Pharmacokinetics of stavudine in patients with AIDS or AIDS-related complex.

The pharmacokinetics of stavudine (d4T; 2',3'-didehydro-3'-deoxythymidine) were studied in patients with AIDS-related complex or AIDS enrolled in a dose-ranging phase I/II study. Twenty-two patients were studied after the first oral dose of 0.67, 1.33, 2.67, or 4 mg/kg of body weight; 17 of them underwent an additional steady-state pharmacokinetic evaluation after thrice-daily dosing of the above doses. Stavudine absorption was rapid, with mean peak concentrations of 1.2-4.2 mg/L over the four dose levels studied. From 34% to 41% of an oral dose was excreted as unchanged drug in the urine. The mean values for plasma elimination half-life ranged from 1 to 1.6 h. The absolute bioavailability of a 4 mg/kg oral dose exceeded 80%. There was no change in pharmacokinetic parameters measured after the first dose and after chronic dosing. Stavudine is a new dideoxynucleoside with more complete and less variable oral absorption than existing nucleosides used for treatment of human immunodeficiency virus infection.     

Impaired neutrophil function in patients with AIDS or AIDS-related complex: a comprehensive evaluation

We measured the neutrophil function of 6 patients with AIDS and Kaposi's sarcoma (KS); 22 patients with AIDS-related complex (ARC); and 28 healthy, heterosexual controls. Neutrophils from patients with ARC showed significantly less chemotaxis (P less than or equal to .025) than did those from patients with AIDS and KS or from controls. Serum from patients with AIDS and KS or with ARC significantly (P less than or equal to .05) inhibited chemotaxis of neutrophils from controls; heat treatment of the serum abolished this inhibitory effect. Bacterial killing by neutrophils from patients with AIDS and KS or with ARC was also significantly (P less than or equal to .05) less than for neutrophils from controls, as was neutrophil phagocytosis binding of Candida albicans (P less than or equal to .05). Expression of OKM1 antigen was increased in the patients studied. Enzyme degranulation, adherence, and aggregation were also examined. The defects found in neutrophil function are selective and may be important in the increased susceptibility of patients with human immunodeficiency virus infection to bacterial and fungal infections.     

Fungal infections in patients with AIDS and AIDS-related complex

Persons with AIDS are predisposed to a variety of previously rare bacterial and fungal infections. Improvement in the quality and duration of survival of AIDS patients depends on the efficacy of treatment for these infections. Between 58-81% of AIDS patients contract fungal infections at some time, and 10-20% of AIDS patients die as a direct consequence of such infections. Oral candidiasis, commonly known as thrush, is the most common fungal infection among AIDS and AIDS Related Complex patients, occurring in 80-90% of cases. In a recent U.S. study, 59% of persons with oral candidiasis who were at high risk of contracting AIDS went on to develop Kaposi's sarcoma and other life- threatening infections. The most common life-threatening fungal infection experienced by AIDS patients is cryptococcosis, a disease occurring among 6% of American AIDS patients and having a mortality rate of 17% during initial infections and 75-100% on relapse. Other opportunistic infections associated with AIDS and AIDS Related Complex are bronchial candidiasis, invasive aspergillosis, disseminated histoplasmosis, and disseminated coccidioidomycosis. All are treatable but eradication i s difficult and relapse common.     

Pseudomonas infections in patients with AIDS and AIDS-related complex.

We identified and reviewed retrospectively all the cases of infection by Pseudomonas and related genera in patients with AIDS and AIDS-related complex (ARC) who were hospitalized at our Institution over a 36-month period. We recorded 48 episodes of infection in 34 of 355 patients with AIDS, and in two of 73 patients with ARC: 25 pneumonias (9 community-acquired and 16 of nosocomial origin). 20 urinary tract infections, two soft tissue infections and one sepsis. In 14 of 16 patients with nosocomial pneumonia but in only one of nine patients with community-acquired pneumonia did we find coexisting opportunistic lung diseases. The following micro-organisms were isolated: P. aeruginosa in 41 cases, P. fluorescens in three cases, Xanthomonas maltophilia (P. maltophilia) in two cases, P. putida in one case. Comamonas testosteronis (P. testosteronis) and Comamonas acidovorans (P. acidovorans) in one case. Amikacin and ceftazidime, alone or in combination, appear to be the optimal choice of therapy for severe Pseudomonas infections in HIV-infected patients, although in our study six of 47 isolates were resistant in vitro to amikacin, and nine of 31 isolates were resistant to ceftazidime.     

Immunoglobulin G subclass deficiency and susceptibility to pyogenic infections in patients with AIDS-related complex and AIDS

Total immunoglobulin (Ig) and IgG subclass levels were measured in 72 patients with AIDS or AIDS-related complex (ARC). IgG2 subclass levels were found to be significantly decreased in the AIDS/ARC patients with pyogenic infections compared with both similar individuals without bacterial disease and the HIV-negative control group.     

Changes in neuropsychological performance of AIDS-related complex patients who progress to AIDS.

OBJECTIVE: To investigate the changes in neuropsychological performance associated with progression from AIDS-related complex (ARC) to AIDS. DESIGN: A repeated measures design was used to compare three groups: ARC patients who progressed to AIDS (n = 15), those who did not (n = 19) and seronegative controls (n = 16). METHODS: The three groups were compared on tests of memory, information processing, motor performance, attention and conceptual flexibility. Clinical and immunological characteristics were recorded. Rates of neuropsychological impairment among the three groups were calculated and compared. RESULTS: The only significant difference between the groups at baseline was for one measure of motor performance. Repeated measures analysis indicated that there was a differential rate of change for the three subject groups for tasks of motor performance and attention. ARC patients who progressed to AIDS did not differ significantly from the non-progressors, although both groups showed significant deterioration over time compared with seronegative controls. Although there was a tendency for the progressors to have a higher rate of impairment, there were no consistent significant differences between visits. CONCLUSION: There were no significant changes in performance exclusively associated with progression to AIDS.     

The effect of treatment with zidovudine with or without acyclovir on HIV p24 antigenaemia in patients with AIDS or AIDS-related complex.

OBJECTIVE: To evaluate changes in serum HIV p24-antigen levels in a subset of patients who participated in a European/Australian double-blind, placebo-controlled trial evaluating the efficacy of zidovudine (250 mg every 6 h) alone or in combination with acyclovir (800 mg every 6 h) in patients with AIDS, AIDS-related complex (ARC) or Kaposi's sarcoma (KS). DESIGN: Double-blind, placebo-controlled randomized clinical trial of less than or equal to 6 months' therapy. SETTING: Samples were obtained from patients attending teaching hospital outpatient clinics in seven European countries and Australia. SUBJECTS: One hundred and ninety-seven HIV-infected patients (60 with AIDS and 137 with ARC or KS). MAIN OUTCOME MEASURES: Serum HIV p24-antigen levels measured using the Abbott HIV solid-phase enzyme immunoassay. RESULTS: Of 76 ARC/KS patients who were initially HIV p24-antigen-positive, one out of 25 randomized to placebo, eight out of 23 to zidovudine and 11 out of 28 to the zidovudine/acyclovir combination became antigen-negative. The proportion of patients who became antigen-negative was significantly higher in both the zidovudine group (P = 0.016) and the zidovudine/acyclovir group (P = 0.004), compared with the placebo group. There were no statistical differences between the zidovudine and the zidovudine/acyclovir groups. During the trial p24-antigen levels in the zidovudine-treated patients reached their minimum after 4-8 weeks of therapy, and tended to increase gradually thereafter. Disease progression occurred irrespective of whether p24-antigen levels declined during therapy. No association between p24-antigen responses to therapy and baseline disease stage, Karnofsky score or baseline CD4 cell count was detectable. CONCLUSION: Acyclovir does not potentiate the effect of zidovudine on p24-antigen levels. Change in antigen level in response to antiviral therapy needs further investigation before it is used as a surrogate marker for clinical efficacy of antiviral therapy.     

Enhanced serological and virological findings of Epstein-Barr virus in patients with AIDS and AIDS-related complex

The potential involvement of Epstein-Barr virus (EBV) in AIDS was examined by determining the type of EBV-specific antibody responses and the EBV content or lymphoproliferative ability present in selected body fluids of patients with AIDS or AIDS-related complex. The results were compared with two control groups. An enhanced antibody response to a broad spectrum of EBV antigens was found in patients with AIDS or AIDS-related complex. The pattern of virus-specific antibody responses resembled that associated with a persistent or reactivated infection. The content of EBV in oropharyngeal secretions and the lymphoproliferative ability in peripheral blood from patients with AIDS or AIDS-related complex was significantly greater than that from healthy controls and approached levels detected in the control group with infectious mononucleosis. These findings, together with recent reports of cellular-level interaction between EBV and human T lymphotropic virus type III, suggest that EBV may have a contributory role in these disorders.     

Once-weekly fluconazole to prevent recurrence of oropharyngeal candidiasis in patients with AIDS and AIDS-related complex: a double-blind placebo-controlled study

Fluconazole 50 mg daily for 14-28 days was effective in the treatment of patients with AIDS and AIDS-related complex with severe oropharyngeal and oesophageal candidiasis. Of 24 patients entered, 17 (81%), including seven with oesophageal candidiasis, were clinically cured and two (9.5%) improved at the end of treatment. Following clinical cure, 14 patients were entered into the double-blind phase of the study, where fluconazole (150 mg) or placebo capsules were given once weekly. Treatment was double blind. Fluconazole 150 mg once weekly was found to be effective in maintaining patients both clinically and mycologically free of oropharyngeal candidiasis.     

Zidovudine improves response to pneumococcal vaccine among persons with AIDS and AIDS-related complex

Antibody responses to 23-valent pneumococcal vaccine were studied in 38 individuals infected with human immunodeficiency virus (HIV), including 6 with asymptomatic infection, 24 with AIDS or AIDS-related complex (ARC) receiving treatment with zidovudine, and 8 untreated AIDS/ARC patients. Antibody responses were significantly higher for asymptomatic persons (aggregate geometric mean, 972 ng of antibody nitrogen (AbN)/ml; P less than .001) and AIDS/ARC patients receiving a median of 12 weeks (range, 4-54) of zidovudine therapy (mean, 369 ng of AbN/ml; P less than .001) when compared with untreated AIDS/ARC patients. Antibody responses among zidovudine-treated AIDS/ARC patients were independent of the dose (mean, 629.2 mg/day; range, 100-1200 mg) or duration of zidovudine therapy. For zidovudine-treated AIDS/ARC patients, persistence of an aggregate antibody response 8 months after vaccination was associated with survival at 14 months after vaccination, whereas waning of response was not. Pneumococcal vaccine should be administered as early as possible in the course of HIV infection. Immunization should be delayed for at least 4 weeks for AIDS/ARC patients initiating zidovudine therapy.     

Phase I study of 2'-3'-dideoxyinosine administered orally twice daily to patients with AIDS or AIDS-related complex and hematologic intolerance to zidovudine.

PURPOSE: To evaluate the safety and hematologic tolerance of 2'-3'-dideoxyinosine (didanosine, ddI) in subjects with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and prior hematologic intolerance to zidovudine. PATIENTS AND METHODS: A Phase I trial with two dose groups at a single-center, university-affiliated hospital ambulatory care center. Of 30 subjects enrolled, 21 had AIDS and nine had AIDS-related complex. All had CD4 lymphocyte counts less than 0.2 x 10(9)/L at entry. Didanosine was administered orally twice daily at a total daily dose of 750 mg or 1,500 mg for 12 weeks. Subjects who completed the 12-week study continued to receive ddI at the lower dose. All subjects were monitored for toxicity. Virologic and immunologic response markers were also measured. RESULTS: For the group as a whole, there was no significant decrease in mean hemoglobin level or leukocyte or platelet counts. The dose-limiting toxicity was peripheral neuropathy. Other significant toxicities included pancreatitis and hypocalcemia. Uric acid elevations were common but were without clinical consequence. A sustained decrease in serum p24 antigen of at least 50% was noted in 42% of subjects who were p24 antigen-positive at entry. The mean CD4 lymphocyte count showed an initial increase that was not sustained over the 12-week study. All subjects remained anergic to skin testing. CONCLUSIONS: Didanosine is well tolerated hematologically in some patients with prior significant hematologic intolerance to zidovudine. The toxicity profile for ddI differs from that of zidovudine and includes peripheral neuropathy and pancreatitis. Changes in CD4 lymphocyte number and HIV p24 antigen levels in some patients suggest antiviral activity of ddI in this population.     

Progression of diffuse esophageal spasm to achalasia: incidence and predictive factors

The progression of certain primary esophageal motor disorders to achalasia has been documented; however, the true incidence of this decay is still elusive. This study aims to evaluate: (i) the incidence of the progression of diffuse esophageal spasm to achalasia, and (ii) predictive factors to this progression. Thirty‐five patients (mean age 53 years, 80% females) with a manometric picture of diffuse esophageal spasm were followed for at least 1 year. Patients with gastroesophageal reflux disease confirmed by pH monitoring or systemic diseases that may affect esophageal motility were excluded. Esophageal manometry was repeated in all patients. Five (14%) of the patients progressed to achalasia at a mean follow‐up of 2.1 (range 1–4) years. Demographic characteristics were not predictive of transition to achalasia, while dysphagia (P= 0.005) as the main symptom and the wave amplitude of simultaneous waves less than 50 mmHg (P= 0.003) were statistically significant. In conclusion, the transition of diffuse esophageal spasm to achalasia is not frequent at a 2‐year follow‐up. Dysphagia and simultaneous waves with low amplitude are predictive factors for this degeneration.     

Enhancement of erythrocytic adenosine deaminase following treatment of AIDS-related complex/AIDS patients with zidovudine

The levels of adenosine deaminase (ADA) were determined in the erythrocytes of 10 patients with sexually transmitted HIV-1 infection [five cases with AIDS-related complex (ARC) and five with AIDS] before and after therapy with zidovudine (azidothymidine; AZT). A linear increase in ADA activity was observed during the second and third months of zidovudine treatment, with a final increase of about threefold after 3 months of drug administration. The concentration of adenosine triphosphate (ATP) was significantly lower in the erythrocytes of the same group of patients with respect to healthy controls, and a further decrease was noted after 3 months of zidovudine treatment. The results obtained indicate that treatment of ARC/AIDS subjects with zidovudine induces metabolic changes which could be responsible for the development of anaemia, an adverse effect frequently associated with zidovudine therapy.     

Echocardiographic findings in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC)

Although a variety of cardiac abnormalities have been described in AIDS patients, it is unclear whether these are incidental findings or they presage clinically important heart disease. Also, because AIDS-related complex (ARC) is, in general, a milder form of AIDS, we wondered if echocardiographic abnormalities would differ in kind or in frequency, when compared with AIDS. To answer these questions, we studied the echocardiographic findings and the demographic features of 15 patients with AIDS and 24 patients with ARC. The ARC group had abnormalities in the same proportion as in our AIDS group, except for echocardiographic mitral valve prolapse. The MVP, however, did not appear to be due to intrinsic valvular disease. Rather, echocardiographic MVP was associated with low body weight (P = .02) but not with the cardiac signs or symptoms of MVP. Four AIDS patients had LV dysfunction. Of the echocardiographic variables, only a wide EPSS was significantly correlated with survival, as it is in other populations. We conclude that although echocardiographic abnormalities are common in AIDS and ARC patients, most of these abnormalities lack clinical significance.