Meds, Mind, Body & Benefits > Questions About Treatment & Side Effects

06/10 Starting Viramune (Nevirapine) + Kivexa (Epzicom = 3TC / abacavir)

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eric48:
Hi,

Thanks for the question. Happens that I have an appointment soon with a cardiovascular specialist, and, since taking ABC, the question will be on the table.
So I hope to get more for you soon...
Back in the old (sad) days, that inflammation question was really invisible, well behind a crucial survival crisis. Even weight gain (a concern for some of us) was way out of scope (in an intriguing article published recently an MD said: where is all the wasting gone ? my HIV patients are getting obese ! (LOL) )

You have several issues and they are difficut to sort and rank:
- the virus
- the virus induced inflammation (or inflamaging)
- are the meds enhancing or reducing this inflammation
- drug (meds) toxicity

My gut feeling is that the Virus is the key and prime problem including in those inflammaging issues.
Clearing the virus is our new target. Maybe we will not be able to eliminate the virus entirely, but we can find hints or better ways to reduce the number of infected cells.

This is a concept very little discussed in the scientific litterature.

When VL is down to UD the disease progression has slowed down. Fine.
But how many (CD4) cells remain infected ? 50% , 25%, 10 %, 1 %, 0.1% ?

From an escape from certain death pespective, if you are starting at CD4 = 10 drug efficiency is more or less defined by the abilty of the drug to increase that number (definition #1). and if that number can slowly go up to 350 who care if X % are monoinfected or moderately infected as long as they can survive and fulfil their role. So from a disease non-progression perspective it does not really matter.

But, an other efficiency definition for drug efficiency (definition # 2) would be the ability to enrich the pool of non-infected cells and reduce the pool of mono or low infected cells.
That definition of efficiency is irrelevant when your strategy is to increase the CD4 cell count at what ever cost
But now that people are initiating treatment sometimes at CD4 600 or even more, that other definition of drug efficacy (the ability to 'cleanse' the infected cell pool)
starts making sense for some patients

I'll document this in a future post.

The '90s or '2000 paradigm was to find an escape route (from certain death)
The '2010s for many people this is still the same
BUT, seen from the 'younger' generation patient, initiating with better meds, at a higher CD4 count (a small fraction, but say even if this is only 1-2 % of patients) it is legitimate to live with the expectation that they are engaging a route towards a cure. And all the argumentation about a phamaceutical cure being impossible can be revisited

I think this is the key to the apparent Nevirapine paradox:
- as par definition #1, other drugs have proven superior
- as per definition #2, a less documented concept, NVP might faring much better

Stay tuned for more

Eric

eric48:
recession hitting badly. Little time to work on this thread. Will comme back later Eric

eric48:
just switched to Viramune 400 mg XR. pill is a little (ca 15%) bigger than one 200 mg immediate release, yellowish vs white. The change was easy enough, but, somehow makes me feel the Kivexa (which I have always suspected to give me anxiety) is a little harder to get by with.
Well ... I am on anti-depressants and anti-anxiety for treating depression as well. so it is hard to say.

Eric 

eric48:
Can't kept this for myself...

CD4 : 779 (46%) ; CD8 : 400 (24%) and ... CD4/CD8 ratio : 1.9 !...

CCR5 test came back favorable, which my doc says it is quite common for people who could start treatment early. So at least CCR5 antagonist are an open option.

Why so excited about CD4/CD8 ratio : 1.9 ?

Chomont classification and sieve for identifying patient's with lower active sub-clinical replication

Chomont article demonstrates 2 modes of viral persistence: TCM and TTM CD4+ T cells define distinct HIV reservoirs.
HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation
http://www.nature.com/nm/journal/v15/n8/abs/nm.1972.html

This results in 2 distinct regimes (either steady state or dynamic) as well as, in some patients a combination of both.
This article is not free and not easy to understand...
Fortunately, the supporting data, the table of 34 patients (all with VL <50) is in a freely available supplement. Here again not easy to read unless you type the data into a spreadsheet and plot the data with X axis being CD4/C8 ratio and Y axis being the estimated size of infected cells (in part per million, of CD4)
(because they have been introduced only recently, very modern drugs such as RAL are not found in patient's regimens)
http://www.nature.com/nm/journal/v15/n8/extref/nm.1972-S1.pdf
table is in page 6

The relationship between CD4/C8 ratio and infected poll becomes clearly visible. and 4 rectangles (areas) can be identified on the diagramm.

A- CD4/CD8 ratio less than 1 and infected cell > 200 ppm
B- CD4/CD8 ratio less than 1 and infected cell < 200 ppm
C- CD4/CD8 ratio more than 1 and infected cell < 200 ppm
D- CD4/CD8 ratio more than 1 and infected cell > 200 ppm

Remarkably, there are not a single of the 34 patients in area D, in other word, in this limited, but well studied group, no-one with a ratio > 1 has a pool of infected cells (in blood) > 200 ppm

On the other hand, whenever the ratio is less than 1 relatively nothing can be said, the infected pool can be just anything from 10 ppm upwards to thousands.

This table provides an interesting snapshot, and, while generalization is questionable, it offer an interesting perspective on dynamics. CD4/CD8 ratio is equal to CD4% divided by CD8 %, and is relatively stable and steady, in the same fashion that CD4 % is. It is moving, but not jumping around especially in those patients where CD4 is on the higher end.



Enjoy !

Eric

eric48:
Hi,

On the graph above, I have marked in red patients using Viramune. non users are in blue. Two  thirds of Viramune (nevirapine) users have a low reservoir.

Chomont has published a recent article (not free):

CD4 T cell nadir independently predicts the magnitude of the HIV reservoir after prolonged suppressive antiretroviral therapy
http://www.ncbi.nlm.nih.gov/pubmed/22019250

in which he reckons
(quote:)
Previous small studies have reported that HIV-1 proviral DNA levels are inversely correlated with CD4/CD8 ratio or CD4 T cell counts in successfully ART-treated or na´ve HIV-1-infected subjects. Our results confirm and further extend these studies showing a negative correlation between the frequency of
CD4 T cells carrying HIV-1 proviral DNA and CD4/CD8 ratio or CD4 T cells, in infected individuals receiving ART and in whom plasma viremia had been suppressed below the limit of detection for prolonged periods of time. (end of quote)

this article also refers to this (older, but free) article
Relationship between the size of the human immunodeficiency virus type 1 (HIV-1) reservoir in peripheral blood CD4+ T cells and CD4+:CD8+ T cell ratios in aviremic HIV-1-infected individuals receiving long-term highly active antiretroviral therapy.

http://www.ncbi.nlm.nih.gov/pubmed/12023777

This other study includes ca. 30 patients. In figure 1 diagram C:
http://jid.oxfordjournals.org/content/185/11/1672/F1.expansion.html

you will recognize the same L shaped scatter plot with the same A, B, C, D areas as on my diagram above (the only difference is that the vertical boundary is, here, at CD4/CD8 = 1.2, whereas in Chomont's data plot the boundary is at CD4/CD8 = 1.0)

In figure 2 (especially the diagram named 'combined') shows that HIV-specific cytotoxic CD8+ T lymphocytes are much lower when CD4+:CD8+ ratios is over 1.2.

Therefore, while the CD4/CD8 is not a absolute surrogate for a low reservoir (one can have a low reservoir and a lower ratio), anyone with a 'higher' ratio
is very likely to have a low reservoir and therefore a good candidate for eradication trials.

In next post we will see the triple play CD4/CD8 ratio, CMV and cancer risk

I hope the above will be usefull to Nevirapine users...

Cheers

Eric

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