To Stop, or Not To Stop?
Jun 24, 2002
Thanks for all the great work you all do. It sure is appreciated by many.
I have been on a combination of D4T, 3TC and Neviripine since diagnosis 5 years ago. VL prior to start was 12,500 and CD4 was around 500. Have been undetectable VL ever since and latest CD4 was 660. Overall I am doing well. My GP has asked if I wanted to come off treatment for awhile and is leaving it up to me. I am very unsure about what to do. Could you give me your opinion? There seems to be good reasons for both staying on and coming off, but none that are compelling either way. I only have mild lipoatrophy at present and no other side-effects that I am aware of, so that is not a reason either.
I will appreciate having your words of wisdom.
Response from Dr. Cohen
Well, thanks for the thanks, and the opportunity to address this key issue. As there is much uncertainty to the answer. And much interest in it. It is perhaps not surprising your clinician is offering you the option - but I can imagine the dilemma in answering it - since as you mention, the meds are working well, HIV is controlled, and there are only a few side effects noted after all these years - so why stop? And if your MD doesn't have a recommendation - how would you be able to decide what to do given the ambiguity??
Let's start with the basic premise. IF HIV treatment were perfect, fewer of us would be doing research into what happens after stopping it. Since most of us agree that HIV is worth controlling each and every day if we can do it. Although it is fair to say that our bodies are amazing in how much we can repair the damage and control this virus. And there are many who live and do just fine with the low viral load you noted prior to starting meds -- without any evidence of harm from having HIV infection. For years. And in fact, we lack any proof that starting treatment with a CD4 count above 250 prolongs life as compared to waiting. We know we can delay until about 250 based on what we've been monitoring for the past several years. But this delay and discussion about when to treat and for how long is justified by two things - first is that we can delay and do perhaps just as well as compared to starting treatment at higher CD4 cell counts.
But, the other part of the equation is that treatment is not perfect. We do see toxicities and side effects in just the few years we've been at this. You mention one - lipodystrophy. Which is showing up in many of our combinations in many people. And there is still no antidote for this one. And unclear even how well it reverses once present. And for some it is not mild, and for others it is progressive and we've only been treating for a few years - and expect to be treating HIV for decades, not just a few years. And this, along with other potential drug side effects such as increases in cholesterol, blood sugar, and even concerns for thinning of the bones, has led to a sharp focus on not just better meds, but less time on them.
Now, it is fair to say that people do stop meds. Initially this was haphazard and done for all sorts of personal reasons. And it was noted that when people do stop, HIV usually comes roaring back after some time - if HIV is suppressed to well below 50 copies, it appears to take at least a week before it does come back over 50 copies. What's more, at least for some meds, we've also noted that after stopping, and after HIV rebound, some have CD4 count drops, while others don't. But, when people did restart, the meds would usually work again, and the CD4 cell counts would rise back up. This is where we were about 1 or 2 years ago - a series of observations about how much we can get away with stops and starts.
But the NIH and other international researchers took this to the next step - can we do these stops and starts in a way that preserves the effectiveness of the meds, not allowing resistance to occur, and either decrease the toxicity of the meds by giving people time off of them, or even stimulate some response by our immune system, like a vaccination, so that the viral load off meds would go lower and lower each time we stopped because of what happened when we stop?
That has been the focus of much research for the past few years. And each step has been informative. First - can we stop these meds? We can - but there is some concern for some meds - including both 3TC and nevirapine - that stopping combination based on them might result in resistance of HIV to them. This is because these meds stay in the body for several days even after you stop taking them - so that if HIV starts to regrow while there is still even a little drug left in the body - it may be that HIV can create resistance to them on the way back up. And this of course is worth avoiding - since a stop in the meds is likely to only be a temporary holiday - and you want the simple effective combo you were on to work again. So there is controversy about this issue - but some would stop a combo such as yours by stopping nevirapine (and perhaps 3TC) by first adding other meds for a week or so that are not as vulnerable as nevirapine or even 3tc, allowing those drugs to fade away while HIV is still controlled, and then stopping the combo.
Now, in studies of stopping for more than a week - there is some reason to hope that a few - perhaps 10% or so - of those who started treatment months or years after initial infection will respond well to these stops. Meaning that there are some who do seem to have lower viral load set points from stopping/restarting, and that each stop might stimulate something in the immune system so that perhaps the next time you stop your viral load is 5000, not 12,000. This appears to be true for only a few - but those with a viral load set point below 60 thousand appear to be the most likely to alter the set point. So that is one issue to consider. Second, the CD4 counts can drop if we stop HIV for a few weeks - and for some, these drops can fall back to your lowest ever count. For you this may not be a concern - but for someone who started treatment with a very low Cd4 count, there are observations that the counts can fall quickly, and so this is another part of the equation.
Now - there are a few kinds of interruptions. They fit into three main categories. First, are long stop approaches. This means stopping treatment for not just weeks but as long as possible until you "need" to restart based on Cd4 counts or symptoms. And this is the focus of the largest trial ever attempted in HIV - in which half of those who enroll will be randomized to a strategy of taking meds for as little time as possible based on stopping the meds, and only restarting when you need to, based on CD4 cell counts and symptoms. You can read more about this SMART study by clicking here.
Another approach are stops that are long enough to allow HIV to come back, but still brief - like two weeks or so. This is more for the intent to stimulate an immune response but not allow Cd4 cell counts to fall. There is much of this research going on for those with initial infection - acute seroconverters. Since the information about these approaches in this group are pretty interesting in teaching the immune system how to control HIV on its own. As far as I know there is less work going on with this approach right now in those with chronic infection - mainly because the info we have suggests it worked in only 10% as I mentioned above.
Finally there are brief interruptions - for less than a week. Here the goal is to just have a break from meds but short enough so that HIV does not come back. This is just to have a break from med toxicity. And that work is being done by the NIH group, as well as a few others in the US, including our group in Boston.
So what to do? We don't have a recommendation yet since we are still learning. How long a break do we need to reverse or prevent the side effects of these meds? Don't know. Would a week off meds, such as the 7 day off/7 day on trial be long enough to reverse some of the side effects seen? Or do we need much longer time off meds - as is being done in the SMART trial? Don't know yet. Is stopping a good idea at all? Don't even know that part - which is why staying on meds each day is the other comparison arm in the SMART trial. And to get answers research is underway - and it'll take a bit to get these answers for you.
A long answer to a very important issue. And still no answers. But options. About the only thing I would say is that I wouldn't just stop the combo you are on for more than a week - as the concern for creating resistance to these meds is there. Other than that, you have options to consider, and researchers ready to work with you to answer some of these very key concerns.
Hope that helps.
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