Synergy, activity and tolerability of zidovudine and interferon-alpha in patients with symptomatic HIV-1 infection: AIDS Clincal Trial Group 068.

Thirty-four subjects with symptomatic HIV-1 infection, p24 antigenaemia, and CD4 cell counts > 200/mm3 were randomly assigned to receive treatment with either zidovudine (ZDV) orally, interferon-alpha (IFN-alpha) subcutaneously, or both at respective low (200 mg ZDV/ 2 million international units IFN-alpha (MIU)), middle (400 mg/4 MIU) or high (600 mg/6 MIU) daily dose levels for 12 weeks. Thereafter, all patients received combination therapy at the initially assigned dose level to a total of 96 weeks. This design permitted analysis by the combination index (CI) method, which demonstrated antiretroviral synergy between ZDV and IFN-alpha with respect to p24 antigen suppression. Over the first 12 weeks, combination therapy was acceptably tolerated, more so than IFN-alpha monotherapy, and it was significantly more active in suppressing antigenaemia than either of the monotherapies. Similarly, the high-dose combination was the most active dose level over weeks 12 to 96. Combination ZDV/IFN-alpha at the optimal dose level defined by this trial merits further study. In addition, the CI design strategy employed here may be useful for the investigation of new antiretroviral combinations.

Concentration-targeted phase I trials of atevirdine mesylate in patients with HIV infection: dosage requirements and pharmacokinetic studies. The ACTG 187 and 199 study teams.

RATIONALE: To determine the dosage requirements and pharmacokinetics of atevirdine, a non-nucleoside reverse transcriptase inhibitor and its N-dealkylated metabolite (N-ATV) during phase I studies in patients receiving atevirdine alone or in combination with zidovudine. DESIGN: Two open label, phase I studies conducted by the adult AIDS Clinical Trials Group (ACTG) in which atevirdine was administered every 8 h with weekly dosage adjustments to attain targeted trough plasma atevirdine concentrations. SETTING: Five Adult AIDS Clinical Trials Units. PATIENTS: Fifty patients (ACTG 199; n = 20 and ACTG 187; n = 30) with HIV-1 infection and < or =500 CD4+ lymphocytes/mm3. INTERVENTION: ACTG 199; 12 weeks of therapy with atevirdine (dose-adjusted to achieve plasma trough atevirdine concentrations of 5-10 microM) and zidovudine (200 mg every 8 h). ACTG 187: 12 weeks of atevirdine monotherapy with atevirdine doses adjusted to achieve escalating, targeted trough plasma concentration ranges (5-13, 14-22, and 23-31 microM). MEASUREMENTS: ACTG 199: atevirdine, N-ATV and zidovudine trough determinations weekly (all patients) and intensive pharmacokinetics (selected patients) prior to and at 6 and 12 weeks during combination therapy. ACTG 187: atevirdine and N-ATV trough concentrations over a 12 week period. Intensive pharmacokinetic studies were conducted prior to and at 4 and/or 8 weeks during atevirdine monotherapy in female patients. RESULTS: Atevirdine plasma concentrations demonstrated considerable interpatient variability which was minimized by the adjustment of maintenance doses (range: 600-3900 mg/day) to achieve the desired trough concentrations. In ACTG 187, the mean number of weeks to attain the target value, and the percentage of patients who attained the target, was group I (5-11 microM): 2.7+/-2.4 weeks (92%); group II (12-21 microM): 2.6+/-1.8 (64%); and group III (22-31 microM): 7.0+/-5.6 weeks (27%). In ACTG 199 it was 3.2+/-5.2 weeks (95%) to achieve a 5-10 microM trough. Atevirdine demonstrated a mono- or bi-exponential decline among most of the patients studied after the first dose. During multiple-dosing a number of patterns of atevirdine disposition were observed including; rapid absorption with Cmax at 0.5-1 h, delayed absorption with Cmax at 3-4 h; minimal Cmax to Cmin fluctuation and Cmax to Cmin ratios of > 4. N-ATV (an inactive metabolite) patterns were characterized on day one by rapid appearance of the metabolite which peaked at 2-3 h after the dose and declined in a mono- or bi-exponential manner. At steady-state N-ATV patterns demonstrated minimal Cmax to Cmin fluctuations with some of the patients having more stable plasma N-ATV concentrations, while others had greater fluctuations week to week. CONCLUSIONS: Considerable interpatient variability was noted in the pharmacokinetics of atevirdine. The variation in drug disposition was reflected in the range of daily doses required to attain the targeted trough concentrations. Atevirdine metabolism did not appear to reach saturation during chronic dosing in many of our patients, as reflected by the pattern of N-ATV/ATV ratios in plasma and saturation was not an explanation for the variation in dosing requirements. No apparent differences were noted between males and females, and atevirdine did not appear to influence zidovudine disposition.

Imbalance of tissue-type plasminogen activator (t-PA) and its specific inhibitor (PAI-1) in patients with rheumatoid arthritis associated with disease activity.

The relationship between plasma fibrinogen, D-dimer (DD), t-PA and PAI-1 and their correlation with disease activity (DA) were studied in 45 patients with rheumatoid arthritis (RA) (group B) to further understand the implication of fibrinolysis in the pathophysiology of RA. The control group constituted 24 healthy subjects (group A). A Stoke index (SI) of DA was assigned to each patient. Patients were divided into two groups: C, minimal-mild DA (SI 1-7); D, moderate-severe DA (SI 8-17). Fibrinogen was elevated in RA correlating positively with SI and CRP. Hypercoagulability counteracted by reactive fibrinolysis was inferred from a 10-fold increase of DD in group B as compared to group A. The relatively lower levels of DD in group D compared to group C and their negative correlation with SI (r(s) = -0.49, p = 0.0006) indicate the tendency of fibrinolysis to decrease with the increase of DA. Significant elevation of t-PA and PAI-1 were found in group B compared to group A. While t-PA progressively decreased with the increase of DA (r(s) = -0.45, p = 0.0019), a positive relation of PAI-1 to DA was observed (r = 0.42, p = 0.0042). A 2-fold increase of PAI-1/t-PA molar ratio in group D compared to groups A and C as well as its positive correlation with SI (r(s) = 0.63, p = 0.0001) indicate the displacement of balance between t-PA and PAI-1 in favour of the inhibitor with the increase of DA in RA. The involvement of inflammatory mediators in PAI-1/t-PA imbalance was proposed from the relation of fibrinolytic abnormalities with the activity of systemic inflammatory process.

Energy intake and monounsaturated fat in relation to bone mineral density among women and men in Greece.

BACKGROUND: Several variables have been established as risk factors for osteoporosis: it is more common among women and the gender difference increases with age and with years since menopause. Estrogens, androgens, physical activity, and body mass index have been previously shown to be positively associated with bone mineral density and inversely with risk for fractures. METHODS: To assess the effect on bone mineral content of energy-generating nutrients, healthy men (n = 36) and women (n = 118) ages 25-69 years were interviewed among visitors and staff of the University of Athens Department of Medical Physics. Bone mineral density (BMD) was measured by single photon absorptiometry. RESULTS: Demographic and lifestyle variables were not significantly related to BMD in this study, although the patterns were consistent with those previously reported by other investigators. Total energy intake, which also reflects energy expenditure through physical activity, was positively associated with BMD among both men (P = 0.003) and women (P = 0.04). After adjustment for nonnutritional variables and energy intake, monounsaturated fat, which in the Greek population is mostly derived from olive oil, was associated with BMD. The association was positive among both men (P = 0.01) and women (P = 0.03). There was evidence for an inverse association between carbohydrate intake and BMD, but the association was significant only with respect to mono- and disaccharides. CONCLUSIONS: In this population, consumption of monounsaturated fat and physical activity were predictive of bone mineral density, but larger studies are needed.

Aetiology of fever in patients with acute stroke.

OBJECTIVE: Fever in patients with acute stroke is usually related to infectious complications. In some cases, a focus of infection cannot be identified, fever does not respond to empirical antibiotic treatment and is thought to be due to the central nervous system lesion. The aim of this study was to determine the frequency and origin of fever in patients with acute stroke and the characteristics associated with the presence of fever. DESIGN: A retrospective study of 36 months' duration. SETTING: The study was carried out at 'Alexandra' Hospital, a tertiary care teaching centre in Athens, Greece. SUBJECTS: A total of 330 patients hospitalized for acute stroke from June 1992 until July 1994. RESULTS: In 37.6% of 330 patients, fever was noted; 22.7% had a documented infection and 14.8% had fever without a documented infection. In univariate analysis, older age was associated with the presence of fever (P = 0.001). The development of fever was associated with intracerebral haemorrhage versus ischaemic infarct (P < 0.001) and with the presence of mass effect (P < 0.001), transtentorial herniation (P < 0.001), intraventricular blood (P < 0. 001), and larger size of ischaemic infarct (P = 0.0001) and of haemorrhage (P = 0.0002). Patients with fever had lower scores on admission on the Glasgow Coma Scale (P = 0.0001) and the Scandinavian Stroke Scale (P = 0.0001). The development of fever was associated with prior use of an invasive technique (P < 0.001) and more specifically with urinary catheterization (P < 0.001), but not with the presence of risk factors for infection. Patients with fever had a worse outcome assessed by the Modified Rankin Scale (P = 0. 0001) and the Barthel Index (P = 0.0001). In multivariate analysis, age, Scandinavian Stroke Scale score and mass effect were found to be significantly associated with fever (P = 0.035, P = 0.0001 and P = 0.0004, respectively). Patients with fever without documented infection had an earlier onset of fever than those with infection (P = 0.0061). In a logistic regression analysis, the only factor predictive of fever without documented infection versus infection was earlier onset of fever (P = 0.029). CONCLUSION: Patients with acute stroke who develop fever are older, suffer severe stroke, their fever is associated with the use of invasive techniques, and they have a poor outcome. In patients with fever without a focus of infection, the only characteristic that is different from patients with known infection is earlier onset of fever.

Phase I study of atevirdine, a nonnucleoside reverse transcriptase inhibitor, in combination with zidovudine for human immunodeficiency virus type 1 infection. ACTG 199 Study Team.

Twenty patients were enrolled in a phase I clinical trial of atevirdine, a nonnucleoside reverse transcriptase inhibitor (NNRTI), given in combination with zidovudine for treatment of human immunodeficiency virus type 1 (HIV-1) infection. Fifteen patients had received no previous antiretroviral therapy. HIV-1 isolates obtained at 6-week intervals were tested for sensitivity to atevirdine and zidovudine. Two patients developed a rash within 2 weeks of enrollment, and 1 of these developed concomitant fever and hepatitis. No hematopoietic, neurologic, or pancreatic toxicities were observed. Atevirdine had considerable initial interpatient pharmacokinetic variability. Forty-seven percent of patients treated with atevirdine plus zidovudine had increased CD4 lymphocyte counts, and HIV isolates from 62% of patients remained sensitive to atevirdine after 24 weeks of therapy. Atevirdine plus zidovudine was well-tolerated. Additional studies should be done to determine the role of atevirdine in the therapy for HIV infection.

Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. A phase I/II study.

OBJECTIVE: To evaluate the safety and immunologic and antiviral effects of combination therapy with zidovudine and dideoxycytidine (ddC) in patients with advanced human immunodeficiency virus type 1 (HIV) infection. DESIGN: A phase I/II open-label, dose-ranging study. SETTING: Two AIDS Clinical Trials Group units. PATIENTS: Patients (56) with advanced HIV disease. INTERVENTIONS: Patients were randomly assigned to one of three paired regimens of zidovudine and ddC. We evaluated six dosing regimens, each involving oral administration of the study drugs at 8-hour intervals. MEASUREMENTS: Pharmacokinetics, toxicity, CD4 counts, p24 antigenemia and clinical end points. MAIN RESULTS: The median follow-up period was 40.6 weeks (range, 0.3 to 70 weeks). Neither drug affected the pharmacokinetic profile of the other. Episodes of serious hematologic toxicity were infrequent, occurring in only 17.9% of patients, and did not differ among the regimens (P = 0.15). Severe sensory peripheral neuropathy occurred in two patients (one patient each in regimens 1 and 4). One patient receiving regimen 4 died. The mean maximal increase in CD4 counts exceeded 109 cells/mm3, and 69% of patients receiving combinations containing 300 or 600 mg of zidovudine daily had an increase in CD4 counts of 50 cells/mm3 or greater. Regimens containing 600 mg of zidovudine daily (regimens 2 and 5) were also more likely to result in persistent increases in CD4 counts above pretreatment values than were the two lowest dose regimens (P = 0.003). The decline in CD4 counts was more rapid, and the suppression of the p24 antigenemia was less rapid and less sustained in patients receiving the lowest zidovudine dose alone (regimen 6). The addition of ddC to regimen 6 (regimen 3) resulted in a slower decline in the CD4 counts (P = 0.06). CONCLUSIONS: Combination therapy with zidovudine and ddC at the doses tested was well tolerated and did not result in toxicity. A daily oral dose of 150 mg of zidovudine appeared to produce a suboptimal effect on p24 antigenemia and CD4 counts. Combination therapy with ddC and higher doses of zidovudine produced greater and more persistent effects in patients with advanced HIV infection compared with other study regimens and with the results of previous trials of zidovudine monotherapy.

Randomized phase I trial of two different combination foscarnet and ganciclovir chronic maintenance therapy regimens for AIDS patients with cytomegalovirus retinitis: AIDS clinical Trials Group Protocol 151.

AIDS patients with newly diagnosed cytomegalovirus (CMV) retinitis who had just completed a 14-day course of ganciclovir induction therapy were randomly assigned to an alternating or concurrent combination regimen of chronic ganciclovir-foscarnet therapy for CMV retinitis. Each regimen used lower weekly cumulative doses of each drug than standard monotherapy maintenance treatment regimens. Dose-limiting toxicity attributable to foscarnet occurred in only 2 (7%) of 29 evaluatable patients, and no patients experienced dose-limiting nephrotoxicity. Although absolute neutrophil counts < 500 cells/microL occurred in 11 (38%) of 29 patients, all who subsequently used adjunctive granulocyte colony-stimulating factor had severe neutropenia prevented. Severe toxicity of any type and neutropenia, in particular, occurred significantly more frequently in patients assigned to the concurrent treatment regimen. CMV was isolated from none of 21 patients who had urine cultured and from only 1 of 24 who had blood cultured while being treated during the study (median evaluation, 12 weeks). This suggests that combination therapy provides better in vivo antiviral activity in suppressing CMV replication than previously reported with monotherapy regimens.

A phase-I study of the safety, pharmacokinetics, and antiviral activity of combination didanosine and ribavirin in patients with HIV-1 disease. AIDS Clinical Trials Group 231 Protocol Team.

A phase-I study was conducted to examine the safety, pharmacokinetics, and activity of combination 2',3'-dideoxyinosine (ddI) and ribavirin against human immunodeficiency virus type 1 (HIV-1)-positive individuals with CD4+ cell counts of < or = 500/microliter. Nineteen patients were enrolled into the study in which ddI monotherapy (200 mg p.o.b.i.d.) was administered for the first 4 weeks, followed by the coadministration of ribavirin (600 mg p.o.q.d.) and ddI (200 mg p.o.b.i.d.) for 8 or 20 additional weeks. The combination regimen was safe and well tolerated. Three patients did not complete 12 weeks of the study because of adverse events or voluntary withdrawal. The pharmacokinetic studies performed at weeks 4, 6, and 12 on specimens collected from the 15 individuals who completed 12 weeks of therapy revealed no pharmacokinetic interaction between ddI and ribavirin. A significant decline from baseline in HIV-1 titer as measured by quantitative HIV-1 culture was detected both during the ddI-monotherapy phase (week 4, p < 0.001) and during the combination-therapy ddI + ribavirin phase (week 12, p < 0.001); the median drop observed was 0.90 log10 at week 4 and 0.92 log10 at week 12. While the addition of ribavirin did not result in further reductions in viremia in the following weeks on study treatment, 13 (81%) of the 16 patients had at least a -0.5 log10 change in viral titer at week 12. The median decline in plasma viral RNA was 0.68 log10 at week 4(p < 0.001) and 0.67 log10 at week 12 (p = 0.005). CD4+ cell counts increased above baseline significantly during the ddI-monotherapy phase of the study (p = 0.0038). The median increase was +26 cells/mm3 at week 4 and +11 cells/mm3 at week 12; for patients who remained on treatment through 24 weeks, the median CD4+ cell count increase was +10 cells/mm3. The L74V ddI resistance-conferring HIV-I reverse-transcriptase mutation emerged in 53% of the patients. Patients with non-syncytium-inducing HIV variants demonstrated greater responses to treatment with larger decreases in virus load and greater increases in CD4+ cell count. Our results reveal that the combination of ddI and ribavirin in HIV-positive patients is safe, well tolerated, without adverse pharmacologic interaction, and associated with significant and sustained declines in virus load over 12 weeks of therapy.