Tenofovir in de behandeling en prophylaxis van HIV ......Tenofovir in de behandeling en prophylaxis...
Transcript of Tenofovir in de behandeling en prophylaxis van HIV ......Tenofovir in de behandeling en prophylaxis...
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Tenofovir in de behandeling en prophylaxis van HIV infecties (AIDS)
Erik De Clercq
Rega Institute for Medical Research, KU Leuven, Belgium
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Symposium on Synthetic Nucleosides, Nucleotides and Polynucleotides, Max-Planck-Institut für Biophysikalische Chemie, Göttingen, Germany, 3-5 May 1976
2
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E. De Clercq, A. Holý, I. Rosenberg, T. Sakuma, J. Balzarini & P.C. Maudgal.A novel selective broad-spectrum anti-DNA virus agent.Nature, 323: 464-467 (1986).
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OPHO
HO
O
HO
N
N
N
N
NH2
(S)-HPMPA(S)-9-(3-Hydroxy-2-phosphonomethoxypropyl)adenine
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J. Balzarini, A. Holý, J. Jindrich, L. Naesens, R. Snoeck, D. Schols & E. De Clercq.Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirusactivities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine.Antimicrob. Agents Chemother., 37: 332-338 (1993).
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N
N
NH2
N
N
CH2PO
HO CH2
OHO
CH
CH3
(R)-9-(2-phosphonylmethoxypropyl)adenine
(R)-PMPATenofovir
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C.C. Tsai, K.E. Follis, A. Sabo, T.W. Beck, R.F. Grant, N. Bischofberger, R.E. Benveniste & R. Black.Prevention of SIV infection in macaques by (R)-9-(2-phosphonyl-methoxypropyl)adenine.Science, 270: 1197-1199 (1995).
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Protein immunoblot analysis of SIV-specific antibody response in macaques 20 weekspost infection with SIV. Mock-treated control macaques (n = 10) and macaquestreated with PMPA (tenofovir) starting at 24 hours post infection (n = 5) arepresented. Antibodies to env glycoprotein gp120, gag proteins p28, p16 and p8 andvpx protein p14 were detected in all of the control macaques. None of the macaquestreated with PMPA starting 24 hours post infection showed SIV-specific antibodies
Tsai et al. Science 270, 1197-1199 (1995)
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“Ich wäre nichts ohne De Clercq”, sagt er und fügt mit einem schweijkschenAugenzwinkern hinzu: “De Clercq wäre aber auch nichts ohne mich”. Unddie Leute bei Gilead ? “Sie lieferten das Sahnehäubchen”, sagt er, der Erfolghätte demnach “drei gleichberechtigte geistige Väter”.
Der Spiegel, 12.08.96
Antonín Holý legacy
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Rio Grande Gorge, New Mexico, 1995
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The Holý Trinity: at Gilead Sciences (2003)
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Holy Trinity monument in Olomouc
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The Holý Trinity in České Budějovice, 4 June 2009
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CHEMISTRY
BIOMEDICINE INDUSTRY
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(R)-PMPA(R)-9-(2-Phosphonomethoxypropyl)
adenineTenofovir
Bis(POC)PMPABis(isopropyloxycarbonyloxymethyl)PMPA
Tenofovir disoproxil fumarate TDF
Viread®
N
N
N
N
P O
NH2
HO O
HO
CH3
N
N
N
N
P O
NH2
O O
O
CH2OCO
O
CH2OCO
O CH3
(CH3)2CH
(CH3)2CH
HOOCCH
HCCOOH
(Treatment of HIV infections)(Treatment of HBV infections)
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Tenofovir disoproxil fumarate (TDF)Viread®
S
O
HO
N
N
F
NH2
O
(-)-FTCEmtricitabine
Emtriva®
Truvada®
(Treatment of HIV infections)(Prevention of HIV infections)
CH
HC
HOOC
COOH
N
N
N
N
P O
NH2
O O
O
CH2OCO
O
CH2OCO
O CH3
(CH3)2CH
(CH3)2CH
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Tenofovir disoproxil fumarate (TDF)Viread®
S
O
HO
N
N
F
NH2
O
(-)-FTCEmtricitabine
Emtriva®
Atripla®
O
N O
ClF3C
H
EfavirenzSustiva®, Stocrin®
(Treatment of HIV infections)
CH
HC
HOOC
COOH
N
N
N
N
P O
NH2
O O
O
CH2OCO
O
CH2OCO
O CH3
(CH3)2CH
(CH3)2CH
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Tenofovir disoproxil fumarate (TDF)Viread®
S
O
HO
N
N
F
NH2
O
(-)-FTCEmtricitabine
Emtriva®
Complera®/Eviplera®
Rilpivirine Edurant®
(Treatment of HIV infections)
HN
N
N NH
N
N
CH
HC
HOOC
COOH
N
N
N
N
P O
NH2
O O
O
CH2OCO
O
CH2OCO
O CH3
(CH3)2CH
(CH3)2CH
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Tenofovir disoproxil fumarate (TDF)Viread®
S
O
HO
N
N
F
NH2
O
(-)-FTCEmtricitabine
Emtriva®
Stribild®Elvitegravir Cobicistat
N NH
O
HN N
HO
O
N
O
SN
O
N
S
(Treatment of HIV infections)
N
OH
OOF
Cl
HOH
O
CH
HC
HOOC
COOH
N
N
N
N
P O
NH2
O O
O
CH2OCO
O
CH2OCO
O CH3
(CH3)2CH
(CH3)2CH
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N
N
N
N
OP
CH3
O
O
NH2
HN
O
O
CH3
GS-7340TAF
Tenofovir alafenamide
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Birkus et al. Antimicrob. Agents Chemother., 60: 316-322 (2015)
Intracellular metabolism of TAF
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Buti et al. Lancet Gastroenterol. Hepatol., 1: 196-206 (2016)
HBV suppression in a comparative study of TAF vs TDF in patients with HBeAg-negative chronic HBV infection
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N
N
OH
HN
O
F
O
HN
O
N
O
N
Raltegravir (RAL)
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Elvitegravir (EVG)
N
OHO
FHO
OO
Cl
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Dolutegravir (DTG)
N
ON N
H
O
H
O OH
O F
F
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Bictegravir (BIC)
N
N
O
NH
F
F
F
O
O OH
OHH
H
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Resistance profiles of 47 HIV-1 isolates against INSTIs: RAL: raltegravir; EVG: elvitegravir; DTG: dolutegravir; BIC: bictegravir
Tsiang et al. Antimicrob. Agents Chemother., 60: 7086-7097 (2016)
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Sax et al. Lancet HIV, 4: e154-e160 (2017)
Mean change from baseline in HIV-1 RNA load following 48 weeks of treatment withbictegravir or dolutegravir, each with emtricitabine and TAF
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Vemlidy®: TAF (25 mg)
Approved in US on 10 November 2016
Japan on 19 December 2016
EU on 11 January 2017
for treatment of chronic HBV infection
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Descovy®: TAF (25 mg) + emtricitabine (200 mg)
Approved in US on 4 April 2016
EU on 25 April 2016
for treatment of HIV infections
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Odefsey ®: TAF (25 mg) + emtricitabine (200 mg) + rilpivirine
(25 mg)
Approved in US on 1 March 2016
EU on 29 April 2016
for treatment of HIV infections
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Genvoya®: TAF (10 mg) + emtricitabine (200 mg) +
cobicistat (150 mg) + elvitegravir (150 mg)
Approved in US on 5 November 2015
EU on 23 November 2015
for the treatment of HIV infections
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Biktarvy®: TAF (25 mg) + emtricitabine (200 mg) + bictegravir
(50 mg)
Approved in US on 7 February 2018
EU on 27 April 2018
for the treatment of HIV infections
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Symtuza®: TAF (10 mg) + emtricitabine (200 mg) + darunavir
(800 mg) + cobicistat (150 mg)
Approved in EU on 26 September 2017
Approved in US on 17 July 2018
for the treatment of HIV infections
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Tenofovir disoproxil fumarate (TDF)Viread®
S
O
HO
N
N
F
NH2
O
(-)-FTCEmtricitabine
Emtriva®
Truvada®
(Treatment of HIV infections)(Prevention of HIV infections)
CH
HC
HOOC
COOH
N
N
N
N
P O
NH2
O O
O
CH2OCO
O
CH2OCO
O CH3
(CH3)2CH
(CH3)2CH
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Truvada® approved for prophylaxis of HIV infections in
US on 16 July 2012 and on 22 August 2016 in EU
Forthcoming ?: Descovy® for the pre-exposure
prophylaxis (PrEP) of HIV infections.
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