A Comparison of Adherence Timeframes Using Missed Dose Items and Their Associations with Viral Load in Routine Clinical Care: Is Longer Better?

Questions remain regarding optimal timeframes for asking about adherence in clinical care. We compared 4-, 7-, 14-, 30-, and 60-day timeframe missed dose items with viral load levels among 1099 patients on antiretroviral therapy in routine care. We conducted logistic and linear regression analyses examining associations between different timeframes and viral load using Bayesian model averaging (BMA). We conducted sensitivity analyses with subgroups at increased risk for suboptimal adherence (e.g. patients with depression, substance use). The 14-day timeframe had the largest mean difference in adherence levels among those with detectable and undetectable viral loads. BMA estimates suggested the 14-day timeframe was strongest overall and for most subgroups although findings differed somewhat for hazardous alcohol users and those with current depression. Adherence measured by all missed dose timeframes correlated with viral load. Adherence calculated from intermediate timeframes (e.g. 14-day) appeared best able to capture adherence behavior as measured by viral load.

Evaluation of the single-item self-rating adherence scale for use in routine clinical care of people living with HIV.

The self-rating scale item (SRSI) is a single-item self-report adherence measure that uses adjectives in a 5-point Likert scale, from "very poor" to "excellent," to describe medication adherence over the past 4 weeks. This study investigated the SRSI in 2,399 HIV-infected patients in routine care at two outpatient primary HIV clinics. Correlations between the SRSI and four commonly used adherence items ranged from 0.37 to 0.64. Correlations of adherence barriers, such as depression and substance use, were comparable across all adherence items. General estimating equations suggested the SRSI is as good as or better than other adherence items (p's <0.001 vs. <0.001-0.99) at predicting adherence-related clinical outcomes, such as HIV viral load and CD4(+) cell count. These results and the SRSI's low patient burden suggest its routine use could be helpful for assessing adherence in clinical care and should be more widespread, particularly where more complex instruments may be impractical.

Association between use of specific drugs and antiretroviral adherence: findings from MACH 14.

To determine the association between individual substances of abuse and antiretroviral adherence, analyses require a large sample assessed using electronic data monitoring (EDM). In this analysis, EDM data from 1,636 participants in 12 US adherence-focused studies were analyzed to determine the associations between recent use of various substances and adherence during the preceding 4 weeks. In bivariate analyses comparing adherence among patients who had used a specific substance to those who had not, adherence was significantly lower among those who had recently used cocaine, other stimulants or heroin but not among those who had used cannabis or alcohol. In multivariate analyses controlling for sociodemographics, amount of alcohol use and recent use of any alcohol, cocaine, other stimulants and heroin each was significantly negatively associated with adherence. The significant associations of cocaine, other stimulants, heroin, and alcohol use with adherence suggest that these are important substances to target with adherence-focused interventions.

Conceptualizing antiretroviral adherence in Beijing, China.

International health experts agree that China is on the verge of an AIDS crisis. In response, the Chinese government initiated the "Four Frees and One Care" policy in 2003 to decrease economic barriers and increase access to antiretroviral therapies for people with HIV. However, long-term treatment success requires not only access, but high rates of medication adherence. This qualitative interview study with 29 persons receiving HIV care at Beijing's Ditan Hospital identified barriers to and facilitators of medication adherence. The interviews were guided by an a priori conceptual model of adherence with four components: access, knowledge about medications, motivation, and proximal cues to action. Barriers to adherence were related to stigma and fear of discrimination; the medications themselves (including side-effects and complicated dosing regimens); and other economic issues (i.e. costs of transportation, lab tests and hospitalizations). Facilitators included participants' strong will to live, use of electronic reminders and family support. These results support the conceptual model and suggest that successful interventions must minimize stigma as it negatively affects all components of the model for adherence.

Reduced extracellular pH increases endothelin-1 secretion by human renal microvascular endothelial cells.

Because dietary acid increases renal secretion of endothelin-1 (ET-1) which is synthesized by renal microvascular endothelium, we examined if reduced extracellular pH increases ET-1 secretion by cultured human renal microvascular endothelial cells (RMVECs). Confluent cells were exposed to serum-free media for 24 h, then incubated in either control, acid, or alkaline serum-free media for 12 h. Standard growth media pH was 7.2 after equilibration with 5% CO2 at 37 degrees C and was made the pH of control media. Acid and alkaline media pH were 7.0 and 7.4, respectively. Added Hepes and Tris maintained all assigned pHs. Media ET-1 measured by RIA after column extraction was higher for RMVECs exposed to acid compared with control media (170.0+/-17.1 vs. 64.6+/-9.6 pM, P < 0.004) but those exposed to alkaline media (56.6+/-25.1 pM, P = NS vs. control) were not. Human aortic endothelial cells exposed to control, acid, and alkaline media had similar ET-1 (166.6+/-18.1, 139.3+/-18.5, and 205.9+/-25.3 pM, P = NS). The data show acid-stimulated ET-1 secretion by RMVECs but not aortic endothelial cells, demonstrating a new environmental factor that influences ET-1 secretion by renal microvascular endothelium and thereby possibly modulates endothelin-dependent processes in vivo.

Radioimmunotherapy of human B-cell lymphoma with 90Y-conjugated antiidiotype monoclonal antibody.

We report the first case of 90Y-conjugated monoclonal antibody (MoAb) administration for human radioimmunotherapy. Ten mCi 90Y-labeled antiidiotype (anti-Id) MoAb were administered to a patient with B-cell lymphoma whose tumor successfully imaged with 111In-labeled anti-Id MoAb. No significant toxicities were observed. More than 2 g of unlabeled anti-Id MoAb were administered while clearing the circulating IgM idiotype prior to administration of the 90Y-MoAb. Transient partial regression of disease was observed. Serial fine needle aspirations of a malignant lymph node documented in vivo anti-Id penetration into a site that did not image by radioimmunoscintigraphy. The radiosensitivity of B-cell lymphoma, the tumor specificity of anti-Id, the antitumor activity of anti-Id alone, and the safe administration of 10 mCi 90Y-labeled anti-Id MoAb in this report suggest further investigation of this radioimmunoconjugate for therapy of B-cell lymphoma is warranted.

Self-disclosure of HIV infection among men who vary in time since seropositive diagnosis and symptomatic status.

OBJECTIVE: To assess self-disclosure of HIV-positive serostatus to family, friends, and intimate lovers among asymptomatic and symptomatic men who varied in length of time since HIV-seropositive diagnosis. Additionally, the study assessed the anticipated and actual interpersonal consequences of disclosure. METHODS: A multiethnic sample of 684 men with HIV/AIDS completed self-administered questionnaires at two HIV-outpatient clinics in Los Angeles. The cross-sectional analysis stratified the men by time since testing HIV-seropositive and symptomatic status. Disclosure to six significant others (intimate lover, close friend, mother, father, sister, brother) was examined in univariate and multivariate analyses. RESULTS: Men recently diagnosed HIV-seropositive (within 2-4 months) were more likely to have informed intimate lovers and friends than family members; disclosure to father was extremely low. Disclosure was generally lower among asymptomatic than symptomatic men; 21% of asymptomatic men who had tested HIV-seropositive in the previous year had not informed any of the six significant others considered in the study. Disclosure rates were higher among men diagnosed less recently. The interpersonal reactions of those informed were more favorable than the reactions non-disclosers anticipated; however, both actual and anticipated reactions were generally supportive. CONCLUSION: Many asymptomatic men inform few or no significant others of their HIV infection in the first few months after HIV diagnosis. Given the generally supportive reactions reported, HIV-seropositive men should be encouraged, when appropriate, to inform family, friends, and intimate lovers of their serostatus.

Culturally sanctioned secrets? Latino men's nondisclosure of HIV infection to family, friends, and lovers.

Spanish-speaking Latino men (n = 107) were more likely than English-speaking Latinos (n = 85) and Whites (n = 206) to withhold their HIV-positive serostatus and their gay or bisexual orientation from significant others, especially family members. Similar effects were observed when Latinos were divided by birthplace and when analyses controlled for sociodemographic and medical factors. Reasons for revealing or concealing an HIV diagnosis varied across targets. Although both Latinos and Whites were more likely to withhold their diagnosis from their parents to prevent worrying them than to avoid personal rejection, this tendency was somewhat stronger among Latinos. Our findings suggest that some traditional values may deter Latinos from seeking HIV-related social support in times of need.

Women's self-disclosure of HIV infection: rates, reasons, and reactions.

A survey of 65 ethnically diverse women at 2 outpatient HIV clinics revealed relatively low rates of disclosure of HIV-positive serostatus to extended family members, somewhat higher rates for immediate family members, and highest rates for lovers and friends. Spanish-speaking Latinas were less likely to disclose their serostatus or to discuss HIV-related worries with others than English-speaking Latinas, African Americans, and Anglo Americans. Reasons for disclosure and nondisclosure varied by target. In general, targets reacted positively to disclosure. Implications for clinicians treating women with HIV infection are discussed.

Stunned myocardium during extracorporeal membrane oxygenation.

The "stunned myocardium" is a syndrome of reversible myocardial dysfunction that may be mediated by oxygen-derived free radicals. This phenomenon has been seen in some neonates undergoing extracorporeal membrane oxygenation. We performed echocardiograms and measured creatine phosphokinase isoenzymes and lipid peroxide levels in 16 neonates before, during, and after extracorporeal membrane oxygenation. Infants who developed stunned myocardia by echocardiography did so shortly after initiation of bypass and exhibited concurrent elevations of the MB fraction of creatine phosphokinase. Lipid peroxide levels did not simultaneously rise. These data suggest that oxygen-derived free radicals may not cause the stunned myocardium seen in neonates undergoing extracorporeal membrane oxygenation.

Attenuating tumor necrosis factor alpha does not ameliorate other cytokine and peroxidase products during sepsis.

BACKGROUND: Recent trials utilizing single anticytokine agents have shown no consistent survival benefit in improving the outcome of sepsis. Since an entire cascade of mediators contributes to the underlying pathophysiology, it is not surprising that monotherapy has proven unsuccessful. The purpose of this study was to measure the effects of attenuating tumor necrosis factor (TNF)alpha early in sepsis. METHODS: Three groups of Sprague-Dawley rats were studied. All animals were infused with live Escherichia coli, with group I and group II rats additionally receiving a matrix metalloproteinase inhibitor. Serum levels of TNFalpha, interleukin (IL)-6, malondialdehyde (MDA), and lipid hydroperoxide (LOOH) were compared. RESULTS: TNFalpha showed a significant decrease, yet IL-6, MDA, and LOOH (markers of sepsis) levels remained abnormally elevated. CONCLUSION: Despite significantly attenuating TNFalpha, the septic response continued. This supports the concept that in sepsis, monotherapy directed at attenuating a single cytokine cannot overcome the tissue-damaging effects of an entire cascade of mediators.

Sex trading and psychological distress among women on methadone.

This study examined the relationship between sex trading and psychological distress among a nonrandom sample of women recruited from 3 methadone maintenance clinics in New York City. Face-to-face interviews with 280 women (M age = 40.7) revealed that 32% had traded sex for money or drugs in the previous year. Compared to other participants, these women reported less education and higher rates of incarceration in the past year, sexually transmitted diseases, childhood sexual abuse, partner abuse, and current regular crack/cocaine and alcohol use. Hierarchical multiple regression analysis indicated that sex traders scored 0.41 units higher than non-sex traders on the General Severity Index of the Brief Symptom Inventory after controlling for all relevant covariates. The findings emphasize the need to consider the interrelation of psychological distress, abuse, and addiction in designing public health interventions addressing methadone maintained women.

Elevated levels of endotoxin, oxygen-derived free radicals, and cytokines during extracorporeal membrane oxygenation.

It has been demonstrated that the initiation of extracorporeal membrane oxygenation (ECMO) is associated with an increase in the circulating plasma levels of inflammatory mediators. We have expanded the study of these substances to include measurements of complement activation, prostaglandin production, endotoxin appearance, oxygen-derived free radical generation, and cytokine release before, during, and after ECMO. A reproducible second phase of complement activity and prostaglandin synthesis was associated with the appearance of detectable circulating endotoxin (0.04 U/mL pre-ECMO to 0.07 U/mL at 36 hours, P less than .05). Oxygen-derived free radical activity also increased (2 ng/mL to 3 ng/mL at 36 hours, P less than .05), as did plasma levels of tumor necrosis factor (40 pg/mL to 70 pg/mL at 36 hours, nonsurvivor group: P less than .05). Interleukin-1 was elevated above normal, but there were no significant variations noted during the time period studied. Small amounts of interleukin-6 were also detected in the occasional patient. None of these mediators differed significantly between survivors and nonsurvivors. These data indicate that ECMO is associated with a previously undescribed, endotoxin-related, generalized inflammatory state after 36 hours of support. The pulmonary, renal, and cardiac dysfunctions documented with prolonged bypass can all be related to a classic sepsis syndrome.

An improved blood substitute. In vivo evaluation of its renal effects.

Nephrotoxicity of free hemoglobin (Hb) based blood substitutes still awaits full elucidation. Previous reports attributed Hb passage through the renal glomeruli to a tendency of the Hb tetramer to dissociate into dimers. Now it has become more evident that the Hb tetramer is able to extravasate. It appears that the electrical charge of proteins plays an important role, with electronegativity and a low isoelectric point favoring intravascular persistence. This effect was utilized in the development of an improved blood substitute, comprising Hb reacted with o-ATP and o-adenosine, to form an intra- and intermolecularly cross linked product, which is reduced with glutathione. The modification reagents possess the desired pharmacologic activities and produce an increase in the electronegative charges on the Hb surface. All Hb polymers and chemically modified tetramers present in this solution have a uniform electronegative charge, with a pl of 6.1-6.2. In this present study, unmodified bovine Hb and an improved blood substitute were used for the replacement of 40% of the total blood volume in rats. The nephrotoxic effect was investigated by the determination of urinary output, glomerular filtration rate (GFR), fractional excretion of sodium (FENa), potassium (FEK), and chloride (FECl), urine/plasma osmolality ratio, and urine N-acetyl-beta-D-glucosaminidase (NAG) level. The free Hb and non heme protein contents in the urine were analyzed by using isoelectric focusing and size exclusion liquid chromatography methods. The results indicate that unmodified Hb is nephrotoxic. An initially elevated urinary output was followed by a significant oliguria associated with decreased GFR, FEK, and FECl and elevated FENa and NAG. Severe hemoglobinuria was associated with proteinuria. Analysis of urine from unmodified Hb treated rats revealed the presence of Hb tetramers. Histopathological examination of the kidneys showed cytoplasmic vacuolization of proximal tubular epithelium. On the contrary, an improved blood substitute did not produce any nephrotoxic reactions. It was found that this Hb solution did not pass through the renal glomerular barrier and was not present in urine samples. In conclusion, such a chemical and pharmacological alteration of Hb molecules reduced their interaction with renal glomeruli and suspended nephrotoxicity.

An improved blood substitute. In vivo evaluation of its hemodynamic effects.

The purpose of the present study was to assess the ability of an improved free hemoglobin based blood substitute to serve as a resuscitative fluid in the treatment of hemorrhagic shock. Comparison studies were performed by using blood autotransfusion as a positive control. The hemodynamic parameters studied included cardiac index, mean arterial pressure, pulse pressure, heart rate, stroke volume index, and total peripheral resistance. Tissue oxygenation was measured in the biceps femori muscle by polarography. Hemorrhagic shock (at 40% of the total blood volume) in anesthetized rats caused severe disturbances in hemodynamic parameters and tissue oxygenation. Shock was characterized by a 66% drop in cardiac index, a 67% drop in mean arterial pressure with a significant increase in total peripheral resistance, and a 78% reduction in tissue oxygenation, all lasting 30 min. Resuscitation from shock with the blood substitute was effective in restoring hemodynamic parameters, producing vasodilation, and improving tissue oxygenation. Autotransfusion with blood also restored hemodynamics. However, lower tissue oxygenation and lack of vasodilation were noted. Therefore, the modified hemoglobin solution yielded better results than blood in the resuscitation of rats after hemorrhagic shock. The vasodilatory activity and the reduction of vasoconstriction that followed hemorrhage can be primarily linked with adenosine, which possesses vasodilatory and anti-inflammatory properties, and is used in our technology as an intermolecular cross linking reagent and hemoglobin surface modifier.

A novel hemoglobin-adenosine-glutathione based blood substitute: evaluation of its effects on human blood ex vivo.

Chemically modified hemoglobin (Hb) solutions are under current investigation as potential red cell substitutes. Researchers at Texas Tech University have developed a novel free Hb based blood substitute product. This blood substitute is composed of purified bovine Hb cross-linked intramolecularly with o-adenosine-5'-triphosphate and intermolecularly with o-adenosine, and conjugated with reduced glutathione (GSH). In this study, we compared the effects of our novel blood substitute and unmodified (U) Hb, by using allogenic plasma as the control, on human blood components: red blood cells (RBCs), platelets, monocytes (Mo), and low-density lipoproteins (LDLs). The pro-oxidant potential of both Hb solutions on RBCs was examined by the measurement of osmotic and mechanical fragility, conjugated dienes (CD), lipid hydroperoxides (LOOH), thiobarbituric acid reactants (TBAR-S), isoprostanes (8-iso PGF2alpha) and intracellular GSH. The oxidative modification of LDLs was assessed by CD, LOOH, and TBAR-S, and the degree of apolipoprotein (apo) B cross-linking. The effects of Hb on platelets have been studied by monitoring their responses to the aggregation agonists: collagen, ADP, epinephrine, and arachidonic acid. Monocytes were cultured with Hb solutions or plasma and tested for TNF-alpha and IL-1beta release, then examined by electron microscopy. Results indicate that native UHb initiates oxidative stress of many blood components and aggravates inflammatory responses of Mo. It also caused an increase in RBC osmotic and mechanical fragility (p < 0.001). While the level of GSH was slightly changed, the lipid peroxidation of RBC increased (p < 0.001). UHb was found to be a stimulator of 8-iso PGF2alpha synthesis, a potent modulator of LDLs, and an effective potentiator of agonist induced platelet aggregation. Contrarily, our novel blood substitute did not seem to induce oxidative stress nor to increase Mo inflammatory reactions. The osmotic and mechanical fragility of RBCs was similar to that of the control. Such modified Hb failed to alter LDLs, increase the production of 8-iso PGF2alpha, but markedly inhibited platelet aggregation. The effect of this novel blood substitute can be linked with the cytoprotective and anti-inflammatory properties of adenosine, which is used as a cross-linker and surface modifier, and a modification procedure that lowers the hemoglobin pro-oxidant potential.

Evidence for the direct inhibition of endothelin-1 secretion by hemoglobin in human endothelial cells.

The actual hemoglobin (Hb) contribution to endothelin-1 (ET-1) production in human umbilical vein endothelial cells (EC) was investigated. Cells were incubated with 0.1 mmol or 0.3 mmol of bovine: 1) unmodified (U) ferrous-Hb; 2) U-ferric-Hb; 3) U-ferryl-Hb; 4) polymerized low molecular weight (m.w.) Hb with chemically modified surface (< 400 kDa); and 5) glutaraldehyde polymerized, high m.w. Hb (< 1020 kDa). The incubation medium was tested at 6 and 24 hr for lactate dehydrogenase (index of cellular injury), and for ET-1 release by the cells. Before radioimmunoassay, the ET-1 was extracted from cell culture medium by a two-step purification procedure: 1) ultrafiltration, and 2) column extraction with C18 cartridges. The data suggested that the oxidation status of Hb and its concentration play an important role in causing EC injury. The highest toxicity was observed when EC were incubated with 0.1 mmol of ferryl-Hb, and there was no toxicity with 0.3 mmol of ferric-Hb. These results indicate that the ferric-Hb and low m.w. polymerized Hb at a concentration of 0.1 mmol did not alter ET-1 synthesis and produced a level similar to that of the control. However, it was found that ferryl-Hb and ferrous-Hb in a concentration of 0.1 mmol significantly reduced ET-1 release. All Hbs at a concentration of 0.3 mmol markedly inhibited the production of ET-1. The greatest decrease in ET-1 levels was produced by ferryl-Hb, and the lowest by ferric-Hb and low m.w. polymerized Hb. The Hb's inhibitory effect was more pronounced at 24 hr of incubation. It was also found that although Hb molecules showed a high degree of cross-reactivity with polyclonal anti ET-1 antibodies, the presence of different Hb solutions in the EC culture medium did not change the immunologic properties of ET-1 peptide. In conclusion, Hb inhibitory activity toward ET-1 production might be related to Hb mediated endothelial oxidative injury.

Improved blood substitute: evaluation of its effects on human endothelial cells.

The authors have previously documented that appropriate chemical and pharmacologic modification of the hemoglobin molecule are required to attenuate certain pathophysiologic reactions of the reticuloendothelium. The current study further investigates the molecular responses of human coronary artery endothelial cells to a high concentration (0.4 mmol) of 1) unmodified bovine hemoglobin; and 2) an improved blood substitute that comprises hemoglobin cross-linked intramolecularly with o-adenosine triphosphate and intermolecularly with o-adenosine, and conjugated with reduced glutathione. In this study, the scavenging effect of hemoglobins toward nitric oxide (NO) was evaluated by the measurement of nitrite (NO2-) and nitrate (NO3-) formation. The pro-oxidant effect of hemoglobin on endothelial cells was examined by the measurement of intracellular reduced glutathione, and by monitoring the formation of lipid hydroperoxides and 8-iso prostaglandin F2alpha, a novel potent vasoconstrictor, which is produced by a noncyclooxygenase mechanism involving free radical catalyzed peroxidation of arachidonic acid. The inflammatory reactions of endothelial cells were evaluated by the expression of the adhesion molecule, intracellular adhesion molecule-1, and the activation of nuclear transcription factor, nuclear factor kappaB. In additional, endothelial cell responses were investigated by analysis of intracellular ionized calcium concentrations. Results indicate that unmodified hemoglobin in a concentration of 0.4 mmol/L can aggravate endothelial cell oxidative and inflammatory responses. This hemoglobin produced a significant (p < 0.01) depletion of reduced glutathione, acceleration of lipid peroxidation, and a greater influx of Ca2+. The formation of 8-iso prostaglandin F2alpha increased compared with the control cells (p < 0.01). Unmodified hemoglobin was found to be a potent scavenger of NO, great activator of nuclear factor kappaB, and a stimulator of intracellular adhesion molecule-1 expression. Contrarily, the improved blood substitute did not appear to induce oxidative stress nor to increase the intracellular Ca2+. The concentration of 8-iso prostaglandin F2alpha was similar to that in the control cells, whereas the formation of NO2-/NO3- was much lower (p < 0.05) than in the unmodified hemoglobin group. The effect of an improved blood substitute can be linked with the anti-inflammatory and cytoprotective properties of adenosine, which is used as a cross-linker and surface modifier, and the type of the chemical modification procedure that lowers hemoglobin pro-oxidant potential.

Toxic epidermal necrolysis complicated by severe wound sepsis: a case study.

The case of a 74-year-old female who developed toxic epidermal necrolysis (30% TBSA) is presented. Despite early, aggressive treatment, the patient developed severe wound sepsis and multiple-system organ failure. The fulminant wound sepsis was preceded by early endotoxemia. Patient serum suppressed T lymphocyte blastogenesis in the mixed lymphocyte reaction test and neutrophil chemotaxis in vitro. Endotoxin removal (affinity chromatography) resulted in a reverse of serum suppressive activity against T lymphocytes but did not reverse inhibition of PMN chemotaxis. Circulating endotoxin levels remained detectable during the entire course while blood cultures remained negative. It is our belief that early endotoxemia (detected before clinical signs of wound sepsis becomes apparent) leads to immunosuppression and other systemic complications.