Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study.

OBJECTIVE: To determine if the long-term incidence of the acquired immunodeficiency syndrome (AIDS) is related to human immunodeficiency virus type 1 (HIV-1) RNA levels measured early in HIV-1 infection. DESIGN: Epidemiologic cohort study. SETTING: Five hemophilia treatment centers in the United States. SUBJECTS: A total of 165 subjects with hemophilia and HIV-1 infection (age at HIV-1 seroconversion, 1-66 years) followed from 1979 to 1995. METHODS: The HIV-1 RNA level was measured by polymerase chain reaction over a range of 200 to 1 million or more HIV-1 RNA copies/mL in archived serum specimens collected 12 to 36 months (median, 27 months) after the estimated date of HIV-1 seroconversion. Kaplan-Meier methods were used to examine the risk of AIDS and proportional hazards models were used to estimate relative hazards. RESULTS: The HIV-1 RNA values were similar in subjects younger than 17 years at seroconversion (median, 5214 copies/mL) and those 18 to 34 years old (median, 4693 copies/mL), but higher in those 35 years or older (median, 12069 copies/mL) (P = .02 compared with each younger group). At 10 years after seroconversion, the proportions of subjects with AIDS were 72% among subjects with 100,000 or more HIV-1 RNA copies/mL measured 12 to 36 months after HIV-1 seroconversion (n = 9), 52% among subjects with 10,000 to 99,999 copies/mL (n = 55), 22% among subjects with 1000 to 9,999 copies/mL (n = 82), and 0% among subjects with fewer than 1000 copies/mL (n = 19) (P < .001). The age-adjusted relative hazard for AIDS for subjects with 10,000 or more copies/mL was 14.3 (95% confidence interval, 1.9-105.6) compared with subjects with fewer than 1000 copies/mL. CONCLUSIONS: The HIV-1 RNA level during early chronic HIV-1 infection is a strong, age-independent predictor of clinical outcome; low levels define persons with a high probability of long-term AIDS-free survival.

Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group protocol 062).

The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over a 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 +/- 192 ng.h/ml), maximum concentration of drug in serum (1,751 +/- 180 ng/ml), and half-life (2.04 +/- 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 +/- 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 +/- 1,222 ng.h/ml) and maximum concentration of drug in serum (5,220 +/- 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2.79 +/- 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 +/- 0.15 in HIV-infected patients with hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy-proven cirrhosis, our results suggest that ZDV, could accumulate in HIV-infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.

National Head and Spinal Cord Injury Prevention Program of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons.

Organized neurosurgery has developed and promoted a national educational program for adolescents to reduce the number of head and spinal cord injuries sustained by this group of young people. The program has been adopted widely, with over 1,000,000 teenagers exposed to it since its inception in 1986. Preliminary data suggest that the program has had a favorable impact on the knowledge and attitudes of young people regarding head and spinal cord injuries, risk-taking behavior, and incidence of injuries.

Lumbar synovial cysts: report of eleven cases.

Over the past 18 months we have encountered 11 cases of symptomatic lumbar synovial cysts. This experience occurred during a period during which some 1,800 lumbar computed tomographic scans were done. The apparent increased incidence of these lesions is most likely due to the increased diagnostic ability made possible by the advent of high-resolution computed tomography and magnetic resonance imaging. This is a report and discussion of our 11 cases with a review of the literature. There is nothing distinctive in the physical findings or in the histories of our patients, but we have found, as have others, that high-resolution computed tomographic scanning and magnetic resonance imaging significantly enhance the diagnosis of such lesions.

Relationship of factor VIII-like antigen (VIII AGN) and clot promoting acitivty (VIII AHF) as measured by one- and two-stage assays in patients with liver disease.

We recently observed a increase in factor-VIII clot promoting activity as measured by a one-stage assay (VIII AHF) in a haemophiliac with hepatitis. However, VIII AHF as measured by a two-stage assay (VIII AHF) was 0.013 u/ml at a time when VIII AHF measured 0.38 u/ml. We then studied seven non-haemophiliacs with liver disease, and attempted to correlate the lvels of VIII AHF and VIII AHF with factor VIII-like antigen (VIII AGN) as measured by quantitative immunoelectrophoresis. In four of the seven patients, disproportionate elevations of VIII AHF compared to VIII AHF were found. Furthermore, VIII AHF values correlated well with VIII AGN vales . No such discrepancy was apparent in four normal control subjects. These findings emphasize the necessity for performing two-stage assays in haemophiliacs as well as non-haemophiliacs with liver disease to assess factor-VIII levels. In addition, they suggest that confirmation of the diagnosis of haemophilia may not be possible in the haemophiliac with hepatitis unless VIII AHF determinations are performed. The reason for the disparity between VIII ahf and VIII AHF levels is not apparent. However, the correlation of VIII AGN and VIII AHF levels in the non-haemophiliacs with liver disease provides further support for the concept that VIII AGN and VIII AHF are closely related or identical molecular entities.

Immunosuppressive therapy of Factor VIII inhibitors.

Immunosuppressive therapy was used in seven hemophiliac and three nonhemophiliac patients with factor VIII inhibiors. Permanent disappearance of the inhibitor occurred in three hemophiliac and two nonhemophiliac patients following treatment with cyclophosphamide and factor VIII. Critical factors influencing the response to therapy may include both the titer and duration of the inhibitor and the degree of intervening factor VIII exposure prior to immunosuppressive therapy. Two severe hemophiliacs with low titer inhibitors that disappeared without specific therapy are also reported.