Meds, Mind, Body & Benefits > Questions About Treatment & Side Effects

New Regimen-Class based solely on entry inhibitors possible?

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Customer:

http://www.aidsmap.com/en/docs/BA7BF47D-D8FF-4CC8-8B8F-4FBA8775C32C.asp

In vitro research has suggested that T-20 and other entry inhibitors may produce a synergistic antiviral effect, although this is yet to be demonstrated in clinical studies (Nagashima 2001; Tremblay 2001).

Furthermore, HIV that is resistant to T-20 is less fit that wild type virus, suggesting that people may continue to get clinical benefit from T-20 even after the development of resistance (Reeves 2005).


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There will soon be a few new entry inhibitors on the market. Combining 3 or so entry inhibitors each having a diffirent target (gp41, CCR5..) could potentially form (an independent) regimen class.

The entry inhibitors do not mess with protein encoding and production process inside the cell, and therefore the side effects are milder, if any.




Customer:

http://cmbi.bjmu.edu.cn/cmbidata/SARS/pdf/86.pdf


...These findings suggest that there may be good prospects for potent combinations of entry
inhibitors,just as HIV-1 protease inhibitors or reverse-transcriptase inhibitors are administered together today.

Tremblay C,Kollman C,Giguel F,ChouTC,Hirsch MS.Strong in vitro synergy observed between the fusion inhibitor T-20 and a CXCR4 blocker,AMD3100.cell fusion.J Infect Dis 2001;183:1121-5.

Customer:
http://www.aidsmap.com/en/docs/41FC5E2A-7CCC-482E-AC20-137D77F93229.asp

Researchers from Progenics have tested a combination of T-20, PRO 542 and PRO 140 individually and in combination against test tube samples of HIV to see whether the drugs could boost each otherís effects (synergy). T-20 (Fuzeon) and PRO 542 were found to be synergistic, to such an extent that when used together, concentrations of the drugs required to inhibit HIV replication could be reduced 30-fold in comparison with the concentrations required when used individually.  

http://jac.oxfordjournals.org/cgi/content/full/54/2/333

Combining bicyclams (CXCR4 antagonists) with fusion blockers such as T-20 is also a developing area of research. Such a combination would target several sites of fusion, potentially creating a potent anti-HIV treatment. Strong synergy between AMD3100 and T-20 was observed in test-tube studies, but AMD3100 has now been discontinued due to cardiac toxicity.

A further strength of enfuvirtide and other entry inhibitors lies in their potential inter-class synergy.27,34,36,39 Enfuvirtide is the fourth drug in treatment options available to antiretroviral-experienced patients, including HAART regimens using NRTIs, NNRTIs and PIs. The development of drugs with different extracellular targets in the future may even lead to the possibility of potent extracellular regimens (E-HAART).53 Synergy has already been seen with enfuvirtide and the other entry inhibitors (i.e. AMD3100 and SCH-C)34,39 and in the future there may be the potential for E-HAART regimens.




Customer:
How i understand the synergetic effect: If the probability of HIV developing a resistant mutant to drug A is 0.05% during one day of drug usage, then the probability of HIV developing a resistant mutant to combination regimen containing three drugs A, B, C (each attacking different protein), is 0.05% * 0.05% *  0.05% = 0.00000001250 %. All mutatations need to occur simultaneously, to generate a surviving species, which reduces the probability exponentially.

As it was mentioned in the texts above, even if mutation occurs, the HIV-species is less fit, not able to multiply rapidly. This also applies to E-HAART (extra-cellular HAART): if a super mutation would take place, the strain that would be able to survive in E-HAART environment would be seriously disabled/handicapped.

HIVworker:
All good stuff customer. What do they say of the potential tropic switch from CCR5 to CXCR4. I know there have been some studies on this and they did see it, but the million dollar question is does this tropic switch speed the progression to AIDS? I have heard second hand of the tropic switch from a conference, but not about AIDS. Any news?

R

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