Rapid Rebound of Serum Human Immunodeficiency Virus Antigen After Discontinuing Zidovudine Therapy

Jb, Spear; Ca, Benson; Jc, Pottage; Da, Paul; Al, Landay; Ha, Kessler

doi:10.1093/infdis/158.5.1132

Cited by 14 publications

(8 citation statements)

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“…As a surrogate indicator of anti-HIV activity, serum p24 is the only marker shown to respond within 1 to 4 weeks of therapy with zidovudine or other promising anti-HIV drugs. A 50% or greater fall in p24 occurs within 14 days after starting zidovudine in the majority of patients (6,27), and significant falls may occur as early as 1 week after beginning zidovudine (14); p24 levels decline similarly after administration of other potential anti-HIV drugs, including foscarnet (15), dideoxycytidine (22), and dideoxyinosine (18). Serum p24 levels return to baseline within 14 days of stopping zidovudine (27).…”

Section: Discussionmentioning

confidence: 99%

“…A 50% or greater fall in p24 occurs within 14 days after starting zidovudine in the majority of patients (6,27), and significant falls may occur as early as 1 week after beginning zidovudine (14); p24 levels decline similarly after administration of other potential anti-HIV drugs, including foscarnet (15), dideoxycytidine (22), and dideoxyinosine (18). Serum p24 levels return to baseline within 14 days of stopping zidovudine (27). In addition, serum p24 levels rarely fall spontaneously, vary little over short periods of time, and can be shown to change significantly even with small sample sizes in subjects given zidovudine (10).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection

Flexner

Barditch‐Crovo

Kornhauser

et al. 1991

Antimicrob Agents Chemother

143

103

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Polysulfated polysaccharides are attractive candidates for antiviral drug development because of their potent in vitro activities against human immunodeficiency virus (HIV), herpesviruses, and other enveloped viruses. To determine the potential anti-HIV activity of a prototypical polysulfated polysaccharide, we administered the maximally tolerated dose of dextran sulfate by continuous intravenous infusion to 10 subjects with symptomatic HIV infection for up to 14 days. Since parenteral dextran sulfate is an anticoagulant, the infusion was adjusted to produce the greatest acceptable increase in activated partial thromboplastin time. Drug concentrations in plasma achieved with this protocol were up to 200-fold greater than the 50% inhibitory concentration for free HIV infectivity in vitro. Despite this, circulating HIV antigen (p24) levels increased in all eight subjects who received the drug for more than 3 days (median proportional increase, 73.5%; range, 32 to 130%); this increase was highly significant when it was compared with that in a large cohort of untreated historical controls (Fisher's exact test, P < 0.001). Frequent decreases in infusion rate were required in all subjects to maintain a constant activated partial thromboplastin time; plasma dextran sulfate levels did not fail as the infusion rate decreased, suggesting a decline in estimated drug clearance over time. Continuous intravenous dextran sulfate was toxic, producing profound but reversible thrombocytopenia in all eight subjects who received drug for more than 3 days and extensive but reversible alopecia in five of these subjects. Because of its toxicity and lack of beneficial effect on surrogate markers, dextran sulfate is unlikely to have a practical role in the treatment of symptomatic HIV infection.Polysulfated polyanions, including heparin, pentosan polysulfate, and dextran sulfate, are potent inhibitors of human immunodeficiency virus (HIV) infectivity and syncytium formation in vitro (2,13,23,30). In addition, these compounds inhibit other retroviruses, herpes simplex viruses, cytomegalovirus, and paramyxoviruses (4). These compounds are believed to block virus binding and penetration into target cells (3, 23) and, specifically, to block the binding of the HIV envelope protein to the CD4 receptor (25). They may also exert activity at a second step in infectivity, such as membrane fusion (8, 28).Potential advantages of polysulfated polysaccharides as antiviral agents include their broad-spectrum activity and simple chemical structure, which allows production costs to be low compared with those of the available nucleoside analogs or synthetic polypeptides. Clinical trials of oral dextran sulfate in HIV-infected patients (1) were terminated soon after the drug was shown to be poorly absorbed (21) In order to assess the potential anti-HIV activity of parenteral polysulfated polysaccharides, we selected dextran sulfate as a prototypical agent for study in patients with AIDS or AIDS-related complex (ARC). We chose dextran sulfate because it is...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection

Flexner

Barditch‐Crovo

Kornhauser

et al. 1991

Antimicrob Agents Chemother

143

103

View full text Add to dashboard Cite

show abstract

“…In patients with AIDS or AIDS-related complex, high-dose zidovudine (1,200 to 1,500 mg daily) prolongs survival, reduces the frequency of opportunistic infections, and improves functional capacity, weight gain, and immunologic function (116,146). Viremia or HIV (p24) antigenemia also decreases during therapy (218,446). Al-though the survival benefit remains after 1 to 2 years of therapy (81,145), the other benefits tend to disappear, with a return of antigenemia and opportunistic infections and a deterioration of immunologic function.…”

Section: Zidovudinementioning

confidence: 99%

Antiviral therapy: current concepts and practices

Bean

1992

Clin Microbiol Rev

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Drugs capable of inhibiting viruses in vitro were described in the 1950s, but real progress was not made until the 1970s, when agents capable of inhibiting virus-specific enzymes were first identified. The last decade has seen rapid progress in both our understanding of antiviral therapy and the number of antiviral agents on the market. Amantadine and ribavirin are available for treatment of viral respiratory infections. Vidarabine, acyclovir, ganciclovir, and foscarnet are used for systemic treatment of herpesvirus infections, while ophthalmic preparations of idoxuridine, trifluorothymidine, and vidarabine are available for herpes keratitis. For treatment of human immunodeficiency virus infections, zidovudine and didanosine are used. Immunomodulators, such as interferons and colony-stimulating factors, and immunoglobulins are being used increasingly for viral illnesses. While resistance to antiviral drugs has been seen, especially among AIDS patients, it has not become widespread and is being intensely studied. Increasingly, combinations of agents are being used: to achieve synergistic inhibition of viruses, to delay or prevent resistance, and to decrease dosages of toxic drugs. New approaches, such as liposomes carrying antiviral drugs and computer-aided drug design, are exciting and promising prospects for the future.

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“…In patients with AIDS or AIDS-related complex, high-dose zidovudine (1,200 to 1,500 mg daily) prolongs survival, reduces the frequency of opportunistic infections, and improves functional capacity, weight gain, and immunologic function (116,146). Viremia or HIV (p24) antigenemia also decreases during therapy (218,446). Although the survival benefit remains after 1 to 2 years of therapy (81, 145), the other benefits tend to disappear, with a return of antigenemia and opportunistic infections and a deterioration of immunologic function.…”

Section: Zidovudinementioning

confidence: 99%

Antiviral therapy: current concepts and practices.

Bean

1992

Clinical Microbiology Reviews

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Rapid Rebound of Serum Human Immunodeficiency Virus Antigen After Discontinuing Zidovudine Therapy

Cited by 14 publications

References 0 publications

Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection

Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection

Antiviral therapy: current concepts and practices

Antiviral therapy: current concepts and practices.

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