Christopher J. Lahart

Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial.

BACKGROUND Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week. METHODS We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drug-susceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat. FINDINGS 1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin twice a week (relative risk 1.64, 95% CI 1.04-2.58, p=0.04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2.8, 95% CI 1.7-4.6); cavitation on chest radiography (3.0, 1.6-5.9); being underweight (3.0, 1.8-4.9); bilateral pulmonary involvement (1.8, 1.0-3.1); and being a non-Hispanic white person (1.8, 1.1-3.0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1.34; 0.83-2.18; p=0.23). Of participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the twice a week group (relative risk 1.15; 95% CI 0.38-3.50; p=0.81). Rates of adverse events and death were similar in the two treatment groups. INTERPRETATION Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.

A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. Results of the Veterans Affairs Cooperative Study.

BACKGROUND Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established. METHODS We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2 x 10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed. RESULTS During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash. CONCLUSIONS In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects.

Factors associated with the use of highly active antiretroviral therapy in patients newly entering care in an Urban clinic

Ethnic minority, female, and drug-using patients may be less likely to receive highly active antiretroviral therapy (HAART), despite its proven benefits. We reviewed the medical records of a consecutive population of 354 patients entering care in 1998 at the Thomas Street Clinic, an academically affiliated, public, HIV-specialty clinic in Houston, to determine the factors associated with not receiving HAART as recorded in pharmacy records. Ninety-two patients (26.0%) did not receive HAART during at least 6 months of follow-up. Patients who did not receive HAART were more likely to be women and to have missed more than two physician appointments and were less likely to have a CD4 count <200 cells/microL or a viral load > or = 10 copies/mL. In multivariate logistic analysis, missed appointments (OR = 5.85, p<.0001), female sex (OR = 2.53, =.001), and CD4 count > or = 200 cells/microL (OR = 2.50, p=.001) were independent predictors of not receiving HAART. More than half the patients who never received HAART never returned to the clinic after their first appointment. Among patients new to care, women and those with poor appointment adherence were less likely to receive HAART. Efforts to improve clinic retention and further study of the barriers to HAART use in women are needed.

Abnormal effects of hypertriacylglycerolemic very low-density lipoproteins on 3-hydroxy-3-methylglutaryl-CoA reductase activity and viability of cultured bovine aortic endothelial cells

Abstract Our previous studies showed that hypertriacylglycerolemic very low-density lipoproteins (VLDL) are functionally abnormal. Hypertriacylglycerolemic VLDL, but not normal VLDL, suppress 3-hydroxy-3-methylglutaryl-CoA reductase in fibroblasts cultured from normal human subjects. To determine if hypertriacylglycerolemic VLDL also differ from normal VLDL in their interaction with vascular cells, their effects on the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase in cultured subconfluent bovine endothelial cells were quantified. All hypertriacylglycerolemic VLDL subclasses (S f 100–400, S f 60–100 and S f 20–60) from a Type III hyperlipoproteinemic subject were even more effective than normal low-density lipoproteins ( d 1.006−1.063) (LDL) in suppression; 50 and 100% suppression by S f 100–400 hypertriacylglycerolemic VLDL occurred at 0.5 and 5 μg protein/ml, respectively. The VLDL subclasses from two subjects with Type V hyperlipoproteinemia were comparable to LDL in suppression. By contrast, under experimental conditions when normal LDL gave 50% suppression at 1–5 μg protein/ml, neither normal S f 100–400 VLDL nor high-density lipoproteins (HDL) ( d 1.063−1.21) suppressed, even at lipoprotein concentrations of 35 and 200 μg protein/ml, respectively. The smaller S f 20–60 VLDL subclass from normal plasma suppressed, but with less than 20% of the potency of LDL. LDL and hypertriacylglycerolemic VLDL also suppressed the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase in confluent endothelial cell cultures. Moreover, exposure to low levels of hypertriacylglycerolemic VLDL, but not normal VLDL or LDL, reduced the number of viable endothelial cells up to 2-fold. We suggest that cytotoxic effects of hypertriacylglycerolemic VLDL on endothelial cells could impair the normal function of the endothelium in vivo.

Potential role for white matter lysosome expansion in HIV-associated dementia.

Expansion of the lysosomal apparatus occurs in subcortical white matter in brains from persons with AIDS. This study examined whether HIV-associated subcortical dementia (HAD) is significantly related to this lysosomal anomaly. Brain cortex and adjacent white matter from the middle frontal gyrus were obtained from the National NeuroAIDS Tissue Consortium. Lysosomal hydrolase activity was assayed in 57 subjects who underwent neuropsychological testing within 6 months prior to autopsy. Decedents were evaluated from 4 geographical sites in the United States: Galveston/Houston, Texas (n = 36), Los Angeles, California (n = 5), New York, New York (n = 5), and San Diego, California (n = 11). Increased β-glucuronidase activity, a representative lysosomal glycosidase, was correlated with the amount of neurocognitive impairment. Significant correlation was present in 5 of 7 functional testing domains, including some that draw upon frontal lobe output (r = 0.419; P < 0.002). The biochemical anomaly was negligible in cerebral cortex and cerebrospinal fluid and was not correlated with brain dysfunction in those compartments. Glycosidase activation was associated significantly with increased HIV RNA concentration in brain tissue (r = 0.469; P < 0.021) and possibly with HIV RNA in cerebrospinal fluid (r = 0.266; P < 0.067). HIV RNA in blood plasma was not correlated. These results support the suggestion that abnormal metabolism in white matter glial cells contributes to cognitive slowing in persons with HAD. Because membrane turnover is routed through the endosome-lysosome apparatus, these data are in agreement with brain spectroscopic data that have suggested that there is an increase in membrane turnover in white matter glia.

The Incidence of Perioperative Myocardial Infarction with Transurethral Resection of the Prostate

We performed a prospective study of 250 men undergoing transurethral resection of the prostate to determine the incidence of perioperative myocardial infarction. The prevalence of coronary artery disease in the study group was 27%. Patients had measurement of total creatine kinase and its MB isoenzyme and electrocardiography preoperatively and on the first three postoperative days. Only one myocardial infarction was diagnosed, an incidence rate of 0.4%. The overall rate of serious postoperative complications was 3.6%. No deaths occurred during the operative hospitalization. We conclude that with transurethral resection perioperative myocardial infarction is a rare event despite the high prevalence of coronary artery disease in this surgical population. Routine postoperative surveillance with electrocardiograms and creatine kinase determinations in asymptomatic patients is not warranted.

Long-term follow-up of symptomatic HIV-infected patients originally randomized to early versus later zidovudine treatment: Report of a Veterans Affairs Cooperative Study

Following a 4-year controlled trial comparing early and later zidovudine treatment, we conducted an additional 3-year follow-up. Of the original 338 patients, 275 participated. Clinical outcome measures were AIDS and death. In the early therapy group (n = 170), 67 patients progressed to AIDS compared with 85 in the later therapy group (n = 168); the relative risk (RR) comparing early with later therapy was 0.72% (95% confidence interval [CI] 0.52-0.99; p = 0.044). The early therapy group had 74 deaths compared with 73 in the later therapy (RR = 0.98; 95% CI, 0.71-1.36; p = 0.91). The early group had a peak CD4+ count increase at 1-2 months and a delay of 1 year before CD4+ counts fell below baseline. For patients who received zidovudine for more than the median duration (20.3 months) before their first AIDS diagnosis, the RR for death was 2.08 (95% CI, 1.36-3.19, p = 0.001). Additional factors independently associated with poor prognosis following AIDS were a CD4+ count of < 100 cells/mm3 and increased severity of the first AIDS diagnosis, whereas use of another antiretroviral agent was associated with improved survival. We conclude that early zidovudine therapy delays progression to AIDS but does not affect survival. Patients who progress to AIDS while on prolonged zidovudine monotherapy many benefit from a change to other antiretroviral therapy(ies).

Determinants of sustained virological suppression in indigent, HIV-infected patients: Is single protease inhibitor-based antiretroviral therapy truly highly active?

Abstract Background: Effective virological suppression with HAART is dependent on strict adherence to therapy. Compliance with therapy is influenced by clinical and psychosocial factors. Method: We performed a retrospective study investigating determinants of effective virological suppression, defined as <400 RNA at 11-13 months of HAART, in an urban indigent population. The study included 366 new patients presenting for care to the Thomas Street Clinic, Houston, Texas, between April and December 1998. Median age, CD4 count, and viral load (VL) of the study population were 37.5 years, 189 cells/mm3, and 53,000, respectively. Thirty-nine percent had AIDS, 20% had cocaine-positive drug screens, and 64% were antiretroviral naïve. Two hundred and sixty-seven patients were started on HAART. Thirty-four percent showed virological suppression. Results: In multivariate analysis, adherence to HAART, care by experienced primary provider, baseline VL <100,000 copies/mL, age >35 years, and no active substance use were associated with virological suppression. Rates of virological suppression with HAART are unacceptably low in this urban indigent population. Conclusion: Low rates of virological suppression are primarily due to lack of adherence rather than late utilization of care among ethnic minorities. Single protease-inhibitor-based antiretroviral therapy does not appear to be highly active in this patient population.

The Frequency and Significance of ECG Changes after Transurethral Prostate Resection

Although many clinicians routinely recommend a baseline preoperative electrocardiogram (ECG) and obtain frequent postoperative ECGs to screen for myocardial infarction or ischemia, the diagnostic utility of screening perioperative ECGs is unknown. The present analysis evaluates the sensitivity and specificity of the perioperative ECG and examines its value as a predictor of early postoperative cardiac events and outcomes during the postoperative year. ECGs obtained preoperatively and on the first 3 postoperative days in 206 men undergoing transurethral prostate resection were analyzed using the Minnesota Code. The occurrence of cardiac events during the operative stay was assessed by measurement of the cardiospecific MB creatine kinase isoenzyme on the first 3 postoperative days and review of the entire clinical course. Twenty‐one percent of patients developed postoperative ECG changes, mostly involving the T wave; none had cardiac symptoms or sustained creatine kinase MB elevation. Changes were not significantly more common in men known to have coronary disease. The single patient who had a perioperative myocardial infarction confirmed by enzymes had no codable ECG changes. The specificity of any ECG change for perioperative infarction was 78%; of ST segment changes only, 95%. Only one of the patients (2%) who had postoperative ECG changes had a cardiac event in the year after surgery. Routine perioperative ECGs is of little diagnostic/predictive utility in situations in which the incidence of perioperative myocardial infarction is low.