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Published Online:https://doi.org/10.2217/17460794.1.6.709

With the recent approvalof Atripla™ by the US FDA for the treatment of AIDS as the first triple-drug combination one-a-day pill, it would appear appropriate to review both the origin and development of this anti-HIV medicine. Atripla consists of three active ingredients, a nucleotide reverse transcriptase inhibitor (NtRTI), a nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI). The cornerstone in Atripla is the NtRTI tenofovir disoproxil fumarate (Viread™) complemented by the NRTI emtricitabine (Emtriva™) and the NNRTI efavirenz (Sustiva™). This triple-drug combination offers a number of advantages compared with the single-drug regimens, such as synergistic mechanism of action, decreased risk of drug-resistance development and reduction of toxic side effects of the individual drugs, while increasing drug compliance (based on once-daily dosing). Since the first NtRTI, adefovir, was described as an antiretroviral agent, it has taken exactly 20 years to successfully develop its combination with emtricitabine and efavirenz as the ‘combo’ pill Atripla for the treatment of AIDS.

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

Bibliography

  • De Clercq E, Holý A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC: A novel selective broad-spectrum anti-DNA virus agent. Nature323,464–467 (1986).•• First paper describing the antiviral activity of the acyclic nucleoside phosphonates (ANPs) with a prototype 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, from which all ANPs (e.g., adefovir, cidofovir and tenofovir) were derived.
  • Pauwels R, Balzarini J, Schols D et al.: Phosphonylmethoxyethyl purine derivatives: a new class of anti-human immunodeficiency virus agents. Antimicrob. Agents Chemother.32,1025–1030 (1988).
  • Balzarini J, Naesens L, Herdewijn P et al.: Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective antihuman immunodeficiency virus agent. Proc. Natl Acad. Sci. USA86,332–336 (1989).
  • Balzarini J, Holý A, Jindrich J et al.: 9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo.Proc. Natl Acad. Sci. USA88,4961–4965 (1991).
  • Balzarini J, Holý A, Jindrich J et al.: Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of(R)-9-(2-phosphonomethoxypropyl)- 2,6-diaminopurine. Antimicrob. Agents Chemother.37,332–338 (1993).•• First paper describing the anti-HIV activity of tenofovir, later to become a key component in anti-HIV combination regimens.
  • Balzarini J, Aquaro S, Perno CF, Witvrouw M, Holý A, De Clercq E: Activity of the (R)-enantiomers of 9-(2-phosphonylmethoxypropyl)-adenine and9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine against human immunodeficiency virus in different human cell systems. Biochem. Biophys. Res. Commun.219,337–341 (1996).
  • Naesens L, Bischofberger N, Augustijns P et al.: Antiretroviral efficacy and pharmacokinetics of oral bis-(isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl)adenine in mice. Antimicrob. Agents Chemother.42,1568–1573 (1998).• Together with [8], was the first to describe the anti-HIV activity and efficacy of tenofovir disoproxil.
  • Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A: Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob. Agents Chemother.42,612–617 (1998).• Together with [7], was the first to describe the anti-HIV activity and efficacy of tenofovir disoproxil.
  • De Clercq E, Holý A: Acyclic nucleoside phosphonates: a key class of antiviral drugs. Nat. Rev. Drug Discovery4,928–940 (2005).•• History on how the ANPs originated and evolved to their present state as antiviral drugs for the treatment of DNA virus and retrovirus infections.
  • 10  Helliot B, Panis B, Frison E et al.: The acyclic nucleoside phosphonate analogues, adefovir, tenofovir and PMEDAP, efficiently eliminate banana streak virus from banana (Musa spp.). Antiviral Res.59,121–126 (2003).• A side observation that needs to be followed up in a socio-economic context totally different from, but tangential to, the AIDS context.
  • 11  Suo Z, Johnson KA: Selective inhibition of HIV-1 reverse transcriptase by an antiviral inhibitor, (R)-9-(2-phosphonylmethoxypropyl)adenine. J. Biol. Chem.273,27250–27258 (1998).
  • 12  Cherrington JM, Allen SJW, Bischofberger N, Chen MS: Kinetic interaction of the diphosphates of 9-(2-phosphonylmethoxyethyl)adenine and other anti-HIV active purine congeners with HIV reverse transcriptase and human DNA polymerases α, β and γ. Antiviral Chem. Chemother.6,217–221 (1995).
  • 13  Cihlar T, Chen MS: Incorporation of selected nucleoside phosphonates and anti-human immunodeficiency virus nucleotide analogues into DNA byhuman DNA polymerases α, β and γ. Antiviral Chem. Chemother.8,187–195 (1997).
  • 14  Birkus G, Hitchcock MJM, Cihlar T: Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother.46,716–723 (2002).
  • 15  Biesecker G, Karimi S, Desjardins J et al.: Evaluation of mitochondrial DNA content and enzyme levels in tenofovir DF-treated rats, rhesus monkeys and woodchucks. Antiviral Res.58,217–225 (2003).
  • 16  Gallant JE, Staszewski S, Pozniak AL et al.: Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients. JAMA292,191–201 (2004).
  • 17  Domingo P, Labarga P, Palacios R et al.: Improvement of dyslipidemia in patients switching from stavudine to tenofovir: preliminary results. AIDS18,1475–1478 (2004).
  • 18  Moyle G, Sabin C, Cartledge J et al.:A 48-week, randomized, open-label comparative study of tenofovir DF versus abacavir as substitutes for a thymidine analog in persons with lipoatrophy and sustained virological suppression on HAART. Presented at: 12th Conference on Retroviruses and Opportunistic Infections. Boston, MA, USA, 22–25 February 2005.
  • 19  Izzedine H, Hulot JS, Vittecoq D et al.: Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naive HIV-1-infected patients. Data froma double-blind randomizedactive-controlled multicentre study. Nephrol. Dial. Transplant.20,743–746 (2005).
  • 20  Gallant JE, DeJesus E, Arribas JR et al.: Tenofovir DF, emtricitabine, and efavirenz versus zidovudine, lamivudine, and efavirenz for HIV. N. Engl. J. Med.354,251–260 (2006).•• Of pivotal importance in the development of the combination pill consisting of tenofovir disoproxil fumarate (TDF), emtricitabine and efavirenz for the treatment of HIV infections.
  • 21  Schooley RT, Ruane P, Myers RA et al.: Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS16,1257–1263 (2002).
  • 22  Squires K, Pozniak AL, Pierone G Jr et al.: Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann. Intern. Med.139,313–320 (2003).
  • 23  Nelson M, Cooper D, Schooley R et al.: The safety of tenofovir DF for the treatment of HIV infection: the first 4 years. Presented at: 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, USA, 5–8 February 2006.
  • 24  Miller MD, Margot N, Lu B et al.: Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J. Infect. Dis.189,837–846 (2004).
  • 25  White KL, Margot NA, Ly JK et al.: A combination of decreased NRTI incorporation and decreased excision determines the resistance profile of HIV-1 K65R RT. AIDS19,1751–1760 (2005).
  • 26  Margot NA, Isaacson E, McGowan I, Cheng AK, Schooley RT, Miller MD: Genotypic and phenotypic analyses of HIV-1 in antiretroviral-experienced patients treated with tenofovir DF. AIDS16,1227–1235 (2002).
  • 27  Deval J, White KL, Miller MD et al.: Mechanistic basis for reduced viral and enzymatic fitness of HIV-1 reverse transcriptase containing both K65R and M184V mutations. J. Biol. Chem.279,509–516 (2004).
  • 28  Frankel F, Turner D, Spira B, Wainberg M: Molecular characterization of HIV-1 reverse transcriptase harboring the K65R and L74V mutations. Presented at: 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, USA, 5–8 February 2006.
  • 29  Weber J, Chakraborty B, Weberova J, Miller MD, Quinones-Mateu ME: Diminished replicative fitness of primary human immunodeficiency virus type 1 isolates harboring the K65R mutation. J. Clin. Microbiol.43,1395–1400 (2005).
  • 30  White KL, Chen JM, Feng JY et al.: The K65R reverse transcriptase mutation in HIV-1 reverses the excision phenotype of zidovudine resistance mutations. Antiviral Ther.11,155–163 (2006).
  • 31  Sluis-Cremer N, Torres PA, Grzybowski J, Parikh U, Mellors J: Molecular mechanism of tenofovir, abacavir, and lamivudine resistance by the K70E mutation in HIV-1 reverse transcriptase. Presented at: 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, USA, 5–8 February 2006.
  • 32  Kearney BP, Flaherty JF, Shah J: Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin. Pharmacokinet.43,595–612 (2004).
  • 33  León A, Mallolas J, Martinez E et al.: High rate of virological failure in maintenance antiretroviral therapy with didanosine and tenofovir. AIDS19,1695–1706 (2005).
  • 34  Maitland D, Moyle G, Hand J et al.: Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial. AIDS19,1183–1188 (2005).
  • 35  Gallant JE, Rodriguez AE, Weinberg WG et al.: Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naivesubjects. J. Infect. Dis.192,1921–1930 (2005).
  • 36  Hawkins T, Veikley W, St Claire RL 3rd, Guyer B, Clark N, Kearney BP: Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens. J. Acquir. Immune Defic. Syndr.39,406–411 (2005).
  • 37  Lanier ER, Hazen R, Ross L, Freeman A, Harvey R: Lack of antagonism between abacavir, lamivudine, and tenofovir against wild-type and drug-resistant HIV-1. J. Acquir. Immune Defic. Syndr.39,519–522 (2005).
  • 38  Ray AS, Myrick F, Vela JE et al.: Lack of a metabolic and antiviral drug interaction between tenofovir, abacavir and lamivudine. Antiviral Ther.10,451–457 (2005).
  • 39  Delaunay C, Brun-Vézinet F, Landman R et al.: Comparative selection of the K65R and M184V/I mutations in human imunodeficiency virus type 1-infected patients enrolled in a trial of first-line triple-nucleoside analog therapy (Tonus IMEA 021). J. Virol.79,9572–9578 (2005).
  • 40  Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G: Tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. Clin. Infect. Dis.42,283–290 (2006).
  • 41  Tsai CC, Follis KE, Sabo A et al.: Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine. Science270,1197–1199 (1995).•• Pioneering observation describing the potential value of tenofovir in the prevention of HIV infections, heralded in the present study by the prevention of simian immunodeficiency virus infection in rhesus macaques, and later followed up by similar prophylactic studies in macaques [42,43].
  • 42  Otten RA, Smith DK, Adams DR et al.: Efficacy of postexposure prophylaxis after intravaginal exposure of pig-tailed macaques to a human-derived retrovirus (human immunodeficiency virus type 2). J. Virol.74,9771–9775 (2000).
  • 43  Van Rompay KK, McChesney MB, Aguirre NL, Schmidt KA, Bischofberger N, Marthas ML: Two low doses of tenofovir protect newborn macaques against oral simian immunodeficiency virus infection. J. Infect. Dis.184,429–438 (2001).
  • 44  Mayer KH, Maslankowski LA, Gai F et al.: Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS20,543–551 (2006).
  • 45  Garcia-Lerma J, Otten R, Qari S et al.: Prevention of rectal SHIV transmission in macaques by tenofovir/FTC combination. Presented at: 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, USA, 5–8 February 2006.
  • 46  Johnson J, Van Rompay K, Delwart E, Heneine W: Rapid emergence of drug-resistant SIV in tenofovir-treated macaques: implications for tenofovir chemoprophylaxis against HIV. Presented at: 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, USA, 5–8 February 2006.
  • 47  Benhamou Y, Fleury H, Trimoulet P et al.: Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology43,548–555 (2006).• Study pertaining to the role of TDF in the treatment of chronic hepatitis B in hepatitis B virus (HBV)/HIV coinfected patients.
  • 48  Nelson M, Bhagani S, Fisher M et al.: A 48-week study of tenofovir or lamivudine or a combination of tenofovir and lamivudine for the treatment of chronic hepatitis B in HIV/HBV coinfected individuals. Presented at: 13th Conference on Retroviruses and Opportunistic Infections. Denver, CO, USA, 5–8 February 2006.
  • 49  Yang H, Qi X, Sabogal A, Miller M, Xiong S, Delaney WE 4th: Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV. Antiviral Ther.10,625–633 (2005).
  • 50  Delaney WE 4th, Ray AS, Yang H et al.: Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob. Agents Chemother.50,2471–2477 (2006).
  • 51  Schildgen O, Sirma H, Funk A et al.: Variant of hepatitis B virus with primary resistance to adefovir. N. Engl. J. Med.354,1807–1812 (2006).• Study suggesting the potential of TDF in the treatment of chronic hepatitis B in HBV/HIV co-infected patients.