper and same effect on kidneys function as etv

or you may try intf+etv 1mg, intf should work on the partial response of etv and little hbvdna detactable might stimulate intf response more

yes make tests to check for resistance mutations, genotype, hbsag quantity, whatever the results i d try intf anyway unless we find a very high hbsag up to 10.000-20.000iu/ml

[StephenCastlecrag]

Just want to mention some latest research findings:
1. The rate of HBeAg seroconversion using antivirals is lower in real practice than those reported in clinical trial
2.  Intensifying entecavir (Baraclude) treatment for hepatitis B by adding pegylated interferon lowers HBV viral load and increases the likelihood of hepatitis B "e" antigen (HBeAg) loss, according to a report at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) last month in Boston. A related study found that hepatitis B surface antigen (HBsAg) levels during treatment can be used to predict response to interferon.

Nucleoside/nucleotideanalog antivirals that interfere with the hepatitis B virus (HBV) lifecycle are standard treatment for chronic hepatitis B. They perform well for lowering HBV DNA levels, but serological response, including HBeAg and HBsAg loss or seroconversion, occurs in only a minority of patients.

Interferon -- long the mainstay of hepatitis C treatment -- stimulates the natural immune response against viral infections and may contribute to improved outcomes for hepatitis B as well.

Milan Sonneveld from Erasmus University Medical Center in Rotterdam and the ARES study team conducted a controlled trial that enrolled 184 HBeAg positive patients with compensated liver disease at 15 sites in Europe and China. About 60% were of Asian ethnicity and all major HBV genotypes were represented.

One group was randomly assigned to take 0.5 mg/day entecavir monotherapy for 48 weeks; the other group received the same dose of entecavir, but after 24 weeks of monotherapy they added 180 mcg/week pegylated interferon alfa-2a (Pegasys) and continued on triple therapy through week 48.

Results

    74% of participants in the entecavir monotherapy group and 83% in the interferon add-on group achieved HBV DNA < 200 IU/mL, but the difference did not reach statistical significance
    53% and 61%, respectively, reached HBV viral load < 20 IU/mL, again not a significant difference.
    8% of patients the entecavir-only group and 18% in the add-on group experienced HBeAg loss, which just missed being significant (P=0.068).
    In a multivariate analysis, the only factors independently associated with combined response were:

o   HBsAg level at baseline: odds ratio 0.42, indicating that a lower level raised the likelihood of response;

o   Addition of pegylated interferon: odds ratio 3.78, or nearly quadruple the likelihood of response.

    Adding pegylated interferon to entecavir was generally safe and well-tolerated.
    5 people experienced serious adverse events, including 3 ALT flares during the entecavir monotherapy phase.
    Neutropenia (0% vs 23%) and thrombocytopenia (0% vs 8%) were significantly more common in the add-on group compared with the monotherapy group; no one in either arm developed anemia.
    2 people developed severe neutropenia while on pegylated interferon.

"Addition of pegylated interferon alfa-2a to entecavir monotherapy increases HBV DNA, HBeAg, and HBsAg decline," the reseachers concluded. "Addition of pegylated interferon alfa-2a to potent [nucleoside/nucleotide] analogue therapy may increase chances of finite therapy."

[cyrus131]

Thanks Stefano for your prompt advice.  I am a bit afraid of the heavy side effects of interferon.  

[veteranB]

How about side effects after a liver transplant not afraid of those? You have e antigen positive hbv. Why they were treating you with nucs then interferon was the rightvway tovgo about it. These doctors who prescribe anti aids drugs to us kill us really. Speak with honest docs they will tell you

[cyrus131]

With this study result, should I still try interferon?

Entecavir and interferon-α sequential therapy in Japanese patients with hepatitis B e antigen-positive chronic hepatitis B.
Enomoto M, Nishiguchi S, Tamori A, Kobayashi S, Sakaguchi H, Shiomi S, Kim SR, Enomoto H, Saito M, Imanishi H, Kawada N.
Source
Department of Hepatology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.

Abstract
BACKGROUND:
The outcomes of sequential therapy with lamivudine followed by interferon have been unsatisfactory in Japanese patients with hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B. However, the efficacy of sequential therapy with entecavir and interferon remains unclear.
METHODS:
Twenty-four HBeAg-positive patients (23 men and 1 woman; mean age 39 ± 7 years) received entecavir 0.5 mg alone for 36-52 weeks, followed by entecavir plus interferon-α for 4 weeks, and lastly by interferon-α alone for 20 weeks. Twenty-three patients had genotype C infection, and one had genotype A infection.
RESULTS:
No entecavir-resistant mutant variants emerged in any patient. Hepatitis flare occurred in three patients during interferon-α treatment after the withdrawal of entecavir, but none had hepatic decompensation. Serum hepatitis B surface antigen levels did not change during or after therapy. Serum hepatitis B core-related antigen levels were significantly decreased at the start (P < 0.0001) and at the end of interferon-α treatment (P < 0.0001), but returned to baseline levels after treatment. Twenty-four weeks after the completion of the sequential therapy, a sustained biochemical, virological, and serological response was achieved in 5 (21 %) patients. The proportion of patients in whom HBeAg was lost during entecavir treatment was significantly higher among those with a sustained response than among those with no response (P = 0.015).
CONCLUSIONS:
The rate of response to sequential therapy with entecavir and interferon-α in Japanese patients with HBeAg-positive chronic hepatitis B was not higher than the rate in previous studies of lamivudine followed by interferon.

[cyrus131]

Any advice, please?

[StephenCastlecrag]

No advice, just some opinions. As you can see from both studies, responses to ENT + PEGINFN combo vary. Of course, your situation is not typical of both studies. Firstly, I want to ensure that you have complied with your daily intake of ENT on an empty stomach. HK has some of the most experienced liver doctors in the world, so you have an advantage there. Finally, I would check your quantitative HBsAg level before deciding.

[cyrus131]

Dear Stephen,

Thanks for your prompt advice / opinions.

I had been taking entecavir at 1700 hrs everyday (I would finish taking my lunch at 1400 hrs and would start my dinner after 1900 hrs).  A few months ago, I changed to take entecavir at 2300 hrs (just before sleep) and I would normally finish my dinner before 2030 hrs.  Is this routine ok for the empty stomach requirement?

Yes, I agree that Hong Kong has some of the most experienced liver doctors (as we have my Hep B carriers here).  But my doctor would like to prescribe entecavir 1mg and I don't want to take entecavir indefinitely (due to its carcinogenicity).  That's why I ask if my chance for ent + interferon combo.  I will definitely ask him to test my HBsAg quantity today.

Regards,

Cyrus

[StephenCastlecrag]

Thanks for the info. Yes, most people ENT just before going to bed. As for carcinogenicity, I believe there is on-going monitoring of this since ENT was approved by FDA because ENT tested positive in for carcinogenicity in an animal study. So far, FDA has not issued any warning nor made changes to the label information.
Still 180 copies/ml, i.e. 33 iu/ml, is a very very low number, below the "detectable limit" of many assays. Some research indicated INTFN can reduce level of HBeAg (as well as HBsAg), so it should help with your seroconversion, whether it is desirable to have the e-Antigen seroconversion is not clear to me.
Just my opinions.

[cyrus131]

Today I met my doctor and get my latest result:

Fibroscan : 4.2kPa
HBV DNA : undetectable

He advised me to continue 0.5mg entecavir monotherapy as I am still HBeAg+ as he predicted that my outcome using ent + intf combo will be the same as the ent mono.  I did request to test for HBsAg quantity and will discuss with my doctor again when I know my baseline HBsAg to see if it is worthwhile to add intf.

Thank you all for sparing your time in giving me valuable opinions.

[cyrus131]

Dear Stephen,

      May I know that if my HBV DNA is now undetectable, will it rebound soon or later?  Many thanks.

Regards

Cyrus

[StephenCastlecrag]

I am sure it will not rebound soon, but in the future, I would say no too. Of course, it is just my opinion. So far, research indicates response to Entecavir continues to be durable, that is, if you keep on taking Entecavir, you keep getting response. It seems your liver is in good condition (4.2Kp), hbvdna undetectable and I bet your ALT is also normal. So what can you expect in the future? I think, after you seroconvert your e-antigen, after a further 12 month consolidation, you may consider stopping all treatment and see whether your immune system can maintain control on its own. This seems to the view favored by researchers in Taiwan. Or you may consider combination with Peg INFN with the view to aim at clearing your HBsAg. Or you may just continue Entecavir until you seroconvert your s-antigen too.
So I think you are in a very good position, your HBsAg level may give you a better prediction of what is going to happen next.

[cyrus131]

Dear Stephen,

Thanks a lot for your response.

Regards,

Cyrus

[cyrus131]

Dear Stefano and Stephen,

Thanks a lot for your valuable advice before.  I just got my HBsAg quantitative result which is 456 IU/ml.

With this result, should I start interferon and what is the estimated chance of a  complete cure?

Many thanks.

Regards,

Cyrus

[StephenCastlecrag]

HBsAg of 456 iu/ml is a very good number. If you were HBeAg negative, you would be considered "inactive". It is certainly favorable to clearance by PegIFN treatment. I cannot give you an estimate. You may like to consult your doctor or seek an opinion from one of the experts.

In a recent study in China, 16 HBeAg negative inactive carriers with HBsAg < 200 iu/ml received PegIFN treatment and all of them cleared their HBsAg. Your situation is different as you are on antiviral treatment and still HBeAg positive. However there are studies that indicate PegIFN is more effective for HBeAg positive patients than HBeAg negative.

[stef2011]

immediately start peginterferon with entecavir add on and ezetimibe add on, chance to clear is highest and you may clear in just 24 to 48weeks

see otan results, she/he had about same hbsag level and cleared hbsag in just about 16weeks

[Ashi2010]

My ALT are normal  SGPT  35  limit is 15-72
                             SGOT  38  limit is  20-52

HBsag =Reactive
HBeag= Non Reactive
Anti-Hbeag= Possitive.

Is i am inactive and is there any cure for this

[stef2011]

your alt are not normal, those ranges are so obsolete alt range has been updated few years ago to alt less than 30 for men and less than 19 for women

to know if you are inactive you need fibroscan less than 6kpa, hbsag quantity in iu/ml less than 1000iu/ml genotype A and D, less than 100iu/ml C and B (not sure about b and c so i ve used a very low level) and hbvdna quantity in iu/ml less than 2000iu/ml

even your alt are not normal so you are not an inactive carrier at all, your doctors may be very very ingnorant on hbv and not updated on the diseases since years better change doctors

[Ashi2010]

Recently i have done the alpha feto protein AFP 2.91 ng/ml Reference range is upto 20 ng/mL is this within range.

My doctor told me as ALTs are within range no need to do the HBV DNA and no need to take medicine is it write.