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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.

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

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.

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.

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.

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.