Debra Benator

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.

BACKGROUNDnRifapentine 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.nnnMETHODSnWe 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.nnnFINDINGSn1004 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.nnnINTERPRETATIONnRifapentine 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.

Association between Acquired Rifamycin Resistance and the Pharmacokinetics of Rifabutin and Isoniazid among Patients with HIV and Tuberculosis

BACKGROUNDnThe occurrence of acquired rifamycin resistance despite use of directly observed therapy for tuberculosis is associated with advanced human immunodeficiency virus (HIV) disease and highly intermittent administration of antituberculosis drugs. Beyond these associations, the pathogenesis of acquired rifamycin resistance is unknown.nnnMETHODSnWe performed a pharmacokinetic substudy of patients in a trial of treatment with twice-weekly rifabutin and isoniazid.nnnRESULTSnA total of 102 (60%) of 169 patients in the treatment trial participated in the pharmacokinetic substudy, including 7 of 8 patients in whom tuberculosis treatment failure or relapse occurred in association with acquired rifamycin-resistant mycobacteria (hereafter, ARR failure or relapse). The median rifabutin area under the concentration-time curve (AUC(0-24)) was lower for patients with than for patients without ARR failure or relapse (3.3 vs. 5.2 microg*h/mL; P = .06, by the Mann-Whitney exact test). In a multivariate analysis adjusted for CD4+ T cell count, the mean rifabutin AUC(0-24) was significantly lower for patients with ARR failure or relapse than for other patients (3.0 microg*h/mL [95% confidence interval {CI}, 1.9-4.5] vs. 5.2 microg*h/mL [95% CI, 4.6-5.8]; P = .02, by analysis of covariance). The median isoniazid AUC(0-12) was not significantly associated with ARR failure or relapse (20.6 vs. 28.0 microg*h/mL; P = .24, by the Mann-Whitney exact test). However, in a multivariate logistic regression model that adjusted for the rifabutin AUC(0-24), a lower isoniazid AUC(0-12) was associated with ARR failure or relapse (OR, 10.5; 95% CI, 1.1-100; P = .04).nnnCONCLUSIONSnLower plasma concentrations of rifabutin and, perhaps, isoniazid were associated with ARR failure or relapse in patients with tuberculosis and HIV infection treated with twice-weekly therapy.

Is Frequent CD4+ T-Lymphocyte Count Monitoring Necessary for Persons With Counts ≥300 Cells/µL and HIV-1 Suppression?

Among patients infected with human immunodeficiency virus (HIV), those with HIV-1 RNA <200 copies/mL and CD4 counts ≥300 cells/µL had a 97.1% probability of maintaining durable CD4 ≥200 cells/µL for 4 years. When non-HIV causes of CD4 lymphopenia were excluded, the probability rose to 99.2%. Our data support less frequent CD4 monitoring during viral suppression.

Isospora belli Infection Associated with Acalculous Cholecystitis in a Patient with AIDS

Biliary disease is not uncommon in patients with the acquired immunodeficiency syndrome (AIDS) and is a cause of significant morbidity [1, 2]. Possible manifestations include sclerosing cholangitis, papillary stenosis, extrahepatic bile duct strictures, and acute or chronic cholecystitis. The pathogens most commonly associated with biliary disease are cytomegalovirus and Cryptosporidium. Microsporidia, Mycobacterium avium complex, Candida albicans, Pneumocystis carinii, and usual enteric bacteria have been identified less frequently [1-3]. Malignancies, including lymphoma and Kaposi sarcoma, have also been associated with biliary tract disease. However, in as many as 55% of cases, a potential cause cannot be identified [1]. We report the first case of Isospora belli infection associated with biliary disease, specifically with acalculous cholecystitis. Case Report The patient was a 39-year-old homosexual man with a history of injection drug use. The acquired immunodeficiency syndrome was diagnosed in 1985 on the basis of Kaposi sarcoma of the skin; esophageal candidiasis was diagnosed in 1987. He began receiving aerosolized pentamidine as prophylaxis for P. carinii pneumonia. Between 1987 and 1991, he had intermittent diarrhea that was variably associated with night sweats and weight loss. Initial stool examination in 1987 showed Endolimax nana, Entamoeba coli, and Blastocystis hominis; however, fecal samples obtained between 1988 and 1991 were repeatedly negative. Examination of duodenal biopsy specimens on two occasions showed inflammation but no enteric pathogens on hematoxylin and eosin, acid-fast, and cytomegalovirus immunohistochemical stains. In April 1991, the patient developed right upper-quadrant pain, nausea, postprandial vomiting, and diarrhea. Physical examination showed a temperature of 38.9 C and right upper-quadrant tenderness. Noteworthy laboratory findings included a CD4 count of 0.072 109/L, a leukocyte count of 2.4 109/L with 6% eosinophils, and normal alkaline phosphatase, bilirubin, and aminotransferase levels. Ultrasound of the abdomen showed a thick-walled gallbladder with normal biliary ducts; the gallbladder was not seen on radionucleotide biliary scintigraphy. Laparoscopic cholecystectomy for presumed cholecystitis showed a grossly thickened gallbladder wall. Microscopic examination showed marked chronic cholecystitis with architectural atrophy and nonspecific inflammation. No pathogen was identified on hematoxylin and eosin, Brown-Hopps, acid-fast, and Gomori Methenamine Silver stains. Continued nausea, vomiting, abdominal pain, diarrhea, and weight loss characterized the postoperative course. The patient died 4 months later, shortly after a right hemicolectomy for a colo-colic intussusception of the midtransverse colon. Examination of bacterial cultures and the histopathologic findings of operative specimens showed no evidence of enteric pathogens. Permission for postmortem examination was not obtained. Postmortem Review of Pathologic Findings Two years later, during a pathologic review of gallbladders from patients with AIDS, infection with I. belli was diagnosed, first on sections previously stained with hematoxylin and eosin and then confirmed by Giemsa stain of recuts from the paraffin block. Many parasites in all stages of development with distinctive features of I. belli were noted within parasitophorous vacuoles in the cytoplasm of numerous epithelial cells [4] (Figure 1). Free merozoites were noted in areas of epithelial disruption and within the gallbladder lumen. Parasites were not identified in the lamina propria. Associated nonspecific findings that constituted chronic cholecystitis included simplification of the trabecular architecture, diffuse expansion of the lamina propria by a dense lymphoplasmacytic infiltrate and eosinophils, epithelial disarray, and prominent intra-epithelial lymphocytes. A thorough review of all of the patients gastrointestinal biopsy specimens and the colectomy specimen failed to show additional foci of Isospora infection or infection with other enteric pathogens. Figure 1. Isospora belli in the gallbladder. arrow Discussion Isospora belli, a relative of Toxoplasma, Cryptosporidium, and Sarcocystis species, is a protozoan parasite of the Phylum Apicomplexa, Class Sporozoea, Subclass Coccidia, and Family Eimeriidae [5]. It was first recognized as a human pathogen in 1915 [6]. Although numerous species of Isospora are known to infect reptiles, birds, and mammals, only I. belli is known to infect humans [5]. The parasite is acquired after ingestion of a sporulated oocyst, which excysts in the small intestine, invades small intestinal epithelial cells, and undergoes asexual schizogony to form merozoites. The merozoites may undergo further asexual replication (merogony) or sexual replication (gametogony), ultimately forming oocysts that are excreted in the stool, sporulated outside the body in 24 to 48 hours, and again become infectious. Pathologic examination of the duodenum and jejunum typically shows mucosal atrophy with crypt hyperplasia and shortened or fused villi and infiltration of the lamina propria with eosinophils and other inflammatory cells [4]. Isospora belli infection usually causes a gastrointestinal illness that is characterized by loose stools or watery diarrhea and is often associated with abdominal pain, malabsorption, weight loss, and peripheral eosinophilia. Although chronic and severe illness in infants and otherwise healthy adults has been reported [4, 5, 7, 8], in normal hosts the illness is typically self-limited. However, in patients with AIDS and other immunodeficient states, the illness is chronic and may be associated with severe dehydration and debilitation [9-11]. Although isosporiasis is primarily an illness of tropical or subtropical areas, sporadic cases have developed in patients who have not left the mainland United States. Prevalence is estimated to be 15% in the AIDS population in Haiti but less than 0.2% in the U.S. AIDS population [10, 11]. Isospora organisms may be difficult to identify by stool examination because the diagnostic oocysts, seen best by a modified acid-fast stain of concentrated stool, may not be abundant during the initial phase and height of illness, when asexual replication predominates. Diagnosis may require numerous stool examinations and possibly duodenal aspirate or biopsy [9-11]. In 1987, Restrepo and colleagues [12] reported a case of disseminated isosporiasis found during an autopsy of a patient with AIDS. In addition to finding I. belli organisms in all stages of the life cycle in the small and large intestine, Restrepo and colleagues identified merozoites within histiocytes of mediastinal, periaortic, and mesenteric lymph nodes. They suggested that coinfection and ulceration of the intestine caused by cytomegalovirus may have permitted an otherwise unusual lymphohematogenous spread of the parasite. Except for this report of lymphatic dissemination, I. belli infection was thought to be confined to the columnar cells or lamina propia of the intestinal epithelium. To our knowledge, the finding of I. belli in the gallbladder in association with cholecystitis is unique. It is notable that Isospora was never identified in the stool of our patient nor in duodenal biopsy specimens obtained 15 months before and 1 month after his cholecystectomy. Although it could be theorized that sporozoites made their way to the gallbladder without active replication in the intestinal epithelium, this seems unlikely. We suspect that the patient had localized, undetected intestinal infection with subsequent spread from a periampullary focus retrograde into the gallbladder. Because isosporiasis of the gastrointestinal tract responds readily to therapy with trimethoprim-sulfamethoxazole, an associated case of cholecystitis might also resolve with medical treatment. Although the prevalence of this pathogen is low in the United States, and the use of trimethoprim-sulfamethoxazole as prophylaxis for P. carinii pneumonia has probably further reduced its occurrence, I. belli should be considered a part of the spectrum of potentially treatable infectious agents that can cause biliary disease in patients with AIDS.

NONTUBERCULOUS MYCOBACTERIAL INFECTIONS

The acquired immunodeficiency syndrome (AIDS) pandemic has led to greater understanding and respect for the pathogenic potential of non-tuberculous mycobacteria. Mycobacterium avium complex (MAC) has emerged as the most common systemic bacterial infection in AIDS, causing debilitating disseminated disease in late-stage HIV-infected patients. With the release of the macrolide antibiotics, clarithromycin and azithromycin, effective and well-tolerated therapeutic regimens for MAC have been developed which prolong survival and increase quality of life. The macrolides and rifabutin are also effective as preventive therapy for MAC in patients with AIDS. Mycobacterium kansasii, which causes pulmonary disease similar to tuberculosis as well as disseminated disease in AIDS, is treatable with isoniazid, rifampin and ethambutol. Clinical syndromes and therapeutic options for other non-tuberculous mycobacteria in AIDS are also reviewed.

Successful Treatment of Human Immunodeficiency Virus-Related Castleman's Disease with Interferon-α

Multicentric Castlemans disease is an atypical lymphoproliferative disorder for which multiple chemotherapeutic regimens have been used without much success. Role of biological response modifiers like interferon used as a single agent is discussed in this case report.

Evaluation of Xpert MTB/RIF Versus AFB Smear and Culture to Identify Pulmonary Tuberculosis in Patients with Suspected Tuberculosis from Low and Higher Prevalence Settings

BACKGROUNDnThe Xpert MTB/RIF (Xpert) assay is a rapid nucleic acid amplification test widely used in settings of high tuberculosis prevalence to detect tuberculosis as well asrpoBmutations associated with rifampin resistance. Data are needed on the diagnostic performance of Xpert in lower-prevalence settings to inform appropriate use for both tuberculosis detection and the need for respiratory isolation.nnnMETHODSnXpert was compared to 2 sputum samples, each evaluated with acid-fast bacilli (AFB) smear and mycobacterial culture using liquid and solid culture media, from participants with suspected pulmonary tuberculosis from the United States, Brazil, and South Africa.nnnRESULTSnOf 992 participants enrolled with evaluable results, 22% had culture-confirmed tuberculosis. In 638 (64%) US participants, 1 Xpert result demonstrated sensitivity of 85.2% (96.7% in participants with AFB smear-positive [AFB(+)] sputum, 59.3% with AFB smear-negative [AFB(-)] sputum), specificity of 99.2%, negative predictive value (NPV) of 97.6%, and positive predictive value of 94.9%. Results did not differ between higher- and low-prevalence settings. A second Xpert assay increased overall sensitivity to 91.1% (100% if AFB(+), 71.4% if AFB(-)), with specificity of 98.9%. In US participants, a single negative Xpert result predicted the absence of AFB(+)/culture-positive tuberculosis with an NPV of 99.7%; NPV of 2 Xpert assays was 100%, suggesting a role in removing patients from airborne infection isolation. Xpert detected tuberculosis DNA and mutations associated with rifampin resistance in 5 of 7 participants with rifampin-resistant, culture-positive tuberculosis. Specificity for rifampin resistance was 99.5% and NPV was 98.9%.nnnCONCLUSIONSnIn the United States, Xpert testing performed comparably to 2 higher-tuberculosis-prevalence settings. These data support the use of Xpert in the initial evaluation of tuberculosis suspects and in algorithms assessing need for respiratory isolation.

Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons.

Objective: Compare the effectiveness, tolerability, and safety of 3 months of weekly rifapentine and isoniazid under direct observation (3HP) versus 9 months of daily isoniazid (9H) in HIV-infected persons. Design: Prospective, randomized, and open-label noninferiority trial. Setting: The United States , Brazil, Spain, Peru, Canada, and Hong Kong. Participants: HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases. Intervention: 3HP versus 9H. Main outcome measures: The effectiveness endpoint was tuberculosis; the noninferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation because of adverse drug reaction. Results: Median baseline CD4+ cell counts were 495 (IQR 389–675) and 538 (IQR 418–729) cells/&mgr;l in the 3HP and 9H arms, respectively (Pu200a=u200a0.09). In the modified intention-to-treat analysis, there were two tuberculosis cases among 206 persons [517 person-years (p-y) of follow-up] in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01 versus 3.50% in the 3HP and 9H arms, respectively (rate difference: −2.49%; upper bound of the 95% confidence interval of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (Pu200a<u200a0.001), and drug discontinuation because of an adverse drug reaction was similar (3 vs. 4%; Pu200a=u200a0.79) in 3HP and 9H, respectively. Conclusion: Among HIV-infected persons with median CD4+ cell count of approximately 500 cells/&mgr;l, 3HP was as effective and safe for treatment of latent Mycobacterium tuberculosis infection as 9H, and better tolerated.

Better But Not Ideal Acceptance of Routine Inpatient HIV Point-of-Care Testing Among Veterans in a High Prevalence Area

Background:The most recent guidance statement from The American College of Physicians recommends that clinicians adopt human immunodeficiency virus screening as part of routine medical care. Inpatient HIV testing at the Vetarns Affairs Medical Center in Washington, DC has been predominantly targeted at patients with disclosed risk factors. Method:We implemented the first voluntary inpatient HIV testing program within a Veterans Affairs hospital using the OraQuick Advance Rapid HIV-1/2 Antibody Test on both oral secretion and whole blood samples. Results:During a 17 month period we offered 3,467 inpatients testing and performed 824 rapid HIV tests. All reactive results were Western blot confirmed. Ten patients (1.2%) had reactive test results. Seven (0.8%) represented new HIV diagnoses, and three had been previously diagnosed outside the VA. Five patients had AIDS at the time of testing by CD4 criteria. Nine patients were linked to care and six patients were started on antiretroviral therapy. There were no false-positive results. Conclusion:We have demonstrated how expanding HIV-POC testing among hospitalized patients can enhance patients acceptance for screening, can detect HIV-infected individuals who might not have been tested with conventional targeted testing, and can improve linkage to care for those with HIV infection.

Vitamin D Deficiency is Less Common Among HIV-infected African-American Men Than in a Matched Cohort.

The aim of this study was to compare the prevalence of vitamin D sufficiency and deficiency in a HIV-infected cohort of African–American men with that of a general population. We found median vitamin D concentrations were significantly greater in the HIV-infected cohort, 18 ng/ml as compared to the National Health and Nutrition Examination Survey cohort, 14 ng/ml (P < 0.0001). Thus, factors other than measured vitamin D are likely to be responsible for higher rates of bone disease in this population.