Articles tagged as "Avoid TB deaths"

TB treatment associated with loss of virologic suppression on ART

Temporal association between incident tuberculosis and poor virological outcomes in a South African antiretroviral treatment service.  

Gupta-Wright A, Wood R, Bekker LG, Lawn SD. J Acquir Immune Defic Syndr. 2013 Nov 1;64(3):261-70. doi: 10.1097/QAI.0b013e3182a23e9a.

Introduction: The temporal relationship between incident tuberculosis (TB) and virological outcomes during antiretroviral therapy (ART) is poorly defined. This was studied in a cohort in Cape Town, South Africa.

Methods: Data regarding TB diagnoses, ART regimens, and 4-monthly updated viral load (VL) and CD4 count measurements were extracted from a prospectively maintained database. Rates of virological breakthrough (VL > 1 000 copies/mL) and failure (VL > 1 000 copies/mL on serial measurements) following initial VL suppression were calculated. Poisson models were used to calculate incidence rate ratios (IRRs) and identify risk factors for these virological outcomes.

Results: Incident TB was diagnosed in 391 (28.5%) of 1 370 patients during a median of 5.2 years follow-up. Five hundred seventy-eight episodes of virological breakthrough and 231 episodes of virological failure occurred, giving rates of 10.0 episodes per 100 person-years and 4.0 episodes per 100 person-years, respectively. In multivariate analyses adjusted for baseline and time-updated risk factors, TB was an independent risk factor for adverse virological outcomes. These associations were strongly time dependent; the 6-month period following diagnosis of incident TB was associated with a substantially increased risk of virological breakthrough (IRR: 2.3, 95% confidence interval: 1.7 to 3.2) and failure (IRR: 2.6, 95% confidence interval: 1.6 to 4.3) compared with time without a TB diagnosis. Person-time preceding TB diagnosis or more than 6 months after a TB diagnosis was not associated with poor virological outcomes.

Conclusion: Incident TB during ART was strongly associated with poor virological outcomes during the 6-month period following TB diagnosis. Although underlying mechanisms remain to be defined, patients with incident TB may benefit from virological monitoring and treatment adherence support.

Abstract  Full-text [free] access 

Editor’s notes: Concurrent treatment with antiretroviral therapy (ART) and anti-tuberculous treatment presents multiple challenges for patients. These challenges include increased pill burden, increased risk of adverse effects, potential for drug-drug interactions and, if services are not integrated, the need to attend separate services for TB and HIV care. In this observational study among people taking ART in a Cape Town clinic, viral load monitoring was routinely performed every four months. The study only included patients who achieved initial virologic suppression; most were taking efavirenz-based ART. Loss of virologic suppression was more common among patients --- whose most recent CD4 count was low, with the longest duration of time on ART, and who were within 6 months of starting TB treatment.  The reason for this was not clear but possible explanations include poorer adherence to treatment when the pill burden is higher, adverse effects, or drug-drug interactions. If similar results are found elsewhere, it will be important to understand the reasons, so that appropriate interventions can be implemented. Virologic monitoring may be more important among people taking TB treatment concurrently with ART.

Avoid TB deaths
Africa
South Africa
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TB-IRIS is not an important risk factor for mortality

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome after early initiation of antiretroviral therapy in a randomized clinical trial.

Laureillard D, Marcy O, Madec Y, Chea S, Chan S, Borand L, Fernandez M, Prak N, Kim C, Dim B, Nerrienet E, Sok T, Delfraissy JF, Goldfeld AE, Blanc FX; CAMELIA (ANRS 1295 – CIPRA KH001) Study Team. AIDS. 2013 Oct 23;27(16):2577-86. doi: 10.1097/01.aids.0000432456.14099.c7.

Objective: To analyze cases of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in the CAMbodian Early versus Late Introduction of Antiretrovirals (CAMELIA) randomized trial designed to compare early (2 weeks) versus late (8 weeks) antiretroviral therapy (ART) initiation after tuberculosis treatment onset in Cambodia (NCT00226434).

Methods: ART-naive adults with CD4 cell count of 200 cells/μl or less, newly diagnosed tuberculosis, and at least one follow-up visit after ART initiation were included in this analysis. Each case of suspected TB-IRIS was systematically validated by two physicians not involved in patients' management. Factors associated with occurrence of TB-IRIS were identified using the Cox proportional hazard model.

Results: Among 597 patients, 26% experienced TB-IRIS with an incidence rate of 37.9 cases per 100 person-years [95% confidence interval (CI) 32.4-44.4]. Main clinical manifestations included new or worsening lymphadenopathy (77.4%) and fever (68.4%). Chest radiograph revealed new or worsening abnormalities in 53.4%. Symptoms resolved in 95.5% of patients. Six deaths were directly related to TB-IRIS. Initiating ART early increased the risk of TB-IRIS by 2.61 (95% CI 1.84-3.70). Extrapulmonary or disseminated tuberculosis, CD4 cell count of 100 cells/μl or less, and HIV RNA concentration more than 6 log10 copies/ml were also significantly associated with higher risk of TB-IRIS.

Conclusion: Shortening the delay between tuberculosis treatment onset and ART initiation to 2 weeks was associated with an increased risk of developing TB-IRIS. However, TB-IRIS was generally easily manageable. Given the marked reported survival advantage of early ART initiation after tuberculosis treatment onset, these data indicate that fear of TB-IRIS should not be an impediment to early ART in adults with advanced immunodeficiency in resource-limited, high burden settings.

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Editor’s notes: This study consolidates our knowledge about TB-IRIS. It reports the presentation, risk factors and outcomes of a very large series of cases (n=155) within two arms of a randomized trial comparing early versus late antiretroviral therapy (ART) in patients treated for HIV-associated TB. The findings are entirely consistent with the existing literature. Those in the early ART arm had a greater risk of TB-IRIS compared to those in the late ART arm (36% vs. 16%) with adjusted hazards of 2.6 (95%CI 1.8-3.7). Of those who developed TB-IRIS, 3.9% died with no other identifiable cause. However, development of TB-IRIS was not a risk factor for mortality (proportion of total patients who died = 14.8%) and overall survival was improved in the early ART arm of the trial as reported in the parent study. The median duration of symptoms was 7.4 weeks but overall outcomes were good. 

Avoid TB deaths
Asia
Cambodia
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Xpert MTB/RIF accelerates TB treatment start but does not reduce morbidity

Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial.

Theron G, Zijenah L, Chanda D, Clowes P, Rachow A, Lesosky M, Bara W, Mungofa S, Pai M, Hoelscher M, Dowdy D, Pym A, Mwaba P, Mason P, Peter J, Dheda K; for the TB-NEAT team. Lancet. 2013 Oct 25. pii: S0140-6736(13)62073-5. doi: 10.1016/S0140-6736(13)62073-5. [Epub ahead of print]

Background: The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical effect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa.

Methods: In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from five primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT01554384.

Findings: Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not differ between groups at 2 months (2 [IQR 0-3] in the smear microscopy group vs 2 [0•25-3] in the MTB/RIF group; p=0•85) or 6 months (1 [0-3] vs 1 [0-3]; p=0•35), nor did median KPS at 2 months (80 [70-90] vs 90 [80-90]; p=0•23) or 6 months (100 [90-100] vs 100 [90-100]; p=0•85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0•0001) but similar specificity (517 [95%] 544 vs 540 [96%] of 560; p=0•25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0•99) but higher specificity (952 [92%] of 1037; p=0•0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1 411 with laboratory-based MTB/RIF failed (p=0•22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p<0•0001) and same-day treatment initiation (168 [23%] of 744 vs 115 [15%] of 758; p=0•0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0•0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0•6408).

Interpretation: Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients.

Funding: European and Developing Countries Clinical Trials Partnership, National Research Foundation, and Claude Leon Foundation. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Editor’s notes: Xpert MTB/RIF is a major advance in tuberculosis diagnostics. Xpert MTB/RIF has higher sensitivity than sputum smear microscopy (but lower than mycobacterial culture) and a rapid turn-around time. Previous evaluations have been based on laboratory-based assessment of Xpert MTB/RIF’s sensitivity and specificity. This study differs in that it assessed the effect of the test on clinical outcomes, among patients in southern Africa with a high prevalence of HIV infection. The individually-randomised trial compared Xpert MTB/RIF to smear microscopy, each used as the first diagnostic test for TB. Both tests were performed at primary care facilities, rather than at centralised laboratories. Morbidity was measured after two months among participants who had a positive sputum culture. Results demonstrated no difference between study arms. Patients with a positive sputum culture started treatment sooner in the Xpert MTB/RIF group, as might be expected.

Perhaps the most interesting result was that, by 56 days, the proportion of people in each group who had started TB treatment was no different between groups. This study illustrates that “empirical” TB treatment of people with TB symptoms, but without microbiological confirmation, is common. The trial result is consistent with programmatic data from South Africa, where Xpert MTB/RIF has been implemented nationally, with apparently no increase in TB case notifications. The most likely explanation is that diagnosis with Xpert MTB/RIF is replacing, rather than adding to, empirical treatment for TB. Further evaluations of the effect of Xpert MTB/RIF on clinical outcomes are underway. Evaluations will be important, along with economic evaluations, to guide how this new technology can be most effectively used to improve TB control.   

Avoid TB deaths
Comorbidity, HIV Treatment
Africa
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Is Xpert MTB/RIF affordable?

Xpert MTB/RIF for diagnosis of tuberculosis and drug-resistant tuberculosis: a cost and affordability analysis.

Pantoja A, Fitzpatrick C, Vassall A, Weyer K, Floyd K. Eur Respir J. 2013 Sep;42(3):708-20. doi: 10.1183/09031936.00147912. Epub 2012 Dec 20.

Xpert MTB/RIF is a rapid test to diagnose tuberculosis (TB) and rifampicin-resistant TB. Cost and affordability will influence its uptake. We assessed the cost, globally and in 36 high-burden countries, of two strategies for diagnosing TB and multidrug-resistant (MDR)-TB: Xpert with follow-on diagnostics, and conventional diagnostics. Costs were compared with funding available for TB care and control, and donor investments in HIV prevention and care. Using Xpert to diagnose MDR-TB would cost US$70-90 million per year globally and be lower cost than conventional diagnostics globally and in all high-burden countries. Diagnosing TB in HIV-positive people using Xpert would also cost US$90-101 million per year and be lower cost than conventional diagnostics globally and in 33 out of 36 high-burden countries. Testing everyone with TB signs and symptoms would cost US$434-468 million per year globally, much more than conventional diagnostics. However, in European countries, Brazil and South Africa, the cost would represent <10% of TB funding. Introducing Xpert to diagnose MDR-TB and to diagnose TB in HIV-positive people is warranted in many countries. Using it to test everyone with TB signs and symptoms is affordable in several middle-income countries, but financial viability in low-income countries requires large increases in TB funding and/or further price reductions.

Abstract  Full-text [free] access

Editor’s notes: The Xpert MTB/RIF assay represents a substantial advance that was endorsed by WHO in 2010 for diagnosis of pulmonary disease and simultaneous detection of rifampicin resistance. The benefits of using this technology are greatest in populations with high burden of HIV-associated TB (in view of the limited sensitivity of smear-microscopy) and with high prevalence of multi-drug resistant TB (MDR-TB). Cost remains a substantial hurdle to implementation and economic analyses are needed to guide implementation. Both the potential benefits of implementing this technology and its affordability vary substantially between countries; depending on the overall burden of TB, rates of HIV-associated TB, rates of MDR-TB and the wealth of the country. This economic analysis supports implementation of Xpert MTB/RIF in place of conventional diagnostics for diagnosis of HIV-associated TB and MDR-TB in many counties. And its use as a first-line diagnostic in all patients in several high-burden middle-income countries. 

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Isoniazid preventive therapy reduces tuberculosis incidence and death in Brazil

Effect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: a stepped wedge, cluster-randomised trial.

Durovni B, Saraceni V, Moulton LH, Pacheco AG, Cavalcante SC, King BS, Cohn S, Efron A, Chaisson RE, Golub JE. Lancet Infect Dis. 2013 Aug 14. doi:pii: S1473-3099(13)70187-7. 10.1016/S1473-3099(13)70187-7. [Epub ahead of print]

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.

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Editor’s notes: There is a wealth of evidence supporting the efficacy of isoniazid preventive therapy in preventing tuberculosis among people with HIV, but implementation has been disappointingly slow. In Brazil, isoniazid preventive therapy is recommended in guidelines but has not been widely implemented. In this large, pragmatic trial with a stepped wedge design, clinic staff were trained to deliver isoniazid preventive therapy for HIV-positive people with a positive tuberculin skin test, in line with national guidelines. Coverage of antiretroviral therapy was relatively high (60% at baseline). Tuberculosis incidence and death was lower in the intervention period, supporting the wider use of isoniazid preventive therapy as part of care for people living with HIV. More than one-third of tuberculosis cases in the intervention period occurred among people who had not yet had a tuberculin skin test. This underlines the need for increased coverage of HIV testing, aiming to reduce the number of people living with HIV who first present for care with active tuberculosis, and that screening for tuberculosis and provision of isoniazid for those without active disease is a priority for people entering HIV care. The study also illustrates that tuberculin skin tests are cumbersome to administer, highlighting the need for tests to identify individuals at highest risk of developing active tuberculosis which are easier to deploy.

Avoid TB deaths
Latin America
Brazil
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Household interventions have potential to reduce tuberculosis burden in Southern Africa

Effect of household and community interventions on the burden of tuberculosis in southern Africa: the ZAMSTAR community-randomised trial.

Ayles H, Muyoyeta M, Du Toit E, Schaap A, Floyd S,Simwinga S,  Shanaube K, Chishinga N, Bond V, Dunbar R, De Haas P, James A, van Pittius NC,  Claassens M,  Fielding K, Fenty J, Sismanidis C, Hayes RJ, Beyers N, Godfrey-Faussett P,  the ZAMSTAR team †  Lancet  2013 Jul 31. pii: S0140-6736(13)61131-9. doi: 10.1016/S0140-6736(13)61131-9. [Epub ahead of print]

Background: Southern Africa has had an unprecedented increase in the burden of tuberculosis, driven by the HIV epidemic. The Zambia, South Africa Tuberculosis and AIDS Reduction (ZAMSTAR) trial examined two public health interventions that aimed to reduce the burden of tuberculosis by facilitating either rapid sputum diagnosis or integrating tuberculosis and HIV services within the community.

Methods: ZAMSTAR was a community-randomised trial done in Zambia and the Western Cape province of South Africa. Two interventions, community-level enhanced tuberculosis case-finding (ECF) and household level tuberculosis-HIV care, were implemented between Aug 1, 2006, and July 31, 2009, and assessed in a 2×2 factorial design between Jan 9, 2010, and Dec 6, 2010. All communities had a strengthened tuberculosis-HIV programme implemented in participating health-care centres. 24 communities, selected according to population size and tuberculosis notification rate, were randomly allocated to one of four study groups using a randomisation schedule stratified by country and baseline prevalence of tuberculous infection: group 1 strengthened tuberculosis-HIV programme at the clinic alone; group 2, clinic plus ECF; group 3, clinic plus household intervention; and group 4, clinic plus ECF and household interventions. The primary outcome was the prevalence of culture-confirmed pulmonary tuberculosis in adults (≥18 years), defined as Mycobacterium tuberculosis isolated from one respiratory sample, measured 4 years after the start of interventions in a survey of 4000 randomly selected adults in each community in 2010. The secondary outcome was the incidence of tuberculous infection, measured using tuberculin skin testing in a cohort of schoolchildren, a median of 4 years after a baseline survey done before the start of interventions. This trial is registered, number ISRCTN36729271.

Findings:  Prevalence of tuberculosis was evaluated in 64 463 individuals randomly selected from the 24 communities; 894 individuals had active tuberculosis. Averaging over the 24 communities, the geometric mean of tuberculosis prevalence was 832 per 100 000 population. The adjusted prevalence ratio for the comparison of ECF versus non-ECF intervention groups was 1·09 (95% CI 0·86-1·40) and of household versus non-household intervention groups was 0·82 (0·64-1·04). The incidence of tuberculous infection was measured in a cohort of 8809 children, followed up for a median of 4 years; the adjusted rate ratio for ECF versus non-ECF groups was 1·36 (95% CI 0·59-3·14) and for household versus non-household groups was 0·45 (0·20-1·05).                                                                                                                                  

Interpretation: Although neither intervention led to a statistically significant reduction in tuberculosis, two independent indicators of burden provide some evidence of a reduction in tuberculosis among communities receiving the household intervention. By contrast the ECF intervention had no effect on either outcome.       

Funding: Bill & Melinda Gates Foundation.

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Editor’s notes: This huge trial, covering a population of almost one million people in Zambia and South Africa, was designed to determine whether interventions in communities (rather than within the health system) could reduce the burden of active tuberculosis at community level.  In the enhanced tuberculosis case finding (ECF) intervention, community mobilization aimed to promote early diagnosis of tuberculosis and thus reduce the duration of infectiousness, by encouraging people with cough to submit a sputum sample to be tested for tuberculosis. In the household intervention, households of people with sputum smear-positive tuberculosis were offered household-based testing for tuberculosis and HIV with linkage to care. The enhanced case-finding intervention had no impact on tuberculosis at community-level: possible explanations include basing diagnosis on sputum smear microscopy, the standard first investigation when the trial was planned, but with suboptimal sensitivity, particularly for people living with HIV. The household intervention had an effect on the burden of tuberculosis which did not fulfil the traditional criteria for “statistical significance” in that the confidence interval around the estimate of both prevalence and incidence included one, and thus a chance effect cannot be ruled out. However the point estimates are consistent with an 18% reduction in the prevalence and a 55% reduction in the incidence of tuberculosis attributable to the intervention, effect sizes which are arguably of public health significance. This study is a major contribution to the increasing body of evidence concerning active case finding for tuberculosis.

Avoid TB deaths
Africa
South Africa, Zambia
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Pneumococcal disease: the leading cause of bacteraemia among children starting ART in Uganda and Zimbabwe

Bacteremia, Causative Agents and Antimicrobial Susceptibility Among HIV-1-infected Children on Antiretroviral Therapy in Uganda and Zimbabwe.

Musiime V, Cook A, Bakeera-Kitaka S, Vhembo T, Lutakome J, Keishanyu R,Prendergast AJ, Lubwama S, Robertson V, Hughes P, Nathoo K, Munderi P, Klein N, Musoke P, Gibb DM; on Behalf of the ARROW Trial Team. Pediatr Infect Dis J. 2013 Aug;32(8):856-862.

Background:  Bacteremia is common in HIV-infected children in Africa, including after start of antiretroviral therapy (ART), but there are limited data on causative pathogens and their antimicrobial sensitivity patterns in this population.

Methods:  We analyzed data on blood cultures taken from HIV-infected children developing acute febrile illness after enrollment to the Antiretroviral Research for Watoto (ARROW) clinical trial in Uganda and Zimbabwe. Patterns of bacterial pathogens and their antimicrobial susceptibilities were determined and bacteremia rates calculated over time from ART initiation.

Results:  A total of 848 blood cultures were obtained from 461 children, of which 123 (14.5%) from 105 children (median age 3.5 years, 51% girls) were culture positive, including 75 (8.8%) with clearly pathogenic organisms. The event rates for positive cultures with clearly pathogenic organisms after 0-1, 2-3, 4-11 and ≥12 months on ART were 13.3, 11.4, 2.1 and 0.3 per 1000 person-months of follow-up, respectively. The pathogens isolated (n; %) were Streptococcus pneumoniae (36; 28.3%), Staphylococcus aureus (11; 8.7%), Klebsiella pneumoniae (6; 4.7%), Pseudomonas aeruginosa (6; 4.7%), Salmonella spp (6; 4.7%), Escherichia coli (5; 3.9%), Haemophilus influenzae (1; 0.8%) and fungal spp (4; 3.1%). Other bacteria of doubtful pathogenicity (n = 52; 42%) were also isolated. Most isolates tested were highly (80-100%) susceptible to ceftriaxone, cefotaxime and ciprofloxacin; very few (~5%) were susceptible to cotrimoxazole; S. pneumoniae had high susceptibility to amoxicillin/ampicillin (80%).

Conclusions:  Rates of proven bacteremia were >20-fold higher immediately after starting ART compared with 12 months later in African HIV-infected children. S. pneumoniae was most commonly isolated, suggesting need for pneumococcal vaccination and effective prophylactic antibiotics.

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Editor’s notes: Children with HIV are at increased risk of bacteraemia with substantial effects on morbidity and mortality amongst those affected. This study aimed to investigate event rates, pathogen type and antimicrobial sensitivities amongst children from the ARROW trial initiated on ART. Event rates for culture-positive bacteraemia dropped substantially over time since ART initiation, with pathogenic culture-positive bacteraemia falling from 13.3 per 1 000 person-months in those on ART for <1 month, to 0.3 per 1 000 person-years in those receiving treatment for over a year. Importantly, 7% of children died within a month of their episode of bacteraemia and nearly half were hospitalized.

Pneumococcus was a key organism isolated, responsible for more than a quarter of positive blood cultures. Although few isolates (5%) were susceptible to cotrimoxazole there was minimal resistance seen to other first and second line antibiotics commonly available in sub-Saharan Africa. Also of concern, 60% of Klebsiella pneumoniae isolates (4.7% of positive cultures) were multi-resistant extended-spectrum beta-lactamase (ESBL) producers. The results of the study suggest that targeted prophylaxis including pneumococcal vaccination and prophylactic antibiotic strategies using alternatives to cotrimoxazole may be appropriate for children in the first few months after ART initiation.

Avoid TB deaths
Africa
Uganda, Zimbabwe
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CMV retinitis in resource-limited settings

Burden of HIV-related CMV retinitis in resource-limited settings: a systematic review.

Ford N, Shubber Z, Saranchuk P, Pathai S, Durier N, O'Brien D, Mills EJ, Pascual F, T' Hoen E, Holland GN, Heiden D., Clin Infect Dis. 2013 Jul 29. [Epub ahead of print]

Background: Cytomegalovirus (CMV) is a late stage opportunistic infection in people living with HIV/AIDS. Lack of ophthalmological diagnostic skills or convenient CMV treatment and increasing access to antiretroviral therapy, have all contributed to an assumption that CMV retinitis is no longer a concern in low- and middle-income settings.

Methods: We conducted a systematic review and meta-analysis of published and unpublished studies reporting prevalence of CMV retinitis in low- and middle-income countries. Eligible studies assessed the occurrence of CMV retinitis by fundoscopic examination within a cohort of at least 10 HIV-positive adult patients.

Results: We identified 65 studies from 24 countries, mainly in Asia (39 studies, 12 931 patients) and Africa (18 studies, 4 325 patients). By region, the highest prevalence was observed in Asia with a pooled prevalence of 14.0% (11.8-16.2%). Almost a third (31.6%, 27.6-35.8%) had vision loss in one or both eyes. Few studies reported immune status but, where reported, CD4 count at diagnosis of CMV retinitis was <50 cells/µL in 73.4% of cases. There was no clear pattern of prevalence over time, which was similar for the period 1993-2002 (11.8%, 95%CI 8-15.7%) and 2009-2013 (17.6%, 95%CI 12.6-22.7%).

Conclusions: Prevalence of CMV retinitis in resource-limited settings, notably Asian countries, remains high and routine retinal screening of late presenting HIV-positive patients should be considered. HIV programmes must ensure capacity to manage the needs of patients who present late for care.

Abstract access

Editor’s notes: Cytomegalovirus (CMV) can reactivate in the context of advanced immune suppression with a proportion of patients going onto develop end-organ damage. In HIV-positive patients, CMV retinitis is the most common site of end-organ damage, and if left untreated leads to blindness. This systematic review of published and unpublished studies summarises current knowledge on CMV retinitis in low and middle income settings. Of concern, the authors report a high prevalence of CMV retinitis, particularly in Asia (14% in Asia, 2.2% in Africa) with bilateral disease and visual loss commonly reported. Although the overall methodological quality of the studies was low with the findings subject to selection bias (43/64 studies were conducted on high-risk patients), this systematic review does give an indication of the scale of the problem. Unfortunately diagnosing CMV retinitis is not straightforward as it requires dilated fundoscopy by trained healthcare workers. However current technological advances, such as PEEK (a smart phone based system for comprehensive eye examinations), could help researchers document the burden of disease in resource-limited settings and facilitate the integration of retinal examinations into the routine care of late presenters. Finally, as current treatment costs are prohibitively high, a key priority must be improving access to oral valganciclovir.    

Avoid TB deaths
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Outcomes among people investigated for TB with point-of-care Xpert MTB/RIF assay

Time to treatment and patient outcomes among TB suspects screened by a single point-of-care Xpert MTB/RIF at a primary care clinic in Johannesburg, South Africa.

Hanrahan CF, Selibas K, Deery CB, Dansey H, Clouse K, Bassett J, Scott L, Stevens W, Sanne I, Van Rie A. PloS ONE 2013; 8(6): e65421 doi: 10.1371/journal.pone.0065421

Introduction: In December 2010, the World Health Organization recommended a single Xpert MTB/RIF assay as the initial diagnostic in people suspected of HIV-associated or drug resistant tuberculosis. Few data are available on the impact of this recommendation on patient outcomes. We describe the diagnostic follow-up, clinical characteristics and outcomes of a cohort of tuberculosis suspects screened using a single point-of-care Xpert.

Methods: Consecutive tuberculosis suspects at a primary care clinic in Johannesburg, South Africa were assessed for tuberculosis using point-of-care Xpert. Sputum smear microscopy and liquid culture were performed as reference standards. Xpert-negatives were evaluated clinically, and further assessed at the discretion of clinicians. Participants were followed for six months.

Results: From July-September 2011, 641 tuberculosis suspects were enrolled, of whom 69% were HIV-infected. Eight percent were positive by a single Xpert. Among 116 individuals diagnosed with TB, 66 (57%) were Xpert negative, of which 44 (67%) were empirical or radiological diagnoses and 22 (33%) were Xpert negative/culture-positive. The median time to tuberculosis treatment was 0 days (IQR: 0–0) for Xpert positives, 14 days (IQR: 5–35) for those diagnosed empirically, 14 days (IQR: 7–29) for radiological diagnoses, and 144 days (IQR: 28–180) for culture positives. Xpert negative tuberculosis cases were clinically similar to Xpert positives, including HIV status and CD4 count, and had similar treatment outcomes including mortality and time to antiretroviral treatment initiation.

Conclusions: In a high HIV-burden setting, a single Xpert identified less than half of those started on tuberculosis treatment, highlighting the complexity of TB diagnosis even in the Xpert era. Xpert at point-of-care resulted in same day treatment initiation in Xpert-positives, but had no impact on tuberculosis treatment outcomes or mortality.

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Editor’s notes: This is one of the first reports of clinical outcomes for people with suspected TB undergoing investigation using Xpert MTB/RIF in routine clinical care in South Africa. The data are from a single primary health care clinic in Johannesburg which had an on-site Xpert instrument. 69% of the people with suspected TB also had HIV infection; among those, 45% were on ART at enrolment and the median CD4+ cell count was 276 cells/µl. The diagnostic performance of Xpert was similar to that previously reported with sensitivity of a single Xpert (compared to culture) of 66%. Only 8% of suspects were Xpert positive, but Xpert positives accounted for fewer than half of those started on TB treatment within two months, with many diagnoses still based on clinical and radiological grounds. Over three-quarters of Xpert positive cases were started on treatment on the same day as sputum collection which demonstrates the potential impact of point-of-care placement. The authors attempted to explore the impact of Xpert on treatment outcomes and mortality by comparing outcomes between Xpert-positive cases and Xpert-negative cases but this requires cautious interpretation since it is not a comparison between randomised groups. Overall mortality was very low (by 6 months, <1% in all people with suspected TB, and only 2% among people starting TB treatment), perhaps partly a reflection of the high proportion of people already taking ART and relatively high CD4+ cell counts. One concerning finding was a relatively high proportion of TB cases who started treatment but had defaulted before 6 months (23% vs. 12% for Xpert-positive vs. Xpert-negative cases), but there is no comparison with the ‘usual’ default rates at this clinic. Further studies reporting clinical outcomes of people investigated for TB using Xpert are awaited.

Avoid TB deaths
Africa
South Africa
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Dynamic model of active versus passive TB case finding

Identifying dynamic tuberculosis case-finding policies for HIV/TB co-epidemics.

Yaesoubi R, Cohen T. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9457-62.

The global tuberculosis (TB) control plan has historically emphasized passive case finding (PCF) as the most practical approach for identifying TB suspects in high burden settings. The success of this approach in controlling TB depends on infectious individuals recognizing their symptoms and voluntarily seeking diagnosis rapidly enough to reduce onward transmission. It now appears, at least in some settings, that more intensified case-finding (ICF) approaches may be needed to control TB transmission; these more aggressive approaches for detecting as-yet undiagnosed cases obviously require additional resources to implement. Given that TB control programs are resource constrained and that the incremental yield of ICF is expected to wane over time as the pool of undiagnosed cases is depleted, a tool that can help policymakers to identify when to implement or suspend an ICF intervention would be valuable. In this article, we propose dynamic case-finding policies that allow policymakers to use existing observations about the epidemic and resource availability to determine when to switch between PCF and ICF to efficiently use resources to optimize population health. Using mathematical models of TB/HIV co-epidemics, we show that dynamic policies strictly dominate static policies that pre-specify a frequency and duration of rounds of ICF. We also find that the use of a diagnostic tool with better sensitivity for detecting smear-negative cases (e.g., Xpert MTB/RIF) further improves the incremental benefit of these dynamic case-finding policies.

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Editor’s notes: There is increasing recognition that to control the HIV-associated TB epidemic settings with high HIV prevalence, especially in southern Africa, that intensive TB case finding (ICF) rather than passive case finding (PCF) may be required. However, this is very resource-intensive and systematic reviews recently conducted by the WHO found weak evidence for an impact at an epidemiological level. Much more research is needed to define whether ICF is feasible, has a population level impact and is economically viable. The present modelling study suggests that dynamic case finding policies that switch between ICF and PCF based on simple inputs such as TB notification rate, budget etc. may provide a more cost-efficient means of case finding.

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