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      Differences in response to antiretroviral therapy in HIV-positive patients being treated for tuberculosis in Eastern Europe, Western Europe and Latin America

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          Abstract

          Background

          Efavirenz-based antiretroviral therapy (ART) regimens are preferred for treatment of adult HIV-positive patients co-infected with tuberculosis (HIV/TB). Few studies have compared outcomes among HIV/TB patients treated with efavirenz or non-efavirenz containing regimens.

          Methods

          HIV-positive patients aged ≥16 years with a diagnosis of tuberculosis recruited to the TB:HIV study between Jan 1, 2011, and Dec 31, 2013 in 19 countries in Eastern Europe (EE), Western Europe (WE), and Latin America (LA) who received ART concomitantly with TB treatment were included. Patients either received efavirenz-containing ART starting between 15 days prior to, during, or within 90 days after starting tuberculosis treatment, (efavirenz group), or other ART regimens (non-efavirenz group). Patients who started ART more than 90 days after initiation of TB treatment, or who experienced ART interruption of more than 15 days during TB treatment were excluded. We describe rates and factors associated with death, virological suppression, and loss to follow up at 12 months using univariate, multivariate Cox, and marginal structural models to compare the two groups of patients.

          Results

          Of 965 patients (647 receiving efavirenz-containing ART, and 318 a non-efavirenz regimen) 50% were from EE, 28% from WE, and 22% from LA. Among those not receiving efavirenz-containing ART, regimens mainly contained a ritonavir-boosted protease inhibitor (57%), or raltegravir (22%). At 12 months 1.4% of patients in WE had died, compared to 20% in EE: rates of virological suppression ranged from 21% in EE to 61% in WE. After adjusting for potential confounders, rates of death (adjusted Hazard Ratio; aHR, 95%CI: 1.13, 0.72–1.78), virological suppression (aHR, 95%CI: 0.97, 0.76–1.22), and loss to follow up (aHR, 95%CI: 1.17, 0.81–1.67), were similar in patients treated with efavirenz and non-efavirenz containing ART regimens.

          Conclusion

          In this large, prospective cohort, the response to ART varied significantly across geographical regions, whereas the ART regimen (efavirenz or non-efavirenz containing) did not impact on the proportion of patients who were virologically-suppressed, lost to follow up or dead at 12 months.

          Electronic supplementary material

          The online version of this article (10.1186/s12879-018-3077-x) contains supplementary material, which is available to authorized users.

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          Most cited references34

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          Prevalence of tuberculosis in post-mortem studies of HIV-infected adults and children in resource-limited settings: a systematic review and meta-analysis

          Objectives: Tuberculosis (TB) is estimated to be the leading cause of HIV-related deaths globally. However, since HIV-associated TB frequently remains unascertained, we systematically reviewed autopsy studies to determine the true burden of TB at death. Methods: We systematically searched Medline and Embase databases (to end 2013) for literature reporting on health facility-based autopsy studies of HIV-infected adults and/or children in resource-limited settings. Using forest plots and random-effects meta-analysis, we summarized the TB prevalence found at autopsy and used meta-regression to explore variables associated with autopsy TB prevalence. Results: We included 36 eligible studies, reporting on 3237 autopsies. Autopsy TB prevalence was extremely heterogeneous (range 0–64.4%), but was markedly higher in adults [pooled prevalence 39.7%, 95% confidence interval (CI) 32.4–47.0%] compared to children (pooled prevalence 4.5%, 95% CI 1.7–7.4%). Post-mortem TB prevalence varied by world region, with pooled estimates in adults of 63.2% (95% CI 57.7–68.7%) in South Asia (n = 2 studies); 43.2% (95% CI 38.0–48.3) in sub-Saharan Africa (n = 9 studies); and 27.1% (95% CI 16.0–38.1%) in the Americas (n = 5 studies). Autopsy prevalence positively correlated with contemporary estimates of national TB prevalence. TB in adults was disseminated in 87.9% (82.2–93.7%) of cases and was considered the cause of death in 91.4% (95% CI 85.8–97.0%) of TB cases. Overall, TB was the cause of death in 37.2% (95% CI 25.7–48.7%) of adult HIV/AIDS-related deaths. TB remained undiagnosed at death in 45.8% (95% CI 32.6–59.1%) of TB cases. Conclusions: In resource-limited settings, TB accounts for approximately 40% of facility-based HIV/AIDS-related adult deaths. Almost half of this disease remains undiagnosed at the time of death. These findings highlight the critical need to improve the prevention, diagnosis and treatment of HIV-associated TB globally.
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            Tuberculosis case fatality rates in high HIV prevalence populations in sub-Saharan Africa.

            Tuberculosis is a leading cause worldwide of morbidity and mortality among HIV-infected people. The HIV era has seen a dramatic increase of the tuberculosis case fatality rate (CFR) in high HIV prevalence populations. Providing care for HIV-infected people must include measures to tackle this high tuberculosis CFR. To analyse the extent of the increased tuberculosis CFR in high HIV prevalence populations in sub-Saharan Africa, the reasons for this increase and the causes of death, in order to identify possible ways of tackling this problem. References were obtained by searching the MEDLINE on 'tuberculosis', 'HIV infection', and 'mortality' (MesH or textword). In addition, available data from National Tuberculosis Programme reports were reviewed. Tuberculosis CFR is closely linked to HIV prevalence. Limited autopsy data suggest that death from HIV-related diseases other than tuberculosis is probably the main reason for the increased CFR in HIV-infected tuberculosis patients. Among HIV-infected tuberculosis patients, the higher tuberculosis CFR in sputum smear-negative and extrapulmonary than in sputum smear-positive tuberculosis cases can also be attributed to misdiagnosis of HIV-related diseases as tuberculosis. The adverse effect of the HIV/AIDS epidemic on general health service performance probably accounts for the higher tuberculosis CFR among HIV-negative tuberculosis patients in high prevalence populations than that in low HIV-prevalence populations. Tackling the problem of the increased tuberculosis CFR in high HIV prevalence populations requires collaboration between tuberculosis control and HIV/AIDS programmes in implementing measures such as improved health services, tuberculosis and HIV control services, preventive treatment for HIV-related diseases and anti-HIV treatment.
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              Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis.

              Tuberculosis remains an important cause of death among patients infected with the human immunodeficiency virus (HIV). Robust data are lacking with regard to the timing for the initiation of antiretroviral therapy (ART) in relation to the start of antituberculosis therapy. We tested the hypothesis that the timing of ART initiation would significantly affect mortality among adults not previously exposed to antiretroviral drugs who had newly diagnosed tuberculosis and CD4+ T-cell counts of 200 per cubic millimeter or lower. After beginning the standard, 6-month treatment for tuberculosis, patients were randomly assigned to either earlier treatment (2 weeks after beginning tuberculosis treatment) or later treatment (8 weeks after) with stavudine, lamivudine, and efavirenz. The primary end point was survival. A total of 661 patients were enrolled and were followed for a median of 25 months. The median CD4+ T-cell count was 25 per cubic millimeter, and the median viral load was 5.64 log(10) copies per milliliter. The risk of death was significantly reduced in the group that received ART earlier, with 59 deaths among 332 patients (18%), as compared with 90 deaths among 329 patients (27%) in the later-ART group (hazard ratio, 0.62; 95% confidence interval [CI]; 0.44 to 0.86; P=0.006). The risk of tuberculosis-associated immune reconstitution inflammatory syndrome was significantly increased in the earlier-ART group (hazard ratio, 2.51; 95% CI, 1.78 to 3.59; P<0.001). Irrespective of the study group, the median gain in the CD4+ T-cell count was 114 per cubic millimeter, and the viral load was undetectable at week 50 in 96.5% of the patients. Initiating ART 2 weeks after the start of tuberculosis treatment significantly improved survival among HIV-infected adults with CD4+ T-cell counts of 200 per cubic millimeter or lower. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis and the National Institutes of Health; CAMELIA ClinicalTrials.gov number, NCT01300481.).
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                Author and article information

                Contributors
                yanink.caro@infecto.mx
                a.schultze@ucl.ac.uk
                anne.marie.werlinrud.efsen@regionh.dk
                frank.post@kcl.ac.uk
                alpanteleev@gmail.com
                aliaksandr_skrahin@tut.by
                miro97@fundsoriano.es
                girardi@inmi.it
                daria.podlekareva@regionh.dk
                jens.lundgren@regionh.dk
                jsmadero@yahoo.com
                jtoibaro@hivramos.org.ar
                drjandradev@gmail.com
                alcorsimona@gmail.com
                jan.fehr@usz.ch
                jcayla@aspb.es
                mlosso@hivramos.org.ar
                robert.miller@ucl.ac.uk
                a.mocroft@ucl.ac.uk
                Ole.Kirk@regionh.dk
                +525554870900 , brenda.crabtree@infecto.mx
                Journal
                BMC Infect Dis
                BMC Infect. Dis
                BMC Infectious Diseases
                BioMed Central (London )
                1471-2334
                23 April 2018
                23 April 2018
                2018
                : 18
                : 191
                Affiliations
                [1 ]ISNI 0000 0001 0698 4037, GRID grid.416850.e, Department of Infectious Diseases, , Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, ; Vasco de Quiroga 15, Col. Belisario Domínguez sección XVI, Tlalpan, CP 14080 Mexico City, Mexico
                [2 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Infection and Population Health, , University College London Medical School, ; London, UK
                [3 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Centre for Health and Infectious Disease Research (CHIP), Department of Infectious Diseases, Finsencentret, Rigshospitalet, , University of Copenhagen, ; Copenhagen, Denmark
                [4 ]ISNI 0000 0004 0391 9020, GRID grid.46699.34, Department of Sexual Health, Caldecot Centre, , King’s College Hospital, ; London, UK
                [5 ]Department of HIV/TB, TB hospital 2, St. Petersburg, Russia
                [6 ]Clinical Department, Republican Research and Practical Centre for Pulmonology and TB, Minsk, Belarus
                [7 ]ISNI 0000 0004 1937 0247, GRID grid.5841.8, Infectious Diseases Service, Hospital Clinic – IDIBAPS. University of Barcelona, ; Barcelona, Spain
                [8 ]Department of Infectious Diseases INMI “L. Spallanzani”, Ospedale L Spallanzani, Rome, Italy
                [9 ]HIV Unit, Hospital J.M. Ramos Mejia and CICAL, Fundación IBIS, Buenos Aires, Argentina
                [10 ]ISNI 0000 0001 0432 668X, GRID grid.459608.6, Infectious Diseases Service, , Hospital Civil de Guadalajara, ; Guadalajara, Mexico
                [11 ]ISNI 0000 0000 9828 7548, GRID grid.8194.4, Dr Victor Babes’ Hospital of Tropical and Infectious Diseases, , Bucharest AND ‘Carol Davila’ University of Medicine and Pharmacy, ; Bucharest, Romania
                [12 ]ISNI 0000 0004 0478 9977, GRID grid.412004.3, Division of Infectious Diseases and Hospital Epidemiology, , University Hospital Zurich, ; Zurich, Switzerland
                [13 ]ISNI 0000 0004 1756 6246, GRID grid.466571.7, Agencia de Salud Pública de Barcelona: Programa Integrado de Investigación en Tuberculosis de SEPAR (PII-TB); Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), ; Barcelona, Spain
                [14 ]ISNI 0000000121901201, GRID grid.83440.3b, Centre for Clinical Research in Infection and Sexual Health, Institute for Global Health, , University College London, ; London, UK
                Article
                3077
                10.1186/s12879-018-3077-x
                5914014
                29685113
                4b1221b1-f5aa-4411-a6bc-8e75b968e9cb
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 28 June 2017
                : 3 April 2018
                Funding
                Funded by: European Union’s Seventh Framework Programme for research
                Award ID: FP7/2007–2013
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2018

                Infectious disease & Microbiology
                hiv,tuberculosis,art,efavirenz,protease inhibitor,outcomes,eastern europe

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