Summary The link between diabetes mellitus and tuberculosis has been recognised for centuries. In recent decades, tuberculosis incidence has declined in high-income countries, but incidence remains ...high in countries that have high rates of infection with HIV, high prevalence of malnutrition and crowded living conditions, or poor tuberculosis control infrastructure. At the same time, diabetes mellitus prevalence is soaring globally, fuelled by obesity. There is growing evidence that diabetes mellitus is an important risk factor for tuberculosis and might affect disease presentation and treatment response. Furthermore, tuberculosis might induce glucose intolerance and worsen glycaemic control in people with diabetes. We review the epidemiology of the tuberculosis and diabetes epidemics, and provide a synopsis of the evidence for the role of diabetes mellitus in susceptibility to, clinical presentation of, and response to treatment for tuberculosis. In addition, we review potential mechanisms by which diabetes mellitus can cause tuberculosis, the effects of tuberculosis on diabetic control, and pharmacokinetic issues related to the co-management of diabetes and tuberculosis.
Summary The billions of people with latent tuberculosis infection serve as the seedbeds for future cases of active tuberculosis. Virtually all episodes of tuberculosis disease are preceded by a ...period of asymptomatic Mycobacterium tuberculosis infection; therefore, identifying infected individuals most likely to progress to disease and treating such subclinical infections to prevent future disease provides a crucial opportunity to interrupt tuberculosis transmission and reduce the global burden of tuberculosis disease. Programmes focusing on single strategies rather than comprehensive programmes that deliver an integrated arsenal for tuberculosis control might continue to struggle. Tuberculosis preventive therapy is a poorly used method that is essential for controlling the reservoirs of disease that drive the epidemic. Comprehensive control strategies that combine preventive therapy for the most high-risk populations and communities with improved case-finding and treatment, control of transmission, and health systems strengthening could ultimately lead to worldwide tuberculosis elimination. In this Series paper we outline challenges to implementation of preventive therapy and provide pragmatic suggestions for overcoming them. We further advocate for tuberculosis preventive therapy as the core of a renewed worldwide focus to implement a comprehensive epidemic control strategy that would reduce new tuberculosis cases to elimination targets. This strategy would be underpinned by accelerated research to further understand the biology of subclinical tuberculosis infections, develop novel diagnostics and drug regimens specifically for subclinical tuberculosis infection, strengthen health systems and community engagement, and enhance sustainable large scale implementation of preventive therapy programmes.
Background Of patients undergoing cardiac surgery in the United States, 15% to 20% are re-hospitalized within 30 days. Current models to predict readmission have not evaluated the association between ...severity of postoperative acute kidney injury (AKI) and 30-day readmissions. Methods We collected data from 2,209 consecutive patients who underwent either coronary artery bypass or valve surgery at 7 member hospitals of the Northern New England Cardiovascular Disease Study Group Cardiac Surgery Registry between July 2008 and December 2010. Administrative data at each hospital were searched to identify all patients readmitted to the index hospital within 30 days of discharge. We defined AKI stages by the AKI Network definition of 0.3 or 50% increase (stage 1), twofold increase (stage 2), and a threefold or 0.5 increase if the baseline serum creatinine was at least 4.0 (mg/dL) or new dialysis (stage 3). We evaluate the association between stages of AKI and 30-day readmission using multivariate logistic regression. Results There were 260 patients readmitted within 30 days (12.1%). The median time to readmission was 9 (interquartile range, 4 to 16) days. Patients not developing AKI after cardiac surgery had a 30-day readmission rate of 9.3% compared with patients developing AKI stage 1 (16.1%), AKI stage 2 (21.8%), and AKI stage 3 (28.6%, p < 0.001). Adjusted odds ratios for AKI stage 1 (1.81; 1.35, 2.44), stage 2 (2.39; 1.38, 4.14), and stage 3 (3.47; 1.85 to 6.50). Models to predict readmission were significantly improved with the addition of AKI stage (c-statistic 0.65, p = 0.001) and net reclassification rate of 14.6% (95% confidence interval: 5.05% to 24.14%, p = 0.003). Conclusions In addition to more traditional patient characteristics, the severity of postoperative AKI should be used when assessing a patient's risk for readmission.
Summary Background New treatments are needed to shorten the time required to cure tuberculosis and to treat drug-resistant strains. The fluoroquinolone moxifloxacin is a promising new agent that ...might have additive activity to existing antituberculosis agents. We assessed the activity and safety of moxifloxacin in the initial stage of tuberculosis treatment. Methods We undertook a phase II, double-blind, randomised controlled trial of a regimen that included moxifloxacin in adults with sputum smear-positive tuberculosis at one hospital in Rio de Janeiro, Brazil. 170 participants received isoniazid, rifampicin, and pyrazinamide at standard doses and were assigned by permuted block randomisation to receive either moxifloxacin (400 mg) with an ethambutol placebo (n=85) or ethambutol (15–20 mg/kg) plus moxifloxacin placebo (n=85) 5 days per week for 8 weeks. The primary endpoint was the proportion of patients whose sputum culture had converted to negative by week 8. Analysis was by modified intention to treat (ITT); patients whose baseline cultures were negative, contaminated, or contained drug-resistant Mycobacterium tuberculosis were excluded from the analysis. Additionally, all missing 8-week results were deemed treatment failures. This study is registered with ClinicalTrials.gov , number NCT00082173. Findings 74 patients assigned to the moxifloxacin group and 72 in the ethambutol group were included in the modified ITT population. 125 patients had 8-week data (moxifloxacin n=64, ethambutol n=61); the main reason for absence of data was culture contamination. At 8 weeks, culture conversion to negative had occurred in 59 (80%) of 74 patients in the moxifloxacin group compared with 45 (63%) of 72 in the ethambutol group (difference 17·2%, 95% CI 2·8–31·7; p=0·03). There were 16 adverse events (eight in each group) in 12 patients. Only one event was judged related to study drug (grade 3 cutaneous reaction in the ethambutol group). Interpretation Moxifloxacin improved culture conversion in the initial phase of tuberculosis treatment. Trials to assess whether moxifloxacin can be used to shorten the duration of tuberculosis treatment are justified. Funding US Food and Drug Administration Office of Orphan Product Development, with additional support from the US National Institutes of Health.
Summary Background Preventive therapy for tuberculosis in patients with HIV is effective, but it has not been widely implemented in moderate or high-burden settings. We assessed the effect of ...widespread use of isoniazid preventive therapy on rates of tuberculosis and death in people with HIV in Brazil. Methods We did a stepped wedge, cluster-randomised trial with patients actively enrolled in 29 HIV clinics in Rio de Janeiro. Clinic staff were trained in tuberculosis screening, use of tuberculin skin tests, and use of isoniazid preventive therapy. Clinics were randomly allocated a date to begin the intervention period, with two clinics beginning the intervention every 2 months starting from Sept 1, 2005. The primary outcome was tuberculosis incidence alone or combined with death in the control versus intervention periods until Aug 31, 2009. This trial is registered at ClinicalTrials.gov , number NCT00107887. Results Of 17 413 patients in the cohort, 12 816 were eligible for the intervention. Overall, there were 475 tuberculosis cases and 838 deaths. The intervention increased the rate of patients receiving skin tests from 19 per 100 person-years to 59 per 100 person-years, and from 36 per 100 person-years to 144 per 100 person-years for those eligible for isoniazid preventive therapy. In the control period, 221 cases of tuberculosis were diagnosed (1·31 per 100 person-years) compared with 254 (1·10 per 100 person-years) in the intervention period (unadjusted hazard ratio HR 0·87; 95% CI 0·69–1·10). Rates of tuberculosis incidence or death were 3·64 and 3·04 per 100 person-years, respectively (0·76; 95% CI 0·66–0·87). When adjusted for age, sex, entry CD4 count, and use of antiretroviral therapy, the HR for tuberculosis was 0·73 (95% CI 0·54–0·99) and for tuberculosis or death was 0·69 (0·57–0·83). Interpretation Operational training aimed at increasing tuberculosis screening, provision of tuberculin skin tests, and use of isoniazid preventive therapy in Brazilian HIV clinics significantly reduced incident tuberculosis and death. Thus, scale-up of preventive therapy for HIV-infected patients in settings of moderate tuberculosis incidence is achievable and should be widely implemented in Brazil and elsewhere. Funding Bill & Melinda Gates Foundation and the National Institutes of Health.
CONTEXT Because of problems with adherence, toxicity, and increasing resistance
associated with 6- to 12-month isoniazid regimens, an alternative short-course
tuberculosis preventive regimen is ...needed. OBJECTIVE To compare a 2-month regimen of daily rifampin and pyrazinamide with
a 12-month regimen of daily isoniazid in preventing tuberculosis in persons
with human immunodeficiency virus (HIV) infection. DESIGN Randomized, open-label controlled trial conducted from September 1991
to May 1996, with follow-up through October 1997. SETTING Outpatient clinics in the United States, Mexico, Haiti, and Brazil. PARTICIPANTS A total of 1583 HIV-positive persons aged 13 years or older with a positive
tuberculin skin test result. INTERVENTIONS Patients were randomized to isoniazid, 300 mg/d, with pyridoxine hydrochloride
for 12 months (n = 792) or rifampin, 600 mg/d, and pyrazinamide, 20 mg/kg
per day, for 2 months (n = 791). MAIN OUTCOME MEASURES The primary end point was culture-confirmed tuberculosis; secondary
end points were proven or probable tuberculosis, adverse events, and death,
compared by treatment group. RESULTS Of patients assigned to rifampin and pyrazinamide, 80% completed the
regimen compared with 69% assigned to isoniazid (P<.001).
After a mean follow-up of 37 months, 19 patients (2.4%) assigned to rifampin
and pyrazinamide and 26 (3.3%) assigned to isoniazid developed confirmed tuberculosis
at rates of 0.8 and 1.1 per 100 person-years, respectively (risk ratio, 0.72
95% confidence interval, 0.40-1.31; P = .28). In
multivariate analysis, there were no significant differences in rates for
confirmed or probable tuberculosis (P = .83), HIV
progression and/or death (P = .09), or overall adverse
events (P = .27), although drug discontinuation was
slightly higher in the rifampin and pyrazinamide group (P = .01). Neither regimen appeared to lead to the development of drug-resistant
tuberculosis. CONCLUSIONS Our data suggest that for preventing tuberculosis in HIV-infected patients,
a daily 2-month regimen of rifampin and pyrazinamide is similar in safety
and efficacy to a daily 12-month regimen of isoniazid. This shorter regimen
offers practical advantages to both patients and tuberculosis control programs.
There are now several alternative drug regimens that have been shown to be effective in preventing
Mycobacterium avium complex (MAC) disease in human immunodeficiency virus (HIV)-infected patients. ...The effectiveness and the costs of these drugs should be taken into account when choosing a specific drug regimen, as the cost of treating MAC can be relatively high. Our results are formulated from an analysis to assess the comparative cost-effectiveness of available prophylactic drugs for MAC. A decision analysis was undertaken comparing no prophylaxis and prophylaxis with either rifabutin, clarithromycin, azithromycin, or azithromycin and rifabutin in combination. Estimates of effectiveness of prophylaxis and costs of illness were obtained from published literature. Drug costs were based on national average wholesale prices. Sensitivity analyses were done over plausible ranges of estimates of cost and effectiveness. Given our baseline assumptions, the most cost-effective regimen in regard to cases of avoided MAC or death is azithromycin used alone. Clarithromycin used alone is the next most cost-effective approach. Combination therapy with azithromycin and rifabutin is less cost-effective than macrolide monotherapy, and rifabutin used alone is less cost-effective than any of the macrolide-containing regimens. Using some type of MAC prophylaxis is preferable to no prophylaxis when considering cost as well as efficacy. At current prices and using currently available effectiveness data, azithromycin is probably the most cost-effective choice of prophylactic therapy for MAC. Not using MAC prophylaxis is the least cost-effective option. Prevention of MAC with drug therapy provides clinical benefit at a reasonable cost.
Baltimore is an urban center that has been highly impacted by human immunodeficiency virus (HIV) and hepatitis C virus (HCV); however, many individuals are unaware of their HIV and/or HCV status. In ...2013, the Johns Hopkins Center for AIDS Research (CFAR) developed Generation Tomorrow, an HIV and HCV education, testing, and counseling program with community input and collaboration.
The aims of Generation Tomorrow are to increase HIV and HCV awareness and detection in Baltimore and engage the next generation of health professionals (students) and community members (peers) in HIV and HCV outreach services.
The Generation Tomorrow educational component includes formal HIV and HCV testing and counselling training, and a lecture series for students and peers. The participants then engage in field assignments and outreach events with Johns Hopkins associated programs or community-based organizations.
Generation Tomorrow trained 71 students and peers in three cohorts, 70% of whom reported that they planned to stay in HIV- and/or HCV-related work. From October 2014 to May 2015, which represents the first year that Generation Tomorrow ran with the full academic calendar, Generation Tomorrow students and peers worked with partner organizations to conduct 1,104 HIV rapid antibody tests and found 19 individuals (1.72%) to be HIV positive. Additionally, 778 HCV rapid antibody tests were conducted and 175 individuals (22.5%) were HCV antibody positive.
Generation Tomorrow has been successful in engaging students and community peers in HIV and HCV education, testing, and counseling, and has documented HIV and HCV positivity rates well above general community prevalence.
We assessed the effect of antiviral therapy on serum human immunodeficiency virus core antigen (HIV-Ag) levels in patients enrolled in the phase II trial on zidovudine for acquired immunodeficiency ...syndrome (AIDS) and AIDS-related complex. Human immunodeficiency virus core antigen was detected in 45% of subjects at entry (59% with AIDS and 37% of patients with AIDS-related complex). Median HIV-Ag levels in zidovudine-treated subjects fell from 111 pg/mL at entry to 46 pg/mL at four weeks, while levels in placebo recipients did not change significantly. Decline in HIV-Ag in zidovudine recipients was sustained through 16 weeks of treatment and was significantly different from the placebo group. Anti-p24 antibody levels did not change in either group. We conclude that in patients with HIV-antigenemia changes in HIV-Ag level are an important marker of anti-retroviral activity.
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