Efficacy, effectiveness, and safety of integrase inhibitors in the treatment of HIV/AIDS in patients with tuberculosis: systematic review and meta-analysis

Authors

DOI:

https://doi.org/10.33448/rsd-v11i10.32636

Keywords:

HIV; AIDS; Tuberculosis; Integrase inhibitor; Systematic review.

Abstract

Integrase Inhibitors are a promising new class of antiretroviral.  However, studies of these drugs in tuberculosis (TB) and, HIV/aids coinfection are scarce. Therefore, the aim of this review was evaluate the efficacy, effectiveness, and safety of integrase inhibitors in the treatment of HIV/AIDS in patients coinfected with tuberculosis (TB). The searches were performed in the MEDLINE, EMBASE, LILACS, COCHRANE, Web of Science, Scopus, and CINAHL databases using the terms “HIV”, “AIDS”, “tuberculosis”, “raltegravir potassium”, “dolutegravir”, “elvitegravir”, “bictegravir”, “integrase inhibitor”, and their respective synonyms. Reports from three randomised clinical trials and a historical cohort were included. Patients coinfected with TB and HIV/AIDS showed a good response to TB treatment (cure or treatment completed), which was above 85% in all arms of the evaluated studies. As a primary outcome, the HIV viral load suppression rates at week 48 were greater than 60% in all arms. The therapies evaluated in patients coinfected with TB and HIV/AIDS were also within the limits of the included studies, there were no significant drug-related adverse events. However, there was no significant difference in the efficacy outcomes viral load suppression between the efavirenz and integrase inhibitor arms, and regarding safety outcomes, there were few events compared with the total. Integrase inhibitors in patients co-infected with TB and HIV/AIDS appear to be effective, well tolerated and constitute an alternative to efavirenz in clinical protocols. However, the use of this drug twice a day compromises adherence to treatment. The role of these drugs should be better determined by further good methodological quality studies to assess their long-term efficacy, effectiveness and safety.

References

Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J,…Guyatt GH. (2011) GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 64(4):401-406

Blanc, F. X., Sok, T., Laureillard, D., Borand, L., Rekacewicz, C., Nerrienet, E., . . . Goldfeld, A. E. (2011). Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med, 365(16), 1471-1481.

Bonnet, M., Bhatt N., Baudin E., Silva, C., Michon, C., Taburet, A.M.,… Calmy, A. (2013). Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: a randomised non-inferiority trial. Lancet Infect. Dis. 13(4):303-312.

Calmy, A., Tovar Sanchez, T., Kouanfack, C., Mpoudi-Etame, M., Leroy, S., Perrineau, S., . . . Delaporte, E. (2020). Dolutegravir-based and low-dose efavirenz-based regimen for the initial treatment of HIV-1 infection (NAMSAL): week 96 results from a two-group, multicentre, randomised, open label, phase 3 non-inferiority trial in Cameroon. Lancet HIV, 7(10), e677-e687.

da Silva, D., Van Wesenbeeck, L., Breilh, D., Reigadas, S., Anies, G., Van Baelen, K., . . . Masquelier, B. (2010). HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens. J Antimicrob Chemother, 65(6), 1262-1269.

De Castro N., Marcy O., Chazallon C., Messou E., Eholié S., Ntak-pé J.B.,... Grinsztejn B. (2021). Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial. Lancet Infect. Dis. 21(6):813-822.

Delagreverie H.M., Bauduin C., De Castro N., Grinsztejn B., Chevrier M., Jouenne F.,…Delaugerre, C. (2020). Impact of Raltegravir or Efavirenz on Cell-Associated Human Immunodeficiency Virus-1 (HIV-1) Deoxyribonucleic Acid and Systemic Inflammation in HIV-1/Tuberculosis Coinfected Adults Initiating Antiretroviral Therapy. Open Forum Infect. Dis. 7(2):ofz549.

Dirk M. & Elston M.D. (2021).. The Hawthorne effect. J. Am. Acad. Dermatol.

Dooley, K.E., Kaplan R., Mwelase, N., Grinsztejn, B., Ticona, E., Lacerda, M. (2020). Dolutegravir-based Antiretroviral Therapy for Patients Coinfected With Tuberculosis and Human Immunodeficiency Virus: A Multicenter, Noncomparative, Open-label, Randomized Trial. Clin. Infect. Dis. 70(4):549-556

Dooley, K. E., Sayre, P., Borland, J., Purdy, E., Chen, S., Song, I., . . . Flexner, C. (2013). Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr, 62(1), 21-27.

Efficacy and Safety of 2 Raltegravir Doses in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis. https://www.clinicaltrials.gov/ct2/show/NCT00822315?term=REFLATE&draw=2&rank=2 Accessed 07 july 2022.

Freemantle, N., & Strack, T. (2010). Real-world effectiveness of new medicines should be evaluated by appropriately designed clinical trials. J Clin Epidemiol, 63(10), 1053-1058.

Global tuberculosis report. Geneva: World Health Organization; 2021. Available at: < https://www.who.int/publications/i/item/9789240037021 > Accessed 07 july 2022.

Griesel R., Hill A., Meintjes G. & Maartens G. (2021). Standard versus double dose dolutegravir in patients with HIV-associated tuberculosis: a phase 2 non-comparative randomised controlled (RADIANT-TB) trial. Wellcome Open Res. 6:1.

Grinsztejn, B., De Castro, N., Arnold, V., Veloso, V. G., Morgado, M., Pilotto, J. H., . . . Molina, J. M. (2014). Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis, 14(6), 459-467.

Havlir, D. V., Kendall, M. A., Ive, P., Kumwenda, J., Swindells, S., Qasba, S. S., . . . Sanne, I. (2011). Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med, 365(16), 1482-1491.

Kolakowska, A., Maresca, A. F., Collins, I. J., & Cailhol, J. (2019). Update on Adverse Effects of HIV Integrase Inhibitors. Curr Treat Options Infect Dis, 11(4), 372-387.

Lawn, S. D., Bekker, L. G., & Miller, R. F. (2005). Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis, 5(6), 361-373.

Lemos L. A., Fiuza, M. L., Reis, R. K., Ferrer, A. C., Gir, E., & Galvão, M. T. (2016). Adherence to antiretrovirals in people coinfected with the human immunodeficiency virus and tuberculosis. Rev Lat Am Enfermagem, 24, e2691.

Lennox, J. L., DeJesus, E., Lazzarin, A., Pollard, R. B., Madruga, J. V., Berger, D. S., . . . Sklar, P. (2009). Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet, 374(9692), 796-806.

Luo D, Wan X, Liu J & Tong T (2018). Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 27(6):1785-1805.

Manosuthi W., Wiboonchutikul S. & Sungkanuparph S. (2016). Integrated therapy for HIV and tuberculosis. AIDS Res. Ther. 13:22.

Mariano AS, Magnabosco GT & Orfão NH. (2021). Epidemiological profile of Tuberculosis/HIV coinfection in a prioritary city of Western Amazon. J Manag Prim Health Care;13:e08

McIlleron H., Meintjes G., Burman W.J. & Maartens G. (2007). Complications of antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and immune reconstitution inflammatory syndrome. J. Infect. Dis. 196 (1):S63-75.

Methley, A.M., Campbell S., Chew-Graham, C., McNally, R. & Cheraghi-Sohi, S. (2014) PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Services Research, 14:579

Modongo, C., Wang, Q., Dima, M., Matsiri, O.,Kgwaadira, B., Rankgoone-Pono, G. (2019). Clinical and Virological Outcomes of TB/HIV Coinfected Patients Treated With Dolutegravir-Based HIV Antiretroviral Regimens: Programmatic Experience From Botswana. J. Acquir. Immune Defic. Syndr. 82(2):111-115.

Nabisere R, Musaazi J, Denti P, Aber, F., Lamorde, M., Dooley, K.E.,… Sekaggya-Wiltshire, C. (2020). Pharmacokinetics, SAfety/tolerability, and EFficacy of high-dose Rifampicin in tuberculosis-HIV co-infected patients on efavirenz- or dolutegravir-based antiretroviral therapy: study protocol for an open-label, phase II clinical trial (SAEFRIF). Trials 21(1):181.

Namale, P. E., Abdullahi, L. H., Fine, S., Kamkuemah, M., Wilkinson, R. J., & Meintjes, G. (2015). Paradoxical TB-IRIS in HIV-infected adults: a systematic review and meta-analysis. Future Microbiol, 10(6), 1077-1099.

National Library of Medicine (U.S.). Efficacy and Safety of 2 Raltegravir Doses in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis Disponível em: https://www.clinicaltrials.gov/ct2/show/NCT00822315?term=REFLATE&draw=2&rank=2 Accessed 07 july 2022.

National Library of Medicine (U.S.). HIV Drug Resistance Among Individuals Failing Tenofovir/Lamivudine and Dolutegravir First Line Regimen in Brazil https://www.clinicaltrials.gov/ct2/show/NCT04453436?term=dolutegravir&draw=3&rank=98 Accessed 07 july 2022.

National Library of Medicine (U.S.). Impact of Different Integrase Inhibitor Based Regimen on Immune Activation Among HIV naïve Patient (INTATTI) https://www.clinicaltrials.gov/ct2/show/NCT03280940?term=raltegravir&draw=6&rank=278 Accessed 07 july 2022.

National Library of Medicine (U.S.). Raltegravir Versus Efavirenz in Naive HIV-1-infected Patients Receiving Rifampin for Active Tuberculosis (REFLATE TB2). https://www.clinicaltrials.gov/ct2/show/NCT02273765?term=REFLATE&draw=2&rank=1 Accessed 07 july 2022.

National Library of Medicine (U.S.)Open-label Study of Dolutegravir (DTG) or Efavirenz (EFV) for Human Immunodeficiency Virus (HIV) - Tuberculosis (TB) Co-infection. Disponível em: https://clinicaltrials.gov/ct2/show/NCT02178592 Accessed 07 july 2022.

Nunes E P (2016). Dolutegravir versus raltegravir em pacientes em falha à terapia antirretroviral: estudo Sailing. Braz. J. Infect. Dis. 2(1): 16-23.

Open-label Study of Dolutegravir (DTG) or Efavirenz (EFV) for Human Immunodeficiency Virus (HIV) - Tuberculosis (TB) Co-infection. Disponível em: https://clinicaltrials.gov/ct2/show/NCT02178592 Accessed 24 March 2022.

Ouzzani, M., Hammady, H., Fedorowicz, Z., & Elmagarmid, A. (2016). Rayyan-a web and mobile app for systematic reviews. Syst Rev, 5(1), 210.

Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., . . . Moher, D. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj, 372, n71.

Pecego, A. C., Amancio, R. T., Ribeiro, C., Mesquita, E. C., Medeiros, D. M., Cerbino, J., . . . Japiassu, A. M. (2016). Six-month survival of critically ill patients with HIV-related disease and tuberculosis: a retrospective study. BMC Infect Dis, 16, 270.

Pinho R.E.G., Pascom A.R.P., Alves K., Oliveira P.B., Menezes A.I., Perini F.B.,...Avelino-Silva, V.I. CD4 count and viral load dynamics under different art regimens in HIV/TB coinfection. Avaible at: https://www.croiconference.org/abstract/cd4-count-and-viral-load-dynamics-under-different-art-regimens-in-hiv-tb-coinfection/ Accessed 07 july 2022.

Raffi, F., Rachlis, A., Stellbrink, H. J., Hardy, W. D., Torti, C., Orkin, C., . . . Min, S. (2013). Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet, 381(9868), 735-743.

Resende NH, Pantuzza LLN, Carvalho WS, Miranda SS, Reis AMR. Systematic Review of Integrase Inhibitors in the treatment of HIV/aids in patients with tuberculosis. PROSPERO 2020 CRD42020185240 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020185240

Rockstroh, J. K., DeJesus, E., Lennox, J. L., Yazdanpanah, Y., Saag, M. S., Wan, H., . . . Sklar, P. (2013). Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr, 63(1), 77-85.

Rosetto M, Brand EM, Hahn GV, Oliveira DLLC, Teixeira LB. (2019). Epidemiological profile of tuberculosis cases with HIV coinfection in Porto Alegre city, Brazil. Rev. Bras. Enferm. 72 (5).

Sterne, J. A. C., Savović, J., Page, M. J., Elbers, R. G., Blencowe, N. S., Boutron, I., . . . Higgins, J. P. T. (2019). RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ, 366, l4898.

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I,…Higgins JPT. (2019). RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366:l4898.

Uthman, O. A., Okwundu, C., Gbenga, K., Volmink, J., Dowdy, D., Zumla, A., & Nachega, J. B. (2015). Optimal Timing of Antiretroviral Therapy Initiation for HIV-Infected Adults With Newly Diagnosed Pulmonary Tuberculosis: A Systematic Review and Meta-analysis. Ann Intern Med, 163(1), 32-39.

Venter, W.D.F., Sokhela, S., Simmons B., Moorhouse M., Fairlie L., Mashabane N.,…Hill, A. (2021). Dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from a randomised, phase 3, non-inferiority trial. Lancet HIV 7(10):e666-e676.

Walmsley, S. L., Antela, A., Clumeck, N., Duiculescu, D., Eberhard, A., Gutiérrez, F., . . . Nichols, G. (2013). Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med, 369(19), 1807-1818.

Wang X, Cerrone M, Ferretti F, Castrillo, N., Maartens, G., McClure, M., Boffito, M. (2019). Pharmacokinetics of dolutegravir 100 mg once daily with Rifampicin. Int. J. Antimicrob. Agents 54(2):202-206

Wells, G.A., Shea, B., O'Connell, D., Peterson, J., Welch, V., Losos, M., Tugwell, P. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute (2014). https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp Accessed 07 July 2022.

Wenning, L. A., Hanley, W. D., Brainard, D. M., Petry, A. S., Ghosh, K., Jin, B., . . . Iwamoto, M. (2009). Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrob Agents Chemother, 53(7), 2852-2856.

WHO, WORLD HEALTH ORGANIZATION. Kanters S, Jansen J, Zoratti M, Forrest J, Humphries B, Campbell J. Web Annex B. Systematic literature review and network meta-analysis assessing first-line antiretroviral treatments In: Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines. Supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization; 2018 (WHO/CDS/HIV/18.25). Licence: CC BY-NC-SA 3.0 IGO. https://apps.who.int/iris/bitstream/handle/10665/276490/WHO-CDS-HIV-18.25-eng.pdf?ua=1 Accessed 24 March 2022.

WHO, WORLD HEALTH ORGANIZATION. Updated recommendations on first-line and secondline antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV Interim guidance. In: Department ST, ed. Geneva, Switzerland: World Health Organization; 2018. https://www.who.int/publications/i/item/WHO-CDS-HIV-18.51 Accessed 24 March 2022.

Wijting, I. E. A., Wit, F., Rokx, C., Leyten, E. M. S., Lowe, S. H., Brinkman, K., . . . Rijnders, B. J. A. (2019). Immune reconstitution inflammatory syndrome in HIV infected late presenters starting integrase inhibitor containing antiretroviral therapy. EClinicalMedicine, 17, 100210.

Wan X, Wang W, Liu J & Tong T. (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med. Res. Methodol. 14:135.

Wong, E., Trustman, N. & Yalong, A. (2016). HIV pharmacotherapy: A review of integrase inhibitors. Jaapa 29(2):36-40.

World Health Organization; 2015 http://apps.who.int/iris/bitstream/10665/204347/1/WHO_HIV_2015.44_ eng.pdf?ua=1. Accessed 24 March 2022.

World Health Organization; Treatment of Tuberculosis Guidelines. Fourth edition, 2009.

Zimba, S., Mbewe, N., Chishimba, L., Chomba, M., & Saylor, D. (2021). Immune reconstitution inflammatory syndrome: a report of TB-IRIS after switching from efavirenz to dolutegravir. Trop Doct, 51(2), 216-218.

Downloads

Published

26/07/2022

How to Cite

RESENDE, N. H. de .; PANTUZZA, L. L. N. .; CARVALHO, W. da S.; MIRANDA, S. S. de .; LAPER, I. Z. .; REIS, A. M. M. . Efficacy, effectiveness, and safety of integrase inhibitors in the treatment of HIV/AIDS in patients with tuberculosis: systematic review and meta-analysis. Research, Society and Development, [S. l.], v. 11, n. 10, p. e174111032636, 2022. DOI: 10.33448/rsd-v11i10.32636. Disponível em: https://www.rsdjournal.org/index.php/rsd/article/view/32636. Acesso em: 26 apr. 2024.

Issue

Section

Review Article