Measurement of VL in first 12 wks of treatment

[Trish77]

I would like to know how important it is to all of you to know your exact VL during treatment at 4 and 8 weeks.  If you have a PCR that measures down to <50IU/ml, are you content with a Pass/Fail until that week 12?

This is the scenario I'm in for and I'm not happy about it, I want to know my exact VL count at 4 weeks and 8 weeks if I fail, as in I'm above <50IU/ml.  Is this reasonable or am I getting uptight for nothing?  I'm thinking if I know at 4 weeks that I'm not doing so well, I can ask the doctor to alter my treatment to increase my odds.  Then I can measure again at 8 weeks how it's going.  A pass/fail doesn't give me enough information, I'm thinking.  Am I off-base there?  Hard to know if I'm letting emotions get in the way of clear thinking at the moment.

(I posted all my questions in one post on the other side..but way too much to slog through I'm thinking so I'm breaking it out individual posts for the questions that are on my mind.)

[merryBe]

if fat is not the vehicle for greater absorption than perhaps the increased bile it creates is the vehicle, which might explain why some folks not on high fat get good absorption?
Maybe they just naturally produce more bile or some other digestive enzyme helping the Riba absorb for which the fat is merely the stimulant???
One would also think intestinal flora, it's health and the general permiability of the intestines would have some effect.
In any case, I'd want some actual data as to WHY Lindahl thinks it makes no difference.
We do know that fat aides digestion, and that fiber tends to bind other things up right??
Well, based on my side effects and blood work both my Riba absorption took a leap when I included fat AND excluded fiber from my dosing times.
While I would be more likely to conclude the elimination f fiber had more to do with my absorption rate, it doesn't rule in or out the role of fat/bile and there are more than a few studies on pubmed noting as much as a 1.5 increase in absoption with fat.
(I think that mean one and a half times greater absorption not 1.5 percent, someone correct me if this is wrong please).

I admire the work K Lindahl has done on Riba absorption, it's a key to SVR and should be monitored through blood work to obtain optimal results for all, but I'd still wonder, if she hasn't done any double blinds herself, then upon what does she base her cynism here. I assume she has some rational.  ????

[willing]

zazza: thank you for posting her dissertation! it's a good wrap-up of her research in this area.

all: That 3-day vs 6-month gap also suggests that the hplc-based plasma concentration tests may not be all that informative, even if they were more readily available. What one would really like to measure is the amount of rbv in cells and, for now,  hgb drop may be the best scale, crude as it is. The take-home message seems to be that if one's hgb drop is closer to 1.5 than to 4 there *may* be grounds to increase the dose...

[zazza]

Fascinating! Thanks for helping me understand this.

[willing]

Lindhal's dissertation which you posted (maybe we can just call her Karin since we're talking about her so much) sheds some light on the numbers  given by your pharmacist. She cites Preston'99

http://www.ncbi.nlm.nih.gov/pubmed/10508023

(free-access) with respect to rbv kinetics, and they largely agree with  your pharmacist. The effect of taking a new dose seems to peak in about 90 minutes "a time to Cmax of 1.33 ± 0.034 h after oral dose administration". Decrease of  plasma concentration varies across individuals, but as shown in Figure 2 of that paper is 0 or near 0 for most after 75 hours.

An important detail however, is that plasma levels don't tell the whole story. The rbv in red blood cells is *not* cleared and the rbv molecules stored there will go back into circulation when the rbc dies off. The wikipedia rbv article

http://en.wikipedia.org/wiki/Ribavirin

puts total turnover of  one's rbcs at 6-months. I didn't follow this up, but this  detail seems to account for the 3 day vs. several month discrepancy.

Interestingly, Lindahl also casts  doubt on the "take it with fat" recommendation:

"The extent to which food affect ribavirin bioavailability differs between studies. It is also unknown whether any food effect might be altered by the type of meal consumed (e.g. high versus low fat content), if a food effect still would be evident upon multiple dosing and what clinical implications this might have (79)."

though more recent data supports the peanut-butter chaser:

http://www.ncbi.nlm.nih.gov/pubmed/17118126

[willing]

bobby: 17->11.7 is about a 31%drop, which would indeed suggest you are strongly responding, even  at 1000. You can get an idea of where that 31% drop puts you relative to others by looking at Fig. 8 from Lindhal's dissertation  which zazza posted above (not many blue dots above 31%..) and  also from the following summary from Dahari'07

(http://www.ncbi.nlm.nih.gov/pubmed/17412448)

"We also evaluated hemoglobin declines stratified by treatment outcome. Although median baseline hemoglobin levels were roughly equivalent in SVRs and NRs (p = 0.20), hemoglobin decline during the first month of therapy was significantly greater in SVRs than NRs (3.9 vs. 1.4 gm/dl, p = 0.002) "

all: the rbv mystery deepens...writing last July in a review comparing two recent assessments of rbv's effect as an hcv mutagen, Perelson, maybe the world's leading hcv kinetics expert,  closed with:

"In summary, both papers[1] and [2] demonstrated that RBV has an early effect in elevating mutation rates, consistent with the mutagenesis hypothesis. Although further tests, using infectious HCV clones or additional sequencing may be performed, the proof may be in the pudding. If RBV is acting mainly as a mutagen, then according to the Dixit et al14 model, it should have little effect in combination with therapies that efficiently block viral production. If a lack of effect of RBV could be shown for combinations of IFN with effective small molecule HCV inhibitors, we can stop arguing about RBV’s mode of action and simply remove it from future therapies."
(from http://www.ncbi.nlm.nih.gov/pubmed/17484896)

however... it looks like the arguing will go on for quite awhile to come since,  as summarized in that quote by Jacobson that mike posted in the r-1626 thread above:
"this study also showed that ribavirin contributes significantly, just as it did with telaprevir, to the antiviral activity seen with combination therapy containing R1626."

not only is rbv not going away, neither the mechanism of its effect nor  the proper way to gauge "optimal" dosage seems to be coming into view.

One interesting point, and perhaps others can tell me if I'm hallucinating or not,
but from both Fig. 10 of Lindahl's dissertation (thanks zazza)  and Fig 1a of Dahari'07 (free access) it seems that the striking difference in rbv plasma levels between svrs and nrs is not so much the mean as the variance. The svrs all cluster around one level whereas the nr values are all over the map...

[jmjm530]

A number of doctors are using weight-based riba for geno 2's and 3's.

At 190 lbs, you just entered the 1200 mg./day dosing range but maybe your doc played it conservative since you weren't a geno 1 -- as he just as easily could have given you 1200 mg. (I started at 1200 mg/day and weighed 176 but was a geno 1).

In any event, you had a significant drop in hgb so one might assume that the current dose is getting into your system efficiently and frankly I'm surprised such a drop didn't land you flat on your back. BTW there's a "helper drug" called Procrit (epo) that helps many of us function better with low hemoglobin. If your symptons are persisting something to talk to your doctor about.

The low range for hgb on my lab report is 13.2, but keep in mind that most of us are anemic to one degree or another on tx.

-- Jim