Background
Globally, tuberculosis (TB) is the commonest opportunistic infection in HIV-infected patients, especially in resource-constrained settings [
1]. Mortality in co-infected patients varies across regions as reported previously [
2,
3], however, in most regions TB is the most common cause of death among the HIV-infected adult population [
4‐
6]. Prospective cohort studies demonstrated that HIV patients co-infected with TB have an increased risk of death [
5], and reduced mortality with appropriate TB treatment and initiation of antiretroviral therapy (ART) [
7,
8]. Additionally, in patients with TB who present with advanced immunodeficiency (CD4 count < 200 cells/mm
3), early initiation of ART (< 8 weeks after TB treatment initiation) increases survival, as demonstrated in several large clinical trials [
9‐
12]. Efavirenz-based regimens were used in all of these studies [
9‐
12]. The efficacy of other ART regimens in TB/HIV co-infected patients, and the relative efficacy of rifampicin- or rifabutin-containing regimens in patients receiving ART remains poorly studied [
13‐
15]. Hence, National and regional guidelines provide minimal guidance on such ART regimens used concomitantly with tuberculosis treatment [
1,
16‐
22].
On the other hand, late presentation of HIV-positive adult patients into care is common in both resource-constrained and high-income settings [
23‐
25] and episodes of opportunistic infection including TB, may occur within the first few months after initiation of ART [
8]. In most parts of the world with limited resources and a high burden of TB, efavirenz remains the preferred agent as the third component of ART regimens, as it has no clinically-significant interaction with rifampicin [
1,
26]. However, tolerability and non-nucleoside reverse transcriptase inhibitor resistance may preclude use of efavirenz. In 2007, the WHO recommended increasing the ritonavir boosting dose to 400 mg every 12 h with lopinavir when concomitantly used in combination with rifampicin [
21] however this has been associated with poor tolerability and hepatotoxicity [
27‐
29]. More recently, raltegravir was reported to be an adequate alternative to efavirenz in TB/HIV co-infected patients in a phase 2 trial [
30]. Therefore, CDC and WHO both indicate raltegravir to be the preferred option when efavirenz is contraindicated, or the use of rifabutin when ritonavir-boosted protease inhibitors are necessary [
1,
16,
18,
31]. However, access to rifabutin and raltegravir in low- and middle-income countries, is often difficult or impossible [
30]. The aim of this study was to assess clinical outcomes (mortality, virological suppression, loss to follow-up during the first year following TB diagnosis) across different regions (Eastern Europe, Western Europe, and Latin America) among HIV-positive adult patients treated with efavirenz and non-efavirenz containing ART regimens.
Discussion
In this prospective observational study, there were major differences in outcomes that were predicated by patients’ region of residence. The mortality in Eastern Europe was significantly higher than in other regions, as described previously [
3,
34,
35], but this did not differ significantly according to ART regimen (either efavirenz or non-efavirenz containing ART). Although ART-naïve patients had slightly better survival in comparison to ART non-naïve patients, this was similar for patients receiving efavirenz and non-efavirenz containing ART regimens. Furthermore, the proportions of patients who became lost to follow up and who had undetectable viral loads at 12 months following diagnosis of TB did not differ according to whether efavirenz was included in the ART regimen.
The observed similar survival in patients treated with efavirenz or non-efavirenz regimens may have several explanations, including that the non-efavirenz group was heterogeneous. Although inverse probability weighting was used to balance the differences in the co-variables between groups, it is possible that not all confounders including socio-demographic factors, comorbidities and/or concomitant (opportunistic) infections, diagnostic delay, and access to anti-TB drug susceptibility tests were included. In contrast with previously described findings in this cohort, MDR-TB was not associated with mortality at 12 months, probably because those with MDR-TB were less likely to start antiretroviral therapy and were therefore not included in the current study: moreover, a resistance test was performed in only 54% of the selected population. In the main model used, no differences in mortality between regimes was observed, but in an explorative marginal structural model restricted just to patients treated with a boosted protease inhibitor or efavirenz, survival was statistically different, favoring the group receiving efavirenz-based ART. This finding may reflect poorer tolerability of protease inhibitors, greater frequency of drug-drug interactions, or previous virological failure that could additionally impact on mortality. Surprisingly, there was a high proportion of subjects receiving PI-based ART as their first regimen (57%). This group of patients were mostly in the Eastern European region (61%), and most likely the reason for initiating ART with a PI-containing regimen was because of the local availability. Moreover, only 22% of those on non-efavirenz regimens received integrase inhibitors, a majority from Western Europe. Any inferences based on outcomes with this class of ART should be interpreted with caution as the study was not designed to directly compare integrase inhibitors with efavirenz, and additionally, the main analysis may have lacked power to detect a survival benefit.
The proportion of patients who were lost to follow up was high, especially among patients from Eastern Europe, irrespective of ART regimen. This is consistent with findings from other studies in countries with a high burden of TB [
36]. Higher rates of loss to follow up in some other studies may be explained by differences in patient populations, health care provision models including more assertive outreach to patients who have dropped out of care. Although frequency of patients with virological suppression at 12 month was overall acceptable (77%), the proportion of plasma HIV-RNA determinations was heterogeneous between regions. Nevertheless, if the goal is to reach the 90–90-90 target, this rate of virological suppression is still some way from being accomplished. No clinical factors associated with an undetectable HIV viral load were found in this study, however it was less likely to be achieved in Eastern Europe. In general, unfavorable outcomes such as loss to follow-up, proportion of detectable viral load and mortality were more frequent in the Eastern European region, which is consistent with previous publications from our study [
2,
3]. Factors such as characteristics of the HIV population (i.e. the high proportion of IDU), education and health care barriers, less access to HIV monitoring such as HIV-RNA determinations, and the feasibility of implementing current recommendations on ART initiation in the context of an AIDS-defining event [
37], might have an important role when patients are compared with other regions with limited healthcare resources, such as Latin America.
Our study has several limitations. These include the relatively short follow-up period, differences between regions in terms of routine care such as access to HIV-RNA determinations, heterogeneity of use of ART, availability of rifabutin and integrase inhibitors, and timing of ART initiation at TB diagnosis. In terms of data availability, we recognize limitations in information regarding reasons for initiating or changing specific ART regimens, which did not allow us to accurately distinguish between changes due to adverse effects or changes due to ART failure and we cannot exclude the possibility that some naïve patients might have been receiving ART – although this was not detected during our quality assurance procedures. However, this is the largest multi-regional TB:HIV cohort and the first to comprehensively compare the concomitant use of TB treatment and efavirenz and non-efavirenz containing ART regimes. Using marginal structural models, there was a slightly better outcome for patients treated with efavirenz-containing ART, although this was not consistent in all analyses and therefore not categorical. These results warrant further analyses.
Acknowledgements
We thank the patients who participated in the study and the staff involved at the participating hospitals in the TB:HIV study group.
TB:HIV Study group.
Eastern Europe: Belarus: Belarusian State Medical University, Department of Infectious Disease: I. Karpov (PI), A. Vassilenko; Republican Research and Practical Centre for Pulmonology and TB (Minsk): A. Skrahina (PI), D. Klimuk, A. Skrahin, O. Kondratenko and A. Zalutskaya; Gomel State Medical University (Gomel): V. Bondarenko (PI), V. Mitsura, E. Kozorez, O. Tumash; Gomel Region Centre for Hygiene: O. Suetnov (PI) and D. Paduto. Estonia: East Viru Central Hospital (Kohtla-Jarve): V. Iljina (PI) and T. Kummik. Georgia: Infectious Diseases, AIDS and Clinical Immunology Research Center (Tiblisi): N. Bolokadze (PI), K. Mshvidobadze and N. Lanchava; National Center for Tuberculosis and Lung Diseases of Georgia (Tibilisi): L. Goginashvili, L. Mikiashvili and N. Bablishvili. Latvia: Infectology Centre of Latvia (Riga): B. Rozentale (PI), I. Zeltina and I. Janushkevich. Lithuania: Centre for Communicable Diseases and AIDS (Vilnius): I. Caplinskiene (PI), S. Caplinskas, Z. Kancauskiene. Poland: Wojewodski Szpital Zakanzy/Medical University of.
Warsaw (Warszawa): R. Podlasin (PI), A. Wiercinska-Drapalo (PI), M. Thompson and J. Kozlowska; Wojewodski Szpital Specjalistyczny/Medical University Teaching Hospital (Bialystok): A. Grezesczuk (PI); Jozef Strus Multidisciplinary City Hospital (Poznan): M. Bura (PI); Wroclaw University School of Medicine (Wroclaw): B. Knysz (PI) and M. Inglot; Jagiellonian University Medical College (Krakow): A. Garlicki (PI) and J. Loster. Romania: Dr. Victor Babes Hospital (Bucharest): D. Duiculescu († PI) and S. Tetradov. Russia: Botkin Hospital of Infectious Diseases (St. Petersburg): A. Rakhmanova († PI), O. Panteleeva, A. Yakovlev, A. Kozlov, A. Tyukalova and Y. Vlasova; City TB Hospital No. 2 (St. Petersburg): A. Panteleev (PI); Center for Prevention and Control of AIDS (Veliky, Novgorod): T. Trofimov (PI); Medical University Povoljskiy Federal Region. Ukraine: Crimean Republican AIDS Centre (Simferopol): G. Kyselyova (PI).
Western Europe: Belgium: CHU Saint-Pierre (Brussels): M.C. Payen (PI), K. Kabeya and C. Necsoi. Denmark: Rigshospitalet (Copenhagen): N. Obel (PI); Hvidovre University Hospital: K. Thorsteinsson. France: Aquitaine Cohort. Cohort administration: F. Dabis (PI) and E. Pernot. Participating Centers and Physicians: Bordeaux University Hospital: P. Morlat; Arcachon Hospital: A. Dupont; Dax Hospital: Y. Gerard; Bayonne Hospital: F. Bonnal; Libourne Hospital: J. Ceccaldi; Mont-de-Marsan Hospital: S. De Witte; Pau Hospital: E. Monlun; Périgueux Hospital: P. Lataste; Villeneuve-sur-Lot Hospital: I. Chossat. Switzerland: Swiss HIV Cohort Study (SHCS,
www.shcs.ch): Cohort administration: M. Sagette and M. Rickenbach. Participating Centers and Physicians: University Hospital Basel: L. Elzi and M. Battegay; University Hospital Bern: H. Furrer (PI); Hopital Cantonal Universitaire, Geneve: D. Sculier and A. Calmy; Centre Hospitalaire Universitaire Vaudois, Lausanne: M. Cavassini; Hospital of Lugano: A. Bruno and E. Bernasconi; Cantonal Hospital St. Gallen: M. Hoffmann and P. Vernazza; University Hospital Zurich: J. Fehr and R. Weber. This study has been co-financed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #148522) and by SHCS project 666. The data are gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians). The members of the Swiss HIV Cohort Study are: V. Aubert, M. Battegay, E. Bernasconi, J. Böni, H.C. Bucher, C. Burton-Jeangros, A. Calmy, M. Cavassini, G. Dollenmaier, M. Egger, L. Elzi, F. Fehr, J. Fellay, H. Furrer (Chairman of the Clinical and Laboratory Committee), C.A. Fux, M. Gorgievski, H. Günthard (President of the SHCS), D. Haerry (deputy of “Positive Council”), B. Hasse, H.H. Hirsch, M. Hoffmann, I. Hösli, C. Kahlert, L. Kaiser, O. Keiser, T. Limkait, R. Kouyos, H. Kovari, B. Ledergerber, G. Martinetti, B. Martinez de Tejada, K. Metzner, N. Müller, D. Nadal, D. Nicca, G. Pantaleo, A. Rauch (Chairman of the Scientific Board), S. Regenass, M. Rickenbach (Head of Data Center), C. Rudin (Chairman of the Mother & Child Sub-study), F. Schöni-Affolter, P. Schmid, J. Schüpbach, R. Speck, P. Tarr, A. Telenti, A. Trkola, P. Vernazza, R. Weber, S. Yerly. United Kingdom: Mortimer Market Centre (London): R.F. Miller (PI) and N. Vora; St. Mary’s Hospital (London): G. Cooke (PI) and S. Mullaney; North Manchester General Hospital: E. Wilkins (PI) and V. George; Sheffield Teaching Hospitals: P. Collini (PI) and D. Dockrell; King’s College Hospital (London): F.A. Post (PI), L. Campbell, R. Brum, E. Mabonga and P. Saigal. Queen Elizabeth Hospital: S. Kegg (PI); North Middlesex University Hospital: J. Ainsworth (PI) and A. Waters. Leicester Royal Infirmary: J. Dhar (PI) and L. Mashonganyika. Southern Europe: Italy: IRCCS - Ospedale L. Spallanzani (Rome): E. Girardi (PI), A Rianda, V. Galati, C. Pinnetti and C. Tommasi; AO San Gerardo (Monza): G. Lapadula (PI); IRCCS AOU San Martino – IST di Genoa (Genova): A. Di Biagio (PI) and A. Parisini; Clinic of Infectious Diseases, University of Bari (Bari): S. Carbonara (PI), G. Angarano and M. Purgatorio; University of Brescia Spedali Civili: A. Matteelli (PI) and A. Apostoli. Spain: Barcelona Cohort funded by the Spanish HIV/AIDS Research Network: Hospital Clinic of Barcelona: J.M. Miro (PI), C. Manzardo, C. Ligero and J. Gonzalez; Hospital del Mar: F. Sanchez, H. Knobel, M. Salvadó and J.L. Lopez-Colomes; Mutua de Terrassa: X. Martínez-Lacasa and E. Cuchí; Hospital Universitari Vall d’Hebrón: V. Falcó, A. Curran, M.T. Tortola, I. Ocaña and R. Vidal; Hospital Universitari de la Santa Creu i Sant Pau: M.A. Sambeat, V. Pomar and P. Coll; Hospital Universitari de Bellvitge: D. Pozamczer, M. Saumoy and F. Alcaide; Agencia de Salud Pública de Barcelona: J. Caylà, A. Moreno, J.P. Millet, A. Orcau, L. Fina, L. del Baño, L.L. Roldan. Hospital Universitario Donostia (San Sebastian): JA. Iribarren (PI) and M. Ibarguren; Hospital Universitario Ramon y Cajal (Madrid): S. Moreno (PI) and A. González; Hospital Universitario ‘Gregorio Maranon’ (Madrid): P. Miralles (PI) and T. Aldámiz-Echevarría.
Latin America: Argentina: The CICAL Cohort: Cohorte administration: M. Losso (PI), J. Toibaro and L. Gambardella. Participating Centers and Physicians: Argentina: Hospital J. M. Ramos Mejía (Buenos Aires): J. Toibaro and L. Moreno Macias; Hospital Paroissien (BA): E. W arley (PI) and S. Tavella; Hospital Piñero (BA): O. Garcia Messina and O. Gear; Hospital Nacional Profesor Alejandro Posadas: H. Laplume; Hospital Rawson (Cordoba): C. Marson (PI); Hospital San Juan de Dios (La Plata): J. Contarelia and M. Michaan; Hospital General de Agudos Donación F. Santojani: P. Scapellato and D. D Alessandro; Hospital Francisco Javier Muñiz (BA): B. Bartoletti and D. Palmero; Hospital Jujuy: C. Elias. Chile: Fundación Arriaran (Santiago): C. Cortes. México: INNCMSZ (México DF): B. Crabtree (PI); Hospital Civil de Guadalajara (Guadalajara): J. Andrade (PI); Hospital General Regional de Leon-CAPASITS: J.L. Mosqueda Gomez.
† Deceased.
TB:HIV Steering Committee: H. Furrer, E. Girardi, M. Bruyand, J.A. Caylá, M. Losso, J.D. Lundgren, A. Panteleev (co-chair), R.F. Miller, J.M. Miro, Å.B. Andersen, S. Tetradov, F.A. Post (co-chair), A. Skrahin and J. Toibaro.
Statistical centre: A. Schultze, L. Shepherd, A. Mocroft.
Coordinating centre: A.M.W. Efsen, M. Mansfeld, B. Aagaard, B.R. Nielsen, A H. Fisher, R.S. Brandt, D. Raben, D.N. Podlekareva, O. Kirk.
Ethics approval and consent to participate
The HIV/TB project was an observational study and patients were not exposed to any experimental interventions nor did the study intervene with the clinical management of the patient. The study only collected information from patient records and if necessary, patient interview. The study was conducted according to the current ethical standards including the WMA Declaration of Helsinki and was submitted to the appropriate regulatory authorities including ethical committees in the participating countries, as requested by local regulations. When informed consent was required by the local and/or national Ethics Committees, this was obtained prior to the initiation of any study related data being obtained. The consent form was approved by the IEC/IRB of each participating centre.
In specific, IEC/IRB were obtained from the following commitees:
Le Comité d’Ethique du C.H.U Saint-Pierre, Le Numéra registre AK/12–03-28/4128, Comité.
Ético Cientifico del servicio de Salud Metropolitano Centra, Chil, certificado 452/11, De.
Videnskabsetiske Komiteer i Region Hovedstaden Journal nr.: H-3-2011-095, United Kingdom national ethics approval Reference nr. 11/LO/0713 & R&D Reference nr. CSP 75430 for UK sites: Mortimor Market Centre, London, Imperial College Healthcare, London, St. Marys Hospital, London, North Manchester General Hospital, Manchester, Sheffield Teaching Hospitals, Sheffield, King’s College Hospital, London, North Middlesex University Hospital, London, Queen Elisabeth Hospital, London R&D ref. nr. SLHT/2011/UCSM/HIV/88, Leicester Royal Infirmary, Leicester. El Comité de Etica en Investigación en Salud, Hospital Paroissien Argentina 20/12/2911, Comité de Etica Iniciativa y Reflextion Bioetica Hospital Pineiro & Hospital Ramos Mejia Argentina 12/12/12, Comité de Bioética Reg. nr. 11,743/11 Hospital Nacional Profesor Alejandro Posdas Argentina, Comité Institucional de Ètica de la Investigacion en Salud del Nino u del Adulto Cordoba 16/12/2012 Hospital Rawson, Comité de Etica La Plata 12/11/12 Hospital Sa Juan de Dios Argentina, Comité de Ética en Investigacion Buenos Aires 18/11/12 Hospital Santojani Argentina & 11/05/2012 Hospital Fracisco Javier Muniz Argentina, Docencia e Investigación 15/06/12 Jujuy Argentina, Institutional Review Board Tbilisi Ref. nr. 12–007, Registro delle Sperimentazioni del Comitato Etico Rone nr. 24/2011 Spallanzani, Comitato Etico San Gerardo, Monza 26/05/2011, Comitato Etico Aziendale A.O.U. San Martino Genoa nr. 295 08/04/2011, Comitato Etico Indipendente Locale Policlinio Consorziale Bari nr. 624 28/09/2011, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Ref. nr 437, Comité de Ética del Hospital General Regional de León 10/10/2011, Secretario del Comité de Ensenanza, Investigacion y Ética Hospital Civil de Guadalajara Invest. Nr. 038/12, Comitato Etico Spedali Civili Brescia 07/06/2011 nr.36; Direcció General de Regularcio Barcelona CY-ANT-2011-01, Hospital Universitario Ramón y Cajal Comité Ético de Investigación Clinica 12/07/2011, Comite Etico de Investigation Clinica de Euscadi Vitoria 02/02/2012, Comité Ético de Investigación Clínica Hospital General Universitario Gregorio Maranon Madrid SAS/3470/2009, Kantonale Ethik-Kommission Zürich EK-793, Ethical Committee of Rep. Res. And Practical Centre for Pulmonology Minsk 11/02/2011, Ethical Committee of Gomel State Medical University & Gomel Regional Centre for Hygiene, Ethical Committee for Botkin Hospital & City TB Hospital ref. nr.23, Ethical Committee for Novgorod Centre for AIDS Prevention and Control 11/10/2011, Ethican Committee of Samara State Medical University 10/10/2012, Komisja Bioetycznego Uniwersytetu Medycznego w Bialymstoku Poland R-I-00/85c/2012 –R-I-002/85/2011, Tallinn Medical Research Ethics Committee Appr. Nr. 2555, RSU Etikas Komitejas Lemums Riga Nr. E-9(2), Vilniaus Regioninis Biomedicininiu Tyrimu Etikos Komitetas Nr. 158,200–07–363-90, Dr. Victor Babes Hospital Institutional Ethics Committee nr. 3889, Ethics Committee Crimean Republican AIDS Centre Nr. 462–13–08-12.
Competing interests
YCV, AS1, AMWE, AP, AS2, DNP, JDL, ST, ML, JT, JF, JC, JAV have no competing interests to declare.
FAP, received honoraria and/or research funding from Abbvie, Gilead, ViiV, BMS, MSD and Janssen.
JMM received a personal intensification research grant (number INT15/00168) during 2016 from the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain, and a personal 80:20 research grant from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–19.
RFM has received honoraria from Gilead, Janssen, Merck, and ViiV for giving non-promotional lectures on clinical aspects of HIV; is a member of the British HIV Association Tuberculosis/HIV Guidelines Committee; and is a panel member for the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents (National Institutes of Health, Centers for Disease Control and Prevention, HIV Medicine Association of the Infectious Diseases Society of America).
JSM has received lecture fees, sponsorship, honoraria from Gilead, Stendhal, Abbvie, ViiV, Janssen and MSD.
EG, Consultancy for Otsuka Novel Products, Speaker’s fee from Janssen, Gilead sciences, Angelini, Research Grant from Gilead sciences, Travel Grant from Janssen.
AM, has have received lecture fees, sponsorship, honoraria or consultancy fees from ViiV, Pfizer, BMS, BI, Merck and Wragge LLC.
OK had prior board membership at ViiV Healthcare, Gilead Sciences and Merck, received payment for lectures and/or for development of educational presentations from Abbott, Gilead Sciences, Tibotec and Quagen, and had travel/accommodations/meeting expenses paid by Abbott, BMS, Gilead Sciences, Merck and ViiV Healthcare – all outside the submitted work.
BCR, has received lecture fees, sponsorship, honoraria from Gilead, Stendhal, Abbvie, Janssen and MSD.