Articles tagged as "Avoid TB deaths"

Efavirenz dose adjustments are probably not required in patients taking concurrent rifampicin

Relationship between weight, efavirenz exposure and virologic suppression in HIV-infected patients on rifampin-based TB treatment in the ACTG A5221 STRIDE study

Luetkemeyer AF, Rosenkranz SL, Lu D, Marzan F, Ive P, Hogg E, et al. Adult AIDS Clinical Trials Group A5221 Study Team. Clinical Infectious Diseases Advance Access published April 19, 2013.

Background: Rifampin (RIF) upregulates CYP 450 isoenzymes potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends EFV dose increase for patients on RIF weighing ≥50 kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations (Cmin) and HIV virologic suppression in patients on EFV (600 mg) and RIFbased TB treatment as part of a multicenter randomized trial (ACTG A5221)

Methods: EFV Cmin was measured using HPLC 20‐28 hours post‐EFV dose at weeks 4,8,16,24 on‐RIF and weeks 4,8 off‐RIF. Results evaluated with two‐sided Wilcoxon rank‐sum, chi‐square and Fisher's Exact tests and logistic regression (5% Type I error rate).

Results: 780 patients from 11 countries received EFV, 543 provided ≥ 1 EFV Cmin. Median (IQR) weight was 52.8 kg (48.0,59.5), BMI 19.4 kg/m2 (17.5,21.6), age 34 (29,41), 63% male, race Black (74%), Hispanic (20%), non‐Hispanic White (5%), Asian (1%). Median Cmin was 1.96μg/mL onRIF vs. 1.80 offRIF (p=0.067). EFV concentrations were significantly higher onRIF vs. offRIF in Blacks (2.08 vs. 1.75, p=0.005). Weight ≥60 kg onRIF, compared to <60 kg, was associated with lower EFV Cmin (1.68 vs. 2.02, p=0.021). However, weight ≥60 kg was associated with more frequent HIV RNA<400 copies/mL at week 48, compared to weight <60 kg (81.9% vs. 73.8%, p=0.023).

Conclusions: Coadministration of EFV and RIFbased TB therapy was associated with a trend toward higher, not lower, EFV Cmin compared to EFV alone, which was statistically significant in Black patients. Patients weighing ≥60 kg had lower median EFV Cmin vs. those <60 kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weightbased dosing of EFV with RIF co-administration.

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Editor’s notes: Effective treatment of HIV-TB co-infection is complicated by drug-drug interactions. Rifampicin, the key component of effective anti-TB therapy, is a potent inducer of the cytochrome P450 enzymes which metabolize many antiretrovirals including efavirenz. Appropriate dosing of efavirenz in patients taking concomitant TB treatment has been debated, with both US and British national treatment guidelines recommending efavirenz dose increases. The WHO does not recommend adjusting dosing. This study, an analysis of efavirenz levels from 543 participants in the STRIDE study of ART timing in TB co-infected patients, suggests that efavirenz dose adjustments are not required in patients taking concurrent rifampicin based TB treatment. Efavirenz levels were not reduced in patients who were taking TB treatment. In fact trough efavirenz levels were slightly increased in patients during TB treatment. This increase in efavirenz levels was most marked in black patients. Virological outcomes with efavirenz based ART in this cohort of patients on TB treatment were good, with 76% fully suppressed at 48 weeks.  Perhaps unsurprisingly, efavirenz levels were slightly lower in patients weighing over 60 kg compared to those below 60 kg, but this did not translate into worse virological outcomes. Given the racial differences seen in efavirenz metabolism in this study there is a question about the generalisability of the study to certain populations, notably Caucasians who only made up 5% of the study population. However the demographics were representative of the vast majority of HIV-TB co-infected patients worldwide. These results strongly suggest that efavirenz at standard doses can be safely used in patients receiving rifampicin based TB treatment, avoiding the need to complicate ART treatment regimens in the large number of individuals receiving TB treatment in resource-limited public health programmes.

Avoid TB deaths
Comorbidity, HIV Treatment
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Combination antifungal therapy reduces mortality in HIV-associated cryptococcal meningitis

Combination Antifungal Therapy for Cryptococcal Meningitis

Day JN, Chau TTH, Wolbers M, Mai PP, Dung NT, Mai NH, et al. N Engl J Med 2013;368:1291-302.

Background: Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days.

Methods: We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks.

Results: A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P = 0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P = 0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P = 0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P = 0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy.

Conclusions: Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.)

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Editor’s notes: Cryptococcal meningitis remains a leading cause of mortality in HIV-infected individuals in much of Africa and parts of South-East Asia, causing an estimated one million cases and 625,000 deaths every year. Previous studies have demonstrated that combination antifungal therapy with amphotericin B and flucytosine leads to more rapid clearance of cryptococci from the cerebrospinal fluid (CSF) of patients with cryptococcal meningitis than amphotericin B alone. This randomized controlled trial from Vietnam is the first to show improved clinical outcomes in patients receiving combination therapy. Amphotericin B plus flucytosine was associated with both faster rates of yeast clearance from the CSF and fewer deaths at two weeks and 10 weeks than monotherapy. The investigators also studied the combination of amphotericin with high dose fluconazole – a relatively inexpensive and widely available antifungal drug. Combination therapy with amphotericin B and high dose fluconazole did not lead to more rapid clearance of infection than amphotericin alone, or to substantial mortality reductions compared to monotherapy.

This important trial confirms amphotericin plus flucytosine combination therapy as the gold standard for treatment of HIV-associated cryptococcal meningitis. Unfortunately flucytosine is not registered or available in the majority of countries in Africa and Asia where cryptococcal disease burden is highest. Efforts are now needed to secure access to both flucytosine and amphotericin B for cryptococcal meningitis treatment worldwide.

Avoid TB deaths
Asia
Viet Nam
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TAG: Integrated TB and HIV care leads to impressive TB treatment outcomes

Comparison of Treatment Outcomes of New Smear- Positive Pulmonary Tuberculosis Patients by HIV and Antiretroviral Status in a TB/HIV Clinic, Malawi.

Tweya H, Feldacker C, Phiri S, Ben-Smith A, Fenner L, Jahn A, Kalulu M, Weigel R, Kamba C, Banda R, Egger M, Keiser O. PLoS One. 2013;8(2):e56248. doi: 10.1371/journal.pone.0056248. Epub 2013 Feb 15.

Smear-positive pulmonary TB is the most infectious form of TB. Previous studies on the effect of HIV and antiretroviral therapy on TB treatment outcomes among these highly infectious patients demonstrated conflicting results, reducing understanding of important issues. All adult smear-positive pulmonary TB patients diagnosed between 2008 and 2010 in Malawi’s largest public, integrated TB/HIV clinic were included in the study to assess treatment outcomes by HIV and antiretroviral therapy status using logistic regression. Results: Of 2,361 new smear-positive pulmonary TB patients, 86% had successful treatment outcome (were cured or completed treatment), 5% died, 6% were lost to follow-up, 1% failed treatment, and 2% transferred-out. Overall HIV prevalence was 56%. After adjusting for gender, age and TB registration year, treatment success was higher among HIV negative than HIV-positive patients (adjusted odds ratio 1.49; 95% CI: 1.14–1.94). Of 1,275 HIV-infected pulmonary TB patients, 492 (38%) received antiretroviral therapy during the study. Pulmonary TB patients on antiretroviral therapy were more likely to have successful treatment outcomes than those not on ART (adjusted odds ratio: 1.83; 95% CI: 1.29–2.60). HIV co-infection was associated with poor TB treatment outcomes. Despite high HIV prevalence and the integrated TB/HIV setting, only a minority of patients started antiretroviral therapy. Intensified patient education and provider training on the benefits of antiretroviral therapy could increase antiretroviral therapy uptake and improve TB treatment success among these most infectious patients.

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Editor’s notes: TB remains the major cause of mortality in people living with HIV in high prevalence countries, but most specifically when ART coverage is low. The HIV prevalence in this review of a large number of patients with pulmonary TB – 56%, was higher than previously cited estimates of 40%, and historical evidence indicates that TB outcomes are better in those patients who are HIV-negative. This study was based at a program that integrates TB and HIV services at a large public facility in Malawi. A virtue of this service integration is that 96% of the TB patients knew their HIV status. It is notable that with this rather large sample, the treatment success rate was only slightly less in those patients living with HIV- 85% TB cure versus 88% in the patients who were HIV-negative. A closer review of the data indicates that those HIV-positive patients on ART had significantly better TB treatment outcome, reinforcing results from other studies.  Given newer recommendations that co-infected patients be started on ART, it is unfortunate that only 38% of the HIV-positive patients in this clinic with TB were started on ART.  As treatment guidelines and recommendations become further integrated into clinic practice we can be optimistic that the TB treatment success rate for patients living with HIV will come even closer to the TB treatment success rate of the patients who are HIV-negative.

Avoid TB deaths
Comorbidity, HIV Treatment
Africa
Malawi
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Preventing nosocomial tuberculosis in health facilities

Assessment of organizational measures to prevent nosocomial tuberculosis in health facilities of 4 sub-Saharan countries in 2010.

Robert J, Affolabi D, Awokou F, Nolna D, Manouan BA, Acho YB, Gninafon M, Trebucq A. Infect Control Hosp Epidemiol. 2013 Feb;34(2):190-5. doi: 10.1086/669085. Epub 2012 Dec 18

The prevention of tuberculosis (TB) transmission in healthcare settings is a major issue, particularly because of the interaction between human immunodeficiency virus and TB and the emergence of multidrug-resistant TB. A questionnaire was developed by representatives of Benin, Cameroon, Cote d'Ivoire, and Togo to evaluate the organizational measures implemented in facilities involved in TB management in healthcare facilities. On-site visits were performed between July 2010 and July 2011. A total of 115 facilities, including 10 university hospitals and 92 basic management units, were visited. None had a TB infection control plan, and only 5.2% provided education for staff about nosocomial TB. Overall, 48.3% of the facilities performed triage of suspected TB cases on hospital arrival or admission, 89.6% provided education for TB cases on cough etiquette, 20.0% segregated smear-positive TB cases, and 15.7% segregated previously treated cases. A total of 15.5% of the facilities registered TB among staff, for a global prevalence rate of 348 cases per 100,000 staff members. This survey identified simple and mostly costless administrative measures to be urgently implemented at the local level to prevent nosocomial TB, such as staff education, triage on admission, and segregation of previously treated patients.

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Editor’s notes: WHO promotes the TB strategy of the “Three Is” – isoniazid prophylaxis, intensified case finding and infection control. Intensified case finding has been promoted by provider and patient education as well as focused screening of patient symptoms suggestive of active tuberculosis. Isoniazid prophylaxis is recommended by WHO, but has not been widely adopted in high TB and TB/HIV settings in many resource challenged settings due to a number of management and diagnostic concerns. Infection control is widely recognized as important to prevent TB transmission in health care settings, but the environmental and administrative interventions have not been widely implemented despite their relatively low cost. The recommendations associated with the Three Is have been disseminated widely – a clearer understanding of the obstacles associated with their adoption may need to be understood and assessed to facilitate better TB control measures.

Avoid TB deaths
Africa
Benin, Cameroon, Côte d'Ivoire, Togo
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Reviewing the treatment and diagnostic challenges of TB/HIV

The Twin Epidemics of Tuberculosis and HIV.

Varghese GM, Janardhanan J, Ralph R, Abraham OC. Curr Infect Dis Rep. 2013 Jan 8. [Epub ahead of print]

The deadly combination of tuberculosis (TB) and human immunodeficiency virus (HIV) currently ravaging the world, taking a toll of about 0.35 million people every year, is one of the major public health crises of the decade. Throughout the course of HIV infection, the risk of acquisition, reactivation, and reinfection of TB keeps increasing substantially as the immune deficiency progresses. TB coinfected patients inadvertently facilitate HIV infection by release of the proinflammatory cytokines and overexpression of coreceptors CXCR4 and CCR5; thereby, the progression of each is facilitated. The difficulties in diagnosing active tuberculosis in HIV-infected individuals poses a great challenge that is further complicated by the challenges in identification of latent TB infection, creating a setback to preventive therapy. Furthermore, prescribing antituberculous therapy and antiretroviral therapy together poses several management challenges, including drug interactions, added toxicities, and TB immune reconstitution inflammatory syndrome. The current approach to diagnosis, prevention, and treatment strategies in TB and HIV coinfected individuals, along with epidemiology and overview of pathogenetic interplay of both microbes, is reviewed here.

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Editor’s notes: The risk of active TB among people with HIV infection is high, and occurs even without severe immunosuppression. Relatively early initiation of ART, as well as anti-TB prophylaxis can reduce the risk of active TB, while early diagnosis and treatment of active TB can minimize morbidity and mortality from TB. The real world challenges should not be minimized – including diagnosis of TB in people living with HIV, and co-administration of antiretroviral and anti-tuberculosis drugs. Clinicians and health systems require significant technical support – while these challenges are significant, successful strategies can be implemented.

Avoid TB deaths
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TB among children living with HIV

Incident tuberculosis and risk factors among HIV-infected children in Dar es Salaam, Tanzania.

Li N, Manji KP, Spiegelman D, Muya A, Mwiru RS, Liu E, Chalamilla G, Fawzi WW, Duggan C. AIDS. 2013 Jan 22. [Epub ahead of print]

This article describes the burden of pediatric tuberculosis (TB) in a HIV-infected population and explores the demographic and clinical factors associated with the occurrence of pediatric TB through a longitudinal analysis of a cohort of HIV-infected children. The endpoint of the study was clinically diagnosed TB. Cox proportional hazard regression was used to explore the predictors of incident TB among HIV-infected children under age 15 years after enrollment into the HIV program. The cohort comprised of 5040 children [median age: 5 years, interquartile range (IQR): 1-9 years]. During a median follow-up of 0.8 (IQR: 0.1-2.5) years, 376 out of 5040 children met the case definition for TB. The overall incidence of TB was 5.2/100 person-years. In multivariate analyses, older age at enrollment [relative risk (RR): 1.7, 95%, confidence interval (CI): 1.5-1.8], severe wasting (RR: 1.8, 95% CI: 1.3-2.5), severe immune-suppression (RR: 2.6, 95% CI: 1.8-3.8), anemia (RR: 1.4, 95% CI: 1.0-1.9) and World Health Organization (WHO) stage IV (RR: 4.5, 95% CI: 2.4-8.5) were all independently associated with a higher risk of TB. In addition, the use of antiretroviral drugs for more than 180 days reduced the risk of TB by 70% (RR: 0.3, 95% CI: 0.2-0.4). ART use is strongly associated with a reduced risk of tuberculosis among HIV-infected children, and should therefore be included in HIV care and treatment programs. Trials of interventions designed to improve the nutritional and hematologic status of these children should also be performed.

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Editor’s notes: Antiretroviral therapy reduces the incidence of tuberculosis for children, as well as for adults, living with HIV. While diagnosis of tuberculosis can be particularly challenging in children, the quite high incidence of active TB (10% in one year) in this study highlights the importance of proactive clinical screening and laboratory diagnosis, and provides additional evidence to the importance ART initiation as a measure that reduces the risk of TB.

Avoid TB deaths
Africa
United Republic of Tanzania
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