Appearance of Drug Resistance Mutations Among the Dominant HIV-1 Subtype, CRF01_AE in Maumere, Indonesia

Author(s): Dwi Wahyu Indriati, Tomohiro Kotaki, Siti Qamariyah Khairunisa, Adiana Mutamsari Witaningrum, Muhammad Qushai Yunifiar Matondang, Shuhei Ueda, Nasronudin, Asep Purnama, Dwi Kurniawan, Masanori Kameoka*

Journal Name: Current HIV Research

Volume 16 , Issue 2 , 2018

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background and Objectives: Human Immunodeficiency Virus (HIV) is still a major health issue in Indonesia. In recent years, the appearance of drug resistance-associated mutations has reduced the effectiveness of Antiretroviral Therapy (ART). We conducted genotypic studies, including the detection of drug resistance-associated mutations (from first-line regimen drugs), on HIV-1 genes derived from infected individuals in Maumere, West Nusa Tenggara. Maumere, a transit city in West Nusa Tenggara, which has a high HIV-1 transmission rate.

Method: We collected 60 peripheral blood samples from 53 ART-experienced and 7 ART-naive individuals at TC Hillers Hospital, Maumere between 2014 and 2015. The amplification and a sequencing analysis of pol genes encoding protease (the PR gene) and reverse transcriptase (the RT gene) as well as the viral env and gag genes were performed. HIV-1 subtyping and the detection of drug resistance-associated mutations were then conducted.

Results: Among 60 samples, 46 PR, 31 RT, 30 env, and 20 gag genes were successfully sequenced. The dominant HIV-1 subtype circulating in Maumere was CRF01_AE. Subtype B and recombinant viruses containing gene fragments of CRF01_AE, subtypes A, B, C, and/or G were also identified as minor populations. The major drug resistance-associated mutations, M184V, K103N, Y188L, and M230I, were found in the RT genes. However, no major drug resistance-associated mutations were detected in the PR genes.

Conclusion: CRF01_AE was the major HIV-1 subtype prevalent in Maumere. The appearance of drug resistance-associated mutations found in the present study supports the necessity of monitoring the effectiveness of ART in Maumere.

Keywords: HIV-1, CRF01_AE, Antiretroviral Therapy (ART), drug resistance-associated mutations, Maumere, Indonesia.

Ministry of Health. 2016 HIV/AIDS status in Indonesia. 2016. Available from: http: // Stats/detailstat.php?no=8 [Accessed 3 April 2017].
Anissa L, Purnama A, Nilasari H, Sakit UI, Mangunkusumo C. Profil Pasien HIV di Klinik VCT Sehati RSUD Dr . T . C . Hillers Maumere Tahun 2014. eJournal Kedokteran Indonesia. August 2015; 2(3): 120-125. Available from: http: // [Accessed 12 May 2017].
Tin EE, Bowonwatanuwong C, Desakorn V, Wilairatana P, Krudsood S, Pitisuttithum P. The efficacy and adverse effects of GPO-VIR (stavudine+lamivudine+nevirapine) in treatment-naïve adult HIV patients. Southeast Asian J Trop Med Public Health 2005; 36: 362-9.
Kumarasamy N, Solomon S, Chaguturu SK, et al. The safety, tolerability and effectiveness of generic antiretroviral drug regimens for HIV-infected patients in south India. AIDS 2003; 17: 2267-9.
Pujari SN, Patel AK, Naik E, et al. Effectiveness of generic fixed-dose combinations of highly active antiretroviral therapy for treatment of HIV infection in India. J Acquir Immune Defic Syndr 2004; 37: 1566-9.
Idigbe EO, Adewole TA, Eisen G, et al. Management of HIV-1 infection with a combination of nevirapine, stavudine, and lamivudine: a preliminary report on the Nigerian antiretroviral program. J Acquir Immune Defic Syndr 2005; 40: 65-9.
Ferradini L, Jeannin A, Pinoges L, et al. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assesment. Lancet 2006; 467: 1335-42.
Chehter EZ, Longo MA, Laudanna AA, Duarte MI. Involvement of the pancreas in AIDS: a prospective study of 109-post mortems. AIDS 2000; 14(13): 1879-86.
Murphy RA, Sunpath H, Kuritzkes DR, Venter F, Gandhi RT. Antiretroviral therapy-associated toxicities in the resource-poor world: The challenge of a limited formulary. J Infect Dis 2007; 196: S449-56.
Dragovic G. Acute pancreatitis in HIV/AIDS patients: an issue of concern. Asian Pac J Trop Biomed 2013; 3(6): 422-5.
Oliveira NM, Ferreira FAY, Yonamine RY, Chehter EZ. Antiretroviral drugs and acute pancreatitis in HIV/AIDS patients: is there any association? A literature review. Einstein (Sao Paulo) 2014; 12(1): 112-9.
Asahchop EL. WAinberg MA, Sloan RD, Tremblay CL. Antiviral Drug Resistance and the Need for Development of New HIV-1 Reverse Transcriptase Inhibitors. Antimicrob Agents Chemother 2012; 56(10): 5000-8.
Pérez L, Kouri V, Alemàn Y, et al. Antiretroviral drug resistance in HIV-1 therapy-naïve patients in Cuba. Infect Genet Evol 2013; 16: 144-50.
Avila-Rios S, Garcia-Morales C, Matias-Florentino M, et al. Pretreatment HIV-drug resistance in Mexico and its impact on the effectiveness of first-line antiretroviral therapy: A nationally representative 2015 WHO survey. Lancet HIV 2016; 3(12): e579-91.
Witaningrum AM, Kotaki T, Khairunisa SQ, et al. Genotypic characterization of human immunodeficiency virus type 1 derived from antiretroviral therapy-naive individuals residing in Sorong, West Papua. AIDS Res Hum Retroviruses 2016; 32(8): 812-7.
Lavu E. KAve E, Mosoro E, High Levels of Transmitted HIV Drug Resistance in a Study in Papua. New Guinea. PLoS One 2017; 12(2): e0170265.
Wensing AM, Calvez V, Günthard HF, et al. 2017 Update of the drug resistance mutations in HIV-1. Top Antivir Med 2016; 24(4): 132-41.
Kotaki T, Khairunisa SQ, Sukartiningrum SD, et al. High prevalence of HIV-1 CRF01_AE viruses among female commercial sex workers residing in Surabaya, Indonesia. PLoS One 2013; 8(12): e82645.
Kotaki T, Khairunisa SQ, Witaningrum AM, et al. HIV-1 transmitted drug resistance mutations among antiretroviral therapy-naïve individuals in Surabaya, Indonesia. AIDS Res Ther 2015; 12: 5.
Merati TP, Ryan CE, Spelmen T, et al. CRF01_AE dominates the HIV-1 epidemic in Indonesia. Sex Health 2012; 9: 414-21.
Jetzt AE, Yu H, Klarmann GJ, Ron Y, Preston BD, Dougherty JP. High rate of recombination throughout the human immunodeficiency virus type 1 genome. J Virol 2000; 74(3): 1234-40.
Taylor BS, Sobieszczyk ME, McCutchan FE, Hammer SM. The Challenge of HIV-1 Subtype Diversity N Eng. J Med 2008; 358(15): 1590-602.
Santoro MM, Perno CF. HIV-1 Genetic variability and clinical implications. ISRN Microbiol 2013; 2013: 481314.
Maldarelli F, Kearney M, Palmer S, et al. HIV populations are large and accumulate high genetic diversity in a nonlinear fashion. J Virol 2013; 87(18): 10313-23.
Nikolaitchik O, Keele B, Gorelick R, et al. High recombination potential of subtype A HIV-1 Virology 2015. 484: 334-40.
Cuevas JM, Geller R, Garijo R, Lopez-Aldeguer J, Sanjuan R. Extremely high mutation rate of HIV-1 in vivo. PLoS Biol 2015; 13(9): e1002251.
Carr JK, Salminen MO, Koch C, et al. Full-length sequence and mosaic structure of a human immunodeficiency virus type 1 isolate from Thailand. J Virol 1996; 70(9): 5935-43.
Gao F, Robetson DL, Morrison SG, et al. The heterosexual human immunodeficiency virus type 1 epidemic in Thailand is caused by an intersubtype (A/E) recombinant of African origin. J Virol 1996; 70(10): 7013-29.
Anderson JP, Rodrigo AG, Learn GH, et al. Testing the hypothesis of a recombinant origin of human immunodeficiency virus type 1 subtype E. J Virol 2000; 74(22): 10752-65.
Li X, Liu H, Liu L, et al. Tracing the epidemic history of HIV-1 CRF_01 AE clusters using near-complete genome sequences. Sci Rep 2017; 7: 4024.
Buonaguro L, Tornesello ML, Buonaguro FM. HIV-1 subtype distribution in the worldwide epidemic: pathogenetic and therapeutic implications. J Virol 2007; 81(19): 10209-19.
Piyasirisiip S, McCutchan FEM, Carr JK, et al. A recent outbreak of human immunodeficiency virus type 1 infection in southern China was initiated by two homogeneous, geographically separated strains, circulating recombinant form AE and a novel BC. J Virol 2000; 74: 11286-95.
Angelis K, Albert J, Mamais I, et al. Global dispersal pattern of HIV type 1 subtype CRF01-AE: A genetic trace of human mobility related to heterosexual sexual activities centralized in southeast Asia. J Infect Dis 2015; 211(11): 1735-44.
Porter KR, Mascola JR, Hupudio H, et al. Genetic, antigenic and serologic characterization of human immunodeficiency virus type 1 from Indonesia. J Acquir Immune Defic Syndr 1997; 14(1): 1-6.
Khairunisa SQ, Kotaki T, Witaningrum AM, et al. Appearance of drug resistance-associated mutations in human immunodeficiency virus type 1 protease and reverse transcriptase derived from drug-treated Indonesian patients. AIDS Res Hum Retroviruses 2014; 31(2): 255-9.
Wainberg MA, Brenner BG. Role of HIV subtype diversity in the development of resistance to antiviral drugs. Viruses 2010; 2(11): 2493-508.
Lessells RJ, Katzenstein DK, de Oliveira T. Are subtype differences important in HIV drug resistance? Curr Opin Virol 2014; 2(5): 636-43.
Kantor R. Imapct of HIV-1 pol diversity on drug resistance and its clinical implications. Curr Opin Infect Dis 2006; 19(6): 594-606.
Brenner BG. Resistance and viral subtypes: how important are the differences and why do they occur? Curr Opin HIV AIDS 2007; 2(2): 94-102.
Wainberg MA, Brenner BG. The impact of HIV genetic polymorphisms and subtype differences on the occurrence of resistance to antiretroviral drugs. Mol Biol Int 2012; 256982.
Diallo K, Götte M, Wainberg MA. Molecular impact of the M184V mutation in human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 2003; 47(11): 3377-83.
Martinez-Cajas JL, Pai NP, Klein MB, Wainberg MA. Differences in resistance mutations among HIV-1 non-subtype B infections: a systematic review of evidence (1996-2008). J Int AIDS Soc 2009; 12: 11.
Prendergast AJ, Penazzato M, Cotton M, et al. Treatment of young children with HIV infection: using evidence to inform policymakers. PLoS Med 2012; 9(7): e1001273.
Rossouw TM, Feucht UD, Melikian G, et al. Factors associated with the development of drug resistance mutations in HIV-1 infected children failing protease inhibitor-based antiretroviral therapy in South Africa. PLoS One 2015; 10(7): e0133452.
Kityo C, Sigaloff KCE, Boender TS, et al. HIV drug resistance among children initiating first-line antiretroviral treatment in Uganda. AIDS Res Hum Retroviruses 2015; 32(7): 628-35.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2018
Published on: 15 August, 2018
Page: [158 - 166]
Pages: 9
DOI: 10.2174/1570162X16666180502114344
Price: $65

Article Metrics

PDF: 23