New anti-HIV compounds discussed at the Seville HIV Drug Resistance Workshop and the Barcelona World AIDS Conference
Mike Youle MD, for HIVandHepatitis.com
The sun-drenched heart of Spain in Seville provided a pleasant setting for the XI International HIV Drug Resistance Workshop. Approximately 250 delegates met to discuss the hot topics in resistance.
As usual, they faced an ever increasing range of agents to study that now spans more areas of the virus life-cycle and a wider selection of tests with which to evaluate resistance to these compounds.
Please note that unless otherwise indicated, all references are to the Programme and Abstracts of the XI International HIV Drug Resistance Workshop, July 2-5, 2002, Seville, Spain OR to the XIV International AIDS Conference, July 7-12, 2002, Barcelona, Spain. The Seville Workshop abstracts are published in Antiviral Therapy Volume 7(2) and are available on-line.
Considering that we have not had a new class of compounds to use for more than six years, the advent of receptor blockers, fusion inhibitors and the integrase inhibitors are great news. Let us hope that physicians have learnt not to burn through these new opportunities without considering the implications of just adding the next new drug to a failing regimen.
Daria Hazuda and Steve Young revealed tantalizing results of their work with the Merck integrase inhibitors [Seville Abs 1, 2, Abs TuPeA4371]. They have modified the diketobutanoic acids structures that had showed efficacy in vitro to produce a series of new compounds with increased activity including against multi-HIV resistant (MDR) strains of HIV and which shows synergy with other available agents. In a macaque model drops of 1-3 log were seen in viral load and the lead compound, L870810, has good bioavailability and a half-life in macaques of 8.6 hours. Mutation at positions 153 and 155 lead to a 9-11 fold reduction in activity but this drug seems to work at much lower (nanomolar concentrations) compared to the Shionogi-GSK compound S1360 presented at the 2002 Retroviruses and OI meeting in Seattle, WA .
At the XIV International AIDS Conference in Barcelona, further data on the oral administration of the latter compound was reported [Abs TuPeB4431, TuPeB4436]. Twenty-four uninfected volunteers were given escalating multiple doses of S1360 of 500mg, 1000mg and -2000mg twice daily under fed conditions. The drug appeared to be well absorbed with the maximum drug level achieved at 2-3 hours without the drug accumulating over time. It was heavily protein bound which might result in problems for the availability of the active drug but tolerability in these subjects seemed good with headache and nightmares being the only consistent side effects reported.
Next old kid on the block was MIV-310 that last saw the light of day in the early 1990’s. This agent is a fluorothymidine related to zidovudine, which is being re-evaluated by Medivir. It appears to work against MDR but has problems with leucopoenia in high doses. In this study conducted in Paris, the drug at a 7.5mg dose was used as an add-on agent in subjects failing virologically between 1-50,000 copies/mL [Seville Abs 3]. The overall median viral load drop was 1.13log10 [n=15] with a lower viral load drop in subjects who also received stavudine. This raises the question as to if there may be a similar inhibitory action as seen with zidovudine and stavudine. During the four weeks of therapy no resistance mutations emerged and although some concerns exist regarding the safety profile of the drug this is an exciting rebirth that should be watched with interest.
Rich Colono from BMS next showed updated data on the resistance patterns of atazanavir [Seville Abs 4]. It appears that when the I50L emerges under the effect of atazanavir [ATZ] in treatment-naïve patients they seem to be more sensitive to the other protease inhibitors. So if ATZ is used as a first-line agent, PI patients should still be sensitive to other agents, the same story the D30N for nelfinavir. In PI-experienced patients who received ATZ with saquinavir they did not see patients developing the I50L but it will now be studied in patients receiving ATZ without saquinavir. Using the ViroLogic replication assay, this virus carrying the I50L did not replicate as easily. At Barcelona in the late breaker session Rob Murphy of Northwestern University Chicago presented data on subjects who completed AI424-008 and then switched from nelfnavir to atazanavir [LbPeB9013]. In the 364 patients a significant reduction in fasted total and LDL cholesterol as well as triglycerides was seen over 12 weeks, once again suggesting that this new protease inhibitor may have significant benefits over the currently available agents.
Marie-Pierre Bethune then updated the story on the Tibotec (now Johnson and Johnson) protease inhibitor TMC 114 [Seville Abs 5]. This agent that appears to be highly active against most currently available isolates was entered into a serial passage experiment. This experiment resulted in no detectable selection of resistance even after 260 days at 100nm compared to selection for resistance to nelfinavir after 20, amprenavir by 30 days, days and lopinavir by 90 days. Finally, at the higher doses viruses were isolated harboring R41T and K70E mutations but with a fold change of only 10. These viruses were sensitive to other PI’s except saquinavir, suggesting little cross-resistance for this drug with a high genetic barrier to resistance.
Another offering from Bristol Myers Squib was BMS-806, their novel HIV-entry inhibitor presented by Ping-Fan Lin [Seville Abs 6]. This agent is reported to bind via gp120 on the CD4 cell to prevent virus entry into the CD4 cell. For the first time two key resistance mutations but their appeared to be no cross resistance in vitro between BMS-806 and other entry inhibitors including T-20, rendering this an important lead compound for those who may not do well on the first generation agents in this class.
Finally, there was an elegant overview by Michael Greenberg of Trimeris of the fusion inhibitors 20 and T 1249 in which he delineated the greater in vitro efficacy and better resistance profile of the latter. Of the identified viral isolates with reduced activity against T 20, all retained sensitivity to T 1249. It would also appear that after a 2.7-8.5 month break some strains of virus resistant to T 20 regain some sensitivity. Concerning T 1249, attempts to generate resistant isolates via site directed mutagenesis were not particularly successful. However, in a 14 day monotherapy study [ Seville Abs 149] eight subjects of 115 developed mutations n gp41 at positions 36-45 which seemed to be associated with reduced susceptibility to the drug.
New antiretroviral drug data presented in Barcelona
Barcelona was a huge gathering of the world leaders in all fields of HIV, but there was little showcasing of really novel antiretrovirals other than the fusion inhibitor T 20 and some new data on atazanavir. Much of the work seen at Seville was rehashed (referenced above) and there were a few new agents presented.
The data on enfurvitide (T-20) included presentations of the TORO 1 and TORO2 studies [Abs LbOr19a, LbOr19b] that are reviewed elsewhere. Although T-20 is an injected agent, patient acceptability, at least in the short term, seemed high with over 75% of subjects finding little or no limitation to their daily activities [Abs TuPeB4480]. How much of this was driven by the fact that this data was at eight weeks and in the setting of good surrogate market outcomes is unclear. When injection sites of the abdomen, arm and leg were compared in 12 subjects in a crossover manner it appeared that the thigh absorbed T-20 better than the abdomen or the arm but that the difference was not statistically significant [AbsTuPeB4542].
On the first day, data on a new purine analogue reverse transcriptase inhibitor called SPD 756 (BCH-13520) was shown [Abs MoPeA3008]. This agent, although a weak inhibitor in the test tube, has been modified by deamination to produce SPD-761 TP, a potent agent that has the advantage of activity against multi-drug resistant strains of HIV which is now being moved into later phase development by Shire Biochem of Canada.
Further compounds tested in vitro included a novel Tat inhibitor/antagonist, NeoR [Abs MoPeA3001]; and a betulinic acid derivative PA-457 coming out of University of North Carolina, Chapel Hill and Panacos Pharmaceuticals [Abs MoPeA3030]. This appears to have a direct effect on virion assembly whilst being orally bioavailable and effective against R5 and X viruses.
This research group also showed data on another unusual drug with unknown site of action, PA-344B, which is under investigation and has activity against drug resistant strains of HIV [Abs TuPe4435]. A novel combination approach to integrase inhibition used the strand transfer blocking diketoacids with L-chicoric acid that appears to not only inhibit integrase activity but to act as a partial entry blockers producing a synergistic effect [Abs MoPeA3021].
Another group from Progenics has humanized an anti-R5 monoclonal antibody, PRO 140 that appears to block HIV-1entry without interfering with the chemokine receptor activity of R5 and has moved it into phase 1 studies [Abs TuPeA4363]. Following a long campaign by some researchers to suggest aspirin has a beneficial effect against HIV, Candida Pereira and co-workers from Amsterdam presented data on an aspirin-like compound that had activity on reverse transcriptase that was synergistic with other RT inhibitors [Abs LbPp2207].
At Barcelona a poster presentation described the surrogate marker outcomes and tolerability of the Phase IIA study of the other Tibotec compound, TMC-125, in subjects with NNRTI resistant strains [Abs TuPeB4438]. Sixteen subjects were given 900 mg TMC-125 twice daily instead of the failing NNRTI but continued on the same background therapy for seven days before constructing their next regimen. The median baseline CD4 count before switching to TMC-125 was 389 cells/mL and viral load 10,700 copies. Before commencing TMC-125 resistance to TMC-125 was 0.5-8 fold. In this study diarrhoea and headache were seen in around 25% of patients and the median viral load drop was –0.86 log (range from -1.95 to +0.09) by day 8.
In the late breaker session two posters examined the antiviral activity and action in conjunction with structured treatment interruptions of Ampligen, a double stranded DNA, poly1:polyC12U [Abs LbPeB9010, LbPeB9011]. This agent given intravenously appeared to achieve a modest drop in HIV RNA or 0.25log10copies/mL after 24 weeks in eight patients.
In the second study that comprised adding poly1:polyC12U [Ampligen] to HAART prior to a structured treatment interruption there was a significantly delayed period, 25+ weeks [n=6] versus a median of seven weeks [n=4] to a persistent viral rebound of >5,000copies/mL in the group randomised to the active therapy. Although these studies are in small numbers they provide some suggestion that these antiviral biologic response modifying RNA molecules may be yet another approach to HIV therapy.
Overall a rather good crop of new agents, which if adequately watered and nurtured, could turn into a bumper harvest of treatment options in the next few years.
- Abstracts 4-8. 9th Conference on Retroviruses and Opportunistic Infections (9th CROI). February 24-28, 2002, Seattle, WA.
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