International AIDS Society–USA Topics in HIV Medicine Perspective Current Status of New Antiretroviral Drugs in Development At the International AIDS Society–USA HIV Nucleoside Reverse (Margolis et al, J Acquir Immune Defic course in Washington, DC, in May Transcriptase Inhibitors Syndr Hum Retrovirol, 1999; Ying et al, 2002, Roy M. Gulick, MD, MPH, dis- Antiviral Res, 2000). Phase 2 studies of cussed characteristics of select investi- Amdoxovir amdoxovir, both with and without gational antiretroviral drugs, including mycophenolic acid, are in progress. new reverse transcriptase and pro- Amdoxovir (DAPD) is an investigational tease inhibitors and drugs that inhibit HIV Nonnucleoside Reverse HIV entry and integration. guanine analogue active in vitro against both HIV and hepatitis B virus. Transcriptase Inhibitors Pharmacokinetic data support twice- Currently, 16 antiretroviral drugs are daily dosing of the compound. BMS 56,1390 (DPC-083) approved for treatment of HIV infection. Amdoxovir is active in vitro against A number of NNRTIs that are structural- However, even the best currently avail- zidovudine-resistant and lamivudine- ly related to efavirenz have been devel- able regimens pose challenges with resistant virus and some multidrug- oped, and the leading clinical candidate regard to adherence, toxicity, antiviral resistant strains with the reverse tran- activity, and resistance. New drug devel- scriptase codon 69 insertion. The Table 1. New Formulations and opment thus confronts the need for reverse transcriptase mutations K65R improved convenience and tolerability, Dosing Strategies of Existing and L74V reduce susceptibility to the Antiretroviral Drugs reduced toxicity, and improved activity compound in vitro. The K103N mutation against both wild-type and drug-resis- associated with efavirenz resistance may tant viruses. Other goals of drug devel- HIV Nucleoside Reverse Transcriptase be associated with hypersensitivity to Inhibitors opment include improved drug penetra- amdoxovir. In animal toxicity studies, • zidovudine bid dosing*; controlled- tion into viral reservoirs (eg, genital tract the compound produced an obstructive release formulation qd and central nervous system) and nephropathy, caused by crystallization exploitation of additional viral targets of the compound in the renal tubules, • didanosine enteric-coated capsule qd* with the aims of achieving additive or that led to hyperglycemia and cataracts • zalcitabine bid synergistic effects with drugs from exist- in some animals. • stavudine extended release 100 mg qd ing classes, reducing or preventing viral In an initial study in 24 patients who • lamivudine qd* resistance, and improving treatment had received prior zidovudine or stavu- • lamivudine/zidovudine fixed-dose options in cases of drug resistance. dine and prior lamivudine, amdoxovir combination* Newly available or investigational was given at 200 mg, 300 mg, or 500 mg • lamivudine/zidovudine/abacavir fixed- formulations or doses of existing nucle- twice daily after drug washout or at 500 dose combination* oside reverse transcriptase inhibitors mg twice daily in addition to the • lamivudine/abacavir fixed-dose (nRTIs), nonnucleoside reverse tran- patients' current regimen (Raffi et al, 5th combination scriptase inhibitors (NNRTIs), and pro- Int Cong Drug Ther HIV Infect, 2000). In HIV Nonnucleoside Reverse tease inhibitors (PIs) are shown in Table patients undergoing drug washout, Transcriptase Inhibitors 1. Selected investigational drugs in amdoxovir 500 mg twice daily reduced existing and new drug classes are shown plasma HIV-1 RNA level by a median of • delavirdine 200-mg tablet* in Table 2; select drugs from this listing 1 log copies/mL at 15 days, with small- • efavirenz 600-mg capsule* are discussed herein. Figures 1 and 2 10 er reductions observed at lower doses. HIV Protease Inhibitors show the HIV-1 life cycle and the stages The addition (without washout) of of the life cycle targeted by available • saquinavir soft-gel formulation*; amdoxovir to background treatment 800-mg hard-gel capsule drug classes and by drugs from newer produced a median 2-log decrease in 10 • nelfinavir bid dosing*; 625-mg tablet and investigational classes such as entry plasma HIV-1 RNA level, although the inhibitors and integrase inhibitors. reason for this greater decrease is not • ritonavir enhancement of saquinavir, clear. Mycophenolic acid inhibits ino- indinavir, or amprenavir* Dr Gulick is Associate Professor of sine 5’-monophosphate dehydrogenase • lopinavir/ritonavir coformulation* Medicine at Weill Medical College of and thereby depletes intracellular dGTP • GW433908 (amprenavir prodrug VX-175) Cornell University and Director, Cornell levels, thus enhancing the in vitro antivi- University HIV Clinical Trials Unit, New ral activity of guanosine nucleoside ana- * Currently approved by the US Food and York Presbyterian Hospital, New York. logues such as abacavir and amdoxovir Drug Administration. 14 Perspective - Antiretroviral Drugs in Development Volume 10 Issue 4 September/October 2002 is BMS 56,1390 (formerly DPC-083). This Table 2. Selected Investigational Antiretroviral Drugs compound exhibits good oral bioavail- ability and has a half-life of greater than HIV nRTIs HIV Entry Inhibitors 90 hours, supporting once-daily and per- • ACH-126,443 (L-Fd4C) • CD4 attachment inhibitors haps less frequent dosing. The com- • alovudine (FLT, MIV-310) — BMS-806 pound undergoes metabolism via the • amdoxovir (DAPD) — PRO 542 cytochrome P450 (CYP) 3A4 and 2B6 • D-FDOC • Coreceptor inhibitors hepatic isoenzyme systems. Compared • DPC 817 (D-d4FC) — CXCR4 inhibitors with efavirenz, BMS 56,1390 exhibits 3- • emtricitabine (FTC) – AMD-3100* fold greater activity in vitro against • SPD 754 – AMD-070 K103N mutants and some double • SPD 756 (BCH-13520) — CCR5 inhibitors mutants. Resistance in vitro appears to – PRO 140 require the presence of more than 1 HIV NNRTIs – SCH-C (SC-351125) reverse transcriptase mutation. The – SCH-D • BMS 56,1390 (formerly DPC-083) – UK-427,857 compound currently is in phase 2 and 3 • calanolide A evaluation. • Fusion inhibitors • capravirine (Ag-1549) — enfuvirtide (T-20) In a recently reported study, 134 • HBY 1293 — T-1249 treatment-naive patients with an aver- • MIV-150 age plasma HIV-1 RNA level of 33,000 • SJ-3366 copies/mL and CD4+ cell count of • TMC 125 HIV Integrase Inhibitors 402/µL received fixed-dose lamivudine/ • L-870810 zidovudine at the standard dose plus HIV Protease Inhibitors • S-1360 efavirenz 600 mg or BMS 56,1390 at 50- • atazanavir (BMS 232632) mg, 100-mg, or 200-mg once-daily • mozenavir (DMP-450) Other doses. In an intent-to-treat analysis, • tipranavir 60% to 70% of patients in the 4 arms had • TMC 114 • PA-344b (double-stranded DNA plasma HIV-1 RNA level reduced to less production inhibitor) than 50 copies/mL at 16 weeks (Ruiz et HIV ntRTIs • PA-457 (maturation/budding inhibitor) al, Abstract 7, 9th CROI, 2002). • GS 7340 In another study, 75 NNRTI-experi- enced/PI-naive patients in whom current therapy was failing received 2 nRTIs NNRTIs indicates nonnucleoside reverse transcriptase inhibtors; nRTIs, nucleoside reverse selected on the basis of genotypic anal- transcriptase inhibitors; ntRTIs, nucleotide reverse transcriptase inhibitors. *Clinical develop- ysis and BMS 56,1390 at 100 mg or 200 ment discontinued. mg once daily (Ruiz et al, Abstract 6, 9th CROI, 2002). At baseline, patients had TMC 125 (Gazzard et al, 9th CROI, 2002). Further an average plasma HIV-1 RNA level of studies are in progress. The blunted 6900 copies/mL and a CD4+ cell count of TMC 125 is an investigational NNRTI antiretroviral response in NNRTI-experi- 518/µL; 61% had received prior nevirap- that exhibits antiretroviral activity in enced subjects compared with NNRTI- ine and 39% had received prior efavirenz. vitro against a high proportion of clini- naive subjects in these pilot studies A total of 31% of patients discontinued cal HIV isolates with resistance to nevi- suggests that some degree of resistance study treatment early. In most cases, rapine, delavirdine, or efavirenz. In a is conferred by NNRTI-associated muta- discontinuation was due to violation of study in treatment-naive, HIV-infected tions. This concern supports the early study protocol by prior receipt of PI patients with an average baseline HIV-1 discontinuation of currently available treatment. Approximately 40% to 50% of RNA level of 58,000 copies/mL and NNRTI-based regimens after confirmed all patients had a plasma HIV-1 RNA CD4+ count of 650 cells/µL, TMC 125 900 virologic failure, in order to avoid the level less than 400 copies/mL at 16 mg twice daily given as monotherapy accumulation of additional NNRTI-asso- weeks in an intent-to-treat analysis. produced a 2-log10 reduction in plasma ciated mutations that may compromise Unexpectedly, adverse effects were more HIV-1 RNA level in 12 patients at 7 days, the activity of investigational NNRTIs, common in patients receiving the 100- compared with no change in 7 placebo including TMC 125. mg dose of BMS 56,1390 than in those recipients (Gruzdev et al, 41st ICAAC, receiving the 200-mg dose. Rash was 2001). In a study in 16 NNRTI-experi- HIV Protease Inhibitors observed in the 100-mg group but not in enced patients (prior nevirapine in 81% the 200-mg group; other adverse effects and prior efavirenz in 19%) with an aver- Atazanavir included headache and somnolence. No age plasma HIV-1 RNA level of 16,000 decision regarding the dose of the com- copies/mL and a CD4+ cell