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HIV Drug ResistanceHIV Drug Resistance
          
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time to switch
Mar 29, 2008

Hello- I've been on boosted reyataz/ truvada/ ziagen for four years. This combo brought me from CD4 44 and VL in the millions, to CD4 of 450+. I've never been undetectable and VL hovers between 60 and 250. My doc finally agreed to switch meds. I'm leaning towards new generation drugs and have wanted to try etravirine but I've heard of liver toxicity? My doc wants to keep the Truvada and add raltegravir and Kaletra (instead of reyataz). I am of the opinion that I should add 3 active compounds (i.e. etravirine, raltegravir, darunavir) and dropping all nukes. As you know I've not had a large enough VL to do a genotype. Is there enough known about sequencing to choose between Kaletra and prezista? Thanks

Response from Dr. Sherer

It is likely that there is some important information in your case that I lack, so the suggestions below will be limited, and you should take them with you to you next doctor's visit and discuss them with him.

As to your question, we do know a fair amount about the resistance mutations needed to confer reduced susceptibility and full resistance to both Kaletra (LPV/r) and darunavir + ritonavir (DRV/RTV). In general, in patients with full susceptibility to both drugs, there is no advantage of DRV/RTV over LPV/r. Also in general, DRV is active against LPV/r-resistant virus. Hence, your doctor's suggestion makes sense in terms of optimally sequencing the remaining PIs by first using LPV/r, and, if and when necessary, using DRV/RTV as part of a subsequent regimen.

I would need to know ALL of your previous regimens, including those with PIs in them, and the responses, as well as results of past resistance tests (if any), and toxicities of the past regimens (if any), to be able to advise you on your current risk of PI mutations and the likely responsiveness of your virus to either LPV/r and DRV. Since you are not suggesting the use of a first line NNRTI like Sustiva (EFV), it may be that you have also failed a first line NNRTI regimen as well, which would also have implications for my advice to you regarding the NRTIs. You may also have had other regimens as well.

There is a cost to ongoing low level viremia, as you have had, particularly on a non-boosted PI like atazanavir. There is a good chance that you have accumulated some PI mutations during this time, starting with the I50L, although you have done well with a strong rise in your CD4 cell count. In one study, the average number of new PI mutations was in patients with low level viremia was 1 after 18 months.

Because it takes 6-8 primary PI mutations to develop resistance to LPV/r, I think that your doctor is correct to think that LPV/r will be active, though it may be less than fully active. The same guess is reasonable for DRV/RTV, and there are no additional reasons to choose DRV/RTV in your next regimen. On the contrary, I would suggest that you go along with your doctor's suggestion and use LPV/r in the next regimen, since DRV/RTV can salvage an LPV/r failure, and so it could be used in a third regimen (if your current regimen is your first).

It is also likely that you have accumulated some NRTI mutations. It is reasonable to think that you would benefit from the activity of 3TC or FTC in your next regimen, even if you have the M184V, because they will still contribute a 0.5 log decline in viral load, and they reduce the fitness of the virus significantly. Similarly, you are likely to retain responsiveness to TDF, and so the continued use of TVD is reasonable.

While I agree with you that 3 active drugs would be most desirable, I think that the regimen that your doctor is recommending is likely to meet that criteria while still allowing you a follow up salvage regimen. Raltegravir is well tolerated and highly potent, so it make sense to anchor your next regimen with that drug. Both LPV/r and TDF/FTC are likely to be active and make a positive contribution, so that your likelihood of achieving a VL < 50 copies/ml is likely to 70% or greater. You and your doctor could choose to increase those odds further by adding another drug such as enfuvirtide or etravirine.

This regimen would allow a follow up regimen in the event of failure that uses the remaining new drugs that you have yet to be exposed to, i.e. etravirine, maraviroc (or another entry inhibitor, if you are CCR5 tropic), DRV/RTV, and enfuvirtide.

As above, I suggest that you talk to your doctor about these suggestions.


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