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  8th European Conference on Clinical Aspects and treatment of HIV-Infection (ECCATHI)
Athens, Greece - October 2001
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Program Abstracts Presented by Tibotec/Virco at the 8th European Conference on Clinical Aspects and Treatment of HIV Infection (ECCATHI) in Athens, Greece
  These two companies have merged and are developing NNRTIs and protease inhibitors for HIV with resistance to NNRTIs and protease inhibitors. One of the lead drug discoverers is John Erickson who played a key role in developing protease inhibitors years ago. He has been presenting at conferences for several years on his work to develop drugs that would be effective against resistant HIV. Data has been previously presented on their NNRTIs and PI. Both preliminarily appear to have antiviral activity against NNRTI and PI resistant virus. They are in the early stages of clinical development, and in Athens Tibotec/Virco reported several abstracts. Further human studies are required and will reveal how effective these drugs are against resistant virus, for whom they will work (will they work against all resistant virus or only virus with a certain degree of resistance?), and the safety profile of these drugs. Although the information in these abstracts are not necessarily new, for your information here they are. Virco is a Belgium based company that offers resistance testing and is developing drug levels testing.
R Pauwels
Tibotec-Virco NV, Mechelen, Belgium
HIV-1 drug resistance is a major cause of treatment failure and there is evidence of increasing transmission of drug resistant virus. Resistance is caused by mutations in the HIV-1 genome coding for structural changes in the target enzymes that can affect the binding or activity of the inhibitors. We are, therefore, developing new compounds that are designed to bind more effectively to mutated virus enzymes and to be highly active against resistant viral strains.
A new, accelerated drug screening strategy is being used to expedite the development of these new HIV drugs. Candidate compounds with anti-HIV activity in a primary screen are evaluated both for antiviral activity against drug-resistant HIV strains and for suitable pharmacokinetic properties, in parallel. Compounds in the non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) classes are under development and currently entering the Phase II and Phase I clinical trials, respectively.
The two lead NNRTIs, TMC120 and TMC125, remain highly active in vitro against most site-directed mutant HIV-1 strains with the 'classic' mutations associated with NNRTI-resistance, as well as against most NNRTI-resistant recombinant clinical isolates. In vitro selection experiments show that these compounds are associated with reduced and delayed resistance development, involving more mutations, compared with the first generation NNRTIs. Phase I monotherapy results with TMC 120/125 demonstrate a 1.5-2.0 log reduction in HIV-1 RNA in drug naive patients.
The PIs, TMC 114 and 126 bind very tightly and flexibly to protease and are highly active at sub-fentomolar concentrations. In vitro selection demonstrates that only low level resistance can be generated after very prolonged passage. HIV-1site-directed mutants with classical PI mutations exhibit reduced fitness in the presence of the compounds, raising the possibility that these inhibitors represent a new class of 'resistant-repellent' compounds that are able to prevent or delay the development of PI-resistance.
H Jonckheere1, H Azijn1, F Roobaert1, L Panitti1, K Andries2, P Lewi3, R Pauwels1 and MP de Béthune1. Tibotec-Virco, Mechelen, Belgium1; Janssen Research Foundation, Beerse, Belgium 2;Janssen Research Foundation, Vosselaar, Belgium3
Background of study: HIV treatment failure is often associated with the development of HIV drug resistance. There is an urgent need for new drugs active against resistant HIV variants. Objective: To accelerate the identification of promising anti-HIV clinical candidates, active against HIV resistant to current inhibitors. Design: A parallel rather than sequential screening strategy has been set up. Compounds showing antiviral activity in the primary screen were evaluated for their capacity to inhibit HIV strains resistant to the current drugs. Simultaneously, other properties of the compounds were assessed to help identify candidates with a "drug-like" profile. Results: The screening process will be illustrated by the data recently obtained with our potent non-nucleoside reverse transriptase inhibitors (NNRTI) TMC120 and TMC125. These drug candidates were first selected phenotypically on the basis of their excellent antiviral profile against a panel of HIV strains exhibiting both phenotypic resistance and mutations that have been characterised as being clinically relevant. For most of the viruses tested the EC50 did not exceed 100nM. These compounds were further profiled against a random selection of about 2000 recent blood samples from routine clinical practice using the Antivirogram® phenotyping assay. Both the influence of human serum proteins on the antiviral activity of candidate compounds and their metabolic stability were also addressed very early in the selection process. These are useful parameters in predicting efficacy of the possible drug candidates in vivo. Preliminary pharmacokinetic experiments were performed to assess the bio-availability in rats and dogs. Furthermore, combination experiments were performed in order to evaluate in vitro the potential for antagonism or synergism between the selected drug candidates and the anti-HIV inhibitors currently in use. Conclusion: We applied a parallel, rather than a sequential screening strategy, in which candidates were simultaneously tested against wild type virus, profiled against a subset of resistant HIV mutants, as well as evaluated for pre-clinical parameters, such as the potential influence of human serum protein binding, metabolic stability, bio-availability and interaction with other HIV inhibitors on efficacy. This accelerated discovery and development process enabled us to enter clinical studies with TMC120 and TMC125, within one year of obtaining their first screening results.
One week of monotherapy with TMC125, a novel highly potent NNRTI, produces a mean 2-log reduction in viral load in antiretroviral-naive, HIV-1 infected volunteers
B. Gruzdev1, A. Rakhmanova2, G. van 't Klooster3, K. De Dier3, S. Comhaire4, P. Baede-Van Dijk5, M.P. de Béthune3, and R. Pauwels3 1Inf. Dis. Hosp., Moscow, Russia; 2Med. Acad. Postgraduate Studies, St. Petersburg, Russia; 3Tibotec-Virco, Mechelen, Belgium; 4MediSearch Int., Mechelen, Belgium, 5Kinesis, Breda, The Netherlands.
Background of study: TMC125 (R165335) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with equipotent in vitro activity (EC50 = 1-10 nM) against wild-type HIV-1 and NNRTI-resistant variants encoding L100I, K103N, Y181C, Y188L or G190A/S mutations.
Objective: To evaluate the antiviral activity of TMC125 as monotherapy in antiretroviral-naive patients.
Design: Randomized, double-blind, placebo-controlled Phase IIA study. Twelve antiretroviral-naive HIV-1 infected volunteers received 900mg TMC125 BID as monotherapy for 7 days, and six patients took matching placebo. Standard-of-care antiretroviral therapy was offered after day 7.
Results: Nineteen male patients were enrolled, with the following median baseline characteristics: age: 23 years; CD4 cell count: 650 cells/µL; HIV-1 RNA: 57,619 copies/ml. One volunteer (placebo) was withdrawn on day 4 because of heartburn. Mean values (± SE) for plasma viral loads by treatment group are tabulated:
After 7 days of dosing, 2 out of 12 TMC125-treated patients, with baseline viral loads of 61,551 cps/ml and 5,643 cps/ml, respectively, achieved plasma viral loads below 50 cps/ml, and 8 of 12 below 400 cps/ml. No viral rebounds were observed. Comparing pre-dose and end-of-treatment RT genotypes, no resistant-associated changes were found. TMC125 was safe and well tolerated. Seven patients (3/placebo, 4/TMC125) reported adverse events. Adverse events in the TMC125 group were mild. Somnolence was most common (n=3 on TMC125, n=1 on placebo). Pharmacokinetic steady state was attained in 4 days. The mean (± SD) TMC125 trough plasma level was 237 ± 76 ng/ml.
Conclusion: TMC125 given as monotherapy at 900 mg BID for 7 days in antiretroviral-naive patients is a safe, well tolerated and highly potent NNRTI.
  The Relative Inhibitory Quotient (RIQ): A Method for Predicting Response to Protease Inhibitors
Background: Resistance testing provides information to clinicians regarding the susceptibility of a patient's HIV-1 to a drug compared to the susceptibility of a reference strain but currently does not include an estimate of whether the patient's drug levels are high enough to inhibit a wild-type or partially resistant strain. Given the wide variability in protease inhibitor concentrations and the common use of pharmacokinetic boosting to achieve higher concentrations, a measure (inhibitory quotient, or IQ) that incorporates both an individual's drug exposure and the drug susceptibility of the infecting virus might prove useful in predicting antiviral outcome. Because intracellular triphosphate concentrations of NRTIs are generally not measured, and because resistance in NNRTIs is less incremental than in PIs, an IQ is likely to be most useful for PIs.
Objective: To develop and validate a tool that is predictive of virologic outcome using the concept of the inhibitory quotient.
Design: To determine the RIQ, the IQ in an individual patient (IQpt) is calculated as the ratio of the patient's trough concentration (Cmin) to the predicted susceptibility of the patient's virus to the drug, expressed as fold change compared to wild type virus (Virtual Phenotype). The IQpt is then related to the reference inhibitory quotient (IQref), in which the mean population trough concentration of the drug is divided by the cut-off value of the fold change for susceptible viruses. Thus, the RIQ = IQpt / IQref in which a value of greater than 1.0 should be targeted to optimize response. To evaluate its predictive ability, the RIQ was evaluated in 17 treatment-experienced patients with viremia despite HAART who received efavirenz, amprenavir (APV), abacavir and either ritonavir (RTV) or nelfinavir (NFV). Pharmacokinetic profiles for all drugs were collected at week 3 of therapy. Genotyping and virtual phenotyping were performed on baseline samples. For each drug, the RIQ, the trough level, and the virtual phenotype were examined for a correlation with the change in viral load from baseline to week 24.
Results: Using a sigmoidal Emax model, the APV RIQ correlated with outcome at 24 weeks. Viral load to < 400 copies/ml at week 24 was seen in 7/8 patients achieving RIQ > 3.0 for APV and 1/9 patients with RIQ < 3.0 (p = 0.003). Cmin or phenotype alone were less predictive of outcome than the RIQ for APV. RIQ values for APV, RTV, and NFV were a median (range) of 2.8 (0.28-41.1), 0.005 (0.002-0.29), and 0.72 (0.15-38.9), respectively. The RIQ, Cmin, or phenotype for the other drugs in the regimen did not correlate significantly with outcome, however, RIQs for NFV and RTV were too low in these PI-experienced patients to suggest response.
Conclusions: The RIQ is a new method to evaluate the relationship between concentrations of amprenavir and possibly other drugs and viral susceptibility that avoids complex protein binding corrections and correlates with clinical outcome.