Evolution of mutations conferring multidrug resistance during prophylaxis and therapy for cytomegalovirus disease.

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.

An economic evaluation of oral compared with intravenous ganciclovir for maintenance treatment of newly diagnosed cytomegalovirus retinitis in AIDS patients.

This prospective, clinical economic study was done to determine the cost impact of oral compared with intravenous (i.v.) 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 i.v. 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 i.v. ganciclovir and 57 days for oral ganciclovir (a nonsignificant difference). he expected mean cost of treatment for i.v. 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 i.v. 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.

The dying process.

AIDS: People with HIV/AIDS progress through four categories, or stages, of the dying process. These categories are: the psychic process of accepting death, which usually follows HIV diagnosis; the sociologic dying process, which involves withdrawal from people and activities; the biological dying process, which involves those characteristics that constitute being human, such as personality; and the physiologic dying process, which represents the failure of the body's organs. The process of dying may be influenced by social stigma, fear, and memories of the deaths of friends. By introducing the categories of dying, health care providers can help patients recognize the difference between living with HIV and dying from it. Four misconceptions about the dying process are noted. Many dying patients do not have severe pain, and those that do may respond to pain management. People with HIV do not starve to death; conversely, the weight loss ultimately results from the dying process. Dehydration is not painful, rather, it allows the body to slip more peacefully into a metabolic coma. Finally, talking about death with the patient should not be avoided. Medical therapy should include as much comfort as possible for the patient.^ieng

Activation of virus replication after vaccination of HIV-1-infected individuals.

Little is known about the factors that govern the level of HIV-1 replication in infected individuals. Recent studies (using potent antiviral drugs) of the kinetics of HIV-1 replication in vivo have demonstrated that steady-state levels of viremia are sustained by continuous rounds of de novo infection and the associated rapid turnover of CD4+ T lymphocytes. However, no information is available concerning the biologic variables that determine the size of the pool of T cells that are susceptible to virus infection or the amount of virus produced from infected cells. Furthermore, it is not known whether all CD4+ T lymphocytes are equally susceptible to HIV-1 infection at a given time or whether the infection is focused on cells of a particular state of activation or antigenic specificity. Although HIV-1 replication in culture is known to be greatly facilitated by T cell activation, the ability of specific antigenic stimulation to augment HIV-1 replication in vivo has not been studied. We sought to determine whether vaccination of HIV-1-infected adults leads to activation of virus replication and the targeting of vaccine antigen-responsive T cells for virus infection and destruction. Should T cell activation resulting from exposure to environmental antigens prove to be an important determinant of the steady-state levels of HIV-1 replication in vivo and lead to the preferential loss of specific populations of CD4+ T lymphocytes, it would have significant implications for our understanding of and therapeutic strategies for HIV-1 disease. To begin to address these issues, HIV-1-infected individuals and uninfected controls were studied by measurement of immune responses to influenza antigens and quantitation of virion-associated plasma HIV-1 RNA levels at baseline and at intervals after immunization with the trivalent influenza vaccine. Influenza vaccination resulted in readily demonstrable but transient increases in plasma HIV-1 RNA levels, indicative of activation of viral replication, in HIV-1-infected individuals with preserved ability to immunologically respond to vaccine antigens. Activation of HIV-1 replication by vaccination was more often seen and of greater magnitude in individuals who displayed a T cell proliferative response to vaccine antigens at baseline and in those who mounted a significant serologic response after vaccination. The fold increase in viremia, as well as the rates of increase of HIV-1 in plasma after vaccination and rates of viral decline after peak viremia, were higher in individuals with higher CD4+ T cell counts.(ABSTRACT TRUNCATED AT 400 WORDS)

Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. Syntex Cooperative Oral Ganciclovir Study 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; photographs were ungradable for 2 of the 117. On the basis of the masked assessment of photographs from 115 subjects, the mean time to the progression of retinitis was 62 days in those given intravenous ganciclovir and 57 days in those given oral ganciclovir (P = 0.63; relative risk [oral vs. intravenous], 1.08; 95 percent confidence interval for the difference in means, -22 to +12 days). On the basis of funduscopy by ophthalmologists who were aware of the subjects' treatment assignments, the mean time to progression was 96 days in subjects given intravenous ganciclovir and 68 days in subjects given oral ganciclovir (P = 0.03; relative risk [oral vs. intravenous], 1.68; 95 percent confidence interval for the difference in means, -45 to -11 days). Survival, changes in visual acuity, the incidence of viral shedding, and the incidence of adverse gastrointestinal events were similar in the two groups. Neutropenia, anemia, intravenous-catheter-related adverse events, and sepsis were more common in the group given intravenous ganciclovir. CONCLUSIONS: Oral ganciclovir is safe and effective as maintenance therapy for cytomegalovirus retinitis and is more convenient for patients to take than intravenous ganciclovir.

Prosthetic joint infection due to Mycobacterium tuberculosis: report of three cases.

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.

Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Atovaquone Study Group.

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 carinii pneumonia in patients with the acquired immunodeficiency syndrome and to detect differences in the toxicity rates of the two treatments. DESIGN: Patients were randomly assigned to receive 21 days of open-label therapy with either atovaquone, 750 mg orally with meals three times daily, or intravenous pentamidine, 3 to 4 mg per kg body weight once daily. SETTING: Multicenter study including university and community treatment facilities. PATIENTS: Patients with human immunodeficiency virus infection and clinical presentations consistent with mild or moderate P. carinii pneumonia were eligible. For efficacy and safety analyses, patients with histologically confirmed P. carinii pneumonia were emphasized. MEASUREMENTS: Patients were monitored by clinical and laboratory evaluations for therapeutic efficacy and adverse events during the acute treatment phase and for 8 weeks after therapy was discontinued. RESULTS: As initial therapy for a histologically confirmed episode of P. carinii pneumonia, 56 patients received atovaquone and 53 received pentamidine. More patients were successfully treated with atovaquone (57%) than with pentamidine (40%), a difference of 17% (95% CI, -3% to 38%; P = 0.085), but more patients failed to respond to atovaquone (29%) than to pentamidine (17%), a difference of 12% (CI, -6% to 29%; P = 0.18). Discontinuation of original therapy because of treatment-limiting adverse events was more frequent in the pentamidine group (36%) than in the atovaquone group (4%) (difference, -32%; CI, -48% to -17%; P < 0.001). Nine patients in each treatment group died during the study. CONCLUSIONS: Oral atovaquone and intravenous pentamidine have similar rates for successful treatment of mild and moderate P. carinii pneumonia, but atovaquone has significantly fewer treatment-limiting adverse events.

Ulcerative and plaque-like tracheobronchitis due to infection with Aspergillus in patients with AIDS.

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.

Zalcitabine compared with zidovudine in patients with advanced HIV-1 infection who received previous zidovudine therapy.

OBJECTIVE: To evaluate the safety and efficacy of zalcitabine (also known as dideoxycytidine [ddC]) in patients with advanced human immunodeficiency virus (HIV) infection. DESIGN: Open-label, randomized study. SETTING: AIDS Clinical Trials Units, university-affiliated medical centers, and private practice groups. PATIENTS: Patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex who had tolerated zidovudine for 48 weeks or more. INTERVENTION: Fifty-nine patients received zidovudine (500 to 1200 mg/d) and 52 patients received zalcitabine (2.25 mg/d). MEASUREMENTS: The primary end points were survival and time to an AIDS-defining event or death. RESULTS: 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. CONCLUSIONS: 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.

A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group.

BACKGROUND: After primary treatment for cryptococcal meningitis, patients with the acquired immunodeficiency syndrome (AIDS) require some form of continued suppressive therapy to prevent relapse. METHODS: We conducted a multicenter, randomized trial that compared fluconazole (200 mg per day given orally) with amphotericin B (1 mg per kilogram of body weight per week given intravenously) in patients with AIDS who had completed primary therapy for cryptococcal meningitis with amphotericin B (greater than or equal to 15 mg per kilogram). To be eligible, patients had to have at least two negative cultures of cerebrospinal fluid immediately before randomization. The primary end point was relapse of cryptococcal disease as confirmed by biopsy or culture. RESULTS: Of 218 patients initially enrolled, 119 were assigned to fluconazole and 99 to amphotericin B. Twenty-three patients were found not to have met the entry criteria; six other patients assigned to amphotericin B did not receive it and were lost to follow-up. Of the remaining 189 patients, after a median follow-up of 286 days 14 of 78 receiving amphotericin B (18 percent) and 2 of 111 assigned to fluconazole (2 percent) had relapses of symptomatic cryptococcal disease (P less than 0.001 by Fisher's exact test). There was a difference of 19 percent in the estimated probability of remaining relapse-free at one year between the fluconazole group (97 percent) and the amphotericin B group (78 percent) (95 percent confidence interval, 7 percent to 31 percent; P less than 0.001). Serious drug-related toxicity was more frequent in the amphotericin B group (P = 0.02), as were bacterial infections (P = 0.004) and bacteremia (P = 0.002). CONCLUSIONS: Fluconazole taken by mouth is superior to weekly intravenous therapy with amphotericin B to prevent relapse in patients with AIDS-associated cryptococcal meningitis after primary treatment with amphotericin B.

Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection.

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.

Pulmonary aspergillosis in the acquired immunodeficiency syndrome.

BACKGROUND AND METHODS: 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. RESULTS: 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). CONCLUSIONS: Pulmonary aspergillosis is a possible late complication of AIDS; if diagnosed early, it may be treated successfully.

Foscarnet therapy for severe acyclovir-resistant herpes simplex virus type-2 infections in patients with the acquired immunodeficiency syndrome (AIDS). An uncontrolled trial.

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.

An outbreak of Pneumocystis carinii pneumonia in homosexual men.

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.