UPDATE. New antiretroviral drugs R. M. Gulick

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1 UPDATE New antiretroviral drugs R. M. Gulick Cornell HIV Clinical Trials Unit, Division of International Medicine and Infectious Diseases, Weill Medical College of Cornell University, New York, New York, USA Despite the availability of 16 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens present challenges. Newer antiretroviral drugs are needed to improve convenience, reduce toxicity and, of particular importance, to provide antiretroviral activity against viral strains resistant to the currently available antiretroviral agents. Candidate drugs with novel properties are in development in the two currently available drug classes: HIV reverse transcriptase inhibitors (nucleoside analogs, non-nucleoside analogs and nucleotide analogs) and HIV protease inhibitors (PI). Investigational nucleoside analog reverse transcriptase inhibitors (nrti) include emtricitabine (FTC) and amdoxovir (DAPD), and investigational non-nucleoside reverse transcriptase inhibitors (NNRTI) include DPC 083 and TMC 125. New protease inhibitors under investigation include atazanavir (BMS ), tipranavir, and TMC 114. In addition, newer agents with novel mechanisms of action such as HIV entry inhibitors (that inhibit the three steps of HIV entry: CD4 attachment, chemokine receptor binding and membrane fusion) and HIV integrase inhibitors are under investigation. Investigational entry inhibitors include PRO 542 (a CD4 attachment inhibitor), Schering C (a chemokine receptor inhibitor), enfuvirtide (T-20) and T-1249, inhibitors of membrane fusion. Investigational HIV integrase inhibitors include S Continued progress in the treatment of HIV disease will result from the development of new antiretroviral drugs. Keywords HIV therapy, antiretroviral drugs, reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, integrase inhibitors Accepted 29 July 2002 Clin Microbiol Infect 2003; 9: INTRODUCTION Currently, there are 16 antiretroviral drugs approved for the treatment of HIV infection [Table 1]. Treatment guidelines recommend constructing multidrug combinations of these agents [1 4] and their widespread use has resulted in a significant decrease in HIV-related morbidity and mortality in the developed world [5,6]. However, current regimens continue to present challenges with issues of adherence, tolerability, long-term toxicity, and drug- and cross-resistance. Further Corresponding author and requests for reprints: Roy M. Gulick, MD, Cornell Clinical Trials Unit, Box566, Weill Medical College of Cornell University, 525 East 68th Street; New York, NY 10024; USA Tel: þ Fax: þ rgulick@med.cornell.edu progress in treating HIV infection will result from the development of antiretroviral drugs that are convenient, tolerable, less toxic and demonstrate activity against drug-resistant viruses. In addition to improvements to the currently available antiretroviral drugs, investigational agents are in development both in existing classes (reverse transcriptase inhibitors, protease inhibitors) and in new classes (entry inhibitors, integrase inhibitors) [Table 2]. IMPROVEMENTS IN APPROVED ANTIRETROVIRAL DRUGS Currently available antiretroviral drugs have improved over the last few years. New drug formulations that allow once-daily dosing include an approved enteric-coated formulation of didanosine and an extended release formulation of stavudine. A sustained release formulation of ß 2003 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

2 Gulick New antiretroviral drugs 187 Table 1 Currently approved antiretroviral drugs HIV reverse transcriptase inhibitors Nucleoside analogs zidovudine (ZDV, AZT) didanosine (ddi) zalcitabine (ddc) stavudine (d4t) lamivudine (3TC) abacavir (ABC) Non-nucleoside analogs (NNRTI) nevirapine (NVP) delavirdine (DLV) efavirenz (EFV) Nucleotide analogs tenofovir (TDF) HIV protease inhibitors saquinavir (SQV) ritonavir (RTV) indinavir (IDV) nelfinavir (NFV) amprenavir (APV) lopinavir/ritonavir (LPV/r) Table 2 Investigational antiretroviral drugs (partial list) HIV reverse transcriptase inhibitors Nucleoside analogs emtricitabine (FTC) amdoxovir (DAPD) Non-nucleoside analogs DPC-083 capravirine (Ag 1549) TMC 125 calanolide A Nucleotide analogs GS-7340 (tenofovir pro-drug) HIV protease inhibitors atazanavir (ATV, BMS ) tipranavir (TPV, PNU ) mozenavir (DMP-450) TMC 114 HIV entry inhibitors CD4 attachment inhibitors PRO 542 BMS-806 Chemokine receptor inhibitors CXCR4 AMD-3100 Chemokine receptor inhibitors CCR5 Schering C (SCH-C, SCH ) PRO 140 Schering D (SCH-D) UK 427,857 Fusion inhibitors enfuvirtide (T-20) T-1249 HIV integrase inhibitors S-1360 development discontinued zidovudine is also under investigation. Pharmacokinetic and clinical analyses have suggested twice-daily dosing is appropriate for zidovudine, zalcitabine, and nelfinavir, and once-daily dosing is appropriate for lamivudine and possibly nevirapine. Exploiting the pharmacokinetic properties of ritonavir, a potent inhibitor of the cytochrome P450 3A4 hepatic enzyme system, allows combinations with other protease inhibitors (e.g. saquinavir, indinavir, amprenavir, lopinavir) that enhance drug levels, decrease pill counts, and remove fasting requirements. Fixed-dose multidrug formulations including zidovudine/lamivudine, abacavir/zidovudine/ lamivudine and lopinavir/ritonavir reduce pill counts and improve convenience. Improved dosing formulations also are available for delavirdine (200 mg tablet) and efavirenz (600 mg tablet) and are under investigation for saquinavir (800 mg hard gel capsule) and nelfinavir (625 mg tablet). Finally, pro-drug formulations are under investigation that reduce pill counts (e.g. GW433908, a pro-drug of amprenavir) [7] or have potential to increase lymphoid tissue penetration (e.g. GS 7340, a pro-drug of tenofovir) [8]. Improved combination antiretroviral regimens will result from these and other innovations. NEW HIV REVERSE TRANSCRIPTASE INHIBITORS Emtricitabine (FTC) is an investigational analog of the nucleoside, cytosine. The compound has activity against both hepatitis B virus [9] and HIV [10], and it is incorporated ten-fold more efficiently than lamivudine during HIV reverse transcription [11]. Resistance to emtricitabine is conferred by the M184V substitution in the reverse transcriptase, a property shared with lamivudine [12]. The pharmacokinetic profile of emtricitabine supports once-daily dosing [13] and the compound has been studied as part of a once-daily regimen (combined with didanosine and efavirenz) [14], with 93% of subjects suppressing HIV RNA levels to <50 copies per ml (cpm) by 24 weeks and continued suppression through 96 weeks [15]. Emtricitabine also was investigated in a study where subjects on a stable regimen substituted emtricitabine for lamivudine, and virologic suppression was maintained [16]. In a study of treatment-naïve subjects in South Africa randomized to receive stavudine and nevirapine (or efavirenz) together with either

3 188 Clinical Microbiology and Infection, Volume 9 Number 3, March 2003 emtricitabine or lamivudine, five deaths due to hepatic failure thought related to nevirapine occurred [17]. Amdoxovir (DAPD, diaminopurine dioxolane) is an investigational analog of the nucleoside guanosine that is deaminated in vivo to DXG (dioxolane guanine), the active compound with activity against both HIV and HBV [18]. In vitro, the compound demonstrates activity against some nucleoside-resistance viruses, including those with the 69 insertion (that confers multinucleoside resistance) [19]. However, reverse transcriptase substitutions at K65R or L74V reduce susceptibility to amdoxovir. Animal toxicity studies demonstrated obstructive nephropathy (due to crystallization of the drug in the renal tubules) leading to hyperglycemia and cataracts in some animals. A clinical study in treatment-naïve and treatment-experienced subjects demonstrated potent antiretroviral activity (HIV RNA changes of 1.5 log 10 cpm in treatment-naïve and 1.1 log 10 cpm in nucleosideexperienced subjects over 14 days) [20,21]. Further studies are in progress. DPC 083 is an investigational quinazolinone NNRTI that is a derivative of efavirenz. In vitro, the compound has increased activity against HIV with reverse transcriptase substitutions at positions K103N, K101E and G190S, and resistance to DPC 083 requires more than one substitution (in contrast to currently available NNRTIs) [22,23]. The half-life of the compound is >90 h, supporting once-daily (or perhaps less frequent) dosing [23]. Recent phase II studies demonstrate the antiretroviral activity of the compound in both treatmentnaïve and NNRTI-experienced subjects. In one study, treatment-naïve individuals received zidovudine/lamivudine in combination with 50, 100 or 200 mg of DPC 083 or efavirenz [24]. Virologic response rates were similar at week 16 for all of the combination regimens with about 60 70% of subjects with HIV RNA levels of <50 cpm. In a study of NNRTI-experienced subjects, subjects received two nucleoside analogs in combination with DPC mg or 200 mg once daily [25]. At 16 weeks, about 40 50% of subjects had HIV RNA levels of <400 cpm, suggesting the activity of DPC 083 against viral variants with resistance to currently available NNRTI. TMC 125 is an investigational NNRTI with potent antiretroviral activity in vitro against viruses resistant to currently available NNRTI, and that requires at least two substitutions in the reverse transcriptase gene for resistance to develop [26]. In a pilot study in treatment-naïve subjects, TMC mg bid monotherapy was associated with a 2.0 log 10 cpm HIV RNA change from baseline over 7 days [27]. In another pilot study of NNRTI-experienced subjects, TMC 125 was associated with about a 1 log10 cpm HIV RNA change over 7 days [28]. Longer-term studies are in progress. HIV PROTEASE INHIBITORS Atazanavir (BMS ) is an investigational protease inhibitor (PI) with in vitro activity against wild-type virus and some viral variants with PIassociated mutations [29,30]. However, in a pediatric study, cross-resistance among protease inhibitors occurred in heavily pretreated subjects [31]. Pharmacokinetics support once-daily dosing [32]. Large phase III studies were reported recently. In one study, treatment-naïve subjects received stavudine/lamivudine with either atazanavir (400 or 600 mg qd) or nelfinavir 1250 mg bid [33]. At 24 weeks, 60 70% of the subjects had HIV RNA levels of <400 cpm. In another study, treatmentexperienced subjects received two nucleoside analogs with either atazanavir (400 or 600 mg)/saquinavir (1200 mg) qd or ritonavir (400 mg)/ saquinavir (400 mg) bid [34]. Overall at 48 weeks, HIV RNA change from baseline was log 10 cpm. In both of these studies, serum lipid levels increased in the comparator arms, but not with the atazanavir regimens [34,35]. An expanded access program for atazanavir is now available. Tipranavir (PNU ) is a nonpeptidic investigational PI with potent HIV activity in vitro [36] with drug levels increased markedly by coadministration with ritonavir [37]. A new self-emulsifying drug delivery system (SEDDS) formulation of the drug is under investigation. Tipranavir demonstrated antiretroviral activity in vitro against viral isolates with phenotypic resistance to currently available PIs [38]. In one study, single- PI-experienced subjects were randomized to receive two nucleoside analogs with tipranavir (500 or 1250 mg)/ritonavir (100 mg) or saquinavir (400 mg)/ritonavir (400 mg) given twice daily [39]. At 16 weeks, median HIV RNA changes from baseline were log 10 cpm. In a study of patients experiencing virologic failure on their second PI regimen, subjects were randomized to receive tipranavir (500 or 1000 mg)/ritonavir (100 mg)

4 Gulick New antiretroviral drugs 189 twice daily [40]. At 48 weeks in the lower-dose group, the mean change in HIV RNA was 2.4 log 10 cpm for subjects with 5 PI-associated resistance mutations vs. 2.2 log 10 cpm with >5 mutations. Further studies in both treatment-naïve and treatment-experienced patients are in progress. TMC 114, an analog of TMC 126, a resistancerepellant PI [41], is an investigational nonpeptidic PI with in vitro activity against viral isolates, some of which had high-level resistance to currently available PIs [42]. The first study of TMC 114 was conducted in healthy volunteers who received escalating single doses of the drug ( mg) [43]. For doses of 800 mg and higher, plasma levels exceeded the protein-adjusted 50% inhibitory concentration for some PI-resistant viral isolates. Studies in HIV-infected subjects are in progress. HIV ENTRY INHIBITORS HIV entry, the first step in the viral life cycle, is composed of three steps: (1) CD4 cell receptor binding; (2) chemokine receptor (CCR5 or CXCR4) binding; and (3) membrane fusion. HIV entry inhibitors target each of these steps: CD4 attachment inhibitors; chemokine receptor inhibitors, and fusion inhibitors. PRO 542, an investigational CD4 attachment inhibitor, is an antibody-like fusion protein of CD4 and IgG2. The compound binds HIV gp120 and showed activity against primary viral isolates in vitro [44], and in animal models [45]. In a singledose phase I study, HIV-infected adults received one intravenous infusion of PRO 542 at doses of 0.2, 1, 5 or 10 mg/kg and dose-dependent HIV RNA decreases were observed [46]. In another study of single and multiple intravenous doses of PRO 542 in 18 HIV-infected children, subjects received four-weekly 10 mg/kg doses of PRO 542 and four of six demonstrated HIV RNA decreases of > 0.7 log 10 cpm [47]. Further studies are in progress. Schering C (SCH , SCH-C) is an investigational orally bioavailable chemokine receptor (CCR5) inhibitor with potent antiretroviral activity and pharmacokinetics to support twice-daily dosing [48]. In vitro, the development of resistance to SCH-C was not accompanied by receptor switching (from CCR5 to CXCR4) [49]. The first study of the compound in healthy volunteers assessed single doses of up to 600 mg and 14 days of dosing with 400 mg, and demonstrated QTc interval prolongation at the highest doses tested in both studies [50]. In a pilot study of HIV-infected patients, subjects received SCH-C 25 mg every 12 h and the median HIV RNA decrease from baseline was 0.7 log 10 cpm at 10 days [51]. Further testing at higher doses is in progress. Enfuvirtide (T-20) is an investigational peptide inhibitor of HIV fusion that must be given parenterally. The compound binds to a portion of the HIV gp41 molecule and thereby inhibits fusion of the viral and cell membranes [52]. The first study of enfuvirtide in HIV-infected subjects demonstrated up to a median 2.0 log 10 cpm change in HIV RNA levels over 14 days [53]. In some subjects randomized to lower doses with partial virologic suppression, drug resistance associated with substitutions in envelope protein genes was observed [54]. A phase II study of heavily treatment-experienced subjects tested antiretroviral regimens selected with genotypic testing plus the addition of T mg bid, and demonstrated significant virologic activity in a substantial proportion of subjects [55]. In another study, PI-experienced subjects were randomized to abacavir, amprenavir, ritonavir and efavirenz T-20 (50, 75, or 100 mg bid) for 48 weeks and demonstrated better virologic suppression in the T-20 groups ( log 10 cpm HIV RNA change) than in the control group ( 1.9 log 10 cpm HIV RNA change) [56]. Results from two phase III studies were released recently, demonstrating the additional virologic benefits of using T-20 as part of a regimen for treatment-experienced subjects and complete results are anticipated [57, 58]. T-1249 is a second investigational HIV fusion inhibitor that is two to 100-fold more active than T-20 in vitro, with pharmacokinetics to support once- or twice-daily dosing. The first study in HIVinfected, treatment-experienced subjects tested T-1249 as a single agent at escalating subcutaneous doses ranging from 6.25 mg to 50 mg [59]. HIV RNA changes of up to 1.4 log 10 cpm were demonstrated at the highest dose tested and preexisting resistance to reverse transcriptase and protease inhibitors did not impact virologic response [60]. HIV INTEGRASE INHIBITORS HIV integration is catalyzed by the viral enzyme HIV integrase and consists of three steps: (1) viral DNA complex assembly; (2) viral DNA complex processing; and (3) strand transfer linking viral

5 190 Clinical Microbiology and Infection, Volume 9 Number 3, March 2003 and cellular DNA and a number of inhibitors have been identified [61]. The first to reach clinical studies is S-1360, an investigational integrase inhibitor that showed potent antiretroviral activity in vitro and in an animal model [60]. S-1360 selected resistance mutants with amino acid substitutions close to the active site of integrase in vitro. The drug is orally bioavailable and phase I/II studies with HIV-infected subjects are underway. CONCLUSIONS Despite dramatic improvements in the morbidity and mortality of HIV-infected patients directly resulting from antiretroviral therapy, better antiretroviral drugs are needed. In addition to innovations that continue to improve the currently available antiretroviral drugs, a number of promising compounds are under investigation. Newer agents in existing classes (reverse transcriptase and protease inhibitors) and newer mechanistic classes (entry inhibitors, integrase inhibitors) have the potential to improve convenience, reduce toxicity and enhance activity against drug-resistant virus. Further basic and clinical research is necessary. REFERENCES 1. Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents February 4, 2002: 2. Yeni PG, Hammer SM, Carpenter CCJ et al. Antiretroviral treatment for adult HIV infection in 2002 updated recommendations of the International AIDS Society USA Panel. JAMA 2000; 283: BHIVA Writing Committee on behalf of the BHIVA Executive Committee. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med 2001; 2: Delfraissy J-F. New French guidelines for antiretroviral treatment. HIV Med 2000; 1: Mouton Y, Alfandari S, Valette M et al. Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centers. AIDS 1997; 11: F101 F Palella FJ Jr, Delaney KM, Moorman AC et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infections. N Engl J Med 1998; 338: Gatell JM. From amprenavir to GW (review). J HIV Ther 2001; 6: Lee W, He G, Mulato A et al. In vivo and in vitro characterization of GS 7340, an isopropylalaninyl phenyl ester prodrug of tenofovir; selective intracellular activation of GS 7340 leads to preferential distribution in lymphatic tissues. In: Abstracts of the 9th Conference on Retroviruses and Opportunistic Infections. Seattle, 2002: abstract 384 T. 9. Gish RG, Leung NWY, Wright TL et al. Dose range study of pharmacokinetics, safety, and preliminary antiviral activity of emtricitabine in adults with hepatitis B virus infection. Antimicrob Agents Chemother 2002; 46: Schinazi RF, McMillian A, Cannon D et al. Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1- [2-(hydroxymethyl) -1,3-oxathiolan-5-yl]-cytosine. Antimicrob Agents Chemother 1992; 36: Feng JY, Shi J, Schinazi RF, Anderson KS. Mechanistic studies show that (-) -FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC- TP. FASEB J 1999; 13: Tisdale M, Kemp SD, Parry NR, Larder BA. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3 0 -thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc Natl Acad Sci USA 1993; 90: Lascoux-Combes C, Peytavin G, Perusat S et al. Pharmacokinetics (PK) of a once-daily combination with emtricitabine, didanosine and efavirenz in treatment naive HIV-infected adults (ANRS 091 Trial). In: Abstracts of the 8th European Conference on Clinical Aspects and Treatment of HIV Infection. Athens, 2001: abstract P Molina J-M, Ferchal F, Rancinan C et al. Once-daily combination therapy with emtricitabine, didanosine, and efavirenz in human immunodeficiency virus-infected patients. J Infect Dis 2000; 182: Molina JM, Ferchal F, Journot V et al. Once-daily combination therapy with emtricitabine, didanosine and efavirenz in treatment naive HIV-infected adults 96 week follow-up of the ANRS 091 trial. In: Abstracts of the 8th European Conference on Clinical Aspects and Treatment of HIV Infection. Athens: 2001; abstract P Van der Horst C, Benson C, Rodriguez A, Hulett L, Wakeford C, Quinn J. Long-term efficacy and safety of emtricitabine (FTC) in HIVþ adults switching from a lamivudine (3TC) containing HAART regimen. In: Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, 2001; abstract I Zeier M, Sanne I, Van der Berg M, Quinn J, Shaw A. Efficacy and safety of emtricitabine (FTC) triple combination therapy in HIV-1 infected treatmentß 2003 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 9,

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