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New antiretroviral drugs

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Abstract

Despite the availability of 21 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens remain hampered by issues of toxicity, convenience, cost, incomplete viral suppression, and drug resistance. Expansion of the currently available therapeutic options through the reformulation of available agents, discovery of new compounds with antiretroviral activity, and the exploitation of novel drug targets are critical. This review describes the status of new nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. We also summarize new classes of antiretroviral therapy in clinical development including the attachment inhibitors, chemokine receptor antagonists, integrase inhibitors, and maturation inhibitors.

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References and Recommended Reading

  1. Mahungu T, Ballinger J, Swaden L, et al.: Switching to Saquinavir 500/r-based regimens in subjects on HAART is not associated with loss of virologic control [abstract# PE1.1/5]. Paper presented at the 10th European AIDS Conference. Dublin, Ireland; November 17–20, 2005.

  2. Awni W, Chiu Y-L, Zhu T, et al.: Significantly reduced food effect and pharmacokinetic variability with a novel lopinavir/ritonavir tablet formulation [abstract# We0206]. Paper presented at the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil; July 24–27, 2005.

  3. Geleziunas R, Gallagher K, Zhang H, et al.: HIV-1 resistance profile of the novel nucleoside reverse transcriptase inhibitor beta-D-2′,3′-dideoxy-2′,3′-didehydro-5-.uorocytidine (Reverset). Antivir Chem Chemo 2003, 14:49–59.

    CAS  Google Scholar 

  4. Hammond JL, Parikh UM, Koontz DL, et al.: In vitro selection and analysis of human immunodeficiency virus type 1 resistant to derivatives of beta-2′,3′-didehydro-2′,3′-dideoxy-5-.uorocytidine. Antimicrob Agents Chemother 2005, 49:3930–3932.

    Article  PubMed  CAS  Google Scholar 

  5. Murphy RL, Schürmann D, Kravec I, et al.: Pharmacokinetics, safety and antiviral activity of the nucleoside Reverset following single doses in HIV-1 infected patients [abstract# 545]. Paper presented at the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Paris, France; July 13–17, 2003.

  6. Murphy RL, Schürmann D, Beard A, et al.: Potent anti-HIV-1 activity of Reverset™ following 10 days of monotherapy in treatment-naïve individuals [abstract# MoOrB1056]. Paper presented at the 15th International AIDS Conference. Bangkok, Thailand; July 11–16, 2004.

  7. Cohen C, Katlama C, Murphy R, et al.: Antiretroviral activity and tolerability of Reverset (D-d4FC), a new fluorocytidine nucleoside analog, when used in combination therapy in treatment-experienced patients: results of phase IIb study RVT-203 [abstract# WeOaLB0103]. Paper presented at the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil; July 24–27, 2005.

  8. Bethell R, Collins P, Holdich T, et al.: In vitro and in vivo antiviral activity of SPD754 against wild-type and NRTI-resistant viruses [abstract# WePeA5642]. Paper presented at the 15th International AIDS Conference. Bangkok, Thailand; July 11–16, 2004.

  9. Holdich T, Dennis K: Influence of food upon the pharmacokinetics of SPD754 [abstract# 119]. Paper presented at the 9th European AIDS Conference. Warsaw, Poland; October 25–29, 2003.

  10. Bethell R, Adams J, De Muys J, et al.: Pharmacological evaluations of a dual deoxycytosine analogue combination: 3TC and SPD754 [abstract #138]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infection. San Francisco, CA; February 8–11, 2004.

  11. Cahn P, Lange J, Cassetti I, et al.: Anti HIV-1 activity of SPD754 a new NRTI: Results of a 10 day monotherapy study in treatment naïve HIV patients [abstract# LB15]. Paper presented at the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Paris, France; July 13–17, 2003.

  12. Bethell RC, Collins P: Genotypic and phenotypic analysis of HIV-1 isolates from patients after 10 days monotherpay with SPD754 [abstract# 268]. Paper presented at the 44th Interscience Conference on Antimicrobial Agents Chemotherapy. Washington, DC; October 30–November 2, 2004.

  13. Das K, Clark AD Jr, Lewi PJ, et al.: Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J Med Chem 2004, 47:2550–2560.

    Article  PubMed  CAS  Google Scholar 

  14. Andries K, Azijn H, Thielemans T, et al.: TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004, 48:4680–4686.

    Article  PubMed  CAS  Google Scholar 

  15. Piscitelli S, Baede P, Vant Klooster G, et al.: Pharmacokinetics of TMC 125 in HIV-infected patients and healthy volunteers [abstract# 5.3]. Paper presented at the 3rd International Workshop on the Clinical Pharmacology of HIV Therapy. Washington, DC; April 11–13, 2002.

  16. Gruzdev B, Rakhmanova A, Doubovskaya E, et al.: A randomized, double-blind, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects. AIDS 2003, 17:2487–2494.

    Article  PubMed  CAS  Google Scholar 

  17. Gazzard BG, Pozniak AL, Rosenbaum W, et al.: An openlabel assessment of TMC 125 — a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS 2003, 17:49–54.

    Article  Google Scholar 

  18. Montaner J, Domingo P, Junod P, et al.: Safety and tolerability of TMC125 in 3-class-experienced HIV-infected patients: 24-week primary analysis of trial TMC125-C203 [abstract# LBPS3/7B]. Paper presented at the 10th European AIDS Conference. Dublin, Ireland; November 17–20, 2005.

  19. Nadler JP, Grossman HA, Hicks C, et al.: Efficacy and tolerability of TMC125 in HIV patients with NNRTI and PI resistance at 24 weeks: TMC125-C223 [abstract# LBPS3/7]. Paper presented at the 10th European AIDS Conference. Dublin, Ireland; November 17–20, 2005.

  20. de Bethume MP, Andries K, Azijn H, et al.: TMC278, a new potent NNRTI, with an increased barrier to resistance and favorable pharmacokinetic profile [abstract# 556]. Paper presented at the 12th Conference on Retroviruses and Opportunistic Infection. Boston, MA; February 22–25, 2005.

  21. Hoetelmans R, Van Heeswijk R, Kestens D, et al.: Effect of food and multiple-dose pharmacokinetics of TNC278 as an oral tablet formulation [abstract# TuPe3.1B10]. Paper presented at the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil; July 24–27, 2005.

  22. Goebel F, Yakovlev A, Pozniak A, et al.: TMC278: Potent anti-HIV activity in antiretroviral therapy-naïve patients [abstract# 160]. Paper presented at the 12th Conference on Retroviruses and Opportunistic Infection. Boston, MA; February 22–25, 2005.

  23. De Meyer S, Azijn H, Surleraux D, et al.: TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother 2005, 49:2314–2321.

    Article  PubMed  CAS  Google Scholar 

  24. van der Geest R, van der Sandt I, Gille D, et al.: Safety, tolerability and pharmacokinetics of escalating single oral doses of TMC 114, a novel protease inhibitor (PI) highly active against HIV-1 variants resistant to other PIs [abstract# I-1934]. Paper presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL; December 16–19, 2001.

  25. Katlama C, Carvalho MTM, Cooper D, et al.: TMC114/r outperforms investigator-selected PI(s) in 3-class-experienced patients: week 24 primary analysis of POWER 1 (TMC114-C213) [abstract# WeOaLB0102]. Paper presented at the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil; July 24–27, 2005.

  26. Grinsztejn B, Arasteh K, Clotet B, et al.: TMC114/ritonavir is well tolerated in 3-class-experienced patients: week 24 primary analysis of POWER 1 (TMC114-C213) [abstract# WeOaLB6.2C01]. Paper presented at the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil; July 24–27, 2005.

  27. Wilkin T, Haubrich R, Steinhart CR, et al.: TMC114/r superior to standard of care in 3-class-experienced patients: 24-wks primary analysis of the power 2 study (C2020) [abstract# H-413]. Paper presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; December 15–19, 2005.

  28. Ward D, Lalezari J, Thompson M, et al.: Preliminary activity and safety of 640385/ritonavir in HIV-infected patients (Study HPR10006); an 8-week interim analysis [abstract# H-412]. Paper presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; December 15–19, 2005.

  29. Dai SJ, Dou GF, Qiang XH, et al.: Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro. Acta Pharmacol Sin 2005, 26:1274–1280.

    Article  PubMed  CAS  Google Scholar 

  30. Lin P, Blair W, Wang T, et al.: A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc Natl Acad Sci U S A 2003, 100:11013–11018.

    Article  PubMed  CAS  Google Scholar 

  31. Moore PL, Cilliers T, Morris L: Predicted genotypic resistance to the novel entry inhibitor, BMS-378806, among HIV-1 isolates of subtypes A to G. AIDS 2004, 18:2327–2330.

    Article  PubMed  Google Scholar 

  32. Burkly LC, Olson D, Shapiro R, et al.: Inhibition of HIV infection by a novel CD4 domain 2-specific monoclonal antibody. Dissecting the basis for its inhibitory effect on HIV-induced cell fusion. J Immunol 1992, 149:1779–1787.

    PubMed  CAS  Google Scholar 

  33. Godofsky E, Zhang X, Sorensen M, et al.: In vitro antiretroviral activity of the humanized anti-CD4 monoclonal antibody, TNX-355, against CCR5, CXCR4, and dual-tropic isolates and synergy with enfuvirtide [poster# 3844]. Poster presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; December 15–19, 2005.

  34. Reimann KA, Burkly LC, Burrus B, et al.: In vivo administration to rhesus monkeys of a CD4-specific monoclonal antibody capable of blocking AIDS virus replication. AIDS Res Hum Retroviruses 1993, 9:199–207.

    PubMed  CAS  Google Scholar 

  35. Reimann KA, Khunkhun R, Lin W, et al.: A humanized, nondepleting anti-CD4 antibody that blocks virus entry inhibits virus replication in rhesus monkeys chronically infected with simian immunodeficiency virus. AIDS Res Hum Retroviruses 2002, 18:747–755.

    Article  PubMed  CAS  Google Scholar 

  36. Kuritzkes DR, Jacobson J, Powderly WG, et al.: Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J Infect Dis 2004, 189:286–291.

    Article  PubMed  CAS  Google Scholar 

  37. Reimann KA, Lin W, Bixler S, et al.: AIDS Res Hum Retroviruses 1997, 13:933–943.

    Article  PubMed  CAS  Google Scholar 

  38. Jacobson JM, Kuritzkes DR, Godofsky E, et al.: A phase I multiple dose study of the anti-CD4 monoclonal antibody, TNX-355, in multiple doses in HIV-infected subjects [abstract# 536]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.

  39. Norris D, Morales J, Gathe J, et al.: TNX-355 in combination with optimized background regimen (OBR) exhibits greater antiviral activity than OBR alone in HIV-treatment experience patients. Paper presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; December 15–19, 2005.

  40. Macartney MJ, Dorr PK, Smith-Burchnell C, et al.: In vitro antiviral profile of UK-427,857: a novel CCR5 antagonist [abstract# H-875]. Paper presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL; September 14–17, 2003.

  41. McHale M, Abel S, Russell D, et al.: Overview of phase 1 and 2a safety and efficacy data of maraviroc (UK-427,857) [abstract# TuOa0204]. Paper presented at the 3rd International AIDS Society. Rio de Janeiro, Brazil; July 24–27, 2005.

  42. Fatkenheuer G, Pozniak L, Johnson M, et al.: Evaluation of dosing frequency and food effect on viral load reduction during short-term monotherapy with UK-427,857 a novel CCR5 antagonist [abstract#TuPeB4489]. Paper presented at the 15th International AIDS Conference. Bangkok, Thailand; July 11–16, 2004.

  43. Pozniak AL, Fatkenheuer G, Johnson M, et al.: Effect of short term monotherapy with UK-427,857 on viral load in HIV-infected patients [abstract# H-443]. Paper presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL; September 14–17, 2003.

  44. Rosario MC, Poland W, Felstead S, et al.: Modeling of UK-427,857, a novel CCr5 antagonist, efficacy in short-term monotherapy [abstract# TuPeB4479]. Paper presented at the 15th International AIDS Conference. Bangkok, Thailand; July 11–16, 2004.

  45. Fatkenheuer G, Pozniak AL, Johnson MA, et al.: Efficacy of short-term monotherapy with maraviroc, a new CCr5 antagonist, in patients infected with HIV-1. Nat Med 2005, 11:1170–1171.

    Article  PubMed  CAS  Google Scholar 

  46. Westby M, Whitcomb J, Huang W, et al.: Reversible predominance of CXCR4 utilizing variants in a nonresponsive dual tropic patient receiving the CCR5 antagonist UK-427,857 [abstract #538]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.

  47. Baroudy B: Coreceptor inhibitors [abstract# MoOrAI38]. Paper presented at the 14th International AIDS Conference. Barcelona, Spain; July 7–12, 2002.

  48. Schurmann D, Rouzier R, Nougarede R, et al.: SCHD: antiviral activity of a CCR5 receptor antagonist [abstract# 140LB]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.

  49. Roschke V, Clark S, Branco L, et al.: Characterization of a panel of novel human monoclonal antibodies that specifically antagonize CCR5 and block HIV-1 entry [abstract #2871]. Paper presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; October 30–November 2, 2004.

  50. Olson WC, Rabut GE, Nagashima KA, et al.: Differential inhibition of human immunodeficiency virus type 1 fusion, gp120 binding, and CC-chemokine activity by monoclonal antibodies to CCR5. J Virol 1999, 73:4145–4155.

    PubMed  CAS  Google Scholar 

  51. Trkola A, Ketas TJ, Nagashima KA, et al.: Potent, broadspectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140. J Virol 2001, 75:579–588.

    Article  PubMed  CAS  Google Scholar 

  52. Murga J, Olson W, Pevear DC: Antiviral synergy between the CCR5 mAb PRO 140 and small-molecule CCR5 antagonists [abstract# TuOa0206]. Paper presented at the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil; July 24–27, 2005.

  53. Schols D, Claes S, Hatse S, et al.: Anti-HIV activity profile of AMD070, an orally bioavailable CXCR4 antagonist [abstract# 563]. Paper presented at the 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 10–14, 2003.

  54. Schols D, Vermeire K, Hatse S, et al.: In vitro anti-HIV activity profile of AMD887, a novel CCR5 antagonist, in combination with the CXCR4 inhibitor AMD070 [abstract# 539]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.

  55. Stone N, Dunaway S, Flexner C, et al.: Biologic activity of an orally bioavailable CXCR4 antagonist in human subjects [abstract# TuPeB4475]. Paper presented at the 15th International AIDS Conference. Bangkok, Thailand; July 11–16, 2004.

  56. Morales-Ramirez JO, Teppler H, Kovacs C, et al.: Antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in ART-naive HIV-1 infected patients [abstract # LBPS1/6]. Paper presented at the 10th European AIDS Conference. Dublin, Ireland; November 17–20, 2005. Along with Li et al. [57], this paper represents first-in-class agents targeting new steps in the HIV life cycle.

  57. Li F, Goila-Guar R, Salzwedel K, et al.: PA-457: A potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc Nat Acad Sci 2003, 100:13555–13560. Along with Morales-Ramirez et al. [56], this paper represents first-in-class agents targeting new steps in the HIV life cycle.

    Article  PubMed  CAS  Google Scholar 

  58. Beatty G, Lalezari J, Eron J, et al.: Safety and antiviral activity of PA-457, the first in class maturation inhibitor, in a 10-day monotherapy study in HIV-1 infected patients [abstract# H-416d]. Paper presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; December 15–19, 2005.

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  1. Division of Infectious Diseases and International Health, Duke University Medical Center, Box 3879, 27710, Durham, NC, USA

    Kimberly Hanson MD

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  1. Kimberly Hanson MD
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  2. Charles Hicks MD
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Correspondence to Kimberly Hanson MD.

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Hanson, K., Hicks, C. New antiretroviral drugs. Curr HIV/AIDS Rep 3, 93–101 (2006). https://doi.org/10.1007/s11904-006-0024-z

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