A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS.

The safety and efficacy of cidofovir gel for treatment of acyclovir-unresponsive herpes simplex virus infections in AIDS patients was evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3% or 1%) or placebo gel was applied once daily for 5 days. Ten of 20 cidofovir-treated and none of 10 placebo-treated patients had complete healing or >50% decreased area (P = .008); 30% of cidofovir-treated patients versus 0 placebo recipients had complete healing (P = .031). Viral shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9 placebo-treated patients (P = .00004). For cidofovir-treated patients, median time to complete or good response was 21 days, and median time to negative viral culture was 2 days (P = .025, P = .0001, respectively). Median lesion area decreases were 58% for cidofovir-treated versus 0 for placebo-treated patients (P = .005), and mean pain score changes were -1.84 versus -0.34 (P = .042). Application site reactions occurred in 25% of cidofovir-treated and 20% of placebo-treated patients; none was dose-limiting. Cidofovir therapy provided significant benefits in lesion healing, virologic effect, and pain reduction.

Treatment with intravenous (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS.

(S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is a nucleotide analogue with potent in vitro and in vivo activity against a broad range of herpesviruses, including acyclovir-resistant herpes simplex virus (HSV). A patient with severe acyclovir-resistant perineal HSV infection received intravenous HPMPC at 5 mg/kg/week, with concomitant oral probenecid and prehydration, and had 95% healing after four infusions. The patient developed a hypersensitivity reaction to probenecid and discontinued HPMPC after the fourth infusion. Recurrence of the perineal lesions 2 weeks later prompted initiation of an oral desensitization program to probenecid and enabled the patient to resume therapy. The lesions again responded to infusions of HPMPC, but the drug was discontinued before complete healing because of transient nephrotoxicity (proteinuria, 2+; creatinine, 1.7 mg/dL). HPMPC is a potent antiviral agent that holds promise as a potential treatment for acyclovir-resistant HSV infection.

Correlation between response to acyclovir and foscarnet therapy and in vitro susceptibility result for isolates of herpes simplex virus from human immunodeficiency virus-infected patients.

In vitro susceptibility testing of herpes simplex virus (HSV) isolates will play an increasingly important role in guiding the clinical management of immunocompromised hosts who have lesions that are poorly responsive to therapy with standard antiviral agents. We assessed the correlation between the in vitro susceptibility result using a plaque reduction assay in Vero cells and the response to antiviral therapy with acyclovir or foscarnet for 243 clinical isolates of HSV collected from 115 human immunodeficiency virus-infected patients. The in vitro results and clinical responses were highly associated for both acyclovir and foscarnet (P < 0.001 and P < 0.001, respectively). The predictive values of a susceptible result (50% effective concentrations, < 2 micrograms/ml for acyclovir and < 100 micrograms/ml for foscarnet) for complete healing of lesions were 62% for acyclovir and 82% for foscarnet; the predictive values of a resistant result for failure to heal were 95% for acyclovir and 88% for foscarnet. Thus, in vitro testing has clinical utility in guiding therapy, although the 1 to 2 weeks required to derive a definitive result by the plaque reduction assay is a major limitation.

Foscarnet-resistant herpes simplex virus infection in patients with AIDS.

Six human immunodeficiency virus-infected patients had clinical lesions of herpes simplex virus (HSV) type 2 that showed in vitro resistance to foscarnet. In each patient, lesions were unresponsive to foscarnet therapy or developed during daily suppressive foscarnet. Five patients had a history of intermittent or chronic foscarnet use for the management of acyclovir-resistant HSV infection, and 1 was receiving daily foscarnet for suppression of cytomegalovirus retinitis. Seven of 10 foscarnet-resistant isolates from 6 patients were susceptible to acyclovir in vitro, and 1 was of borderline susceptibility. In 3 patients, the administration of acyclovir, either alone or in combination with foscarnet, resulted in healing. Clinically significant resistance to foscarnet may occur in immunosuppressed patients with prior foscarnet exposure. Addition or substitution of acyclovir to foscarnet therapy may be a useful strategy for patients in whom foscarnet resistance is suspected, pending the results of in vitro susceptibility testing.

SP-303, an antiviral oligomeric proanthocyanidin from the latex of Croton lechleri (Sangre de Drago).

SP-303, a large proanthocyanidin oligomer isolated from the latex of the plant species Croton lechleri (Eupborbiaceae) has demonstrated broad activity against a variety of DNA and RNA viruses. In cell culture, SP-303 exhibits potent activity against isolates and laboratory strains of respiratory syncytial virus (RSV), influenza A virus (FLU-A) and parainfluenza virus (PIV). Parallel assays of SP-303 and ribavirin showed comparable activity against these viruses. SP-303 also exhibits significant inhibitory activity against herpesvirus (HSV) types 1 and 2, including herpesviruses resistant to acyclovir and foscarnet. Inhibition was also observed against hepatitis A and B viruses. The antiviral mechanism of SP-303 seems to derive from its direct binding to components of the viral envelope, resulting in inhibition of viral attachment and penetration of the plasma membrane. Antiviral effects of SP-303 were measured by three distinct methods: CPE, MTT and precursor uptake/incorporation. Cytotoxicity endpoints were markedly greater than the respective antiviral endpoints. SP-303 exhibited activity in RSV-infected cotton rats and African green monkeys, PIV-3-infected cotton rats, HSV-2 infected mice and guinea pigs and FLU-A-infected mice. The most successful routes of SP-303 administration for producing efficacy were: topical application to HSV-2- genital lesions in mice and guinea pigs, aerosol inhalation to FLU-A-infected mice and PIV-3-infected cotton rats, and oral dosage to RSV-infected cotton rats. A variety of toxicological evaluations demonstrated the safety of SP-303, particularly orally, which was predictable, since condensed tannins are a common dietary component. It is notable that the larger proanthocyanidins as a class have high antiviral activity, whereas most of the monomers are inactive. Clinical trials are ongoing to evaluate SP-303 as a therapeutic antiviral agent.

Foscarnet therapy for acyclovir-resistant mucocutaneous herpes simplex virus infection in 26 AIDS patients: preliminary data.

Mucocutaneous herpes simplex virus (HSV) infections that are resistant to therapy with acyclovir have been recognized with increasing frequency in patients with the acquired immunodeficiency syndrome, although alternative therapies in this setting have not been widely studied. Twenty-six consecutive patients are reported with human immunodeficiency virus infection, who received foscarnet therapy for acyclovir-resistant HSV. Clinical response was noted in 81% of patients; complete reepithelialization of HSV lesions occurred in 73%. Cessation of viral shedding was documented in all of the 11 patients who were recultured. Although adverse effects were frequent, in only 3 patients (12%) did toxicity necessitate discontinuation of therapy. Before foscarnet therapy, 14 patients received vidarabine for acyclovir-resistant HSV. The infection did not resolve in any of the vidarabine-treated patients, and therapy was discontinued in 4 (29%) due to toxicity.

Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with the acquired immunodeficiency syndrome (AIDS). An uncontrolled trial.

STUDY OBJECTIVE: To determine whether trisodium phosphonoformate (foscarnet) is efficacious in treating severe mucocutaneous disease due to acyclovir-resistant herpes simplex virus type-2 (HSV-2) infection in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Open-labeled drug administration to patients with AIDS and severe ulcerative disease due to acyclovir-resistant HSV-2 infection. SETTING: Medical floors of acute care hospital. PATIENTS: Four patients with AIDS who developed progressive ulcerative mucocutaneous lesions of the genitals, perineum, perianal region, or finger due to acyclovir-resistant, thymidine-kinase (TK)-negative strains of HSV-2. INTERVENTION: Foscarnet, 60 mg/kg body weight intravenously every 8 hours (with reduced dosage for renal impairment), for 12 to 50 days. MEASUREMENT AND MAIN RESULTS: All patients receiving foscarnet had dramatic improvement in their clinical findings with marked clearing of mucocutaneous lesions and eradication of HSV from mucosal surfaces. CONCLUSION: Foscarnet may be an effective treatment for severe mucocutaneous disease due to acyclovir-resistant, TK-negative strains of HSV-2.