Elevations in ALT Late in Course of Tx is Associated with Relapse

[CoWriter]

Elevations in Alanine Aminotransferase Levels Late in the Course of Antiviral Therapy in Hepatitis C Virus RNA–Negative Patients Are Associated with Virological Relapse.  

(HEPATOLOGY 2009;49:000-000.)

The incidence and clinical meaning of elevated alanine aminotransferase (ALT) in chronic hepatitis C patients who are hepatitis C virus (HCV)-RNA negative during pegylated interferon (PEG-IFN) and ribavirin therapy have not been completely characterized.

In this study our aim was to assess the incidence, pattern, predictive factors, and clinical meaning of elevated ALT in a cohort of 173 chronic hepatitis C patients who obtained viral clearance during either PEG-IFNa2a or a2b and weight-based ribavirin therapy.

Patients were defined sustained viral responders (SVRs) or relapser responders (RRs) on the basis of a serum HCV-RNA result at 24-week follow-up. SVR and RR were obtained in 141 (58%) and 32 patients (13%), respectively. Among the 173 study patients, 57 patients (33%) had undetectable serum HCV-RNA and elevated ALT in at least one evaluation (weeks 2, 4, 12, 24 in all genotypes, and week 48 in HCV genotype 1 and 4 alone), and this phenomenon was not differently distributed between SVRs and RRs. No pretreatment demographic (age, gender), clinical (ALT levels, histological grade and stage, body mass index) and viral (load, genotype) parameter was associated with this phenomenon. The incidence of elevated ALT levels was not associated with type of PEG-IFN and ribavirin dose.

Elevated ALT levels showed a different longitudinal pattern, occurring more frequently between week 12 and the end of treatment in RR as compared to SVR patients (90% versus 9%, P= 0.000001).

Conclusion:
The occurrence of elevated ALT levels in HCV-RNA-negative patients during PEG-IFN and ribavirin therapy is a fairly frequent and unpredictable phenomenon.  Although ALT elevation per se is not associated with a greater risk of relapse, its occurrence in the later phases of therapy is more common in relapsing patients.

During antiviral treatment of HCV infection, early viral response (EVR)—defined as a 2.0 log drop of viral load or HCV-RNA clearance at week 12—is a good predictor of SVR and has a negative predictive value above 95% for nonresponse (NR) to treatment.  Furthermore, a rapid decrease of alanine aminotransferase (ALT) and its normalization during treatment can be considered an indicator of favorable response to treatment, although this biochemical feature has no role in predicting SVR in patients treated with standard interferon.

On the other hand, viral response is not always associated with biochemical response, as previously observed in patients treated with standard interferon and ribavirin, and with PEG-IFN a2a monotherapy.  In fact, Hung et al. observed that 13% of chronic hepatitis C patients who obtained SVR to standard interferon and ribavirin treatment showed persistently elevated ALT during treatment, whereas in the study by Zeuzem et al.6 41% of patients did not achieve ALT normalization until the end of therapy.

These findings seem to suggest that lack of ALT normalization is not necessarily associated with a decreased efficacy of treatment. However, this phenomenon has not been characterized in a systematic fashion, and little is known about its incidence, clinical characteristics, longitudinal pattern, and clinical relevance in chronic hepatitis C patients treated with PEG-IFNa and ribavirin combination therapy.

In this study we analyzed a cohort of chronic hepatitis C patients who became HCV-RNA-negative during treatment with PEG-IFNa and ribavirin.  We compared the pretreatment demographic, clinical, and viral characteristics of patients who showed elevated ALT levels with those of patients who obtained ALT normalization so as to identify parameters associated with this phenomenon.  Furthermore, we evaluated whether discordance between viral (i.e., negative HCV-RNA) and biochemical (i.e., elevated ALT levels) responses were associated with response relapse (RR). Lastly, we assessed whether elevated ALT levels showed a peculiar longitudinal pattern in SVR and RR patients.

Results
Overall, SVR was obtained in 141 patients (58% of the study population: 83/151 treated with PEG-IFN_2b, 58/93 treated with PEG-IFN_2a), whereas RR and NR were observed in 32 (13%) and 71 (29%) patients, respectively, without a statistically significant difference in treatment response between the two PEG-IFNs (P _ 0.340).  SVR was obtained in 102 genotype 2 and 3 patients (80%) and in 39 genotype 1 and 4 patients (34%).  Neither the baseline (1,000 mg/day versus 1,000 mg/day) and on-treatment (992 mg/day and 13.8 mg/kg/day versus 1,000 mg/day and 13.3 mg/kg/day) median ribavirin doses were significantly different between RR and SVR patients.

Incidence of Elevated ALT Levels and Baseline Patient Characteristics.
Overall, among the 173 patients who had undetectable serum HCV-RNA during treatment, 57 patients (33%) showed elevated ALT levels (i.e., >40 IU/L) in at least one programmed evaluation.

The incidence of elevated ALT levels was not significantly different between SVR (47/141 patients, 33% of all SVRs) and RR patients (10/32 patients, 31% of all RRs) (P = 0.987). Table 2 summarizes the main baseline characteristics of the 173 patients who had undetectable serum HCV-RNA during therapy, subdivided according to the presence of normal and elevated ALT levels. As far as age, gender, BMI, baseline ALT levels, and HCV genotype and load are concerned no significant difference was observed between the two subgroups of patients.

A similar proportion of patients in the two subgroups had HCVRNA serum levels above 400,000 IU/mL (70% versus 71%, P = 1.0).  Significant histological fibrosis (score_2) had a similar prevalence in patients with normal and elevated ALT (34% versus 47%, P = 0.547), and median histological grading was not significantly different in the two subgroups of patients (score 6 versus score 6, P = 0.163).
Influence of Treatment.

The baseline (1,000 mg/day versus 1,000 mg/day) and on-treatment (967 mg/day and 13.0 mg/kg/day versus 1,000 mg/day and 13.5 mg/kg/ day) median ribavirin dose was not significantly different between patients with normal and elevated ALT levels, and during treatment daily ribavirin dose had to be reduced in a similar proportion of patients in the two groups (normal ALT = 21%, elevated ALT = 16%, P =0.539).  The occurrence of elevated ALT levels showed a trend toward a greater incidence in patients treated with PEG-IFNa2a (29/71, 44%) as compared to patients treated with PEG-IFNa2b (28/102, 27%), although this difference was not statistically significant (P = 0.095).  The same analyses carried out further subdividing patients into SVRs and RRs showed no statistically significant difference (data not shown).

Pattern of Elevated ALT Levels.
Among SVR patients who showed elevated ALT levels, the majority (37/47 patients, 79%) showed a constant decrease of ALT levels as compared to baseline at all the programmed evaluations, whereas six patients (13%) showed an increasing ALT pattern, and four patients (8%) showed a fluctuating ALT pattern. In SVR patients who showed a constant decrease in ALT levels, the median time from HCV-RNA clearance to ALT normalization was 10 weeks.

[jmjm530]

Except you missed the most important part in the sentence that follows your quote -- at least to the authors given the title of their study -- which stated

"...However, a peculiar finding of our study was that longitudinal evaluation of elevated ALT identified a significantly different pattern of ALT elevation in RR as compared to SVR patients.  Indeed, in the majority of RR patients, elevated ALT levels appeared during the late phase of treatment and showed no fluctuating pattern, whereas in SVR patients this phenomenon was mainly observed during the early phase of treatment."

Peculiar indeed, but since when is "peculiar" a basis to publish a study when everyone seems to agree there is no prognostic value.

[apache1]

I read the WHOLE study... thanks for posting it Co.

This is a controversial subject that is hard to substantiate with all the variables. Plus throwing in a less than <50 pcr didn't help the matter.  

Imo it is very dangerous to take % numbers and findings out of context from any study. All findings have to considered as a whole.

Here is a direct quote from the study's conclusion,,, it says it all.

" When we analyzed whether the incidence of elevated ALT levels had any prognostic value, we observed that this phenomenon was similarly distributed between HCV-RNA-negative patients who showed SVR and RR(relapse), and therefore, as such, cannot be considered a parameter associated with a greater risk of relapse."

apache

[CoWriter]

"although I'm not sure it justifies the title of the post "
------------------
It's taken directly from the study's title.

"Elevations in Alanine Aminotransferase Levels Late in the Course of Antiviral Therapy in Hepatitis C Virus RNA–Negative Patients Are Associated with Virological Relapse."

Co

[jmjm530]

I do find the article interesting and I'm glad Cowriter posted it although I'm not sure it justifies the title of the post
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The reason I keep asking the questions is because I'm not even convinced the study justifies the study :) Seems they might have done a bit more homework before publishing but maybe I'm missing something.

[Marc1955]

If my reading is correct, there were six patients in the SVR category who had an increasing ALT pattern (13% of the cohort) whereas there were two patients in the RR category who showed this pattern (20% of the cohort). If this is correct, it doesn't seem very convincing. Here is the relevant text:

"Among SVR patients who showed elevated ALT levels, the majority (37/47 patients, 79%) showed a constant decrease of ALT levels as compared to baseline at all the programmed evaluations, whereas six patients (13%) showed an increasing ALT pattern, and four patients (8%) showed a fluctuating ALT pattern. In SVR patients who showed a constant decrease in ALT levels, the median time from HCV-RNA clearance to ALT normalization was 10 weeks."

"A reduction trend in ALT levels was observed also in the majority (8/10 patients, 80%) of RRs with elevated ALT, whereas two patients (20%) showed an increasing ALT pattern, and none had a fluctuating pattern.  "

I do find the article interesting and I'm glad Cowriter posted it although I'm not sure it justifies the title of the post. I think it's most important not to lose sight of this statement:

"To translate this observation into clinical practice means that the decision of discontinuing treatment solely on the basis of elevated ALT levels in patients who are HCV-RNA-negative would result in a substantial proportion of patients not being cured of infection." In other words, there's nothing in this current study to warrant any changes in treatment based on ALT levels. You should not use ALT levels to make a decision about continuation of treatment.

[jmjm530]

CO:

Call it a lazy weekend (and a lazy Mon morning) cause I still didn't get a meaningful clinical answer from even your condensed version :) So here's the question again, because the rest, while interesting, doesn't really give even quasi-firm direction.

Question:

What are the SVR figures for Group "A" versus Group "B" per the below definitions.

Group A: sub group of serum negatives with elevated ALTs late in treatment

Group B: sub-group of serum negatives but without elevated ALTs late in treatment.

MB: whose to say that slight elevations towards end of tx might not just as easily be from the liver getting sick and tired of the tx drugs...and in the weariness enyzmes rising again slightly.
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Yes, that is more or less the reasoning most use, i.e. it's the tx drugs elevating the enzymes and indeed this study does not disprove otherwise, at least to me.

[copyman]

Thanks Co for condensing & for your reply to me.

[geterdone]

laymen here... So, in other words if the ALT’s are elevated the inflammation is at its greatest and the flxuations in alt is the body combating the inflammation, right? So, if it goes above the base line while treating, to me it would mean there is a blockage in the plumbing. If I had one piece of paper and cut it up into 3 pieces of paper I now have three pieces of paper and if one was hard to process the two extra would overload the process of elimination causing a back up thus raising the ALT’s.

[merryBe]

on the other hand, I've been having fun with the tutorials in clinical options on depression.

a common occurance in later stages of tx is to have to up the dosage or even switch to heavier, less liver friendly antidepressants as time goes on. Some tutorials present with patients in the last 2-3 months of tx having this weariness and having to have large dose adjustments, plus I've seen and read of many in here....one just yesterday wanting to quit because the toll is so great.

So might not that have something to do with it? Especially with the SSRI's we know they are hardest that way.

You are right, I skimmed rather than ruminated...but that was the one glaring defect I noticed.

of course they did say
>>>>>>>Finally, at the time of identification of biochemical abnormality we performed a thorough investigation of the putative causes associated with elevated ALT levels in each patient (i.e., hepatitis A and B infection, cytomegalovirus and Epstein-Barr virus infection, autoimmunity, thyroid dysfunction, metabolic derangement, iron overload drugs, alcohol abuse), and all these tests resulted completely negative in all patients.

but what did they mean by drugs, illicit or prescribed? I for one would want this question answered since this one class of drugs could indeed be the culprit.
I would just not want someone to be fearful should their liver become tired, have a reaction due to inhibitor reactions or the standard modus operadi of SSRI's elevating enzymes to be thinking fearfuly that they are immediately doomed should their Alt increase.

maybe someone should write the researcher and ask what drugs, alcohol abuse, all referred to and what it did not cover.

mb

[merryBe]

>>>>>>remember the RVR is highly predictive of SVR.

before this study everyone agreed to that.

http://www.jstage.jst.go.jp/article/internalmedicine/47/14/1301/_pdf

respectfully however, RVR also reflects one other thing that confirms the study I just gave, and that being that EVR means THOSE patients spent therefore THE MOST time treating while in the UND mode.
That being the case, it confirms that the more extended the time spent treating after going under has more impact than the other factors.

For instance, typically when the original predictives wer done tx remained at one year regardless.  Ergo some patients were getting 50 wks UND tx, while LVR or SLVR were only getting 26 or 36 weeks UND to treat.

as you can see by the 10% increase in each 10 weeks added the SVR increases with time spent. So this increase in time on the tx drugs may have been the real predictive all along, but until the extended tx'er were really studied the last 2 years they just had no way of knowing that.  Just my theory.

mb

[CoWriter]

"Would this study apply to me since I'm in the Telaprevir study?
I have interest in this because my ALT has not decreased during TX. My ALT has stayed bascially the same from Pre-tx to now 28 weeks, around 65 IU/L."
-------------------

No, I don't think this applies to you.  The study refers to elevations in ALT from the baseline level.....and you said your ALT has remained the same.  

The study says that an elevation in ALT happening after week 12 on patients who RVR'd may suggest the possiblility of relapse.  But not on people who had ALT elevations before week 12.  

Plus it also mentioned that some people who SVR'd had an elevated ALT from early on to the end of treatment and 6 months after the end of Tx, the level was fine.  

Remember that RVR is highly predictive of SVR.  You're almost there.

Co

[merryBe]

that's a good point Jim....but here's something else to contemplate...

whose to say that slight elevations towards end of tx might not just as easily be from the liver getting sick and tired of the tx drugs...and in the weariness enyzmes rising again slightly.

You are right though, since the PCR's aren't telling us who is truly negative....and even the NGI PCR >1 can't do that if you believe there can be undetectable floaters as per HR's discourses, then the very real puzzlements as to why may forever remain.

What I don't get...and maybe I'm too dense who knows....but why the plethora of SVR predictives??  I mean at some point do they really plan on offering patients zero treatment because their predictive stats aren't the best??
I'm really not getting why researchers are so big on this.

Also, remember the latest ACHIEVE type 1B study showed time spent treating AFTER going UND was a greater predictive of SVR than early response, so just the opposite of previous conceptions.
In my mind that alone calls into question all the previous predictive models.

http://www.jstage.jst.go.jp/article/internalmedicine/47/14/1301/_pdf

mb

[smaug48]

Thanks Co for the study, link, and especially the condensed version :-)

smaug

[CoWriter]

"Forgot to add that this study refers to elevated ALTs late in treatment. You would be mid treatment if you were in SOC, not late, if I understand things correctly. The study did not find any correlation for elevations earlier in treatgment."
------------------

By "late in treatment" they mean between week 12 and end of treatment.....and "early in treatment" between weeks 2 and 12.

Co

[CoWriter]

Okay, so it WAS a super long study....LOL and I can tell nobody read the whole thing because you missed the main point.  

Here's my condensed version.....

SVR 58% ... RR 13%, Non-responders 29% respectively.
SVR in Geno 2/3..80%  and Geno 1/4...34%

33% had undetectable serum HCV-RNA and elevated ALT in at least one evaluation.  Since this is such a frequent ocurrence, the decision to discontinue Tx should not be made solely on the basis of elevated ALT levels.

Elevated ALT levels showed a different longitudinal pattern, occurring between weeks 2 and 12 in 91% of SVR patients (with a constant decrease after that).

On the other hand, elevated ALT levels occurred more frequently between week 12 and the end of treatment in 90% of RR patients.

(In SVR's the median serum ALT increase as compared to baseline was 11 IU/L.......and 30 IU/L in RR patients).

Patients who obtained SVR more frequently showed elevated ALT levels during the first phase of treatment; it is likely that in these patients elevated ALT levels can be the result of an early and stronger immunomodulatory effect exerted by the Peg.  On the other hand, elevated ALT levels observed during the late phase of treatment despite HCVRNA negativity in RR patients might be due to viral activity that emerges at the end of therapy.  

(However, as Jim mentioned, the lower limit of detection of the viral load test used was 50 IU so using a more sensitive test may have been able to detect residual viremia).

The most important finding of this study was that elevated ALT showed a peculiar pattern in SVR and RR patients. This finding, if confirmed in further studies, may suggest that patients with elevated ALT levels during the late phase of treatment may hypothetically be in need of a prolonged course of treatment so as to avoid relapse.

Co

[Marc1955]

Let's not forget that the basic conclusion of the study was that ALT levels were NOT a predictable indicator of success in treatment. They happened to notice this one pattern of a late elevation, but even in that case they were not certain enough about their findings to recommend any change in treatment based on the elevation. The basic takeaway is that people clear with many different ALT patterns.

[copyman]

thanks jim

[jmjm530]

Forgot to add that this study refers to elevated ALTs late in treatment. You would be mid treatment if you were in SOC, not late, if I understand things correctly. The study did not find any correlation for elevations earlier in treatgment.

[jmjm530]

I would read the study VERY carefully and if there's a fit to the elevation numbers (compare your "slight" to what they are talking about) , then get an answer to the question I posed before making any decisions as well as factor in that they did not use a sensitive TMA as I assume you are using or will be.

[copyman]

Thanks Co for posting this study. The timing of this could not have come at a better time for me.

Perhaps you, jim or the others could comment on how you read this study and how it would affect someone in my position?

I have been thinking about my slightly elevated Alt.  I read your post but having a hard time understanding (tx brain fog) . Would this study apply to me since I'm in the Telaprevir study?
I have interest in this because my ALT has not decreased during TX. My ALT has stayed bascially the same from Pre-tx to now 28 weeks, around 65 IU/L.  I'm in week 28 of the Telaprevir study. This study is where everyone gets the real drug for first 12 weeks . I was UNDE at 3, 8, 12, 16, weeks using the Labcorp <10 test. My 24 week test was also Neg using the Labcorp UltraQual <2 test.  

Thanks

[jmjm530]

Not to come off lazy LOL but can anyone tell me the SVR figures that would most interest someone treating -- specifically what are the SVR figures for the sub-group of serum negative with elevated ALTs late in treatment versus those who are serum negative but do not have elevated ALTs late in treatment. It should also be noted that the study did not use a very sensitive TMA so it is quite possible that a significant percentage of the PCR negative/late elevated ALT group was indeed TMA positive. This is unfortunate because we know from prior studies that 100% of EOT PCR negative/TMA positives will relapse. And in fact, this alone could be the only reason the late elevated ALT figures have any significance.

[CoWriter]

Hi Marc:

Here's the full study....

http://www3.interscience.wiley.com/cgi-bin/fulltext/121582705/HTMLSTART

Co

[Marc1955]

Many thanks. This addresses a question that's interested me. Is it possible for you to give a fuller reference? I can't find the article in the new issue of Hepatology. Do you have the publication date and volume?

[CoWriter]

(Continuation same study... part 3)

A large study reported that biochemical abnormalities, including liver enzymes alteration, led to discontinuation of treatment in 12% of chronic HCV patients treated with PEGIFN a2a,15 whereas another study found an ALT doubling with respect to baseline values in 2% to 3% of patients treated with PEG-IFN_2b and ribavirin.16 Neither of these studies, however, indicated if serum HCV-RNA was detectable when ALT levels were higher than normal.

In this study we identified no parameter, either of the patient or of the virus, that was able to predict liver enzyme alteration despite viral clearance. In particular, viral genotype and load and advanced fibrosis seemed to play no role in ALT elevation. Although elevated ALT levels were not associated with treatment schedule, this study cannot prove/disprove the possibility that in some patients ALT elevation was possibly due to a mild PEGIFN-induced liver toxicity.

Finally, although we cannot rule out a specific role played by other histological characteristics that we did not take into account (e.g., pre-treatment steatosis), we observed that both BMI (i.e., a metabolic determinant of steatosis) and HCV genotype 3 (i.e., a viral determinant of steatosis) were not significantly associated with elevated ALT levels, therefore indirectly ruling out steatosis as a possible culprit for the observed phenomenon.

Indeed, the most important finding of our study was that elevated ALT showed a peculiar pattern in SVR and RR patients. This finding, if confirmed in further studies, may suggest that patients with elevated ALT levels during the late phase of treatment may hypothetically be in need of a prolonged course of treatment so as to avoid relapse.

However, what are the bases for this suggestion?
In order to explain this phenomenon we formulated two hypotheses.  Patients who obtained SVR more frequently showed elevated ALT levels during the first phase of treatment; it is likely that in these patients elevated ALT levels can be the result of an early and stronger immunomodulatory effect exerted by both (PEG)-IFN and the modified cytokines milieu, eventually determining clearance of infected hepatocytes.  

On the other hand, elevated ALT levels observed during the late phase of treatment despite HCVRNA negativity in RR patients might be due to a subclinical viral activity that emerges at the end of therapy, once pharmacological pressure is withdrawn. Indeed, although the HCV-RNA assay we used in this study is commonly used in clinical practice (lower limit of detection 50 IU/mL), we cannot exclude that in RR patients the use of a more sensitive technique such as transcription-mediated amplification (TMA) would have been able to detect the presence of minimal residual viremia before the clinical diagnosis of relapse.

Unfortunately, the recent studies that assessed minimal residual viremia by means of TMA in patients who relapsed after PEG-IFN and ribavirin therapy did not report the biochemical status of patients who were HCV-RNA-negative/TMA-positive during treatment.

In conclusion, our study showed that mildly elevated ALT levels can be observed rather frequently in chronic hepatitis C patients who clear HCV-RNA during PEGIFN and ribavirin therapy, although there are no pre-treatment clinical predictors of this phenomenon.

Noteworthy, if viral clearance occurs the presence of elevated ALT is not a poor prognostic factor per se, and although its appearance during the late phase of therapy may suggest a higher risk of relapse, its occurrence should not be a reason for treatment discontinuation.  As far as the mechanism(s) underlying ALT elevation are concerned, an immunomodulatory effect exerted by IFN and minimal residual viremia may play a role in patients who obtain SVR and RR, respectively, although further studies are needed so as to better clarify these aspects.