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

[eric48]

Hi,

I had been turned on by the fact my doc spent most of the interview looking at me, hum..., carefully, intensely. I had expressed concerns that my cheeks had sunken a bit. I was a bit defiant.
He said that , being an MSM community doc, he never hesitates to prescribe treatment, that they actually perform in his same clinic and that first justified request will grant me immediate access, no questions asked. Yet, he insisted, that I have to come to realize that aging (and a bit of anxiety) will change my face, eventually. He was adamant that this is not Lipo and that he will keep it under surveillance.
Why did he had to add that my skin and other anatomical features are actually well preserved for our (same) age ? and with that charming smile of his, then ...

<tears>

Eric

[eric48]

Why the Abacavir associated MI risk is so confusing
***************************************************

Reading the original document:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688660/

I have recently realized that I had made 2 big MISTAKES in MY understanding of the MI risk associated with ABACAVIR.

These 2 easy to make mistakes should be demystified.

Turning 50 soon, I was really unhappy to hear about that DADS outcome, given my obsession on that subject (family history...)
Quite naturally, I had second thoughts and somehow wished I had been offered Truvada (which may be a nice drug otherwise, I do not know, so please, do not drag me into a discussion on Truvada itself, this is not the point, here)

Here, I will mention a medication I do not take (Truvada, the most common current alternative to Kivexa), something I usually refrain from, but this is where MY mistake lies.

MY FIRST MISTAKE
*****************

My (false) understanding was to consider that the original DADS shows that ABC demonstrates an ADDITIONAL risk compared to OTHER NRTIs (which in MY mind included Tenofovir and FTC, the components of Truvada, the most currently used combined NRTI) and therefore to think (falsely) that DADS demonstrates an additional MI risk between KIVEXA and TRUVADA.

The truth is the original report for DADS DO NOT demonstrates an additional cardiologic risk of KIVEXA vs TRUVADA.
I though it did, after (wrongfully, my bad...) understanding second hand reports, review and comments or posts on this forum.
But the fact is that the original paper DOES NOT demonstrates an additional cardiologic risk of KIVEXA vs TRUVADA. (the 3TC component of Kivexa is usually considered as being so similar to the FTC component of Truvada, so that the differentiator is ABC vs TNF).

Because this is what the original (first) DADS report says about Tenofovir:

quote: Patients participating in D:A:D have also received other drugs as part of their nucleoside/nucleotide backbone, including emtricitabine and tenofovir.
There is currently insufficient follow-up time (<2 years on average) among patients receiving these drugs to assess reliable associations with the rate of myocardial infarction.(unquote)

In other words Tenofovir is not part of the 'OTHERS NRTIs' category. It is simply not covered by the FIRST DADS original report.

Nonetheless, it is included in further reports (as DADS is an on going follow up study)

http://jid.oxfordjournals.org/content/201/3/318.full

But, here, the authors are very cautious... Because ABC was introduced on the market MUCH before (5 years?) TNF, the data collected do not span over the same period and less data is collected on TNF

As of 2011, there are, to my knowledge 3 longitudinal studies including cardialogic risk evaluation, including ABC, AND VERY LARGE, multi ethnic cohorts. (IMHO, the smaller danish cohort, does not qualify in that definition).
They are DADS, ANRS and VA cohort.

Here below is the comparison table, with conclusions relative to ABC vs TNF (who cares about other NRTIs in 2011...)

DADS : ABC vs TNF : additional risk but to be considered cautiously as TNF was included later.
ANRS : ABC vs TNF : no difference in risk (after screening out IDUs, a potential source of bias effect aka channeling effect)
VA Cohort : ABC vs TNF : no major difference in risk (a slight advantage in favor of ABC, though...)

This was MY first mistake: to think that DADS was CLEARLY demoting ABC vs TNF.

A side note: same caution if you are considering modern PIs that were NOT included in early DADS reports

Duration of inclusion (hence statistical relevance) can not be ignored.

MY SECOND MISTAKE
*****************

was to consider that ABC is multiplying MY MI risk by the (usually referred to) risk ratio of 1.9 (later downgraded to 1.7) (which is almost as high as smoking) (note: the multiplicative risk ratio for smoking is 2 to 3 depending on studies).

Here again this is NOT true. DADS itself points out that the additional risk is VERY HIGHLY stratified per baseline (i.e. pre-meds) cardiovascular risk.

The risk (if any) is ONLY for those with a higher baseline cardiovascular risk (scored, I suppose, on the pretreatment Framingham score-sheet).

The evidence provided by DADS original report itself is EXTREMLY GRAPHIC:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688660/figure/F1/

For those with low or medium baseline risk, the additional risk is hardly noticeable (if any); on the other hand very much associated with the higher baseline risk group


From the (new) patient perspective:
***********************************

If you are offered ABC, your doctor has heard about DADS, and has done due diligence, in particular with regards to baseline cardiovascular risk.

So, do not make the same mistake I made and take it easy.

Cheers, Eric (who still has another cardiologist appointment coming up, just to be on the safer side)

[Peacock]

Thank you Eric for all your information from the viewpoint of a patient starting Viramune and Kivexa (Epzicom). I found it VERY interesting, especially as Im currently on Nevirapine and the very 'outdated' Combivir. Ive been looking at replacing the Combivir with something else and the choices so far are between Truvada or Epzicom.
Your letters have been informative and great to read, Thanks!!!
Steve

[eric48]

Hi,

Thanks for the comments. Appreciated. (BTW, my PM box receives this kind of nice comments on a regular basis: thanks you all!)

The good news for you is that, since you have tolerated your current combo for long, you can always switch back to V&C, should you find V&T or V&K not of your liking. The switch would simplify your schedule to once daily, which I find convenient, because except for business trips, I do not have to bother about carrying pills. I just keep some spares in car/backpack. The alarm by the bed does the trick for me. I do not even have a wristwatch

I recently found some statistics (which I'll post soon) that support the general understanding about that combo: discontinuation rate is a bit higher than others at initiation, but continuation rate after year 2 seems extremely stable

Be well !  Eric 

[eric48]

test results, cute cardiologist and one excellent surprise
******************************************

I knew the test results would be good (but I did not know yet it would bring an additional bonus):
UD (hey, what would you expect?)
CD4:  739
CD8:  738
CD4%:  31,2
CD4/CD8 ratio : 1.0
HDL: 0.70 ; LDL: 1.45, everything else well within range...
No single health issue during this long and rainy winter (except a bit of tiredness, fatigue, lack of energy...)

http://vacs.med.yale.edu/IC/

yielded a 3% 5 year mortality risk (the lowest value that this calculator can provide, given my age , which I can not change, is 2% i.e. if VAcs index = 0)
(I get a slightly higher score (6) due to a lower level of platelets, eventhough, they have increased recently)

Had a bit of discussion with Doc about a few people who had kindly PM'd me and expressed fears about NVP
He said that Doc who are careful in patient selection before choosing Viramune are equally happy than with EFV, that he prescribes EFV more often that NVP, but has had more adverse events with EFV than NVP.

Discussed that I am feeling a bit alone on this less usual combo.
He said that NVP had been banned from some hospital because of patient death, but that was before the screening rules were implemented.
That it also depends on doctors education, experience and confidence, (and availability...) which leads to a situation where NVP is never used in some parts of the country
He said that, on the other hand, there are others regions where V&K is 'hype' and the trendiest thing in town . Patients show up and demand this combo
May be some people are reading this thread after all...

Discussed the new cardiologist who will now be in charge of my 'yearly' check up. Brillant HIV/cardio specialist (wrote books, publications, etc.) and extremely cute, assistant doctor, who is right on my type!
(I wonder if this will show on the cardio test when he performs it...)
Sex drive is back somehow, which he commented was a good therapy... Well... In our offer and demand local gay scene there is little room for courting and romance... So, I am not always very comfortable with my doc 'recommendation' that I should have more (extramarital) activities. I fell like a dinosaur in this sex consumption scene. I prefer to have an open discussion with doc, rather than be offended by comments that are, IMHO, out of the main scope of a doc visit. Nonetheless, my position of a listed (ex-) gay activist who happened to have found happiness with the (most unexpected) person he loves most ( and happens to be of the opposite gender)  is a very sensitive subject. A bit more tact in this matter would be nice, but I think this is way out of his mind set.

The good news
*************
When he gave me the prescription he underlined one new thing:
The prescription is valid for 6 months !!
He said that one benefit of V&K is that once people are stable on it, they are very stable and with this kind of numbers, there is no point in seeing me as often as before.
And that unless something shows up the 'yearly full hospital check up' is from now on once every 2 years!

Boy!.. after all the stress of this fancy combo initiation, here comes the reward
I was not even looking forward to less doc visits (*) and blood work, but, this, indeed will lower the burden by ca. 50%

I have regained a confidence in myself that I though was gone for ever...I feel suddenly much better!

(*) I like my Doc, but with regards to his color matching taste, there is room for improvement

Cheers!

Eric

[nvhorseman]

Doctors have hundreds of patients. To expect them to remember the co-habitation situation of all of them is naive. I'll take brains over social banter any day and be happy with the results of less pills, increased efficacy and stabilization beyond expectations. As a patient, if I were to notice how "cute" my cardiologist was and "just my type", I would be the last to criticize my physician's bedside manner.http://forums.poz.com/Smileys/default/shocked.gif I'd gladly settle for doctor's visits of 2-3 times a year vs. the 6 I endure, especially if I was told I could "date" again. Your physician didn't say to go out and have unsafe sex, he said to have more sex. Now that you are feeling better, I hope you do just that with any consensual and educated person you choose.http://forums.poz.com/Smileys/default/wink.gif The choice is yours, not his.http://forums.poz.com/Smileys/default/kiss.gif

[eric48]

Doctors have hundreds of patients.

Thanks  for posting. While this thread is focused on treatment, (especially when on a less common, once demoted, combo) and not about doc and patient relationship, I do not mind commenting on doc patient relationship as it is a significant part of treatment/healing. (and otherwise would be a boring medical thread)

I am more than happy with the choices he has made with/for me thus far. He a fabulous doctor. he's got lot's of good connections.
I have also expressed my interest in participating in clinical trials (and we are doing prescreening tests), but, I'll live the final say up to him.
Doc and I have concording/converging views on a number of issues and discordant on some other.
The 'special' relationship is not on a personal level. It is on a risk management which goes beyond routine clinical care. And I do not mind giving some insights:

Just to give some background, in our local socialized health care, HIV is ONLY handled through hospital. There is no such thing as private practice. This may sound 19th century to a lot of people, especially in the US. Nonetheless, my doc was authorized, on an experimental basis, to open the first ever  (and so far only) private practice in our country (based on his long hospital experience and contribution as a board member of local guidelines). This experimental private pratice is actually partly subsidized (by the state) and he still works at he hospital.

I feel privileged (and gratefull) for the extra care and time he gave me.
That my doc is a more-than-usual important person to me may have transpired through this thread. It is a given fact. My choice. While I have received some PMs asking if I am attracted/in love with doc: the answer is simply NO
Am I a more-than-usual patient to him ? I hope not, I am sure he treats other patients with the attention they deserve according too their specifics (treatment failure, (illegal) migrant status, complication of any sort, etc). But there is a bit more to it:
A- I know for a fact that I am (one of) the very first patient in his all new private practice, and most certainly the first newly diagnosed to be sent to him directly rather than hospital first (as is standard practice here). His other first patients were old timers on follow up. (originally this experimental private practice was started to take some burden off the state hospital and restricted to follow up of 'stable' patients). He did show obvious surprise when I showed up as a newly -diagnosed and his office was still humid with the all new paint and furniture still wrapped in plastic!
B- I am (by far) not the first patient he initiates on Viramune. I am not the first patient he initiate on Kivexa. But the first he initiate on both (his hospital boss forbids that...)

Treatment is a journey. A special one for me (obviously) and also for him (not medically speaking, but as the sole, unsupervised, decision maker, in an entrepreneurial sense)

The (visible) success of his experimental private clinic and of (so far so good) success of my own treatment makes me a special-patient no more.

In a sense, the fact that I am put on the lightest possible maintenance schedule makes me happy, but, sure, I'll lose that special care and doc availability that this 'unusual' combo initiation requires.

Commenting on sex / doc / love (and doc taste in clothes) is normally not part of this thread and I will refrain from now on.

Through this forum and other reading I realize how lucky I am (in a sense): less than 25 % of US Hivers are UDs, and about 50% where I live...

I have just lost a special status (my initial doc visits were twice a month!) and gained a new one ('stable' patient) and I hope the readers will excuse a bit of venting and whining

I also hope that prospective users of this 'fancy' combo will still like reading this one single, no-more-unique patient experience

Cheers and stay tuned ! (I have more on tweaking this combo....)

Eric

[eric48]

How many of us ?
*************
Hi,

this post:
http://www.thebody.com/Forums/AIDS/Aging/Q221359.html

citing this publication:

http://www.hivandhepatitis.com/hiv-aids/hiv-aids-topics/hiv-treatment/3552-croi-hiv-people-with-cd4-counts-above-500-match-life-expectancy-of-general-population

CROI: HIV+ People with CD4 Counts Above 500 Match Life Expectancy of General Population

and other life expectancy articles are among most popular story on aidsmeds as well. Earlier reports had looked at people with CD4 > 500 AND VL < 50.

Needless to say, for people like myself who could be treated early and have, thus far, been good responders, this is good news.

The stats are one thing and the patient perspective, another.

This less than usual combo (Viramune / epzicom) is not for every one: treatment naives with higher CD4s are excluded, and, since the risk of failure at initiation is higher, may be not for people with low nadir (at least a a first line combo), as they do not have the luxury of time. etc...

Yet one question is rarely addressed: how many of people under long term HAART, in a setting of good availability of care and meds are UD and have CD4 > 500.

This free article here:
Cost-effectiveness analysis of initial HIV treatment...
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234156/pdf/ceor-3-197.pdf

addresses mostly economical aspects.
Yet, it provides 3 very interesting tables:
- Patient distribution based on CD4-cell count and viremia
and mortality...
- Patient distribution based on CD4-cell count and
viremia
-Efficacy data: immunologic response per different treatment regimen
(side note: V&K is not listed, but very close combos such as V&T and S&K are listed: initial success rates is lower but extremely stable over the years.)

When care is available, 'normal' life expectancy (the >500 strata) is for 25% of patients and 'near-normal' life expectancy (the 350< CD4 < 500 strata) is for another 25% of patients. That still makes ca. 50% !

half full or half empty glass depending how you look at it, this is still a very good number considering the nasty nature of the virus...

My doc seems happy with the optimal response to my treatment.
Feeling a bit lonely on V&K, it just makes me feel a bit better about it to learn, that, (where meds are accessible) good response is far from rare.

Cheers!

Eric

[eric48]

Hi,

This thread aims at providing patient perspective for those initiating with Nevirapine (or considering it as a second line)
I try to provide usefull information while avoiding useless controversies.

Publication in AIDS 2012, 26:000–000 :
http://www.ncbi.nlm.nih.gov/pubmed/22546987
The effect of efavirenz versus nevirapine-containing regimens on immunologic, virologic and clinical outcomes in a prospective observational study

as well as comments here:
http://www.aidsmeds.com/articles/hiv_efavirenz_nevirapine_1667_22585.shtml

and here (a subtly nevirapine bashing post by Dr Paul SAX)
http://www.thebodypro.com/content/67311/generic-nevirapine-now-available-but-the-big-one.html

cannot be ignored.

I had access to the original article, way before these comments were published, and handed a print out to my doc.

He had no time to go through it and simply shrugged, saying that these larger multi cohorts are suspicious (same as DADS findings on Abacavir)

I would wish anyone could have a first hand read at the original paper (not second or third hand comments). Unfortunately, you will have to pay to have access to it.

In the next few posts, I'll comment on the virologic, immunologic and clinical outcome restricted to NON-AIDS defining patients that this prospective study is supposed to deal with

It is definitively an interesting story... But the previous ABC DADS story teaches us not to rush to conclusions!

It is also a technically difficult article, yet, I have already identified some methodological flaws, conclusion inaccuracies and computational errors (sic) in the original article...

One thing they did not miss though, it is the TIMING: just a few weeks before NVP patent becomes public domain ...

Well... Let's go through this together one step at a time ;-)

Once we have clarified the conclusions of hte above mentionned publication, I'll post some other interesting and unexpected benefits of NVP that I found (by chance) in an unrelated scientific debate.

Stay tuned

Cheers Eric

[eric48]

The above  article is about the virologic, immunologic and clinical outcome restricted to NON-AIDS defining patients ONLY. All patient with and AIDS defining condition are excluded. Only EFV or NVP initiating patients are considered.

Same as DADS, this is a prospective study... Good as a whistle blower, but prone to analysis bias and interpretation. See:

http://www.iwh.on.ca/at-work/59/retrospective-vs-prospective-studies

Virologic failure
*****************

In this post; let's focus on one of the first conclusion: virologic failure is higher, in this asymptomatic virtual cohort, with NVP than with EFV and let's put things in the patient perspective...

Virologic failure rate is higher in the NVP group. (BTW, it is also in cohorts including all patients). This results is far from unexpected. NVP is often said to have a lower barrier to resistance.

This terminology may be a bit improper.

Browsing through available literature I think there are 2 schools:

Concept 1

NVP is resistant to mutations that are less likely to be identified in an initial resistance test. An initial resistance test can only pick up mutations that present at above 20 % level. If NVP is resistant to a mutation that hovers at 10%, it is not picked up at initiation by the first resistance test.
It is sometimes pointed out that a single dose of NVP can built resistance. then that resistance goes in hiding, behind fitter quasispecies. Upon initiation, what was below 10% now becomes 20 % and so on...(*)

Concept 2

The virus can mutate a lot... The high mutation rate is due to inherent infidelity of HIV reverse transcriptase (RT) and RNA polymerase II and may be partly caused by cellular cytidine deaminases such as hA3G (APOBEC3) (which the virus jams thanks to its Vif factor). If a drug allows for more mutants, and replication keeps going, ultimately, by chance, one mutant will be fit enough and resistant, hence the virologic failure. (**). Bad news for those who experience that...The good news for those NOT experiencing virologic failure though, is that those mutants, that might partly refill the reservoir, are most likely defective. This could be extremly Beneficial for people successfull under NVP 

Therefore:
If NVP initiation protocol would call for a resistance test prior to initiation AND a resistance test within the first few weeks (when VL is still > 500 or 1000 depending on labs)(as I did myself), potential Virologic failure would be identified earlier and the virologic outcome would be better.

Therefore it is NOT NVP, per se, which is the problem, it is the way NVP is initiated and resistance monitored...
(if resistance tests were more sensitive or cheaper, then virologic failure would be less likely).
Here the problem is not the drug itself but the initiation protocol or practice.

Is the take home lesson for someone who initiates therapy in 2012 same as for those who did way back in 2000 in this cohort? Of course not...

NVP carries more risk of VF. Fine. We knew that already. I was really scared myself and this is the reason why I started this thread (BTW)
 
Back in the years 2000 this was a definitive lowdown for NVP (vs EFV), because in case of failure your options were limited. But in 2012, early pick up of VF warrants an early switch to Etravirine (same class) or RAL (INSTI class) or even Maraviroc (if applicable and available)

So the risk is (slightly) higher, but you've got your arse covered.

You are jumping with smaller size parachute, but with a big time safety net (RAL/ PIs/ MVC/Etr) that initiators back in 2000 did not have... Yet, so many times I see posts where people are told: take this pill once a day for 2 weeks then twice daily from day 15 and we will see you in 3 months (sometimes 6...) unless you have a rash.

As a patient you want to be damm sure the airbags are available and will trigger on time !

Sorry for the long post. Next post, about immunologic outcome, will be shorter...

Stay tuned

Cheers Eric

PS: for further reading   

(*)
there are many academic reference for this. Let's just quote:

quote:Our study also reveals that the excess treatment failure observed in the NVP arm is strongly associated with detection of NVP-resistant mutants missed by standard population genotype. (unquote)

from:
http://thomasland.metapress.com/content/5h0rudc88rr7xemj/fulltext.pdf
Role of low-frequency HIV-1 variants in failure of nevirapine...

(**)
http://www.hindawi.com/journals/mbi/2012/586401/
HIV-1 Reverse Transcriptase Still Remains a New Drug Target...

This article has an interesting section of pro-mutation differences between various NNRTIs

[friskyguy]

Eric

Thank you for devoting your time on this forum.

I am not sure if you can assist here? Are you able to shed some insight re one of the biggest drawbacks to treatment with NRTIs and that is the decrease in mitochondrial DNA which has with prolonged use has been linked to tissue toxicity including premature aging, body shape changes, peripheral neuropathy (PN) and myopathy.

I am aware that Abacavir is not considered as toxic as previously used NRTIs. Well that is the current thinking now. 

Management of potential mitochondrial toxicity during long term nucleoside analogue therapy would therefore remain a challenge for many of us. 

How would one know of any potential underlying cell damage taking place on NRTI treatment before symptoms would present?  If we decided to continue on NRTI treatment, how could we manage the potential toxicity? Would being pro active in including nutritional supplements help lessen the risk of toxicity in any way?

I tried bringing this to my attention of my specialist but he was not able to shed any real light on this topic. I thought that perhaps during your extensive research you may have stumbled across some relevant information.

cheers
Frisky

[eric48]

Thanks,

One of the above cited article provides in depth explanation about how NRTIs work:

I quote

Importantly, unlike NRTIs, NNRTIs do not require intracellular metabolism to exert their activity...
(unquote)

NRTIs do not have a direct activity, they need some kind of enzymatic transformation and it is the resulting  products that have the inhibitory effect (not the NRTI themselves): hence the mandatory intracellular metabolism

read this:
http://www.thebodypro.com/content/67445/spartan-two-drug-nrti-sparing-strategies-continue.html
and this interesting question:
Do the NRTIs provide some key antiviral component mechanistically?
There seems that (modern) NRTIs have something that makes them unique and, therefore so important, in the HAART weapons.

First, I never (almost) comment on drugs I do not take. Therefore, I cannot state anything on NRTI sparing regimen. Most of them are PI based, and PIs also come with their share of management issues. And depending on the initial resistance test not everyone has the luxury of choice, anyway.

The point that I hope to come to in the next few post, is one key understanding: NRTIs act BEFORE integration of replicate DNA bits in host chromosome, right after viral entry, whereas PIs act at the other end of the cycle, before the exit.

In  layman's words, NRTIs and NNRTIs are trying to prevent the bank robbers (who have successfully passed the entrance door to access the vault room, whereas PIs prevent the bad guys to leave the vault/bank

I think you should put your (legitimate) concerns about these long term toxicities into perspective:
Well treated people (like yourself) may lose a few months to a year of life expectancy to HIV + HAART, admittedly. Blue color workers lose 5 years to white collar, and smokers something between 5 and 10 years.
 
As far as I am concerned, it may well take me 3 years to get adjusted to the meds, but I can see things improving one  tiny step after the other. I hardly ever notice it now on facial change or fatigue, etc.

I will have a post dedicated to liver health management, though, as I have found a few things that I still need to confirm and may be usefull to my pill buddies

I am working on some exciting new findings that may inspire hope to people with a treatment profile like yours

If, indeed, this is a manageable condition, then it needs to be understood and managed...

Stay tuned

Eric

[eric48]

Immunologic response
********************

Dynamics of VL decay are much better understood than CD4 dynamics.

Historically, VL decay was thought to be a single phase logarithmic decay
(for those unfamiliar with logarithmic decay, think of radioactive elements such as iode which has a short half life). It was early understood that the decay was at least bi-phasic (a sharp initial decay, followed by a slower one). At the end of this biphasic decay, the virus should have disappeared and treatment could be ended and the infection made history. Unfortunately not the case ...

Dr Siliciano then introduced the concept of a tri-phasic decay (a model later refined to quadri phasic) in which the last phase has such a long half life (44 months) (think of plutonium) that people would have  to remain on treatment for more than an estimated 66 years

Very few models of CD4 dynamics have been offered until this very recent paper:
HIV Model Parameter Estimates from Interruption Trial Data including Drug Efficacy and Reservoir Dynamics
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0040198

- it is free
- the fit between model and clinical data is really convincing
- it offers a CD4 dynamics that is at the same time simple and convincing enough
- it is consistent with the disappointing results of treatment intensification
- it is compatible with Dr Siliciano's model of a slowly decreasing (non replenishing) reservoir
- it is compatible with the alternative vision that the reservoir replenishes (cell-free transmission as well as
A. Sigal 's Cell-to-cell spread (transplication)
http://www.nature.com/nature/journal/v477/n7362/full/nature10347.html

unfortunately:
- it is difficult to understand
- it applies mostly to the context of successfull treatment and good immunologic response

Finally, it offers an alternative vision to the logarithmic decay paradigm, on which very early works were based. A paradigm that has recently lead to set backs in reservoir suppression trials (as it assumes that the reactivated latent CD4 will have a logarithmic decay by intrinsic self death, which they don't, and do not have the
second chance of a logarithmic decay due to an adverse environment, since the milieu has lost its anti-HIV activity, as demonstrated by Pr. Siliciano himself).

The steady state equations are not very different from Pr. Siliciano's system of three ordinary differential equations published in page 3 of:
Low-level HIV-1 replication and the dynamics of the resting CD4+ T cell reservoir for HIV-1 in the setting of HAART
http://www.biomedcentral.com/1471-2334/8/2/

Steady state equations are just easier to understand...

Here is my humble understanding of the equations as these equations are the key to a-cure-within-one's-lifetime; the set (1) of 3 equations is in page 2

They consider the steady state of healthy CD4S (subtly named 'targets'), steady state of infected CD4s and steady state of VL.

The easiest to understand is the last one:

VL equals virus production from actively producting cells minus the clearance rate of free virus

easy enough...
 
(note: residual free RNA, a measurement surrogate for VL, due to dying CD4s are not accounted for since this applies to post-second decay, here, they imply VL = active virus, which is not exactly the VL reported on one's lab sheet)

the second:
infected CD4s are made of recently infected CD4s, plus reservoir (latent) minus dying (infected) CD4s
the number recently infected CD4s, itself, is the number of CD4s multiplied by VL (in other words exposure the active virus) and attenuated by a factor combining drug efficacy and virus infectivity

(of note: it exposes the Dr Siliciano paradigm that drug efficacy, in a successfull combo, is 100% efficient, which regardless of virus infectivity makes that multiplier equal to zero and and therefore equate the number of infected CD4s to the latent, quiescent reservoir only)

Here, the interesting points are :
- reservoir replenishment is zero if infectivity is zero (i.e. CR and/or X4 receptors are successfully blocked)
- a less efficient drug that would hinder more the infectivity (fitness) of the virus could very well lead to less reservoir replenishment (on the next cycle) than a more efficient drug that would otherwise not change the virus fitness (+)

The third:

Uninfected CD4s are equal to their proliferation (++) (birth, duplication, etc.)  minus their death rate and minus those which have been infected

Okay... This is a long and technical post, and not necessarily bullet proof.
Yet this is the necessary base for next post which is about the Nevirapine (Viramune) immulo-virologic apparent PARADOX

Stay tuned

Eric

[eric48]

Hi,

Each drugs has its pros and cons.

Nevirapine, a fairly 'old', somewhat marginalized (usage ca 16%), drug, receives pretty bad reviews and any article showing its relative inferiority (usually vs EFV) receives wide publicity (including on this site). On the other hand there is a growing evidence that NVP has also some very interesting advantages, but those reports get unnoticed.
I have answered about 15 PMs from people so anxious about NVP, who finally did fine...

Let's expose the Nevirapine Paradox and cheer them up!

For the sake of easier understanding, try to visualize a chart or cursor where we scale virologic and immunologic outcome. Some sort of a 'progress bar'

To the left we place virologic failure along with immunologic non-response: bad news. Here, in that area of the chart, well..., EFV bests NVP. The Odds ratio (risk multiplicator) is ca. 1.5 (most likely less now that closer monitoring and screening is enforced, IMHO)

Somewhat towards the right, we place satisfactory immunologic response (CD4 > 350, for example) and VL < 50 : clinically encouraging news.
In that area, differences are almost inexistant and the pros and cons are more in the range of secondary aspects (cholesterol, CNS effects, ease of use, cost...)

Further to the right, we can place the best that we can measure. It is not necesserally clinically relevant, but there is most likely a status better than just CD4 > 350 / VL < 50

And even much further to the right are 'cures' obtained by medication, which would be the Graal of Pharma-cure; (bio-cure is out of the scope of this efficiency chart). (Thus far considered never-reached, this unchartered area is open to research and speculation)

The 'best' we can quantify (with advanced techniques, as of 2012) are:
A- VL =< 1 (Free RNA)
and/or
B- CD4 >= 500
and/or
C- Integrated DNA =< 10 ppm (that is 10 per 1 million CD4s have integrated HIV-DNA)

Patients who are A and B and C are labelled here 'Full responders'.

Since CD >= 500 and VL < 50 seems to confer a minimal additionnal death risk, there is no evidence that Full-responders will fare better than good responders, but, on our chart they are one step closer to the Graal.

Here is as cohort review of 'full responders':
http://www.ncbi.nlm.nih.gov/pubmed/22915460
Nevirapine use, prolonged antiretroviral therapy and high CD4 nadir values are strongly correlated with undetectable HIV-DNA and -RNA levels and CD4 cell gain.

The 420 patient cohort is restricted to patients who are VL <50 within 6 months and remain stable. The above report looks at 'Full responders'. They represent only 6% of patients who maintain UD (patients who are UD , vl <50 is ca. 50% of treated patients in that region). So, full responders represents ca. 3% of patients under HAART .Current combo is recorded to see if some drugs are more favorable. Obviously, in that socialized health care cohort, the newest, most recently approved drugs are not present. Therefore, the statement below does not include these.

With the sole and only exception of Viramune, no 'classical' drug was associated to 'full-reponse'.

Obviously starting treatment earlier and at higher CD4 Nadir makes it more possible to qualify to this group. After all, if your Nadir is 600, it is unlikely that you are to miss one of the 3 criterias (CD4 > 500)...

That NVP is the only drug associated to full-response is already an intriguing observation.

More interesting is the odds ratio: 3 ! this is very high

If you would want to 'rate' NVP vs EFV at the left end of our chart, NVP is 1.5 'lesser' than EFV. but on the other side of the chart NVP bests any other (incl. EFV) by a factor 3

This is what I call the Viramune paradox...

- it is a lesser drug if your fail
- it is a better drug if you succeed.

Why this happens ? is this of importance for moving further to the right (Pharma-cure) ?

Stay tuned and I hope NVP users will enjoy the further developments such as: Is it possible to monitor progress towards full response ? ...

Eric
(Aug. 2012 labs: VL< 20; CD4 : 686 (33%); CD8 : 686 (33%) CD4/CD8: : 1.0)

[eric48]

It did not make the headlines, but, what follows may matter to nevirapine users.

The 'discovery' or 'smoking gun' proof of cell-to-cell transmission by Alex Sigal is a turning point. It made the headlines.

It has lead A. Sigal to write an interesting (although not bullet proof) 'perspective' in Nature

Underlying this publication is a generation as well as a conceptual quarrel between moderns and ancients, between reasoning by infectivity persistence (Sigal) and reasoning by number persistence (Siliciano)

When I read A. Sigal's 'perspective' article (unfortunately, not free..), I had a feeling it would be hurting the numerists feelings and some strong academic response would follow.

Right on: Pr. Siliciano's just published his 'own' 'perspective'... It is strongly worded and tries to establish dominance of his concepts (it is R. Siliciano's numerist concepts that lead to believe that it would take 66 years, hence life long, to eradicate the virus under current, modern HAART). To make his point Robert Siliciano not only used his remarkable crystal clear style, he also made available for free...

Sigal only marginally mentions Siliciano's work. Siliciano minimizes Sigal's... (*)

reference for reading are here:

Original Sigal findings:(not for free, unfortunatly) Aug. 2011
Cell-to-cell spread of HIV permits ongoing replication
http://www.ncbi.nlm.nih.gov/pubmed/21849975

Sigal's 'perspective': (not for free, unfortunatly) Aug 2012
The Problem of HIV Persistence despite Antiretroviral Drugs
http://www.ncbi.nlm.nih.gov/pubmed/22901535

Siliciano's 'perspective': (free, but...) Sept 2012
Redefining the Viral Reservoirs that Prevent HIV-1 Eradication
http://www.ncbi.nlm.nih.gov/pubmed/22999944

Why this is of importance here? because 'numerist' perspective fails to explain the Viramune Paradox, where as a competition between numerical persistence and infectivity persistence may explain it...

Stay tuned, this is going to be a REALLY interesting academic debate that may change the perceptions that we have about competing drugs long term efficiencies and the (somber) perspective of a never ending treatment.

Eric

PS: (*) added on 09/29:
(R. Siliciano writes: (quote)
An interesting recent paper suggests that in the vicinity of a virus-producing cell, the exposure of adjacent cells to multiple infection events reduces the efficacy of antiretroviral drugs on a probabilistic
basis (Sigal et al., 2011). However, cells with multiple proviruses are rare in vivo (Josefsson et al., 2011) (/unquote)

In fact this last point, apparently silencing Sigal, is not as strong as it seems because Josefsson's measurements where made in blood and Josefsson's conclusion is (quote) our results indicate that most CD4+ T cells in the peripheral blood contain only one copy of HIV-1 DNA (/unquote). He did not write in vivo... he wrote in PBMC... and CD4 in blood are ca 2% of all CD4s... And Sigal already acknowledges that cell-to-cell transmission can (almost) not happen in CIRCULATING liquid (such as blood)...

[eric48]

So... Why is 'full response' of interest (A) and is there a status even better than 'full responder' (B) ?

A - As per R. Siliciano's above mentioned article: (quote) Eradication efforts will likely be attempted only in patients on HAART who have had sustained suppression of viral replication for years, and therefore the cells responsible for the second phase (+) may not represent a barrier to eradication(/quote)
(+) he refers, here, to residual replication

In other words, any one interrupting treatment at a point on the treatment progression timeline where residual, under the radar, replication has not ceased is bound for... a viral rebound (no pun intended)

Therefore 'full responders' are among the best candidates for the upcoming eradication trials. So anyone willing to participate in an eradication trial should at least be a full responder (or similar). Not convinced? Then browse for eradication clinical trials and look at the inclusion criterias.

And the best way to actively maximize chances to be a full responder:
- long duration of treatment (not under patient's control, recently treated will have to be patient)
- earlier entry into treatment (not so much under patient's control)
- use of Viramune. (a viable option for some patients, but not all...)
(or modern drugs? we do not know yet, since treatment duration is a main key factor)

My point here is certainly NOT to say that NVP is superior to other meds ... I am not interested in dog fights about drugs. I just want to convey to the 'poor' patient who is not eligible for the newest, fancier caviar regimen, and is being scared of this slightly riskier drug, that, on the long run things may turn out much more favorable than expected 

But there is more...

B - on our progress bar, where the 'Pharma-cure' is at the rightmost end, is there any reachable status that is even better than full responder ? Yes there is... The happy few (may not a few as we might think...) are labelled 'secondary controllers'. Ever heard of Secondary controllers ? Most likely not...

These are patients who, generally disregarding medical advise, have interrupted treatment and have had no need (mostly) to resume treatment.
Elite controllers are 'natural controllers'; 'secondary controllers' are patients who were not natural controllers, but who, after years of successful treatment have been rewarded by this 'secondary control' status.

Say, you go by Barré-Sinoussi's definition of a functional cure :
(quote).. (at) least render the need for lifelong anti-retroviral therapy obsolete (/unquote)

quoted from (free) article: Controversies in HIV cure research
http://www.ncbi.nlm.nih.gov/pubmed/22424402

then, it sounds pretty cool...

So, we have this all new video game, where you can raise up from hell, to reasonable health condition, and then move forward to a 'full responder' status then further to that exciting 'secondary control' status, which, from a patient perspective is just wonderfully great. (to date, 5 years off-treatment with clinically good enough control for some patients...)

'Secondary controllers' are a new urban legend ? Is there a clinical trial to back this up ?
Well... I certainly did not make this up !
Skeptical? Then do you own research or just stay tuned for more on that super status and, more interestingly, how it relates to your current or prospective NVP combo and provides more fuel to that interesting Viramune paradox ...

Stay tuned for more

Eric

PS Abacavir users will love the irony of this finding in here:
http://www.ncbi.nlm.nih.gov/pubmed/22994586
Cardiovascular risk factors and carotid intima-media thickness are associated with lower cognitive performance in HIV-infected patients:
... abacavir use was independently associated with a better cognitive performance  ... (no kidding)

[eric48]

A very good definition of secondary viral control is given here:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0037792
Immune and Viral Correlates of “Secondary Viral Control” after Treatment Interruption in Chronically HIV-1 Infected Patients

The work is based on a small, but well monitored, socialized health care cohort of the Institute of Tropical Medicine of Antwerp, including over 1700 patients. This is more a case report than a clinical trial and one could think it is only anecdotal.

Let's grant those doctors in Antwerpen (Belgium) with an ounce of credibility. HIV is their daily turf. There may be some methodological mistakes in the report, but once again, this is from experienced HIV specialists who are not new to this field.

Once striking number is that about 10% of patients (eligible for free treatment) drop out despite medical advise... It blows my mind, I could not believe it. The younger generation has been 'told' about but has never 'seen' AIDS in action, but still...

Among the drop outs 2.5% have been labelled 'secondary controllers' (4 divided by 160)

Obviously anyone just entering treatment has very little chance to control the virus, thus, it would be inappropriate to think that 2.5% of a given cohort are potentially secondary controllers. On the other hand, it is reasonable to think that among the good eggs who did not drop therapy despite many many years of successful treatment, there are some secondary controllers in the closet. Therefore it is not unreasonable to think that in this particular cohort, ca. 5% are secondary controllers.

Is there something special about Antwerpen ? Why other studies have not picked up those SC ?
Are these fakes ? (people telling their doc they are not taking meds while importing generics on the side ?)
(in socialized healthcare where meds are FREE, why would one want to do that ?)
Are there people out there not telling their docs that they have stopped taking the meds (but with good control, the doc can not find out ?)

Well... That is for those doctors to find out...

This is not a denialist thread (by any means), it is about NVP (and ABC/3TC). What does this have to do with NVP ?
Is this topic going completely out of control ? Without access to patients' treatment history, how can we relate to NVP ? Well... why don't we just try to do that... Hack into the Antwerpen cohort SC's medical history and see the intriguing relationship with Nevirapine (Viramune) ?

We will do that on next post.

Stay tuned for more

Eric

Latest Labs:
Oct 15 2012: VL < 20 CD4: 676 (40%); CD8 : 490 (29%) CD4/CD8: : 1.4 (Yeah!!!)
CD4 count well in line with models derived from above mentioned equations. CD4% jumping from 33 to 40 in 2 months is beyond my expectations... CD8 also may need to be confirmed (potential outlier)
Next Labs around Nov. 15

[eric48]

Hi,

Nevirapine, the little drug that could:
****************************

Well... We do not really have to hack into people's clinical records...
4 patients have been described and reported as secondary controller.
While my current personal target is full control (as described above), this SC status is very attractive and, IMHO, the closest you can get to a Pharma-cure.
Fortunately, a detailled case report of 2 of the 4 patients can be found here:
Control of viral replication after cessation of HAART
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046910/

Those 4 SC (see above post) are very interesting. They divide into 2 subsets:
Secondary viral control and good immunologic standing (SC+/I+) : 2 patients
SC and less favorable immunologic standing (SC+/I-) : 2 patients

The 2 patients for whom we have treatment information are (SC+/I+) : 1 patient and (SC+/I-) : 1 patient. 3 of the 4 had been on treatment more than 10 years.

Unless I have missed something, here is what adds our final touch to the NVP PARADOX exposed earlier: the 2 patients for whom treatment is known were on ... Viramune!
The studied population is very small and this could be only anecdotal, but, as of today, unless I have missed some other studies, the following seem right to claim:
 
100 % of fully described secondary controller were on nevirapine !...
**************************************************

Considering the usage of NVP is of about 16%, in other words one in six patients, the odds of picking randomly 2 patients in a cohort and find that they are both under NVP is like throwing 2 dice, and get ... a double 6
1 in 36, less than 3 percent. Is this just by chance ?
It can be argued that the numbers are too small to draw a conclusion, yes... but this is intriguing enough.

Still anxious about starting or switching to NVP ? Well, I can understand, but, it is also possibly, one of the best way to get as close as possible to a functional cure

In the next posts, we will see why this might be, and how we can monitor our own treatment progression towards full response and, why not ... SC...

If you would want to learn more about the little molecule that could, I recommend this video

http://us.viramune.com/consumer/viramune/how-viramune-works.jsp 

Stay tuned for more

Eric

Latest Labs:
Nov. 15 2012: VL < 20; CD4: 886 (highest ever) (37%); CD8 : 719 (29%) CD4/CD8: : 1.23 ( > 1 is thus confirmed!)CD4 count NOT in line with my models, but flu shot might be the cause

[eric48]

Hi,

Very scarce information has been published to date with the combination of ABC/3TC/NVP
This is why I keep readers of this thread posted about news findings.

For people looking for ressources about this combo, there is actually very little. Which may help explain why this is thread is, as of today, the most read in this section of the forums.

Finally, a scientific poster has been published on this combo...
************************************************************
http://www.jiasociety.org/index.php/jias/article/view/18343
Effectiveness and tolerability of abacavir-lamivudine-nevirapine (ABC/3TC/NVP) in a multicenter cohort of HIV-infected ARV-experienced patients

prospective users may want to review it.

Understanding the Viramune Video
********************************
Last post I linked to a video available on the official Viramune Website.
Actually, in an other post, I had given a simplistic and quite graphic explanation of how NVP works
I am posting here this same description as a supplement to the above mentioned video.
I hope it may help understanding that video, somehow

Variability is due to the infidelity of the reverse transcription process.

The NNRTIS (such as Viramune aka NVP, or Efavirenz aka EFV ) block the reverse transcriptase in a geometrical fashion. (also called steric)

To try to explain in layman's word is kind of difficult.

But think like this.

Visualize a hand holding a baseball, then remove the (large) ball.
You hand now has a shape similar to the reverse transcriptase. keep that shape firm

NVP is a small molecule that will geometrically fit between your thumb and first finger, like a small table tennis ball. When the virus DNA approaches the transcriptase, the small ball gets its way. But in some cases it can manage it way through, but not without damage (mutation)

EFV is a larger molecule (like a tennis ball), it fits between the thumb and second finger, thus better blocking transcription process.

More novel NNRTIs are even bigger and fit between thumb and third or even fourth finger, making a complete blockade. In this respect they are more 'efficient'

only one mutation during a faulty reverse transcription can make the virus resistant to NVP. EFV requires two mutations. In that respect as well EFV may appear more efficient.

Nonetheless, mutations have a cost on the virus, which becomes less fit for the next round of infection. Single round efficiency of EFV is superior to that of NVP. but the infectivity of a virus that may have passed the drug (which is not 100% efficient) is less in case of NVP than in case of EFV

The re-contamination rate is combination of infectivity and efficacy
therefore this combination is similar with NVP than with EFV AS LONG AS the number of rounds and potential events for mutation is not too high (in the case of NVP). IF VL is high or CD4 is high the odds that an unwanted mutation appears increases.

Which is why there is a limitation on NVP initiation on both VL level and CD4 level.
The reason why the cut off value is higher in men than in women is a bit obscure.

It may be related to the fact that proliferation (number of newly created CD4s, hence new 'targets') is higher in women than in men, who, in average have a 100 to 150 higher CD4 count (as observed in the non-HIV infected general population)

The above explanation may have flaws and not scientifically rock solid, but, I hope it helps you...

up-coming posts
***************

In the next posts I'll discuss 2 topics that I have been working on recently:

1- a novel method to evaluate in-vivo drug efficiency. This is some work that I am currently documenting and circulating through research community in order to get it further validated. We hope to publish in a scientific publication. Here, I will only give a layman's approach and outlook of what it implies from the patient perspective

2- a tool to allow users evaluate if they qualify for 'full responder' status, even when they have no access to high resolution VL nor reservoir measurements, as these are out of reach in standard clinical follow up.

I hope this will be of interest to those who found some interest in the Viramune paradox.

The little drug that may be a curse for some and a blessing for others as it may help them get to that secondary controller status, which, from a user perspective, might be just as good as a cure.

Last meeting with Doc
*********************
mix feelings. The cardiologist report had not reached his desk, the CCR5 tropism results had not been provided and we suspect an hospital 'miss'.
That was not a good start. We lost a lot of time looking for these missing reports
Yet, now that I have been put on crestor (rosuvastatin) 5 mg and responding well to it, my lipid profile is a winner:
HDL (the good one) 80 (mg/l)
LDL (the bad one) 90

With such good numbers (CD4 , VL, %, ...), he was quite happy!
Me not. I wanted to discuss a few things, which he was not prepared to hear, and so we ran out of time.
So, I have to redo the CCR5 and go again next month.

Cheers

Eric

[friskyguy]

hi eric,

good to hear that joining the small numbers of elite controllers are secondary controllers.

what about the issue of inflammation in both of these groups?

inflammation is the silent killer that wears down our body as the immune system  is continually being on a high state of alert to control the virus.

meds helps us dampen this immune system hyperactivity.

so one might be lucky to be an elite controller/secondary controller and not need meds but if that means that their body is continually in hyperactive mode to control the virus, not sure if that is a good thing for our bodies due to the negative complications to our bodies arising from inflammation?

anyway just throwing it out there.......

[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