Review Novel Compounds for the Treatment of HIV Type-1 Infection

Antiviral Chemistry & Chemotherapy 19:189–200

Review Novel compounds for the treatment of HIV type-1 infection

Hans-Jürgen Stellbrink1,2*

1Infektionsmedizinisches Centrum Hamburg, Hamburg, Germany 2ICH Study Center, Hamburg, Germany

*Corresponding author: E-mail: [email protected]

Despite the recent licensure of several new antiretroviral inhibitors) and elvitegravir (integrase inhibitor). The compounds, there is still a need to develop additional potential of other compounds with new modes of action agents. Problems with antiviral activity, tolerability, is less clear. Currently, maturation inhibitors appear ease of administration, extent of cross-resistance and promising but for other drugs, obstacles to continued pharmacokinetic as well as pharmacodynamic interac- development, such as the need of parenteral application tions still represent important obstacles to life-long (that is, monoclonal antibodies) or toxicity (for example, control of HIV type-1 replication by highly active anti- immune modulating agents and pegylated interferon), retroviral therapy. Several compounds stem from the are already apparent. For even more compounds in the same classes as currently available drugs: apricitab- preclinical development phase, an assessment of their ine and elvucitabine (nucleoside reverse transcriptase possible clinical role is still premature. This review pro- inhibitors), rilpivirine (non-nucleoside reverse tran- vides an overview and a summary of the current status scriptase inhibitor), vicriviroc and INCB009471 (CCR5 of drug development in the field.

Introduction

Antiretroviral drug combination therapy has been very >20 licensed antiretroviral drugs. Pharmacodynamic successful in reducing morbidity and mortality of HIV interactions, such as the antagonism between zidovu- type-1 (HIV-1) infection [1,2]. Most of the clinical dine and stavudine, high rates of toxicity with didano- benefits have been achieved with combinations of two sine plus stavudine or increased risk of virological fail- nucleoside/nucleotide reverse transcriptase inhibitors ure with didanosine plus tenofovir (reviewed in [3]), as (NRTIs) with either a protease inhibitor (PI) or a non- well as numerous pharmacokinetic interactions actually nucleoside reverse transcriptase inhibitor (NNRTI). limit the number of combination options substantially. The therapeutic development has been greatly acceler- Although infrequent in primary treatment, virologi- ated in comparison with other fields of medicine by the cal failure and development of resistance or class-wide use of validated surrogate parameters in clinical trials cross-resistance remain important issues. Side effects, (plasma viral load and CD4+ T-cell count), which forms however, represent the most important reasons for dis- the basis on which drugs are licensed rapidly. Further- continuing drugs in clinical routine [4,5]. Therefore, more, the principles of combination therapy have been the development of new drugs should aim to reduce incorporated into development strategies, with the con- toxicity, improving the ease of administration without sequence that even novel compounds are tested early as reducing the antiviral effect. part of a combination rather than as individual drugs. Novel galenic preparations of currently licensed The strategic goal of therapy has shifted from short- compounds are not within the scope of this review. term protection from imminent risks to normalization They include a 625 mg preparation of nelfinavir with of life expectancy; however, toxicity, adherence and a 30% higher oral bioavailability, extended-release the development and transmission of resistance remain stavudine, extended-release nevirapine and ritonavir important obstacles to reaching this goal. Moreover, tablets (melt-extrusion preparation circumventing the the actual number of combination options is much requirement for refrigeration). These preparations, more limited than anticipated, given that there are however, despite increasing the ease of administration,

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are unlikely to overcome the treatment-limiting only caused by the positive and negative b-enantiomer toxicities of the parent compounds. of emtricitabine in this setting. The beneficial long-term clinical experience with Unlike other NRTIs, KP-1461 is reported to utilize NRTIs, NNRTIs and PIs stimulates the development of error induction in reverse transcriptase as a mechanism novel compounds from within these groups, which are of action. A Phase IIa study was recently halted, appar- less cross-resistant, easier to administer and have a differ- ently because of a lack of antiviral effect [12]. ent toxicity profile. However, in order to overcome limi- Because zidovudine is licensed but problematic as tations resulting from extended resistance, novel com- a result of its side effects of lipodystrophy and anae- pounds with new modes of action have to be developed mia, fozivudine tidoxil as its prodrug has little chance with the ultimate goal of normalizing life expectancy. for further development. Phosphazid, another zidovudine prodrug, is licensed in Russia, but for the reasons Methods mentioned above is unlikely to reach other markets. Similarly, because the parent compound of fosalvudine, This review summarizes novel compounds under devel- alovudine (MIV-310), was discontinued because of its opment for the treatment of HIV-1 infection. They were limited effect on multidrug-resistant virus, fosalvudine classified as Category 1, which included compounds that is unlikely to be developed further. In December 2006, were in Phase II or III or had passed Phase II successfully, Medivir outlicensed alovudine to Presidio Pharmaceuti- Category 2, which included compounds that were either cals, so that the fate of the compound remains unclear. in or had passed Phase I, and Category 3, which included Recently, new clinical trial results were presented drugs that had not yet been investigated in human trials regarding amdoxovir. It demonstrated marked antiviral (preclinical). As pharmaceutical companies often do not activity in combination with zidovudine in a very small announce the discontinuation of development of a com- trial [13]. A small but significant decrease in viral load

pound, only those compounds were included for which (0.37 log10 units) was observed in patients with virus published manuscripts, conference abstracts, or internet strains carrying a median of six NRTI mutations (range or press reports after 1 January 2006 indicated contin- 1–8) [14,15]. Lens opacities, observed in monkeys, ued development. Only publicly accessible information were initially reported from a pilot trial [16], but did was evaluated. In Category 3, only lead compounds were not appear to be an issue in larger studies [14,15,17]. included. The most promising drugs, primarily from Cat- egories 1 and 2, are discussed below. Non-nucleoside reverse transcriptase inhibitors New galenic preparations of currently available drugs are not within the scope of this review and are therefore Tibotec has developed rilpivirine (TMC278) as a first-line not included. NNRTI with similar activity to efavirenz and, most likely, The data were acquired by searching scientific data- less neuropsychiatric toxicity and less blood lipid increase bases (Entrez PubMed), conference abstracts, company [18–20]. The drug is active in vitro against variants car- homepages and public patent registries. This review sum- rying key NNRTI resistance mutations and appears to marizes the status in the field as of November 2008. require more mutational steps for a marked reduction of sensitivity than efavirenz or nevirapine. According to cur- Nucleoside reverse transcriptase inhibitors rent trial results, the compound has a high potential for and related compounds first-line therapy. It might be especially helpful in the setting of transmitted NNRTI resistance mutations. In view Apricitabine and elvucitabine have demonstrated anti- of the widespread use of antigastritic medication, how- viral activity in clinical trials [6–8], with apricitabine ever, its pH-dependent absorption [21] might represent a also being active against NRTI-resistant strains in a pilot problem for future routine clinical use. trial [7]. Both are the most promising compounds within UK-453061 by Pfizer is activein vivo [22] and contin- this class; however, as both are cytidine analogues, they ues to be investigated, whereas the fate of GW695634 cannot be combined with lamivudine or emtricitabine. by GlaxoSmithKline is unclear. The same applies Moreover, elvucitabine has exhibited myelosuppression to BILR 355 BS, which requires ritonavir boosting, [9] and is being tested at lower doses now, which casts almost automatically restricting it to a small segment a doubt on its tolerability. Despite induction of cross- of the market. Table 1 shows details of the reverse tran- resistance to lamivudine because of the M184I muta- scriptase inhibitors currently under development. tion [10], it shows activity against virus strains carrying the M184V lamivudine/emtricitabine resistance muta- Protease inhibitors tion [9]. The antiviral activity of racivir in a pilot trial in patients with lamivudine-resistant virus was limited PPL-100 (MK8122), a prodrug of PL-100, is currently but significant [11]. It is currently unclear if the effect is investigated in humans in a cooperation of Merck and

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Table 1. Reverse transcriptase inhibitors

Potential Recent Class Compound Company and drawbacks Development status Category references

NRTI Racivir Pharmasset Racemic mixture of + and - Phase II 1 [11] enantiomers of emtricitabine; active against M184V strains and HBV. Apricitabine (AVX 754, Avexa Active against M184V strains; Phase II 1 [6,7] BCH10618, (-)dOTC, Pharmaceuticals PK interaction with 3TC and SPD754) FTC (phosphorylation). Elvucitabine Achillion Enantiomer of dexelvucitabine Phase II, lower dose 1 [8,9,40] (ACH-126443) Pharmaceuticals (discontinued because of investigated pancreatic toxcixity); active against NRTI-resistant strains and HBV; long half-life (150 h); leukopaenia and rash at 100 mg in 6/56 patients; cross- resistance to 3TC and FTC. Fozivudine tidoxil Heidelberg Pharma/ AZT prodrug. Phase II, little interest 1 [41–43] GlaxoSmithKline in further development Fosalvudine Heidelberg Pharma Alovudine prodrug. Phase II 1 [44,45] KP-1461 (SN1461) Koronis Error induction in viral RT; lethal Phase II, halted 1 [12,46] Pharmaceuticals mutagenesis; prodrug of SN1212. Phosphazid (nicavir) Licensed in Russia, Prodrug of AZT. Licensed in Russia 1 [47] ViscountPharma Amdoxovir (DAPD) RFS Pharma, Active against AZT- and 3TC- Phase II 2 [13,48] formerly Gilead resistant HIV and HBV; ocular toxicity in monkeys; synergism with AZT; appears to have a high genetic barrier to resistance. Stampidine Parker Hughes Institute Primarily investigated as Preclinical 3 [49–52] microbicide; systemic activity in animal models (FIV). Dioxolane-thymine Pharmasset, Inc., Activity against NRTI-resistant Preclinical 3 [53–55] (DOT) formerly Emory strains. University, RFS Pharma LLC d-FDOC Emory University Activity against HIV and HBV. Preclinical 3 [56] 4′-Ed4T Kagoshima University Activity against resistant Preclinical 3 [57–59] variants. E2FdA Kumamoto University Activity against resistant Preclinical 3 [60] variants. Polymerase PPI-801 (MIV-410) Presidio Pharmaceuticals, cDNA chain termination; active Preclinical 3 [61] inhibitors formerly Medivir against NRTI-resistant strains. NcRTI-1 Gilead Blocks DNA polymerase activity Preclinical 3 [62] of HIV RT. Thiovir Adventrx Oral broad antiviral agent; Preclinical 3 [63] Pharmaceuticals comparable to foscarnet. NtRTIs GS9148 Gilead Active against TAM strains; less Preclinical 3 [64] nephrotoxic than tenofovir. GS9131 Gilead Prodrug of GS9148. Preclinical 3 [65] NNRTI Rilpivirine (TMC-278) Tibotec/ High antiviral activity in Phase III 1 [18–20] Janssen & Janssen first-line ART; probably less neuropsychiatric toxicity and lipid increase than with efavirenz.

ART, antiretroviral therapy; AZT, zidovudine; cDNA, complementary DNA; Ed4T, ethynyl stavudine; FIV, feline immunodeficiency virus; FTC, emtricitabine; HBV, hepatitis B virus; NcRTI, nucleoside competing reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NtRTI, nucleotide reverse transcriptase inhibitor; PK, pharmacokinetic; RT, reverse transcriptase; TAM, thymidine analogue mutation; 3TC, lamivudine.

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Table 1. Continued

Potential Recent Class Compound Company and drawbacks Development status Category references

UK-453061 Pfizer Active against NNRTI-resistant Phase Ib/II 1 [22] virus. GW695634, GW5634 GlaxoSmithKline Prodrug of GW8248; reduced Phase II, 1 [66] activity in the presence of some continuation unclear NNRTI mutations. Calanolide A Sarawak MediChem Made from rainforest plant; Phase Ib, 2 [67,68] Pharmaceuticals company announced Phase II continuation unclear studies for 2005. BILR 355 BS Boehringer Ingelheim Ritonavir boosting required; Phase I 2 [69,70] limited activity against NNRTI- resistant strains. IDX12899 Idenix Pharmaceuticals Resistance selection profile Phase I 2 [71,72] different from efavirenz. RDEA806 Ardea Bioscience High genetic resistance barrier. Phase I 2 [73–75] MIV 170 Medivir Development cooperation with Preclinical 3 [76] Bristol–Myers Squibb terminated in 2007. YM-215389 Kyoto University More active against resistant Preclinical 3 [77] strains. IQP-410 ImQuest Pharmaceuticals/ Interferes with HIV entry. Preclinical 3 [78,79] Samjin R1206 Roche Active against NNRTI-resistant Preclinical 3 [80–82] variants; prodrug of R0355. Triol Oswaldo Cruz Foundation Naturally occurring diterpene. Preclinical 3 [83]

Ambrilia Biopharma [23,24] (Table 2). Its potential to in Phase II. HPH116, the new galenic formulation of the boost the levels of other drugs similar to ritonavir rep- zinc finger inhibitor azodicarbamide, might be interest- resents an interesting and possibly attractive feature. ing for salvage therapy, but little efforts appear to have been made, so that its development was probably dis- Integrase inhibitors continued. BIT-225 represents an interesting new concept. Virion maturation is only inhibited in monocytes Raltegravir by Merck is the first licensed integrase and macrophages by this compound, but not in T-cells. inhibitor and has set the standard for other drugs in This could help to inhibit the propagation of infection this class [25–27]. By contrast to raltegravir, elvitegra- by these cells upon interaction with CD4+ T-cells. An vir by Gilead requires ritonavir boosting to achieve interesting feature of the drug is its activity against both adequate drug levels and half-life, which is disadvan- HIV-1 and hepatitis C virus. Table 3 shows details of the tageous with respect to toxicity, but allows for once- maturation, zinc finger and DNA polymerase inhibitors daily dosing. It is active in treatment-experienced currently under development. patients [28], but cross-resistance makes it an alter- native, but foreseeably not a subsequent option for Chemokine receptor blockers raltegravir. The penetration of raltegravir into tis- sues where the virus might find sanctuary (such as the The preferred use of CCR5 as a coreceptor for HIV-1 brain) is clearly an important future consideration. and the inherited deficiency of the expression of a func- Table 3 shows details of the integrase inhibitors cur- tional CCR5 receptor in some phenotypically healthy rently under development. patients have made this coreceptor a target for drug development. Maraviroc by Pfizer is the first licensed Maturation, zinc finger and DNA polymerase compound in this class and is active in patients with inhibitors resistant virus [32]. By contrast to maraviroc, vicriviroc by Schering–Plough requires ritonavir boosting. It is Bevirimat has an in vivo antiviral effect [29–31], the active in untreated as well as in pretreated patients with magnitude of which, however, still remains to be assessed resistant virus [33–35]. INCB009471 is another orally

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Table 2. Protease inhibitors

Compound Company Potential and drawbacks Development status Category Recent references

PPL-100 Merck/Ambrilia Prodrug of PL-100; long half-life; high Phase I 2 [23,24,84] Biopharma genetic resistance barrier; could boost levels of other PIs. AG001859 Pfizer Active against PI-resistant variants. Phase I 2, continuation [85] unclear SM-309515 Sumitomo Little cross-resistance to other PIs. Phase I 2 [86] Pharmaceuticals P-1946 Pharmacor Active against PI-resistant variants. Preclinical 3 [87] SPI-256 Sequoia Pharmaceuticals Active against PI-resistant variants. Preclinical 3 [88] SPI-452 Sequoia Pharmaceuticals Active against PI-resistant variants. Preclinical 3 [88] SPI-390 Sequoia Pharmaceuticals Active against PI-resistant variants. Preclinical 3 [89] SPI-457 Sequoia Pharmaceuticals Active against PI-resistant variants. Preclinical 3 [89] GRL-02031 Kumamoto University High activity against resistant variants. Preclinical 3 [90] UIC-02031 Kumamoto University Active against resistant variants. Preclinical 3 [91]

PI, protease inhibitor.

Table 3. Inhibitors of integrase, maturation, zinc finger and DNA polymerase

Class Compound Company Potential and drawbacks Development status Category Recent references

Integrase Elvitegravir (GS-9137, Gilead Sciences/ Optimal PK profile requires Phase II/III 1 [28] inhibitors JTK-303) Japan Tobacco RTV boosting. BMS 707035 Bristol–Myers Squibb – Phase Ib, Phase II 2 [92] trial terminated GSK 364735 GlaxoSmithKline/Shionogi – Phase I 2 [93] Dicaffeoylquinic acid Academy of Military Drug extract from Chinese Phase I/II 2 [94] Medical Sciences, China herbs; active against HIV and HBV. Maturation Bevirimat (PA-457) Panacos Blocks last step in Gag Phase II 1 [29,31,95,96] inhibitors processing; problems with galenic preparation. PA1050040 Panacos Not cross-resistant with Phase I 2 [97] PA-457 BIT-225 Biotron HIV replication inhibited in Phase I 2 [98] macrophages, not in T-cells; activity against HIV and HCV. UK-201844 Pfizer – Preclinical 3 [99] Zinc finger HPH116 (micronized H-Pharmaceuticals, Glucose increases reported Phase I/II, 2 [100–102] inhibitors azodicarbonamide, Rega Institute with old galena form. continuation unclear ADA)

ADA, azodicarbonamide; HBV, hepatitis B virus; HCV, hepatitis C virus; PK, pharmacokinetic; RTV, ritonavir.

bioavailable agent that has demonstrated activity and attractiveness of all CCR5 blockers for development will probably continue to be developed. and their use in clinical routine. All CCR5 blockers, however, are inactive if the virus Blocking the CXCR4 receptor appears more prob- is capable of using the CXCR4 rather than only the lematic because there is no natural analogue to CXCR4 CCR5 receptor. Therefore, the prediction of their activ- blockade. Not unexpectedly, the development of ity depends on a highly sensitive detection of dual tropic CXCR4 blockers has been hampered by unexpected strains or mixed populations of R5 and X4 strains. toxicities, such as dose-dependent leukocytosis induced These tests are expensive and not yet widely available. by AMD070 [36]. Table 4 shows details of the chemo Unless this issue is resolved, it will most likely limit the kine receptor blockers currently under development.

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Table 4. Inhibitors of HIV attachment, entry and fusion Properties, potential Development Recent Class Compound Company and drawbacks status Category references

Attachment Ibazulimab Tanox, Genentech, Humanized murine α-CD4 Phase II 1 [37,38,103,104] inhibitors (TNX-355, currently TaiMed monoclonal antibody; humAb 5A8) Biologics intravenous application. CCR5 Vicriviroc Schering–Plough Antiviral effect in ART-naive Phase III 1 [33,35] blockers (SCH-D, patients inferior to efavirenz 417690) if unboosted; requires RTV boosting for optimal effect. SCH532706 Schering–Plough Requires RTV boosting. Phase I 2 [105] INCB009471 Incyte High antiviral activity in vivo. Phase II 1 [106] Pro 140 Progenics Monoclonal antibody; Phase II 1 [107] Pharmaceuticals intravenous administration. HGS004 Human Genome Monoclonal antibody; Phase I, 2 [108,109] (CCR5mAb004) Sciences intravenous administration. continuation unclear, might be shifted to HGS101 PF-232798 Pfizer Long half-life; active against Phase I 2 [110] maraviroc-resistant strains. Ro1752 Roche Active against maraviroc- Preclinical 3 [111] resistant strains. AMD-887 Genzyme (Anormed) – Preclinical 3 [112] TAK 652 Takeda/Tobira – Preclinical 3 [113] ESN.196 Euroscreen CCR5 agonist; Preclinical 3 [114] receptor internalization. CXCR4 AMD070 Genzyme (Anormed) Dose-dependent leukocytosis. Phase I, on hold 2 [115,116] blockers (AMD11070) KRH-2731-5HCI Kureha Corp. – Preclinical 3 [117,118] KRH-3140 Kureha Corp. – Preclinical 3 [119] KRH-3955 Kureha Corp. – Preclinical 3 [119] POL3026 Polyphor, Ltd. – Preclinical 3 [120] Fusion FP-21399 Lexigen (Fuji Immuno- Skin discolourations; Phase II 1 [121–123] inhibitors Pharmaceuticals) development probably discontinued. Sifurvitide FusoGen Chinese development; Phase II 1 [124–126] Pharmaceuticals similar to enfuvirtide; parenteral administration. TRI-291144 Trimeris/Roche More convenient than Preclinical 3 [127] enfuvirtide and not continuation cross-resistant. unclear SPC3 Ambrilia Synthetic peptide; Phase I 2 [128] intravenous administration; failed as microbicide. Cell membrane SP-01A Samaritan Inhibits host cell membrane Phase II 1 [129] stabilizer Pharmaceuticals/ events that are required for Pharmaplaz entry; active against resistant strains; low antiviral activity. CCR5 down- Aprepitant Merck Sharp Licensed as antiemetic; Phase I 2 [130] regulator (Emend®) & Dohme downregulates CCR5 expression. gp41 Inhibitors Virip IPF PharmaCeuticals Inhibitory peptide from Preclinical 3 [131] human plasma.

ART, antiretroviral therapy; RTV, ritonavir.

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Attachment and fusion inhibitors Perspectives

TNX-355 is a humanised monoclonal antibody Drug development in the field of HIV-1 infection is still directed against the CD4 receptor molecule. Despite rapid and has so far been a success story largely unprec- antiviral activity in vivo [37,38], its parenteral mode edented in medical history. With the increasing number of of application makes it problematic for earlier lines therapeutic options, however, new drugs must have sig- of therapy. nificant advantages over existing ones in order to make it Sifuvirtide by FusoGen is being developed within to the market. This will probably slow down drug devel- China. It is similar to enfuvirtide and could become a opment. Recently, several new compounds have been local drug, such as Phosphazid in Russia. developed and licensed mainly for the setting of resistant SP-01A, a compound developed by Samaritan Phar- virus. Fortunately, with the recent availability of drugs maceuticals (in cooperation with Pharmaplaz) inhib- like maraviroc, raltegravir and etravirine, treatment its host cell membrane events required for fusion. It is options for patients with resistant virus have expanded, so active against resistant virus strains. A Phase II trial that profound viral suppression is a realistic goal even in is ongoing. Table 4 shows details of attachment and these patients. Therefore the magnitude of the problem of fusion inhibitors currently under development. extended resistance is currently decreasing, as the number of patients with uncontrolled replication grows smaller. Immune therapy and other cellular targets Among patients for whom even combinations compris- ing novel compounds cannot achieve profound viral sup- Pegylated interferon has significant antiretroviral pression, however, resistance will also occur against these activity, as demonstrated in an AIDS Clinical Trials drugs. Therefore, pharmaceutical companies should not Group trial [39]. However, the antiviral effect is lim- reduce their efforts to develop new compounds. With the ited, and its significant toxicity makes it unattractive possible exception of maturation inhibitors, those that for development as an antiretroviral agent (Table 5). are likely to take the next steps in clinical trials stem from MDX-10, a human anti-CTLA4 antibody, represents the established classes of NRTI (apricitabine), NNRTI an interesting immunomodulatory approach to boost (etravirine, rilpivirine and UK-453,061), CCR5 block- HIV-1-specific cytotoxic T-cell responses. No in vivo ers (vicriviroc and INCB009471) and integrase inhibitors experience in HIV-1 infection is reported as yet. Another (elvitegravir). Cross-resistance, albeit to a variable extent, approach is HRG, a polyclonal anti-HIV-1 serum from is likely to occur within the newer classes as well, so that New Zealand generated by immunization of goats with companies should actively investigate compounds with HIV-1 proteins (Table 5). The parenteral mode of appli- new modes of action. cation, side effects and viral escape, however, represent As it is becoming more difficult to develop drugs important obstacles to the development of this thera- specifically for earlier lines of therapy or first-line use, peutic approach. compounds selected for development should have the

Table 5. Drugs with other modes of action

Class Compound Company Properties, potential and drawbacks Development status Category Recent references

Cytokine Pegylated Roche Significant antiviral effect Phase II 1 [39]

interferon-α2a (-0.61 log10 copies/ml). CTLA4 MDX-010 Medarex Human anti-CTLA4 antibody; Phase I 2 [132,133] inhibitor improvement of HIV-specific T-cell responses. DHS Semapimod Cytokine Targets viral regulatory protein Preclinical 3 [134] inhibitor (CNI-1493) PharmaSciences indirectly via inhibition of DHS. Nuclear import ITI-367 International Prevents nuclear transloaction of the Preclinical 3 [135] inhibitor Therapeutics HIV type-1 preintegration complex. Neutralizing HRG214 Virionyx, Goat anti-HIV serum. Phase I, continuation 2 [136–138] antibody Auckland unclear 2F5, 3A4, 2G10 Universität für Broad neutralization capacitiy; Phase II, continuation 1 [139,140] Bodenkultur Wien antiviral effect in vivo unclear KD-247 Kumamoto Broad neutralization capacity. Preclinical 3 [141,142] University

DHS, deoxyhypusine synthase.

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5. Lodwick RK, Smith CJ, Youle M, et al. Stability of potential to be used in any line of therapy because of antiretroviral regimens in patients with viral suppression. high activity in drug-sensitive strains as well as lack of AIDS 2008; 22:1039–1046. cross-resistance to established drugs. Importantly, gov- 6. Cahn P, Cassetti I, Wood R, et al. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral- ernments, especially in industrialized countries, should naive, HIV-infected patients. AIDS 2006; 20:1261–1268. be prepared to provide economical incentives for the 7. Cahn P, Altclas J, Martins M, Losso M, Cassetti I, Cooper D. Superior activity of apricitabine compared to continuation of HIV-1 treatment success. 3TC over 21 days in treatment experienced HIV-1 infected Licensed drugs, such as tipranavir, darunavir and patients failing therapy with M184V and NRTI resistance. 4th International AIDS Society Conference on HIV etravirine, demonstrate that novel options can be Pathogenesis, Treatment and Prevention. 22–25 July 2007, developed successfully within established drug classes, Sydney, Australia. Abstract WESS203. despite the problem of within-class cross-resistance. 8. Colucci P, Cottage J, Robison H, et al. Efficacy and novel pharmacology of elvucitabine in a 7 day placebo controlled This has the advantage of exploiting well established monotherapy study. 46th Interscience Conference on treatment principles, for which long-term clinical expe- Antimicrobial Agents and Chemotherapy. 27–30 September 2006, San Francisco, CA, USA. Abstract H-1670d. rience exists, and carries less risk of unexpected tox- 9. Dunkle LM, Gathe JC, Pedevillano DE, et al. Elvucitabine: icity. The basic treatment paradigm of combining ≥3 potent antiviral activity demonstrated in multidrug-resistant fully active compounds in order to achieve profound HIV infection. Antivir Ther 2003; 8:S5 viral suppression, however, requires the development of 10. Fabrycki J, Zhao Y, Wearne J, et al. In vitro induction of HIV variants with reduced susceptibility to elvucitabine additional drugs with novel modes of action. (ACH-126,443, β-l-Fd4C). Antivir Ther 2003; 8:S8 HIV is a global challenge, and undoubtedly HIV-1 11. Cahn P, Sosa N, Wiznia A, et al. Racivir demonstrates safety represents the largest part of the problem. Unfortu- and efficacy in patients harboring HIV with the M184V mutation and <3 TAM. 14th Conference on Retroviruses nately, however, for those many individuals in develop- and Opportunistic Infections. 25–28 February 2007, Los ing countries who are infected with HIV type-2, most Angeles, CA, USA. Abstract 488. 12. Dalton P. Novel HIV therapy suffers stunning setback. of the compounds under development today hold lit- (Updated 12 June 2008. Accessed 12 April 2009.) Available tle promise. Companies should therefore make greater from http://www.projectinform.org/news/2008/061208.shtml efforts to develop drugs that are active against HIV 13. Murphy R, Zala C, Ochoa C, et al. Pharmacokinetics and potent anti-HIV-1 activity of amdoxovir plus zidovudine in type-2, as well. a randomized double-blind placebo-controlled study. 15th Resistance development is more rapid than drug Conference on Retroviruses and Opportunistic Infections. 3–6 February 2008, Boston, MA, USA. Abstract 794. development. Therefore, with novel drugs becoming 14. Gripshover BM, Ribaudo H, Santana J, et al. Amdoxovir available, clinicians have to avoid the mistakes of the versus placebo with enfuvirtide plus optimized background past, such as functional monotherapy, and use them in therapy for HIV-1-infected subjects failing current therapy (AACTG A5118). Antivir Ther 2006; 11:619–623. an optimal manner in the attempt to achieve the ulti- 15. Margolis DM, Mukherjee AL, Fletcher CV, et al. The mate goal to normalize the life expectancy of HIV-1- use of β-d-2,6-diaminopurine dioxolane with or without infected patients. mycophenolate mofetil in drug-resistant HIV infection. AIDS 2007; 21:2025–2032. 16. Thompson M, Richmond G, Kessler H, et al. Preliminary Disclosure statement results of dosing of amdoxovir in treatment-experienced patients. 10th Conference on Retroviruses and Opportunistic Infections. 10–14 February 2003, Boston, The author has served an an advisor and a speaker for MA, USA. Abstract 554. Roche, MSD, Bristol–Myers Squibb, Tibotec/Janssen 17. Thompson MA, Kessler HA, Eron JJ, Jr, et al. Short-term safety and pharmacodynamics of amdoxovir in HIV- Cilag, Abbott, Boehringer Ingelheim, GlaxoSmithKline, infected patients. AIDS 2005; 19:1607–1615. Gilead and Pfizer, and has received honoraria for these 18. Pozniak A, Morales–Ramirez J, Mohapi L, et al. 48-Week activities. primary analysis of trial TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART- naive patients. 14th Conference on Retroviruses and Opportunistic Infections. 25–28 February 2007, Los References Angeles, CA, USA. Abstract 144LB. 1. Palella FJ, Jr, Delaney KM, Moorman AC, et al. Declining 19. Pozniak A, Steyn D, Grinsztejn B, et al. Neuropsychiatric morbidity and mortality among patients with advanced events with TMC278, an investigational non-nucleoside human immunodeficiency virus infection. N Engl J Med reverse transcriptase inhibitor (NNRTI). 4th International 1998; 338:853–860. AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. 22–25 July 2007, Sydney, Australia. 2. Egger M, May M, Chene G, et al. Prognosis of HIV- Abstract WEPEA105. 1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. 20. Ruxrungtham K, Bellos N, Morales–Ramirez J, et al. Lancet 2002; 360:119–129. The metabolic profile of TMC278, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI). 3. Barreiro P, Jimenez–Nacher I, Garcia B, Garcia–Benayas T, 4th International AIDS Society Conference on HIV Rivas P, Soriano V. Nucleoside/nucleotide backbones for Pathogenesis, Treatment and Prevention. 22–25 July 2007, the treatment of HIV infection. Curr Opin Investig Drugs Sydney, Australia. Abstract TUAB105. 2005; 6:812–822. 21. van Heeswijk R, Hoetelmans R, Kestens D, et al. The 4. Sabundayo BP, McArthur JH, Langan SJ, Gallant JE, pharmacokinetic interaction between famotidine and Margolick JB. 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22. Fatkenheuer G, Staszewski S, Plettenberg A, et al. Short-term 38. Norris D, Morales J, Godofsky E, Garcia F, Hardwicke R, monotherapy with UK-453,061, a novel NNRTI, reduces Lewis S. TNX-355, in combination with optimized viral load in HIV infected patients. 4th International AIDS background regimen (OBR), achieves statistically significant Society Conference on HIV Pathogenesis, Treatment and viral load reduction and CD4 cell count increase when Prevention. 22–25 July 2007, Sydney, Australia. Abstract compared with OBR alone in phase 2 study at week 48. WESS202. XVI International AIDS Conference. 13–18 August 2006, Toronto, ON, Canada. Abstract ThLB0218. 23. Wu JJ, Stranix BR, Milot G, et al. PL-100, a next generation protease inhibitor against drug-resistant HIV: in vitro 39. Asmuth D, Chan E, Cai T, et al. 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Rapid and immunodeficiency virus activity and decreased cytotoxicity. durable antiretroviral effect of the HIV-1 integrase inhibitor Antimicrob Agents Chemother 2004; 48:1640–1646. raltegravir as part of combination therapy in treatment- 41. Bogner JR, Roecken M, Herrmann DB, et al. Phase I/II trial naive patients with HIV-1 infection: results of a 48-week with fozivudine tidoxil (BM 21.1290): a 7 day randomized, controlled study. J Acquir Immune Defic Syndr 2007; placebo-controlled dose-escalating trial. Antivir Ther 1997; 46:125–133. 2:257–264. 26. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup 42. Bogner JR, Boerner D, Muhlhofer A, et al. Single dose, and resistance analyses of raltegravir for resistant HIV-1 dose-escalating trial with fozivudine tidoxil (BM 21.1290). infection. N Engl J Med 2008; 359:355–365. Antivir Ther 1997; 2:249–256. 27. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir 43. Girard PM, Pegram PS, Diquet B, et al. 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Phase-II study of 14 days monotherapy with the nucleoside- activity of PA-457, the first-in-class maturation inhibitor, analogue fosalvudine tidoxil in treatment naive HIV-1 in a 10-day monotherapy study in HIV-1 infected patients. infected adults. 4th International AIDS Society Conference 45th Interscience Conference on Antimicrobial Agents and on HIV Pathogenesis, Treatment and Prevention. 22–25 Chemotherapy. 15–19 December 2006, Washington, DC, July 2007, Sydney, Australia. Abstract WEPEB114LB. USA. Abstract LB-27. 46. Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R. 30. Martin DE, Blum R, Wilton J, et al. Safety and KP-1212/1461, a nucleoside designed for the treatment of pharmacokinetics of bevirimat (PA-457), a novel inhibitor HIV by viral mutagenesis. Antiviral Res 2005; 67:1–9. of human immunodeficiency virus maturation, in healthy volunteers. Antimicrob Agents Chemother 2007; 47. Skoblov Y, Karpenko I, Shirokova E. Intracellular 51:3063–3066. metabolism and pharmacokinetics of 5′-hydrogenphosphonate of 3′-azido-2′,3′-dideoxythymidine, 31. Smith P, Forrest A, Beatty J, et al. Pharmacokinetics/ a prodrug of 3′-azido-2′,3′-dideoxythymidine. Antiviral Res pharmacodynamics of PA-457 in a 10-day multiple 2004; 63:107–113. dose monotherapy trial in HIV-infected patients. 13th 48. Corbett AH, Rublein JC. DAPD (Emory University/Triangle Conference on Retroviruses and Opportunistic Infections. Pharmaceuticals/Abbott Laboratories). Curr Opin Investig 5–8 February 2006, Denver, CO, USA. Abstract 52. Drugs 2001; 2:348–353. 32. Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for 49. Uckun FM, DuMez D, Qazi S, Tibbles H, previously treated patients with R5 HIV-1 infection. N Engl Venkatachalam TK. Anti-retroviral activity of GMP-grade J Med 2008; 359:1429–1441. stampidine against genotypically and phenotypically 33. Gulick R, Su Z, Flexner C, et al. 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Chung KC, Yadav V, Rapp K, Chong Y, Schinazi R. 37. Kuritzkes DR, Jacobson J, Powderly WG, et al. Dioxolane thymine nucleoside is active against a variety of Antiretroviral activity of the anti-CD4 monoclonal antibody NRTI-resistant mutants. 12th Conference on Retroviruses TNX-355 in patients infected with HIV type 1. J Infect Dis and Opportunistic Infections. 22–25 February 2005, 2004; 189:286–291. Boston, MA, USA. Abstract 554.

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55. Liang Y, Narayanasamy J, Schinazi RF, Chu CK. 70. Huang F, Drda K, Macgregor TR, et al. Pharmacokinetics Phosphoramidate and phosphate prodrugs of (-)-β-d- of BILR 355 after multiple oral doses coadministered with (2R,4R)-dioxolane-thymine: synthesis, anti-HIV activity and low dose of ritonavir. Antimicrob Agents Chemother 2009; stability studies. Bioorg Med Chem 2006; 14:2178–2189. 53:95–103. 56. Hernandez–Santiago BI, Chen H, Asif G, et al. 71. Jakubik J, Seifer M, Gray L, et al. IDX12899 anti-HIV-1 Pharmacology and pharmacokinetics of the antiviral agent activity and resistance profile is superior to efavirenz. beta-d-2′,3′-dideoxy-3′-oxa-5-fluorocytidine in cells and Antivir Ther 2007; 12:S32. rhesus monkeys. Antimicrob Agents Chemother 2005; 49:2589–2597. 72. Mayers D, Hard M, Damphousse D, et al. Dose-escalation safety, tolerability, and pharmacokinetics of a novel HIV-1 57. Yang G, Dutschman GE, Wang CJ, et al. 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Anti-HIV-1 activity of a a unique and highly potent nonnucleoside reverse foscarnet analogue, synergy with zidovudine and analysis transcriptase inhibitor of human immunodeficiency virus of resistance variants selected in vitro. 3rd International type 1 (HIV-1) that also inhibits HIV-2. Antimicrob Agents AIDS Society Conference on HIV Pathogenesis and Chemother 2001; 45:393–400. Treatment. 24–27 July 2005, Rio de Janeiro, Brazil. Abstract 79. Kaludov N, Watson K, Buckheit R, Jr. Investigational TuPe6.1B16. new drug-directed development of IQP-0410, a safe and 64. Cihlar T, Ray A, Boojamra D, et al. GS9148: a novel highly potent dual-acting nonnucleoside pyrimidinedione nucleotide active against HIV-1 variants with drug for the therapy of HIV-1 infection. 16th Conference on resistance mutations in reverse transcriptase. 13th Retroviruses and Opportunistic Infections. 8–11 February Conference on Retroviruses and Opportunistic Infections. 2009, Montreal, QC, Canada. 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86. Mimoto T, Nojima S, Terashima K, Takaku H, Shintani M, 101. Goebel FD, Hemmer R, Schmit JC, et al. Phase I/II Hayashi H. Structure-activity relationships of novel HIV-1 dose escalation and randomized withdrawal study with protease inhibitors containing the 3-amino-2-chlorobenzoyl- add-on azodicarbonamide in patients failing on current allophenylnorstatine structure. Bioorg Med Chem 2008; antiretroviral therapy. AIDS 2001; 15:33–45. 16:1299–1308. 102. Berkhout B, Gorelick R, Summers MF, Mély Y, Darlix JL. 87. Sevigny G, Stranix B, Tian B, et al. Antiviral activity 6th international symposium on retroviral nucleocapsid. and cross-resistance profile of P-1946, a novel human Retrovirology 2008; 25:21. immunodeficiency virus type 1 protease inhibitor. Antiviral Res 2006; 70:17–20. 103. Zhang XQ, Sorensen M, Fung M, Schooley RT. Synergistic in vitro antiretroviral activity of a humanized monoclonal 88. 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Received 2 September 2008, accepted 14 January 2009

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