Isabel De Clercq - Social Technologies - Catalyst for Organisational Change
CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq...
-
Upload
duongthien -
Category
Documents
-
view
216 -
download
2
Transcript of CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq...
![Page 1: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/1.jpg)
CIDOFOVIR: CLINICAL APPLICATIONS
Erik De Clercq
Rega Institute for Medical Research, K.U.LeuvenB-3000 Leuven, Belgium
![Page 2: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/2.jpg)
N
N
NH2
O
OPHO
HO
O
HO
HPMPCCidofovirVistide®
(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine
![Page 3: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/3.jpg)
P. Holý E. de Clercq
![Page 4: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/4.jpg)
DHPA
N
NN
N
NH2
OH OH
PHO O
HO C
OH
O PFA
PHO O
HOC
OH
O
PAA
N
N
NH2
O
OPHO
HO
O
HO
HPMPC
OPHO
HO
O
HO
N
N
N
N
NH2
HPMPA
![Page 5: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/5.jpg)
Antiviral activity of HPMPC first described in 1987
Licensed for clinical use for the treatment of CMV retinitisin AIDS patients in June 1996.
E. De Clercq, T. Sakuma, M. Baba, R. Pauwels, J. Balzarini,I. Rosenberg & A. Holý.Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines.Antiviral Res. 8, 261-272 (1987).
![Page 6: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/6.jpg)
Activity of (S)-HPMPA analogues against herpes simplex virus(HSV-1, HSV-2, TK- HSV-1) and vaccinia virus (VV) in primary
rabbit kidney cells
Compound Minimum inhibitory concentration (µg/ml)*HSV-1 HSV-2 TK- HSV-1 VV
(S)-HPMPA 2 4 2 0.7 (S)-cHPMPA 2 4 2 0.7 (S)-HPMPHx > 400 > 400 > 400 > 400 (RS)-HPMPG 7 20 7 2 (RS)-HPMPDAP 10 20 10 2 (S)-HPMPC 4 10 2 4 (S)-HPMPT 70 70 > 400 300 (RS)-HPMPU > 400 > 400 > 400 > 400 PMEA 7 7 7 150 PMEHx > 400 > 400 > 400 > 400 PMEG 4 7 7 10 PMEDAP 2 0.7 1 20 PMEMAP 70 10 150 > 200*Required to inhibit virus-induced cytopathogenicity by 50%.
De Clercq et al., Antiviral Res. 8: 261-272 (1987)
![Page 7: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/7.jpg)
![Page 8: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/8.jpg)
• Papovaviridae– Polyomaviridae– Papillomaviridae
• Adenoviridae• Herpesviridae• Poxviridae• Iridoviridae
Antiviral activity spectrum of cidofovir
![Page 9: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/9.jpg)
Antiviral activity spectrum of the acyclic nucleosidephosphonates
■■■■■■■■HHV-8■■■■■■■■HHV-7■■■■■■■■HHV-6■■■■■■■■CMV■■■■■■■■EBV■■■■■■■■VZV■■■■■■■■HSV-2■■■■■■■■HSV-1
Herpesviridae■■■■Adeno
Adenoviridae■■■■Papilloma■■■■Polyoma
PapovaviridaeDNA virus infections
TenofovirAdefovirCidofovir
![Page 10: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/10.jpg)
Antiviral activity spectrum of the acyclic nucleosidephosphonates (continued)
■■■■■■■■HBVHepadnaviridae
■■■■ASFVIridoviridae
■■■■Orf■■■■MCV■■■■Camelpox■■■■Monkeypox■■■■Cowpox■■■■Variola■■■■Vaccinia
PoxviridaeDNA virus infections
TenofovirAdefovirCidofovir
![Page 11: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/11.jpg)
Antiviral activity spectrum of the acyclic nucleosidephosphonates (continued)
■■■■■■■■FIV■■■■■■■■SIV■■■■■■■■HIV-2■■■■■■■■HIV-1
RetroviridaeRNA virus infections
TenofovirAdefovirCidofovir
![Page 12: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/12.jpg)
Cidofovir: intracellular metabolism
![Page 13: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/13.jpg)
OO
Cidofovir: mechanism of action (HCMV)
![Page 14: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/14.jpg)
N
N
NH2
O
OPO
P
HO
OOOO
O2(CH3)3N
HPMPCp choline
![Page 15: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/15.jpg)
N
N
NH2
O
OP
HO
O
O
O
CH315 3O
HPMPC HDP(HDP: 1-O-hexadecyloxypropyl)
![Page 16: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/16.jpg)
Dose-response curves for anti-CMV activityand cytotoxicity of PFA, DHPG, (S)-HPMPA
and (S)-HPMPC in HEL cells
Snoeck et al., Antimicrob. Agents Chemother. 32, 1839-1844 (1988)
![Page 17: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/17.jpg)
Neyts et al., Virology 179, 41-50 (1990)
CsCl equilibrium gradient analysis of DNA from CMV- and mock-infectedHEL cells exposed for 96 hours to varying concentrations of cidofovir
(HPMPC)
![Page 18: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/18.jpg)
Neyts et al., J. Med. Virol. 37, 67-71 (1992)
Survival of SCID mice infected i.p. with MCMV and treated s.c. withDHPG or HPMPC
For first set of mice, treatment was initiated 2 hours after infection and was continued for thenext 2 days; the second set of mice was treated again during a second period (days 9, 10,and 11 after infection, as indicated by the arrows). Symbols: (__) untreated controls (n = 5);(---) DHPG-treated mice; (_ _) HPMPC-treated mice; (!!!!) DHPG at 20 mg/kg/day at days 0, 1 and2 (n = 4); ("""") DHPG at 20 mg/kg/day at days 0, 1, 2, 9, 10, and 11 (n = 4); (O) HPMPC at 20mg/kg/day at days 0, 1, and 2 (n = 4); ( ) HPMPC at 20 mg/kg/day at days 0, 1, 2, 9, 10 and11 (n = 4).
![Page 19: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/19.jpg)
CidofovirCidofovir
Licensed since 1996 for the treatment of CMVLicensed since 1996 for the treatment of CMVretinitis in AIDS patients.retinitis in AIDS patients.
Aqueous solution of 375 mg/5 ml (Vistide) intendedAqueous solution of 375 mg/5 ml (Vistide) intendedfor intravenous use of maximally 5 mg/kg [once afor intravenous use of maximally 5 mg/kg [once aweek for the first two weeks and thereafter onceweek for the first two weeks and thereafter onceevery other week].every other week].
![Page 20: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/20.jpg)
Lalezari et al., Ann. Intern. Med. 126, 257-263 (1997)
![Page 21: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/21.jpg)
The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group, Am. J. Ophthalmol. 131, 457-467 (2001)
The ganciclovir implant plus oral ganciclovir (Gcv) versus parenteralcidofovir (Cdv) for the treatment of CMV retinitis in AIDS patients
Kaplan-Meier curves showing the probability of retinitis progression.
![Page 22: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/22.jpg)
The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group, Am. J. Ophthalmol. 131, 457-467 (2001)
Kaplan-Meier curves showing the probability of a 15-letter or greater loss of visual acuity.
The ganciclovir implant plus oral ganciclovir (Gcv) versus parenteralcidofovir (Cdv) for the treatment of CMV retinitis in AIDS patients
![Page 23: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/23.jpg)
Berenguer et al., Clin. Infect. Dis. 30, 182-184 (2000)
Kaplan-Meier curve showing the probability of freedom from iritis.
Compassionate use of intravenous cidofovir in AIDS patients with CMVretinitis: risk for iritis development
![Page 24: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/24.jpg)
Antiviral activity spectrum of cidofovir
• Papovaviridae– Polyomaviridae
• Murine polyomavirus• Human polyomavirus
– Papillomaviridae• Rabbit papillomavirus• Human papillomaviruses (several types)
• Adenoviridae– Human adenoviruses (several types)
![Page 25: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/25.jpg)
Antiviral activity spectrum of cidofovir(continued)
• Herpesviridae– HSV-1 (TK+ and TK-)– HSV-2 (TK+ and TK-)– VZV (TK+ and TK-)– EBV– HCMV (PK+ and PK-)– HHV-6– HHV-7– HHV-8
![Page 26: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/26.jpg)
• Poxviridae– Vaccinia virus– Variola virus– Cowpox virus– Monkeypox virus– Camelpox virus– Molluscum contagiosum virus– Orf virus
• Iridoviridae– African swine fever virus
Antiviral activity spectrum of cidofovir(continued)
![Page 27: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/27.jpg)
Liekens et al., Cancer Res. 58, 2562-2567 (1998)
Inhibition of hemangioma formation by cidofovir in rats infected intraperitoneally with murine polyoma virus
Macroscopic view of cerebral hemangiomas at 18 days post infection (p.i.). Subcutaneous treatment withcidofovir at 25 mg/kg, once a week, started at 3 days p.i. completely protected against hemangioma formation (not shown), whereas treatment initiated at 9 days p.i. (b) or 6 days p.i. (c) resulted in a significantdecrease in the number and size of the cerebral hemangiomas, as compared to the control (untreated)group (a).
![Page 28: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/28.jpg)
De Luca et al., AIDS 14, F117-F121 (2000)
Efficacy of cidofovir combined with highly active antiretroviral therapy (HAART)in AIDS-associated progressive multifocal leukoencephalopathy (PML)
Kaplan-Meier curves showing survival for patients on HAART plus cidofovir (continuous line) versus patients on HAART only (dashed line) (log rank, p = 0.01).
![Page 29: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/29.jpg)
De Luca et al., Neurology 52, 891 (1999)
Progressive multifocal leukoencephalopathy (PML):Response to cidofovir after failure of HAART alone
T2-Weighted axial brain MRI: marked neuroradiologic improvement 12 weeks after addition of cidofovir to HAART.
![Page 30: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/30.jpg)
Cidofor topical gelTreatment of rabbit papillomavirus infection
Twice daily treatment (M to F) for 8 weeks beginning 4 weeks post-infection
Christensen et al., Antiviral Res. 48, 131-142 (2000)
![Page 31: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/31.jpg)
Hypopharyngeal papilloma before and after treatmentwith cidofovir (local injection)
Before After
Cidofovir was administered by local injection (directly into the tumor) at 1.25 mg/kgat weekly intervals. Complete regression of the tumor was achieved after 7 injections.
Van Cutsem et al., J. Med. Virol. 45, 230-235 (1995)
![Page 32: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/32.jpg)
Laryngeal papilloma before and after treatment withcidofovir (local injection)
Before After
Cidofovir (2.5 mg/ml) was injected directly into the tumor. Complete regression of thetumor was achieved after 15 injections over 9 months.
Snoeck et al., J. Med. Virol. 54, 219-225 (1998)
![Page 33: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/33.jpg)
Intralesional cidofovir forrecurrent respiratory papillomatosis in children
Before After
Cidofovir (2.5 mg/ml) was injected into the tumor. Complete regression of the tumorwas achieved after 15 injections every 2 to 3 weeks.
Pransky et al., Arch. Otolaryngol. Head Neck Surg. 125, 1143-1148 (1999)
![Page 34: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/34.jpg)
Davis et al., J. Am. Acad. Dermatol. 43, 340-343 (2000)
Topical cidofovir in the treatment of a largeplantar wart (caused by HPV type 66)
Cidofovir was administered topically at 3% in emollient cream twice daily. The wart disappeared within 3 to 4 weeks.
Before After
![Page 35: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/35.jpg)
Snoeck et al., Arch. Intern. Med. 161, 2382-2384 (2001)
Topical cidofovir in the treatment of Bowenoidpapulosis of the penis
Cidofovir was administered topically at 1% in Beeler base. Two months after initiation oftreatment (three courses of once daily applications for 5 days), the lesion hadcompletely disappeared.
Before After
![Page 36: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/36.jpg)
Schürmann et al., AIDS 14, 1075-1076 (2000)
Topical cidofovir in the treatment of extensive penile condylomata
Cidofovir was administered topically at 1% in amphiphile cream once daily for 14 days:3 weeks after discontinuation only a few residual condylomata were noted.
Before After
![Page 37: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/37.jpg)
Protocol GS-95-306
A phase I/II, double-blind, placebo-controlled study of thesafety and efficacy of cidofovir topical gel for thetreatment of patients with human papillomavirus
infections
Snoeck et al., Clin. Infect. Dis. 33, 597-602 (2001)
![Page 38: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/38.jpg)
Protocol GS-95-306Clinical response
11 (100)19 (100)Total
5 (45.5) 0Progression(≥≥≥≥ 25% increase)
4 (36.4) 3 (15.8)No change
2 (18.2) 7 (36.8)Partial response(≥≥≥≥ 50% decrease)
0 9 (47.4)Complete response
Placebo N (%)
1%N (%)
Snoeck et al., Clin. Infect. Dis. 33, 597-602 (2001)
![Page 39: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/39.jpg)
Romanowski & Gordon, Invest. Ophthalmol. Vis. Sci. 41, 460-463 (2000)
Topical cidofovir (twice daily) against adenovirus type 5 infection in rabbits
Adenovirus ocular titers following treatment for 7 days (starting at day 1) with0.5 % cidofovir (O) or placebo(σσσσ)
![Page 40: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/40.jpg)
Adenovirus infections
• Adenoviral (ADV) infections: increasingly recognized ascause of morbidity and mortality in pediatric hematopoieticstem cell transplantation (HSCT).
• Prospective trial with cidofovir (at 1 mg/kg intravenously 3times weekly) in the treatment of ADV infections in HSCTrecipients.
• All patients eventually achieved long-term viralsuppression and clinical improvement, although prolongedcidofovir treatment for up to 8 months was required insome patients.
• Dose-limiting nephrotoxicity was not observed, anddiscontinuation of the drug was not warranted, in anypatient.
Hoffman et al., Biology of Blood and Marrow Transplantation 7, 388-394 (2001)
![Page 41: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/41.jpg)
Kaufman et al., Arch. Ophthalmol. 117, 925-928 (1999)
Prevention of HSV-1 stromal keratitis in rabbits
Treatment started at day 2 and continued through day 21.
![Page 42: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/42.jpg)
De Clercq & Holý, Antimicrob. Agents Chemother. 35, 701-706 (1991)
Inhibitory effects of HPMPC or ACV administration on the developmentof skin lesions and/or paralysis of the hind legs
The compounds were administered i.p. twice a day for 5 days starting 1 h after virus infection atthe following doses: 0 mg/kg/day (control (####), HPMPC at 20 mg/kg/day (σσσσ), HPMPC at 50 mg/kg/day (ρρρρ), HPMPC at 100 mg/kg/day (O), HPMPC at 250 mg/kg/day (≤≤≤≤), and ACV at 100 mg/kg/day(ππππ). There were 10 mice per group.
![Page 43: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/43.jpg)
Cumulative proportion converting to HSV culture negativityPlacebo vs. 1%, 3%, and 5% cidofovir
Sacks et al., Antimicrob. Agents Chemother. 42, 2996-2999 (1998)
![Page 44: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/44.jpg)
Vistide® treatmentAcyclovir-resistant HSV lesions
Baseline Two doses Four doses
Lalezari et al., J. Infect. Dis. 170, 570-572 (1994)
![Page 45: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/45.jpg)
Neyts & De Clercq, J. Med. Virol. 41, 242-246 (1993)
Treatment was initiated at 2 h after infection and was either continued for the next 4 days orrepeated on day 4 p.i. and then twice every week (on day 1 and 4 of each week). Symbols:untreated controls (-) (n=5); treated at 1 mg/kg/day for 5 days (O) (n=5); at 5 mg/kg/day for 5days (#### ) (n=5); at 20 mg/kg/day for 5 days ($$$$) (n=5); or at 20 mg/kg/twice a week for up to 20weeks (∆∆∆∆) (n=5).
Survival of SCID mice infected i.v. with VV and treated s.c. with cidofovir
![Page 46: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/46.jpg)
Bray et al., J. Infect. Dis. 181, 10-19 (2000)
Intranasal cowpox virus infection
(A) Effect of a single s.c. injection of cidofovir (100 mg/kg) on survival.(B) Effect of cidofovir (100 mg/kg on indicated days) on mean body weight.(C) Effect of cidofovir (100 mg/kg on indicated times) on survival.
![Page 47: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/47.jpg)
Intranasal cowpox virus infection
Bray et al., J. Infect. Dis. 181, 10-19 (2000)
Effect of a single s.c. injection of cidofovir (100 mg/kg) on survival
![Page 48: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/48.jpg)
Intranasal cowpox virus infection
Bray et al., J. Infect. Dis. 181, 10-19 (2000)
Effect of cidofovir (100 mg/kg on indicated days) on mean body weight
![Page 49: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/49.jpg)
Intranasal cowpox virus infection
Bray et al., J. Infect. Dis. 181, 10-19 (2000)
Effect of cidofovir (100 mg/kg on indicated times) on survival
![Page 50: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/50.jpg)
Smee et al., Antiviral Res. 52, 55-62 (2001)
Effect of cidofovir treatment on survival (A) and on mean body weight (B) of BALB/c mice infected i.n. with vaccinia virus
A single i.p. injection of cidofovir (100 mg/kg) was given 24 h after virus exposure:("""") uninfected; (####) cidofovir; (O) placebo.
![Page 51: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/51.jpg)
Bray et al., Antiviral Res. 54, 129-142 (2002)
Treatment of aerosolized cowpox virus infection in mice withaerosolized cidofovir
Change in mean body weight of BALB/c mice infected by aerosolized cowpox virus andtreated with aerosolized cidofovir (0.5-5 mg/kg) on day –1, 0 or 1.
![Page 52: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/52.jpg)
Redfield et al., N. Engl. J. Med. 12, 673-676 (1987)
Disseminated vaccinia in an AIDS patientDisseminated vaccinia in an AIDS patient
One month after vaccination 12 weeks after treatment withvaccinia immunoglobulin
![Page 53: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/53.jpg)
Vaccinia lesions in a patient with chronic lymphocytic leukemiaVaccinia lesions in a patient with chronic lymphocytic leukemia
3 weeks after vaccination 5 days after iv therapy with ribavirin
Kesson et al., Clin. Infect. Dis. 25, 911-914 (1997)
![Page 54: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/54.jpg)
Activity of cidofovir (CDV) and HDP-CDV againstvaccinia, cowpox, monkeypox and variola viruses
0.1 0.070.6 ± 0.30.8 ± 0.4HDP-CDV
27.34.644.7 ± 6.346.2 ± 11.9CDV
VariolaMonkeypoxCowpoxVaccinia
EC50 (µM)Compound
Kern, Antiviral Res. 57, 35-40 (2003)
![Page 55: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/55.jpg)
Meadows et al., Arch. Dermatol. 133, 987-990 (1997)
Intravenous cidofovir therapy in the treatment ofmolluscum contagiosum in AIDS patients
Cidofovir was administered intravenously (at 2 mg/kg, once every 2 weeks):after 2 months the lesions had resolved, although scarring remained.
Before After
![Page 56: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/56.jpg)
Ibarra et al., Acta Derm. Venereol. 80, 315-316 (2000)
Intravenous cidofovir therapy in the treatment ofmolluscum contagiosum in AIDS patients
Cidofovir was administered intravenously (at 5 mg/kg once per week, followed by5 mg/kg once every 2 weeks): after 9 cycles (4 months), the lesions had disappeared.
Before After
![Page 57: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/57.jpg)
Orf (ecthyma contagiosum) before and aftertreatment with cidofovir (topical 1% cream)
Before After
Cidofovir was administered topically as a 1% cream in Beeler basis once daily forrepeated courses (5 days on/5 days off therapy), with complete resolution of thelesions after 7 courses (2-3 months).
Geerinck et al., J. Med. Virol. 64, 543-549 (2001)
![Page 58: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/58.jpg)
Indications for the clinical use of the acyclic nucleosidephosphonates
• Systemic adenovirus infections
• Polyomavirus infections [i.e.progressive multifocalleukoencephalopathy (PML)]
• CMV, EBV, HHV-6, HHV-7 and HHV-8[i.e. Kaposi’s sarcoma (KS)]infections
• HSV-1, HSV-2 and VZV infections(particularly those that are resistantto acyclovir)
• CMV retinitis in patients with AIDS(approved)
Systemic (intravenous)Cidofovir (Vistide®)
Clinical indicationRoute of administrationCompound
![Page 59: CIDOFOVIR: CLINICAL APPLICATIONS - · PDF fileCIDOFOVIR: CLINICAL APPLICATIONS Erik De Clercq ... Antiviral activity of HPMPC first described in 1987 Licensed for clinical use for](https://reader031.fdocuments.us/reader031/viewer/2022011723/5a835dd07f8b9a38478eb640/html5/thumbnails/59.jpg)
Indications for the clinical use of the acyclic nucleosidephosphonates (continued)
• CMV retinitisTopical (intravitreal)
• Keratoconjunctivitis due to HSV oradenovirus
Topical (eyedrops)
• Molluscum contagiosum, orf, and,should it be necessary, otherpoxvirus infections (vaccinia,monkeypox, smallpox, ...)
Systemic (intravenous)or topical (gel)
• HPV-associated papillomatouslesions [i.e. recurrent laryngealpapillomas, anogenital warts,cervical intraepithelial neoplasia(CIN) grade III]
Topical (gel or injection)
• Mucocutaneous HSV-1 or HSV-2infections (particularly whenresistant to acyclovir)
Topical gelCidofovir (Vistide®)
Clinical indicationRoute of administrationCompound