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  11th Intl. HIV Drug Resistance Workshop
July 2-5, 2002
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Reported by Jules Levin
  Hello to everybody from the annual HIV Drug Resistance Workshop which this year is in Seville, Spain. This meeting is taking place just prior to the International AIDS Conference which takes place every two years, and this year is in Barcelona, Spain immediately following this Resistance Wksp.
The first session on new drugs for HIV was interesting and exciting. At the annual HIV Retrovirus Conference, which took place in February, there were several exciting reports on the development of truly new drugs in new classes for treating HIV. At this Resistance Workshop new information was reported on these developments. New encouraging research information on entry inhibitors and integrase inhibitors was presented.
BMS-806, Entry Inhibitor
At the Retrovirus Conference, Bristol Myers Squibb presented an initial report of their development of entry inhibitors. They have identified BMS-806 which they label as the prototype for a number of entry inhibitor drugs they hope to develop. At this Resistance workshop BMS researchers made it clear they are committed to developing entry inhibitors and reported new findings from ongoing research. They reported where this 806 drug binds on the CD4 cell to prevent virus entry into the CD4 cell. They reported identifying for the first time 2 key resistance mutations. Importantly, they also reported finding no cross resistance in vitro between BMS-806 and other entry inhibitors including T-20 and perhaps other entry inhibitors. BMS-806 does not bind to the same place as entry inhibitors that target other binding places. Therefore, that explains why they would not be expected to be cross resistant. So, if a patient becomes cross resistant to T-20 they should respond well to BMS-806 or the other entry inhibitors in development behind 806. BMS intends to study 806 while continuing to develop additional entry inhibitors similar to 806. While they should be some cross resistance to these 806-related inhibitors the hope is that each next generation of drug could be used after a person fails the one before. There may be a time in the near future when the currently used drugs for HIV may not be as important. Itıs possible that we may have enough new entry inhibitors to form a regimen of just entry inhibitors. Regimens of the future may include just entry inhibitors and integrase inhibitors. Perhaps these new classes of drugs will not have as much side effects & toxicities and be easier to tolerate and adhere to.
L-870810, Integrase Inhibitor
After years of research into finding integrase inhibitors, it appears as though real progress is being made. At the Retrovirus Conference, GlaxoSmithKline introduced publicly for the first time their development program to find integrase inhibitor drugs. The GSK program is testing an integrase inhibitor in HIV-infected and there is the potential for additional inegrase inhibitors from GSK. Merck has been discussing for several years at small conferences such as the Resistance Workshops their research commitment to finding an integrase inhibitor. Finally, Merck reported publicly here in Seville positive results of a study of an integrase inhibitor in monkeys, and discussed studies in humans. They reported that their integrase inhibitors are active against HIV wild-type virus and multi-drug resistant HIV; and are synergistic with nukes, NNRTIs, and protease inhibitors.
They reported on a proof of concept study in rhesus monkeys, to prove that the drug works. Monkeys received L-870812 to test the drug against SHIV (monkey HIV). Merck found that these monkeys receiving the integrase inhibitors had positive CD4 responses. The monkeys in this study who did not receive the drug experienced declines in CD4 counts, while the monkeys receiving the drug either did not experience CD4 count declines or saw increases in CD4s. Regarding HIV viral load, the untreated monkeys all had ongoing stable viral replication. But all the 812 treated monkeys experienced dramatic decreases in viral load within 2 weeks of receiving 812 monotherapy: (87 days of therapy) 4/6 monkeys achieved undetectable HIV viral load and the other 2 monkeys achieved 1-2 log reductions in viral load. These 2 monkeys who did not reach undetectable were found to have low levels of the drug at the end of the dosing period‹at the trough they had just enough drug on board. Also suggesting that drug levels of 812 are related to antiviral potency. Researchers at Merck identified 2 resistance mutations present in the 2 monkeys who did not achieve full viral suppression. Currently, a sister drug L-870810 is being studied in healthy volunteers. In the Fall Merck expects to begin a 10 day study of 810 in 20 HIV-infected patients. Also, in the monkey study after the drug was stopped virus levels did not appear to rebound quickly. 810 will likely be taken twice a day in humans.
Atazanavir (ATZ)
This is a new protease inhibitor currently in phase 3 development that is taken once per day. Preliminary studies so far shows itıs about equal in potency to Viracept, but a key characteristic is that so far they do not see increases in cholesterol and triglycerides. At this meeting Bristol Myers researchers reported a newly discovered signature mutation has been found for atazanavir, the I50L. This is a new PI mutation and BMS researchers reported here that when this mutation emerges in treatment-naïve patients, patients are more sensitive to the other protease inhibitors. This suggests that if ATZ is used as a firstline PI patients should still be sensitive to other protease inhibitors. BMS researchers are examining if this applies to treatment-experienced patients. In PI-experienced patients who received ATZ plus saquinavir they did not see patients developing the I50L but they will study this in patients receiving ATZ without saquinavir. They also reported that when the I50L developed the virus had reduced replication capacity‹it did not replicate as easily. To test if I50L increases sensitivity to other protease inhibitors they may have to study patients who remain on ATZ after developing this mutation when they add other PI therapy.
Also in this morningıs session Neal Parkin of Virologiv reported finding new Kaletra mutations and extensive cross resistance between amprenavir and Kaletra. From a list of 26 mutations associated with amprenavir 2.5 fold increased resistance, 23 are also associated with Kaletra 2.5 fold increased resistance. However, the presence of amprenavir mutations was not sufficient for Kaletra resistance greater than 10 fold, requiring accumulation of 8 or more mutations. This suggests that Kaletra could still suppress amprenavir resistant virus if you stop amprenavir therapy early before too many mutations accumulate. Parkin also reported finding new Kaletra mutations not before found: V32I, I47V, I50V.
TMC114 is a new protease inhibitor for patients with resistance to current protease inhibitors. Preliminary data has shown this drug to be potent and effective against HIV resistant to protease inhibitors. At this meeting Tibotec (Johnson & Johnson) researchers reported for the first time finding 2 resistance mutations associated with TMC114: 41 and 70. They also reported resistance developed very slowly to TMC114 and that replication capacity was reduced after the mutations developed. In vitro experiments (in the test tube) show a set of viruses with extensive resistance to currently available single protease inhibitors (9 to 250 fold resistance) were sensitive (<4 fold decreased sensitivity) to TMC114. These viruses were 5-6 fold resistant to amprenavir but 1-4 fold sensitive to TMC114.
In vitro (test tube) resistance experiments showed the emergence of resistance to TMC114 was much slower than TMC 114 as compared to nelfinavir, amprenavir, or lopinavir (Kaletra). Resistance to amprenavir and nelfinavir occurred more quickly than to Kaletra. And the slowest with TMC114. When resistance to TMC114 did finally emerge R41T and K70E were the mutations that emerged and investigators reported that viruses with these mutations replicated poorly (they were less potent; they had less replication capacity). Viruses that were resistant (10-fold) to TMC114 appeared to have little or no cross-resistant to other PIs, except saquinavir. TMC resistant viruses with 10-fold resistance had less than 10-fold resistance to the other PIs except saquinavir. The role of 41 and 70 in leading to TMC114 resistance is under investigation.The Tibotec-Virco researcher believes itıs likely that further research will find other mutations than 41 and 70 that will be associated with TMC114 resistance.
This information reported on TMC114 is preliminary and based on studies in the lab with patient blood samples. These findings have to be tested in clinical trials of HIV-infected patients to see if these positive preliminary resistance study results will effect HIV-infected patients with PI resistance the same.
It was previously reported that development of a new nuke, 817, was stopped due to toxicity. I talked to the drug discoverer and the company developing it and was told this is not the case. The drug is in early human studies and a study in HIV-infected is expected to begin this Fall. This drug is expected to be effective against HIV with nuke resistance but not against nuke multidrug resistant virus such as with the 69 mutation.
There was a presentation this morning on a nuke called MIV-310 whose development was stopped before apparently due to toxicity concerns. Researchers reported results from a new study using lower dosing which shows potent virus load reductions in patients with nuke resistance but side effects & toxicity remain a question.