- Research note
- Open Access
Prevalence of resistance to integrase strand-transfer inhibitors (INSTIs) among untreated HIV-1 infected patients in Morocco
BMC Research Notes volume 11, Article number: 369 (2018)
The integrase strand-transfer inhibitors (INSTIs) are an important class in the arsenal of antiretroviral drugs designed to block the integration of HIV-1 cDNA into the host DNA through the inhibition of DNA strand transfer. In this study for the first time in Morocco, the complete HIV-1 integrase gene was analysed from newly diagnosed patients to evaluate the prevalence of natural polymorphisms and INSTIs resistance-associated mutations in the integrase gene.
The 864pb IN coding region was successfully sequenced from plasma sample for 77 among 80 antiretroviral naïve patients. The sequences were interpreted for drug resistance according to the Stanford algorithm. Sixty samples were HIV-1 subtype B (78%), fourteen CRF02_AG (18%), two subtype C and one subtype A. Overall 81 of 288 (28%) amino acid IN positions presented at least one polymorphism each. We found 18 (36.73%), 42 (25.76%) and 21 (27.27%) of polymorphic residues assigned to the N-Terminal Domain, Catalytic Core Domaine and the C-Terminal Domain positions respectively. Primary INSTIs resistance mutation were absent, however secondary mutations L74IM, T97A were detected in four samples (5.2%). These results demonstrate that untreated HIV-1 infected Moroccans will be susceptible to INSTIs.
Since the introduction of combination therapy (highly active antiretroviral therapy, HAART) with protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) in Morocco in 1998, the mortality and morbidity of HIV/AIDS patients has reduced . These drugs suppress viral replication and reduce HIV viral RNA loads in the plasma of patients, thus helping to maintain the immune system, but they do not prevent escape through the emergence of drug resistant viruses and subsequent treatment failure.
According to previous Moroccan studies, the prevalence of resistance to NRTIs, NNRTIs and PIs are continuously increasing among drug-naïve and treatment experienced patients [2,3,4], thus, developing new drugs for AIDS treatment would be needed.
INSTIs are the latest antiretroviral (ARV) drugs class developed for the treatment of HIV-1 infections via the inhibition of DNA strand transfer . To date three INSTIs, raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) are approved for clinical use [6,7,8]. They are potent ARV drugs offering more treatment options in naïve patients as well in pretreated patients with preexisting drug resistance or treatment complication [9,10,11,12,13,14,15]. Therefore, they have become an essential component of HAART used in many countries. Morocco has installed national programs following World Health Organization ARV guidelines and newer ARV salvage regimens including third-line drugs such as INSTIs will been introduced in the upcoming years. The aim of this study is to analyze, for the first time in Morocco, integrase (IN) sequence variability among ARV treatment naïve patients to determine the frequency of resistance mutations and the prevalence of natural polymorphisms of the IN gene and in order to estimate INSTIs efficacy prior to their introduction into the country.
Study population and samples
Plasma samples were collected for genotypic assay of the IN gene region from eighty seven HIV-infected, antiretroviral therapy-naïve patients originating from different geographic parts of the country enrolling at the dermatology department of Mohammed V Military Teaching Hospital in Rabat between the years 2009 and 2015. Demographic, clinical and laboratory data were collected for all patients. The quantitative HIV-RNA tests were performed using Cobas TaqMan HIV-1 Test, version 1.0 (Roche Diagnostics Systems, Germany, P/N: 03542998 190). CD4 cell enumerations were performed using the FacsCount instrumentation. (FacsCount, Becton–Dickinson, P/N: 339010). After viral load testing,eighty samples were used for sequencing assay. The detection of IN mutations by sequencing was unsuccessful for three samples.
The study was approved by the Ethical Committee of Biological Research, Faculty of Medicine and Pharmacy–Rabat, and was conducted with respect to legal aspects. Written informed consent was obtained from all participants before any data analysis procedure.
Genetic analysis and drugs resistance
HIV RNA was extracted from plasma using High Pure Viral RNA Kit (Roche Diagnostics Systems, Germany, P/N: 11858882001) and the integrase coding region (867 bp) was amplified by one-step reverse transcriptase polymerase chain reaction (RT-PCR) using MyTaq One-Step RT-PCR kit (Bioline, London, UK, P/N: BIO-65049) and the primer set KVL068 -KVL069 . The Nested-PCR assay was carried out using MyFi DNA Polymerase kit (Bioline, London, UK, P/N: BIO-21118) and the primer set KVL070 and KVL084 . Sequencing reaction was performed using BigDye Terminator v3.1 Ready Reaction Cycle Sequencing Kit (P/N: 4337455) with an ABI PRISM 3130XL Genetic Analyzer (Applied Biosystems) using the POP-7 polymer (P/N: 4393708). Data were analyzed by sequencing Analysis Software version 5.3.1 (Applied Biosystems, P/N: 4360967).
IN Sequences were assembled and aligned using DNA Dragon Sequence Assembler version 1.6.0 (Sequentix-Digital DNA Processing, Germany) and Muscle method in MEGA 6 software , respectively. All sequences were submitted to GenBank and registered under accession numbers: KU609274–KU609350.
HIV-1 subtyping and screening of IN polymorphisms in comparison with the HxB2 HIV-1 clade B consensus sequence (GenBank accession number K03455.1) were done using geno2pheno subtyping tools . Phylogenetic tree was constructed by using Maximum Likelihood method, and Bootstrap resampling was performed 1.000 times for all sequences with MEGA 6 software (Fig. 1). INSTIs resistance mutations in IN sequences were interpreted using the Stanford HIVdb Program (Version September 23,2016) and screened for the presence of additional changes in 17 positions (V72I, T112I, S119PRTG, T124A, T125K, A128T, Q146K, M154I, K156N, V165I, V201I, I203M,T206S, S230N, D232N, V249I and C280Y) previously related to INIs resistance in vitro and frequently reported by different studies [19,20,21,22,23]. The variability at the D64D116E152 and H12H16C40C43 motifs, the residues that interact with the human lens epithelium derived growth factor (LEDGF/P75) and the degree of variability of the three functional areas of IN were also investigated.
Out of eighty patients, sixty-two (77.5%) were male. Median age was 36 years old, where patients with an age between 25 and 44 years old represent 61%. Sixty-five (81.25%) patients were suspected to have acquired HIV infection through heterosexual contact, four (5%) perinatally, and the mode of infection was unknown for 11 patients. The median of CD4+ T cell count and viral load at the time of sequencing for the available values were 409 cells/mm3 and 95,800 copies/ml respectively (Table 1).
In 3 samples the sequencing failed and subtypes were unavailable. The final dataset for the baseline IN resistance included 77 individuals. IN sequencing was consistently successful at HIV viral loads higher than 66 copies/ml. Sixty (77.92%) were of HIV-1 subtype B, fourteen (18.18%) CRF02_AG, two (2.6%) subtype C and one (1.3%) subtype A. These data are also summarised in the IN phylogenetic tree shown in Fig. 1. The screening of sequences revealed that Overall 81 of 288 (28%) amino acid IN positions presented at least one polymorphism each. we found 18 (36.73%), 42 (25.76%) and 21 (27.27%) of polymorphic residues assigned to the N-Terminal Domain, Catalytic Core Domaine and the C-Terminal Domain positions respectively (Fig. 2). As expected, no polymorphism was found in the HHCC Zn+-binding motif and in the catalytic triad DDE. Also the amino acid in IN positions that have been identified as critical for interaction with LEDGF/P75, H12, L102, A128, A 129, C130, W131, W132, I161, R166, Q168, E170, H171, T174, M178 and Q 214 [24,25,26] were conserved. The substitutions detected in more than 95% of samples were D10E, G123S, R127K and N232D, none of which is ascribed to INI resistance. None of the primary amino acid mutations in IN positions 66, 92, 140, 143, 147, 148 and 155 listed in the Stanford resistance algorithm were found in this study, while secondary mutations L74IM and T97A associated with drug resistance to RAL and EVG were observed only in four patients (5.2%) (Additional file 1). The L74I was observed in two strains, a subtype B (KU609297) and a subtype A (KU609282). The L74M was observed in one subtype B strain (KU609337) and T97A was observed in one CRF02_AG strain (KU609303). No mutation associated with DTG resistance was observed among all studied patients. Other mutations in IN positions not included in Stanford list but frequently reported in regards to INIs resistance in vitro V72I, T112I, S119PRT, T124A, K156N, V165I, V201I, I203M,T206S and S230N have been detected with different frequencies (Fig. 2). Finally there were no significant associations (p > 0.05) between resistance mutations with exposure category, viral load, Transmission route and CD4 T cell count.
Three INSTIs, RAL, EVG and DTG have been approved for clinical use by the FDA and European Medicines Agency [6,7,8]. These compounds have proven to be highly efficient for the treatment of both ARV-naïve and -experienced individuals even with preexisting drug resistance or treatment complication [9,10,11,12,13,14,15], thus INIs has rapidly became an important class in the arsenal of ARV drugs. Eighty HIV-1 untreated patients were recruited in this study in order to examine the variability within the IN gene at positions associated with resistance to INIs. Despite the limited size of the study population, these results are in good agreement with the current situation of HIV in Morocco as reported in the national report on AIDS . The high prevalence of subtype B among infected Moroccan population has been previously reported by other studies which suggested that it was due to the presence of a close relationship between Morocco and European countries [3, 4]. Detailed phylogenetic analysis of IN sequences showed that all CRF02_AG isolates were related to strains found in central Africa and Europe, which agreed with previous reports that suggested that increasing prevalence of CRF02_AG might be associated with increasing immigration from sub-Saharan Africa to Europe via Morocco [27, 28]. Of the 288 IN amino acids positions, 81(28.12%) had one or more variants. This rate (28%) is lower to that reported by Rhee et al. (39.9%) in different subtypes of group M integrase sequences obtained from more than 1500 individuals who were INI-naïve, and either ARV-naïve or ARV-experienced . This digit indicates the relative conservation of the protein in untreated Moroccan’s patients. The analysis showed conservation of the HHCC Zn+-binding motif, the catalytic triad DDE, and several important IN residues involved in the chemical bond and hydrophobic contact with LEDGF/P75; which an essential HIV integration cofactor linking IN to chromatin [24,25,26]. The conservation of these specific structural domains is strictly necessary for the correct performance of HIV-1 IN functions .
Importantly the major resistance mutations with reduced susceptibility to RAL, EVG and DTG were totally absent. The absence of such mutations in our study is consistent with the results of several studies in treatment-naïve patients [19, 20, 31,32,33,34,35] and with the fact that the transmission of the drug resistance is unlikely in populations previously unexposed to INIs treatment . Only three secondary drug resistance mutations included in Stanford list were observed in 4 strains. These mutations have been previously been described as polymorphic, occurring in 1–2% of IN sequences, observed in subtypes A, B, C, D, CRF01_AE and CRF02_AG . These mutations contribute to INI resistance only in the presence of primary INI resistance mutations [19, 37]. Moreover, there were three amino acid substitutions of unknown significance at position 163 that were encountered in subtype B and CRF02-A/G strains: G163E, G163T and G163Q. In IN residues, it is usually considered non polymorphic in all subtypes except subtype F . Regarding DTG R263K resistance mutation, no strain from our study exhibited this mutation, whereas the L101I and T124A mutations were found in 26 and 12 strains, respectively. These mutations were previously shown to be selected in vitro in the presence of DTG and have shown little impact on virological response to DTG [39, 40]. Conversely, specific additional mutations in amino acid IN positions 72, 112, 119,156, 165, 201, 203, 206, and 230 occurred with different prevalence in subtype B and non-B HIV-1 variant were more common. These mutations have not been described to be associated with RAL or EGV resistance [20, 21]. In the same way, it has been reported that in the absence of primary mutation, all these secondary mutations had little if any effect on drug susceptibility in vitro, thus suggesting rather a secondary role for viral fitness rescue and/or increasing resistance . Furthermore many previous genotypic studies on HIV-1 IN in treatment-naïve patients living with various viral subtypes in different countries: England, Spain, South Africa, Sub-Saharan Countries, Thailand, Indonesia and Korea have showed that these differences are natural polymorphisms [32,33,34, 41,42,43]. According to previous studies, and the fact that INIs have not yet been introduced in Morocco, all secondary and additional mutations identified in this study are also likely natural polymorphisms.
In conclusion, these results demonstrate that untreated HIV-1 infected Moroccans are likely to benefit from INSTI-based drug regimens, particularly given the rising issues related to drug resistance against reverse transcriptase inhibitors that are currently used in Morocco.
The authors wish to highlight that our limitation consist on sample size, more participants are necessary before a large introduction of integrase inhibitors into our country.
integrase strand-transfer inhibitor
catalytic core domain
highly active antiretroviral therapy
nucleoside reverse transcriptase inhibitors
non-nucleoside reverse transcriptase inhibitors
reverse transcriptase polymerase chain reaction
UNAIDS, The HIV and AIDS Morocco Country Progress Report. 2015. http://www.unaids.org/sites/default/files/country/documents/MAR_narrative_report_2015.pdf. Accessed 03 March 2016.
El Annaz H, Recordon-Pinson P, Tagajdid R, Doblali T, Belefquih B, Oumakhir S, Sedrati O, Mrani S, Fleury H. Drug resistance mutations in HIV type 1 isolates from patients failing antiretroviral therapy in Morocco. AIDS Res Hum Retrovir. 2012;28(8):944–8.
Annaz HE, Recordon-Pinson P, Baba N, Sedrati O, Mrani S, Fleury H. Presence of drug resistance mutations among drug-naïve patients in Morocco. AIDS Res Hum Retrovir. 2011;27(8):917–20.
Bakhouch K, Oulad-Lahcen A, Bensghir R, Blaghen M, Elfilali KM, Ezzikouri S, Abidi O, Hassar M, Wakrim L. The prevalence of resistance-associated mutations to protease and reverse transcriptase inhibitors in treatment-naïve (HIV1)-infected individuals in Casablanca, Morocco. J Infect Dev Ctries. 2009;3(5):380–91.
Hazuda DJ. Resistance to inhibitors of the human immunodeficiency virus type 1 integration. Braz J Infect Dis. 2010;14(5):513–8.
United States Food and Drug Administration. Drug approval package: Isentress (raltegravir) NDA #022145. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022145_Isentress.cfm. Accessed 24 June 2013.
Abramowicz M, Zuccofti G, Pflomm J-M. Dolutegravir (Tivicay) for HIV. JAMA. 2014. https://doi.org/10.1001/jama.2014.8406.
Alafenamide T. Genvoya: a new 4-drug combination for HIV. Med Lett Drugs Ther. 2016;58(1488):19–21. https://doi.org/10.1001/jama.2016.5945.
Gubavu C, Prazuck T, Niang M, Buret J, Mille C, Guinard J, Avettand-Fenoel V, Hocqueloux L. Dolutegravir-based monotherapy or dual therapy maintains a high proportion of viral suppression even in highly experienced HIV-1-infected patients. J Antimicrob Chemother. 2016;71(4):1046–50.
Liedtke MD, Tomlin CR, Lockhart SM, Miller MM, Rathbun RC. Long-term efficacy and safety of raltegravir in the management of HIV infection. Infect Drug Resist. 2014;7:73–84.
Mesplede T, Quashie PK, Zanichelli V, Wainberg MA. Integrase strand transfer inhibitors in the management of HIV-positive individuals. Ann Med. 2014;46(3):123–9.
Park TE, Mohamed A, Kalabalik J, Sharma R. Review of integrase strand transfer inhibitors for the treatment of human immunodeficiency virus infection. Expert Rev Anti Infect Ther. 2015;13(10):1195–212.
Unger NR, Worley MV, Kisgen JJ, Sherman EM, Childs-Kean LM. Elvitegravir for the treatment of HIV. Expert Opin Pharmacother. 2016;17(17):2359–70.
Wong E, Trustman N, Yalong A. HIV pharmacotherapy: a review of integrase inhibitors. Jaapa. 2016;29(2):36–40.
Xiao H, Xue Y, Gu S, Wang J, Sun H, Lu H. Efficacy and safety of antiretroviral regimens including raltegravir to treat HIV-infected patients with hemophilia. Biosci Trends. 2016;10(1):42–6.
Van Laethem K, Schrooten Y, Covens K, Dekeersmaeker N, De Munter P, Van Wijngaerden E, Van Ranst M, Vandamme A-M. A genotypic assay for the amplification and sequencing of integrase from diverse HIV-1 group M subtypes. J Virol Methods. 2008;153(2):176–81.
Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: molecular evolutionary genetics analysis version 6.0. Mol Biol Evol. 2013;30(12):2725–9.
Max Planck Institut informatic. http://integrase.geno2pheno.org/index.php. Accessed 24 March 2015.
Ceccherini-Silberstein F, Malet I, D’Arrigo R, Antinori A, Marcelin AG, Perno CF. Characterization and structural analysis of HIV-1 integrase conservation. AIDS Rev. 2009;11(1):17–29.
Lataillade M, Chiarella J, Kozal MJ. Natural polymorphism of the HIV-1 integrase gene and mutations associated with integrase inhibitor resistance. Antivir Ther. 2007;12(4):563–70. https://www.intmedpress.com/serveFile.cfm?sUID=25da9db7-9742-4370-827d-516f0653dd17.
Low A, Prada N, Topper M, Vaida F, Castor D, Mohri H, Hazuda D, Muesing M, Markowitz M. Natural polymorphisms of human immunodeficiency virus type 1 integrase and inherent susceptibilities to a panel of integrase inhibitors. Antimicrob Agents Chemother. 2009;53(10):4275–82.
McColl DJ, Chen X. Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy. Antiviral Res. 2010;85(1):101–18.
Sichtig N, Sierra S, Kaiser R, Daumer M, Reuter S, Schulter E, Altmann A, Fatkenheuer G, Dittmer U, Pfister H, et al. Evolution of raltegravir resistance during therapy. J Antimicrob Chemother. 2009;64(1):25–32.
Busschots K, Voet A, De Maeyer M, Rain JC, Emiliani S, Benarous R, Desender L, Debyser Z, Christ F. Identification of the LEDGF/p75 binding site in HIV-1 integrase. J Mol Biol. 2007;365(5):1480–92.
Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A. Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat Struct Mol Biol. 2005;12(6):526–32.
Maertens G, Cherepanov P, Pluymers W, Busschots K, De Clercq E, Debyser Z, Engelborghs Y. LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J Biol Chem. 2003;278(35):33528–39.
El Aouad R, Diez M, Cherkaoui I. Impact of immigration on HIV and tuberculosis epidemiology in the Euro-Mediterranean area. Euro Surveill. 2009;14(15):19173. http://www.eurosurveillance.org/images/dynamic/EE/V14N15/art19173.pdf.
Elharti E, Alami M, Khattabi H, Bennani A, Zidouh A, Benjouad A, El Aouad R. Some characteristics of the HIV epidemic in Morocco. East Mediterr Health J. 2002;8(6):819–25. http://applications.emro.who.int/emhj/0806/emhj_2002_8_6_819_825.pdf?ua.
Rhee SY, Liu TF, Kiuchi M, Zioni R, Gifford RJ, Holmes SP, Shafer RW. Natural variation of HIV-1 group M integrase: implications for a new class of antiretroviral inhibitors. Retrovirology. 2008. https://doi.org/10.1186/1742-4690-5-74.
Delelis O, Carayon K, Saib A, Deprez E, Mouscadet JF. Integrase and integration: biochemical activities of HIV-1 integrase. Retrovirology. 2008. https://doi.org/10.1186/1742-4690-5-114.
Casadella M, van Ham PM, Noguera-Julian M, van Kessel A, Pou C, Hofstra LM, Santos JR, Garcia F, Struck D, Alexiev I, et al. Primary resistance to integrase strand-transfer inhibitors in Europe. J Antimicrob Chemother. 2015;70(10):2885–8.
Fish MQ, Hewer R, Wallis CL, Venter WD, Stevens WS, Papathanasopoulos MA. Natural polymorphisms of integrase among HIV type 1-infected South African patients. AIDS Res Hum Retrovir. 2010;26(4):489–93.
Garrido C, Geretti AM, Zahonero N, Booth C, Strang A, Soriano V, De Mendoza C. Integrase variability and susceptibility to HIV integrase inhibitors: impact of subtypes, antiretroviral experience and duration of HIV infection. J Antimicrob Chemother. 2010;65(2):320–6.
Kim JY, Kim EJ, Choi JY, Kwon OK, Kim GJ, Choi SY, Kim SS. Genetic variation of the HIV-1 integrase region in newly diagnosed anti-retroviral drug-naïve patients with HIV/AIDS in Korea. Clin Microbiol Infect. 2011;17(8):1155–9.
Parczewski M, Bander D, Urbańska A, Boroń-Kaczmarska A. HIV-1 integrase resistance among antiretroviral treatment naïve and experienced patients from Northwestern Poland. BMC Infect Dis. 2012. https://doi.org/10.1186/1471-2334-12-368.
van Hal SJ, Herring B, Deris Z, Wang B, Saksena NK, Dwyer DE. HIV-1 integrase polymorphisms are associated with prior antiretroviral drug exposure. Retrovirology. 2009. https://doi.org/10.1186/1742-4690-6-12.
Ceccherini-Silberstein F, Malet I, Fabeni L, Dimonte S, Svicher V, D’Arrigo R, Artese A, Costa G, Bono S, Alcaro S, et al. Specific HIV-1 integrase polymorphisms change their prevalence in untreated versus antiretroviral-treated HIV-1-infected patients, all naïve to integrase inhibitors. J Antimicrob Chemother. 2010;65(11):2305–18.
Rhee SY, Sankaran K, Varghese V, Winters MA, Hurt CB, Eron JJ, Parkin N, Holmes SP, Holodniy M, Shafer RW. HIV-1 protease, reverse transcriptase, and integrase variation. J Virol. 2016;90(13):6058–70.
Kobayashi M, Yoshinaga T, Seki T, Wakasa-Morimoto C, Brown KW, Ferris R, Foster SA, Hazen RJ, Miki S, Suyama-Kagitani A, et al. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011;55(2):813–21.
Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, Piscitelli SC. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother. 2010;54(1):254–8.
Isarangkura-Na-Ayuthaya P, Kaewnoo W, Auwanit W, de Silva UC, Ikuta K, Sawanpanyalert P, Kameoka M. Appearance of drug resistance-associated mutations in human immunodeficiency virus type 1 CRF01_AE integrase derived from drug-naïve thai patients. AIDS Res Hum Retrovir. 2010;26(12):1341–3.
Kotaki T, Khairunisa SQ, Sukartiningrum SD, Witaningrum AM, Rusli M, Diansyah MN, Arfijanto MV, Rahayu RP, Kameoka M. Detection of drug resistance-associated mutations in human immunodeficiency virus type 1 integrase derived from drug-naïve individuals in Surabaya, Indonesia. AIDS Res Hum Retrovir. 2014;30(5):489–92.
Monleau M, Aghokeng AF, Nkano BA, Chaix ML, Peeters M. Drug resistance mutations of HIV-1 non-B viruses to integrase inhibitors in treatment-naïve patients from sub-saharan countries and discordant interpretations. AIDS Res Hum Retrovir. 2012. https://doi.org/10.1089/aid.2011.0326.
AN, EMA, MS: conceived and designed the study; HEA, BM, HN: clinical studies; EMA, MM: performed the experiments; EEM, TR, and TN: contributed reagents/materials/analysis tools; AN, EMA: statistical analysis, interpretation of the results and wrote the paper. All authors read and approved the final manuscript.
This work was carried out in collaboration between the Military Hospital of Instruction Mohammed V. of Rabat and the National Center for Scientific and Technical Research, Morocco. We thank all patients participating in this study and we thank Pr H. Fleury and his team, Bordeaux University Hospital for their previous collaborations.
The authors declare that they have no competing interests.
Availability of data and materials
All data generated or analyzed during this study are included in this published article. Nucleotide sequences are available under GenBank accession numbers KU609274–KU609350.
Consent for publication
Ethics approval and consent to participate
The study was approved by the Ethical Committee of Biological Research, Faculty of Medicine and Pharmacy—Rabat, and was conducted with respect to legal aspects. Written informed consent was obtained from all participants before any data analysis procedure. Consent was received from adult next-of-kin when the respondent was under 16 years of age.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Additional file 1. Distribution of IN mutations in subtypes B and non-B in therapy-naïve patients. Secondary and additional mutations screened in 17 positions (V72I, T112I, S119PRTG, T124A, T125K, A128T, Q146K, M154I, K156N, V165I, V201I, I203M, T206S, S230N, D232N, V249I and C280Y) using the Stanford HIV Drug Resistance Program (Version September 23, 2016), all mutations identified in this study are likely natural polymorphisms.
About this article
Cite this article
Alaoui, N., El Alaoui, M.A., Touil, N. et al. Prevalence of resistance to integrase strand-transfer inhibitors (INSTIs) among untreated HIV-1 infected patients in Morocco. BMC Res Notes 11, 369 (2018). https://doi.org/10.1186/s13104-018-3492-5
- Resistance mutations
- Naïve patients