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Hoping that there are still options...
Aug 27, 2001

First I would like to thank Dr. Cohen and all of the Doctors and technicians and everyone involved with this site. It truly is a Godsend! And it is done with compassion and humor and most importantly, hope. If we ever have a cure, it will surely come from the hard work and dedication of people such as yourselves.

My partner tested positive in late 1992 with a cd4 count of 800. (Of course no viral load test). In late 1993, he started AZT (I think as monotherapy then). Then a year or so later I remember DDC, DDI, Hydroxyurea. When the protease inhibitors became available, he was given Crixivan, Epivir & Zerit.(I think that was it). Anyway, about 4 years ago he was switched to Viracept, Sustiva, Ziagen & Zerit. I don't recall the Doctor ever saying how high his viral load was but in the first month or so it dropped to undetectable (under 50). It has remained there until the last few months when it started to rise. Of course we were hoping it was a blip. Adherance has never been an issue, with both of us watching, he has never missed a dose. His viral load is now around 5000 and his CD4 is 550 or so. I would imagine that this is time for a resistance test and according to everything I have read here, it would seem that Zerit might be one of the "guilty" components. He is very healthy, never sick. As I said, I don't know how high his viral load ever was but lowest CD4 was 200. Of course we are concerned and he will see his Doctor in 2 weeks. Do you think that given the medications taken so far that they may devise a combination that may drive that viral load back down? I am assuming that some of those meds that he took in the past may still hold some efficacy. He is not ready for it to be over and is hoping you may have some encouraging word til he sees his Doctor. Thank you again for your time and consideration!

James L

Response from Dr. Cohen

Yes, there are some options and all is not lost.

And yes a resistance test might help. And yes some meds from the past may be useful still.

And since there is much to consider - here comes a long answer...

Here are the issues. In sum, the problem was most likely the damage done from prior resistance leading to cross resistance. In other words, since HIV was initially treated with meds that were the best we had at the time but not as effective as we use now, there was resistance that HIV developed to AZT, ddC, and DDI. And so then the next combo which relied to zerit/d4T, epivir/3TC, and indinavir was less that fully potent, since the zerit, and possibly the epivir were already partially impaired, or less than fully potent given the cross resistance that HIV has from the first few nucleosides (azt, ddC, ddI) to the newer ones (d4T, 3TC, abacavir/ziagen). Now, you don't mention why the switch was made from that combo to the next one using Sustiva/Viracept and so on. But if there was some Crixivan/indinavir resistance at that time, this often leads to less potency in the Viracept/nelfinavir. And so while there was initial activity, HIV mutations already gave it an advantage to some day come back as it has. Now, it is a bit surprising that a combo that gets you to below 50 copies and stays there for four years doesn't stay there still. Since most of the time it does stay there. And if adherence is not the issue, we are learning about a few other factors. One is the issue of drug levels that can fluctuate for reasons other than missing doses. Like drug interactions with other medications, even supplements and herbs. Or perhaps some cellular "pumps" which can in time "learn" how to pump these meds out of the cell, allowing HIV to restart growing - remember that our cells don't necessarily recognize antivirals as welcome guests - so we have systems to pump these drugs out of cells. Finally, while not likely applicable here, there are concerns that reexposure to other resistant strains from other people, that have resistance to some of your meds, can take hold and start growing.

So - now what. Well, it is likely that Sustiva is no longer working. Meaning that while it is potent when HIV is sensitive to it, when HIV becomes resistant to it - as it does when it grows while on this med - it generally loses essentially all of its activity. Now since you don't know for sure that pretreatment viral load, it is only a guess that the level of 5000 is still showing us partial activity, but that is a reasonable guess here. So this partial activity is being maintained by the zerit, ziagen, and viracept - and it is here that a resistance test can help, as it can demonstrate what HIV has done to partially ignore these, as well as others from the past... as it has several ways to do this - which may alter what you do next.

Now - there is controversy about WHEN to make the next move. Since a viral load of just 5 thousand can be associated with a stable CD4 count for years. The problem is if you stay on these, then HIV will likely just make more and more mutations to these meds, which leads to less and less activity from not only these meds, but from the others not yet used. And this is a tough dilemma to face. With no easy answer - just judgement.

What could you switch to, when that day arises? Well the biggest advances include the use of "boosted" protease inhibitors - boosted since we increase the blood level of the standard ones, usually using a low dose of ritonavir/norvir as the booster. And this increases the potency of almost all of the remaining PIs - including Crixivan and others not yet used like saquinavir, amprenavir, or lopinavir - which is sold with the ritonavir already mixed together as Kaletra. And we have learned that even if there is partial PI resistance, these boosted PIs can often overcome the partial loss of activity. And some clinicians use not just one but two "boosted" PIs as one way to reestablish control here.

Another new medication expected to be approved in the US soon is called tenofovir - which on average can give about a 0.6 log drop in viral load after this pattern of antiviral use. And is pretty easy to use - just one tab a day.

And not all meds from the past are gone from consideration - abacavir/ziagen for example can retain some activity even after some resistance, as can some of the others - and this can often be evaluated on a resistance test result. If someone knows how to read one...

And finally - how to change. So, one option is to hold the course. One is to just change to the next combo. But one more option is to just stop meds now - and change after a while. Since it may be that the longer we wait off meds - the more likely the next combo can work. Maybe. We in Boston and others in the US are doing large trials trials randomizing people to two approaches: change now or stop and then change. The stop period may help in a few ways, but should only be done with careful monitoring. Since a few can have a worse time when stopping. But not all - some have done well. And depending on what happens to the viral load and CD4 count off meds - some can do well off antivirals for a period of time. Which may be a desirable break - or not. But it is the subject of intensive research since there are reasons to do so.

Much to consider. There is much at stake - since while there are options, there is perhaps one more solid hit at the ball. But not too many others in the near future if this doesn't work out - so it is important to work with a clinician who is focussed on HIV treatment to give every advantage in considering the next step.

Hope that helps.



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