Implications of maturation for viral gene delivery to skeletal muscle.

Different viral vectors have been analyzed as gene delivery vehicles to skeletal muscle for potentially therapeutic purposes. In this review, we evaluate the application of retroviral, adenoviral, and herpes simplex viral vectors to deliver genes to skeletal muscle and focus on the dramatic loss of viral transduction detected throughout muscle maturation. Recent results suggested that there are several factors involved in the reduced viral transducibility of mature skeletal muscle: muscle cells become post-mitotic in an early stage, the extracellular matrix develops into a physical barrier, and a loss of myoblast mediation occurs since myoblasts progressively become quiescent. Approaches to improve viral gene delivery to mature skeletal muscle may include the use of particular enzymes to increase the permeability of the extracellular matrix, the pre-treatment of the muscle with a myonecrotic agent to induce myoblast mediation, or the application of the myoblast-mediated ex vivo gene transfer.

Toxic effects of zidovudine in asymptomatic human immunodeficiency virus-infected individuals with CD4+ cell counts of 0.50 x 10(9)/L or less. Detailed and updated results from protocol 019 of the AIDS Clinical Trials Group.

BACKGROUND: Protocol 019 of the AIDS Clinical Trials Group is a multicenter, double-blind, placebo-controlled trial of zidovudine (3'-azido-3'-deoxythymidine; formerly AZT) in human immunodeficiency virus-infected asymptomatic individuals. The initial results in the stratum of subjects entering with CD4+ cell counts of 0.50 x 10(9)/L or less have been reported, but without a detailed analysis of toxic effects. METHODS: This detailed and updated report analyzes the toxic effects that occurred in 1567 subjects (91% men; 89% white) in this stratum of protocol 019 who received placebo (494 subjects), a 500-mg daily dose of zidovudine (544 subjects), or a 1500-mg daily dose of zidovudine (529 subjects). Hematologic, hepatic, and renal effects and patient-reported symptoms and clinical signs were monitored. RESULTS: Severe anemia (hemoglobin level, < 80 g/L) was associated with both the 500-mg zidovudine group and the 1500-mg group compared with placebo. The estimated 18-month risks of severe anemia were 0.4%, 2.0%, and 9.7% for the placebo, 500-mg zidovudine, and 1500-mg zidovudine groups, respectively. Predictive baseline measures were lower hemoglobin level in the 1500-mg group and the two zidovudine groups combined and lower platelet count in the 500-mg zidovudine group. The risk of a first severe anemia developing was greatest in months 3 through 8 of treatment. Of the 44 subjects with severe anemia in the zidovudine groups, 18 (41%) progressed from mild anemia (hemoglobin level, 95 to 109 g/L) to severe anemia on consecutive visits (usually 2 to 4 weeks apart). Severe neutropenia (absolute neutrophil count, < 750 x 10(6)/L) did not occur significantly more often in the 500-mg zidovudine group but did in the 1500-mg zidovudine group. Moderate neutropenia (absolute neutrophil count, < 1300 x 10(6)/L) did develop significantly more often in the 500-mg zidovudine group (165 subjects) than in the placebo group (71 subjects). Mild (or worse) elevations of bilirubin levels were uncommon but occurred more often with zidovudine. Severe nausea (and/or vomiting) was rare (2.8% of subjects) but was associated with zidovudine. Milder patient-reported events were common, and a number were associated with zidovudine. CONCLUSION: Zidovudine at the 500-mg/d dosage appears to be tolerable in many patients with asymptomatic human immunodeficiency virus infection and CD4+ cell counts of 0.50 x 10(9)/L or less. Increased clinical surveillance for anemia may be warranted in certain patients.

Zidovudine in asymptomatic human immunodeficiency virus infection. A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. The AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases.

Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV.