CIDOFOVIR: CLINICAL APPLICATIONS

Erik De Clercq

Rega Institute for Medical Research, K.U.LeuvenB-3000 Leuven, Belgium

N

N

NH2

O

OPHO

HO

O

HO

HPMPCCidofovirVistide®

(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine

P. Holý E. de Clercq

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

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).

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)

• Papovaviridae– Polyomaviridae– Papillomaviridae

• Adenoviridae• Herpesviridae• Poxviridae• Iridoviridae

Antiviral activity spectrum of cidofovir

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

Antiviral activity spectrum of the acyclic nucleosidephosphonates (continued)

■■■■■■■■HBVHepadnaviridae

■■■■ASFVIridoviridae

■■■■Orf■■■■MCV■■■■Camelpox■■■■Monkeypox■■■■Cowpox■■■■Variola■■■■Vaccinia

PoxviridaeDNA virus infections

TenofovirAdefovirCidofovir

Antiviral activity spectrum of the acyclic nucleosidephosphonates (continued)

■■■■■■■■FIV■■■■■■■■SIV■■■■■■■■HIV-2■■■■■■■■HIV-1

RetroviridaeRNA virus infections

TenofovirAdefovirCidofovir

Cidofovir: intracellular metabolism

OO

Cidofovir: mechanism of action (HCMV)

N

N

NH2

O

OPO

P

HO

OOOO

O2(CH3)3N

HPMPCp choline

N

N

NH2

O

OP

HO

O

O

O

CH315 3O

HPMPC HDP(HDP: 1-O-hexadecyloxypropyl)

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)

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)

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).

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].

Lalezari et al., Ann. Intern. Med. 126, 257-263 (1997)

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.

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

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

Antiviral activity spectrum of cidofovir

• Papovaviridae– Polyomaviridae

• Murine polyomavirus• Human polyomavirus

– Papillomaviridae• Rabbit papillomavirus• Human papillomaviruses (several types)

• Adenoviridae– Human adenoviruses (several types)

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

• 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)

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).

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).

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.

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)

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)

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)

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)

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

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

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

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)

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)

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)

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)

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.

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.

Cumulative proportion converting to HSV culture negativityPlacebo vs. 1%, 3%, and 5% cidofovir

Sacks et al., Antimicrob. Agents Chemother. 42, 2996-2999 (1998)

Vistide® treatmentAcyclovir-resistant HSV lesions

Baseline Two doses Four doses

Lalezari et al., J. Infect. Dis. 170, 570-572 (1994)

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

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.

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

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

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

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.

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.

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

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)

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)

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

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

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)

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

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