J. Allen McCutchan

Treatment of Gram-Negative Bacteremia and Shock with Human Antiserum to a Mutant Escherichia coli

Abstract In an effort to decrease deaths from gram-negative bacteremia and endotoxin shock, we treated bacteremic patients with human antiserum to endotoxin (lipopolysaccharide) core. Antiserum was prepared by vaccinating healthy men with heat-killed Escherichia coli J5; this mutant lacks lipopolysaccharide oligosaccharide side chains, so that the core, which is nearly identical to that of most other gram-negative bacteria, is exposed for antibody formation. In a randomized controlled trial, patients were given either J5 antiserum or preimmune control serum intravenously, near the onset of illness. The number of deaths in the bacteremic patients was 42 of 109 (39 per cent) in controls and 23 of 103 (22 per cent) in recipients of J5 antiserum (P = 0.011). In those with profound shock, mortality was 30 of 39 (77 per cent) in controls and 18 of 41 (44 per cent) in recipients of J5 antiserum (P = 0.003). We conclude that human antiserum to the lipopolysaccharide core can substantially reduce deaths from gram-...

HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors.

Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.

Validation of the CNS Penetration-Effectiveness Rank for Quantifying Antiretroviral Penetration Into the Central Nervous System

OBJECTIVE To evaluate whether penetration of a combination regimen into the central nervous system (CNS), as estimated by the CNS Penetration-Effectiveness (CPE) rank, is associated with lower cerebrospinal fluid (CSF) viral load. DESIGN Data were analyzed from 467 participants who were human immunodeficiency virus (HIV) seropositive and who reported antiretroviral (ARV) drug use. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high) based on their chemical properties, concentrations in CSF, and/or effectiveness in the CNS in clinical studies. The CPE rank was calculated by summing the individual penetration ranks for each ARV in the regimen. RESULTS The median CPE rank was 1.5 (interquartile range, 1-2). Lower CPE ranks correlated with higher CSF viral loads. Ranks less than 2 were associated with an 88% increase in the odds of detectable CSF viral load. In multivariate regression, lower CPE ranks were associated with detectable CSF viral loads even after adjusting for total number of ARV drugs, ARV drug adherence, plasma viral load, duration and type of the current regimen, and CD4 count. CONCLUSIONS Poorer penetration of ARV drugs into the CNS appears to allow continued HIV replication in the CNS as indicated by higher CSF HIV viral loads. Because inhibition of HIV replication in the CNS is probably critical in treating patients who have HIV-associated neurocognitive disorders, ARV treatment strategies that account for CNS penetration should be considered in consensus treatment guidelines and validated in clinical studies.

The HNRC 500-Neuropsychology of Hiv infection at different disease stages

The present study examined neuropsychological (NP) functioning and associated medical, neurological, brain magnetic resonance imaging (MRI), and psychiatric findings in 389 nondemented males infected with Human Immunodeficiency Virus-Type 1 (HIV-1), and in 111 uninfected controls. Using a comprehensive NP test battery, we found increased rates of impairment at each successive stage of HIV infection. HIV-related NP impairment was generally mild, especially in the medically asymptomatic stage of infection, and most often affected attention, speed of information processing, and learning efficiency; this pattern is consistent with earliest involvement of subcortical or frontostriatal brain systems. NP impairment could not be explained on the bases of mood disturbance, recreational drug or alcohol use, or constitutional symptoms; by contrast, impairment in HIV-infected subjects was related to central brain atrophy on MRI, as well as to evidence of cellular immune activation and neurological abnormalities linked to the central nervous system.

Evidence for Early Central Nervous System Involvement in the Acquired Immunodeficiency Syndrome (AIDS) and Other Human Immunodeficiency Virus (HIV) Infections: Studies with Neuropsychologic Testing and Magnetic Resonance Imaging

Although a high prevalence of central nervous system disease is seen in persons with the acquired immunodeficiency syndrome (AIDS), the natural history of brain involvement with human immunodeficiency virus (HIV) remains poorly understood. Neuropsychologic evaluations of 55 ambulatory homosexual men revealed abnormalities in 13 of 15 with AIDS, 7 of 13 [corrected] with AIDS-related complex, 7 of 16 [corrected] with HIV-seropositivity only, and 1 of 11 with HIV-seronegativity. Common neuropsychologic problems included impaired abstracting ability, learning difficulties, and slowed speed of information processing. Magnetic resonance imaging had abnormal findings in 9 of 13 patients with AIDS and 5 of 10 patients with AIDS-related complex who were available for scans. The commonest abnormalities were sulcal and ventricular enlargement and bilateral patchy areas of high signal intensity in the white matter. We postulate that central nervous system involvement by HIV may begin early in the course of AIDS and cause mild cognitive deficits in otherwise asymptomatic persons.

PREVENTION OF GRAM-NEGATIVE SHOCK AND DEATH IN SURGICAL PATIENTS BY ANTIBODY TO ENDOTOXIN CORE GLYCOLIPID

The prophylactic effect of antibody to endotoxin core glycolipid was studied in surgical patients at high risk of gram-negative infection. At randomisation (on admission to intensive care unit), every 5 days thereafter, and at onset of septic shock, patients received plasma taken from donors before (control) or after immunisation with Escherichia coli J5, a mutant with only core determinants in its endotoxin. Gram-negative shock occurred in 15 of 136 controls and 6 of 126 J5 antibody recipients and related deaths in 9 of 136 and 2 of 126, respectively. J5 antibody was most effective in abdominal surgery patients, in whom shock occurred in 13 of 83 controls and 2 of 71 antibody recipients. Although antibody prophylaxis did not lower the infection rate, it prevented the serious consequences of gram-negative infections and thus improved the overall prognosis.

Prophylaxis against Disseminated Mycobacterium avium Complex with Weekly Azithromycin, Daily Rifabutin, or Both

BACKGROUND Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once-weekly dosing. METHODS We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. RESULTS In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. CONCLUSIONS For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated.

Treatment of Toxoplasmic Encephalitis in Patients with AIDS: A Randomized Trial Comparing Pyrimethamine plus Clindamycin to Pyrimethamine plus Sulfadiazine

OBJECTIVE To compare pyrimethamine plus clindamycin (PC) to pyrimethamine plus sulfadiazine (PS) as a treatment for toxoplasmic encephalitis (TE) in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN Randomized, unblinded phase II, multicenter trial with provision for crossover for failure or intolerance of the assigned regimen. SETTING University hospitals. PATIENTS Eighty-four patients with presumptive TE were entered. Thirteen were excluded when they were found to have another diagnosis, and 12 were excluded because they did not meet entry criteria. The baseline characteristics in the remaining 26 patients randomized to PC and 33 randomized to PS were comparable. INTERVENTIONS Patients were treated for 6 weeks with pyrimethamine and folinic acid plus either sulfadiazine or clindamycin. Clindamycin was given intravenously during the first 3 weeks. MEASUREMENTS AND MAIN RESULTS There was a trend toward greater survival in patients randomized to PS (hazard ratio, 3.25; 95% CI, 0.63 to 16.8; P = 0.13), but most study deaths were not directly related to TE. In contrast, patients randomized to PC appeared more likely to achieve complete clinical (odds ratio, 0.67; CI, 0.2 to 1.97; P greater than 0.2) and radiologic responses (odds ratio, 0.28; CI, 0.08 to 0.96; P = 0.02). Multivariate analysis revealed drug effects to be largely independent of other variables. Similar efficacy of the treatments was also suggested by a hazard analysis of resolution of abnormal mental status, fever, and headache. Skin rash was the most common adverse event in both treatment arms. Because of toxicity, six patients randomized to PC and 11 patients randomized to PS had to switch to the alternate treatment, but only three were unable to complete therapy after crossover. CONCLUSIONS The results of several end points of efficacy, taken together, suggest that the relative efficacy of PC approximately equals that of PS. PC appears to be an acceptable alternative in patients unable to tolerate PS.

CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy

Objective:Despite immune recovery in individuals on combination antiretroviral therapy (CART), the frequency of HIV-associated neurocognitive disorders (HANDs) remains high. Immune recovery is typically achieved after initiation of ART from the nadir, or the lowest historical CD4. The present study evaluated the probability of neuropsychological impairment (NPI) and HAND as a function of CD4 nadir in an HIV-positive cohort. Methods:One thousand five hundred and twenty-five HIV-positive participants enrolled in CNS HIV Antiretroviral Therapy Effects Research, a multisite, observational study that completed comprehensive neurobehavioral and neuromedical evaluations, including a neurocognitive test battery covering seven cognitive domains. Among impaired individuals, HAND was diagnosed if NPI could not be attributed to comorbidities. CD4 nadir was obtained by self-report or observation. Potential modifiers of the relationship between CD4 nadir and HAND, including demographic and HIV disease characteristics, were assessed in univariate and multivariate analyses. Results:The median CD4 nadir (cells/&mgr;l) was 172, and 52% had NPI. Among impaired participants, 603 (75%) had HAND. Higher CD4 nadirs were associated with lower odds of NPI such that for every 5-unit increase in square-root CD4 nadir, the odds of NPI were reduced by 10%. In 589 virally suppressed participants on ART, higher CD4 nadir was associated with lower odds of NPI after adjusting for demographic and clinical factors. Conclusion:As the risk of NPI was lowest in patients whose CD4 cell count was never allowed to fall to low levels before CART initiation, our findings suggest that initiation of CART as early as possible might reduce the risk of developing HAND, the most common source of NPI among HIV-infected individuals.

A Placebo-Controlled Trial of Maintenance Therapy with Fluconazole after Treatment of Cryptococcal Meningitis in the Acquired Immunodeficiency Syndrome

BACKGROUND AND METHODS In patients with the acquired immunodeficiency syndrome (AIDS), the rate of relapse after primary treatment for cryptococcal meningitis remains high. We conducted a controlled, double-blind trial to evaluate the efficacy of maintenance therapy with fluconazole. At entry into the study, all participants had sterile cultures of cerebrospinal fluid, blood, and urine after following a standardized course of therapy for culture-proved cryptococcal meningitis. The patients were randomly assigned to take either fluconazole or placebo as maintenance therapy. The dose of fluconazole was 100 mg daily in the first phase of study and 200 mg daily in the second phase. RESULTS Of 84 patients initially enrolled, 16 (19 percent) were found to have silent, persistent infection on the basis of cultures that became positive after entry into the study; 7 other patients were lost to follow-up shortly after entry. Of the remaining 61 patients, 10 of 27 assigned to placebo (37 percent) and 1 of 34 assigned to fluconazole (3 percent) had a recurrence of cryptococcal infection at any site (difference in risk, 34 percent; 95 percent confidence interval, 15 to 53). Of the 11 recurrent infections, 7 were detected in urine obtained after prostatic massage. There were four recurrent meningeal infections in the patients taking placebo, but none in those taking fluconazole (mean duration of follow-up, 164 days) (P = 0.03). In multivariate analyses, the best predictors of recurrence-free survival were fluconazole treatment (P = 0.02; relative hazard, 13.2), a lower serum cryptococcal-antigen titer (P = 0.05; relative hazard, 1.2), and more prolonged primary therapy with flucytosine (P = 0.09; relative hazard, 1.1). Survival and toxicity were similar in the two maintenance-treatment groups. CONCLUSIONS In patients with AIDS, silent persistent infection is common after clinically successful treatment for cryptococcal meningitis. Maintenance therapy with fluconazole is highly effective in preventing recurrent cryptococcal infection.