Volume 8 Issue 4 June 2000 International AIDS Society–USA

Perspectives Investigational Drugs in HIV Therapy: Review of Select New Antiretrovirals

Martin S. Hirsch, MD

New antiretroviral drugs at various kinases. Its predecessor adefovir is no Resistance to tenofovir can be generat- stages of investigation and develop- longer being developed for HIV therapy ed in vitro by a K65R mutation, but thus far ment were reviewed by Martin S. because of concerns related to antiviral this mutation appears to be uncommon in Hirsch, MD, at the Boston course in activity and renal toxicity. Tenofovir tenofovir-treated patients. The insertion March. exhibits a half-life that permits once-daily mutations at positions 69 and 70 of RT dosing and has potent in vitro activity that are associated with multi-nRTI resis- Optimal HIV-1 suppression often is diffi- against HIV (and simian immunodeficien- tance confer cross-resistance to tenofovir. cult to achieve and maintain with current- cy virus [SIV]), including activity against Although available clinical data on teno- ly available antiretroviral drugs, and viral nRTI-resistant HIV and multidrug-resistant fovir use thus far extend only to the 24- to resistance eventually emerges to many virus with the Q151M mutation. 72-week period, significant nephrotoxicity drugs. Chronic antiretroviral therapy is In a short-term clinical study, tenofovir has not been observed to date; adefovir- also associated with complications such produced a clear dose-response in viral associated nephrotoxicity was commonly as body fat redistribution, hypertriglyc- load reduction. Although viral load observed within this time frame. Phase III eridemia and hypercholesterolemia, decreased by approximately 1.5 log in trials of tenofovir are in progress. A limited abnormal glucose metabolism, lactic aci- treatment-naive patients, the decrease expanded access program has been con- dosis, pancreatitis, avascular necrosis of was smaller in treatment-experienced ducted for patients with advanced disease, bone, and osteoporosis. New drugs are patients. In a subsequent study, treat- but is no longer open to enrollment. needed to enhance anti-HIV potency, over- ment-experienced patients with at least 8 come viral resistance, increase tolerability weeks of stable potent therapy (mean, 4.6 and convenience, and reduce toxicity. A years of therapy), viral load of 400 to Nucleoside Reverse number of antiretroviral drugs are in 100,000 HIV RNA copies/mL, and adequate Transcriptase Inhibitors development, including new nucleotide renal function had tenofovir at 75, 150, or reverse transcriptase inhibitors (ntRTIs), 300 mg or placebo added to their current nucleoside reverse transcriptase regimen. In this study, 85% of patients had inhibitors (nRTIs), nonnucleoside reverse -resistant virus, most with mul- Emtricitabine (FTC) is a highly active transcriptase inhibitors (NNRTIs), pro- tiple mutations, and 67% had the lamivu- oxathiolane with tease inhibitors, fusion and coreceptor dine-associated M184V resistance muta- potency against HIV and hepatitis B virus inhibitors, and integrase inhibitors. This tion. As shown in Figure 1, dose-related (HBV) in vitro. Its structure differs from selective review will summarize some of decreases in viral load were observed, with that of only in the presence of the more promising compounds under a maximum decrease of approximately 0.8 a fluoride residue at position 5 on the study. log with the highest dose. A similar pyrimidine ring. Emtricitabine is 4- to 10- response was observed in the initial place- times more potent than lamivudine in Nucleotide Reverse bo group when tenofovir was added at 24 vitro (in some systems) and is synergistic Transcriptase Inhibitors weeks. with a broad range of nRTIs, NNRTIs, and

Tenofovir All Study Groups Switched to 300 mg

0.2 fumarate is an inves- 0.1 Placebo tigational analogue of dAMP that does not 0 require initial phosphorylation by viral -0.1 -0.2 75 mg -0.3

Dr Hirsch is Professor of Medicine at -0.4 150 mg Harvard Medical School and Director -0.5 copies/mL) from Baseline copies/mL) from Mean HIV RNA Change of Clinical AIDS Research at the 10 -0.6 300 mg

Massachusetts General Hospital in (log -0.7 Boston. Dr Hirsch is also a member of -0.8 the International AIDS Society–USA -0.9 0 48 1220 16 32 24 28 Antiretroviral Therapy Guidelines Panel and the chair of the organiza- Weeks tion's panel on guidelines for the clin- ical use of resistance testing in Figure 1. Mean change in plasma viral load according to tenofovir dose group in study 902 in treatment- antiretroviral management. experienced patients. Courtesy of Ian McGowan, MD, PhD, Gilead Sciences, Foster City, Calif.

4 Perspectives - Investigational Drugs Volume 8 Issue 4 June 2000

protease inhibitors. Plasma and intracellu- resistance, including the K103N mutation ment-naive patients received ABT-378/r lar pharmacokinetics support once-daily associated with resistance to currently 200/100 mg (respectively) or 400/100 mg dosing of the drug, with high intracellular approved NNRTIs. It also exhibits activity, twice daily alone for 3 weeks. This was fol- levels of the triphosphate form being albeit reduced, against some HIV isolates lowed by the addition of /lamivu- dose-related (apparent saturation at doses with more than one NNRTI resistance dine (Group 1) or ABT-378/r (400/100 mg or >200 mg). In early clinical studies, admin- mutation. High-level resistance to the 400/200 mg bid) together with stavudine/ istration of doses of 200 mg or higher was drug requires more than one mutation; lamivudine from study day 1 (Group 2). All associated with 1.72- to 1.92-log decreases concomitant V106A and F227L mutations patients converted to open-label in viral load. Clinical studies assessing are associated with a more than 380-fold 400/100 mg twice daily plus the other 2 once-daily dosing are under way. increase in 50% inhibitory concentration drugs at week 48. More than 90% of (IC50). In testing of doses of up to 2100 mg patients had viral load decreases to below DAPD twice daily in NNRTI-naive patients, viral 400 copies/mL at 72 weeks in on-treatment load was reduced by 1.7 log over 10 to 28 analysis. The most common adverse Diaminopurine dioxolane (DAPD), which is days, with minimal toxicity (primarily diar- events were diarrhea (19% and 22% in converted in vivo to the dioxolane guanine rhea and nausea) being observed. Groups 1 and 2, respectively), nausea (6% analogue DXG, also exhibits activity Coadministration with results in and 19%), and abnormal stools (19% and against HIV and HBV. The pharmacokinet- a 5-fold increase in the minimum concen- 3%). Elevations of total cholesterol or ics of the drug support once- or twice-daily tration of . Phase II and III stud- triglyceride levels were observed in 12% to dosing. DAPD retains activity against ies of capravirine have been initiated. 15% of patients respectively in the 2 zidovudine- and lamivudine-resistant groups. mutants, and is active against some virus Protease Inhibitors In Study M97-765, 70 patients who had with codon 69 mutations conferring multi- been receiving a protease inhibitor and 2 nRTI resistance. Virus with the K103N nRTIs for at least 3 months and had single mutation associated with NNRTI resis- Lopinavir protease inhibitor failure with viral loads tance may exhibit hypersensitivity to of 1000 to 100,000 copies/mL received DAPD. Resistance to DAPD is selected in Lopinavir (ABT-378/r) is a combination of ABT-378/r 400/100 mg or 400/200 mg twice vitro by K65R and L74V mutations. Once- and ABT-378, an investigational daily. was added and the nRTIs daily and twice-daily dose schedules cur- protease inhibitor structurally related to were changed to include at least 1 new rently are being assessed in Phase I/II ritonavir. ABT-378 exhibits 10-fold greater drug at day 15. Viral load was reduced to studies. Marked short-term activity has in vitro activity against HIV and retains below 400 copies/mL in 84% of patients at been observed in treatment-naive activity against HIV with the codon 82 week 24 in on-treatment analysis. The patients, with 14-day data indicating viral mutation characteristic of initial resis- mean increase in CD4+ cell count was load decreases of 1.5 to 2 log; treatment- tance to ritonavir and . It is also 125/µL at week 48. This degree of activity in experienced patients currently are being more active than ritonavir against virus treatment-experienced patients appears to enrolled in the early phase studies. with numerous ritonavir resistance muta- be related to the ability of this combina- tions. Each tablet of lopinavir contains tion at either study dose to maintain plas- Nonnucleoside Reverse 133.3 mg of ABT-378 and 33.3 mg of riton- ma ABT-378 concentrations exceeding the avir. Plasma levels of ABT-378 are dramati- 50% effective concentration (EC ) for virus Transcriptase Inhibitors cally increased by coadministration of low 50 in these patients (Figure 2). Lopinavir cur- doses of ritonavir, permitting twice-daily Capravirine rently is being evaluated in a Phase II study dosing. in patients with multiple protease Capravirine (Ag1549) retains activity in Lopinavir has been assessed in treat- inhibitor experience. vitro against virus with some of the single- ment-naive and treatment-experienced Phase III pivotal studies of lopinavir are point mutations characteristic of NNRTI patients. In the M97-720 study, 100 treat- under way. It currently is also available in an expanded access program limited to patients with advanced HIV disease, and 400/200mg/q12h criteria for wider availability are in devel- 10 opment.

400/100mg/q12h

1 Tipranavir is a nonpeptide drug that Range, EC of Viral Isolates 50 exhibits broad activity against protease inhibitor-resistant variants. A study of 107

of Lopinavir (mg/mL) 0.1 highly protease inhibitor-resistant clinical

24-Hour Mean Concentration virus variants (>10-fold reduction in sus- 0 ceptibility to 3 or more drugs) showed that 90% were susceptible to tipranavir. Some variants were hypersensitive to the drug Figure 2. Lopinavir 24-hour mean concentrations at study dosages and 50% effective concentrations (EC50) and only 3% had more than 10-fold reduc- for HIV isolates (adjusted for 50% serum) in study M97-765. Courtesy of Eugene Sun, Abbott Laboratories, tion in susceptibility. In vitro resistance to Abbott Park, Ill. tipranavir is associated with the 82T/84V

5 Volume 8 Issue 4 June 2000 International AIDS Society–USA

Table 1. Early Phase Study of a Pentafuside-Containing Multidrug Salvage Regimen against pentafuside-resistant HIV. The drug was designed to provide improved Patients/ 55 patients/Used a median of 11 prior pharmacokinetics, and Phase I/II dose- Drug History antiretrovirals (93% with exposure to escalating trials including once-daily par- 3 drug classes) enteral administration are under way. Although pentafuside and T-1249 may Median 70 cells/mL prove to be of clinical utility, the need for Baseline long-term subcutaneous administration is CD4+ Count a drawback. Orally available fusion inhibitors directed at the same target are Median 4.9 log10 copies/mL under development. Baseline HIV RNA Drugs Acting on Other Targets At 16 weeks, no. of patients with: Coreceptor Blockers HIV RNA >1 log10 below baseline or 33 of 55 (60%) with <400 copies/mL at 16 weeks Other drugs in development that act at the viral attachment or entry stage include <400 copies/mL 20 of 55 (36%) blockers of the HIV coreceptors CCR5 (AOP-RANTES and Schering-C) and CXCR4 (AMD3100 and T140). Studies in Adapted from Lalezari et al, 39th ICAAC, 1999. vitro have shown that the combination of pentafuside and the CXCR4 blocker and 84V/90M mutations, but these muta- combinations with 2 nRTIs in treatment- AMD3100 is strongly synergistic against tions have not been consistently observed. naive patients and of once-daily adminis- lymphotropic (X4) viral isolates, indicating Development of tipranavir has been tration in combination with in that targeting of sequential steps in hindered by formulation problems and protease inhibitor-experienced patients. attachment or entry may be a useful strat- rapid metabolism by the cytochrome P450 egy. Clinical activity of coreceptor blocker 3A4 isoenzyme. Initial studies indicated Fusion Inhibitors compounds has yet to be demonstrated. that the drug was associated with a mod- est 1.0- to 1.5-log decrease in viral load Pentafuside Integrase Inhibitors over 28 days with 1500 mg 3 times a day; it Pentafuside (T-20), a 36-amino acid pep- appears that adherence to the study regi- The HIV integrase is responsible for insert- tide, is a specific and potent inhibitor of men was poor due to the number of pills ing proviral DNA into the host cell -mediated fusion of HIV with the host required. A new formulation currently is genome. This enzyme, for which there is no cell membrane. It does not exhibit cross- being evaluated, and it has been shown known cellular homologue, is conserved in resistance to other current antiretrovirals that trough concentrations of the drug are all retroviruses and is required for stable and has a synergistic effect in vitro with increased 7- to 40-fold by coadministered maintenance of the viral genome and effi- several reverse transcriptase inhibitors ritonavir, allowing twice-daily dosing of cient viral gene expression. Much work has and protease inhibitors. The drug must be the drug. Phase II studies of the new for- been done over the past several years in administered parenterally and is currently mulation of tipranavir combined with the attempt to develop integrase being evaluated using a twice-daily subcu- ritonavir (1200/200 mg bid, respectively) in inhibitors. Progress has been slowed by taneous injection regimen. In an early- treatment-naive patients are in progress. the difficulty inherent in the in vitro study phase study, pentafuside treatment was of the multistep process culminating in associated with a 1.5- to 2.0-log decrease BMS 232,632 integration of the proviral DNA. Inhibitor in viral load and a mean increase in CD4+ molecules identified in this research have cell count of 215/µL over 32 weeks in treat- BMS 232,632 is an azapeptide drug with been primarily DNA-binding compounds ment-experienced patients. Sixteen-week activity against variants resistant to nelfi- that prevent assembly of the viral preinte- data are presented in Table 1. Systemic navir and saquinavir and partial activity gration complex. These inhibitors are rela- toxicity with the drug has been infrequent. against indinavir- and ritonavir-resistant tively nonspecific for HIV integrase and Resistant isolates have been obtained in virus. It is suspected to have a resistance exhibit poor antiretroviral activity in tissue vitro and resistance in vivo has been pathway unique among protease culture. observed after prolonged therapy in asso- inhibitors. Bioavailability of the drug is However, a recent report indicates the ciation with mutations in HIV gp41. 53% to 72% and the terminal half-life is 3 development of a class of integrase Pentafuside currently is in Phase II trials. to 7 hours, suggesting that once-daily dos- inhibitors that bind to the preintegration ing may provide adequate minimum con- T-1249 complex and inhibit the strand-transfer centrations. The drug also exhibits favor- reaction in integration. These molecules able pharmacokinetics in combination T-1249, a 39-amino acid hybrid peptide of exhibit potent inhibition of HIV replication with saquinavir. Phase II studies of BMS HIV-1, HIV-2, and SIV, was designed to in tissue culture; their activity against HIV 232,632 are in progress, including evalua- bind to a different gp41 region than penta- integrase is indicated by the development tion of short-term activity of once-daily fuside. It is 2- to 100-times more active in of resistance mutations mapping to the monotherapy and longer-term activity of vitro than pentafuside and is highly active integrase int region of the HIV pol gene with

6 Perspectives - Investigational Drugs Volume 8 Issue 4 June 2000

serial passage of virus in the presence of Gulick R, King M, Brun S, et al. ABT-378/ritonavir advanced human immunodeficiency virus (HIV) the inhibitors. Candidate molecules in this (ABT-378/r) in antiretroviral-naive HIV+ disease receiving chronic therapy: class currently are undergoing modifica- patients: 72 weeks. [Abstract 515.] 7th Canadian HIV trials network protocol 080. J Infect tion to generate clinically useful com- Conference on Retroviruses and Opportunistic Dis. 1997;175:801-806. . January 30-February 2, 2000; San pounds. Francisco, Calif. Robbins BL, Srinivas RV, Kim C, et al. Anti- human immunodeficiency virus activity and cel- Hazuda DJ, Felock P, Witmer M, et al. Inhibitors lular metabolism of a potential prodrug of the Suggested Reading of strand transfer that prevent integration and acyclic nucleoside phosphonate 9-R-(2-phos- inhibit HIV-1 replication in cells. Science. phonomethoxypropyl)adenine (PMPA), Bis(iso- Blanco J, Barretina J, Henson G, et al. The 2000;287(5453):646-650. propyloxymethylcarbonyl) PMPA. Antimicrob CXCR4 antagonist AMD3100 efficiently inhibits Agents Chemother. 1998;42(3):612-617. cell-surface-expressed human immunodeficien- Kempf D, Xu Y, Brun S, et al. Baseline genotype cy virus type 1 envelope-induced apoptosis. and phenotype do not predict response to ABT- Rutschmann OT, Opravil M, Iten A, et al. A Antimicrob Agents Chemother. 2000;44(1):51-56. 378/ritonavir in PI-experienced patients at 24 placebo-controlled trial of didanosine plus and 48 weeks. [Abstract 731.] 7th Conference on stavudine, with and without hydroxyurea, for Bleul CC, Farzan M, Choe H, et al. The lympho- Retroviruses and Opportunistic Infections. HIV . The Swiss HIV Cohort Study. cyte chemoattractant SDF-1 is a ligand for January 30-February 2, 2000; San Francisco, AIDS. 1998;12(8):F71-F77. LESTR/fusin and blocks HIV-1 entry. Nature. Calif. 1996;382(6594):829-833. Sham HL, Kempf DJ, Molla A, et al. ABT-378, a Kilby JM, Hopkins S, Vennetta TM, et al. Potent highly potent inhibitor of the human immunod- Deeks SG, Barditch-Crovo P, Lietman PS, et al. suppression of HIV-1 replication in humans by eficiency virus protease. Antimicrob Agents Safety, pharmacokinetics, and antiretroviral T-20, a peptide inhibitor of gp41-mediated virus Chemother. 1998;42:3218-3224. activity of intravenous 9-[2-(R)-(Phosphono- entry. Nat Med. 1998;4:(11)1302-1307. Simmons G, Clapham PR, Picard L, et al. Potent methoxy)propyl]adenine, a novel anti-human inhibition of HIV-1 infectivity in macrophages immunodeficiency virus (HIV) therapy, in HIV- Lalezari J, Eron J, Carlson M, et al. Sixteen week and lymphocytes by a novel CCR5 antagonist. infected adults. Antimicrob Agents Chemother. analysis of heavily pre-treated patients receiv- Science. 1997;276:276-279. 1998;42(9):2380-2384. ing T-20 as a component of multi-drug salvage therapy. [Abstract LB-18.] 39th Interscience Srinivas RV, Fridland A. Antiviral activities of 9- Donzella GA, Schols D, Lin SW, et al. AMD3100, Conference on Antimicrobial Agents and R-2-phosphonomethoxypropyl adenine (PMPA) a small molecule inhibitor of HIV-1 entry via the Chemotherapy. September 26-29, 1999; San and bis(isopropyloxymethylcarbonyl)PMPA CXCR4 co-receptor. Nat Med. 1998;4(1):72-77. Francisco, Calif. against various drug-resistant human immun- McDougall B, King PJ, Bor WW, et al. odeficiency virus strains. Antimicrob Agents Eckert DM, Malashkevich VN, Hong LH, et al. Dicaffeoylquinic and dicaffeoyltartaric acids are Chemother. 1998;42(6):1484-1487. Inhibiting HIV-1 entry: discovery of D-peptide selective inhibitors of human immunodeficien- inhibitors that target the gp41 coiled-coil pock- cy virus type 1 integrase. Antimicrob Agents Szczech GM, Furman P, Painter GR, et al. Safety et. Cell. 1999;99(1):103-115. Chemother. 1998;42:140-146. assessment, in vitro and in vivo, and pharma- cokinetics of , a potent and selective Fujiwara T, Sato A, el-Farrash M, et al. S-1153 Miller MD, Margot NA, Robinson M, et al. HIV-1 nonnucleoside reverse transcriptase inhibitor of inhibits replication of known drug-resistant RT mutations in patients after 24 weeks of teno- human immunodeficiency virus type 1. strains of human immunodeficiency virus type fovir disoproxil fumarate (formerly PMPA pro- Antimicrob Agents Chemother. 2000;44(1):123-130. 1. Antimicrob Agents Chemother. 1998;42(6):1340- drug) therapy added to stable background ART. 1345. [Abstract 740A.] 7th Conference on Retroviruses Tsai C-C, Folis KE, Sabo A, et al. Prevention of and Opportunistic Infections. January 30- SIV infection in macaques by (R)-9-(2-phospho- Giacca M, Zanussi S, Comar M, et al. Treatment February 2, 2000; San Francisco, Calif. nylmethoxypropyl)adenine. Science. 1995;270: of human immunodeficiency virus infection with hydroxyurea: virologic and clinical evalua- Montaner JSG, Zala C, Conway B, et al. Pilot 1197-1199. tion. J Infect Dis. 1996;174(1):204-209. study of hydroxyurea among patients with

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