Human Immunodeficiency Virus type 1 Drug Resistance Mutations in Patients Failing Antiretroviral Therapy in Lebanon from 2009 to 2013

Authors

  • Ahmad A. Hachem
  • Essa H. Hariri
  • Anthony Mansour
  • Jacques Mokhbat

DOI:

https://doi.org/10.38179/ijcr.v1i1.20

Keywords:

HIV-1, ART, ART failure, resistance mutations, NRTIs, NNRTIs, PIs, Lebanon

Abstract

Background: Antiretroviral drug resistance remains a significant problem in the clinical management of patients infected with the Human Immunodeficiency Virus type-1.

Aim: This study investigates and reports data on the molecular characterization of HIV-1 isolates from patients who are in a state of therapy failure.

Methods: This is a retrospective study conducted on 65 patients in therapy failure. Inclusion criteria included patients diagnosed as being in therapy failure between the years 2009 and 2013. We defined ART failure as either a failure to achieve viral suppression or a failure to detect viral loads below 500 copies/mL after virological suppression in at least two plasma samples.  We used the published WHO list for surveillance of transmitted resistance and the Stanford HIV Drug Resistance Database to identify drug resistance mutations.

Results: 65% of the participants had at least one drug resistance mutation (DRM). 12% of the population sampled had resistance to only one ART class, 32% presented with resistance to two classes of antiretroviral drugs, and 20% had resistance to all three classes of drugs. The prevalence of nucleoside transcriptase inhibitor (NRTI) mutations was 55%, the most common DRM being M184V. The prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations was 58%, with the most common mutation being the K103N mutation. The prevalence of protease inhibitors drug resistance mutations was 23%, with mutations V82A and I47V being present in 10% of the study population.

Conclusion: Our study is the first molecular characterization of DRM emergence in HIV-1 strains from patients failing antiretroviral therapy in Lebanon. Continuous monitoring of resistance patterns for HIV in the country is necessary to tackle the emergent drug resistance.

References

Deeks SG, Gange SJ, Kitahata MM, et al. Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America. Clin Infect Dis. 2009;49(10):1582-1590. PMid:19845473 PMCid:PMC2871149. https://doi.org/10.1086/644768

Couto-Fernandez JC, Silva-de-Jesus C, Veloso VG, et al. Human immunodeficiency virus type 1 (HIV-1) genotyping in Rio de Janeiro, Brazil: assessing subtype and drug-resistance associated mutations in HIV-1 infected individuals failing highly active antiretroviral therapy. Mem Inst Oswaldo Cruz. 2005;100(1):73-78. PMid:15867968. https://doi.org/10.1590/s0074-02762005000100014

Jaka HM, Mshana SE, Liwa AC, et al. Prevalence of immunological failure and durability of first line antiretroviral therapy at Bugando Hospital Mwanza, Tanzania. Tanzania Medical Journal. 2009;24(2). https://doi.org/10.4314/tmj.v24i2.53278

Marconi VC, Sunpath H, Lu Z, et al. Prevalence of HIV-1 drug resistance after failure of a first highly active antiretroviral therapy regimen in KwaZulu Natal, South Africa. Clin Infect Dis. 2008;46(10):1589-1597. Expert Rev Anti Infect Ther. 2004;2(1):147-151. PMid:15482179. https://doi.org/10.1586/14787210.2.1.147

Mokhbat JE, Ibrahim NK, Abdul-Karim FW, et al. The acquired immunodeficiency syndrome (AIDS): report of the first case in Lebanon and a review of the literature. Lebanese Medical Journal. 1985;35(4):295-319.

UNAIDS. Global Aids Update 2020 [Available from: https://www.unaids.org/en/regionscountries/countries/lebanon.

Mokhbat JM, Melhem NM, El-Khatib Z, Zalloua P. Screening for antiretroviral drug resistance among treatment-naive human immunodeficiency virus type 1-infected individuals in Lebanon. J Infect Dev Ctries. 2014;8(3):339-348. Published 2014 Mar 13. PMid:24619266. https://doi.org/10.3855/jidc.3593

WHO. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. 2010.

Imaz A, Olmo M, Peñaranda M, et al. Short-term and long-term clinical and immunological consequences of stopping antiretroviral therapy in HIV-infected patients with preserved immune function. Antivir Ther. 2013;18(1):125-130. PMid:22805174. https://doi.org/10.3851/IMP2249

Kuritzkes DR, Grant RM, Feorino P, et al. Performance characteristics of the TRUGENE HIV-1 Genotyping Kit and the Opengene DNA Sequencing System. J Clin Microbiol. 2003;41(4):1594-1599. PMid:12682150 PMCid:PMC153857. https://doi.org/10.1128/jcm.41.4.1594-1599.2003

Bennett DE, Camacho RJ, Otelea D, et al. Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update. PLoS One. 2009;4(3):e4724. PMid:19266092 PMCid:PMC2648874. https://doi.org/10.1371/journal.pone.0004724

Liu TF, Shafer RW. Web resources for HIV type 1 genotypic-resistance test interpretation. Clin Infect Dis. 2006;42(11):1608-1618. PMid:16652319 PMCid:PMC2547473. https://doi.org/10.1086/503914

Gifford RJ, Liu TF, Rhee SY, et al. The calibrated population resistance tool: standardized genotypic estimation of transmitted HIV-1 drug resistance. Bioinformatics. 2009;25(9):1197-1198. PMid:19304876 PMCid:PMC2672634. https://doi.org/10.1093/bioinformatics/btp134

Kasang C, Kalluvya S, Majinge C, et al. HIV drug resistance (HIVDR) in antiretroviral therapy-naïve patients in Tanzania not eligible for WHO threshold HIVDR survey is dramatically high. PLoS One. 2011;6(8):e23091. PMid:21886779. PMCid:PMC3158766. https://doi.org/10.1371/journal.pone.0023091

Paredes R, Clotet B. Clinical management of HIV-1 resistance. Antiviral Res. 2010;85(1):245-265. PMid:19808056. https://doi.org/10.1016/j.antiviral.2009.09.01516

Wainberg MA. The impact of the M184V substitution on drug resistance and viral fitness. Expert Rev Anti Infect Ther. 2004;2(1):147-151. PMid:15482179. https://doi.org/10.1586/14787210.2.1.147

Turner D, Brenner B, Wainberg MA. Multiple effects of the M184V resistance mutation in the reverse transcriptase of human immunodeficiency virus type 1. Clin Diagn Lab Immunol. 2003;10(6):979-981. PMid:14607855 PMCid:PMC262455. https://doi.org/10.1128/cdli.10.6.979-981.2003

Loveday C. International perspectives on antiretroviral resistance. Nucleoside reverse transcriptase inhibitor resistance. J Acquir Immune Defic Syndr. 2001;26 Suppl 1:S10-S24. PMid:11264998. https://doi.org/10.1097/00042560-200103011-00003

Winston A, Stebbing J. The K65R mutation in HIV-1 reverse transcriptase. J HIV Ther. 2004;9(2):25-27.

Rhee SY, Liu T, Ravela J, Gonzales MJ, Shafer RW. Distribution of human immunodeficiency virus type 1 protease and reverse transcriptase mutation patterns in 4,183 persons undergoing genotypic resistance testing. Antimicrob Agents Chemother. 2004;48(8):3122-3126. PMid:15273130 PMCid:PMC478552. https://doi.org/10.1128/AAC.48.8.3122-3126.2004

Wang Y, Xing H, Liao L, et al. The development of drug resistance mutations K103N Y181C and G190A in long term Nevirapine-containing antiviral therapy. AIDS Res Ther. 2014;11:36. Published 2014 Nov 21. PMid:25926857 PMCid:PMC4414387. https://doi.org/10.1186/1742-6405-11-36

Quiñones-Mateu ME, Arts EJ. Fitness of drug resistant HIV-1: methodology and clinical implications. Drug Resist Updat. 2002;5(6):224-233. https://doi.org/10.1016/s1368-7646(02)00123-1

Vandamme AM, Sönnerborg A, Ait-Khaled M, et al. Updated European recommendations for the clinical use of HIV drug resistance testing. Antivir Ther. 2004;9(6):829-848.

Peeters M, Nijs S, Vingerhoets J, Tambuyzer L, et al. Determination of phenotypic clinical cut-offs for etravirine: pooled week 24 results of the DUET-1 and DUET-2 trials. Workshop, June 10–14, 2008, Sitges, Spain. XVII HIV Drug Resistance Antiviral therapy. 2008;13(Suppl. 3):A133.

Vingerhoets J, Peeters M, Azijn H, Tambuyzer L, et al. An update on the list of NNRTI mutations associated with decreased virological response to etravirine: multivariate analysis on the pooled DUET-1 and DUET-2 clinical trial data. XVII HIV Drug Resistance Workshop, June 10–14, 2008, Sitges, Spain. . Antiviral therapy. 2008;13(Suppl. 3, A134 (abstract 24).

Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature. 1995;374(6522):569-571. PMid:7700387. https://doi.org/10.1038/374569a0

Zhang YM, Imamichi H, Imamichi T, et al. Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J Virol. 1997;71(9):6662-6670. PMid:9261388 PMCid:PMC191944. https://doi.org/10.1128/JVI.71.9.6662-6670.1997

Richman DD, Morton SC, Wrin T, et al. The prevalence of antiretroviral drug resistance in the United States. AIDS. 2004;18(10):1393-1401. PMid:15199315. https://doi.org/10.1097/01.aids.0000131310.52526.c7

Toledo PV, Carvalho DS, Romagnoli L, et al. HIV-1 genotypic resistance profile of patients failing antiretroviral therapy in Paraná, Brazil. Braz J Infect Dis. 2010;14(4):360-371. https://doi.org/10.1590/S1413-86702010000400009. https://doi.org/10.1016/S1413-8670(10)70076-3

Tamalet C, Fantini J, Tourres C, Yahi N. Resistance of HIV-1 to multiple antiretroviral drugs in France: a 6-year survey (1997-2002) based on an analysis of over 7000 genotypes. AIDS. 2003;17(16):2383-2388. PMid:14571191. https://doi.org/10.1097/00002030-200311070-00014

Gallego O, Ruíz L, Vallejo A, Clotet B, Leal M, Soriano V. Rate of virological treatment failure and frequencies of drug resistance genotypes among human immunodeficiency virus-positive subjects on antiretroviral therapy in Spain. J Clin Microbiol. 2002;40(10):3865-3866. PMid:12354903 PMCid:PMC130857. https://doi.org/10.1128/jcm.40.10.3865-3866.2002

Costagliola D, Descamps D, Assoumou L, et al. Prevalence of HIV-1 drug resistance in treated patients: a French nationwide study. J Acquir Immune Defic Syndr. 2007;46(1):12-18. PMid:17514016. https://doi.org/10.1097/QAI.0b013e318074eb73

Scott P, Arnold E, Evans B, et al. Surveillance of HIV antiretroviral drug resistance in treated individuals in England: 1998-2000. J Antimicrob Chemother. 2004;53(3):469-473. PMid:14749345. https://doi.org/10.1093/jac/dkh102

El Annaz H, Recordon-Pinson P, Tagajdid R, et al. Drug resistance mutations in HIV type 1 isolates from patients failing antiretroviral therapy in Morocco. AIDS Res Hum Retroviruses. 2012;28(8):944-948. PMid:21919803 PMCid:PMC3399567. https://doi.org/10.1089/AID.2011.0278

Sukasem C, Churdboonchart V, Chasombat S, et al. Prevalence of antiretroviral drug resistance in treated HIV-1 infected patients: under the initiative of access to the NNRTI-based regimen in Thailand. J Chemother. 2007;19(5):528-535. PMid:18073152. https://doi.org/10.1179/joc.2007.19.5.528

Hosseinipour MC, van Oosterhout JJ, Weigel R, et al. The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy. AIDS. 2009;23(9):1127-1134. PMid:19417582 PMCid:PMC2896488. https://doi.org/10.1097/QAD.0b013e32832ac34e

Gupta R, Hill A, Sawyer AW, Pillay D. Emergence of drug resistance in HIV type 1-infected patients after receipt of first-line highly active antiretroviral therapy: a systematic review of clinical trials. Clin Infect Dis. 2008;47(5):712-722. PMid:18662137. https://doi.org/10.1086/590943

Fantini J, Tamalet C, Yahi N. Secondary structure predictions of HIV-1 reverse transcriptase provide new insights into the development of drug-resistance genotypes. AIDS. 2001;15(9):1191-1192. PMid:11416728. https://doi.org/10.1097/00002030-200106150-00021

Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2018 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2018;320(4):379-396. PMid:30043070 PMCid:PMC6415748. https://doi.org/10.1001/jama.2018.8431

HIV

Published

2021-01-27

How to Cite

Hachem, A. A., Hariri, E. H., Mansour, A., & Mokhbat, J. (2021). Human Immunodeficiency Virus type 1 Drug Resistance Mutations in Patients Failing Antiretroviral Therapy in Lebanon from 2009 to 2013. International Journal of Clinical Research, 1(1), 113-123. https://doi.org/10.38179/ijcr.v1i1.20