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The objective of this randomized, double-blind, controlled multicentre study was to evaluate the efficacy of saquinavir alone or in combination with zalcitabine compared to zalcitabine monotherapy in reducing progression of human immunodeficiency virus (HIV) disease. Nine hundred and forty HIV-infected patients with more than 16 weeks of prior zidovudine therapy and pre-study entry CD4 cell counts between 50 and 300 cells/mm3 were randomized to saquinavir 600 mg every 8 h, zalcitabine 0.75 mg every 8 h or the combination of both drugs. In an intent-to-treat analysis, the treatment arms were balanced with respect to demographics, baseline HIV RNA (mean 5.0 log10 copies/ml) and CD4 lymphocyte count (mean 170 cells/mm3). More patients in the zalcitabine arm stopped therapy because of toxicity than in the other two arms (25% versus 16%; P=0.005). Peripheral neuropathy was the most common treatment-limiting toxicity. Fifty-one patients in the saquinavir plus zalcitabine group developed an AIDS-defining event or died compared to 84 and 88 in the saquinavir and zalcitabine monotherapy groups respectively. Combination treatment with saquinavir plus zalcitabine reduced the risk of progression to AIDS by 49% (95% confidence interval 0.36 to 0.72, P=0.0001) and reduced death by 68% (95% confidence interval 0.16 to 0.64, P=0.001) compared to zalcitabine monotherapy. The addition of saquinavir to zalcitabine resulted in a significant reduction in progression to AIDS or death compared with zalcitabine alone.

In a human immunodeficiency virus-infected subject, cytomegalovirus (CMV) isolated 9 months after the patient began oral ganciclovir prophylaxis was resistant to ganciclovir and cidofovir and contained mutations in both UL97 and Pol coding regions. At 1 year, retinitis developed, which progressed despite intravenous ganciclovir followed by foscarnet and then cidofovir. A subsequent buffy coat virus isolate was resistant to all three drugs and contained new mutations in UL97 and Pol. By individually transferring the observed mutations to laboratory strain AD169, it was shown that a mutation at codon 603 of UL97 conferred resistance to ganciclovir, a mutation at codon 412 of Pol conferred resistance to both ganciclovir and cidofovir, and a mutation at codon 802 of Pol conferred resistance to ganciclovir and foscarnet. This case illustrates the development of multidrug resistance during prolonged exposure to antiviral therapy for CMV and cross-resistance arising from point mutations in the CMV Pol gene.

Branched chain DNA assay (bDNA), cytomegalovirus (CMV) antigen assay, and cerebrospinal fluid (CSF) viral culture were studied for their utility in the diagnosis of CMV polyradiculopathy and for documenting in vivo antiviral effects. CMV was demonstrated in 15 of 16 patients by bDNA assay, 15 of 16 by CMV antigen assay, and 11 of 15 by CSF culture. When clinical criteria and results of the other two assays were used as reference standards, the sensitivity of bDNA was 94% and 100% and the specificity 95.2% and 100%; the CMV antigen assay sensitivity was 94% and 100% and specificity was 85.7% and 100%. Nine (90%) of 10 patients with polyradiculopathy and follow-up CSF culture showed a drop in CMV DNA after treatment; however, only 2 (20%) improved clinically. These results suggest that bDNA and antigen assays may be useful methods for the diagnosis of CMV polyradiculopathy, but treatment failures may not be due to inadequate antiviral activity.

Background In the advanced stages of the acquired immunodeficiency syndrome (AIDS), cytomegalovirus (CMV) disease, particularly vision-damaging retinitis due to CMV, is common. We evaluated prophylactic treatment with orally administered ganciclovir as a way to prevent CMV disease. Methods We conducted a prospective, randomized, double-blind, placebo-controlled study of CMV-infected persons with AIDS with either CD4+ lymphocyte counts of

This prospective, clinical economic study was done to determine the cost impact of oral compared with intravenous (IV) ganciclovir for the maintenance treatment of newly diagnosed cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). Efficacy and safety data were extracted from a trial of oral and IV ganciclovir. Medical care utilization and reimbursement data were obtained from the clinical trial, a survey of home care and nursing companies, an 11-member physician panel, and a Medicaid cost database. The primary outcome measures were time to first retinitis progression and associated direct medical care expenditures. Nonmedical costs and quality-of-life benefits were not considered. Based on masked evaluation of retinal photographs, the Kaplan-Meier mean time to first progression was 62 days for IV ganciclovir and 57 days for oral ganciclovir (a nonsignificant difference). The expected mean cost of treatment for IV ganciclovir was significantly different at $8587.00 compared with $4938.00 for oral treatment. Sensitivity analysis using funduscopically determined mean time to first progression showed similar cost savings. We concluded that oral ganciclovir is a cost-saving alternative to IV ganciclovir for the maintenance treatment of AIDS patients with newly diagnosed CMV retinitis. Cost differences are attributable to reduced home care expenditures and lower incidence and costs of treating major adverse events in the oral treatment group.

Background Cytomegalovirus retinitis, a sight-threatening infection associated with the acquired immunodeficiency syndrome (AIDS), currently requires lifelong intravenous treatment. An effective oral treatment would be an important advance. Methods We compared oral with intravenous ganciclovir in an open-label, randomized study in patients with AIDS and newly diagnosed, stable cytomegalovirus retinitis (the disease was stabilized by three weeks of treatment with intravenous ganciclovir). Sixty subjects were randomly assigned to maintenance therapy with intravenous ganciclovir at a dose of 5 mg per kilogram of body weight daily, and 63 to maintenance therapy with oral ganciclovir at a dose of 3000 mg daily. The subjects were followed for up to 20 weeks, with photography of the fundi conducted every other week. The photographs were evaluated at the completion of the study by an experienced grader who was unaware of the subjects' treatment assignments. Results Efficacy could be evaluated in 117 subjects; pho...

A phase I/II study evaluated the pharmacokinetics, tolerability, and antiviral activity of oral ganciclovir in persons infected with human immunodeficiency virus (HIV). Oral bioavailability ranged from 2.6% to 7.3%. The mean maximum serum concentration achieved at 1000 mg every 8 h was 1.11 micrograms/mL, and mean trough level was 0.54 microgram/mL. The time to maximum serum drug concentration was 1.0-2.9 h, with a serum half-life of 3.0-7.3 h, suggesting prolonged oral absorption. Serious adverse events were uncommon. Decreased cytomegalovirus (CMV) shedding was observed from all sites. The median days (by dosage) to retinitis progression assessed by retinal examination after initiation of oral ganciclovir were 62 (1000 mg every 8 h), 148 (500 mg every 3 h), 75 (750 mg every 3 h), 148 (1000 mg every 3 h), and 139 (2000 mg every 8 h). Thus, oral ganciclovir has pharmacokinetic, toxicity, and antiviral profiles that may prove beneficial for both maintenance therapy of CMV retinitis and prevention of CMV disease in HIV-infected persons.

Seventy-two AIDS patients treated with ganciclovir for cytomegalovirus (CMV) disease were prospectively monitored for the development of drug-resistant virus. No resistant strains were found in 31 patients before therapy or among seven culture-positive patients treated for less than or equal to 3 months. Of 13 culture-positive patients treated for greater than or equal to 3 months, 5 excreted virus resistant (ED50, greater than 12 microM, or ED90, greater than 30 microM) to ganciclovir. Thus, 38% of patients and receiving ganciclovir for greater than 3 months and excreting virus or, overall, 7.6% of the patients were excreting CMV resistant to the drug.

Mucocutaneous herpes simplex virus (HSV) infections that are resistant to therapy with acyclovir have been recognized with increasing frequency in patients with the acquired immunodeficiency syndrome, although alternative therapies in this setting have not been widely studied. Twenty-six consecutive patients are reported with human immunodeficiency virus infection, who received foscarnet therapy for acyclovir-resistant HSV. Clinical response was noted in 81% of patients; complete reepithelialization of HSV lesions occurred in 73%. Cessation of viral shedding was documented in all of the 11 patients who were recultured. Although adverse effects were frequent, in only 3 patients (12%) did toxicity necessitate discontinuation of therapy. Before foscarnet therapy, 14 patients received vidarabine for acyclovir-resistant HSV. The infection did not resolve in any of the vidarabine-treated patients, and therapy was discontinued in 4 (29%) due to toxicity.

Prosthetic joint infection due to Mycobacterium tuberculosis is uncommon. We describe three patients with delayed tuberculous prosthetic joint infection and review the eight other cases reported in the English-language literature. Infection results from local reactivation, which can occur up to 40 years after the initial infection, or from hematogenous spread. The diagnosis is often delayed because it is not considered in the initial evaluation, because it is difficult to confirm microbiologically, or because other bacteria may be isolated from the synovial fluid and thus be considered the etiology of the infection. Treatment usually consists of removal of the prosthesis in addition to administration of antituberculous agents.

Expanded access programs (EAPs) provide medication to patients with life-threatening, treatment-refractory illnesses before regulatory approval and allow the acquisition of safety information. A 2-part, multisite EAP to evaluate abacavir, a carbocyclic nucleoside reverse-transcriptase inhibitor for use in combination antiretroviral therapy, was conducted. The EAP involved >13,000 adults infected with human immunodeficiency virus type 1 (HIV-1) who no longer responded to commercially available treatment regimens. Part A (open-label trials) examined the efficacy, safety, and tolerance of abacavir, and part B (provision of abacavir through expanded access) assessed only the occurrence of serious adverse events. By month 2 of abacavir-containing treatment, plasma HIV-1 RNA levels decreased by > or =0.5 log(10) in 31.4% of patients, and 5.6% of the patients had HIV-1 RNA levels decrease to

Recent research advances have afforded substantially improved understanding of the biology of HIV infection and the pathogenesis of AIDS. With the advent of sensitive tools for monitoring HIV replication in infected persons, the risk for disease progression and death can be assessed accurately and the efficacy of anti-HIV therapies can be determined directly. Furthermore, when used appropriately, combinations of newly available, potent antiviral therapies can effect prolonged suppression of detectable levels of HIV replication and circumvent the inherent tendency of HIV to generate drug-resistant viral variants. However, as antiretroviral therapy for HIV infection has become increasingly effective, it has also become increasingly complex. Familiarity with recent research advances is needed to ensure that newly available therapies are used in ways that most effectively improve the health and prolong the lives of HIV-infected persons. To enable practitioners and HIV-infected persons to best use rapidly accumulating new information about HIV disease pathogenesis and treatment, the Office of AIDS Research of the National Institutes of Health (NIH) sponsored the NIH Panel To Define Principles of Therapy of HIV Infection. This Panel was asked to define essential scientific principles that should be used to guide the most effective use of antiretroviral therapies and viral load testing in clinical practice. On the basis of detailed consideration of the most current data, the Panel delineated 11 principles that address issues of fundamental importance for the treatment of HIV infection. These principles provide the scientific basis for the specific treatment recommendations made by the Panel on Clinical Practices for the Treatment of HIV Infection sponsored by the Department of Health and Human Services and the Henry J. Kaiser Family Foundation. The reports of both of these panels are provided in this supplement. Together, they summarize new data and provide both the scientific basis and specific guidelines for the treatment of HIV-infected persons. This information will be of interest to health care providers, HIV-infected persons, HIV and AIDS educators, public health educators, public health authorities, and all organizations that fund medical care of HIV-infected persons.

The steady-state pharmacokinetics of oral ganciclovir in the fasting versus fed state were studied in 20 patients infected with human immunodeficiency virus and with a seropositive test result for cytomegalovirus in a two-way crossover study. Patients received oral ganciclovir at a dose of 1000 mg every 8 hours for 8 days. On days 4 and 8, subjects were randomly assigned to receive the morning dose either after an overnight fast or after a standardized 602-calorie, high-fat (46.5%) breakfast. Serial blood samples were obtained over the 8-hour morning dose interval. The mean time to maximum concentration (tmax) was increased from 1.8 hours in the fasting state to 3.0 hours in the fed state. Mean maximum serum concentration (Cmax) and area under the concentration-time curve from time 0 to 8 hours (AUC0-8) of ganciclovir were significantly higher in the fed state than after an overnight fast. Because food could potentially increase the bioavailability of oral ganciclovir, patients should be instructed to take each dose of oral ganciclovir with food.

As of November 1994, there were two medications approved in the USA for the treatment of cytomegalovirus (CMV) retinitis in the immunocompromised patient These are the intravenous formulations of ganciclovir and foscarnet In addition, the intravenous formulation of ganciclovir is approved for the prevention of CMV disease in organ transplant recipients. Clinical investigations of an oral administration of ganciclovir were begun in 1986,1 and an encapsulated oral formulation was approved in the USA in December 1994 for management of CMV retinitis in patients with AIDS. Oral therapy with ganciclovir offers several potential advantages over intravenous therapy, including more convenient administration and the lack of long term complications and expense related to intravenous access. In addition, because oral ganciclovir has a very different pharmacokinetic profile compared to the intravenous formulation, it was postulated that it might offer improved efficacy or decreased toxicity. This paper will review the pharmacokinetics, safety, and efficacy of oral ganciclovir, summarized from a number of studies investigating this agent in various clinical settings.

Tracheobronchitis is an uncommon manifestation of infection due to Aspergillus species, occurring in < 7% of cases of pulmonary aspergillosis. At least 58 cases of invasive aspergillus tracheobronchitis have been described since 1962. We describe four patients with AIDS, all of whom were severely immunocompromised, who had ulcerative tracheobronchitis due to Aspergillus species demonstrated histologically. Three patients had received corticosteroids or were neutropenic at presentation. At bronchoscopy, three patients had some degree of diffuse tracheobronchitis, multiple ulcerative or "plaque-like" inflammatory lesions, and occasionally nodules involving the mainstem and segmental bronchi. The remaining patient had a single deep ulceration of the proximal trachea. Aspergillus was isolated from biopsy specimens from all four patients. There were varied degrees of invasion of the mucosa, submucosa, and cartilage on histological examination in three patients, one of whom had evidence of disseminated aspergillosis. Two patients subsequently developed pulmonary parenchymal disease due to Aspergillus. A review of aspergillus tracheobronchitis, including a discussion of airway disease in patients infected with human immunodeficiency virus, is presented.

Symptomatic pulmonary aspergillosis has rarely been reported in patients with the acquired immunodeficiency syndrome (AIDS). We describe the predisposing factors, the clinical and radiologic features, and the therapeutic outcomes in 13 patients with pulmonary aspergillosis, all of whom had human immunodeficiency virus (HIV) infection and 12 of whom had AIDS.Pulmonary aspergillosis was detected a median of 25 months after the diagnosis of AIDS, usually following corticosteroid use, neutropenia, pneumonia due to other pathogens, marijuana smoking, or the use of broad-spectrum antibiotics. Two major patterns of disease were observed: invasive aspergillosis (in 10 patients) and obstructing bronchial aspergillosis (in 3). Cough and fever, the most common symptoms, tended to be insidious in onset in patients with invasive disease (median duration, 1.3 months before diagnosis). Breathlessness, cough, and chest pain predominated in the three patients with obstructing bronchial aspergillosis, who coughed up fungal casts. Radiologic patterns included upper-lobe cavitary disease (sometimes mistaken for tuberculosis), nodules, pleural-based lesions, and diffuse infiltrates, usually of the lower lobe. Transbronchial biopsies were usually negative, but positive cultures were obtained from bronchoalveolar-lavage fluid or percutaneous aspirates. Dissemination to other organs occurred in at least two patients, and direct invasion of extrapulmonary sites was seen in two others. The results of treatment with amphotericin B, itraconazole, or both were variable. Ten of the patients died a median of 3 months after the diagnosis (range, 0 to 12 months).Pulmonary aspergillosis is a possible late complication of AIDS; if diagnosed early, it may be treated successfully.

Objective: To test the hypothesis that the therapeutic success rate of oral atovaquone is not worse than that of intravenous pentamidine in the primary treatment of mild and moderate Pneumocystis c...

To evaluate the safety and efficacy of zalcitabine (also known as dideoxycytidine [ddC]) in patients with advanced human immunodeficiency virus (HIV) infection.Open-label, randomized study.AIDS Clinical Trials Units, university-affiliated medical centers, and private practice groups.Patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex who had tolerated zidovudine for 48 weeks or more.Fifty-nine patients received zidovudine (500 to 1200 mg/d) and 52 patients received zalcitabine (2.25 mg/d).The primary end points were survival and time to an AIDS-defining event or death.Because significantly more patients withdrew from zidovudine therapy, the median duration of treatment was greater in the zalcitabine group than in the zidovudine group (279.0 days compared with 174.5 days; P = 0.001). The estimated 12-month, event-free probabilities were 53% for the zalcitabine group and 57% for the zidovudine group (relative risk, 1.02; 95% CI, 0.5 to 2.2). The estimated 12-month survival rates were 81% for the zalcitabine group and 75% for the zidovudine group (relative risk, 1.39; CI, 0.5 to 3.8). The rate of decline in CD4 lymphocyte counts was significantly slower in the zalcitabine group than in the zidovudine group (-0.08 cells/day compared with -0.17 cells/day). Patients in the zalcitabine group had gained an average of 0.5 kg at week 20 and 0.4 kg at week 24, whereas patients in the zidovudine group had lost an average of 1.8 kg at week 20 and 2.4 kg at week 24 (P = 0.04 and P = 0.05, respectively). Moderate to severe peripheral neuropathy and ulcerative stomatitis occurred in 10 and 9 patients, respectively, in the zalcitabine group.The sample size for this study was smaller than planned, and no differences in survival and clinical end points were found. Slower rates of decline in CD4 lymphocyte counts and weight, however, were noted for the zalcitabine group.

RECURRENT herpes simplex virus (HSV) infections are frequent in patients with the acquired immunodeficiency syndrome (AIDS). Although they are usually self-limiting in the normal host, such infecti...

Mutants of bacteriophage T4D have been isolated whose phenotype differs from that of T4D + in two respects: (1) the plaque morphology of the mutants is distinguishable from that of T4D + , and (2) the mutants adsorb to bacterial cells at a concentration of polyethylene glycol restrictive for the adsorption of T4D + . These mutants are named CBW mutants. In addition, we received a mutant, T4D. wac , which possesses the phenotype of the CBW mutants. No conditions have been found which are restrictive for the growth of the mutants but permissive for growth of T4D + . The CBW mutants and T4D. wac have been mapped at eight recombinationally distinct sites. These eight loci map into three clusters within which the mutants are genetically linked. One mutant maps in gene 36. Two sites are found in gene 18. The remaining five mutants map at sites lying between the most C-terminal amber mutant mapped in gene 12 and the most N-terminal marker mapped in gene 13. Electron micrographs of the mutants indicate that the five mutants mapping between the terminal markers in genes 12 and 13 are missing the collar and whiskers seen on T4D + and on the mutants mapping in genes 18 and 36. SDS-polyacrylamide gel electrophoresis of labeled lysates of phage-infected cells shows that these mutants are missing a single, identical protein band, distinct from the protein products of genes 12 and 13. A band of the same molecular weight is missing from gels of purified phage of these five mutants. From this, and the genetic and physiological data, it is suggested that these four CBW mutants and T4D. wac map in a previously undefined gene. It is suggested that this gene is responsible for the presence of collar and whiskers on the phage particle. The gene is called wac (whisker antigen control).

Pneumocystis carinii pneumonia has rarely been reported in previously healthy persons over the age of 6 months. Five cases of P. carinii pneumonia in adult homosexual men, confirmed by biopsy results, are reported. All five patients were seropositive when tested for antibodies to cytomegalovirus and four had evidence of active concurrent cytomegalovirus infections. Kaposi's sarcoma was shown in two of the patients and one had possible Pneumocystis infection of the central nervous system as well as P. carinii pneumonia. Three patients had second episodes of Pneumocystis pneumonia. Four of the five patients have died. Past or concurrent cytomegalovirus infection and homosexuality were the only common epidemiologic features in all five patients.

Study objective To determine whether trisodium phosphonoformate (foscarnet) is efficacious in treating severe mucocutaneous disease due to acyclovir-resistant herpes simplex virus type-2 (HSV-2) infection in patients with the acquired immunodeficiency syndrome (AIDS). Design Open-labeled drug administration to patients with AIDS and severe ulcerative disease due to acyclovir-resistant HSV-2 infection. Setting Medical floors of acute care hospital. Patients Four patients with AIDS who developed progressive ulcerative mucocutaneous lesions of the genitals, perineum, perianal region, or finger due to acyclovir-resistant, thymidine-kinase (TK)-negative strains of HSV-2. Intervention Foscarnet, 60 mg/kg body weight intravenously every 8 hours (with reduced dosage for renal impairment), for 12 to 50 days. Measurement and main results All patients receiving foscarnet had dramatic improvement in their clinical findings with marked clearing of mucocutaneous lesions and eradication of HSV from mucosal surfaces. Conclusion Foscarnet may be an effective treatment for severe mucocutaneous disease due to acyclovir-resistant, TK-negative strains of HSV-2.