Treatment neutropenia, causes and therapy

Several questions were raised in the thread:
http://www.medhelp.org/posts/Hepatitis-C/What-is-absolute-Neutrophils/show/1280368

about the causes of HCV treatment induced neutropenia (low neutrophil counts) and I thought it would be interesting to learn more about this part of treatment.

Specifically, they are:
- what is the incidence of neutropenia due to interferon monotherapy?
- what is the incidence of neutropenia due to ribavirin monotherapy?
- what is the incidence of neutropenia due to SOC treatment?
- how does interferon lower neutrophil counts?
- how does ribavirin lower neutrophil counts?
- what are appropriate steps in dealing with treatment neutropenia?

I will start by setting what I think I know about the subject aside and go to my personal treatment history, but hope to follow up with some answers sourced in literature.

First of all, neutropenia may be defined in a number of ways so we need to keep in mind that different studies may use different levels. The normal range for absolute neutrophil counts in a healthy person is 2,000-10,000 cells per microliter of blood syrum and doctors start to get concerned when the number drops below around 1,000. Both upper and lower limits vary by lab doing the bloodwork.

My own personal absolute neutrophil counts from SOC treatment were:
baseline prior to treatment  ~4,000
at the start of the 3rd week ~3,200
at the start of the 5th week ~2,100
in the 8th week they were ~1,900
in the 12th week they were ~1,100
they continued to slowly decline until week 21 when they reached a low of 860 and have bounced back to fluctuate around 1,200 ever since. I have never taken any neupogen although I have been on and off of procrit for my hemoglobin. I'm currently in week 51 of treatment.

HCVguy

[frijole]

"A common side effect of interferon alfa therapy is bone marrow suppression and particularly a reduction in white blood cell counts. Absolute neutrophil and lymphocyte counts typically decrease by 30% to 50% of baseline during therapy with the doses of
interferon required to treat hepatitis"

This is a good study done by:
Alejandro Soza
James E. Everhart
Marc G. Ghany
Edward Doo
Theo Heller
Kittichai Promrat
Yoon Park
T. Jake Liang
Jay H. Hoofnagle

This is a good study in that the conclusion was that low neutrophils do not particularly mean high bacterial infection with hep C patients

source:   http://www.google.com/#hl=en&source=hp&q=interferon+neutropenia&aq=f&aqi=g1&aql=&oq=&gs_rfai=C8hS0yR8vTNrjHYrAM6CPoYEKAAAAqgQFT9DahjI&fp=39029c7429b4ffaa

[frijole]

MY personal ANC history was:
2800 baseline
800    week 4
700    week 8
400    week 15 (start neupogen)
Neupogen kept me at about 1000 until about week 26. From there to week 56 my ANC stayed about 500-700 even with the neupogen.

I was not prone to infection even though I had low ANC.  

Your ANC did remarkably well .  I assume you are doing 72?

frijole
ps - it was thoughtful of you to change your screenname

[HCVguy]

So, from the prior thread, I had this backwards. I thought ribavirin had the main impact on neutrophils and interferon had a secondary effect. The Soza paper and many others I came across indicate that interferon has the pirmary effect on neutrophil count reduction with only a small if any effect by ribavirin.

Patient neutrophil counts as a function of time into treatment also support this. If ribavirin was the primary cause then it would take 4 or more weeks before neutrophil counts were impacted. My personal neutrophil counts do not support this well but frijole's counts do and literature indicates that most of the drop in neutrophil counts occurs by the second week of treatment.

While a lot of literature says that "Interferon suppresses bone marrow production of leukocytes", I have yet to come across an explanation of how this occurs. So while I continue to learn about this, I can answer some questions posed by my initial post:

- what is the incidence of neutropenia due to interferon monotherapy?
It appears that this incidence is between 15 and 20% depending on study and the cutoff level used to qualify as neutropenia

- what is the incidence of neutropenia due to ribavirin monotherapy?
I could not find evidence in literature showing neutropenia incidence as a result of ribavirin treatment alone.

- what is the incidence of neutropenia due to SOC treatment?
This appears to be around 20%

[HCVguy]

In the prior thread, you wrote that your doctor stated that, "INF is the destroyer and NEUP is the creator." If the two counteract, then doesn't taking neupogen effectively lower interferon's ability to inhibit the hep c virus?

I have seen explanations for how interferon works to reduce viral replication but  so far, the only explanation for how interferon reduces neutrophil counts I have come across has been in:
http://pathmicro.med.sc.edu/mhunt/interferon.htm

This article describes a process which would be responsible for early neutrophil death and possibly reduced neutrophil creation as is often referred to in other papers as "bone marrow suppression", called myelosuppression. Here's the quote I'm talking about:

"INTERFERON-alpha AND INTERFERON-beta (TYPE I INTERFERONS)

These interferons induce about 20-30 proteins, and the function of many of these is not fully understood. However, three of the proteins that appear to play an important role in the induction of the anti-viral state have been intensively studied. Expression of one of these proteins (2’5’ oligo A synthase) results in activation of the second of these proteins (a ribonuclease) which can break down mRNA, and expression of the third protein (a protein kinase) results in inhibition of the initiation step of protein synthesis. These activities target viral protein synthesis, but also result in inhibition of host protein synthesis."

But I don't know enough about the life cycle of a neutrophil to understand how break down of mRNA would affect its production in the bone marrow. The third protein this article mentions would be responsible for early neutrophil death.