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  10th Conference on Retroviruses and Opportunistic Infections
Boston, Mass, Feb 10-14, 2003
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New HIV Drugs at Retrovirus 2003
Written by Mike Youle, MD, Royal Free Hospital, London, UK
  CONTENTS: --protease inhibitor TMC114
--R0-033-4649 a protease inhibitor
--UK427,857: CCR5 antagonist
--CCR5 inhibitor AK602
--betulinic acid derivative PA-457
--protease inhibitor tipranavir looks good in phase II study results & resistance
--integrase inhibitor, V-165, new class of compounds that inhibit integrase
--fusion inhibitor T1249
--RNA interference, new concept
The first time I visited Boston was 25 years ago and I remember being fascinated by the juxtaposition of the glittering reflections from the then newly built Hancock Tower against the backdrop of the oldest major settlement in New England. The entire history of the HIV epidemic has unfolded since then although a fascinating talk by John Coffin at the opening session of the 10th CROI gave an insight into how recently this retrovirus has encroached on the human genome. His description of pro-viral remnants of retroviruses as molecular fossils brought home the frailty of humanity against the onslaught of repeated integration of novel viral DNA's.
However we in 2003 need to focus on the current threat of HIV to mankind. Leaving aside the political issues of access to treatment and care discussed in a rather Americacentric manner by William Jefferson Clinton the near future seems very rosy. The last year has seen the first drug in the fusion inhibitor class, T20, reach clinic practice whilst several exciting proteases are near, or have already been, licensed.
So the first morning opened with an oral session of riveting data covering two new protease inhibitors, a class of nonncleoside reverse transcriptase inhibitors, a novel group of agents working on 3' processing of integrase, three exciting blockers of the CCR5 co-receptors, a betulinic acid derivative and a second fusion inhibitor T-1249.
Nick Cammack from Roche Palo Alto presented R0-033-4649 a protease inhibitor developed through their optimised synthesis program [abstract 7]. This drug features a resistance profile showing no significant loss of activity against a panel of triple site directed mutant viruses. When tested against a selection of 50 highly resistant clinical isolates from ViroLogic with at least 60% exhibiting greater than ten-fold resistance the drug showed good efficacy, which seemed to map somewhat to amprenavir. The drug has a moderate interaction with the CYP3A4 but with no in vitro induction and phase one clinical studies are underway.
The second protease inhibitor, TMC114, presented by Kiki Arasteh from Berlin is further along in development [abstract 8]. In a group of 50 protease inhibitor resistance patients TMC114 combined with ritonavir was assessed at three dose levels as a liquid gel form for 14 days before subjects moved on to an optimized salvage regimen. At baseline the 46 males and 8 females had a medium viral load of 4.3 log10 copies/ml (20,000 copies/ml) and a T4 count of 305 cells. By phenotype 46% of subjects were resistant to all drugs with 27% sensitive to one agent, 3% to two, and 24% greater than two drugs. By two weeks 42% of subjects had reached more than 400 copies/ml and viral load was still decreasing in all individuals, with a maximum HIV RNA decline of 2.49 log10 copies/ml. Thirty-two percent developed diarrhea and 18% flatulence, with dizziness occurring in 11%. There was one grade 4 rash and four serious central nervous system events over the study period.
The receptor blockers offer a novel group of agents being developed by several pharmaceutical companies. The ones nearest to the clinic are targeted at the CCR5 receptor and Manos Perros of Pfizer based in the UK presented their lead compound UK427,857 which has recently been administered to HIV positive individuals for the first time with a IC50 of 0.7mM which compares to that of the natural ligand RANTES at 2.6mM [abstract 12]. He showed a disassociation study of 3H-labelled drug demonstrating binding to the R5 receptor is reversible and with favorable pharmacokinetics and good tolerability in healthy volunteers the sights for the agent should be set high.
Harold Mitsuya, the grand old man of drug development presented data on another CCR5 inhibitor AK602 that appears to bind to the extra-cellular loop 2B of the receptor with site directed mutants at positions 188, 197 and particularly 191 producing to the receptor reduced binding of the drug [abstract 10]. However this agent at present appears to only partially block the CCR5 receptor so whether it will produce adequate in vivo efficacy remains unclear. It does however remain bound to the CCR5 receptor for a significant period, which may mean the agent would provide a persistent blockade of this target. In a mouse knockout animal model AK602 reduced viral load by approximately 2 log in a similar manner to the comparator arm of ddI.
An interesting novel agent derived from betulinic acid called PA-457 was presented by Carl Wild from Panacos Pharmaceuticals of Gaithersburg Maryland [abstract 14]. With an IC50 of 6.1mM and no cross-resistance to any available antiretrovirals it appears to have an action at the site of gag clearage. It is 60% bioavailable but work is being undertaken on a new salt to try and optimize the formulation for clinical trials.
There were several presentations on the latest protease inhibitor to reach clinical practice, tipranavir from Boehringer-Ingelheim. Joe Gathe from Houston, Texas presented the safety and efficacy of the drug in multiple protease inhibitor (PI) experience patients [abstract 179]. The trial was a randomized blind study in 216 subjects who had at least one primary PI mutation and a viral load > 1000 copies/ml. The doses tested were tipranavir (TPV/r) 500mg/100mg, 500mg/200mg and 750mg/100mg. Background therapy was optimized after two weeks of functional mono-therapy with TPV/r. The median baseline viral load was 4.5 log10 copies/ml (31,000 copies/ml) and CD4 Count 153 cells/mm3. After two weeks the median change in viral load was -0.9 log, -1.0 log and -1.2 log in the three arms respectively on an intent to treat analysis overall 15% of patients experienced moderate diarrhea and 12% had nausea and vomiting. No clear dose response was identified but the 500mg/200mg dose has now been chosen to move forward for further clinical development.
David Cooper showed additional data on the baseline phenotypic susceptibility of tipranavir/ritonavir in subjects in this study [abstract 596]. The median baseline fold wild-type (WT) IC50 of 157 isolates from the study was 1.0 (0.3-100) for tipranavir, 76.5 (0.5-165) for lopinavir, 8.7 (0.3-150) for amprenavir, 7 (0.1-109) for saquinavir, 12.2 (0.4-197) for indinavir and 36.8 (0.3-96) for nelfinavir. The distribution of TPV sensitivity in these isolates was 42% < 1 fold WT, 27% > 1-2 fold WT, 18% > 2-4 fold WT and 12% > 4 WT. The median viral load drop after two weeks for these strata was -1.23 log, -1.24 log, -0.21 log and -0.19 log. This suggests that tipranavir exhibits a robust antiviral response when TPV IC50 is < 2-fold WT, although this level of resistance required the accumulation of a large number of PI mutations. Phenotypic susceptibility was maintained in the majority (69.4%) of HIV isolates that were highly resistant to available PI's.
Finally Patrick Yeni from the Hopital Bichat-Claude in Paris showed data on the correlation of viral load responses with plasma levels in the same study [528]. Whilst 79% and 77% of patients in the 500mg/200mg and 750mg/200mg achieved the target concentration of 10x the protein adjusted IC90 for TPV (> 20 mM) only 48% of the 500mg/100mg managed this. The viral load responses were consistently better for subjects on the two highest doses at -1.14 log and -1.10 log respectively. So clearly tipranavir looks like it will provide a new line of defense for those individuals who have exhausted their current PI based regimens.
Diego Moralles gave new data on the 39 amino-acid second generation Roche fusion inhibitor T1249 derived from the sequence of the HR2 domain of gp41 [abstract 141b]. T1249-102 was a 10 day study with an optimized background in salvage patients who had VL 5-500,000 copies/ml for at least 8 weeks, whilst on T20, 53 subjects were dosed (76% from the pivotal TORO 1 study, 88% male] and 63% showed a > 1 log drop in viral load, median reduction over the dosing period was -1.12 log (CI -1.50 - -0.83). Of the 24 subjects whose virus could be amplified for resistance testing, 96% showed reduced susceptibility to enfurvitide (T20). The median change was 77-fold compared to only a 2-fold increase in resistance to T1249. The viral response to the new fusion inhibitor was related to the duration of prior T20 exposure with a 50% worse response in those with > 48 weeks duration of prior fusion inhibitor (p = 0.0014). In this study, which was small, there did not appear to be a relationship between exposure to drug and subsequent development of resistance.
Zeger Debyser from the influential Rega Institute, Louvain Belgium, whetted the appetite of the HIV drug junkies with an entire new class of compounds that work on integrase [abstract 9]. The pyramidopyrimidines include a lead molecule, V-165, that appears to both have early activity about reverse transcription as well as inhibiting the 3' processing and strand transfer of viral RNA into the cellular DNA by integrase. This agent thus has an additional activity over and above that of the current most developed integrase inhibitor from Merck Pharmaceuticals L-708-906. Although low level phenotypic resistance was achieved after 80 passages in vitro it appears to still have activity against L-708-906 resistant isolates [abstract 556]. No data is yet available on the utility of this agent.
A fascinating, if complex, session was held on RNA interference (RNAi) as a potential therapeutic strategy. Phillip Zamore from the University of Massachusetts Medical School explained the background to this machinery which involves double stranded RNA suppressing the expression of particular genes [abstract 49]. The RNAi pathway appears to have developed as a defense against molecular parasites such as viruses but in higher animals now encompasses a range of functions including the elimination of abundant but defective messenger RNAs and regulating the production of developmentally important proteins. The double stranded RNA-specific endonucleose, Dicer, produces two classes of functionally distinct small RNA's: micro RNAs (mi RNAs) and small interfering RNAs (si RNAs). The specifically regulate MRNA translation and direct RNA destruction.
John Rossi form the Beckman Research Institute, Duarte, California presented an exploratory study of inserting HIV targeting siRNA encoding sequences into a lentiviral vector backbone and then testing the effect by transducing T-lymphocytes and haemapoetic progenitor cells (CD34+) [abstract 50]. He showed data that siRNA's, expressed seperately as sense and antisense, potently inhibit HIV gene expression following transient transfection with HIV-1 proviral DNA in well culture. When transfected CD34+ cells were infused into SCID-hu mice they underwent normal differentiation into T-lymphocytes which were then resistant to infection with HIV.
Although this area of research is in its infancy it appears to hold immense promise in harnessing the naturally evolved mechanism of genetic waste disposal and dry cleaning to purge infections or prevent them occurring. Watch this space.