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ACTG 5095 - keep Trizivir alone for VL suppressed patients ?
Oct 12, 2003

Dear Dr. Cohen,

I take the chance to heartly thank you all for the wonderful service you provide to us :-))

Issues similar to mine have been raised frequently in the past few months. However the answer to my specific issue is not clear to me yet. My virologic history is at the bottom of the question. In short, I switched to Trizivir alone 9 months ago, after a prolonged succesful viral suppression.

I have been reading about the potential risk of virologic failure under trizivir alone, and also that adding one drug (efavirenz) can reduce the risk of roughly a factor two at week 24, according to the large clinical trial ACTG5095. Although this trial was involving patients in settings completely different than mine (to mention one patients were treatment naive). I believe that adding sustiva to my regimen would bring a benefit. My doctor, however, doen't seem to agree, arguing that as long as I mantain viral suppression there is no need to modify the current regimen. Now, my question is obviously about what strategy shoud I follow, in your personal opinion. Moreover I would like to know (even though I know these are open questions):

1) Supposing I follow my doctor's perspective, what do I lose if I experience virologic failure in the near future ? I mean will it still be possible to have such a simple therapy, once that I become more or less resistant to the class of the NRTIs ?

2) Isn't it better to just add one pill now, gaining some time for new drugs to be available on the market, rather than having to run into a more complicate therapy ?

Thanks, in advance for your reply :-)

HISTORY:

Diagnosed as acute HIV+ in early 1997, CD4=480/ml VL=500.000/ml. Suddenly initiated Indinavir(400mg every 8 h)/ AZT/3TC (2X daily); VL<50 after three months, CD4 above 1000 within 6 months.

Continued this therapy until July 1999, VL constantly < 50, CD4 dropping slowly from 1400 to 800. July 1999 - December 2001: Off drugs (STI). VL up to 3,000 in 3 months, and up to 30,000 in December 2001. CD4 oscillating between 800-500, finally drop to 300 in only three months.

January 2002 - December 2002: Resume same therapy (with large side effects!). VL<50 after only 50 days (!) and kept like that. CD4 up to 600 by the end of 2002.

January 2003: switch to Trizivir alone, due mainly to evident signs of lipodystrophy (high blood lipids, and visible fat redistribution). VL kept always undetectable (thanks God), CD4 drop (strange!) to 400 in three months, and rebound up to 550 up till now.

Response from Dr. Cohen

Thanks for the very detailed history you provided. Perhaps you are also one of those people who are good at doing your taxes on time every year...

I will assume that your viral load has been <50 since Jan 03 when you have changed to Trizivir since you don't comment otherwise. Your history certainly provides a sense of all you've been thru, and how much the field of treatment has improved since you have gone from a successful regimen that was pretty difficult to do and an excess of side effects to something much simpler and fewer side effects. Again, you don't comment as to whether your visible lipodystrophy has improved while on Trizivir but I'll assume you are doing better and want to stay on this as at least a backbone.

So -- we've seen the recent data presented earlier this year to document that there is still a risk that this suppression may not be as durable as we want it to be. Specifically the study ACTG 5095 did show that even though some had achieved viral suppression to "below detection" even to below 50 copies, there was still some risk of seeing viral escape despite staying on Trizivir. Now, this is not unique to Trizivir. In this same study, patients were randomized either to Trizivir or to a regimen containing Sustiva. And there were also some who experienced viral rebound on Sustiva based combinations. There always are some in trials who will have rebound on every combination. But the rate of rebound for those on Sustiva was lower than seen on Trizivir suggesting that Sustiva plus either Combivir or Trizivir is a more potent combination of drugs and therefore could have a more durable response in terms of how long this degree of suppression will last. Now, to be precise for those who did get to <50 copies, the numbers who did experience rebound is low in all of these regimens. And the difference in rebound rates between Trizivir and the Sustiva-based combinations did not achieve the standard of statistical significance for those who did get to <50 on their regimen. Nevertheless, there was a strong trend suggesting that overall Trizivir may not give as durable a response compared to regimens based on Sustiva plus either 2 or 3 NRTIs (Combivir or Trizivir).

And so then, what to do now?

You have clearly done well for years on Trizivir alone. Do you need to "intensify" it to prevent virus escape given how long you have been successful on it? The short answer is maybe. Based on ACTG 5095 - we know that some will have escape on Trizivir, but at least in that trial most did not experience viral rebound at least in the few years of observation. And there clearly are people whose HIV will stay controlled on this combination for longer. The challenge however is that while it may stay suppressed on just Trizivir, there is some suggestion from this study that we might be able to do even better than Trizivir alone. Not that everyone needs to intensify but more that we just don't know how to predict who is going to rebound after suppression and some do and so people have differed in how they'd respond to your question. Some say that the rates of rebound are low enough so as to be comfortable with stating that you are one of the majority who, once suppressed after a prolonged period of time on just Trizivir, can do well for these next years on this regimen. But others look at the rate of rebound, and feel that acting now to prevent rebound is a better strategy than just monitoring. Indeed, the study team has redesigned their study and has recommended that everyone on Trizivir only add a fourth drug to "intensify" this and prevent any risk of failure.

So then if you do decide to intensify by adding something what to add? The ACTG study team is actually planning to study this adding either Sustiva or Viread (tenofovir). There clearly are more study results from Sustiva based combinations there are far few data that currently support the use of Viread when used in an all-nucleoside approach, and there is some controversy about this based on some of the studies already presented. Overall - there are just no data yet when Viread is added to Trizivir after suppression and there are a few studies evaluating this type of approach that are underway. Other options might also include adding a protease inhibitor for example, one could add atazanavir (boosted or unboosted) or Kaletra to the Trizivir. And, finally there is no reason you must maintain the Trizivir. For example, you can separate out the component of Trizivir, using say two of the three NRTIs in this combination tablet and add them to a third drug. So, for example, you could just take 3TC (Epivir), plus Ziagen two of the three antivirals in Trizivir - and add Sustiva, dropping the AZT component. And so on. Or even drop 2 of the 3 components - for example switch to tenofovir / Viread, plus 3TC, plus Sustiva - one of the best studied and most durable regimens we have. There are actually many options to do if you want to do something different.

In sum. If you do want to stay on this with continued regular monitoring you might be one of the luckier ones whose HIV stays controlled. And if there is rebound and if the rebound is caught soon after there are several pretty easy combinations that work after Trizivir rebound. But you might prefer to increase the odds now that HIV will stay controlled. And therefore you might want to either intensify now or change to a different triple. There are several that are easy to do and should be even more potent than Trizivir based on what we've learned about the power of Sustiva plus 2 NRTIs vs Trizivir. And the choice of what to do given all of these options is up to you

Hope that helps...



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