Inhibition of reverse transcriptase

[Andrew, Tel. +396-91093434]

On 20 May 1995 Patrick O'Neil <patrick at corona> wrote:

On 19 May 1995, Andrew, Tel. +396-91093434 wrote:

>> 2) Treatment with even safe and "test tube effective" compounds results
>> in the rapid appearance of mutant HIV strains which are resistant to the
>> drug.
>
>[...]
>> with a variety of different protease inhibitors. In all cases drug-resistant
>> strains of the virus eventually emerged which were not only resistant to the
>> original drug used on the patient but were also cross-resistant to the other
>> anti-protease drugs tested.
>> 
>>    They are now hoping that treatment with combinations of drugs having
>> different activities will be effective. I hope so.
>> 

>Theoretically, if enough different (largely unrelated by structure or 
>specific function) chemicals/drugs are developed with antiviral activity, 
>such that treatments with one constellation of agents can then be 
>replaced with another, etc, it should be effective.  
>
>Treatment with AZT and a specific protease inhibitor, for instance, will 
>invariably lead to selection of resistant strains.  If there are other 
>drugs available that are only loosely related to the previous treatments, 
>then hopefully, the mutant/resistant variant will not carry a resistance 
>to the next treatment constellation.

{snip}

   I agree with you that theoretically, this should be an effective approach
and ought to keep the virus "on the hop" as it were, with constantly changing
selection pressures preventing the buildup of large virion numbers and thus
improving the patient's chances, perhaps even eliminating the virus
completely. One problem is that I don't think there are enough drugs with
truly different modes of action available yet. We'll just have to keep on
spending those research dollars until there are... 

By the way, here are some references on HIV resistance to chain-terminating RT
inhibitors:

   Husson, R.N. et al., J. Pediatr. 123, 9-16 (1993)
   Richman, D.D. et al., J. AIDS 7, 135-138 (1994)
   Lin, P.-F. et al., J. Infect. Dis. 170, 1157-1164 (1994)

As well as the reference to the multiple-protease inhibitor resistance work:

   Condra, J.H. et al., Nature 374, 569-571 (6th April 1995) and the News and
Views article on p. 494 of the same issue, from which the above references
come.

   Andrew
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        Andrew Wallace, IRBM P. Angeletti, Pomezia, Italy.

               	Voice: +39-6-91093434
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 Discussion on phage display, combinatorial libraries, etc. - molreps at irbm.it
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