Foscarnet for suppression of human immunodeficiency virus replication

Abstract

The effect of foscarnet against human immunodeficiency virus (H1V) was evaluated in nine HIV-infected individuals; six completed 28 days of induction therapy. The overall mean increase in CD4+ lymphocytes was 64 cells per mm3. The mean decline in the HIV antigen concentration was 108 pg/ml (P = 0.03), and suppression was related to systemic foscarnet exposure by a maximum-effect pharmacodynamic model.Foscarnet has in vitro activity against a broad spectrum of viruses, including herpes simplex virus, varicella-zoster virus, cytomegalovirus (CMV), hepatitis B virus, and human immunodeficiency virus (HIV) (8,12). Several investigations of foscarnet therapy for CMV retinitis in patients with AIDS have described a decrease in the concentration of HIV antigen in serum (6,9,11). The present study (designated protocol 028 by the AIDS Clinical Trials Group [ACTG]) was designed to evaluate the safety, pharmacokinetic disposition, and anti-HIV effect of foscarnet in HIV-infected individuals.The criteria for participation in this trial included confirmed HIV infection with CD4+ lymphocyte count of less than 500/mm3 (on two separate occasions), detectable concentration of HIV antigen in serum equal to or greater than 25 pg/ml, age of .12 years, Karnofsky performance status of at least 60%, granulocyte count of >1,000 cells per mm3, platelet count of >75,000/mm3, hemoglobin concentration of .9 g/dl, and serum creatinine and bilirubin levels within the normal range. Primary and secondary chemoprophylaxis of Pneumocystis carinii pneumonia was permitted but not required; antiretroviral agents were not allowed. This investigation was approved by the institutional review board of each participating site, and all subjects gave written consent before participation.Study participants were randomly assigned to groups given 12.5, 25, or 50 mg of foscarnet per kg of body weight every 8 h for the first 28 days. Individuals who were clinically stable after 28 days had the option of receiving maintenance therapy that consisted of a dose of 50 mg/kg given once daily 5 days per week for an indefinite period. During the 28-day induction period, foscarnet was administered in a double-blind manner. The dose was adjusted in any participant whose estimated creatinine clearance was .1.3 ml/min/kg. Study participants were required to spend a minimum of 48 h after initiation of therapy as inpatients, after which they were monitored as outpatients.Patients responses to therapy. CD4+ lymphocyte cell counts were obtained at screening, entry into study, the second and fourth week of treatment, and then monthly. Serum HIV antigen tests were collected weekly during induction but were otherwise obtained according to the same schedule as that for CD4+ lymphocyte counts. Serum HIV antigen levels were measured with an enzyme-linked immunosorbent assay kit (Abbott Laboratories, North Chicago, Ill.), using purified virion p24 (ACTG Virology Reference Laboratory) as the calibration standard; the limit of detection was 10 pg/ml. All serum samples were stored at -...

Foscarnet Decreases Human Immunodeficiency Virus RNA

“…As reported previously [3,4], we also observed a decrease in p24 antigen level. However, p24 antigen was not detectable at baseline in all patients.…”

“…However, foscamet has the potential advantage of also inhibiting HIV replication. Foscamet decreases p24 antigen levels [3,4], but no data on the impact of foscamet therapy on HIV viremia are available. Our results show that foscamet has a measurable effect on HIV RNA in patients with CMV disease.…”

“…In AIDS patients treated with foscamet for cytomegalovirus (CMV) retinitis, a decrease in p24 antigenemia was observed, suggesting an inhibition of HIV replication in vivo [3,4]. In a large randomized study comparing foscamet with ganciclovir for the treatment of CMV retinitis, the effect on retinitis was similar, but patients treated with foscamet survived longer, leading to speculation that foscamet's anti-HIV effect might be of clinical importance [5].…”

In vitro Anti-HIV-1 Activity of sn-2-Substituted 1-O-Octadecyl-sn-Glycero-3-Phosphonoformate Analogues and Synergy with Zidovudine

“…Treatment of patients with AIDS and cytomegalovirus (CMV) retinitis with foscarnet has shown that this agent has antiretroviral activity in vivo (Farthing et al, 1987;Fletcher et al, 1994;Jacobson et al, 1988;Reddy et al, 1992). A study comparing PFA and ganciclovir treatment of CMV retinitis in patients with AIDS showed a survival advantage for the PFA-treated patients (Reddy et al, 1992).…”

Foscarnet alters antidiuretic hormone-mediated transport

“…It inhibits herpes virus DNA polymerase (4,7,26,27), influenza virus RNA polymerase (22), and retroviral reverse transcriptase (9,16,25,28). Foscarnet directly inhibits eucaryotic NaPO 4 (17,21,23,29) and NaSO 4 cotransport (1).…”