Pre-therapy inflammation and coagulation activation and long-term CD4 count responses to the initiation of antiretroviral therapy.

OBJECTIVES: Pre-antiretroviral therapy (ART) inflammation and coagulation activation predict clinical outcomes in HIV-positive individuals. We assessed whether pre-ART inflammatory marker levels predicted the CD4 count response to ART. METHODS: Analyses were based on data from the Strategic Management of Antiretroviral Therapy (SMART) trial, an international trial evaluating continuous vs. interrupted ART, and the Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial, evaluating three first-line ART regimens with at least two drug classes. For this analysis, participants had to be ART-naïve or off ART at randomization and (re)starting ART and have C-reactive protein (CRP), interleukin-6 (IL-6) and D-dimer measured pre-ART. Using random effects linear models, we assessed the association between each of the biomarker levels, categorized as quartiles, and change in CD4 count from ART initiation to 24 months post-ART. Analyses adjusted for CD4 count at ART initiation (baseline), study arm, follow-up time and other known confounders. RESULTS: Overall, 1084 individuals [659 from SMART (26% ART naïve) and 425 from FIRST] met the eligibility criteria, providing 8264 CD4 count measurements. Seventy-five per cent of individuals were male with the mean age of 42 years. The median (interquartile range) baseline CD4 counts were 416 (350-530) and 100 (22-300) cells/µL in SMART and FIRST, respectively. All of the biomarkers were inversely associated with baseline CD4 count in FIRST but not in SMART. In adjusted models, there was no clear relationship between changing biomarker levels and mean change in CD4 count post-ART (P for trend: CRP, P = 0.97; IL-6, P = 0.25; and D-dimer, P = 0.29). CONCLUSIONS: Pre-ART inflammation and coagulation activation do not predict CD4 count response to ART and appear to influence the risk of clinical outcomes through other mechanisms than blunting long-term CD4 count gain.

Decision Making in Fuzzy Discrete Event Systems1.

The primary goal of the study presented in this paper is to develop a novel and comprehensive approach to decision making using fuzzy discrete event systems (FDES) and to apply such an approach to real-world problems. At the theoretical front, we develop a new control architecture of FDES as a way of decision making, which includes a FDES decision model, a fuzzy objective generator for generating optimal control objectives, and a control scheme using both disablement and enforcement. We develop an online approach to dealing with the optimal control problem efficiently. As an application, we apply the approach to HIV/AIDS treatment planning, a technical challenge since AIDS is one of the most complex diseases to treat. We build a FDES decision model for HIV/AIDS treatment based on expert's knowledge, treatment guidelines, clinic trials, patient database statistics, and other available information. Our preliminary retrospective evaluation shows that the approach is capable of generating optimal control objectives for real patients in our AIDS clinic database and is able to apply our online approach to deciding an optimal treatment regimen for each patient. In the process, we have developed methods to resolve the following two new theoretical issues that have not been addressed in the literature: (1) the optimal control problem has state dependent performance index and hence it is not monotonic, (2) the state space of a FDES is infinite.

Efficacy and safety of abacavir plus lamivudine versus didanosine plus stavudine when combined with a protease inhibitor, a nonnucleoside reverse transcriptase inhibitor, or both in HIV-1 positive antiretroviral-naive persons.

PURPOSE: The combination of abacavir + lamivudine (ABC+3TC) versus didanosine + stavudine (ddI+d4T), each combined with other classes of antiretrovirals (ARVs) in ARV-naive patients, was compared for the combined endpoint of time to plasma HIV RNA >50 copies/mL (at or after the 8-month visit) or death (primary endpoint) in a nested substudy of an ongoing multicenter randomized trial. METHOD: The substudy enrolled 182 patients; mean HIV RNA and CD4+ cell counts at baseline were 5.1 log10 copies/mL and 212 cells/mm3, respectively. RESULTS: After a median follow-up of 28 months, rates of primary endpoint were 57.2 and 67.8 per 100 person-years for the ABC+3TC and ddI+d4T groups (hazard ratio [HR]=0.81, 95% confidence interval [CI] 0.58-1.14, p=.23). CONCLUSION: There was a trend for treatments containing ABC+3TC to be better than treatments containing ddI+d4T with respect to HIV RNA decreases, CD4+ cell count increases, and tolerability.

The rationale and design of the CPCRA (Terry Beirn Community Programs for Clinical Research on AIDS) 058 FIRST (Flexible Initial Retrovirus Suppressive Therapies) trial.

The CPCRA (Terry Beirn Community Programs for Clinical Research on AIDS) 058 FIRST (Flexible Initial Retrovirus Suppressive Therapies) trial is a large, long-term, randomized, prospective comparison of three different antiretroviral strategies in highly active antiretroviral therapy-naïve, HIV-1-infected persons. The trial was designed as a flexible framework upon which other studies could be added to answer more limited, but still important, questions. This article presents the study design, discusses the challenges we have faced in implementing the trial, and describes our preliminary experiences. Control Clin Trials 2001;22:176-190

The effects of massage therapy alone and in combination with other complementary therapies on immune system measures and quality of life in human immunodeficiency virus.

OBJECTIVES: Determine effects of massage therapy alone and in combination with exercise or stress management-biofeedback treatment on enumerative immune measures, and quality of life in moderately immunocompromised human immunodeficiency virus (HIV) subjects. DESIGN: Randomized prospective controlled trial with 42 subjects randomly assigned to one of three treatment groups or a control group receiving standard care and intervention over a 12-week period. SETTING: Academic medical center. SUBJECTS: Forty-two (42) subjects with HIV infection (40 males; 2 females; aged 27-50 years) met eligibility requirements of CD4+ lymphocyte cell count greater than 200 cells per microliter; no present or recent signs or symptoms of acquired immunodeficiency syndrome (AIDS), and were not hospitalized. INTERVENTIONS: A 45-minute overall body massage once per week; similar massage and supervised aerobic exercise 2 other days per week; similar massage and biofeedback stress management once per week; control receiving standard treatment. OUTCOME MEASURES: Changes in peripheral blood levels of CD4+ lymphocytes, CD8+ lymphocytes, CD4+/CD8+ lymphocyte ratio and natural killer cells; six dimension quality-of-life assessment. RESULTS: No significant changes (p > 0.05) were found in any enumerative immune measure. Significant (p < 0.05) differences for quality-of-life assessment were in health care utilization and health perceptions, favoring massage and stress management compared to massage only and controls. CONCLUSIONS: Massage administered once per week to HIV-infected persons does not enhance immune measures. Massage combined with stress management favorably alters health perceptions and leads to less utilization of health care resources. This suggests that HIV-infected persons receiving massage and stress management would tend to not overutilize health care services, thus possibly reducing health care costs.

Antiretroviral therapy. Sequencing antiretrovirals.

Sequencing of antiretroviral agents is of interest because the majority of HIV-infected individuals in clinical practice experience virologic rebound after 1 to 2 years of therapy. Sequencing strategies are based on the observation that different mutational patterns arise after exposure to particular antiretroviral agents within the same class and on preliminary data suggesting that not all mutations impart the same degree of cross-resistance to other agents of the same class. The ultimate goal of sequencing is to maximize the number of effective antiretroviral combinations available. While convincing data on the efficacy of sequencing strategies from large, randomized clinical trials are lacking, early data suggest that some sequencing strategies may be of benefit.

An overview of HIV infection and AIDS: etiology, pathogenesis, diagnosis, epidemiology, and occupational exposure.

Thanks to a worldwide collaborative effort among health care providers, academia, governments, and industry, our knowledge base about infection caused by the human immunodeficiency virus (HIV) has expanded exponentially. During the past 2 decades, we have learned about its pathogenesis, virology, immunology, epidemiology and treatment. In the developed world, the approach to persons with HIV disease has evolved from palliative disease care to use of a chronic disease model, where survival is measured by decades, not months or years. More and more, clinical decision-making for HIV-infected patients is driven by comorbidities, including cardiothoracic disease. Thus, our clinically stable HIV population is increasingly accessing those health care services required by any maturing population, including the usual services of cardiothoracic surgeons. In this article, we review the basic facts of HIV disease, with an emphasis on occupational risks and infection control procedures.

Treatment of HIV disease in the new millennium.

Highly active antiretroviral therapy (HAART), which typically consists of 3-drug combinations of antiretroviral agents, has decreased dramatically the incidence of AIDS and death among HIV-infected persons in the United States. HIV infection no longer is viewed as a death sentence. Complete suppression of viral replication through the use of HAART can reverse the immune deficits formerly thought to be inevitable. However, drug toxicity, cross-resistance, and less-than-perfect adherence to prescribed antiretroviral regimens make the medical management of the HIV-infected person complex. An overview of the current approach to antiretroviral therapy is presented in this article.

Effects of Mycobacterium avium complex-infection treatment on cytokine expression in human immunodeficiency virus-infected persons: results of AIDS clinical trials group protocol 853.

Human immunodeficiency virus (HIV) type 1-infected persons with newly diagnosed Mycobacterium avium complex (MAC) bacteremia were enrolled in an 8-week study to determine whether treatment of MAC infection is associated with decreases in plasma tumor necrosis factor (TNF)-alpha levels. Blood specimens were obtained for quantitative MAC cultures and to determine plasma levels of HIV RNA, TNF-alpha, and other proinflammatory cytokines. MAC levels decreased by 1.75 log at week 4 (P=.008) and by 2.48 log at week 8 (P=.001). Plasma TNF-alpha decreased by 0.15 log at week 4 (P=.042) and by 0. 40 log at week 8 (P=.027). Plasma interleukin (IL)-6 decreased by 0. 56 log at week 8 (P=.039). There were nonsignificant trends (P<.10) for plasma levels of IL-1beta and HIV RNA to decrease at week 8. Nonsignificant decreases in plasma levels of TNF-alpha, IL-1beta, IL-6, and HIV RNA were also seen in those individuals who remained on stable antiretroviral therapy throughout the 8 weeks of the study.

Acetylator phenotype and genotype in patients infected with HIV: discordance between methods for phenotype determination and genotype.

The acetylator phenotype and genotype of AIDS patients, with and without an acute illness, was compared with that of healthy control subjects (30 per group). Two probe drugs, caffeine and dapsone, were used to determine the phenotype in the acutely ill cohort. Polymerase chain reaction amplification and restriction fragment length polymorphism analysis served to distinguish between the 26 known NAT2 alleles and the 21 most common NAT1 alleles. The distribution (%) of slow:rapid acetylator phenotype seen among acutely ill AIDS patients differed with the probe substrate used: 70:30 with caffeine versus 53:47 with dapsone. Phenotype assignment differed considerably between the two methods and there were numerous discrepancies between phenotype and genotype. The NAT2 genotype distribution was 45:55 slow:rapid. Control subjects, phenotyped only with caffeine, were 67:33 slow:rapid versus 60:40 genotypically. Stable AIDS patients, phenotyped only with dapsone, were 55:45 slow:rapid versus 46:54 genotypically. Following resolution of their acute infections, 12 of the acutely ill subjects were rephenotyped with dapsone. Phenotype assignment remained unchanged in all cases. The distribution of NAT1 alleles was similar in all three groups. It is evident from the amount of discordance between caffeine phenotype and dapsone phenotype or genotype that caution should be exercised in the use of caffeine as a probe for NAT2 in acutely ill patients. It is also clear that meaningful study of the acetylation polymorphism requires both phenotypic and genotypic data.

Drug resistance. An updated, user-friendly guide to genotype interpretation.

Genotypic antiretroviral resistance testing (GART) has been shown to be of value in selecting antiretroviral therapy. Unfortunately, GART reports often are difficult to interpret and, at times, can be misleading. Published lists of "primary" resistance mutations often do not include the combinations of "secondary" mutations, which also limit the efficacy of antiretroviral agents. This article tries to rectify this situation by introducing a general approach to genotype interpretation and by providing more "user-friendly" tables of key single mutations and key mutation combinations.

Is hydroxylamine-induced cytotoxicity a valid marker for hypersensitivity reactions to sulfamethoxazole in human immunodeficiency virus-infected individuals?

Hypersensitivity (HS) reactions to sulfonamides and sulfones continue to limit their use in human immunodeficiency virus (HIV)-infected individuals. In vitro cytotoxicity of hydroxylamine metabolites toward peripheral blood mononuclear cells (PBMCs) has been proposed as a marker for these HS reactions. To test the validity of this in vitro system, we determined the selective susceptibility of PBMCs from HIV-infected patients to the cytotoxic effects of hydroxylamine metabolites of sulfamethoxazole (SMX) and dapsone (DDS). Concentration-cytotoxic response data were collected using PBMCs from 12 sulfa-HS (10 SMX-HS and 2 SMX/DDS-HS) and 10 sulfa-tolerant HIV-infected individuals. Although sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone hydroxylamine (DDS-NOH) both caused concentration-dependent increases in cell death, DDS-NOH was significantly more potent in each subject (P <.0001). A comparison of a variety of mean data for sulfa-HS and -tolerant patient populations failed to demonstrate the increased susceptibility of PBMCs from HS patients, noted by others, to either SMX-NOH or DDS-NOH. Moreover, any trend toward an increased susceptibility of PBMCs from HS patients was eliminated when adjusted for control cell death. PBMCs from sulfa-HS patients showed significantly greater susceptibility to the stress of short term in vitro incubation (P <. 02). Mean (S.D.) vehicle control cell death values were 24.1% (7.6%) for HS patients and 17.1% (4.4%) for tolerant patients. No significant correlation was observed between hydroxylamine-induced or control cell death and any of the recorded clinical parameters. Although several potential reasons are proposed to explain the disparity with past investigations, the data suggest that in vitro cytotoxicity is not a valid marker for HS reactions in HIV-infected individuals using currently accepted experimental procedures.

Bordetella bronchiseptica infection in human immunodeficiency virus-infected patients.

Bordetella bronchiseptica is a pleomorphic gram-negative coccobacillus that commonly causes respiratory tract infections in dogs. We identified nine human immunodeficiency virus (HIV)-infected persons with culture-confirmed B. bronchiseptica infections (eight respiratory tract and one disseminated infection). The respiratory illnesses ranged in severity from mild upper respiratory tract infection to pneumonia. All nine patients had had at least one AIDS-defining condition before the B. bronchiseptica infection. Two patients had household contact with dogs before their illnesses, and one had household contact with cats. Infection due to B. bronchiseptica is uncommon in HIV-infected persons. Additional data are needed to fully define the spectrum of disease due to B. bronchiseptica infections and to evaluate the possibility that this infection may be acquired from pets. Treatment of B. bronchiseptica infection should be tailored to the patient and should be based on the results of susceptibility testing.

Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party.

BACKGROUND: The reverse-transcriptase inhibitor lamivudine has in vitro synergy with zidovudine against the human immunodeficiency virus (HIV). We studied the activity and safety of lamivudine plus zidovudine as compared with either drug alone as treatment for patients with HIV infection, most of whom had not previously received zidovudine. METHODS: Three hundred sixty-six patients with 200 to 500 CD4+ cells per cubic millimeter who had received zidovudine for four weeks or less were randomly assigned to treatment with one of four regimens: 300 mg of lamivudine every 12 hours; 200 mg of zidovudine every 8 hours; 150 mg of lamivudine every 12 hours plus zidovudine; or 300 mg of lamivudine every 12 hours plus zidovudine. The study was double-blind and lasted 24 weeks, with an extension phase for another 28 weeks. RESULTS: Over the 24-week period, the low-dose and high-dose regimens combining lamivudine and zidovudine were associated with greater increases in the CD4+ cell count (P = 0.002 and P = 0.015, respectively) and the percentage of CD4+ cells (P < 0.001 for both) and with greater decreases in plasma levels of HIV-1 RNA (P < 0.001 for both) than was treatment with zidovudine alone. Combination therapy was also more effective than lamivudine alone in lowering plasma HIV-1 RNA levels and increasing the percentage of CD4+ cells (P < 0.001 for all comparisons), and these advantages persisted through 52 weeks. Adverse events were no more frequent with combination therapy than with zidovudine alone. CONCLUSIONS: In HIV-infected patients with little or no prior antiretroviral therapy, treatment with a combination of lamivudine and zidovudine is well tolerated over a one-year period and produces more improvement in immunologic and virologic measures than does treatment with either agent alone.

Comparison of tobramycin pharmacokinetics after administration by CRIS and a traditional intravenous piggyback infusion.

OBJECTIVE: To compare the administration pharmacokinetics of a 30-minute intravenous piggyback (ivpb) infusion of tobramycin with those of controlled-release infusion system (CRIS) using a 20-mL vial at rates of 60 and 120 mL/h. DESIGN: Randomized, controlled, crossover, prospective, open-label trial. SETTING: Medical college-affiliated hospital. PARTICIPANTS: Eight healthy volunteer men between the ages of 22 and 24 years weighing between 60 and 90 kg. INTERVENTIONS: Volunteers received, in random order, tobramycin sulfate 2 mg/kg i.v. on 3 occasions separated by 1 week. The drug was administered using a 50-mL ivpb infusion at 100 mL/h for 30 minutes, and with the CRIS using a 20-mL vial with flow rates of 60 mL/h for 1 hour (slow) and 120 mL/h for 1 hour (fast). MAIN OUTCOME MEASURES: Primary endpoints were area under the time-concentration curve (AUC), time to reach maximum concentration (tmax), and maximum concentration (Cmax). Secondary endpoints were elimination rate constant (ke), clearance (Cl), and half-life (t1/2). RESULTS: Six volunteers successfully completed the trial. The tmax values observed following fast CRIS and ivpb were 28 +/- 8 and 32 +/- 4 minutes, respectively, and not significantly different from each other. Both occurred significantly earlier than the tmax associated with slow CRIS (44 +/- 7 min). The Cmax values observed following ivpb (11.2 +/- 1.5 mg/L) and slow CRIS (10.9 +/- 0.9 mg/L) administration were not significantly different from each other, but both were significantly lower than that of fast CRIS (13.4 +/- 1.5 mg/L). The AUCs of slow and fast CRIS were 29.8 +/- 4.8 and 31.2 +/- 3.8 mg/L.h, respectively, and were not significantly different from each other. The AUC of fast CRIS was significantly greater than that observed with ivpb (27.4 +/- 4.3 mg/L.h). No significant difference in ke (fast CRIS 0.32 +/- 0.03 h-1; slow CRIS 0.33 +/- 0.04 h-1; ivpb 0.34 +/- 0.0 h-1) was observed among any of the methods. CONCLUSIONS: CRIS administration of tobramycin resulted in higher AUCs than did ivpb administration. Compared with ivpb, fast CRIS resulted in a higher Cmax, but the tmax values of fast CRIS and ivpb administration were not statistically different. Compared with ivpb, slow CRIS resulted in a more delayed tmax, but the Cmax values of slow CRIS and ivpb were not statistically different.

Relationship of intraabdominal fat as measured by magnetic resonance imaging to postprandial lipemia in middle-aged subjects.

Adipose distribution has been associated with coronary artery disease and its risk factors. We previously described an association between postprandial triglyceride response (pptg response) to a standard high-fat meal and extracranial carotid atherosclerosis. This study was designed to evaluate the association between intraabdominal fat and pptg response. Twenty-nine subjects were recalled for determination of intraabdominal fat by magnetic resonance imaging (MRI). Fat was quantified according to an inversion recovery protocol previously validated and the cross-sectional area of intraabdominal fat at the umbilicus was analyzed as an independent variable. We observed a strong independent correlation between intraabdominal fat and pptg response to a fatty meal (r = 0.521, P < 0.05). Baseline triglyceride was also independently correlated with postprandial triglycerides (r = 0.631, P < 0.05). In univariate analysis, intraabdominal fat was correlated with age, sex, body mass index (BMI), waist-to-hip ratio (WHR), and dietary saturated fatty acids. The association with age and BMI persisted in multivariate analyses.

Didanosine compared with continuation of zidovudine in HIV-infected patients with signs of clinical deterioration while receiving zidovudine. A randomized, double-blind clinical trial. The Bristol-Myers Squibb AI454-010 Study Group.

OBJECTIVE: To determine the benefits of switching to didanosine compared with continuing zidovudine among patients infected with human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration. DESIGN: Randomized, double-blind, two-armed, parallel, comparative clinical trial with a blinded, compassionate crossover provision at 12 weeks. SETTING: Outpatient clinics at 19 tertiary care medical centers. PATIENTS: 312 patients infected with HIV who had received zidovudine for 6 months or more, had CD4 cell counts of 300/mm3 or less, and had signs of clinical deterioration within 12 weeks before study entry. INTERVENTION: Peroral didanosine tablets (600 mg/d adjusted for weight, "high dose") or zidovudine capsules (600 mg/d). MEASUREMENTS: Primary study end points were death, a new acquired immunodeficiency syndrome (AIDS)--defining event, or the combination of two new or recurrent HIV-related diagnoses with a 50% decrease in CD4 cells. RESULTS: Switching to didanosine was associated with fewer end points than continuing zidovudine (relative risk [RR] for zidovudine:didanosine = 1.5; 95% Cl, 1.1 to 2.0). This benefit was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent among those with a CD4 count at entry of 100/mm3 or more (RR = 2.2; Cl, 1.1 to 4.4). CONCLUSIONS: This study shows a positive treatment effect for switching from zidovudine to didanosine among patients with either AIDS-related complex or AIDS and validates the common practice of using clinical signs or a decrease in the CD4 count as an indication for changing therapy.

Disseminated cutaneous and meningeal sporotrichosis in an AIDS patient.

We report the first proven case of Sporothrix meningoencephalitis in an AIDS patient. The patient had dramatic, wide-spread ulcerative and infiltrative disease with progressive meningoencephalitis in spite of amphotericin and itraconazole therapy. Sporothrix was cultured from premortem cerebrospinal fluid and seen in the meninges and in brain vessels at autopsy.

Supervised exercise training improves cardiopulmonary fitness in HIV-infected persons.

We attempted to measure cardiopulmonary effects, CD4 counts, and perceived sense of well-being in 25 individuals moderately to severely immunocompromised from HIV infection (mean entry CD4 count = 144.microliters-1) before and after a 24-wk program of exercise training. Only six subjects completed the 24-wk program. All six showed evidence of a training effect. Statistically significant improvements were seen in maximal oxygen consumption (VO2max), oxygen pulse, and minute ventilation. Submaximal exercise performance improved significantly by 12 wk in the 10 individuals available for testing: decreases were seen in heart rate, rate pressure product, and rate of perceived exertion. White blood cell counts and T-lymphocyte subsets were stable at 12 and 24 wk in the subjects available for testing. High depression/anxiety scores on a mental health inventory (General Health Questionnaire) correlated with low CD4 counts. Scores did not correlate with compliance with the exercise program. There was a trend (P < 0.10) for scores to improve over time among those individuals who attended > or = 80% of scheduled exercise sessions. We conclude that exercise training is feasible and beneficial for some HIV-infected individuals.

Branhamella catarrhalis peritonitis in two continuous ambulatory peritoneal dialysis patients.

Two cases of peritonitis caused by Branhamella catarrhalis are presented. Both occurred in CAPD patients dialyzed and hospitalized at the same institution, but no common source of infection could be found. Branhamella catarrhalis infections can be difficult to treat and cause significant morbidity if not recognized early and treated aggressively with appropriate antibiotics.