David J. Gocke

Hepatitis B Immune Globulin as a Prophylactic Measure for Spouses Exposed to Acute Type B Hepatitis

Because the value of usual immune globulin preparations in preventing Type B hepatitis is doubtful, we carried out a double-blind comparison of a control human immune globulin preparation with one--identified as HBIG--that had a high concentration (442 mug per milliliter) of antibodies to surface components of hepatitis B virus. Effectiveness was tested in spouses of patients with acute Type B hepatitis. Within 150 days after injection, nine of 33 spouses in the control group had symptomatic Type B hepatitis, compared with one of 25 spouses receiving HBIG. One non-B case also occurred in the HBIG group. Five control globulin recipients had evidence of subclinical hepatitis B infection, compared with one HBIG recipient. Thus, HBIG appeared effective in suppressing not only disease, but also infection itself. Prophylactic value has been demonstrated in persons who should now be recognized as being at exceptionally high risk.

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex

Zidovudine is a nucleoside analog that reduces progression of human immunodeficiency virus type 1 (HIV)-associated disease and prolongs survival [1-3]. The use of this drug at high doses in patients with advanced disease has been limited by hematologic toxicity [4-6]. Initial studies of another nucleoside analog, 2,3-dideoxycytidine (ddC), have shown that it is a potent inhibitor of HIV replication; therapy with ddC results in both the rapid suppression of serum p24 antigen levels and increases in CD4 cell counts [7, 8]. The principal dose-limiting toxicity of ddC is sensory peripheral neuropathy, which is related to both dose and duration of therapy [7-10]. Both zidovudine and ddC have been studied at lower doses to construct a tolerable monotherapy regimen [2, 6, 9, 11]. Alternating courses of zidovudine and ddC have been studied in an attempt to reduce dose-limiting toxicity. By limiting the continuous administration of each drug, the use of alternating therapy may allow any short-term toxicity from one drug to resolve during the administration of the other, and cumulative toxicity may be avoided. In addition to a reduction in toxicity, several other benefits of alternating therapy have been suggested. First, such combination therapy may have a synergistic or additive effect on virologic and immunologic markers; preliminary studies in vitro and in vivo suggest that alternating regimens have an enhanced antiretroviral effect [7, 12]. Concurrent zidovudine and ddC therapy has shown similar in vitro and in vivo effects and has recently been approved for use by the Food and Drug Administration [13, 14]. Second, it may be possible to maintain continuous high-dose therapy, thereby maximizing central nervous system concentrations. Third, in limiting the time of exposure to each drug, the sequential use of two agents may reduce or retard the emergence of drug-resistant isolates. We evaluated monthly and weekly alternating schedules of zidovudine and ddC to determine whether a reduction in toxicity or an enhanced antiretroviral effect, or both, could be achieved by this method of administration of the two agents. Intermittent zidovudine and ddC limbs were included to assess the relative contribution of each of the components to the overall effect. Continuous zidovudine, 1200 mg/d, served as the control treatment regimen. Methods Patients The study sample consisted of patients with AIDS-related complex or AIDS. We defined AIDS-related complex as the documented presence of one of the following: weight loss exceeding 15 pounds or 10% of body weight within 120 days before entry; a temperature greater than 38.5 C that persisted for more than 14 consecutive days or was documented on more than 15 days in a 30-day interval; diarrhea (three or more liquid stools per day) for at least 30 days without a definable cause; recurrent oral candidiasis; hairy leukoplakia; or a history of herpes zoster. We defined AIDS according to Centers for Disease Control criteria [15]. All study patients had circulating serum p24 antigen levels of 70 pg/mL or more on two occasions before enrollment. No restriction was placed on entry CD4 cell count. Patients were excluded from the study if they met any of the following criteria: a hemoglobin concentration of less than 95 g/L; transfusion dependence; an absolute granulocyte count less than 1.2 109/L; a platelet count less than 100 109/L; a calculated creatinine clearance rate of 50 mL/min per 1.73 m2 body surface area or less; transaminase levels 5 or more times the upper limit of normal; a Karnofsky performance score of less than 60; pregnancy or lactation; significant malabsorption; cardiac or liver disease; or AIDS-defining conditions requiring systemic maintenance chemotherapy. Patients with evidence of preexisting peripheral neuropathy and those who had had previous ddC treatment were also excluded. We encouraged all patients with less than 200 CD4 cells/mm3 to undergo aerosolized pentamidine prophylaxis (300 mg every month) for Pneumocystis carinii pneumonia. Study Design An unblinded, randomized trial (Protocol 047) was conducted at 12 AIDS Clinical Trials Units. Seven regimens were tested (Figure 1). At the time the study began, the standard zidovudine dose was 200 mg every 4 hours. Figure 1. The seven treatment regimens. Randomization was stratified by center and according to CD4 cell count (> 200 cells/mm3 or 200 cells/mm3). At least 16 patients were assigned to each limb. Patients who did not complete the first 8 weeks of therapy for any reason other than toxicity were replaced. All study patients gave informed consent and institutional review board approval was obtained at each institution. Study medication was to be administered for up to 49 weeks, with an additional follow-up period of 3 weeks. Study patients being treated with an intermittent regimen who had less than a 50% reduction in the serum p24 antigen level at 6 months had the option to change to an alternating regimen. Patients who completed 49 weeks of therapy and showed evidence of a beneficial response (defined as a 50% reduction in p24 antigen level or an improvement in CD4 cell count) had the option to continue therapy past 52 weeks. For the present analyses, only the first 48 weeks of data were used. Patient Evaluation Pretreatment evaluations included a medical history, physical examination, weight measurement, Karnofsky score, complete blood count, hepatic and renal function studies, T-cell subset analysis, and serum p24 antigen determination (Abbott Laboratories, North Chicago, Illinois). Follow-up evaluation was done weekly for the first 8 weeks and every 4 weeks thereafter. Serum specimens for p24 antigen determination were collected weekly for the first 8 weeks and then 3 of every 4 weeks thereafter. An evaluation for peripheral neuropathy was done on enrollment and was repeated as follows: neuropathy symptom questionnaire every 2 weeks, peripheral neurologic examination every 4 weeks, and quantitative sensory testing of vibration every 8 weeks [10]. Signs or symptoms suggestive of opportunistic infection or malignancy were evaluated according to standard AIDS Clinical Trials Group guidelines [15]. Hematologic toxicity for patients being treated with a zidovudine-containing regimen was defined and managed as follows: Transfusion was allowed for symptomatic grade 2 anemia (hemoglobin, 80 to 94 g/L) and for grade 3 (hemoglobin, 65 to 79 g/L) or grade 4 anemia (hemoglobin < 65 g/L). Study drug dosage was reduced or held in cases of grade 3 or 4 anemia if the patient declined transfusion or required more than 4 units of packed red blood cells in 6 weeks; or in cases of grade 3 (granulocyte count, 500 to 750; leukocyte count < 1.5 109/L) or grade 4 (granulocyte count >500, leukocyte count < 1.0 109/L) granulocyte-leukocyte toxicity. Patients were removed from the study if they developed grade 3 or 4 anemia or granulocyte-leukocyte toxicity that either failed to respond to dose adjustment or recurred. Patients treated with intermittent ddC were removed from the study for the following reasons: a first episode of grade 3 anemia if the patient declined transfusion or required more than 4 units of packed red blood cells in 6 weeks; grade 3 granulocyte-leukocyte toxicity that either failed to respond to dose adjustment or recurred; or a first episode of grade 4 anemia or granulocyte-leukocyte toxicity. Dose-limiting peripheral neuropathy was defined by the occurrence of bilateral burning or shooting pains in the lower extremities that were of moderate (grade 2) intensity and persisted for 72 hours or more; a symptom of severe (grade 3) intensity of any duration; or a symptom of moderate intensity of any duration plus either a supporting abnormality in the affected limb on standardized peripheral nerve examination or a supporting abnormality in the affected limb on quantitative sensory testing. Statistical Analysis Data from all enrolled patients were used in the analyses; however, data collected beyond the point at which patients switched from their initially assigned therapy were not included in the analysis. The Fisher exact test and chi-square tests were used to compare subgroups when the data were discrete [16] and Wilcoxon-Mann-Whitney tests were used for continuous data [17]. The Kaplan-Meier method and log-rank tests were used to analyze time-to-event data [18]. All P values were two-sided. The area under the curve (AUC) of absolute CD4 cells/mm3 was calculated, and the resulting total area was divided by time on therapy (T) to derive AUC/T [19]. The baseline CD4 count was subtracted from AUC/T to obtain the average change in CD4 cell count from baseline. A linear regression model was then calculated, with the average change in CD4 cell count as the dependent variable and both the baseline CD4 cell count and the assigned treatment limb as the independent variables. Results Patients One hundred thirty-one patients were enrolled in the study between 24 June 1988 and 17 October 1989 (Table 1). Most patients were male (96%) and white (76%) and had not received zidovudine within 90 days of study entry (96%). Seventy-seven percent had AIDS-related complex and 23% had AIDS. The median CD4 cell count at entry was 142 cells/mm3, and the median serum p24 antigen level was 257 pg/mL. Table 1. Patient Characteristics at Study Entry* The median follow-up for the entire study group was 40 weeks. Fifty-nine patients (45%) completed 48 weeks of therapy (Table 2). Twenty patients were withdrawn from the study because of toxicity related to ddC or zidovudine. Twenty-eight patients were removed because of AIDS-related opportunistic infection, malignancy, or dementia; 13 of these patients were removed from the study before completing 8 weeks of therapy. These 13 patientsalong with 4 patients who voluntarily withdrew from the study, were lost to follow-up, or were removed from the study for protocol violations in the first 8 weekswere

Low-dose oral recombinant interferon-αA in patients with HIV-1 infection : a blinded pilot study

ObjectiveTo evaluate the efficacy of low-dose oral recombinant interferon-α (IFN-αA) on clinical parameters, body weight, CD4+ lymphocyte counts and natural killer cell cytoiytic activity in HIV-infected patients. DesignBlinded crossover trial with controls for the protein and diluent components of the drug preparation. SettingMedical school outpatient referral center. Patients, participantsEight patients with HIV-1 infection and a CD4+ lymphocyte count between 150 and 600 χ 106/1. Concurrent use of zidovudine was permitted. InterventionsPatients received (daily, by mouth) 10 ml of a study solution of 2.5% albumin for 6 weeks, 150 IU IFN-αA for 6 weeks, and normal saline for 6 weeks. Main outcome measuresAfter two baseline visits, clinical assessments, vital signs, body weight, and laboratory tests, including enumeration of number and percentage of CD4+ and CD8+ lymphocytes and natural killer cell cytoiytic activity, were performed every 3 weeks. Complete physical examinations were conducted every 6 weeks. ResultsNo significant clinical or laboratory changes were observed during treatment with IFN-αA. Peak CD4+ lymphocyte counts were achieved at baseline in one patient, during albumin treatment in two patients, during IFN-αA treatment in one patient, and during saline treatment in four patients. All patients remained HIV-seropositive. Treatments were well-tolerated. ConclusionThis blinded pilot study of orally administered IFN-αA (150IU daily for 6 weeks) did not demonstrate clinical benefit in HIV-infected patients.

Transmission of hepatitis B in a classroom setting.

DISCUSSION Although previous studies 4. ~ showed that the morbidity of the infants born to anti-HBe positive carrier mothers was minimal, our study demonstrates that nearly onethird of the infants born to the anti-HBe positive mothers were infected with HB virus, and some of them actually developed acute hepatitis B. Since the development of acute hepatitis was at the age of 3 months and no case of acute hepatitis B was found during the follow-up period, we consider that acute hepatitis in these infants was caused by the vertical transmission of HB virus from their mothers. The occurrence of acute hepatitis B following the vertical transmission of HB virus and the subsequent development of antibodies indicate that immunologic tolerance was not induced and that a normal immunologic response occurred in these infants born to anti-HBe positive carrier mothers, in contrast to the infants born to HBeAg positive mothers, who frequently became HBsAg carriers, presumably owing to immunologic tolerance. Since HBeAg positive blood contains many more full Dane particles (HB virus) than that with anti-HBe, 7 the immunologic tolerance in the infants born to HBeAg positive mothers may be considered to be secondary to immunologic paralysis due to an excessive amount of antigen in relation to the immature immunologic function. In infants with anti-HBe positive mothers, it is assumed that the HB virus particles transmitted to the infants may be much fewer and that a normal immunologic response will be triggered. Since hepatitis is not caused by HB virus itself, as evidenced by the presence of healthy carriers, and the immunologic response to this virus is presumably responsible for the hepatic damage, it may not be surprising to find acute hepatitis in some of the infants born to anti-HBe positive carrier mothers. Our study indicates that even if a carrier mother is positive for anti-HBe, the infant should be carefully followed so as not to overlook the occurrence of acute or possibly fulminant hepatitis.

A comparative trial of zidovudine administered every four versus every twelve hours for the treatment of advanced HIV disease

Zidovudine is approved for administration in doses given every 4 hours. Less frequent dosing has been used in many clinical trials, but the toxicity and efficacy of such regimens have not been formally compared with the approved regimen. In this multicenter, randomized, double-blind, controlled trial, the safety, tolerance and efficacy of 600 mg of zidovudine given daily in two or six divided doses were compared. Three hundred and twenty patients with a CD4 lymphocyte count < 250 cells/mm3 (mean, 104 cells/mm3) or a prior AIDS-defining illness were treated with zidovudine 100 mg every 4 hours (regimen A) or 300 mg every 12 hours (regimen B). Eighty-eight patients (56%) and 94 patients (58%), assigned to regimens A and B, respectively, completed the planned 48 weeks of treatment. Serious anemia (hemoglobin < or = 7.5 g/dl) occurred in 13% and 7% of patients treated with regimens A and B, respectively (difference, 6%, 95% confidence interval [CI], 2, 12%; p = .13). The mean duration of treatment and the frequency of neutropenia and symptomatic complaints including nausea and headache were similar in the two treatment groups. The number of patients experiencing a new opportunistic infection (18% versus 20% for regimens A and B, respectively), and the number of deaths (five in each group) did not differ significantly between groups. The effect of treatment on CD4 lymphocyte counts and HIV p24 antigenemia also was similar for both regimens. Zidovudine given at the more convenient dose of 300 mg twice daily has similar safety, and tolerance and appears to have similar efficacy to the currently approved regimen. Use of this regimen should help simplify the treatment of HIV disease.

Hepatitis A Revisited

Excerpt The perception seems widespread that hepatitis A virus does not cause chronic disease, rarely causes fulminant hepatitis, is not associated with extrahepatic manifestations, and results in ...

Planning a medical school teaching hospital in an era of cost containment. The CMDNJ-Rutgers Medical School experience.

Rutgers Medical School was started in 1962 as a two year medical school. By 1976 its basic science enrollment had grown to 108 and it retained 56 students each year for clinical instruction. During the early 1970s the medical school had been frustrated on three different occasions in its attempts to build an on-campus teaching hospital. This paper describes the schools successful post-1976 planning efforts to provides its faculty and students with the appropriate clinical facilities by a model which would generate support among external constituencies. The history of the medical school prior to 1976 is presented briefly. The paper then develops the rationale for the new planning model and shows the relationship of the model to the educational bases of the institution. It then tracks the planning process from program development through approvals by the external constituencies and brings the schools experience to the present where ¿ million dollars of construction is under contract for health care delivery and medical education facilities.