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, both with and without gational antiretroviral drugs, including mycophenolic acid, are in progress. new 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 . Amdoxovir is active in vitro against A number of NNRTIs that are structural- However, even the best currently avail- -resistant and - ly related to 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, • enteric-coated capsule qd* with the aims of achieving additive or that led to and cataracts • bid synergistic effects with drugs from exist- in some animals. • 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/ 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 • 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 • 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 • 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 • enhancement of saquinavir, clear. Mycophenolic acid inhibits ino- , or * Dr Gulick is Associate Professor of sine 5’-monophosphate dehydrogenase • /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- • (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- • (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 • evaluation. • Fusion inhibitors • (Ag-1549) — (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- • (BMS 232632) mg, 100-mg, or 200-mg once-daily • (DMP-450) Other doses. In an intent-to-treat analysis, • 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 in 81% the 200-mg group; other adverse effects and prior efavirenz in 19%) with an aver- Atazanavir included 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 count of Atazanavir is an azapeptide PI in devel- pound to be employed in subsequent 464/µL, TMC 125 900 mg twice daily opment. It exhibits a 90% inhibitory con- clinical evaluation could be made on the reduced mean plasma HIV-1 RNA level centration (IC90) for HIV in vitro of 60 to basis of this study. by nearly 1 log10 from the baseline value 80 nM (adjusted for protein binding).

15 International AIDS Society–USA Topics in HIV Medicine

Pharmacokinetic data support once- atazanavir at a daily dose of 400 mg exhibit a pharmacokinetic interaction daily dosing, which would make the (n=181) or 600 mg (n=195) or nelfinavir that increases blood levels of both compound unique among currently 1250 mg twice daily (n=91; Sanne et al, drugs. Analysis of observed data in a approved PIs without ritonavir boosting; 41st ICAAC, 2001). In an intent-to-treat total of 51 patients at 48 weeks showed the proposed dose is two 200-mg pills analysis, approximately 65% had a plas- that all 3 treatment regimens were asso- with food once daily. The drug is metab- ma HIV-1 RNA level less than 400 ciated with median reductions in viral olized by the CYP 3A4 hepatic enzyme copies/mL and approximately 40% of load of approximately 1.2 to 1.6 log10 system. Adverse effects include an indi- patients in each arm had a level less (Haas et al, 9th CROI, 2002). rect hyperbilirubinemia, similar to that than 50 copies/mL at 48 weeks. Overall, Recent data suggest atazanavir may observed with indinavir. Minimal or no virologic response rates in both arms of have a unique initial resistance profile lipid changes have been observed with this study were somewhat lower than among the PIs. In a substudy of 76 sub- administration of the drug in clinical other phase 3 studies of PIs, including jects from phase 3 studies treated with studies. nelfinavir, for unclear reasons. There was atazanavir-based regimens who experi- Atazanavir is in phase 3 testing. It is a significant difference in the change in enced virologic failure, 17 subjects dis- also currently available through an total cholesterol levels between the played reduced susceptibility (5- to 141- expanded-access program for patients groups, with an approximate 25% in- fold) to atazanavir, and resistance pat- with CD4+ cell count less than 300/µL crease from baseline observed in the terns depended on prior PI experience and plasma HIV-1 RNA level greater nelfinavir group compared with a 5% (Colonno et al, Antivir Ther, 2002). Of 9 than 5000 copies/mL, or with any viral increase in the atazanavir groups by treatment-naive subjects who experi- load if triglyceride or total cholesterol week 48. enced virologic failure on atazanavir, 8 levels are greater than 750 mg/dL and In another study in patients failing had a unique substitution at protease the patient is not responding to lipid- current therapy, 85% of whom had I50L, and this substitution actually lowering therapy. Information about the received prior PI treatment, 85 patients appeared to increase susceptibility in expanded access program is available by with a plasma HIV-1 RNA level of 2000 to vitro to many of the currently available calling 1-877-726-7327. 100,000 copies/mL and a CD4+ cell PIs. In contrast, the 8 PI-experienced In a phase 3 study in 467 treatment- count greater than 100/µL received patients lacked the I50L substitution naive patients with a plasma HIV-1 RNA atazanavir 400 mg or 600 mg plus and demonstrated a loss of susceptibili- level greater than 2000 copies/mL and a saquinavir 1200 mg once daily, or riton- ty to both atazanavir and the other PIs. CD4+ cell count greater than 75/µL, avir 400 mg plus saquinavir 400 mg twice Further resistance studies are in stavudine/lamivudine was given with daily. Of note, saquinavir and atazanavir progress.

Viral RNA

Viral dsDNA REVERSE Preintegration Viral DNA Complex ENTRY Virion Viral RNA 1. CD4 ENTRY receptor binding Assembly 2. Chemokine receptor binding Viral Viral RNA 3. Membrane fusion Precursor INTEGRATION Proteins Budding CD4 Receptor Translation

REVERSE TRANSCRIPTION Viral mRNA Chemokine (By HIV reverse Coreceptor transcriptase enzyme) Activation

VIRAL PROTEIN INTEGRATION PROCESSING (By HIV integrase enzyme) 1. Viral DNA complex binding VIRAL PROTEIN PROCESSING 2. Viral DNA processing (By HIV protease enzyme) 3. DNA strand transfer

Figure 1. The life cycle of HIV-1. At left, the virion is shown attaching to the CD4 receptor and chemokine coreceptor and subsequently enter- ing the host CD4 cell. Inside the cell, transcription of HIV RNA to HIV DNA is catalyzed by the HIV reverse transcriptase enzyme. The HIV DNA then forms a double-stranded DNA (dsDNA) complex, enters the host cell nucleus and integrates with the host genetic material via the HIV integrase enzyme. Upon activation, the viral DNA is transcribed into viral messenger RNA (mRNA) that in turn is translated into viral precur- sor proteins. The new HIV RNA and viral precursor proteins are assembled and the virus buds and is released from the cell surface. After bud- ding, viral precursor proteins undergo processing by the HIV protease enzyme and form a mature, infectious viral particle.

16 Perspective - Antiretroviral Drugs in Development Volume 10 Issue 4 September/October 2002

HIV Reverse Transcriptase Inhibitors

HIV Entry Viral RNA Inhibitors ENTRY Viral dsDNA REVERSE Preintegration Viral DNA 1. CD4 TRANSCRIPTION Complex Virion X receptor binding Viral RNA HIV ENTRY Integrase 2. Chemokine Inhibitors receptor binding Assembly 3. Membrane fusion Viral Viral RNA Precursor INTEGRATION Proteins X X Budding CD4 Receptor Translation REVERSE TRANSCRIPTION X Viral mRNA Chemokine (By HIV reverse X Coreceptor transcriptase enzyme) Activation

VIRAL PROTEIN INTEGRATION HIV Protease PROCESSING Inhibitors X (By HIV integrase enzyme) 1. Viral DNA complex binding 2. Viral DNA processing VIRAL PROTEIN PROCESSING 3. DNA strand transfer (By HIV protease enzyme)

Figure 2. Stages of the HIV-1 life cycle targeted by currently approved and new investigational classes of anti-HIV drugs. The dsDNA indi- cates double-stranded DNA; mRNA, messenger RNA.

Tipranavir 50% of those receiving the saquinavir inhibitors, chemokine coreceptor inhib-

regimen had a greater than 1-log10 itors, and fusion inhibitors (Figure 2). Tipranavir is a nonpeptidic investiga- decrease in plasma HIV-1 RNA level at tional PI with a 90% effective concentra- 16 weeks (Slater et al, 41st ICAAC, 2001). SCH-C tion (EC90) of 0.5 to 1.0 µM for HIV in The effectiveness of tipranavir in PI- vitro. It is active in vitro against a large experienced patients requires further SCH-C (SC-351125) is a small-molecule majority of clinical HIV isolates resistant evaluation. binder of the CCR5 chemokine corecep- to indinavir, ritonavir, nelfinavir, and tor with in vitro activity against HIV TMC 114 saquinavir. Coadministration with riton- strains using the CCR5 coreceptor (IC90 avir increases trough tipranavir concen- TMC 114 demonstrates in vitro activity ~20 nM) and against hybrid strains trations by 7- to 40-fold, allowing the against a majority of clinical HIV iso- using both the CXCR4 and CCR5 core- compound to be dosed twice daily, and lates with resistance to saquinavir, indi- ceptors. Although there is a theoretical absorption is increased if the drug is navir, ritonavir, nelfinavir, and ampre- concern that a CCR5 inhibitor could pro- taken with a high-fat meal. The com- navir. The first study of this investiga- mote a switch to the CXCR4 coreceptor pound has been developed with a new tional PI in healthy volunteers has been (present with more virulent X4 viral self-emulsifying drug delivery system reported and studies in HIV-infected strains), in mouse studies, emergence of (SEDDS). It is metabolized via the CYP patients are under way. resistance to SCH-C did not result in 3A4 hepatic enzyme system. Tipranavir coreceptor switch (Moore, 1st IAS Conf currently is in phase 1/2 testing. on HIV Pathog and Treat, 2001). SCH-C Tipranavir was evaluated in a pilot HIV Entry Inhibitors is orally bioavailable, and pharmacoki- study in patients in whom treatment HIV enters target (CD4) cells by initially netic data indicate a half-life of 4 to 6 with 1 PI had failed. Enrollment criteria binding to the CD4 receptor (Figure 1). hours, supporting twice-daily dosing. were baseline plasma HIV-1 RNA level Interaction with the CD4 receptor in- The mechanisms of metabolism of the greater than 1000 copies/mL and any duces a conformational change in the drug have not been fully defined, but CD4+ cell count. Sixty-two patients HIV gp120 that allows binding to a sec- they do not appear to involve cyto- received one of 2 regimens: 2 new nRTIs ond receptor, the chemokine coreceptor chrome P450 hepatic metabolism. In a with either tipranavir 500 mg or 1250 mg (CCR5 and/or CXCR4). This induces phase 1 dose-escalation study in twice daily plus ritonavir 100 mg twice another conformational change in the healthy volunteers given single doses of daily, or saquinavir (soft gel capsule) 400 HIV protein, bringing the viral and SCH-C, a prolongation (>50 msec) of the mg plus ritonavir 400 mg twice daily. cell surfaces into contact. Fusion of the QTc interval was observed in 1 subject at Intent-to-treat analysis showed that viral and cell membranes completes the highest dose tested, 600 mg. In a approximately 60% of patients receiving viral entry. Candidate drugs for blocking phase 1 study in 28 HIV-infected tipranavir regimens and approximately HIV entry thus include CD4 attachment patients, treatment with SCH-C 25 mg

17 International AIDS Society–USA Topics in HIV Medicine

twice daily produced a 0.5- to 0.7-log10 intent-to-treat, last-observation-carried- This enzyme promotes 3 specific steps decrease and treatment with 50 mg forward analysis demonstrated a highly of HIV integration: (1) binding to the twice daily produced a 1.0-log10 decrease significant mean change from baseline viral DNA complex; (2) processing of − from baseline plasma HIV-1 RNA levels plasma HIV-1 RNA of 1.7 log10 viral DNA; and (3) DNA strand transfer at 10 days (Baroudy, 14th Int AIDS Conf, copies/mL (enfuvirtide plus optimized whereby viral DNA is inserted into host − 2002). With proof of concept that a regimen group) versus 0.8 log10 copies/ cell DNA (Figure 1). As a unique viral- chemokine receptor inhibitor demon- mL (optimized regimen only group). The specific enzyme, it is an attractive target strates antiretroviral activity in clinical TORO-2 study of 504 patients demon- for antiretroviral drug development studies, further dose-escalation studies strated similar results. In both studies, (Figure 2). are anticipated. A related compound, the most common adverse experience SCH-D, is also under investigation. was injection site reactions, but drug S-1360 discontinuation for that reason was Enfuvirtide uncommon. S-1360, a small-molecule HIV , is the first of the HIV integrase Enfuvirtide (T-20) is a peptide fusion in- T-1249 inhibitors to reach clinical testing. S- hibitor that is given subcutaneously at a 1360 has an EC50 value of 0.025 to 0.074 proposed dose of 90 mg twice daily. T-1249 is structurally similar to enfuvir- µg/mL for HIV in vitro before protein Adverse effects are primarily injection tide and was constructed by combining binding. Pharmacokinetic data suggest site reactions. Resistance mutations to gp41 sequences from HIV-1, HIV-2, and that the drug can be dosed orally 2 or 3 enfuvirtide have been observed in vitro simian immunodeficiency virus. The times daily; it is greater than 99% pro- and in vivo and appear to involve muta- drug is also administered subcuta- tein bound and is not metabolized via tions in gp41. neously. T-1249 is 2 to 100 times more the CYP 3A4 system. Emergence of resis- In a phase 1 study (Kilby et al, Nat active against HIV in vitro than enfuvir- tance in vitro has been associated with Med, 1998) in which 16 patients received tide and retains significant activity novel mutations in the HIV integrase 4 different intravenous doses for 14 against enfuvirtide-resistant strains active site. Administration in healthy (Greenberg et al, Antivir Ther, 2002). days, a 2-log10 decrease in plasma HIV-1 volunteers has produced few adverse RNA level was observed at the highest Because enfuvirtide-associated resis- effects. S-1360 is currently being evalu- dose. Activity of the subcutaneous for- tance substitutions may confer some ated in phase 1 studies in treatment- mulation has been demonstrated in degree of cross-resistance to T-1249, experienced HIV-infected patients with both phase 2 and 3 studies, and the consideration should be given to early CD4+ cell counts greater than 100/µL drug is now available under an expand- discontinuation of enfuvirtide-contain- (Yoshinaga et al, 9th CROI, 2002). ed-access program. ing regimens after virologic failure In 2 recently presented phase 3 stud- develops, to avoid the accumulation of L-870812 and L-870810 ies, the use of enfuvirtide led to additional substitutions. The investiga- improved virologic suppression when tional drug is currently in phase 1/2 eval- In vitro, diketoacids demonstrated added to an optimized antiretroviral uation. potent anti-HIV integrase activity as regimen in treatment-experienced sub- In a phase 1/2 dose-escalation study, strand transfer inhibitors, but these neg- jects (Henry et al, 14th Int AIDS Conf, the area under the drug concentration- atively charged compounds were not 2002; Clotet et al, 14th Int AIDS Conf, time curve and the minimum blood con- clinical candidates. Modification of 2002). In the TORO (T-20 vs optimized centration were dose-proportional with these compounds led to the identifica- regimen only)-1 study, HIV-infected once-daily dosing for 14 days. After a 4- tion of a series of compounds with patients with at least 6 months of prior week washout period, 63 patients improved antiretroviral potency and treatment experience with all 3 classes received T-1249 6.25 mg, 12.5 mg, or 25 pharmacokinetic characteristics, in- of available antiretroviral drugs and an mg once or twice daily for 14 days. Sixty- cluding good oral . In HIV-1 RNA level of greater than 5000 two patients were antiretroviral-experi- monkeys, L-870812 was administered copies/mL underwent both genotypic enced, with prior exposure to an average orally as a single agent and demonstrat- of 10 drugs. At day 14, reductions in and phenotypic resistance testing and ed virologic suppression of 1 to 3 log10 selected a new antiretroviral regimen. plasma HIV-1 RNA level were approxi- copies/mL and preserved CD4+ cell They were then randomized 2:1 to add mately 1.3 log10 in the 25 mg twice-daily counts for a 75-day period (Hazuda et al, enfuvirtide to the regimen (90 mg sub- group, and 0.7 log10 in the 25 mg once- Antivir Ther, 2002). A related compound, cutaneously twice daily) or not. A total daily group (Eron et al, 8th CROI, 2001). L-870810, currently is under investiga- of 491 subjects were randomized with a Data from additional studies of the drug tion in healthy volunteers, and studies baseline HIV-1 RNA level of 159,000 should be available in the near future. in HIV-infected subjects are anticipated. copies/mL and CD4+ count of 80 cells/µL. The subjects had taken an aver- HIV Integrase Inhibitors Conclusion age of 12 prior antiretroviral drugs and 80% had demonstrated 5 or more prima- In addition to the HIV reverse transcrip- New antiretroviral drugs are needed to ry resistance mutations to all 3 anti- tase and protease enzymes, the third improve convenience, tolerability, safe- retroviral drug classes. At 24 weeks, an viral-specific enzyme is HIV integrase. ty, and antiviral activity of antiretroviral

18 Perspective - Antiretroviral Drugs in Development Volume 10 Issue 4 September/October 2002

therapy. Promising agents are in devel- Eron JJ, Vernazza P. Alternative strategies for Drusano G, Redfield R. Abacavir and mycophe- opment in existing classes (ie, reverse anti-HIV treatment. AIDS. 2001;15(suppl 5): nolic acid, an inhibitor of inosine monophos- transcriptase and protease inhibitors) S161- S169. phate dehydrogenase, have profound and syner- gistic anti-HIV activity. J Acquir Immune Defic and in new classes (eg, HIV entry and Gazzard B, Pozniak A, Arasteh K, et al. TMC125, Syndr. 1999;21:362-370. HIV integrase inhibitors). Additional a next-generation NNRTI, demonstrates high steps in the viral life cycle, including potency after 7 days therapy in treatment-expe- Michael NL, Moore JP. HIV-1 entry inhibitors: viral uncoating and viral assembly, and rienced HIV-1-infected individuals with pheno- evading the issue. Nat Med. 1999;5:740-742. other enzymes, such as RNAase H, can typic NNRTI resistance. [Abstract 4.] 9th Conference on Retroviruses and Opportunistic Moore J. HIV-1 Escape from small molecule and should be targeted in future drug . February 24-28, 2002; Seattle, Wash. inhibitors in PBMC does not involve co-receptor development. Additional approaches switching to CXCR4 use. [Abstract LB-05.] 1st using immune therapies such as inter- Greenberg ML, Sista P, Miralles GD, et al. IAS Conference on HIV Pathogenesis and leukin-2 and therapeutic HIV vaccines Enfuvirtide (T-20) and T-1249 resistance: obser- Treatment. July 8-11, 2001; Buenos Aires, may complement the use of current and vations from Phase II clinical trials of enfuvirtide Argentina. future antiretroviral agents. Further in combination with oral antiretrovirals and a Phase I/II dose-ranging monotherapy trial of T- Raffi F, Kessler H, Thompson M, et al. Anti-HIV basic and clinical research aimed at 1249. [Abstract 128.] Antivir Ther. 2002;7(suppl activity of DAPD monotherapy in treatment- identifying and developing promising 1):S106-S107. naive and treatment-experienced subjects. antiretroviral agents is needed. [Abstract P5.] 5th International Congress on Gruzdev B, Rakhmanova A, De Dier K, Comhaire Drug Therapy in HIV Infection. October 22-26, S, Baede-Van Dijk P, Van ‘T Klooster G. TMC125 2000; Glasgow, UK. Presented in May 2002. First draft prepared from tran- is a highly potent non-nucleoside reverse tran- scripts by Matthew Stenger. Reviewed and updated by Dr scriptase inhibitor (NNRTI) in antiretroviral Ruiz N, Nusrat R, Lauenroth-Mai E, et al. Study Gulick in July 2002. therapy (ART)-naive, HIV-1 infected subjects. DPC 083-203, a phase II comparison of 100 and [Abstract I-668.] 41st Interscience Conference 200 mg once-daily DPC 083 and 2 NRTIs in Financial Disclosure: Dr Gulick has received grant sup- on Antimicrobial Agents and Chemotherapy. patients failing a NNRTI-containing regimen. port from or served as a consultant to or on the speakers September 22-25, 2001; Chicago, Ill. [Abstract 6.] 9th Conference on Retroviruses bureau of Abbott, Bristol-Myers Squibb, GlaxoSmith- and Opportunistic Infections. February 24-28, Kline, Merck, Shionogi, Trimeris, and ViroLogic. His Haas D, Zala C, Schrader S, Thiry A, McGovern R, 2002; Seattle, Wash. unit has also received unrestricted educational grants Schnittman S. Atazanavir plus saquinavir once from numerous companies for an annual Cornell CME daily favorably affects total cholesterol (TC), course held in November. Ruiz N, Nusrat R, Lazzarin A, et al. Study DPC fasting triglyceride (TG), and fasting LDL choles- 083-201: a phase II double-blind (DB) compari- terol (LDL) profiles in patients failing prior ther- son of 3 once-daily doses of the NNRTI DPC 083 apy (Trial AI424-009, Week 48). [Abstract 42.] 9th vs 600 mg efavirenz (EFV) in combination with 2 Conference on Retroviruses and Opportunistic NRTIs in HIV antiretroviral (ARV) treatment Suggested Reading Infections. February 24-28, 2002; Seattle, Wash. naive patients. [Abstract 7.] 9th Conference on Retroviruses and Opportunistic Infections. Hazuda DJ, Felock P, Witmer M, et al. Inhibitors February 24-28, 2002; Seattle, Wash. Baroudy B. Co-receptor inhibitors. [Abstract of strand transfer that prevent integration and MoOrAI38]. 14th International AIDS Conference. inhibit HIV-1 replication in cells. Science. July 7-12, 2002; Barcelona, Spain. Sanne I, Cahn P, Percival L, et al. Comparative 2000;287:646-650. results (phase II 48-week): BMS-232632, stavu- Clotet B, Lazzarin A, Cooper D, et al. Enfuvirtide dine, lamivudine as HAART for treatment-naive Hazuda D, HIV-1 Integrase Inhibitor Discovery (T-20) in combination with optimized back- HIV(+) patients (AI424-008). [Abstract 667.] 41st Team. A novel HIV-1 integrase inhibitor medi- ground (OB) regimen vs OB alone in patients ates sustained suppression of viral replication Interscience Conference on Antimicrobial with prior experience or resistance to each of and CD4 depletion in a SHIV rhesus macaque Agents and Chemotherapy. September 22-25, the three classes of approved antiretrovirals model of infection. [Abstract 1.] Antivir Ther. 2001; Chicago, Ill. (ARVs) in Europe and Australia. [Abstract 2002;7(suppl 1):S3. LBOr19A.] 14th International AIDS Conference. Slater L, Farthing C, Jayaweera J, et al. Safety July 7-12, 2002; Barcelona, Spain. Henry K, Lalezari J, O'Hearn M, et al. Enfuvirtide and efficacy of tipranavir (TPV), a novel non- (T-20) in combination with an optimized back- peptidic protease inhibitor, plus ritonavir (RTV), Colonno RJ, Friborg J, Rose RE, Lam E, Parkin N. ground (OB) regimen vs OB alone in patients in PI-failure patients. [Abstract LB15.] 41st Identification of amino acid substitutions corre- with prior experience or resistance to each of Interscience Conference on Antimicrobial lated with reduced atazanavir susceptibility in the three classes of approved antiretrovirals Agents and Chemotherapy. September 22-25, patients treated with atazanavir-containing reg- (ARVs) in North America and Brazil. [Abstract 2001; Chicago, Ill. imens. [Abstract 4.] Antivir Ther. 2002;7 (suppl LbOr19B.] 14th International AIDS Conference. 1):S4-S5. July 7-12, 2002; Barcelona, Spain. Ying C, De Clercq E, Neyts J. Ribavirin and D’Souza MP, Cairns JS, Plaeger SF. Current evi- mycophenolic acid potentiate the activity of dence and future directions for targeting HIV Kilby JM, Hopkins S, Venetta TM, et al. Potent guanine- and diaminopurine-based nucleoside entry: therapeutic and prophylactic strategies. suppression of HIV-1 replication in humans by analogues against hepatitis B virus. Antiviral Res. JAMA. 2000;284:215-222. T-20, a peptide inhibitor of gp41-mediated virus 2000;48:117-124. entry. Nat Med. 1998;4:1302-1307. Eron J, Merigan T, Kilby M, et al. A 14-day Yoshinaga T, Sato A, Fujishita T, Fujiwara T. S- assessment of the safety, , and Lee K, Gulick RM. New drugs for the treatment 1360: in vitro activity of a new HIV-1 integrase antiviral activity of T-1249, a peptide inhibitor of of HIV infection. Curr Infect Dis Rep. 2001;3:193- inhibitor in clinical development. [Abstract 8.] membrane fusion. [Abstract 14.] 8th Conference 200. 9th Conference on Retroviruses and Opportun- on Retroviruses and Opportunistic Infections. istic Infections. February 24-28, 2002; Seattle, February 4-8, 2001; Chicago, Ill. Margolis D, Heredia A, Gaywee J, Oldach D, Wash.

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