Other new antiretrovirals at Denver: the future seems bright

12 April 2006. Related: Conference reports, Antiretrovirals, CROI 13 (Retrovirus) 2006.

Mike Youle, MD for NATAP.org

Like a kid in a candy store, there was so much new data at this meeting that it was hard to concentrate. The possibilities now for our patients are immense. Notwithstanding the early stage of development of most of the new agents shown, the future seems bright. After the disappointment of the recent loss of one or maybe two out of three CCR5 inhibitors in clinical studies, the integrase inhibitors from Merck and Gilead burst onto the scene and the latter looked even better than the first set of data shown at the Dublin EACS conference last November. (see March HTB for coverage of integrase inhibitors).

In addition, there were many new agents in the wings such as the once weekly fusion inhibitors from Trimeris and further information on those drugs closest to availability, TMC114 and TMC125. This was all good news.

So here is the selection of new drug data presented at the meeting.

In the main body of the report I will focus on those agents that have clinical data or are nearer to development. However, there are some compounds in earlier stages of development that, in the future, may lead to useful classes of drugs.

One study, presented by Donahue and co-workers from Vanderbilt, screened peptide inhibitors of the binding of HIV-vif to human APOBEC3G. [1] HIV-vif inactivates a host cell antiviral defence mechanism mediated by the cytidine deaminase APOBEC3G and thus inhibition of this interaction may be a disadvantage to viral replication. A novel innate protein, G9, blocks the HIV life-cycle at two stages: it inhibits HIV production prior to release of virus particles and inhibits an entry-dependent step at reverse transcription. Findings by a group at King’s College London suggest this to be a potential immunotherapeutic. [2]

Several studies furthered the knowledge base on short interfering RNA’s (siRNA’s) by evaluating the utility of targeting the U3 region of the 3’LTR, which is utilised in all viral transcription [3]; and in the second study showing that for the full effect of an siRNA, a full homology (complete matching) is required with the target sequence of the gene [4]. A third study, from Pauls and co-workers in Badalona, suggested that it is important to develop siRNA sequences that are devoid of unwanted inflammatory activity that may increase rather than reduce HIV activity. [5] Although this area of research is clearly very complex, the goal of safe targeted silencing of HIV-replication with all cells is one worth fighting for.

Robert Gallo and his group in Maryland investigated indirubin 3’-monoxime, a derivative of a Chinese medicine used to treat leukaemia, and showed that in non-toxic concentrations that did not affect cell proliferation the compound can reduce tat-mediated transactivation, a necessary step in the production on HIV-1; the drug is effective against wild-type and resistant strains of HIV. [6]

Thomas Duensing from Tanox Inc showed new data on the in vitro characteristics of HIV isolated from patients treated with the novel entry inhibitor. [7] TNX-355 is a monoclonal antibody that targets conformational changes in gp120 and data was presented on ongoing phase II study, first shown at ICAAC 2005. In this presentation, they showed the first data on resistance to TNX-355; IC50 was 10-230ng/mL and there appeared to be no effect due to co-receptor tropism. From baseline to week 9, three of 19 subjects remained fully susceptible to the agent, whilst the other sixteen had reduced activity by 19-60%. Sub-clones were isolated and grouped into sensitive 90%, intermediate 42% and resistant 17%. Using soluble CD4 it appears that there is an increased risk of neutralisation when there is increased exposure to the CD4 binding site in TNX-355 resistant env proteins. Further studies are ongoing to correlate baseline susceptibility with virological outcomes.

There was a little more information pertaining to maraviroc (formerly UK427,857), the only CCR5 currently left in the running at the level of clinical trials, although Schering-Plough may enter the race once again with higher doses of vicriviroc. The group from Pfizer Global R&D, based in Sandwich in the UK, examined the activity of the agent on human CCR5 and related this to its binding characteristics. [8] They showed that against another CCR5 blocking compound, maraviroc exhibited marked viral suppression commensurate with a long dissociation half life of 16 hours, suggesting that the better activity was due in a major part to the prolonged drug binding to the receptor. Resistance work, performed by this unit in collaboration with Monogram Biosciences, characterised resistant NL4-3 clones which resulted in dose response curves that did not produce 100% inhibition of CCR5 receptor, potentially due to the selection of viral variants which recognise receptor: inhibitor complexes. [9]

The pharmacokinetics of CCR5 antagonist vicriviroc (VVC) in combination with ritonavir were assessed in cohorts of 8 healthy volunteers given atazanavir, indinavir, nelfinavir, saquinavir or fosamprenavir. [10] There were no significant changes in plasma concentrations when combined with any of these agents, irrespective of p-glycoprotein or CYP450 interactions.

Wayne Greaves from Schering-Plough presented study P03802, a phase 2 randomised placebo-controlled study of vicriviroc in treatment naive patients with R5-tropic virus. Patients were randomised to 2 weeks monotherapy with 25mg, 50mg 75mg VVC or placebo, after which Combivir was added to the VVC arms and efavirenz added to the placebo arm. In October 2005, the study was terminated early by the Data and Safety Monitoring Board. [11]

In hindsight it appears as if vicriviroc may have been dosed too low. The relative rates of virologic breakthroughs in the vicriviroc arms compared to the placebo arm were 56% (13/23) in the 25 mg dose arm (vs control, p<0.001), 41% (9/22) in the 50 mg arm (vs control, p=0.003), and 17% (4/23) experienced viral breakthrough in the 75 mg (vs control, p=0.188). At the time of study termination, there was no significance difference in viral failure breakthrough between the 75 mg arm & the EFV/CBV arm.

22 of 26 of breakthroughs on vicriviroc had evaluable genotypes and of these 100% had M184V and one had M184V and M41L, resistance to the CCR5 inhibitor is still being investigated, no correlation was seen with IC50 and no consistent mutations in envelope arose. There were no safety concerns and specifically no liver function abnormalities were seen. The assessment of a more appropriate dose will now take place to see if this compound has a future.

Down regulation of CCR5 expression on monocyte-derived macrophages was achieved using aprepitant (an FDA approved anti-emetic which works by antagonising neurokinin-1 receptors), in a study by Wang in the Children’s Hospital of Philadelphia. [12] Aprepitant worked on AZT-resistant virus, and as an inhibitor of R5 but not X4 viruses. However, it did not work in all isolates.

There were two presentations of human monoclonal antibodies (mAb) targeted at CCR5. PRO140, a humanised IG4 mAb from Progenics was given intravenously to healthy male volunteers as single doses of 0.1, 0.5, 1.0 and 5.0mg/kg in sequential dose rising cohorts in a ration of 4:1 drug:placebo. [13] All 20 subjects finished the study with no reported side effects of ECG changes and the serum concentrations increased proportionally with dose and decreased with a serum half-life of around two weeks. At the 5mg/kg dose there was coating of CCR5 lymphocytes for >60days suggesting that this agent although parenteral may be able to be dosed quite infrequently. A second mAb, in this case from Human Genome Sciences, mAb004 was examined in vitro and showed little tendency to result in resistance over at least 24 weeks. [14]

Another monoclonal antibody approach was taken by Yoshimura and co-workers from Kumamoto University in Japan when they synthesised a mAb, KD-247, focused on the highly conserved V3 sequences and which showed a high degree of synergism with available CCR5 inhibitors. [15] At high concentrations of 1000 mg/mL it was possible to select a mutation, G314E, in the tip of the V3 loop, which conferred complete resistance to the compound, but rendered it hypersensitive to several other agents.

Finally for CCR5 targeting, a novel approach was reported by Elena Perez from Sangamo Biosciences, where they had created a zinc finger protein nuclease (ZFN) to target the CCR5 gene in order to create a double stranded break (DSB) at predetermined sequences, that then are repaired by host DNA repair mechanisms, but the target gene is permanently disrupted. [16] These ZFN can target any sequence in the genome and produce a break that will disrupt transcription and the group picked CCR5 as a suitable target. They showed that a cell line modified by ZFN-targeting of CCR5 was resistant to HIV infection, but that this could be reversed by the restoration of CCR5 by plasmid nucleofection. The group are currently trying to optimise this approach.

In terms of CXCR4 blockade, an oral presentation of two new compounds, KRH-3955 and KRH-3140, was presented by Yuetsu Tanaka. [17] These selectively block binding of SDF-1 and were administered to rats, showing good PK with levels above the EC90 for 23 hours. No toxicity was seen, other than a mild rise in white blood cells. KRK-3955 was present two weeks after a single oral dose of 10mg/kg and was protective to a high degree against an X4 virus challenge.

The last group of agents, that act on the entry mechanism of HIV into the cell, and that were show-cased at the conference, were very exciting. The joint-venture between Trimeris and Roche has already produced enfurvitide (T-20), which in the TORO studies showed a marked benefit compared to the optimised background alone. In further studies of newer drugs, such as tipranavir (RESIST) and TMC114 (POWER), T-20 has also marked itself out as the best companion agent for the new PIs, in three-class failing patients. However, with twice-daily injections, injection site reactions and mismatch between patients wishes and physician willingness to offer and prescribe, T-20 has not been used optimally to date. However, after an aborted attempt to improve the agent with T-1249, there now appears to be the possibility of once-weekly dosing with new lead compounds TR290999 and TR29144. [18]

In an excellent presentation by Barbara Delmedico, we were given an overview of these exciting new generation fusion inhibitors (NGFI), which not only have pharmacokinetic properties that allow for once-weekly dosing, but also appear to be significantly more potent against HIV, and also to have activity against enfurvitide -resistant strains.

They developed a lead compound, T 651, which spanned more of the HR2 domain of gp41, and represented an optimal slice of this, with which to bind and disrupt the process of fusion. This agent had an 85-fold greater activity than T-20, but unfortunately did not have good pharmacokinetic properties.

However, further work produced two other chemical series with enhanced properties and much improved PK, raising the possibility of once-weekly dosing, by the addition of helix stabilisation motifs (TRI-1144 series) or fatty acid acylation (TRI-999 series).

Lead compounds from these were then evaluated against a panel of viruses resistant to T-20, and showed between 150 and 250 fold improvement over the current compound.

In addition, the NGFI retain sensitivity against mutants with up to 4 codon changes in gp41, whilst T-20 loses activity after the acquisition of only one mutation. This bodes well for the development of once weekly agents with a high genetic barrier, which will be useful both in patients naive to T-20 and in those who have acquired resistance.

Non-nucleoside reverse transcriptase inhibitor (NNRTI) data at the conference was focused on the Tibotec compound, TMC125. TMC125-C223, was a randomised dose finding study, run in the USA in 199 subjects with documented resistance to NNRTIs and >3 PI primary mutations. [19]

Subjects either received TMC125 (400mg or 800mg) with an optimised background regimen (OBR), or OBR alone. Median CD4 and VL at baseline were around 100 cells/mm³ and 4.7 log respectively. Baseline genotypic resistance is shown below.

Table 1: % of patients with NNRTI-associated mutations

For the 800mg dose, no single mutation was associated with a >10 fold reduction in sensitivity, whilst the following mutations, always in combination with up to 4 other mutations, produced a >10 fold-change in sensitivity; K10P, V179E, V179F, Y181C, Y181V, G190S, M230L. These mutations were all previously found in vitro to be associated with an increased fold-change to TMC125.

Viral load reduction was around 1 log, but number of baseline NNRTI mutation predicted the change in viral load; -1.8, -1.6 and -1.0 with 0, 1 and 2 mutations respectively. Even with 3 NNRTI mutations, a -0.66 log reduction was seen, compared to only -0.19 for the control subjects.

This is a 48-week study so further data will become available for the target dose of 800mg bid, but at this mid-point analysis. TMC125 retained activity in the presence of multiple NNRTI mutations. However, as with all new agents, it is vital that this drug be used in the setting of an active background and data suggest that TMC125 can be used successfully with TMC114. [20]

Gilead Sciences has emerged as one of the most innovative drug companies in the HIV field and their new nucleotide reverse transcriptase inhibitor is GS-9148, active as an active diphosphate metabolite. The compound uses amidate pro-drug technology to maximise the intracellular levels of active compound, and in this study in beagles the drug accumulated substantially within PBMCs and has low mitochondrial toxicity in renal, bone marrow and liver cell lines. [21]

Tomas Cihlar presented in vitro data on GS-9148, tested against a wide variety of NRTI resistant strains. [22] It showed that activity of GS-9148 was unaffected (FC<1) by K65R, L74V, M184V or any of these in combination as well as retained sensitivity to up to four TAMs (FC<2) making this drug an attractive candidate for further studies.

A nucleotide-competing reverse transcriptase inhibitor (NcRTI-1), was showcased by Matthias Götte from McGill University, Montreal. [23] This agent blocks DNA polymerase, and appears to occupy the nucleotide biding site of HIV-1 RT, forming a dead-end complex that prevents the incorporation of dNTP substrates. This prototype compound is active against NNRTI resistant viruses but is adversely affected by M184V (reduced by 5-fold). This is clearly a problem for this particular compound whereas K65R confers hyper susceptibility.

NcRTI-1 was examined for its’ sensitivity to isolates and site directed mutants containing many different NRTI mutations and showed 39-fold decreased susceptibility to the combination Q151M and M184V. However, thymidine analogue mutations (TAMs) 69 insertion or Q151M alone, showed no decrease. [24]

A potent thymidine kinase RTI with low toxicity would be useful to replace zidovudine and stavudine, and dioxolane thymidine (DOT) was presented as a candidate by John Lennerstrand of Emory University. [25] It seemed to work well against most NRTI mutations other than Q151M but the presenter seemed reticent to clearly answer questions regarding pharmacokinetics.

Further NRTI titbits included an in vitro study of E2fDA, which has a long intracellular half-life, minimal inhibition of DNA polymerase-gamma and good activity against resistant strains. [26] Resistance to dexelvucitabine (formerly Reverset) was assessed in a study whose clinical data was presented in Rio last summer. [27] Apart from reduced sensitivity to Q151M, no other mutations were associated with baseline phenotypic resistance or poor virological outcomes over 16 weeks of therapy.

Two new protease inhibitors had their first showing at this meeting. SPI-256 developed by Sequoia Pharmaceuticals was assessed in vitro against a panel of resistant viruses by Monogram Biosciences. [28] In a subset of isolates with >50-fold resistance to current licensed PIs, and at least 6 primary mutations, average IC50 values to SP-256 were 12.9nM compared to >937nm for the reference agents, giving  a 50-fold increase in efficacy. The second new kid on the block was a novel non-peptidic PI, GRL-02031 which although tested against less resistant strains than the former compound seemed to be sensitive to many currently resistant isolates. [29] It is comforting that there still seems to be a pipeline of new agents in this class.

Kim Strubble from the FDA, in her talk on drug-drug interactions highlighted the difficulties inherent in PK studies in highly experienced patients, and noted that the use of historical control data instead of monotherapy arms, may be permitted. [30]

More data was shown on TMC114 including a pharmacokinetic (PK) study to assess the effect this drug on the levels achieved when given in combination with TMC125 by Marta Boffito from London (see also PK report later in this issue of HTB. [31]

This combination of TMC114 600mg/ritonavir100mg/TMC125 200mg twice daily was given to 10 subjects with multi-drug resistance as a part of a salvage regimen. The median CD4 at baseline was 75 cells/mm³ and viral load 4.6log. All patients had a -2 log drop by week 6 (median -2.55log) and 8/10 achieved a viral load <400. As compared to historical controls exposure to TMC114 was unchanged and that to TMC 125 modestly reduced by 30%, a change deemed non-significant. A second PK study examined the PK/pharmacodynamic analyses of TMC114 in the POWER studies and found that the outcomes were strongly influenced by baseline TMC114 fold change, viral load and use of sensitive drugs in the optimised background. [32] However, the strongest predictor of response was the sensitivity to TMC114.

In an oral presentation by Marie-Pierre de Béthune from Tibotec this relationship was examined further. The drug has shown good responses compared to the comparator PIs even if there was retained susceptibility to those drugs. [33

The group analysed all of the data available for the 600mg/100mg dose from the two presented POWER studies, and additional information from the POWER 3 study, which had the same entry criteria and increased the sample size of the original studies to 458, of which 377 have reached week 24 or have discontinued. As compared to the comparator PI background TMC114 was relatively unaffected by PI resistance at baseline until there were 12 or more mutations.

No particular mutation was associated with virological failure, but some mutations developed commonly during treatment with TMC114, as shown in Table 2 below. However, when these were inserted as codon changes in site directed mutants along with 1-2 other mutations, this did not affect sensitivity to TMC114.

Table 2: Mutations associated with TMC114/r 600/100 BID

* Mutations present in >10% rebounders and never suppressed

In rebounders, the fold-change for TMC114 was 8.14-fold but that for tipranavir was only 0.82-fold, suggesting that cross-resistance between these two drugs may not be an issue.

There were three presentations on PA-457, the derivative of betulinic acid, and the first in class of maturation inhibitor. In vitro data where the agent was tested against a panel of site directed mutants showed no resistance and either an additive or synergistic effect with all available antiretroviral classes. [34] In a PK/PD study, 32 subjects were given oral liquid doses of 25, 50, 10, 200mg once daily for 10 days as monotherapy, after a one-day double loading dose (6 received active drug and 2 placebo in each dose group). [35] PA-457 was well tolerated, had a half life of 72.8 hours and produced up to a -1.1log drop at the highest dose. Using an E-max model to assess optimal dose, it seems that the dose can be increased substantially. There were two subjects who did not show any response, and this did not correlate with drug exposure. The final talk on this drug, by Catherine Adamson from the HIV Drug Resistance Program at NCI, examined the resistance patterns in vitro by serial passage and from gag sequences selected from the phase I study above. [36] This very clear description showed two groups of identified mutations located at the C-terminus of the capsid protein and in the first and third residues of the spacer peptide SP1. The clustering of these PA-457 resistance mutations at the CA/SP1 junction confirms this as the site of action of the drug. No resistance was seen in the clinical isolates.

Finally in the early stages of evaluation is a compound by Pfizer, UK201844, found by high throughput screening at the rate of 72,000 compounds per week, which appears to be a maturation inhibitor focused on gp160 processing, inhibiting the incorporation of functional HIV-env into virions. [37] The lead compound does not have overall strain inhibition (only 1/15 clade B isolates) and further work will be needed to ascertain how active agents may be created.

The full report with slides is available in the 13th CROI section of the NATAP website:

http://www.natap.org

References:

All references are to the Abstracts and Programme of the 13th Conference on Retroviruses and Opportunistic Infections, 5-8 February 2006, Denver.

1. Donahue J, D’Aquila R et al. Peptide Inhibitors of in vitro Binding of HIV-1 Vif to Human APOBEC3G. 13th CROI. Abstract 200.
2. Vyakarnam A, Alvarez R, King D. HIV Infection Is Suppressed by G9, a Novel Innate Effector Protein. 13th CROI. Abstract 210
3. Suzuki K, Ishida T et al. Promoter Targeted siRNAs Silence HIV-1 by a Transcriptional Gene Silencing, with Minimal Contribution from a Post-Transcriptional Mechanism. 13th CROI. Abstract 266.
4. Gimenez-Barcons M, Sabariegos R, Tapia N et al. HIV-1 Sequence Homology Requirements to Escape from Short Interfering RNA. 13th CROI. Abstract 267.
5. Pauls E, Clotet B, Bofill M et al. siRNA-directed against HIV Co-receptor CCR5 Modulate IL-6 and IL-8 Secretion in a Sequence-specific Manner. 13th CROI. Abstract 514.
6. Heredia A, Davis C, Bamba D et al. Indirubin-3’-monoxime, a Derivative of a Chinese Antileukemia Medicine, Inhibits P-TEFb Function and HIV-1 Replication: Potential Role of CDK9 Inhibition as a New Therapeutic Target. 13th CROI. Abstract 510.
7. Duensing T, Fung M, Lewis S et al. in vitro Characterization of HIV Isolated from Patients Treated with the Entry Inhibitor TNX-355. 13th CROI. Abstract 158LB.
8. Pullen S, Sale H, Napier C et al. Maraviroc Is a Slowly Reversible Antagonist at the Human CCR5 in a CRE Luciferase Reporter Gene Assay. 13th CROI. Abstract 504.
9. Mosley M, Smith-Burchnell C et al. Resistance to the CCR5 Antagonist Maraviroc Is Characterised by Dose-Response Curves that Display a Reduction in Maximal Inhibition. 13th CROI. Abstract 598.
10. Sansone A, Keung A, Tetteh E et al. Pharmacokinetics of Vicriviroc are not Affected in Combination with Five Different Protease Inhibitors Boosted by Ritonavir. 13th CROI. Abstract 582.
11. Greaves W, Landovitz R, Fatkenheuer G et al. Late Virologic Breakthrough in Treatment-naive Patients on a Regimen of Combivir + Vicriviroc. 13th CROI. Abstract 161LB.
12. Wang X. Neurokinin-1 Receptor Antagonist Inhibits Drug-resistant HIV-1 Infection of Monocyte-derived Macrophages in vitro. 13th CROI. Abstract 511.
13. Olson WC, Doshan H, Zhan C et al. Prolonged Coating of CCR5 Lymphocytes by PRO 140, a Humanized CCR5 Monoclonal Antibody for HIV-1 Therapy. 13th CROI. Abstract 515.
14. Giguel F, Beebe L, Migone TS et al. The Anti-CCR5 mAb004 Inhibits HIV-1 Replication Synergistically in Combination with Other Antiretroviral Agents but Does not Select for Resistance during in vitro Passage. 13th CROI. Abstract 505.
15. Yoshimura K, Shibata J, Honda A et al. Resistance Profile of a Novel Broadly Neutralizing Anti-HIV Monoclonal Antibody, KD-247, that Has Favorable Synergism with Anti-CCR5 Inhibitors in vitro. 13th CROI. Abstract 506.
16. Jouvenot Y, Perez E, Urno F et al. Toward Gene Knock-out Therapy for AIDS/HIV: Targeted Disruption of CCR5 Using Engineered Zinc Finger Protein Nucleases. 13th CROI. Abstract 51.
17. Tanaka Y, Okuma K, Tanak R et al. Development of Novel Orally Bioavailable CXCR4 Antagonists, KRH-3955 and KRH-3140: Binding Specificity, Pharmacokinetics and Anti-HIV-1 Activity in vivo and in vitro. 13th CROI. Abstract 49LB.
18. Delmedico M, Bray B, Cammack N et al. Next Generation HIV Peptide Fusion Inhibitor Candidates Achieve Potent, Durable Suppression of Virus Replication in vitro and Improved Pharmacokinetic Properties. 13th CROI. Abstract 48.
19. Vingerhoets J, Peeters M, Corbett C et al. Effect of Baseline Resistance on the Virologic Response to a Novel NNRTI, TMC125, in Patients with Extensive NNRTI and PI Resistance: Analysis of Study TMC125-C223. 13th CROI. Abstract 154.
20. Boffito M, Winston A, Fletcher C et al. Pharmacokinetics and ART Response to TMC114/r and TMC125 Combination in Patients with High-level Viral Resistance. 13th CROI. Abstract 575c.
21. Ray A, Vela J, Mackman R et al. Amidate Prodrug of a Nucleotide Analog GS9148 Enhances the in vitro Intracellular Delivery of the Active Diphosphate Metabolite: Potential for Clinical Efficacy 13th CROI. Abstract 498.
22. Cihlar T, Ray A, Boojamra D et al. GS9148: A Novel Nucleotide Active against HIV-1 Variants with Drug-resistance Mutations in Reverse Transcriptase. 13th CROI. Abstract 45.
23. Ehteshami M, Deval J, Barry S et al. Nucleotide-competing Reverse Transcriptase Inhibitors form a Stable Dead-end Complex with the HIV-1 Enzyme. 13th CROI. Abstract 47.
24. Jochmans D, Van Marck H, Van Ginderen M et al. Mutational Patterns Associated with Reduced and Increased Susceptibility to NcRTI in >6000 Clinical HIV-1 Isolates. 13th CROI. Abstract 500.
25. Lennerstrand J, Bluemling G, Ruckstuhl M et al. 1-(ß-D-Dioxolane) Thymine Is Effective against HIV-1-containing TAM and M184V. 13th CROI. Abstract 46.
26. Nakata H, Koh Y, Kodam E et al. Intracellular Metabolism of 2’-Deoxy-4’-C-Ethynyl-2-Fluoroadenosine, a Novel 4’-C-Ethynyl Nucleoside Analog Potent against Multidrug-resistant HIV-1 Variants. 13th CROI. Abstract 499.
27. Erickson-Viitanen S, Hou K, Lloyd Jr R et al. Baseline Genotype/Phenotype, Virological Response, and Lack of de novo Resistance Mutation Generation during Therapy with Dexelvucitabine (Formerly Reverset) in Study RVT-203. 13th CROI. Abstract 632.
28. Gulnik S, Afonina E, Eissenstat M et al. SPI-256, a Highly Potent HIV Protease Inhibitor with Broad Activity against MDR Strains. 13th CROI. Abstract 501.
29. Koh Y, Nakata H et al. Determination of Resistance Profile of GRL-02031, a Novel Nonpeptidic Protease Inhibitor Containing a Cyclopentanyltetrahydrofuran Moiety. 13th CROI. Abstract 503.
30. Strubble K. The Role of Drug Interaction Studies in Early Antiretroviral Drug Development. 13th CROI. Abstract 53.
31. Boffito M, Winston A, Fletcher C et al. Pharmacokinetics and ART Response to TMC114/r and TMC125 Combination in Patients with High-level Viral Resistance. 13th CROI. Abstract 575c.
32. Sekar V, De Meyer S, Vangeneugde T et al. Pharmacokinetic/Pharmacodynamic Analyses of TMC114 in the POWER 1 and POWER 2 Trials in Treatment-experienced HIV-infected Patients. 13th CROI. Abstract 639b.
33. de Bethune MP et al. Effect of Baseline Susceptibility and On-Treatment Mutations on TMC114 and Control PI Efficacy: Preliminary Analysis of Data from PI-Experienced Patients from the POWER 1 and POWER 2. Oral Abstract.
34. Kilgore N, Reddick M, Zuiderhof M et al. The First-in-Class Maturation Inhibitor, PA-457, Is a Potent Inhibitor of HIV-1 Drug-resistant Isolates and Acts Synergistically with Approved HIV Drugs in vitro. 13th CROI. Abstract 509.
35. Smith P, Forrest A et al. Pharmacokinetics/Pharmacodynamics of PA-457 in a 10-day Multiple Dose Monotherapy Trial in HIV-infected Patients. 13th CROI. Abstract 52.
36. Adamson C, Salzwedel K et al. Viral Resistance to PA-457, a Novel Inhibitor of HIV-1 Maturation. 13th CROI. Abstract 156.
37. Blair W, Cao J, Jackson L et al. Execution of a High Throughput HIV-1 Replication Screen and the Identification of a Novel Small Molecule Inhibitor that Targets HIV-1 Envelope Maturation. 13th CROI. Abstract 50LB.