Quick Reference Guide to New Antiretrovirals

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Quick Reference Guide to New Antiretrovirals Malte Schütz, MD Last Updated: January 3, 2002 -------------------------------------------------------------------------------- This table provides an overview of antiretroviral agents currently under development. Since these compounds are being actively researched and evaluated, the information in this table may not always be up-to-date, and may change over time; please read and interpret accordingly. If you have further information on a compound, or feel a new drug is missing, please email the author at [email protected] Nucleosides Name & Manufacturer Dosing Description Emtricitabine (aka FTC; Brand: Coviracil) Triangle/Abbott 200 mg once daily Similar to 3TC, more potent in vitro, same resistance pattern via 184 mutation. Currently in phase II/III; 1.9 log HIV RNA reduction demonstrated in vivo at 2 weeks. Liver toxicity in conjunction with nevirapine observed in studies. Anti-HBV activity in vitro. Lodenosine (aka F-ddA ) Triangle/Abbott Once daily Similar to ddI but acid-resistant. Possible activity vs. RT mutants, but questionable overall potency in early trials - 0.44 log HIV RNA reduction at 6 weeks - further development on hold. DOTC (aka BCH 10652) Biochem Pharma Once daily; no food effect Thiacytidine like 3TC, but racemic mixture; enantiomers have different activity. Possibly active against AZT/3TC-resistant strains; first mutation is V75I followed by K65R and M184V; 3TC-resistant strains have 3-fold decreased susceptibility. t_ >12hrs; good CNS penetration. In phase II evaluation, delayed by reports of animal toxicity. Amdoxovir (aka DAPD) Triangle/Abbott 300-500 mg twice daily dosing Guanosine analog with DXG as active metabolite . In vitro activity against AZT/3TC- and multi-resistant strains, including those carrying the codon 69 insertion mutation; resistance with 151M mutation. Currently in phase II. Anti-HBV activity in animal models. D-D4FC Related to 3TC with activity against AZT/3TC-resistant virus. Less potent than 3TC against wild type virus. DPC 817 Cytidine analog active against wild-type, AZT-, and 3TC-resistant HIV. In phase I dose-finding studies in HIV-infected individuals. NNRTIs Name & Manufacturer Dosing Description Emivirine (aka MKC442; Brand: Coactinon) Triangle/Abbott Twice daily; no food effect Structurally an NRTI functioning as NNRTI. 1.4 log HIV RNA reduction at week 8. Currently in phase III. K103N mutation leads to emivirine resistance and cross-resistance to current NNRTIs. Other mutations associated with treatment failure: V108I, Y181C, G190A and E138K. Common side effects: nausea, headache, transient dizziness, rash. Current studies deemed insufficient by the FDA for US market approval DPC 083 DuPont Once daily 2nd generation derivative of efavirenz. Activity against K103N and K103N/Y181C mutant virus. Long t _ of about 150 hrs. Capravirine (aka AG1549 or S-1153) Agouron-Pfizer Twice daily 0.7-2.6 log HIV RNA reduction at week 4. Currently in phase II/III. Some nausea and metallic taste. Twice daily dosing. Decreased bioavailability in presence of gastric pH-lowering agents. Activity vs. K103N mutant; limited activity when Y181C or multiple mutations present. Combination of V106A and F227L leads to high level resistance. Development being resumed after delay due to vasculitis observed in dogs. Calanolide A Naturally-occurring NNRTI from the latex tree. Activity vs. virus with either Y181C, K103N or both mutations. TMC 125 (aka R165335) Tibotec Promises activity in strains resistant to currently available NNRTIs, including variants with L100I, K103N, Y181C, Y188L or G190A/S mutations. Phase 2A studies presented at ICAAC 2001, demonstrating antiviral activity. Protease Inhibitors Name & Manufacturer Dosing Description Tipranavir (aka PNU 140690) Boehringer Ingelheim Twice daily with ritonavir boosting Non-peptic dihydropyrone. Activity vs. certain PI-resistant strains. Reformulated and coadministered with ritonavir, and currently in dose-finding studies. GI side-effects. P450 CYP3A4 inducer. Atazanavir (aka BMS 232632) Bristol-Myers Squibb 400 mg (1-2 tab) once daily Azapeptide. Good in vitro potency; activity against virus with resistance to 1 or 2 PI's. Resistance likely in virus with high-level PI resistance. Selects for N88S mutation, which may hypersensitize to other PIs. Currently in phase 3. >50% bioavailability; PK supports QD dosing. Increased absorption with food. Hyperbilirubinemia common, hyperlipidemias rare. GW-433908 (aka VX-175) Vertex & Glaxo Welcome 2-3 tab twice daily Water soluble phosphate prodrug of amprenavir. May lead to dose simplification of amprenavir and decrease in pill burden Mozenavir (aka DMP 450) Nonpeptomimetic cyclic urea compound, active against D30N and L90M mutant HIV. BID and TID dosing being evaluated (1st IAS conference, 2001) TMC 126, TMC 114 Tibotec Tight binding to protease enzyme; promising resistance profile. Designed to be physically flexible with high affinity to protease active site. DPC 681 & 684 DuPont 2nd generation PIs with activity against resistant strains including mutants at codons 82, 84, and 90. Clinical data pending. Integrase Inhibitors Name & Manufacturer Dosing Description DCQA/DCTA Activity in micromolar range; resistance demonstrated Zintevir (aka AR 177) Arondex Oligonucleotide. Probably acts at cell surface and not as true integrase inhibitor. Fusion Inhibitors Name & Manufacturer Dosing Description Pentafuside (aka T-20) Trimeris & Roche SQ injection twice daily 36 amino acid peptide derived from the gp41 transmembrane protein ectodomain of HIV; binds to resting p41 and prevents transformation to the fusogenic state; blocks HIV cell entry. Currently in phase III. Activity vs. HIV-1; 1.2 log HIV RNA reduction. Resistance can develop. Local irritation at injection site. T-1249 Trimeris SQ injection once daily 2nd generation fusion inhibitor based on T-20. 2-100 times more active than T-20. Promises slower development of resistance. Generally active in T-20 resistant HIV. PRO 542 Parenteral Blocks interaction of gp120 with CD4 receptor. Synergistic in vitro with other fusion inhibitors. Hydroxyurea-like Compounds Name & Manufacturer Description BCX-34 Biocryst Purine nucleoside phosphorylase inhibitor. Didox Molecules for Health Ribonucleotide reductase inhibitor. VX-497 Vertex Inosine monophosphate dehydrogenase (IMPDH) inhibitor. Enhances ddI activity by increasing concentration of triphosphate form of ddI. Mycophenolate Mofetil (Brand: CellCept) Roche Mycophenolic acid, the active form of mycophenolate mofetil, blocks inosine monophosphate dehydrogenase (IMPDH), depleting guanosine and causing a relative increase in adenosine, which results in a similar effect on nucleosides as hydroxyurea. Chemokine Receptor Antagonists Chemokine receptor antagonists include CXCR4 and CCR5 inhibitors. CCR5 and CXCR4 are not the only HIV co-receptors: CCR2B, CCR3 and CCR6 also bind HIV. HIV strains may be dual-tropic for CCR5 and CXCR4 and can change their co-receptor tropism over time. A polyvalent approach to inhibition may be necessary. Activity of some compounds is cell type dependent. A CCR5 inhibitor may drive the virus to CXCR4 phenotype which frequently is syncytium-inducing and potentially more pathogenic. CXCR4 deficiency is associated with developmental defects and embryonic death in mice; thus inhibition may have negative consequences in humans. First studies with CXCR4 inhibitors have not demonstrated clinical efficacy. Cardiac conduction abnormalities have