Dec 30, 2003
Dr. Cohen, I'm a bit concerned. My AZT/3TC/Viramune regimen stopped working after only about six months. The doctor wants to change me to viread/kaletra/? My last t-cell count reading was 300. Would it be better to delay treatment for a while? I'm afraid of using up all my alternatives too quickly.
Response from Dr. Cohen
Well - first it helps to address what went wrong.
What happened that the AZT/3TC/Viramune stopped working after just 6 months? This combination has been studied over the years - and usually - certainly over half the time - results in viral suppression for well more than a year. So - what contributes to the other half of the time when it doesn't last? There are the obvious problems - like side effects leading to stopping - but you don't mention any. Then there are problems with erratic adherence - this can be a big factor to address - since if erratic adherence to this pretty simple combo led to its failure with viral escape -- we must address the adherence challenge before starting again - so we don't burn through more alternatives as you note.
What else could have led to such early failure? There can be pre-existing virus resistance in some who have HIV. Meaning even before you took any antivirals - the virus you acquired came from someone whose virus already had resistance to one or more of the meds you took - giving your virus a head start in "ignoring" this combination. This has been seen in anywhere from 5 to 25% percent of people who have never been treated - this varies in likelihood depending on many factors including how long you've had HIV infection. Getting a resistance test even at this point might have some useful info to see what to do next.
And so let's assume that you've addressed adherence issues if there were any, and that your HIV strain shows no resistance to protease inhibitors. What to do next?
Well - the first issue to address is this concept of treatment as "using up" alternatives. Our goal - and yours of course - is to keep you well for a long time. Which means - whenever we do treat - we do so in a way that does not burn thru options but keeps them going for months and years and even decades. And a highly suppressive regimen can do exactly that - keep going for years and years. And Kaletra plus nucleosides has shown in several studies to result in durable suppression. Especially if there is no pre-existing viral resistance to the protease inhibitor class. And IF the other factors are still in place - meaning you are able to adhere to the regimen - of several capsules twice a day (though there is some encouraging data to support that Kaletra is successful even just once a day). And ultimately - if your viral load goes to "undetectable" while on whatever combination you go on next -- since in general - when HIV goes to "undetectable" on a good regimen - it usually stays there.
So is kaletra/viread likely to be enough to do this? It might be. This is only two antivirals -- and our standard has been to use three antivirals. However - some work done in the past year has been encouraging to show that kaletra can be powerful enough to act - even alone - to drive the virus to undetectable in many who take it. And so adding even just one additional drug should increase the odds even more the combo should work. And adding a third drug to this might improve the odds of success that much more for you. Since your goal is to make this last - and in general - the more antivirals you take - the more potent the combo. Now - the alternative issue we always consider is that more antivirals can for some be more burdensome (more pills more side effects) and so for some - a more "compact" combo can ultimately be more successful rather than a standard triple combo. And perhaps that is part of the reason your clinician is suggesting a combo of just 2 meds?
In any case - you ask not just about what combo to go on but when to make the change? Now - or after waiting some more?
One issue we've learned is that while you are on a combination and your virus has started to become resistant to it - like viral load rebound on the AZT/3TC/Viramune combo --- the longer you stay on a 'nonsuppressive' combination, the more resistant HIV will become to these drugs. And this can cause trouble. Meaning - the more resistance that HIV acquires to the AZT - the more it can ignore other meds you've not yet taken. Such as Viread. And other meds like ziagen, videx and so on. So one way to 'run out' of new meds is by staying on a combination that is not working. Because then HIV will be better able to ignore the next combo - whenever it is you do start it. There are a few meds - like 3TC - that as far as we know don't have this problem - meaning the resistance pattern that HIV creates at the beginning is the only "trick" it needs - and so staying on it doesn't create more resistance. But that is pretty unique - with most of our meds - including AZT and viramune - the longer HIV can grow with these drugs around - the more it mutates and these mutations often undermine the success of the next combo we pick. Note that this is a problem just within a drug class - the rebound you had already should not alter the potency of the protease inhibitors or the fusion inhibitors (like Fuzeon) for example. But in general - there are reasons to change soon after the first regimen rebound to a combination that is predicted to reestablish viral suppression.
But with a CD4 count of 300 there is one other option that you imply - and that is to wait before starting a new combo. Since our guidelines remind us that it is optional for someone with this CD4 count to start on treatment - and so it might be optional to change to a new combo at this point as well. Which doesn't mean staying on the failing combo - but it can mean you might be able to take a break instead of changing to your new combo.
Now --- this is another big topic. Since for example we don't know how low your T4 counts were in the past - it is not possible to know if you should just switch to a new combo now - or if it might be OK to take a break in between. Those people with a history of low T4 counts in the past - that have improved as a result of treatment - often find that if they stop meds - the counts plummet back down off of them. So for these people we usually recommend just getting onto another effective combination. But if you have never had counts below, say 200, then another option is to take a break - be on no meds for a while - and postpone the timing of when you do go on your next combo. This approach is more controversial - but has been done for years in several studies.
Which approach is better?? Well - turns out we don't know for sure. As a result - these two approaches are being compared in one of the largest HIV studies ever attempted - comparing the approach of keeping HIV under control at all times - meaning just go on another potent combo now without a break - to a strategy of taking a break - and then restarting treating if your T4 counts get closer to about 250 cells. You can read more about that study - and perhaps even consider your own participation - on this SMART study web site.
Hope that helps to clarify your options - and what you can do next. In sum however - there is no reason to predict that all combinations will last just 6 months - you can do much much better than this. Hopefully you'll find that is true -- whenever it is you start that next combo, whatever it might be.
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