Apr 14, 2004
I've got some resistance and need to pick a new regimen. RT: 67N 70R 184V 219Q 333E 103N 106I PI: 10I 30N 36I 71T 88D Drug history: AZT, d4T, AZT/3TC; at this point I added IDV, which reduced my VL from 300K to <400 over about a year; swapped NFV for IDV due to kidney stones and within a year VL was up to 30K; tried ddI/d4T/HU for a while, VL stayed under 10K; switched to EFV/ABC/adevofir/3TC/HU and was <40 within 4 months; almost immediately became detectable, but never more than a few hundred copies; went back to the ddI/d4T/HU to avoid accumulating resistance; quit that in 2002 due to incipient neuropathy.
So... I think that since the IDV suppressed my virus, with little or no help from the AZT/3TC, with which I had prior experience, I probably don't have much PI resistance other than the 30N mutation that shows up on my tests. This would account for the NFV failure. In a similar way, the fact that I was suppressed or had low viral loads on EFV/ABC/adefovir/3TC/HU even though I have 103N indicates that I probably don't have much nuke resistance other than the 67N/70R/219Q TAM pattern. Otherwise, what's suppressing the virus if the EFV is knocked out by the 103N?
This leads me to a combination that includes a PI, obviously, and maybe TDF. I'm thinking either LPV/r/TDF/AZT/3TC/T20 or LPV/r/SQV/T20. The AZT/3TC in the first possible regimen is there because my doctor believes it will prevent K65R and keep the TDF active.
Any thoughts or suggestions you have would be greatly appreciated
Response from Dr. Cohen
Thanks for the complete story you've not only presented the facts, and resistance patterns, you've included analyses of them. In fact, perhaps you'd like to take a shot at writing responses for this forum?
So - to start. I agree with the general conclusions given the K103N the next regimen must be based on a boosted PI(s). Or at least include one. So let's start with each class and explore the options.
You mention the use of LPV/r (Kaletra for those not into the abbreviations). It is fair to state that, at least in terms of efficacy, no other PI has yet surpassed the activity of LPV/r in people facing PI resistance. Some do come close however, and even match it in some patients, especially when there are as few mutations as reported here. For example, in the BMS study comparing LPV to boosted atazanavir (study 045), there was overall a similar response rate for these two drugs, and this was particularly reliable in those with few of the major PI mutations. And your reports contain only one from the list that resulted in comparatively less activity from atazanavir (that list includes mutations at position 10, 46, 54, 32, 82, 84, 90). So another validated approach would be to use atazanavir boosted. Similarly the use of fos-amprenavir (also boosted and taken twice a day, not once daily) has shown similar outcomes to LPV/r and the mutations that resulted in less activity from fos-APV are not in your listing. Indeed, yet another study comparing LPV/r to boosted saquinavir showed overall similar response rates, though there was less data presented in terms of comparing those with pre-existing resistance to be as confident for you. So you perhaps have at least three boosted PIs to consider here. And we're not even including indinavir and newer experimental options like tipranavir or the Tibotec PIs... There are important issues of course to consider in selecting from among these how many pills per day, how many times per day, possible side effects, food requirements, if you are taking acid reducing meds, etc but at least there is some choice based on predicted activity.
Now. One boosted PI? Or two? You mention a regimen of two boosted PIs LPV/r plus SQV. We and others have done several studies demonstrating the success and activity of this combination, and of all the dual boosted PI combinations, it is certainly the most studied, though other combinations are starting to get some attention, such as dual boosted atazanavir and saquinavir. Some PI combinations are interesting but we have no data -- such as LPV/r plus atazanavir. Dual PI combinations using fos-APV are tricky to use and so at least at this point could be reasonably avoided based on the difficulties seen in such combinations. But the basic point to make clear is that, despite all of the studies done on boosted PI combinations, we lack the key study to know if dual boosted PIs are more active than a single boosted PI. It may be the case or at least there may be circumstances when this may be true, such as with certain resistance profiles. But the use of two boosted PIs vs. one is still an open question, and one that is finally getting some attention in these next months from studies getting underway.
The role of T20? No doubt of all the drugs, that is the one with the most potency here given that there is no reason to suspect preexisting resistance. And in many studies, whenever we use a drug from a new class that "anchor" is often far more successful in reestablishing complete suppression than what is seen when we just utilize drugs that are in part hampered by cross-resistance. That does not mean you must use it but it does suggest that your about twice as likely on average to get that viral load to undetectable levels when using t20 than when avoiding it.
So since we've discussed T20 and at least one if not two boosted PIs do we need NRTIs? You mention one regimen above that avoids them, and another with several. From the T20 studies, one of the more interesting analyses done did show that three "active" drugs was about as successful as regimens containing more than three. So if we know that T20 is active, and from your mutation list we know that a boosted PI will be active, we may only need one more drug to get to the count of three. Whether that should just be one additional boosted PI, or whether is should be NRTIs is more a judgment than a science, since we lack good data to guide us here. However, if you do use NRTIs, then I agree that tenofovir should be reasonably active given these mutations. And to provide even more help in that class, the agents you list are reasonable additions. As you point out, the TAM mutation pathway you list has less impact on the activity of the NRTIs so even agents like ddI and abacavir would have residual activity here. It is less clear if you need the AZT to prevent the development of the K65R since the virus already has plenty of TAMs and so from what we've seen, there is just a small chance that HIV would add this pathway on at this point... but there are always exceptions.
So you are certainly on track with the data. And you list two viable and reasonably potent regimens that should do the job. And hopefully this review gives you additional options to consider, and confidence in where you are going
Let us know.
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