June 29 and 30, July 2, 1998
By far greatest amount of new information in Geneva, and the greatest amount of hype was focused on efavirenz (SUSTIVA) and abacavir. Amprenavir (a new protease inhibitor from Glaxo Wellcome, formerly known as 141 and originally by its Vertex designation), and adefovir (PREVEON) are a little farther back in the licensing process but may be licensed by the end of 1998 or early next year. See the summaries elsewhere in conference report.
A pressing question is, "What's out there after that?" Below are a few relevant abstracts from the conference.
Poster Session 12460: Safety and efficacy of ABT-378 ritonavir in antiretroviral naïve patients: preliminary results of a phase II trial
Perhaps two of the most important needs we have right now are for protease inhibitors that work in patients who have developed resistance to other protease inhibitors, and for potent drugs which allow once a day dosing, and ideally have long enough half lives that even a few missed doses will not be critical. ABT-378 is a protease inhibitor designed (by Abbott) to be active against multiple protease-resistant HIV. Ritonavir, even at very small doses, greatly prolongs the half life of ABT-378. In this late-breaker, we learned preliminary results from a study which looked at two different doses of ABT-378 each combined with 100 mg ritonavir, all given once daily. 32 patients were enrolled. Baseline viral load was 5.0 log (100,000 copies) and median CD4 was 454. The patients were all drug naïve and could not have chronic hepatitis. Patients received ABT-378 at 200 or 400 mg with ritonavir 100 mg for 3 weeks and then added d4T and 3TC. 27 patients have made it to 16 weeks; all were below 400 copies. Of the small number who have made to 24 weeks, the average CD4 increase is 150 cells. Diarrhea was reported in 15%. This is very early, and it is important to remember that the key issues here are durability, tolerability, and how it works in heavily pretreated patients. Having said that, things are looking promising so far.
Session 293/41176: The safety, tolerance, pharmacokinetics, and efficacy of PNU-140690, a new non-peptidic HIV protease inhibitor, in a phase I/II study
PNU-140690 is a new nonpeptidic HIV protease inhibitor (PI) effective against ritonavir/indinavir resistant HIV isolates in vitro. I found the preliminary results in humans a bit disappointing, reinforcing the idea that everything sounds great at first, but we need to wait for good data. Three doses (900, 1200 and 1500 mg TID) of PNU-140690 were given to 24 PI naïve patients, with CD4 cell >50 cells/mm3, HIV RNA > 4000 copies/mL, on stable dual nukes for 32 months (median - 10 months). It appeared that the higher doses were needed to get adequated drug levels and effects, meaning there may be a lot of pills, and it is a three times a day drug. Peak viral load reductions were 1.1 to 1.5 log (not bad for adding PI monotherapy, but not earthshattering). About 50% became below 400 copies as some point. What worried many observers was that viral loads were drifting up by about week 12. Resistance has not yet been identified as the cause but it is suggestive. Diarrhea was the major side effect. Remember that this is not a great trial design for seeing the best long term antiviral results, and was designed to find the best dose. We'll need to wait for more information, or maybe one of the other non-peptidic protease inhibitors with a longer half life. By the way, if the Australian group is right, the non peptidic PI's would be predicted NOT to cause lipodystrophy.
Poster Session 60706: Genotypic characterization of HIV-1 isolated from AIDS patients after prolonged therapy with Preveon* (Adefovir Dipivoxil) added to existing regimens
Poster Session 41214: HIV-1 expressing the 3TC-associated M184V mutation in Reverse Transcriptase (RT) shows increased sensitivity to Adefovir and PMPA as well as decreased replication capacity in vitro
Adefovir dipivoxil is a novel drug, a nucleotide inhibitor of reverse transcriptase that can be dosed once a day. It is moderately active alone, similar to older nucleosides with a 0.4 to 0.5 log reduction. There are some troublesome, although apparently fully reversible kidney problems which develop in somewhere around 30% of people taking it for more than 1 year. Use in combination therapy is being evaluated in ongoing trials, and a lower dose (60 mg) is being investigated to see if that will eliminate or reduce the renal toxicity. Currently, adefovir is available in expanded access and is being used as part of salvage therapy in people who have few options. Therefore, it was interesting to see the results of this virologic study from Julie Cherington at Gilead. In the test tube, resistance is hard to create and is caused by somewhat unique mutations at position 69 or 70. Importantly, most AZT, ddI, and ddC resistance mutations don't cause resistance. The 184V mutation, associated with 3TC caused increased susceptibility to adefovir. Therefore, it may be effective to use drugs like 3TC and abacavir which select for M184V in combination with adefovir.
Poster Session 41218: Genotypic changes in HIV RT which develop during Preveon(tm) (Adefovir Dipivoxil) therapy do not decrease susceptibility to PMPA
The next nucleotide coming along, also from Gilead is PMPA, and this drug is much more potent. Therefore, it would be worrisome if using adefovir is going to select for resistance to PMPA and risk "losing the class." This virologic study, also from Gilead, showed that isolates that arose during treatment with adefovir were still fully susceptible to PMPA. Similarly, viruses constructed with the RNA from the breakthrough isolates were still susceptible.
Poster Session 12211: Oral PMPA Prodrug: Relationship between clinical pharmacokinetics, safety and anti-HIV activity
This was a phase 1-2 evaluation of the pharmacokinetics and the antiviral effect of the oral form of PMPA (which is also being evaluated as a topical gel for vaginal and possibly rectal use). To make PMPA adequately absorbed it has been formulated as a prodrug, bis-POC PMPA. If ever a drug needed a new name.... The very first data presented earlier this year as a late breaker looked promising. In this study, 3 different doses of bis-POC PMPA given once a day for 8 days were evaluated in a double blind placebo controlled dose escalating fashion. Baseline RNA was about 30,000 copies (log4.5) and CD4's were fairly high. Blood levels increased in a linear fashion with increasing dose. Bioavailability was 40%. There was an association between levels in the blood and viral load drop. For those with the highest blood viral load dropped by 1.0 to 2.1 logs in only days. This is based on very small numbers of patients, but this suggests very good antiviral potency. Toxicity was minimal, but remember it was an 8 day study. This is a drug to watch closely, and hope it does not share the kidney toxicity over the long haul of adefovir.
Obviously, even 8 days of monotherapy raises some concerns about resistance and ethics. Given the relatively healthy patients, the long time it takes to develop PMPA resistance in lab experiments and the short duration, the risk was relatively low, and it is crucial to get some data on efficacy early on. This would have been a tough call for the volunteers, and I assume they were well informed.
Session 557/41174: Anti-HIV activity, biochemistry, and pharmacokinetics of b-D-2O,3O-didehydro-2O,3O-dideoxy-5-fluorocytidine (D-D4FC)
This is an interesting new nucleoside analogue, being developed by Ray Schinazi of Emory University and Jean Pierre Sommadosi of UAB, two investigators well known for developing nucleosides for HIV and particularly for Hepatitis B. It is the D enantiomer (or one side of the mirror image -- 3TC is another example where only one enantiomer is the active safe drug. In vitro (literally "in glass" -- meaning test tube experiments), it is very potent at low concentrations and does not show toxicity for human cells. It does not appear cross resistant with other nukes. In a mouse model of HIV (the SCID-HU mouse which has human cells infected with HIV transplanted to make a chimera) it is very effective at reducing viral load. It is a cytosine analogue like 3TC and is active in resting cells. It appears that it will be synergistic with d4T and AZT. This one is very early on, but shows that we probably will have more useful nukes over time.