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To Blip Or Not To Blip
Jan 14, 2003

Hi Dr. Cohen, I have not had to pick that wonderful brain of yours in a long time as I've enjoyed almost three full years of viral supression. I went to my doctor today and found that when my VL results came back from my October visit the number had popped up from undetectable (below 50) to 449. It was quite a suprise today to say the least and don't get me started about not being called when the results came back in October. :) Such a shanda. My CD-4 remained stable at 1400 but of course there's usually a 30 day lag so we'll see. Anyway, I'm sure you won't remember me but I was diagnosed in May of 1997 with a 2.2 million VL and a CD-4 of 153 and presented with PCP. I began a regimen AZT/3TC/Nelfinavir upon after diagnosis. Six months later the regimen failed and I was geno-typed and found that I had developed resistance to Nelfinavir along with the standard 215 AZT and 184 3TC Mutations. I switched to AZT/3TC/Norvir/Fortavase and gained full supression within a week. I had to give up that regimen after 18 months because the side effects were too much. I then switched to a study with Ziagen and to Trizivir when it came out and the Ziagen study ended. I've been on Trizivir now for almost three years. I've had a couple of blips around 100 to 150 but that was related to a Remune study I was also doing while on the Trizivir. I've been off the remune now for almost two years. I can't explain any reason for this kind of blip. I had not been sick or had any type of vaccine and 449 is high for a blip on the VL radar. I gave blood for testing today and extra specimens for a geno-type test. I have also arranged a pro-virus analysis. I'm also going to call a couple of my contacts here at Emory but I value your opinion and knowledge. If, as expected the viral load comes back elevated I'd like to also get a pheno-type so I can have the best possible data to look at before making treatment decisions. Is a pheno-type FDA approved and commercially available yet? I'm also worried about the expense if such a test can only be obtained in a research type envrionment. Considering my treatment history I probably only have one good regimen left and I need to make the best possible choices. I can still use NNRTIs, Viread and most Protease since my Nelfinavir mutation was not cross resistant. I don't think I will have any "nuke" options left if my reading serves me right. Any suggestions. Wouldn't it be a hoot if it was just a "bad lab"? :)

Response from Dr. Cohen

Dear tBoNtB -

First - glad to hear that even with an initial VL of 2 million - things have gone great for these past years. To go from PCP and five years later to have a CD4 count of 1400 is just another remarkable statement about the progress we've made...

In any case - first is as you've said - to see if this is just a "blip". Looking up blip in the dictionary - the definition can be summarized as a temporary increase in the viral load followed by resuppression on the same regimen. Sadly - we cannot easily tell from the viral load itself if it is a blip or the beginning of viral rebound - although there are some generalizations we can make - the higher the blip, the less likely it's a blip... But 500 copies need not represent the beginning of a rebound. The test has its inaccuracies and there can be resuppression even with this value. So I agree - rechecking first makes sense.

So - if it is up - why? And the answer is contained in your history that you've so well presented here. And it comes down to the fact that you are on a combo for which your virus has some resistance already. The historic 184V mutation and 215 mutation do lead to resistance to not only AZT and 3TC, but also to some extent to the abacavir - the three components of Trizivir. It is actually reasonably impressive that you've had full (<50) suppression for so long on this combo given this history - since these mutations often lead to a predicted shorter success time on trizivir. I'd guess you didn't have the 215Y mutation - but perhaps some other one... given the success you had.

Now - these same mutations you had in the past would lead to some resistance to not only these three meds you are on -but also to the other NRTIs you've not yet taken -- but it comes down to matters of degrees. If there are only these two mutations - then tenfovir/viread might still have some potency left, as can ddI and d4T. But all of these are expected to be less potent than in the absence of these mutations - so perhaps at about "half strength" to make it simple.

What to do then? Well, if just a blip - or even continued low level rebound - like <1000 - one approach is to "intensify" - which means adding a single drug to reestablish suppression. For example - you might just add tenofovir here - something done in the studies that got tenofovir licensed for sale. At lower viral loads and with few mutations - you'd have a decent chance of getting to <50 with just this single addition. The same might be true of ddI - but there are far more data on the success of tenofovir when used in this way. This is reasonably simple to do - just one more pill - and even if it doesn't work to get you to <50 - it is very unlikely to result in the mutation that confers resistance to tenofovir - so is quite reasonably safe to try as well.

So the next question you ask is what next - if the viral load is higher and let's say intensification didn't work or you didn't want to chance it for some reason. As mentioned you do have the nonnukes - and most of the PI class given that the 30N mutation of nelfinavir is not expected to have much impact on the other PIs. (I'm guessing that's the mutation seen.) So - that fortunately leave plenty of options. Since we have great and impressive data when combining either a nonnuke plus one "boosted PI" together - or even just two "boosted" PIs. These could be used just on their own - or nucleosides such as tenofovir and abacavir could be added/continued for added potency. Our group here in Boston for example did a study where we used the combination of Kaletra (a boosted PI combo capsule) plus saquinavir - either as fortovase like you took in the past - or as invirase, which has fewer GI side effects - with 2 nukes - and this has had excellent results in terms of suppression rates. Others have seen similar high rates of success on this combo. Other combinations that have been tested include Sustiva plus Kaletra (plus 2 nukes) and this too has shown very impressive response rates even with more PI resistance than what you have. It is likely that most any boosted PI - either alone with a nonnuke - OR two boosted PIs - combined with a nonnuke or 2 nukes - would have an excellent chance of maintaining control - and you've got plenty of choices of which PIs boost, and which nonnuke and which nukes to add... Now I do note you've been on a dual PI combo in the past - norvir/fortovase - but we are much more likely to have tolerable boosted PI combos with the current options. So don't be alarmed about trying that again if need be... as we do better these days.

And the big big questions. When to switch - what viral load? Should you even consider - gasp - a treatment interruption before the next combo?

As for when to switch - there is plenty of controversy. The best argument to switch sooner rather than later is to preserve the potency in the nukes - so as to minimize acquiring even more nuke resistant virus by allowing HIV to grow while on trizivir. But some would note that if your viral load stays low and the cd4 counts are stable - you still have your PI/nonnuke combo waiting and can "sacrifice" the nukes by playing this card longer. You could also add the tenofovir - and see what happens even if you don't get full suppression... in any case - that's one debate...

The other is the STI debate. Given your history of a lower CD4 count and very high preRx viral load - there is a chance you'd have a high VL when stopping and even a drop in the counts. But not always. Some have been able to stop for a while - and do fine off meds. It is hard to predict precisely. If you did stop - you'd just need monitoring. And if you, like others, are unsure whether you "should" stop or switch to the next combo -- there is a study that is randomizing people to either stay on meds or stop - you can read more about it on the SMART web site. There are no sites as yet in Atlanta however...

Bottom line - plenty of comfort given your history to recheck and see what's up. Plenty of options and no reason to rush. Whether with geno - or pheno guidance - oh yeah by the way the latter is not officially FDA approved but clinicians can order it. It can be covered by some insurance but not all - if not covered it is about $1000 per test. There is another test called a virtual phenotype - a genotype that then looks up the pheno for that geno - and that costs just a bit more than just a geno - and is likely to be covered if geno itself is...

You're doing fine. You've got options to continue to do well. Let us know what happens.

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