Marc Rubin

Lamivudine as Initial Treatment for Chronic Hepatitis B in the United States

BACKGROUND AND METHODS Although the nucleoside analogue lamivudine has shown promise in patients with chronic hepatitis B, long-term data on patients from the United States are lacking. We randomly assigned previously untreated patients with chronic hepatitis B to receive either 100 mg of oral lamivudine or placebo daily for 52 weeks. We then followed them for an additional 16 weeks to evaluate post-treatment safety and the durability of responses. The primary end point with respect to efficacy was a reduction of at least 2 points in the score on the Histologic Activity Index. On this scale, scores can range from 0 (normal) to 22 (most severe abnormalities). RESULTS Of the 143 randomized patients, 137 were included in the efficacy analysis: 66 in the lamivudine group and 71 in the placebo group. The other six patients were excluded at the base-line visit because of the absence of a documented history of hepatitis B surface antigen for at least six months. After 52 weeks of treatment, lamivudine recipients were more likely than placebo recipients to have a histologic response (52 percent vs. 23 percent, P<0.001), loss of hepatitis B e antigen (HBeAg) in serum (32 percent vs. 11 percent, P=0.003), sustained suppression of serum hepatitis B virus (HBV) DNA to undetectable levels (44 percent vs. 16 percent, P<0.001), and sustained normalization of serum alanine aminotransferase levels (41 percent vs. 7 percent, P<0.001), and they were less likely to have increased hepatic fibrosis (5 percent vs. 20 percent, P=0.01). Lamivudine recipients were also more likely to undergo HBeAg seroconversion, defined as the loss of HBeAg, undetectable levels of serum HBV DNA, and the appearance of antibodies against HBeAg (17 percent vs. 6 percent, P=0.04). HBeAg responses persisted in most patients for 16 weeks after the discontinuation of treatment. Lamivudine was well tolerated. Self-limited post-treatment elevations in serum alanine aminotransferase were more common in lamivudine recipients: 25 percent had serum alanine aminotransferase levels that were at least three times base-line levels, as compared with 8 percent of placebo recipients (P=0.01). The clinical condition of all patients remained stable during the study. CONCLUSIONS In U.S. patients with previously untreated chronic hepatitis B, one year of lamivudine therapy had favorable effects on histologic, virologic, and biochemical features of the disease and was well tolerated. HBeAg responses were generally sustained after treatment.

A Randomized Trial Comparing Ceftazidime Alone with Combination Antibiotic Therapy in Cancer Patients with Fever and Neutropenia

To assess the efficacy of single-agent therapy relative to standard combination antibiotic therapy for the initial management of fever and neutropenia in cancer patients, we conducted a randomized trial comparing ceftazidime alone with a combination of cephalothin, gentamicin, and carbenicillin. Of 550 evaluable episodes of fever and neutropenia, 282 were treated with ceftazidime alone and 268 with the combination. All episodes were evaluated for responses at 72 hours after the start of treatment and at resolution of the neutropenia. Of the patients with unexplained fever who were given ceftazidime alone, 99 percent were alive at 72 hours and 98 percent were alive when the neutropenia resolved, as compared with 100 percent and 98 percent, respectively, of those given combination therapy. Of the patients with documented infection who were given ceftazidime alone, 98 percent were alive at 72 hours and 89 percent when the neutropenia resolved, as compared with 98 percent and 91 percent, respectively, of those given combination therapy. The majority of episodes of documented infection in both treatment groups necessitated additional antimicrobial treatment or other modifications of the initial regimen, as compared with only 22 percent of the episodes of unexplained fever. We conclude that initial single-agent therapy with certain beta-lactam antibiotics is a safe alternative to standard combination antibiotic therapy, although patients with documented infection or protracted neutropenia are likely to require additional or modified treatment.

Treatment with Lamivudine, Zidovudine, or Both in HIV-Positive Patients with 200 to 500 CD4+ Cells per Cubic Millimeter

BACKGROUND The reverse-transcriptase inhibitor lamivudine has in vitro synergy with zidovudine against the human immunodeficiency virus (HIV). We studied the activity and safety of lamivudine plus zidovudine as compared with either drug alone as treatment for patients with HIV infection, most of whom had not previously received zidovudine. METHODS Three hundred sixty-six patients with 200 to 500 CD4+ cells per cubic millimeter who had received zidovudine for four weeks or less were randomly assigned to treatment with one of four regimens: 300 mg of lamivudine every 12 hours; 200 mg of zidovudine every 8 hours; 150 mg of lamivudine every 12 hours plus zidovudine; or 300 mg of lamivudine every 12 hours plus zidovudine. The study was double-blind and lasted 24 weeks, with an extension phase for another 28 weeks. RESULTS Over the 24-week period, the low-dose and high-dose regimens combining lamivudine and zidovudine were associated with greater increases in the CD4+ cell count (P = 0.002 and P = 0.015, respectively) and the percentage of CD4+ cells (P < 0.001 for both) and with greater decreases in plasma levels of HIV-1 RNA (P < 0.001 for both) than was treatment with zidovudine alone. Combination therapy was also more effective than lamivudine alone in lowering plasma HIV-1 RNA levels and increasing the percentage of CD4+ cells (P < 0.001 for all comparisons), and these advantages persisted through 52 weeks. Adverse events were no more frequent with combination therapy than with zidovudine alone. CONCLUSIONS In HIV-infected patients with little or no prior antiretroviral therapy, treatment with a combination of lamivudine and zidovudine is well tolerated over a one-year period and produces more improvement in immunologic and virologic measures than does treatment with either agent alone.

Effect of Continuous Intravenous Infusion of Zidovudine (AZT) in Children with Symptomatic HIV Infection

Abstract To produce concentrations of zidovudine (AZT) in plasma and cerebrospinal fluid that would provide constant inhibition of the replication of human immunodeficiency virus (HIV), we gave AZT by continuous intravenous infusion to 21 children ranging in age from 14 months to 12 years who had acquired HIV infection through transfusions or perinatally. All patients were symptomatic before AZT treatment (Class P2 of the Centers for Disease Control); 13 (62 percent) had evidence of neurodevelopmental abnormalities. The mean CD4/CD8 ratio was 0.18; 11 patients had CD4 counts below 0.2X109 per liter. We administered AZT at four dose levels: 0.5, 0.9, 1.4, and 1.8 mg per kilogram of body weight per hour. The plasma drug concentrations achieved at the respective dose levels were 1.9±0.3, 2.8±1.4, 3.1 ±1.1, and 4.5±1.0 μM. The steady-state cerebrospinal fluid:plasma ratio was 0.24±0.07. The only evidence of toxicity was bone marrow suppression. Transfusion was required in 14 patients because of low levels of ...

Gram-Positive Infections and the Use of Vancomycin in 550 Episodes of Fever and Neutropenia

STUDY OBJECTIVE To determine the appropriate role for vancomycin in neutropenic patients with cancer. To review the incidence, types, and outcome of gram-positive infections in a series of neutropenic patients with cancer. DESIGN Retrospective review. SETTING Inpatient units of the Medical and Pediatric Oncology Branches of the National Cancer Institute. PATIENTS Five hundred and fifty consecutive episodes of fever and neutropenia in patients with cancer randomized prospectively on another study to receive either ceftazidime alone or combination antibiotics for initial empirical therapy. INTERVENTION Intravenous vancomycin (dosage adjusted by serum levels). MEASUREMENTS AND MAIN RESULTS Gram-positive organisms were the commonest of the bacterial pathogens isolated (63%). Of the 53 gram-positive organisms accounting for primary infections (isolated at initial presentation), there were 36 staphylococcal isolates (19 coagulase-negative and 17 coagulase-positive), 13 streptococcal isolates (8 non-group D and 5 group D), and 4 polymicrobial isolates. Of the 22 secondary gram-positive infections (occurring after institution of initial antibiotics), there were 10 streptococcal isolates (9 group D and 1 non-group D), 7 staphylococcal isolates (6 coagulase-negative and 1 coagulase-positive), and 5 polymicrobial isolates. Vancomycin was used to treat 26 of the 53 primary infections, but was begun only after knowledge of the isolate in 25. Vancomycin was used to treat 17 of the 22 secondary infections, and begun only after knowledge of the isolate in 14. This approach resulted in no treatment failures for the primary infections, and a single microbiological failure for the secondary infections. There was a tendency towards a greater proportion of secondary gram-positive infections in the monotherapy group compared to the combination therapy group (16 of 282 compared with 6 of 268 respectively, P2 = 0.04 by the chi-squared test); but all were treated successfully. CONCLUSION Vancomycin need not be included in routine empirical therapy for febrile neutropenic patients, but should be added when clinical or microbiological data suggest the need.

Drug resistance and virologic response in NUCA 3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients.

Objective:To study the effect of HIV-1 resistance to lamivudine (3TC) and zidovudine (ZDV), and syncytium-inducing (SI) phenotype on virologic response to treatment with ZDV, 3TC, or ZDV plus 3TC in previously untreated individuals with HIV-1 infection. Design:A prospective virologic substudy of GlaxoWellcome protocol NUCA 3001. Methods:HIV-1 isolates obtained at study entry and at week 12 were expanded in peripheral blood mononuclear cell (PBMC) culture, titered, and assayed for phenotypic and genotypic evidence of resistance to ZDV and 3TC, and for syncytium formation on MT-2 cells. Results:Phenotypic and genotypic resistance to 3TC was detected in the majority of HIV-1 isolates from patients who received 3TC alone or in combination with ZDV. Despite showing 3TC resistance, subjects who received 3TC in combination with ZDV had significantly greater decreases in plasma HIV-1 RNA levels compared with those who received ZDV alone. Occurrence of the K70R ZDV resistance mutation was significantly reduced in patients who received the 3TC/ZDV combination as compared with patients on ZDV monotherapy. Plasma HIV-1 RNA returned to near-baseline levels more quickly in patients with SI isolates at study entry. Conclusions:Despite the rapid emergence of 3TC resistance, combination therapy with 3TC plus ZDV resulted in greater reduction in plasma HIV-1 RNA levels over 24 weeks as compared to ZDV monotherapy. Prevention of ZDV resistance may contribute to the sustained activity of the combination therapy.

Impairment of neutrophil chemotactic and bactericidal function in children infected with human immunodeficiency virus type 1 and partial reversal after in vitro exposure to granulocyte-macrophage colony-stimulating factor

Because polymorphonuclear neutrophils are the most important component of host defense against bacteria, we assessed their function in 13 children with asymptomatic and 12 with symptomatic infection with human immunodeficiency virus type 1 (HIV-1), and compared their values with healthy adult control values. The functions assessed were (1) chemotaxis, (2) bacterial phagocytosis, (3) superoxide generation, and (4) bactericidal activity. Chemotaxis of polymorphonuclear neutrophils toward the chemoattractant N-formylmethionyl leucyl phenylalanine (FMLP) was significantly decreased in symptom-free infected children compared with control subjects (p less than 0.0001), but was increased in children with symptomatic infection (p less than 0.025). Bactericidal activity of the neutrophils against Staphylococcus aureus was defective in 8 of 12 children with asymptomatic infection (p = 0.016), and in 8 of 9 children with symptomatic infection (p less than 0.00001). Superoxide generation by polymorphonuclear neutrophils on stimulation with FMLP and phagocytosis of S. aureus were normal. Serum from patients with symptomatic HIV-1 infection was not as efficient in low concentrations as normal serum in the ability to opsonize S. aureus. The in vitro bactericidal defect was partially corrected by granulocyte-macrophage colony-stimulating factor (GM-CSF). The results suggest that both cellular (neutrophils) and humoral defects contribute to the increased incidence of bacterial infections in HIV-1-infected children, and that GM-CSF may improve the defective bactericidal activity of polymorphonuclear neutrophils in these patients.

Lamivudine Plus Zidovudine Compared with Zalcitabine Plus Zidovudine in Patients with HIV Infection: A Randomized, Double-Blind, Placebo-Controlled Trial

For the treatment of human immunodeficiency virus (HIV) type 1 infection, five nucleoside reverse transcriptase inhibitors are currently available: zidovudine, didanosine, zalcitabine, stavudine, and lamivudine. The results of clinical trials to date [1-7] suggest that the effectiveness of monotherapy with these agents is time limited. This may be because the regimens incompletely suppress viral burden and allow the emergence of drug-resistant virus populations and because of the dynamic nature of HIV infection. Combinations of anti-HIV agents in vitro provide more thorough viral suppression and may limit the emergence of drug resistance [8]. Numerous clinical trials of zidovudine plus zalcitabine or zidovudine plus didanosine [9-13] have suggested that suppression of HIV replication and increases in absolute CD4+ cell counts are greater with combination therapy than with monotherapy. Several recent trials [3, 14] have shown improved clinical outcomes for patients receiving combination therapy, including those who had previously received zidovudine monotherapy. These results have encouraged further evaluation of antiretroviral drug combinations for the treatment of HIV infection. Lamivudine ([minus]-2,3-dideoxy-3-thiacytidine; 3TC) is a nucleoside reverse transcriptase inhibitor and a potent, relatively nontoxic, selective inhibitor of HIV replication [15, 16]. It is active against zidovudine-resistant HIV isolates and is synergistic with zidovudine in vitro [17, 18]. Lamivudine is well tolerated and effectively improves prognostic virologic and immunologic markers during the treatment of HIV-infected patients [19-21]. Lamivudine-resistant HIV isolates have been identified both in vitro and in vivo during therapy in association with the development of a mutation at codon 184 in the HIV pol gene [22-27]. In vitro studies have shown that inserting the lamivudine resistance-conferring codon 184 mutation into zidovudine-resistant viruses restores phenotypic zidovudine sensitivity in tissue culture [22, 27]. Despite the rapid appearance of lamivudine-resistant viruses in clinical trials of lamivudine monotherapy or therapy with lamivudine-containing drug combinations, sustained reductions in viral burden have been seen [26, 27]. Therefore, the combination of lamivudine and zidovudinebecause of its in vitro synergy; its potential reversal of zidovudine resistance; its antiretroviral activity, seen in vivo despite the emergence of lamivudine resistance; and its favorable safety profilemay be particularly promising as therapy for HIV-infected patients previously treated with zidovudine. This NUCA 3002 study was designed to compare the safety and activity of two doses of lamivudine plus zidovudine with the safety and activity of zalcitabine plus zidovudine in patients with moderately advanced HIV infection who had previously received zidovudine. Methods Study Sample To be eligible for the study, patients had to meet all of the following criteria: age at least 18 years; documented HIV infection; absolute CD4+ cell count between 100 and 300 cells/mm3; at least 6 months of previous zidovudine therapy, including current zidovudine use at time of study entry; either no experience with didanosine, zalcitabine, or investigational antiretroviral drugs or a maximum of 4 weeks of previous treatment with didanosine; Karnofsky score of at least 60; hemoglobin concentration of at least 92 g/L for men and 88 g/L for women; absolute neutrophil count of at least 1000 cells/mm3; platelet count of at least 5 107/L; hepatic aminotransferase and alkaline phosphatase levels no greater than five times the upper limit of normal; serum bilirubin level less than 25.65 mg/L; serum creatinine concentration less than 132.6 mg/L; and total serum amylase level no greater than 1.5 times the upper limit of normal. Patients receiving chemoprophylaxis for Pneumocystis carinii pneumonia, candidiasis, or herpes simplex infections and those receiving erythropoietin or granulocyte colony-stimulating factor were eligible for inclusion. Exclusion criteria were evidence of active acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections for which therapy had not been completed; current peripheral neuropathy of mild to moderate or greater severity; significant cardiac, hepatic, renal, or neurologic disease; active cancer; or intractable diarrhea or severe malabsorption. Patients were also ineligible if they were pregnant, were breastfeeding, or had childbearing potential and were not using adequate contraception. Study Design Our study was a multicenter, randomized, double-blind (the use of zidovudine was open-label) clinical trial designed to compare the safety and activity of two different doses of lamivudine plus zidovudine with the safety and activity of zalcitabine plus zidovudine. The study was originally intended to last 24 weeks, but the duration was amended during the course of the trial so that all patients who completed 24 weeks of study therapy could continue their assigned treatment in a double-blind manner through at least 52 weeks. The study was done at 21 sites in the United States, Canada, and Puerto Rico. The institutional review board at each institution approved the study, and all patients gave written consent. Glaxo Wellcome, Inc., collected and analyzed the primary study data, and the study investigators reviewed and interpreted the results. Treatment Regimens Patients were randomly assigned to receive one of three treatment regimens: 150 mg of lamivudine every 12 hours, 200 mg of zidovudine every 8 hours, and zalcitabine placebo every 8 hours (low-dose lamivudine group); 300 mg of lamivudine every 12 hours, 200 mg of zidovudine every 8 hours, and zalcitabine placebo every 8 hours (high-dose lamivudine group); or 0.75 mg of zalcitabine and 200 mg of zidovudine every 8 hours and lamivudine placebo every 12 hours (zalcitabine group). Each dose of zidovudine (Retrovir; Glaxo Wellcome, Inc., Research Triangle Park, North Carolina) was given as two 100-mg capsules; each dose of zalcitabine (Hivid; Hoffman-La Roche, Inc., Nutley, New Jersey) was given as two 0.375-mg tablets; and each dose of lamivudine (Epivir; Glaxo Wellcome, Inc.) was given as two 75-mg tablets or as one 300-mg tablet with a matching placebo. All adjustments of medications for management of adverse events were made by each study center in a standardized and blinded manner. Adverse events and abnormal laboratory results were graded according to a toxicity rating scale developed by the Division of AIDS, National Institutes of Health. Study Assessments The primary outcome measure was the change from baseline in absolute CD4+ cell counts during the first 24 weeks of the study. The secondary outcome measures were the change in log10 plasma HIV RNA levels, clinical progressions of HIV disease, percentages of cells that were CD4+ cells, serum 2-microglobulin and neopterin levels, and serum immune complex-dissociated p24 antigen levels. Each patient was evaluated within 14 days of randomization, at least 72 hours before randomization, at the time of randomization (day 1), at study weeks 2 and 4, and every 4 weeks thereafter. Safety of the study regimens was evaluated through medical histories and physical examinations, clinical laboratory tests, and the reporting of adverse events. All laboratory studies were done by the Laboratory Corporation of America (formerly Roche Biomedical Laboratories, Research Triangle Park, North Carolina, and Raritan, New Jersey). Virologic activity was evaluated through the measurement of plasma HIV RNA levels by reverse transcriptase quantitative polymerase chain reaction (PCR) (Roche Quantiplex PCR, Laboratory Corporation of America) and the measurement of serum immune complex-dissociated p24 antigen levels (Coulter Corp., Hialeah, Florida) in all patients. The lower limit of detection for the reverse transcriptase PCR assay was 200 copies of HIV RNA per mL. Human immunodeficiency virus isolates were banked for future drug-resistance studies. Immunologic activity was evaluated through the measurement of T-lymphocyte subsets, 2-microglobulin levels, and neopterin levels in all patients. T-lymphocyte subsets were determined three times before therapy with study medications was initiated, and the baseline absolute CD4+ cell count was defined as the mean of the final two values obtained at the last visit made before and at the time of randomization. Clinical progressions of HIV disease were classified according to the criteria from the Centers for Disease Control and Prevention (CDC); these criteria consist of commonly recognized AIDS-related events (class B conditions) and AIDS-defining events (class C conditions) [28]. All diagnoses were reviewed by clinical research personnel who were blinded to treatment assignments. The criteria for the discontinuation of assigned treatment included serious adverse events; a 50% decline from baseline in absolute CD4+ cell counts on two consecutive occasions at least 28 days apart or a new AIDS-indicator illness (at the discretion of the center); pregnancy; unreliable follow-up (at the discretion of the center); or noncompliance. Patients who discontinued treatment were asked to return for monitoring of CD4+ cell counts every 4 weeks until study week 52. Statistical Analysis An equal number of patients was randomly assigned to the three treatment regimens through the use of permuted blocks at each study center. A sample size of 75 participants per treatment group was chosen to allow 80% power to detect a difference of 25 CD4+ cells/mm3 between the mean CD4+ cell counts of the three groups at the 0.05 level of significance. A summary metric [29] was used to characterize the HIV disease marker profile during the first 24 weeks of the study for the analyses of primary study outcomes. The time-weighted area under the curve (trapezoidal rule) minus the baseline value (DAVGT) was used to compare the profi

Gastrointestinal-motility dysfunction in amyloidosis.

SYSTEMIC amyloidosis frequently involves the gastrointestinal tract and may result in obstruction, malabsorption, ulceration, hemorrhage or perforation as well as impaired motility.1 2 3 It is uncl...

Controversies in the Management of Febrile Neutropenic Cancer Patients

AbstractINTRODUCTION The management of infections in cancer patients has evolved both conceptually and practically over the past twenty years. The advent of cytotoxic therapy opened new horizons on the road toward improved survival and even cure of some malignancies. With it, however, came an unprecedented and previously unrecognized array of abnormalities in host defense systems (Fig. 1), and consequendy, infectious complications that at first threatened to undermine any potential benefits of cancer therapy. The most profound of these alterations was granulocytopenia. Early on, it was recognized that successful management of the granulocytopenic patient required new and unique therapeutic guidelines. More traditional approaches for the treatment of infection in these patients, such as identification of a pathogen prior to institution of antibiotics, often led to disasterous consequences. Thus, the concept of empirical antibiotic therapy emerged, with routine empirical therapy now accepted as the standard...