Woman with AIDS presented for elective termination of pregnancy.
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
R C Reichman
Publications and source records attributed to R C Reichman.
Human immunodeficiency virus (HIV-1) gp160-specific lymphocyte proliferative responses of mononuclear leukocytes from HIV-1 recombinant gp160 vaccine recipients.
The lymphocyte proliferative responses were studied of 12 volunteers enrolled in a phase I trial of a baculovirus-expressed recombinant human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (rgp160) vaccine. Six subjects received rgp160 and three subjects each received recombinant hepatitis B vaccine or placebo at 0, 1, and 6 months. rgp160 and a control preparation, baculovirus-expressed recombinant HIV-1 p24, were used as in vitro antigens. At day 56, all rgp160 recipients had stimulation indexes (rgp160/rp24) greater than 3.0, and five of six had differences in counts per minute (cpm) greater than 1000. Stimulation indexes were less than 2.0 and cpm differences were less than 150 in all six who did not receive rgp160. Lymphocyte proliferative responses were first noted 2 weeks to 5 months before initial Western blot reactivity and persisted for greater than or equal to 540 days, even among subjects who lost detectable antibody. Thus, the HIV-1 rgp160 vaccine induces persistent cellular immune recognition as demonstrated by lymphocyte proliferation.
Adult↗
A double-blind, placebo-controlled cytogenetic study of oral acyclovir in patients with recurrent genital herpes.
The antiherpes drug acyclovir breaks chromosomes in vitro at millimolar concentrations and at highly toxic doses in rodents but does not induce single-gene mutations. Recurrent genital herpes patients were examined to determine if such chromosomal damage occurs in peripheral lymphocytes during acute or chronic acyclovir therapy. Patients were randomly assigned to receive acyclovir suppressively and for recurrences, placebo suppressively and acyclovir for recurrences, or placebo suppressively and for recurrences (n greater than or equal to 20 for each group; all treatment double-blind). Normal volunteers and acyclovir-treated cultures served as additional controls. Cytogenetic analyses were done at enrollment (pretreatment), on day 5 of acute acyclovir or placebo treatment for the first postenrollment recurrence (postacute), and at the end of a year on study (postchronic). Cells in metaphase, 150 for each patient, were examined at each time point for structural and numerical chromosomal abnormalities. No cytogenetic effects of chronic or acute oral acyclovir treatment were found relative to lifestyle controls, pretreatment controls, or placebo treatment.
Acyclovir↗
Use of human papillomavirus type 11 virions in an ELISA to detect specific antibodies in humans with condylomata acuminata.
Human papillomavirus types 6 and 11 (HPV-6 and HPV-11) are the major aetiological agents of condylomata acuminata. Serological studies of this disease have been difficult to perform and interpret because native, type-specific antigens have not been available. In particular, since these viruses have not been propagated in vitro and sufficient quantities of virions are not present in lesions, virus particles have been difficult to obtain. In the present study, we used HPV-11 particles, obtained from human tumours produced in athymic mice, as antigen in an ELISA to compare antibody responses between 46 patients with biopsyproven condylomata acuminata and 44 controls. The median [interquartile range] of the absorbance values for the condylomata acuminata and the control groups were respectively 0.324 [0.183, 1.029] and 0.118 [0.047, 0.286] (P = 0.0001). Thirty-three per cent of the absorbance values in the condylomata acuminata group were higher than any of those of the control group. Sera from patients whose biopsies contained the papillomavirus common antigen were more reactive than sera from patients whose biopsies did not contain it (P = 0.0014). This study demonstrates the presence of specific antibodies directed at native HPV-11 viral particles in the sera of patients with condylomata acuminata, and describes a test which can be used in future serological studies of this common sexually transmitted disease.
Adult↗
Single-dose trospectomycin for chlamydial urethritis in men.
Trospectomycin is an aminocyclitol analog of spectinomycin with significant in vitro activity against Chlamydia trachomatis. A single 1-g intramuscular dose was administered to 10 men with symptomatic, culture-positive chlamydial urethritis. Trospectomycin was well tolerated but failed to eradicate chlamydial infection, as determined by cultures obtained approximately 1 week after treatment.
Adolescent↗
In vitro interactions between bovine papillomavirus and human monocytes and macrophages.
Limited data suggest that macrophages play a role in the pathogenesis of bovine papillomavirus (BPV) infections. In the present study, interactions between these cells and BPV-1 were explored by exposing in vitro human blood monocytes and monocyte-derived macrophages to purified virions. Immediately or up to 28 days after exposure, cell culture supernatants as well as cell lysates were collected. Interleukin 1 activity was detected in the supernatants of monocytes early after exposure to BPV (0-3 days), but little was found after exposure of macrophages to BPV. In addition, both monocyte and macrophage cell lysates contained episomal BPV DNA which, after an initial decrease in copy number, increased 14-28 days later. Concomitantly, there was progressive disappearance of detectable BPV major capsid protein in cell lysates. These observations support the concept that monocytes and macrophages play a role in the pathogenesis of papillomavirus infections.
Animals↗
Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. An AIDS Clinical Trials Group Study.
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.
Acquired Immunodeficiency Syndrome↗
2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial.
2',3'-Dideoxyinosine (ddI) is a purine analogue that after intracellular metabolic conversion suppresses the replication of the human immunodeficiency virus (HIV). We conducted a Phase I dose-escalation study of ddI in 17 patients with the acquired immunodeficiency syndrome (AIDS) and 20 patients with AIDS-related complex. The drug was administered twice daily over a dose range of 0.4 to 66 mg per kilogram of body weight per day for 2 to 44 weeks. The maximal tolerated oral dose of ddI was estimated to be 12 mg per kilogram per day. The major dose-limiting toxic effects were a painful peripheral neuropathy (in eight patients) and pancreatitis (in five). Asymptomatic elevations of the serum aminotransferase levels (in 13 patients) and the serum urate level (in 10) were also noted, but there was no dose-related hematologic toxicity. At the maximal tolerated dose, the peak plasma levels of ddI were 6.3 to 9.6 mumol per liter 0.6 to 1 hour after oral administration; the mean plasma half-life was 1.5 hours. The administration of ddI was associated with statistically significant decreases in serum level of p24 antigen and increases in the numbers of CD4 cells at 2, 6, 10, and 20 weeks. These changes were seen at all dose levels studied. Either a clinical improvement or a weight gain of greater than or equal to 2 kg was observed in 25 of 34 patients at six weeks. We conclude that ddI is a promising therapeutic agent in patients with AIDS or AIDS-related complex. Its efficacy is currently being evaluated in large-scale, controlled clinical trials.
AIDS-Related Complex↗
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.
AIDS-Related Complex↗
Treatment of condyloma acuminatum with three different interferon-alpha preparations administered parenterally: a double-blind, placebo-controlled trial.
One hundred seventy-eight patients were enrolled in a placebo-controlled trial to evaluate three interferon-alpha preparations administered parenterally for the treatment of condyloma acuminatum. When all interferon groups were combined and compared with placebo, interferon recipients had greater rates of complete, 75%, 50%, and 25% lesion resolution than did placebo recipients (P = .21, P = .14, P = .02, and P = .02, respectively). Rates of lesion resolution were higher among women than among men, and women were more likely than men to respond to interferon. Virologic measurements in paired lesion biopsies did not correlate with interferon treatment or disease outcome. Although interferon toxicity was observed frequently, no participant withdrew from the study because of side effects, and dosage alterations were not required. Parenterally administered interferon-alpha is more effective than placebo in treating condyloma acuminatum, although rates of complete response are low. Different regimens, including combination therapy, should be evaluated for treatment of this common sexually transmitted disease.
Adult↗
Expression of the full-length products of the human papillomavirus type 6b (HPV-6b) and HPV-11 L2 open reading frames by recombinant baculovirus, and antigenic comparisons with HPV-11 whole virus particles.
The L2 open reading frames (ORFs) of human papillomavirus (HPV) types 6b and 11 were expressed as full-length non-fusion proteins in Spodoptera frugiperda (Sf-9) cells using recombinant baculovirus. Both proteins were detected on Western blots as immunoreactive bands which migrated with apparent Mrs of 76K and 78K, respectively, and contained both cross-reactive and type-specific epitopes, as determined by polyclonal antisera directed against defined subregions of the HPV-6b and HPV-11 L2 ORFs. In addition, the minor capsid protein of HPV-11 particles co-migrates with the HPV-11 L2 ORF product and is immunoreactive with HPV-11 L2-specific antisera. These observations indicate that the anomalous electrophoretic mobilities of papillomavirus L2 ORF proteins can be explained without invoking post-transcriptional processing events and that the minor capsid protein of HPV-11 is antigenically and biophysically related to the HPV-11 L2 ORF product.
Animals↗
Multiple-dose pharmacokinetics of oral zidovudine in hemophilia patients with human immunodeficiency virus infection.
The disposition of zidovudine (ZDV) was examined during chronic oral dosing (300 mg every 4 h while awake) for 12 weeks in eight asymptomatic patients with hemophilia who were infected with the human immunodeficiency virus. Pharmacokinetic studies were conducted at the initiation of drug administration and after 6 and 12 weeks. Baseline liver function tests indicated normal values for bilirubin, albumin, and prothrombin time, while hepatic enzyme levels ranged from one to three times the normal levels. Initially, the mean peak ZDV concentration in plasma was 2,052 ng/ml with a range of 1,033 to 3,907 ng/ml, while during chronic dosing the peaks were 1,619 +/- 1,062 ng/ml and 1,711 +/- 786 ng/ml at weeks 6 and 12, respectively. ZDV concentrations at 4 h declined to 77 +/- 53 ng/ml, 110 +/- 43 ng/ml, and 101 +/- 49 ng/ml at weeks 1, 6, and 12, respectively. Initially, the plasma concentration-versus-time decay in three patients was linear, with a mean half-life (t1/2) of 1.3 +/- 0.5 h, while five patients had detectable concentrations in plasma after 4 h with an apparent delayed terminal-phase t1/2 of 4.8 +/- 2.8 h. At week 6 the prolonged elimination pattern was noted in all patients (terminal t1/2 = 4.1 +/- 2.0 h). No correlation between hepatic enzyme levels and t1/2 was noted. These findings suggest that ZDV may display a prolonged elimination phase during multiple dosing. Further studies utilizing a more sensitive assay may help to further define this later phase of ZDV elimination.
Administration, Oral↗
Pharmacokinetics of orally administered zidovudine among patients with hemophilia and asymptomatic human immunodeficiency virus (HIV) infection.
Zidovudine (formerly azidothymidine, AZT) is used to treat certain patients infected with the human immunodeficiency virus (HIV). However, the clinical use of zidovudine (ZDV) in hemophilia patients may be complicated by the high incidence of chronic hepatitis in this patient population. To examine the pharmacokinetics of ZDV eight asymptomatic HIV-infected hemophilia patients received a single oral dose (300 mg). ZDV and its glucuronide metabolite (GZDV) were measured in serum by HPLC. ZDV was rapidly absorbed with a wide range of peak serum concentrations (2052 +/- 970 ng/ml) at 0.5 h. Peak GZDV serum concentrations were 4751 +/- 2269 ng/ml at 1 h. Both ZDV and GZDV declined in a biexponential manner over 4 h. After 4 h, the ZDV serum concentration decay in three patients continued a log-linear decline, while five patients demonstrated a tri-exponential curve which had a mean terminal elimination half-life of 4.8 +/- 2.8 h. No relationship between ZDV or GZDV kinetics and the degree of hepatic enzyme elevation was observed. Although a therapeutic window for ZDV has yet to be described, the wide range of serum concentrations that result from a standard dose suggests that clinical monitoring of ZDV levels may be of value in certain patients. In addition, the prolonged elimination half-life of ZDV in the present study may provide a rationale for less frequent dosing in certain patients.
Administration, Oral↗
Pathogenesis and treatment of human genital papillomavirus infections: a review.
HPV infection of the genital tract is common and anogenital warts or condyloma acuminatum is increasing rapidly in incidence. In addition, certain HPV types are closely associated with genital tract malignancies. Although recent advances in molecular biology have led to an increased understanding of the organization and functions of the papillomavirus genome, the pathogenesis of HPV infections and host responses to these diseases remain poorly understood. Treatment of anogenital warts is difficult and no completely satisfactory treatment modality is currently available. Comparatively few therapeutic modalities have been thoroughly evaluated, although recent studies of intralesionally and parenterally administered interferons have demonstrated beneficial effects of interferon compared to placebo. Additional studies of treatment for condyloma acuminatum are needed and should include the use of biologic response modifiers such as interferons, as well as antiviral drugs, with or without conventional methods of local therapy.
Anus Diseases↗
Expression in Escherichia coli of seven DNA fragments comprising the complete L1 and L2 open reading frames of human papillomavirus type 6b and localization of the 'common antigen' region.
Molecular cloning was used to express human papillomavirus type 6b (HPV-6b) antigens in Escherichia coli. Seven genomic DNA fragments of HPV-6b which together comprise the complete L1 and L2 open reading frames, known to code for capsid proteins, were cloned and expressed in E. coli as both beta-galactosidase and TrpE fusion proteins. Western blots of HPV-6b beta-galactosidase fusion proteins using 'genus-specific' antisera produced by immunization of rabbits with disrupted bovine papillomavirus type 1 (BPV-1) showed that polypeptides encoded by two DNA fragments from the mid portion of L1 of HPV-6b were cross-reactive. Only one of these two polypeptides reacted with antisera raised against disrupted HPV-1, directly demonstrating that this polypeptide contains the papillomavirus 'common antigen'. The cross-reactive region was confirmed by reversing antigen and antibody. Polyclonal antisera were raised against the seven HPV-6b beta-galactosidase fusion proteins and tested against BPV-1 virion proteins on Western blots. Only antiserum against the mid portion of L1 of HPV-6b reacted with the BPV-1 major capsid protein. HPV-6b fusion proteins were also used to test human sera for antibodies reactive in Western blots. Serum samples from 38 patients with documented HPV-6 infections and from 22 presumably uninfected controls were tested. Antibodies were not detected in any of the sera to any of the seven fusion proteins. HPV-6b beta-galactosidase fusion proteins are antigenic and can be used on Western blots to localize immunologically reactive sub-regions of proteins by reacting protein fragments with antisera from immunized animals. However, alternative methods will be required to detect anti-HPV antibodies in human sera.
Adult↗
Enterococcal meningitis: a subacute presentation.
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Humans↗
Double-blind, placebo-controlled trial comparing long-term suppressive with short-term oral acyclovir therapy for management of recurrent genital herpes.
A total of 156 patients with frequently recurring genital herpes were enrolled in a randomized, double-blind, one-year trial comparing long-term suppressive and intermittent oral acyclovir therapy with placebo in the management of recurrent genital herpes. Subjects received either suppressive treatment with acyclovir, 400 mg twice daily for one year, and 200 mg five times per day for five days, for short-term treatment of recurrences; intermittent treatment with placebo, twice daily for one year, and oral acyclovir, 200 mg five times per day for five days, for short-term treatment of recurrences; or treatment with placebo, twice daily for one year, and five times per day for five days for short-term treatment of recurrences. Median time to first recurrence was 250 days for the suppressive group, 28 days for the intermittent group, and 23 days for the placebo group (p = 0.001). The median number of days per month with active disease was 0.32 for the suppressive group, 4.18 for the intermittent group, and 4.72 for the placebo group (p less than 0.001), with a median recurrence rate per 30-day treatment period of 0.08 recurrences/patient in the suppressive group, 0.70 in the intermittent group, and 0.74 in the placebo group (p less than 0.001). Median duration of recurrence was 5.0 days in the suppressive group compared with 6.0 days in the combined intermittent acyclovir plus placebo group (p = 0.001), and was reduced from 7.0 to 6.0 days when intermittent acyclovir treatment was compared with placebo treatment (p = 0.05). Daily administration of oral acyclovir for one year is superior to intermittent or placebo treatment in the management of patients with frequently recurring genital herpes.
Acyclovir↗
Interferon alpha-n1 (Wellferon) for refractory genital warts: efficacy and tolerance of low dose systemic therapy.
This multi-center trial compared two doses of parenterally administered interferon alpha-n1 (Wellferon) in men and women with recurrent/resistant genital warts. Patients received either 1 or 3 MU/m2 daily for 14 days, then 3 times weekly for 4 weeks; non-responders could receive an additional four weeks of treatment. A total of 107 patients were enrolled, and 102 were evaluable after six weeks of study. The principal dose comparison was in 57 women assigned alternately to the two doses. Median lesion measurements were reduced significantly from baseline at weeks 2, 4 and 6 in both groups. Statistical analysis showed no difference in response to 1 versus 3 MU/m2. The overall complete response (CR) plus partial response (PR) rate at week 6 was 69% for the two doses. Two additional groups of 21 women and 24 men were treated at the higher dose with CR plus PR rates of 75 and 50%, respectively. Week 10 disease evaluations for all groups showed 19 of 77 patients to be completely cleared. Of these 19, only one had recurrent disease at the end of the 6-month study period. Analysis of the incidence of symptomatic side effects showed a significantly higher frequency among women treated with 3 MU/m2 than among women treated with 1 MU/m2. Five dose reductions and two withdrawals for toxicity occurred, all in the high dose group. This study demonstrates that parenterally administered Wellferon produces clearance of resistant genital warts in many patients, and that rates of clearance do not appear to vary between groups receiving moderate or low dose therapy.
Adult↗