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Clinical research has undergone remarkable and beneficial expansion in the past 25 years, but with this growth has come an unprecedented increase in workload for the human subjects protection system. Recently, a major change in federal oversight of local institutional review boards (IRBs) became evident. Although it was not announced publicly, in 1998 and 1999 federal regulatory actions against local IRBs increased threefold. Particularly notable was the marked increase in regulatory actions taken against the IRBs of academic medical centers (1 in 1997 compared with 14 in 1999). Ironically, this apparent federal crackdown began at the same time that two federal review panels called for major changes in the regulations governing local IRBs. A key factor in the current crisis in the function of local IRBs is the ascendance of multicenter clinical trials as the dominant form of clinical research. Local IRBs were not designed to handle the initial evaluation and ongoing review required by the rapidly increasing number of multicenter clinical trials. Furthermore, local IRB review of the thousands of safety reports from multicenter clinical trials monopolizes resources without promoting patient safety. Instead of rigid enforcement of outmoded regulations that do not contribute to patient safety, the responsibilities of the local IRB in the oversight of multicenter clinical trials must be systematically evaluated.

Objective: To determine the extent to which lymphocytes, particularly those with the CD4 surface antigen, are a surrogate marker for the development of the acquired immunodeficiency syndrome (AIDS) in persons with asymptomatic human immunodeficiency virus (HIV) infection., Design: Analysis of data from the AIDS Clinical Trials Group Protocol 019, a placebo-controlled, double-blind, randomized trial., Setting: University-based referral centers., Patients: Asymptomatic HIV-infected patients with 500 or fewer CD4+ cells/mm3 at baseline who were given placebo (350 patients) or one of two daily doses of zidovudine (725 patients)., Measurements: Baseline and interim measurements of CD4+ and other leukocytes were assessed. Patients were followed for progression to AIDS., Results: Patients' lymphocyte levels were correlated with progression to AIDS (P < 0.001; relative risk for each depletion of 50 CD4+ cells/mm3, 1.75; 95% CI, 1.53 to 2.01); however, only a small portion (0% to 37%) of the effect of zidovudine on this progression was statistically explained by its effect on CD4+ lymphocyte levels. A substantial portion of zidovudine's effect on delaying progression to AIDS that was independent of the levels of these markers occurred within the first 16 weeks of therapy. In patients who had not progressed to AIDS by week 16, most of the subsequent zidovudine effect in reducing the risk for progression could be explained by its effect on net CD4+ percent (percentage of CD4+ lymphocytes among all leukocytes) for the first 16 weeks of therapy., Conclusion: Levels of CD4+ lymphocytes are an incomplete surrogate marker for progression to AIDS, and the association is especially weak during the first 16 weeks of zidovudine therapy.

Study Objective: To study the safety and pharmacokinetics and to derive preliminary evidence on surrogate indicators of efficacy of recombinant soluble CD4 (rsCD4) in patients with the acquired immunodeficiency syndrome (AIDS) and advanced AIDS-related complex., Design: Open label, escalating dosage, phase I-II tolerance trial., Setting: Massachusetts General Hospital, Cedars-Sinai Medical Center, and Stanford University Medical School, three tertiary care institutions and members of the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group., Instructions: Cohorts of 3 to 11 patients received rsCD4 by intravenous infusion or intramuscular injection in dosages of up to 30 mg per day for 28 days., Measurements and Main Results: Recombinant soluble CD4 was tolerated by these patients with no significant clinical or immunologic toxicities. Serum levels of rsCD4 in patients receiving doses of 9 or 30 mg per day administered intramuscularly were in the range of rsCD4 concentrations required to inhibit replication of human immunodeficiency virus 1 (HIV-1) in vitro. A decline in serum HIV-1 p24 antigen was seen in patients receiving 30 mg of rsCD4 daily, but no such changes were noted at lower dosages., Conclusions: Recombinant soluble CD4 is well tolerated by patients with AIDS or advanced AIDS-related complex. Our study has also provided preliminary evidence of antiviral activity of rsCD4 in vivo. Our data suggest that further trials of receptor-based therapies against HIV-1 are warranted.

A homosexual man had Kaposi's sarcoma of the skin and lymph nodes. After a brief response to interferon, the patient developed new skin lesions. Massive bleeding in the gastrointestinal tract prompted endoscopy, which showed tumor involvement of the stomach, believed to be Kaposi's sarcoma. At autopsy, a diffuse lymphoma was found involving the skin and gastrointestinal tract, forming collision tumors in regions that contained Kaposi's sarcoma. Lymphomatous tissue, but not uninvolved lymph node or spleen, contained Epstein-Barr virus DNA, as shown by DNA hybridization studies. Epstein-Barr virus may play a role in the development of lymphoma in immunosuppressed patients. Unusual manifestations of tumors, such as the massive gastrointestinal bleeding seen in this case, may indicate the development of a second neoplasm.

Two patients developed fever, interstitial pneumonitis, and pancytopenia associated with extremely high titers of antibody to replicative antigens of the Epstein-Barr virus. In contrast to most patients seropositive for Epstein-Barr virus, neither patient had an antibody response to the Epstein-Barr nuclear antigen K polypeptide. In addition, virus isolated from one patient had a deletion of the B95-8 type in the EcoRI C region of the genome. An etiologic relation between Epstein-Barr virus replication and the clinical manifestations of this syndrome is further shown by the response of each patient to acyclovir therapy. These patients have a new Epstein-Barr-virus-associated syndrome and provide additional evidence that acyclovir may play a role in therapy for selected patients with Epstein-Barr virus infection.

Cytomegalovirus infections can cause significant morbidity and mortality in immunosuppressed patients, and present antiviral agents have had little efficacy against these infections. We describe the use of an acyclic nucleoside 9-[2-hydroxy-1-(hydroxymethyl) ethoxy methyl]guanine (BW B759U), in the treatment of two patients with cytomegalovirus retinitis. The efficacy of this agent was evident, with healing of retinal lesions and resolution of viremia and viral shedding. BW B759U appears to be similar pharmacokinetically to intravenous acyclovir in terms of half-life, peak serum levels, and renal excretion.

Human immunodeficiency virus (HIV) has been isolated from both male and female genital secretions. We evaluated the pattern of female genital carriage during the menstrual cycle, and its relationship to HIV viremia. Seven menstruating seropositive women and one seronegative control had cervical secretions and venous blood samples cultured at weekly intervals during a single menstrual cycle. The virus was isolated from cervical secretions in four of seven women. No specific cycle pattern was seen, and positivity for HIV at one site (blood or cervical) did not correlate with positivity at another site. Blood cultures generally, but not always, became positive earlier than cultures from cervical specimens, suggesting higher titers of virus in blood. Thus, HIV secretion may be intermittent. These findings, together with earlier reports, suggest that seropositive women may transmit HIV at any time during the menstrual cycle.