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Treatment Options after Genotype
Jun 21, 1999

Hi Dr. Cohen: I'd be lost without this website. Thanks to you and your colleagues for your time. I'm HIV+ at least 10yrs. Started AZT monotherapy in '90, added DDC in '93, switched DDC for 3TC in '96, and added Viracept in '97. (I know this is all taboo now, but my HIV doc was following current procedures way back then.) Since 1994, VL has bounced from undetectable to a max of 1500...it was undetectable by ultrasensative test for a few months after starting Viracept. CD4% was in 40's until mid-'96, in 30's until end of '98, and is now 25. I stopped combo of AZT/3TC/Viracept about 6 weeks ago when VL was 1000 and CD4% 31. This week VL is 5000, CD4% 25. VL and CD4 have consistently been in this range since I stopped antivirals. Not currently on any antivirals. My plan is to closely monitor my VL and CD4 and go back on medications if the VL approaches 10,000.

I was very proud of my ability to understand my lab reports until along comes my first genotype, which was taken one week after I stopped drugs. Reported mutations: RT gene: 62V, 184V, 215Y, 214F. PI gene: 30N, 63P, 77I, 88D. I have a Dr appt after July 4th and I want to be as informed as I can be. At my last appt (before the genotype was back) my Dr suggested that I start a combo of DDI, D4T, Sustiva and maybe HU. A copule of questions, please:

(1) What is your interpretation of my genotype mutations. Do I have any viable drug combinations left? (2) Would the combo that my HIV doc suggested be prudent? and (3) What would be your recommendation for a new combo given my drug history and genotype?

Thanks so much for your time. I hope that you realize what a service this site provides to the HIV+ community. Dave.

Response from Dr. Cohen

Thanks for your comments, dave. I do it because I hear from you and others on what a service it is...

An important question. A long answer.

Your genotype confirms your past Rx use, and yes, is a reminder of how much we've learned in a short period of time of why we shouldn't just add a drug...

First - with a good CD4 count and low viral load - like around 5K - starting meds can be optional for you. And as new meds are in development - there is some good reason to wait while off of them as long as it is safe for you to do so - and a low viral load means it is relatively safe as there will be only a slow loss of CD4 cells with a viral load below 10K. In fact, countries differ as to how high the viral load should be before suggesting meds, and 10K is the lower end of this suggestion. You mention your cd4 percent but not count - that value is of course the other reason to restart - if that count/percent get too low... your percents are usually associated with a count over 400 cells - so you are in that category where most agree it is OK to monitor and start if it drops to some lower number. How low to let it go before restarting is again another controversy...

You have a genotype which confirms your past med use. The 184V is associated with 3TC resistance. The 215 is AZT, and maybe a loss of benefit from d4T as well tho this is less clear. I think 214 is similar to 215 in impact, and I am not familiar with the 62, tho in that region we see mutations associated with ddC. On the PI end - you have the nelfinavir pattern - a 30 mutation with some 'secondary' mutations. And it is these secondary mutations that lead us to want to stop antivirals once we see rebound of viral load - since the longer you stay on a combo - the more we see new secondary mutations show up. And these secondary mutations can increase the risk for other meds in this same med category to not work either. So this leads to the approach of interrupting meds at the time of a rebound to avoid more of these other mutations. And the choices then are to switch to some newer combo to shut off viral replication, versus wait off meds if that is reasonable, as you have done. There is a third option - waiting on meds with a low viral load - and at low viral load values there is the possible 'stalemate' with only a slow development of newer mutations - but for someone like you this can be a bit perilous - since your next combo in part depends on avoiding these other mutations. And you've now got reasonably well defined options.

For others who don't have access to genotypes - there are studies ongoing to do them to see what happens when we use them. In addition, there is a study going on (in Boston and elsewhere) testing the use of a phenotype - in addition to genotype - to see how well it helps us at the time of a switch.

What to do? Well - one factor that makes me optimistic is your lower viral load off meds - that suggests that a reasonable combo has a good chance of working well for you. The meds to choose from include, in the nukes - d4T and ddI as you mentioned, and also abacavir, the newest one. Your resistance pattern makes it a bit less likely for the d4T and abacavir to fully work for you - but both could still have some potency in them. And the hydroxyurea is one of the best ways we know to increase the potency from this class of meds - especially from the ddI - to overcome the impact of these mutations. We in Boston are involved in a study being done in cities in three countries to use exactly the combo you've mentioned for people in this circumstance - you might want to see if there is a study site near you.

On the PI side - we have learned from several studies that the dual combo of ritonavir and saquinavir are successful against the nelf resistant strain. Other PI's or combos could also be successful as well - tho are less well studied here - like ritonavir plus indinavir, or amprenavir.

And there are experimental PI options - like ABT 378 - that should work well here - there is another study going on (again in Boston and elsewhere) for people in this situation that you may want to investigate - as it offers a chance to use this newer PI in combination with nevirapine and nukes, versus any of the available PI's with nevirapine and nukes. Either way it could work, and 378 is a well tolerated and potent PI to know about.

As expected you don't show any nonnuke resistance - and that class can be the key anchor to your next combo. The question is do you have enough meds available to play this card now, versus hold it until later. Based on what you have mentioned - you could play this card now (you mentioned sustiva) with reasonable confidence of success - as you mentioned with just the d4T, ddI and hydroxyurea. You can consider abacavir, either initially, or as an intensification. You could consider the PI's as well, either initially or as intensification. You could hit now, or wait - since meds like 378 are coming and should be helpful for those like you.

There are several options, and we don't know the best one to choose since each option has a pro and a con... but with carefully monitoring you should be able to get an excellent response from this next combo.

Hope that clarifies. Let us know what happens. CC



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