Cidofovir in the treatment of poxvirus infections

Abstract

Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, HPMPC] has since 1996 been licensed for clinical use in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Cidofovir has broad-spectrum activity against virtually all DNA viruses, including herpes-, adeno-, polyoma-, papilloma- and poxviruses. Among the poxviruses, vaccinia, variola (smallpox), cowpox, monkeypox, camelpox, molluscum contagiosum and orf have proven sensitive to the inhibitory effects of cidofovir. In vivo, cidofovir has shown high efficacy, even after administration of a single systemic (intraperitoneal) or intranasal (aerosolized) dose, in protecting mice from a lethal respiratory infection with either vaccinia or cowpox. Cidofovir has also demonstrated high effectiveness in the treatment of vaccinia virus infection in severe combined immune deficiency mice. In humans, cidofovir has been used successfully in the treatment, by both the topical and intravenous route, of recalcitrant molluscum contagiosum and orf in immunocompromised patients. Taken together, these data indicate that cidofovir should be effective in the therapy and short-term prophylaxis of smallpox and related poxvirus infections in humans, as well as the treatment of the complications of vaccinia that may arise in immunocompromised patients inadvertently inoculated with the smallpox vaccine (vaccinia).

Fig. 1

(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC, HPMPC, Cidofovir, Vistide®].

Fig. 2

Mechanism of action of cidofovir (HPMPC). For detailed explanation, see text. () represents a phosphonate group, whereas () corresponds to a phosphate group.

Fig. 3

Inhibitory effects of (S)-HPMPA on tail lesion formation in NMRI mice inoculated i.v. with VV. (S)-HPMPA was administered intraperitoneally for 5 days (starting 1 h after infection) at the indicated doses. Pox tail lesions were enumerated at 7 days after infection (De Clercq et al., 1989).

Fig. 4

Survival of SCID mice infected i.v. with VV and treated s.c. with cidofovir. Treatment was initiated at 2 h after infection and was either continued for the next 4 days or repeated 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 (○) (n=5); at 5 mg/kg day for 5 days (●) (n=5); at 20 mg/kg/day for 5 days () (n=5); or at 20 mg/kg/twice a week for up to 20 weeks (▵) (n=5) (Neyts and De Clercq, 1993).

Fig. 5

Effect of cidofovir treatment on survival (A) and on mean body weight (B) following i.n. infection of BALB/c mice with VV. A single intraperitoneal injection of cidofovir (100 mg/kg) was given 24 h after virus exposure. (■) uninfected; (●) cidofovir; (○) placebo (Smee et al., 2001b).

Fig. 6

Intranasal cowpox virus infection. (A) Effect of a single s.c. injection of 100 mg of cidofovir per kg on survival after i.n. infection. Crosses mean percent survival in two to six experiments, except for days -6 and -4, when one experiment was done. Vertical bars indicate standard deviations. (B) Effect on mean body weight of groups of 10 mice treated with 100 mg of cidofovir per kg on indicated days or mock-treated with phosphate-buffered saline on day 0. (C) Effect of drug treatment on the course of i.n. cowpox virus infection in SCID mice. Mice were treated with 100 mg of cidofovir per kg on day 0 only or every 3 or 6 days, beginning on day 0, or were mock-treated with phosphate-buffered saline on day 0 (Bray et al., 2000).

Fig. 7

Molluscum contagiosum in a 29-year-old AIDS patient, presenting with nodular, confluent and crusting plaques (panel A). Resolution of lesions, with remaining scarring, following i.v. cidofovir therapy (2 mg/kg once every 2 weeks) (panel B) (Meadows et al., 1997).

Fig. 8

Molluscum contagiosum in a 32-year-old man with AIDS (panel A). Resolution of the molluscum contagiosum lesions after i.v. cidofovir therapy (5 mg/kg once every 2 weeks) (panel B) (Ibarra et al., 2000).

Fig. 9

Orf (ecthyma contagiosum) in a 39-year-old renal transplant patient (under immunosuppression) before (panel A) and after (panel B) topical (1%) cidofovir treatment (Geerinck et al., 2001).

Fig. 10

Disseminated vaccinia in a military recruit with HIV disease: lesions at about 1 month after primary smallpox vaccination (A), and 12 weeks later after treatment with vaccinia immune globulin, 50 ml given intramuscularly weekly (B) (Redfield et al., 1987).

Fig. 11

Vaccinia lesion on the upperarm of a 67-year-old man with metastatic melanoma and chronic lymphocytic leukemia who received, inadvertently, a vaccinia melanoma oncolysate vaccination, at 3 weeks after vaccination (left panel), and 5 days later after i.v. therapy with ribavirin (every 8 h for 5 days) (Kesson et al., 1997).