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Agenerase Dose w/ Delavirdine & Abacavir
May 15, 2001

Dear Dr. Cohen,

Having been on nearly every drug available for the past 11 of my 42 years, my most recent geno and phenotypes show that my least resistance is to the drug combo of delavirdine/agenerase/abacavir. I had been on AMP/ABV/EFV since my 2nd bout of pancreatitis in Sept 1999. However, the tests showed a very high resistance to Sustiva, and not so much to DLV. I cannot tolerate Norvir at all, due to the pancreatitis issue. My question is what the proper or estimated dosage should be for the AMP when it's being boosted by DLV instead of Norvir. There is next to nothing written, except for the report I saw that you authored here on The XIII International AIDS Conference Posters 3296 and 3305.

It has been 10 days now since I switched EFV to DLV and we changed the AMP from the 1,200 mg t.i.d. (extra dose when using EFV) to the standard 1,200 mg b.i.d. of AMP. I've had no rash, but without a doubt, the GI effects of the AMP have escalated, i.e. nausea, abdominal pain, and an unusual amount of very foul gas. It was symptoms like that that preceded my pancreatitis episodes, so you can see my fear. After reading the above mentioned report that DLV seems to give AMP the same boost as 100 mg of Norvir ("in children"), I must wonder if only 600 to 750 mg bid of AMP is enough when combining with DLV, like recommended w/Norvir. I've also read in several places, including package inserts, that the AUC of AMP increases 27-29 when using abacavir with it.

Anyway, last night (4/17) I dropped my AMP dosage from 1,200 to 900 mg to see if the side effects decrease. Can I safely go even lower with the AMP dose?

My pheno/geno also shows partial resistance to AMP, so I need all I can tolerate (but it's not nearly as highly resistant as the other PIs). I hope I have made myself clear and would welcome any comment you may have about this. I have a long and complicated history, and I'll ask you to trust me and my doctor that this is my last available salvage therapy. My CD4 is 223 and VL is 134,000 -- even though I show mega-resistance on paper, my numbers have pretty much been going in the right directions for the past 18 months now, esp the CD4, which for me, is the bottom line. When I've had drug holidays due to pancreatitis, the CD4 drops in half, so I'm still getting a significant benefit from these meds w/out a low VL.

I'd also like to get into Tenofovir, but 223 CD4 disqualifies me for expanded access.

Thank you so much! Paul

Response from Dr. Cohen

Well, Paul, Congrats on first doing your homework. Here are a few thoughts to add.

First - the tenofovir expanded access recently expanded - now anyone with any CD4/viral load may be eligible - so this is again an option. Whether you should play this card now or not is a difficult decision but based on what you've written it may be a reasonable addition as even with significant resistance with other nucleosides, tenofovir on average contributed about a 0.7 log drop. And combines easily with the other meds.

As for dosing amprenavir - other than the poster you summarized I have not seen much done. And we are entering, although in the US pretty gradually, an era where testing the drug level in you will be an option. Since the reason you are wondering about what dose to take is that we don't have levels to make this much less complex. If on 900 mg ampren your level is low, you would try taking more, and vice versa, less if you were too high.

However, one of the lingering issues is knowing what the target blood level should be in your case. Since the recent lesson of "boosting" levels of a PI such as amprenavir with another antiviral such as ritonavir or delavirdine is that there is a level of drug predicted to be active given the degree of resistance that HIV has created by exposure to other agents. And if you can safely get the level up there - you may be able to regain at least better control. And tests such as either a virtual phenotype or real phenotype may help guide what that level should be. This is done by taking the blood level of the drug which is needed to control a fully susceptible strain of HIV to the drug, and then multiplying this level by the degree of resistance measured on these tests to get the new target. For example, if we need 1 mg/ml for a wild strain, and you have 10 fold resistance, you would need a dose that got you up to 10 x 1mg /ml = 10 mg/ml in the blood. Maybe. This is pretty new stuff and we have still much to learn, but this is the basic idea.

But - we are not quite in the era of drug level testing. So in the meantime, it is reasonable to do what you are doing - just to take the maximal tolerable dose of delav plus ampren and see what happens. Can you go lower than where you are now? Well, we just don't know for sure - but if the GI upset is not tolerable, then it must be lowered. But keep in mind that going back to three times a day dosing may decrease some of the GI upset - since taking a large dose at one time is sometimes harder than taking the same amount spread out over a few dosing intervals.

Now, there probably won't be much antiviral effect from the delavirdine - as the phenotypes for the nonnukes may not be as helpful as the genotypes and the predicted cross resistance. Although there is one mutation in the nonnukes that may help to preserve the delavirdine if that is what you are dealing with. But even if it is not active as a drug, it may be a good booster to use. When there is >7 fold abacavir resistance, then that drug is not contributing much either - so I gather your test showed better than this.

What else to do? In general, you are likely trying to create a regimen that will slow HIV down by creating a barrier to even more resistance despite ongoing replication - you may not get back to <50 copies with the available tools. If so, adding a second PI, such as saquinavir, may have some merit here as there are some data to suggest that two boosted PIs may be more potent than one. Again, the same dose uncertainties exist, but it is an option. You might pick another PI based on the lower fold resistance and your history of tolerability. Keep in mind however that we cannot yet rank order these PIs by fold resistance since the missing piece is how well do they boost - which drugs are more readily boosted? And we are still learning. And are especially lacking info as you have noted about how well delavirdine will boost these others.

Last point. You've noted the CD4 "disconnect" - meaning that despite HIV RNA growing, the CD4 counts can continue to improve. This is a well described outcome and appears to be linked to the degree of partial suppression you can achieve. Even without full suppression, these meds can work. So it is not surprising you have a better CD4 count. Hopefully this trajectory will last until the next wave of meds arrive - and you'll be able to reestablish full control at some point.

Hope that helps. Let us know what happened.

combivir/stocrin switch
<6mos. exposure, started/stopped Trizivir, next??

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