Faculty Bibliography

OBJECTIVE: To detect and quantify HIV-1 in the liver in vivo. DESIGN: Fourteen liver biopsy samples and corresponding blood lymphocytes and monocytes from patients with AIDS were studied for HIV-1 using quantitative polymerase chain reaction (PCR). In addition, expression of HIV-1 antigen and messenger (m) RNA in 10 autopsy liver specimens was examined by immunohistochemistry and in situ hybridization. RESULTS: The amount of HIV-1 DNA in nine liver samples ranged from 850 to 27,000 copies per 10(6) cells, with mean and median values of 8150 and 3500 copies per 10(6) cells, respectively. Five other samples had no detectable HIV-1 DNA by PCR. Intracellular expression of HIV-1 antigen and mRNA was also detected in both Kupffer cells and hepatocytes by in situ studies. CONCLUSION: These findings strongly indicate that HIV-1 could replicate in the liver of a majority of patients with AIDS

We report a homosexual patient with the acquired immune deficiency syndrome (AIDS) and histopathologic evidence for cytomegalovirus (CMV) appendicitis in a patient with no prior history of CMV infection. The patient presented with right lower quadrant pain and intermittent fevers. The diagnosis of appendicitis was difficult to make in this patient because of the presumptive diagnosis of tuberculosis ileitis and the frequent presentation of abdominal pain with fever in AIDS patients. Although CMV colitis is frequently seen in AIDS patients, the prevalence of CMV appendicitis is exceedingly rare. The problems related to making a diagnosis of CMV appendicitis and the therapeutic management of CMV infections are reviewed

As part of a double-blind, placebo-controlled study of ganciclovir in cytomegalovirus (CMV) colitis, the clinical characteristics of 44 patients enrolled at one center were analyzed in detail. All were homosexual men who had CMV on colonic biopsy. CMV colitis was the index diagnosis for acquired immune deficiency syndrome (AIDS) in 11 (25%) of the 44 patients. All had diarrhea, but it was intermittent in 13 patients (30%). Bleeding was uncommon, but 35 patients (80%) were febrile (median temperature of 38.9 degrees C). Weight loss was reported by 39 patients (89%), among whom the median loss was 6.8 kg. Endoscopy revealed normal colonic mucosa but CMV on biopsy in 11 patients (25%). Colonoscopic biopsies positive for CMV were found only in the cecum in 7 (39%) of 18 patients. Most patients (54%) had received zidovudine before the diagnosis of CMV colitis. The median time to the development of CMV colitis after the diagnosis of AIDS was 16 months in those patients who had received zidovudine and 3 months in those who had not (p less than 0.02). We conclude that CMV colitis can present early in AIDS and often with such nonspecific signs as fever, intermittent diarrhea, weight loss, and hematochezia. Importantly, it can appear normal on colonoscopy and occurs frequently only in the right colon, necessitating full colonoscopy and multiple biopsies for accurate diagnosis

We have reviewed 28 esophageal biopsies from 28 patients with the acquired immune deficiency syndrome (AIDS), over a 1-yr period. Indications for esophageal biopsy were dysphagia persisting after antifungal therapy and/or radiologic evidence of esophageal ulcer. We compared the frequency of detecting cytomegalovirus (CMV) infection on hematoxylin and eosin (H&E) stain with immunoperoxidase staining for CMV antigens. Five biopsies were positive for CMV by H&E stain and immunoperoxidase. Infected cells could often be identified in the granulation tissue and, in one severe case, in stromal papillae of the intact mucosa. Squamous cells were never positive. Thirteen biopsies consisted only of squamous epithelium, and all of these were negative by both techniques. Among the remaining 10 cases, no CMV inclusions were identified by H&E. Three of these biopsies displayed staining for viral antigens. In all cases positive by immunoperoxidase, numerous cells positive for viral antigens did not display any of the CMV-specific morphologic diagnostic criteria. Other coexisting diagnoses included candidiasis, Kaposi's sarcoma, and malignant lymphoma. We conclude 1) CMV infection of the esophagus is common in AIDS patients with esophageal ulcer or esophagitis resistant to antifungal therapy; 2) multiple infections or neoplasms may coexist; 3) since CMV apparently does not infect squamous epithelium and only rarely endothelium in stromal papillae, deep biopsies are necessary for diagnosis; and 4) immunoperoxidase staining is required for maximum diagnostic yield

HIV-1 neutralizing activity was demonstrated in serum and 200-fold concentrated urine from individuals who were HIV-1 antibody positive in both their serum and urine, including AIDS-KS, AIDS-OI, ARC, and asymptomatic patients. Virus neutralization activity was detected in 23 of 56 (41.1%) of the serum samples and in 19 of 56 (33.9%) of the urine samples tested, with titers ranging from 1:8 to 1:256 and 1:1 to 1:4, respectively. The highest frequency of HIV-1 neutralizing activity (87.5%) and the highest mean neutralization titers (1:65) were found in the ARC patients. A high prevalence of p24 antigen in serum and low numbers of T4-lymphocytes correlated with a low frequency of neutralizing activity in either serum or urine in the infected individuals. HIV-1 neutralizing activity in the urine was shown to be due to immunoglobulins using a Sephadex G-100 filtration gel. All 19 urine samples with neutralizing activity contained antibodies reactive with envelope glycoproteins gp160, gp120, and gp41 by Western blot, similar to that seen with serum. The frequency of HIV-1 neutralizing activity in the urine concentrates was generally associated with high titers of neutralizing antibody in the corresponding serum. These findings suggest that HIV-1 neutralizing antibodies are lost in the urine by an as yet unknown mechanism

OBJECTIVE: To assess the toxicity, efficacy, and pharmacology of combined zidovudine and ganciclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS) and serious cytomegalovirus (CMV) disease. DESIGN: Prospective, phase I multicenter trial (ACTG 004) with patients grouped by previous study drug history. SETTING: Three university-based AIDS Clinical Trials Units sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). PATIENTS: Forty-one patients with AIDS-related CMV disease. Previous therapy with either zidovudine or ganciclovir was allowed. INTERVENTIONS: Patients were treated with zidovudine, 600 to 1200 mg/d; or, if on ganciclovir maintenance, ganciclovir, 5 mg/kg body weight; blood was sampled for pharmacokinetic studies. The other drug was then administered to the patient with blood sampling and, finally, the two drugs in combination were given. Patients were continued on both drug therapies with dose reduction of zidovudine only for grade 3 or 4 toxicity. MEASUREMENTS AND MAIN RESULTS: Forty patients were eligible. Hematologic toxicity was frequent, with 9 of the 10 patients requiring dose reductions for grade 3 or 4 toxicity at zidovudine doses of 1200 mg/d. With zidovudine doses of 600 mg/d, 82% experienced such hematologic toxicity. Median survival was 6 months; 10 patients developed intercurrent infection and 19, progressive CMV disease. Pharmacokinetic variables (alpha and beta half-lives, volume of distribution, clearance) were not affected in combination therapy. CONCLUSION: The combination of zidovudine and ganciclovir is poorly tolerated in patients with AIDS and serious-CMV disease, with 82% developing severe to life-threatening hematologic toxicity. Such toxicity is not a result of pharmacologic interactions, drug metabolism, or excretion

Ganciclovir (DHPG) treatment of 69 AIDS patients with gastrointestinal infection due to cytomegalovirus (CMV) was studied. Sites of infection included the colon (46 patients, 67%), esophagus and stomach (15 patients, 22%), rectum (five patients, 7%), liver (two patients, 3%), and small bowel (one patient, 1.4%). Ganciclovir was given in a dose of 5 mg/kg intravenously every 12 hours for 14 days. Maintenance therapy consisted of 6 mg/kg daily. Positive clinical responses were seen in 52 (75%) of the 69 patients, stable responses in 9 (13%), and worsening in eight (11%). The virologic response was positive in 47 patients (68%), while virologic findings did not change in three patients (4%) and could not be evaluated in 19 patients (28%). Toxicity was mainly hematologic, with moderate leukopenia (1,000-1,900 leukocytes/mm3) in seven patients and severe leukopenia (less than 1,000 leukocytes/mm3) in three patients. The median survival time was 18 weeks (range, 1-68 weeks). Forty-seven patients survived for 4 weeks; of these, 22 (47%) relapsed. The median time to relapse was 9 weeks. Despite the uncontrolled nature of this study, ganciclovir is probably an effective and safe agent for the treatment of gastrointestinal CMV infections. The high probability of relapse (50%) should be considered and maintenance therapy offered to most patients

9-(1,3-dihydroxy-2-propoxymethyl) guanine (ganciclovir) was used to treat 41 patients (median age, 37 years) with the acquired immunodeficiency syndrome and cytomegalovirus gastrointestinal infection. Sites of infection were the colon in 31, the esophagus in 5, the rectum in 4, and the small bowel in 1. Patients received ganciclovir, 5 mg/kg body weight, intravenously every 12 hours for 14 days. Clinical improvement was seen in 30 patients and virologic response in 32. Mainly hematologic toxicity occurred: moderate leukopenia (1000 to 1900/mm3) was seen in 7 patients and severe (less than 1000/mm3) in 1, and moderate neutropenia (500 to 1000/mm3) in 5 and severe (less than 500/mm3) in 1. A cutaneous rash developed in 2 patients. Median overall survival was 16 weeks (range, 2 to 56). Cytomegalovirus recurred in 13 patients; median time to recurrence was 9 weeks from the start of treatment. Ganciclovir may be effective in treating cytomegalovirus gastrointestinal disease in patients with the acquired immunodeficiency syndrome