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Treatment Failure
Oct 4, 2004

Hi Doctor Sherer,

I hope you are the resistance Guru. I'm experiencing treatment failure. I started treatment when diagnosed in May of 1997 with a 2.2 million VL and a CD4 of 153 and 13%(and presented with PCP). I started on AZT/3TC/Viracept. In six months the regimen failed due to a Viracept mutation (can't remember the codon) and the usual M184 seen on 3TC. I kept the AZT/3TC combo due to the increased suseptibility of AZT that comes with the M184 on 3TC. I added Saq400 and Nor400. Killed me!! After a couple of years of supression I got rid of the PIs and added Ziagen and then progressed to Trizivir. Yep, I fell into the Trizivir trap. About a year ago I started to blip a little and that's also when the news came out about Trizivir failures. I intensified the regimen by adding Viread. The regimen has now failed. I'm kicking myself for wasting a drug (Viread). Anyway, the bottom line is that I've used all of my nukes and am only left with NNRTIs and PIs. I remember the Viracept mutation I had only conferred resistance to Viracept. My last geno years ago showed a 215 on AZT, M184 on 3TC and that Viracept mutation. I'm basically left with one last chance at VL supression so I need to select the best (most effective) regimen. I know that I need to do a boosted PI regimen and I need to use the NNRTI. I've read that the NNRTI reduces the efficacy of the PIs and that some PIs actually interfer with each other. T-20 is not an option for me. My work schedule won't allow me to get those two injections in on time every day and also I've not yet tested to see if I have R5 or RX4 although I suspect it will be RX4 based on how sick I was when diagnosed. I'm going in tomorrow to give samples for geno and pheno although I understand it will only be a virtual pheno offered. Any ideas or suggestions. Obvously, salvage therapy is a mine field. I've also read some very discouraging studies that indicate that each regimen after initial failure last less time than the one before even when full supression is reached. Finally, I need to decide which NNRTI to use. I've read that Sustiva is more effective than Viramune and may develope resistance slower but that the 181 mutation on Viramune when combined with the M184 from 3TC and 215 from AZT damage the RC of the virus so much it doesn't know whether to scratch it's watch or wind it's butt. My current CD4 is 1050 and 34%. I would appreciate your thoughts. You can probably tell I'm well read on the issues but I'm always happy to have someone much more knowledgable give me more than their two cents.

Thanks Atlanta undecided

Response from Dr. Sherer

While you have given a very clear review of your treatment history, I offer the opinion below with the understanding that its very difficult to make suggestions regarding treatment options in patients who have failed multiple regimens for a long list of reasons. For example, though you told me about your last genotype, I would need to know ALL of the genotype results to help me asses the problem of 'archived' resistance, i.e. genotypic mutations not seen on the last genotype test that may still effect your next regimen. I urge you only to make the final decision with your physician, who may have access to information that I lack.

Your situation is far from bleak. You have high T cells and more than one option for the next regimen. Most importantly, you have a new class of drugs to use in the next regimen, i.e. the NNRTIs. All of the 'rescue' studies suggest that patients in whom at least one new class of drugs is used have better outcomes than those without a new class. Nonetheless, I agree with you that this next choice is an important one.

First, you may not have lost the effectiveness of tenofovir, based on this last genotype. It may should still be active...unless, as I noted above, in the past you have had the K65R mutation, or multiple TAMs.

You suggest that 3TC may be useful in spite of the M184V due to its effect on replication capacity. While physicians differ in their interpretation of this data, my own opinion is that there is evidence to support its continued use in a next regimen, though I would not go as far as including ZDV, nor choosing NVP over EFV, for its impact.

Secondly, a boosted PI such as lopinavir/r (Kaletra) in the higher dose (4 tabs twice daily) and efavirenz (Sustiva) in standard doses can be highly effective in people with multiple regimen failures. This is particularly true if you only have the D30N from Viracept, as you thought.

Thus one option - LPV/r + EFV + 3TC + TDF - has a good chance of success, if your last genotype is representative.

Finally, I agree with the need for a phenotype test in this setting to clarify the responsiveness of your virus to possible next line agents.

Talk to your doctor about these options and the results of the next resistance tests.

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