When to re-start meds? Need resistance test?
Apr 1, 2001
Dear Dr. Cohen, I had to stop all my meds due to Lactic Acidosis (was 5.8). I was on a very successful combination with an undectable viral load for over two years. Amazingly, after one month on no meds, I have just tested undetectable again! I'm hoping you could please answer several questions for me - 1. Assuming normal lactate levels, is there any benefit to continuing this treatment interruption (now that we've started one anyway), considering that I was undetectable when it started? 2. How long would you wait to re-start a HAART combo? Is it based on a set period of time? or would you wait for a certain viral load level or CD4 count? (I was up to 465 when meds were stopped). 3. I really liked the combination I was on (Sustiva, ddI, hydroxyurea, 3TC). It worked excellent from a virologic standpoint. Will I have to go to a new combination now? 4. I've never had any Geno or Pheno resistance testing done. Should this be done prior to starting back on meds? Thanks!
Response from Dr. Cohen
Well, several important questions that allow clarification of some ongoing confusing issues.
First - there is little controversy about the need to stop with that level of lactate - assuming there were also some symptoms noted that prompted ordering it in the first place. There is more ambiguity about what to do with a random lactate of even that high - but let's assume that it was clearly time to stop with that lactate.
What causes this elevated lactate? We understand this to be an infrequent but important side effect from our nucleoside antivirals. You were on two of them - ddI and 3TC. And you were on hydroxyurea - which increases the relative intracellular concentration of the ddI. So - it is reasonable to guess that this lactate increase was more likely linked to your use of hydroxyurea - and may or may recur if you started these same meds without the hydroxyurea. Since I have no information as to how you chose that regimen - and whether the HU is considered essential to boost the ddI - these are decisions you'll need to review with whoever created this regimen for you initially. But it is fair to say that unless you have some resistance to the nucleosides - the use of ddI and 3TC with Sustiva has been very successful, especially for those whose CD4 count is over 200. It is also very simple as all three meds can be taken just once a day based on some recent study info.
And there is no suggestion of any resistance developing in you as a result of this stop - HIV has not regrown and these meds are out of your system. So the only question is how essential the hydroxyurea was in increasing the potency from the ddI - assuming that if you do restart - you should at minimum not restart this medication.
Now - how long to stay off? It is not a surprise to hear that your viral load is still undetectable (below 50 copies?) after a month - this is noted in others as well. How long before your viral load rebound is a bit unpredictable - although if you had a viral load high enough to suggest it was time to treat - odds are good that one of these weeks in the near future - your viral load will be detectable again. But there are some, for reasons still unclear, whose rebound is delayed, and when it happens, may be a gradual rebound. But most do increase and then the question is to what level. While most would rebound back to the pretreatment set point - some do not go back to that point - but at the current time it is unpredictable who will be this fortunate. But, since there are some whose viral load patterns can result in some surprises - there is some intrigue in seeing what will happen for you. Which means waiting and monitoring.
Now - the most common pattern observed is that at some point in the next few weeks - you'll see a sharp return of the viral load which will, soon after, hit your pretreatment set point. And there is also a risk that your CD4 count will drop towards the level it was before you started treatment. This is one of the risks of these interruptions - the CD4 loss. Which does recover with restarts almost always, but there are reports of some in whom the CD4 recovery was gradual.
So - when to restart? There are three approaches, each with their advocates.
First - restart before the viral load returns, after the side effects have resolved. Which means now. This prevents any loss of CD4 for you, and maintains the benefits of viral suppression. Assuming you can define a combo that works which does not lead to recurrent lactic acidosis - this is probably the most common approach taken at the current time.
Two - wait until you see some amount of virus - enough to act like a "vaccination" to your immune system. This is being explored in several studies, as it currently appears that a minority of those who started treatment years after infection might benefit from this vaccination type approach. When to restart - after what level of virus - is one of the many uncertainties being researched for now.
Third - just take a break and restart based on the CD4 count. Since you have defined a combo that did work - and hopefully can define another that will work equally well without this toxicity - you should be able to resuppress HIV whenever you do restart. And so you could wait a while, since in general people stay healthy with fewer CD4 cells than you now have. Most everyone agrees that the start point is over 200 - but there is controversy about how high above this count that clinicians suggest treatment. So you could wait a while off meds - monitoring the CD4 count - and restart at some point when the CD4 count gets back to some trigger point.
Which of these three - is a big decision for you and your provider. And is a focus of such tremendous uncertainty that the federal government (NIH) in the US is considering support of a study that will randomize hundreds if not thousands to the first versus third strategy.
Oh yeah - resistance testing. It turns out that, in the absence of medication - it is unlikely you will detect any underlying medication resistance. The "wild type" HIV strain often overgrows any resistant strains which may also be present - so our test often misses seeing any resistance when someone is off meds. I am not clear on your history nor how likely you are to have resistance - but this is one shortcoming of these tests at the current time.
One last point - there are anecdotes describing that riboflavin - a B vitamin - may be helpful in decreasing the odds of a recurrence of the lactic acidosis.
Hope that helps. CC
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