Tuberculosis in patients infected with the human immunodeficiency virus

A retrospective study of tuberculosis was undertaken among 125 patients infected with human immunodeficiency virus (HIV) who attended our regional infectious disease unit between 1986 and 1989. Nine TB-positive patients (five English, three Africans, one Indian) were identified. In three patients who presented with pyrexia of unknown origin and no objective evidence of any organ involvement, the diagnosis of TB was established from examination of sputum induced by nebulized hypertonic saline. Four other patients had extrapulmonary disease while another two had only pulmonary manifestations of TB. Chest radiographs from five patients were normal, while the other four showed cavities with consolidation, pleural effusion, miliary opacities and hilar enlargement, respectively. All but two mycobacterial isolates were fully sensitive to standard first-line chemotherapeutic drugs. Response to treatment was rapid and only complicated in one patient. There were no relapses following treatment without maintenance therapy after a mean follow-up of 22.2 months (range 9-48). Three patients died, of causes unrelated to TB. Tuberculosis may occur at any stage of HIV disease and is an important cause of fever in HIV-infected British patients, even when chest radiographs are normal and previous BCG vaccination has been performed.     

Pharmacokinetics and long-term tolerance to ribavirin in asymptomatic patients infected with human immunodeficiency virus.

Single-dose and steady-state pharmacokinetics of the antiviral agent ribavirin were studied in seven male, asymptomatic, human immunodeficiency virus-seropositive subjects. After a single 400 mg intravenous infusion, mean terminal plasma half-life (t1/2) was 27.1 hours, mean volume of distribution was 802 L, and mean total plasma clearance was 26.1 L/hr. Renal clearance was 39% of total clearance and it exceeded creatinine clearance. Oral bioavailability was 44.6%. With long-term dosing (400 mg orally twice a day) ribavirin accumulated, reaching steady state in 2 to 4 weeks in plasma and red blood cells. Red blood cell concentrations greatly exceeded plasma concentrations (60:1). Plasma concentrations at steady state (trough) were 10- to 14-fold higher than the corresponding single-dose concentrations. The terminal t1/2 (washout) after 16 weeks greatly exceeded the t1/2 observed after a single oral dose (151 versus 29.6 hours). Ribavirin-induced reductions in hemoglobin ranging from 0.8 to 3.5 gm/dl were well tolerated. There was no significant reduction in CD4 lymphocytes during treatment with ribavirin for 16 weeks in subjects who had more than 200 CD4 cells at entry and who also remained free of opportunistic infections during 24 weeks of observation.     

Population pharmacokinetics of indinavir in patients infected with human immunodeficiency virus

Indinavir is currently used at a fixed dose of 800 mg either three times a day or twice a day in combination with 100 mg of ritonavir. Dosage individualization based on plasma concentration monitoring might, however, be indicated. This study aimed to assess the pharmacokinetic profile of indinavir in patients infected with human immunodeficiency virus to characterize interpatient and intrapatient variability and to build up a Bayesian approach for dosage adaptation. A population analysis was performed with the NONMEM computer program with 569 plasma samples from a cohort of 239 unselected patients receiving indinavir. A one-compartment model with first-order absorption was adapted, and the influences of clinical characteristics on oral clearance (CL) and distribution volume (V) were examined. Predicted average drug exposure and trough and peak concentrations were derived for each patient and correlated with efficacy and toxicity markers. The population estimates of CL were 32.4 liters/h for female and 42.0 liters/h for male patients; oral V was 65.7 liters; and the rate constant of absorption (K(a)) was 1.0 h(-1). CL decreased by 63% with ritonavir intake and was moderately correlated to body weight. Both interpatient variability, best assigned to oral CL (coefficient of variation [CV], 39%) and K(a) (CV, 67%), and intrapatient variability were large (CV, 41%; standard deviation, 670 microg/liter). In conclusion, initial indinavir dosage should be decided according to ritonavir intake and sex, prior to plasma concentration measurements. The high interpatient pharmacokinetic variability represents an argument for therapeutic drug monitoring.     

Hypogammaglobulinemia in infants infected with human immunodeficiency virus

Two premature infants were infected with HIV via blood transfusions during the neonatal period. Although neither patient had serum antibody to HIV owing to severe hypogammaglobulinemia, HIV infection was confirmed by finding HIV antigen in the sera of both patients. These cases show that HIV infection can produce severe hypogammaglobulinemia, and illustrate the value of HIV antigen detection in the diagnosis of HIV infection in seronegative patients.     

Mucocutaneous abnormalities predicted by lymphocyte counts in patients infected with the human immunodeficiency virus.

Abnormalities of the skin are frequent and troubling problems for patients infected with the human immunodeficiency virus (HIV). A number of studies have assessed the frequency and severity of diseases of the skin and mucous membranes reported from other centers, but relationships between dermatologic signs and symptoms and either the lymphocyte count or the helper T-lymphocyte count have been infrequently noted. In a prospective study of 6 months' duration, one of us (A.F.) examined and questioned 61 HIV-seropositive patients at our infectious disease clinic. We found a significant association between the number and severity of cutaneous abnormalities and the helper T-cell (CD4) count. A trend toward significance was also shown between advanced HIV-disease status or decreased CD4 counts and pruritus. Our findings suggest that both the peripheral blood lymphocyte count and the helper T-cell count are predictive of the frequency, severity, and symptoms of skin diseases.     

Cerebral infarction associated with vasculitis due to varicella zoster virus in patients infected with the human immunodeficiency virus

Cases of herpes zoster ophtalmicus (HZO) with delayed contralateral hemiparesis caused by hemispheric stroke secondary to granulomatous angiitis have been reported and are a well-recognized complication of herpes zoster. Similar cases have been reported more recently during infection with human immunodeficiency virus (HIV). We describe two HIV+ patients without any clinical history of zoster dermatitis who developed a sudden hemiparesis followed 2 weeks later for one by an acute retinal necrosis. Computerized tomography (CT) scan, magnetic resonance imaging (MRI), magnetic resonance angiography (MRA). and digital subtraction angiography (DSA) were performed und showed a hemispheric stroke with evidence of a segmental arteritis of the carotid syphon. Varicella zoster virus (VZV) was found in the cerebro spinal fluid (CSF) in the two patients and after puncture of the vitreous fluid of the patient with the acute retinal necrosis. These two cases exemplify the difficulty of diagnosis of stroke in HIV+ patients, which seems to be more frequent than in similarly aged non-infected patients and demonstrates that VZV needs to be taken in consideration and identified even without any past history of zoster dermatitis.     

Ethics and practice in organ transplantation in patients infected with human immunodeficiency virus

In sum, much more needs to be known about the issue of transplantation in HIV-infected patients before the current state of extremely limited access to transplantation for these patients can be medically and ethically justified. Approaches to remedy this situation may include well-designed outcome studies; revision of existing local, regional, and national policies to better reflect the current state of knowledge; and education of clinicians, patients, and the public about this topic. Nurses can effect change in this area as informed clinicians, patients' advocates, researchers, and policy makers.     

Azole resistance in oropharyngeal Candida albicans strains isolated from patients infected with human immunodeficiency virus.

For 212 oropharyngeal isolates of Candida albicans, the fluconazole MICs for 50 and 90% of strains tested were 0.5 and 16 micrograms/ml, respectively, and those of itraconazole were 0.05 and 0.2 micrograms/ml, respectively. Of 16 isolates for which fluconazole MICs were > 64 micrograms/ml, itraconazole MICs for 14 were < or = 0.8 micrograms/ml and for 2 were > 6.4 micrograms/ml. Most fluconazole-resistant strains remained susceptible to itraconazole; whether itraconazole will prove effective for refractory thrush remains to be shown.     

Depressed activities of purine enzymes in lymphocytes of patients infected with human immunodeficiency virus

Enzyme activities were studied in peripheral blood lymphocytes from patients infected with, or at risk for, infection with human immunodeficiency virus (HIV). No significant differences were observed in the HIV-infected and HIV-seronegative high-risk patients with regard to enzyme activities of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) and purine nucleoside phosphorylase (EC 2.4.2.1) in peripheral blood. Adenosine deaminase (EC 3.5.4.4) was significantly (P less than 0.02) depressed in asymptomatic HIV-seropositive patients and HIV-seronegative patients at high risk of HIV infection as compared with a healthy HIV-seronegative population. Adenosine kinase (AK, EC 2.7.1.20) was significantly increased in the asymptomatic seropositive (P less than 0.02) and also in the HIV-seronegative high-risk groups (P = 0.01) compared with the normal controls. AK activity was significantly lower in subjects with AIDS than in the asymptomatic (P less than 0.002) and high-risk groups (P less than 0.01). Taken together, these results indicate that adenosine deaminase and AK activities are influenced by the health of the patient, and that measurement of AK activity may prove useful in monitoring the clinical progress of patients with HIV infection.     

Affinity of anti-GP41 antibody in patients infected with human immunodeficiency virus type I

Abstract. Anti-gp41 antibody affinity was investigated prospectively in 25 patients with asymptomatic and symptomatic HIV-1 infection for a period of 9–42 months. Major differences in the processs of immune response maturation towards gp41 were observed among individual subjects, however, antibody affinity increased with time in all examined persons including patients with AIDS. Anti-gp41 affinity values were found to reflect both the duration and the clinical stage of HIV infection     

Pharmacokinetics of zidovudine phosphorylation in peripheral blood mononuclear cells from patients infected with human immunodeficiency virus.

As part of an effort towards optimization of dosing of zidovudine (ZDV), formation and elimination of total phosphorylated ZDV (ZDVPt) in peripheral blood mononuclear cells were examined in 21 asymptomatic human immunodeficiency virus-infected patients during their first 24 weeks of therapy (AIDS Clinical Trials Group Protocol 161). Intracellular concentrations of ZDVPt were measured with a previously described and validated radioimmunoassay technique. Although ZDV phosphorylation occurred readily upon initiation of therapy, it declined with time; the area under the concentration-time curve (AUC) at week 4 (mean +/- standard deviation, 3.41 +/- 0.93 pmol.h/10(6) cells) was significantly greater than that at week 24 (2.19 +/- 1.10 pmol.h/10(6) cells). Plasma ZDV AUC did not change with time and did not correlate with ZDVPt AUC. In dose-response experiments (20 to 100 mg orally), phosphorylation did not proportionally increase with increasing plasma ZDV concentrations. Similarly, compared with a single dose, two doses of ZDV over an 8-h period resulted in little ZDVPt increase in cells relative to increase in plasma ZDV concentrations. The half-life of intracellular ZDVPt was twice that of plasma ZDV (4 versus 2 h), suggesting that an every-8-h dosing regimen is justifiable. These findings suggest that metabolism of ZDV to its active intracellular forms may be saturable in some patients, is poorly correlated with plasma concentrations, and diminishes over time. These findings have implications for future development and management of anti-human immunodeficiency virus nucleoside therapy.     

Absence of effect of trimethoprim-sulfamethoxazole on pharmacokinetics of zidovudine in patients infected with human immunodeficiency virus.

Pharmacokinetic parameters of zidovudine (ZDV) were not altered in 16 patients receiving concomitant therapy with ZDV and trimethoprim-sulfamethoxazole by oral administration. ZDV areas under the concentration-time curves were (means +/- standard deviations) 1.80 +/- 0.70 and 1.69 +/- 0.64 micrograms.h/ml in the absence and presence of trimethoprim-sulfamethoxazole, respectively. ZDV clearances were 1.57 +/- 0.61 and 1.74 +/- 0.66 liters/h/kg, respectively.     

Immunologic evaluation of persons infected with human immunodeficiency virus

Persons infected with HIV show changes in all aspects of immunity. Cellular immunity is affected most markedly, with decreased numbers of CD4+ (helper) and CD8+ (suppressor) T cells. Cellular immune function in vitro is frequently abnormal, as assessed by ability of T cells to proliferate in response to antigens or mitogens. Impaired humoral immunity is manifested in polyclonal B-cell activation and in impaired antibody responses to soluble antigens in vivo and in vitro. Numerous functional defects of macrophages have also been reported. The most valuable clinical laboratory tests for evaluation of the immune status of the HIV-infected individual are enumeration of circulating CD4+ and CD8+ cells and quantitation of circulating immunoglobulins. The results of these tests can help differentiate the immunosuppression caused by HIV from other causes of immunodeficiency. Helper T-cell counts are also important for selecting appropriate treatment regimens. Combinations of the results of these tests with those of virus culture or antigen detection assays provide additional prognostic information. Future research may help us recognize other patterns of immunodeficiency with specific clinical implications. It is hoped that new therapies, both antiviral and immune reconstitutive, will soon become available; at such time immunologic testing will be able to chart the return to normal immune function.     

In vitro and in vivo characterization of herpes simplex virus clinical isolates recovered from patients infected with human immunodeficiency virus.

A total of 100 herpes simplex viruses isolated from lesions not responding to acyclovir (ACV) therapy were recovered from 51 patients infected with human immunodeficiency virus. In vitro analysis of these isolates included testing their susceptibility to ACV and determining their thymidine kinase (TK) phenotypes. Of the 100 isolates evaluated, 23 were ACV sensitive and 77 were ACV resistant. Seventy-four of these ACV-resistant isolates were of the TK-deficient or low-TK-producer phenotype and three were of the TK-altered phenotype. The TKs isolates that represented each of the different autoradiographic phenotypes were further characterized by enzyme kinetics. The ability of selected isolates to cause disease in vivo was evaluated by using several mouse virulence models. Cutaneous virulence in normal and immunocompromised mice was evaluated, and neurovirulence in normal mice was determined. Latent infections were assayed by the cocultivation of trigeminal ganglia recovered from mice that had survived acute infection. These reactivated viruses were evaluated in vitro and compared with the original infecting isolate. The mechanisms of resistance and pathogenicity of these herpes simplex virus isolates recovered from patients positive for human immunodeficiency virus are similar to those reported for isolates recovered from normal and immunocompromised patients without AIDS.     

Evaluation of the in vivo effect of naproxen on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus.

OBJECTIVE: To determine if therapeutic doses of naproxen affect the in vivo disposition of zidovudine. METHODS: This was designed as a randomized, two-period, two-treatment, crossover study. The patients were 12 men infected with human immunodeficiency virus who had acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. On two separate occasions 14 days apart, patients received either zidovudine alone (200 mg every 4 hours while awake) or zidovudine (200 mg every 4 hours while awake) and naproxen (500 mg every 12 hours for 4 days). On the morning of the fifth day, each patient received the final dose of each regimen and blood and urine were serially collected for 8 hours. Pharmacokinetic parameters (area under the serum concentration-time curve [AUC], maximum plasma concentration, terminal half-life, renal clearance, and urinary recovery) were assessed for zidovudine and its glucuronide metabolite. MAIN RESULTS: Naproxen had no significant effect (< 10% difference between treatment means, p > 0.15, ANOVA) on the above pharmacokinetic parameters for both zidovudine and its metabolite. Although the power of the study to detect these small differences was < 80% at the 5% significance level, differences ranging from 12.6% for AUC to 38.8% for urinary recovery could be detected with 80% power. CONCLUSION: Therapeutic doses of naproxen do not significantly affect the pharmacokinetic disposition of zidovudine.     

Antibodies to Epstein-Barr virus in patients with chronic fatigue.

To clarify the role of Epstein-Barr virus (EBV) infection and the value of EBV antibody testing in evaluating patients with chronic fatigue, we studied 200 consecutive patients with chronic fatigue (mean duration, 9 years). Complete EBV serologic panels were obtained for 154 patients, 35 (23%) of whom met serologic or clinical criteria for chronic or reactivated EBV infection. We compared these patients with chronic EBV infection (CEBV cases) to 35 age- and sex-matched patients who were selected from the same cohort of fatigued patients but who did not meet the criteria (CEBV control subjects). We found few differences between groups in demographic characteristics, clinical features, and symptoms; CEBV cases were more likely to meet criteria for the proposed chronic fatigue syndrome (14% vs 0%), and to report that they suffered from an influenza-like illness at the onset of their fatigue syndrome (34% vs 12%), that they lost their job because of their fatigue (37% vs 11%), and that their fatigue was improved by recreational activity (26% vs 3%). Physical examination and laboratory testing showed few abnormalities in either group. Psychiatric morbidity was common in both groups, including mood disorders (63% of CEBV cases vs 54% of CEBV controls), anxiety (11% vs 9%) and somatization disorder (9% in each group). We conclude that EBV serologic patterns have little clinical usefulness in evaluating patients with chronic fatigue.