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Best strategy for multiresistant virus?
Jul 19, 1999

Dear Doc, I would like your best shot at the hardest question, treatment for a multiresistant virus after multiple viral breakthroughs and a treatment history starting with early AZT monotherapy. I'm anxious but not in panic, but I'd really like your advice before making the decision with my doctor. I was diagnosed in 1992; after years of AZT monotherapy (brief exposure to d4T ended because of crippling neuropathy,) I had a viral load over 1 million and negligible CD4 count when I started Crixivan/AZT/3TC in 1996. My viral load briefly dropped to "undetectable" (below 500) and CD4 count rose to 200. Viral load slowly rose, reaching 200,000 by 1998 but still at 200 on CD4. Switched in July 1998 to Norvir/Fortovase plus abacavir (briefly also DDI, but stopped DDI because neuropathy recurred severely.) The switch did not improve the labs: viral load reached 500,000 and CD4 dropped to 82 by March 1999, when I switched to amprenavir/adefovir/abacavir/sustiva, hoping the other new meds would make first use of non-nuke effective. My viral load after one month was 250,000 and CD4 back to 200, but viral load is now back to 500,000 and CD4 down to 90, so I assume the Sustiva gamble didn't pay off. I am waiting for genotype results but based on my history, we expect evidence of multiple resistance to all current meds (anything special to watch for on the genotype given this history). Long term, I assume I need to hope for new drugs without cross-resistance, and try to hold out until a new non-resistant combo is better proven; short term, should I just (1) stay on this combo, or (2) try to recycle a different combo (and which one?) or (3) try a "washout" period and then recycle (and which combo?) Thanks so much for your work on this site.

Response from Dr. Cohen

Well, thanks for your thanks. Here goes a very long answer to a critical issue.

Your genotype might help - though it is likely it will just show what your story suggests - which is that there are mutations associated with loss of effect from each of the meds, in each of the three available classes. But studies have shown that sometimes - despite knowing the history of meds used - a combination guided by a genotype could improve our success rate.

As you stated - the current goal has to be doing whatever can be done with the available meds to keep you stable - and healthy - while awaiting the next generation of meds - several of which are in active development. And as it turns out - your story also illustrated another point - which is that you don't always need full suppression to get a T cell boost - yours went from about 100 to 200 (albeit briefly) with just a small viral load reduction. And this observation is reported by many - and would be the foundation for our plan as to what we can accomplish for you now. Because while full suppression would last longer and create a more steady CD4 count rise - we do see some benefit in just partial control. But as you also showed - you can lose T cells when that control is lost again. So what are the options to regain "enough" control to get whatever T4 increase you can - or even just a stabilization of the T4 count to prevent more loss?

Well, we are still learning but here are some clues. There can be some benefit from "recycling" previously used antivirals - this has been reported from several groups. One exploration is whether stopping all of the meds would increase the benefits seen when starting some "new but recycled" combo. There was a report from a German group that suggested this possibility - but we don't know yet how well that works, how often it works and at what risk - like how often stopping meds to obtain this benefit causes some loss of T4 cells, and do they recover, as so on... It is something to consider - but for now we don't know if it helps. In these next months we should hear more about it.

Now - some groups are just trying multidrug "rescue" - meaning to reuse as many antivirals as you can tolerate to see what might happen. And there are some surprising reports - that perhaps 25% or so might actually get a viral load drop from such a combo. There are some approaches that are worth considering that might make this megacocktail more potent, however.

One is to get as high a drug level as you can from these meds. For example, ritonavir/norvir boosted the level of the saquinavir/fortovase you took - but my guess is that you used a dose of 400 mg twice a day of the fortovase. Some research is going on to see if an even higher dose of fortovase with the norvir might be even more effective. Similarly - norvir is being added to indinavir/Crixivan in the attempt to boost the blood level of the latter - and get a second chance from that med. And that principle could even be applied to the amprenavir you recently took - tho we know less about how to dose those two together. Delavirdine - one of the nonnucleosides - is also used to boost levels of the PI's. It is likely that you have high level resistance to the nonnuke class (a mutation at position 103) -- so that if you used a nonnuke at all - you could consider delavirdine, but whether you need it when using ritonavir to accomplish this boost in levels is unclear...

And there is some suggestion that protease inhibitors might not only slow HIV down, but that the resistant HIV that emerges despite these meds might somehow be less destructive to our immune cells - allowing a stalemate of the T4 count. We don't yet know the best way to do this - or even if the PI's are unique in creating this effect - but it is one place to go based on what we know so far.

Now - what about the nucleosides? Your neuropathy makes it sound like any of the three "d" drugs won't work for you - but there is some info that ddI with hydroxyurea gets a bit more potency from that antiviral medication. And you could consider a lower dose ddI when using hydroxyurea - like maybe 200-300 mg a day. While hydroxyurea can blunt the initial CD4 increase seen when suppressing HIV - there is some info to suggest that adding it after week 8-12 might allow that CD4 jump and then get the benefit from any added antiviral potency. And hydroxyurea might boost the benefit from other nucleosides like 3tc, abacavir, and even the adefovir. (We don't know the best dose of hydroxyurea to use - but it now comes in 200, 300, 400 and 500 mg capsules to give you some flexibility...) Finally, the 184 mutation seen when on 3TC also appears to boost adefovir (though this also should happen from the abacavir so the 3TC might not be needed in addition to the abacavir). Other "boosting" agents are under active exploration - but so far little info to guide us to know if they are active.

A genotype might give you some ideas of what not to take - but it doesn't tell us necessarily what meds have absolutely no chance of helping - just that you have some virus that is resistant to the meds. One of the theories of the multidrug approach is that while you have some HIV resistant to all these meds -- there might be a price that HIV pays by becoming resistant. And that price might result in loss of its ability to grow at full power. And the genotype won't tell us that. So some would just give a multidrug combo - (maybe guided by a geno if there are some meds that might be more active than others) - and see what happens. Not only to the viral load - but to the CD4 count. And even if there is minimal HIV control on your best/last combo of these meds - the T4 count might stabilize - long enough to stay well for a while.

While doing all this - don't forget OI prophylaxis as another way to stay well. I trust you are on PCP prophylaxis. You should certainly consider MAI prophylaxis. And some might even consider CMV prophylaxis at some CD4 count - tho this is more controversial...

And don't forget good healthy living either - since it might help, and won't hurt. Like healthy eating - avoiding foods that have a risk of bacteria/parasites (undercooked meat and fish for example). Like maybe antioxidant supplements - since some work suggests this has some theoretical support to help your body cope with this battle. And doing whatever you can to keep a positive mood and spirit - since in many studies - those that are able to fight off depression and stay optimistic - can live longer. And even if life isn't longer, you'd rather not be depressed while you're here in any case...

Hang in. Help is on the way. CC



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