TAMS & Intensifying Treatment (Reposted from the old forums)

[gerry]

Topic Title TAMS & Intensifying Treatment

Date Posted: Thursday February 12, 2004 9:07 PM
Posted By: TexMan

I've seen a few references to TAMS. Based on the context of the discussion, it/they appear to be related to resistance issues. Could someone elaborate as to what are TAMS and how do they differ from typical mutations/resistance issues?

Also, when people decide to intensify their treatment (adding a 4th drug to their regimen) to get their viral load to undetectable, how long does this intensification lasts, (i.e., do you stay on the 4 drug regimen until you reach undetectable status or for an established period of time after you reach undetectable)?

Thanks,

Cliff


Date Posted: Friday February 13, 2004 4:26 PM
Posted By: PozDocinDC

Dear Cliff:

TAMs are thymidine analog mutations meaning mutations that affect the thymidine class of ARV drugs like AZT and d4T. There is a whole list of them. By the way mutations have a spelling meaning. The very common M184V/I mutation that affects Epivir (lamivudine, 3TC) means that at the 184th position on the reverse transcriptase codon (aka gene) the normally found amino acide methionine is replaced with the amino acid valine or isoluecine. In this fashion the virus is able to get around the anti-viral effect of the Epivir.

As to your second question, I would think that it would not be possible to state how long it would take to become undetectable. One would be wise to be regularly monitored to make certain things were headed in the right direction. I would suspect that if there was no response (meaning that the VL was headed down) after 12 weeks then it would probably mean that the 4th drug is not effective. However, if I were going to do an intensified protocol I would think about having a genotype/phenotype done before starting. There is no point taking an additional drug that would be known to be ineffective from square one. All you would be doing is exposing yourself to the side effects. In order to have the resistance testing done you have to have a viral load that is around 500 or so. If it's too low to begin with the test can't be done.

I would also think that if it took a 4th drug to get you undetectable then you would have to stay on it to stay undetectable.

However, it is known that in some cases there are synergistic effects between meds. This means that two (or more) drugs that the virus shows resistance to individually somehow act together to overcome the resistance. I don't believe that the resistance tests as they are currently done reveals this synergy.

Also, certain mutations that make one drug less effective make another more so. An example is the M184V/I mutation for Epivir, which makes the virus more sensitive to AZT. In fact some doctors have used the fact that a person's virus has this mutation to "rescue" the use of AZT. Manipulating mutations is tricky business though and should not thought of as anything routine.

Finally, at one point in the past, Dr. David Ho thought that mega-HAART (5 or more drugs) could eradicate HIV from the body. This has been shown not to work. The danger in trying this approach is that you could end up blowing the wad so to speak in that you could wind up with a multi-drug resistant strain and really be in trouble.

Like I wrote once before - and I thought anesthesiology was complicated!

Hope this helps.

Best regards,
John

-------------------------
Infected June 18, 2003. Became ill July 5, 2003. Severe sero-conversion illness. Initial diagnosis of AIDS (CD4 204 but 12% and HIV Wasting). Now PN + autonomic neuropathy. CD4 normal/undetectable since Nov 2003. On Sustiva/Truvada and too busy working on HIV/AIDS issues to worry about being HIV positive.


Date Posted: Saturday February 14, 2004 2:55 PM
Posted By: gerry

TAMs (thymidine analog mutations) are specific mutations selected for by the thymidine analogs AZT and d4T. As such, and by definition, not all nucleoside/nucleotide analogs cause the emergence of TAMs. However, the accumulation of TAMs does eventually affect the susceptibility of other nucleoside/nucleotide analogs. There are 6 TAMs that have been characterized and these are mutations that occur in positions 41, 67, 70, 210, 215, and 219 of the reverse transcriptase gene. (The common M184V mutation selected for by 3TC is not a TAM; the K65R mutation selected for by Viread, Ziagen and ddI is also not a TAM.)

How do TAMs develop? They develop by being on a nonsuppressive (i.e., failing) combo that contains AZT or d4T. The longer a person remains on a failing combo that contains AZT or d4T, the more TAMs tend to accumulate. While susceptibility to AZT (more than d4T) is the first to be affected by TAM mutations, as one accumulates more TAMs, other drugs in the nucleoside/nucleotide analog class become increasingly affected as well, even if the person has not taken these medications in the past. For instance, K70R, one of the most common TAM to develop initially, causes a 4-fold reduction in susceptibility to AZT, but the rest of the nukes are not appreciably affected. If one develops 4 or more TAMs, susceptibility to AZT drops by over 100 fold, to Ziagen by 5-7 fold, and to Viread and ddI by 2-5 fold. The TAM combination also affects susceptibility to other nukes. For instance, in the presence of a 41L/210W/215Y TAM pattern, Viread works very little against the virus. A 67/70/219 TAM pathway on the other hand has less impact on Viread susceptibility. The presence of M184V also affects drug susceptibility in the presence of TAMs. In general Ziagen and ddI susceptibility decreases further when M184V is present in addition to the TAMs, while susceptibility to Viread may increase somewhat.

Thus, if one develops persistently detectable viral load on a combo that contains AZT or d4T, this needs to be taken seriously, and an attempt to determine development of resistant genotypes, if possible, should be carried out in order to guide changes in treatment when necessary (which is really not any different in approach when one is on a regimen that does not contain AZT or d4T). Depending on the genotype, either a switch or an intensification might be in order. If someone already had documented multiple TAMs, the reliability of the NRTI class in the combo could become questionable. Therefore, in these situations and if the circumstances allow, and NRTIs are still planned to be used actively in the combo, a phenotype test may be helpful in order to determine which NRTI would still work against the virus (by testing for actual reductions in susceptibility).

One of the problems that may arise is when the viral load is persistently detectable but too low to run a reliable resistance test. In this situation, the decision to switch or intensify would be based more on assumptions (i.e., if resistance is involved, which is the most likely drug affected?) rather than actual test results.

[Cliff]

awww, and to think I had forgotten about good old TAMS and Pozdocdc.  I hope the latter is well and the former goes to hell.