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Current HIV Research


ISSN (Print): 1570-162X
ISSN (Online): 1873-4251

Research Article

Survey of Pretreatment HIV Drug Resistance and Genetic Transmission Network Analysis Among HIV Patients in a High Drug-Use Area of Southwest China

Author(s): Lei Liu, Aobo Dong, Lingjie Liao, Yi Feng, Yiming Shao, Shu Liang, Yuhua Ruan* and Hui Xing*

Volume 17, Issue 6, 2019

Page: [441 - 451] Pages: 11

DOI: 10.2174/1570162X17666191128101426

open access plus


Background: Pretreatment drug resistance (PDR) poses an increasing threat to the success of antiretroviral treatment (ART) programs in China. We aimed to conduct a survey of PDR among HIV patients in an area in Southwest China with extensive drug trafficking.

Methods: Consecutive cross-sectional surveys were conducted in Liangshan Prefecture of Sichuan Province from 2009 to 2018 based on the WHO-recommended method. PDR was identified by testing pol region sequences with the Stanford HIVdb algorithm (version 7.0). PDR prevalence and related factors were assessed by multivariable logistic regression. The transmission of HIV drug resistance was analyzed using a genetic transmission network.

Results: HIV-1 pol genes from 1889 patients were successfully amplified. The distribution of HIV- 1 genotypes was as follows: CRF07_BC (94.0%), CRF08_BC (2.3%), CRF01_AE (2.0%) and others (1.4%). Of the participants, 6.9% (95% CI: 4.1-8.1%) had pretreatment resistance to 12 antiretroviral drugs recommended by the WHO, and nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitors (PI) resistance were identified among 1.4% (95% CI: 0.7-3.4%), 5.8% (95% CI: 1.2-8.7%) and 0.4% (95% CI: 0.1- 3.0%) of the patients, respectively. In the multivariate logistic model, the prevalence of PDR was 1.52-fold higher among intravenous drug users (IDUs) than among patients infected by heterosexual transmission (95% CI: 1.07-2.38; P=0.049), and the prevalence of PDR among patients diagnosed from 2017-2018 was 2.03-fold higher than that among patients diagnosed from 2009-2016 (95% CI: 1.18-5.76; P=0.018). A total of 26 clusters containing PDR and a rapidly growing drug resistancerelated cluster containing the E138Q and V179D mutations were identified by genetic transmission network analysis.

Conclusion: The results show a moderate overall level of PDR prevalence and rapidly growing drug resistance over time. Preventive intervention should be focused on controlling the HIV epidemic among drug users, and surveillance is urgently needed to monitor the trend of PDR.

Keywords: HIV, pretreatment drug resistance, transmission, genetic transmission network, cluster, prevention.

Graphical Abstract
UNAIDS. Global HIV & AIDS statistics-2018 fact sheet [Accessed 15 Jan 2019]
van Zyl GU, Bedison MA, van Rensburg AJ, Laughton B, Cotton MF, Mellors JW. Early Antiretroviral Therapy in South African Children Reduces HIV-1-Infected Cells and Cell-Associated HIV-1 RNA in Blood Mononuclear Cells. J Infect Dis 2015; 212(1): 39-43.
[] [PMID: 25538273]
Sempa JB, Rossouw TM, Lesaffre E, Nieuwoudt M. Cumulative viral load as a predictor of CD4+ T-cell response to antiretroviral therapy using Bayesian statistical models. PLoS One 2019; 14(11) e0224723
Pham HV, Ishizaki A, Nguyen LV, et al. Two-year outcome of first-line antiretroviral therapy among HIV-1 vertically-infected children in Hanoi, Vietnam. Int J STD AIDS 2015; 26(11): 821-30.
[] [PMID: 25332224]
Murphy EL, Collier AC, Kalish LA, et al. Viral Activation Transfusion Study Investigators. Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease. [J] Ann Intern Med 2001; 135(1): 17-26.
[] [PMID: 11434728]
Tersmette M, Lange JM, de Goede RE, et al. Association between biological properties of human immunodeficiency virus variants and risk for AIDS and AIDS mortality. Lancet 1989; 1(8645): 983-5.
[] [PMID: 2565516]
Braitstein P, Brinkhof MW, Dabis F, et al. Antiretroviral Therapy in Lower Income Countries (ART-LINC) Collaboration. ART Cohort Collaboration (ART-CC) groups. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Lancet 2006; 367(9513): 817-24.
[] [PMID: 16530575]
Alibhai A, Martin LJ, Kipp W, et al. Quality of life of HIV patients in a rural area of western Uganda: impact of a community-based antiretroviral treatment program. Curr HIV Res 2010; 8(5): 370-8.
[] [PMID: 20353388]
World Health Organization(WHO). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection [Accessed 20 May 2019]
Hemelaar J. The origin and diversity of the HIV-1 pandemic. Trends Mol Med 2012; 18(3): 182-92.
[] [PMID: 22240486]
Abram ME, Ferris AL, Shao W, Alvord WG, Hughes SH. Nature, position, and frequency of mutations made in a single cycle of HIV-1 replication. J Virol 2010; 84(19): 9864-78.
[] [PMID: 20660205]
Perelson AS, Ribeiro RM. Modeling the within-host dynamics of HIV infection. BMC Biol 2013; 11: 96.
[] [PMID: 24020860]
Richman DD, Little SJ, Smith DM, Wrin T, Petropoulos C, Wong JK. HIV evolution and escape. Trans Am Clin Climatol Assoc 2004; 115: 289-303.
[PMID: 17060974]
Clutter DS, Jordan MR, Bertagnolio S, Shafer RW. HIV-1 drug resistance and resistance testing. Infect Genet Evol 2016; 46: 292-307.
[] [PMID: 27587334]
Phillips AN, Cambiano V, Miners A, et al. Effectiveness and cost-effectiveness of potential responses to future high levels of transmitted HIV drug resistance in antiretroviral drug-naive populations beginning treatment: modelling study and economic analysis. Lancet HIV 2014; 1(2): e85-93.
[] [PMID: 26423990]
Hamers RL, Wallis CL, Kityo C, et al. PharmAccess African Studies to Evaluate Resistance (PASER). HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: a multicentre observational study. Lancet Infect Dis 2011; 11(10): 750-9.
[] [PMID: 21802367]
Cambiano V, Bertagnolio S, Jordan MR, Lundgren JD, Phillips A. Transmission of drug resistant HIV and its potential impact on mortality and treatment outcomes in resource-limited settings. J Infect Dis 2013; 207(Suppl. 2): S57-62.
[] [PMID: 23687290]
World Health Organization(WHO). Guidelines on the public health response to pretreatment HIV drug resistance https://www. [Accessed 7 Dec 2018]
Ma Y, Zhang F, Zhao Y, et al. Cohort profile: the Chinese national free antiretroviral treatment cohort. Int J Epidemiol 2010; 39(4): 973-9.
[] [PMID: 19556327]
Zhang F, Dou Z, Ma Y, et al. Five-year outcomes of the China National Free Antiretroviral Treatment Program. Ann Intern Med 2009; 151(4): 241-251, w-252.
Liu H, Ma Y, Su Y, et al. Emerging trends of HIV drug resistance in Chinese HIV-infected patients receiving first-line highly active antiretroviral therapy: a systematic review and meta-analysis. Clin Infect Dis 2014; 59(10): 1495-502.
[] [PMID: 25053721]
Zhang FJ, Maria A, Haberer J, Zhao Y. Overview of HIV drug resistance and its implications for China. Chin Med J (Engl) 2006; 119(23): 1999-2004.
[] [PMID: 17199945]
Liao L, Xing H, Dong Y, et al. Surveys of transmitted HIV drug resistance in 7 geographic Regions in China, 2008-2009. Clin Infect Dis 2012; 54(Suppl. 4): S320-3.
[] [PMID: 22544196]
Zhang F, Liu L, Sun M, Sun J, Lu H. An analysis of drug resistance among people living with HIV/AIDS in Shanghai, China. PLoS One 2017; 12(2) e0165110
[] [PMID: 28187212]
Xu Y, Peng X, Peng X, et al. Characterization of HIV-1 subtypes and transmitted drug resistance among treatment-naive HIV-infected individuals in Zhejiang, China, 2014-2017. Arch Virol 2018; 163(8): 2233-7.
[] [PMID: 29637428]
Yang S, Yang C, Liao Q, et al. Analysis of HIV prevalence among pregnant women in Liangshan Prefecture, China, from 2009 to 2015. PLoS One 2017; 12(9) e0183418
[] [PMID: 28880917]
Liu L, Luan R, Yang W, et al. Projecting dynamic trends for HIV/AIDS in a highly endemic area of China: estimation models for Liangshan Prefecture, Sichuan Province. Curr HIV Res 2009; 7(4): 390-7.
[] [PMID: 19601774]
Su Z, Dong C, Li P, et al. A mathematical modeling study of the HIV epidemics at two rural townships in the Liangshan Prefecture of the Sichuan Province of China. Infect Dis Model 2016; 1(1): 3-10.
[] [PMID: 29928717]
Yin Y, Yang H, Xie X, Wang H, Nie A, Chen H. Status and associated characteristics of HIV disclosure among people living with HIV/AIDS in Liangshan, China: A cross-sectional study. Medicine (Baltimore) 2019; 98(31) e16681
[] [PMID: 31374050]
Beyrer C, Razak MH, Lisam K, Chen J, Lui W, Yu XF. Overland heroin trafficking routes and HIV-1 spread in south and south-east Asia. AIDS 2000; 14(1): 75-83.
[] [PMID: 10714570]
Ruan Y, Qin G, Liu S, et al. HIV incidence and factors contributed to retention in a 12-month follow-up study of injection drug users in Sichuan Province, China. J Acquir Immune Defic Syndr 2005; 39(4): 459-63.
[] [PMID: 16010170]
Ruan Y, Chen K, Hong K, et al. Community-based survey of HIV transmission modes among intravenous drug users in Sichuan, China. Sex Transm Dis 2004; 31(10): 623-7.
[] [PMID: 15389002]
Jordan MR, Bennett DE, Wainberg MA, et al. Update on World Health Organization HIV drug resistance prevention and assessment strategy: 2004-2011. Clin Infect Dis 2012; 54(Suppl. 4): S245-9.
[] [PMID: 22544182]
Mao YR, Wu ZY, Poundstone K, et al. Development of a unified web-based national HIV/AIDS information system in China. Int J Epidemiol 2010; 39(Suppl. 2): ii79-89.
Liao L, Xing H, Su B, et al. Impact of HIV drug resistance on virologic and immunologic failure and mortality in a cohort of patients on antiretroviral therapy in China. AIDS 2013; 27(11): 1815-24.
[] [PMID: 23803794]
Xing H, Ruan Y, Hsi JH, et al. National HIVDR Working Group. Reductions in virological failure and drug resistance in Chinese antiretroviral-treated patients due to lamivudine-based regimens, 2003-12. J Antimicrob Chemother 2015; 70(7): 2097-103.
[] [PMID: 25855758]
Liao L, Xing H, Shang H, et al. The prevalence of transmitted antiretroviral drug resistance in treatment-naive HIV-infected individuals in China. J Acquir Immune Defic Syndr 2010; 53(Suppl. 1): S10-4.
[] [PMID: 20104099]
Zhao S, Feng Y, Hu J, et al. Prevalence of Transmitted HIV drug resistance in antiretroviral treatment naïve newly diagnosed individuals in China. Sci Rep 2018; 8(1): 12273.
[] [PMID: 30115986]
Zhong P, Pan Q, Ning Z, et al. Genetic diversity and drug resistance of human immunodeficiency virus type 1 (HIV-1) strains circulating in Shanghai. AIDS Res Hum Retroviruses 2007; 23(7): 847-56.
[] [PMID: 17678466]
World Health Organization(WHO) Surveillance of HIV drug resistance in adults initiating antiretroviral therapy (pretreatment HIV drug resistance) Concept note Geneva World Health Organization. 2014. [Accessed 16 Jan 2019]
World Health Organization(WHO) Guidelines on the public health response to pretreatment HIV drug resistance Geneva: World Health Organization. 2017. Licence: CC BY-NC-SA 3.0 IGO.
Tamura K, Nei M. Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees. Mol Biol Evol 1993; 10(3): 512-26.
[PMID: 8336541]
Wertheim JO, Kosakovsky Pond SL, Forgione LA, et al. Social and Genetic Networks of HIV-1 Transmission in New York City. PLoS Pathog 2017; 13(1) e1006000
[] [PMID: 28068413]
Li L, Wei D, Hsu WL, et al. CRF07_BC Strain Dominates the HIV-1 Epidemic in Injection Drug Users in Liangshan Prefecture of Sichuan, China. AIDS Res Hum Retroviruses 2015; 31(5): 479-87.
[] [PMID: 25560398]
Hua J, Lin H, Ding Y, Qiu D, Wong F, He N. HIV drug resistance in newly diagnosed adults in a rural prefecture of eastern China. Epidemiol Infect 2015; 143(3): 663-72.
[] [PMID: 24831493]
Silverman RA, Beck IA, Kiptinness C, et al. Prevalence of Pre-antiretroviral-Treatment Drug Resistance by Gender, Age, and Other Factors in HIV-Infected Individuals Initiating Therapy in Kenya, 2013-2014. J Infect Dis 2017; 216(12): 1569-78.
[] [PMID: 29040633]
Ávila-Ríos S, García-Morales C, Matías-Florentino M, et al. HIVDR MexNet Group. 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.
[] [PMID: 27658867]
Yang S, Zhai W, Pei R, et al. Factors associated with HIV infection among Yi minority residents in Liangshan Prefecture, Sichuan Province: A path analysis. Medicine (Baltimore) 2018; 97(14) e0250
[] [PMID: 29620638]
Wang H, Chen AC, Wan S, Chen H. Status and associated factors of self-management in people living with HIV/AIDS in Liangshan area, China: a cross-sectional study. Patient Prefer Adherence 2019; 13: 863-70.
[] [PMID: 31213780]
Epstein BJ. Drug resistance among patients recently infected with HIV. N Engl J Med 2002; 347(23): 1889-90.
[] [PMID: 12466517]
Lai CC, Hung CC, Chen MY, et al. Trends of transmitted drug resistance of HIV-1 and its impact on treatment response to first-line antiretroviral therapy in Taiwan. J Antimicrob Chemother 2012; 67(5): 1254-60.
[] [PMID: 22302562]
Li JF, Linley L, Kline R, Ziebell R, Heneine W, Johnson JA. Sensitive sentinel mutation screening reveals differential underestimation of transmitted HIV drug resistance among demographic groups. AIDS 2016; 30(9): 1439-45.
[] [PMID: 26990626]
Zhang FJ, Pan J, Yu L, Wen Y, Zhao Y. Current progress of China’s free ART program. Cell Res 2005; 15(11-12): 877-82.
[] [PMID: 16354563]
Luo L, Li TS. Overview of antiretroviral treatment in China: advancement and challenges. Chin Med J (Engl) 2011; 124(3): 440-4.
[PMID: 21362348]
Liu P, Liao L, Xu W, et al. Adherence, virological outcome, and drug resistance in Chinese HIV patients receiving first-line antiretroviral therapy from 2011 to 2015. Medicine (Baltimore) 2018; 97(50) e13555
[] [PMID: 30558015]
Mendoza Y, Castillo Mewa J, Martínez AA, et al. HIV-1 Antiretroviral Drug Resistance Mutations in Treatment Naïve and Experienced Panamanian Subjects: Impact on National Use of EFV-Based Schemes. PLoS One 2016; 11(4) e0154317
[] [PMID: 27119150]
Luo XL, Mo LD, Su GS, et al. Incidence and types of HIV-1 drug resistance mutation among patients failing first-line antiretroviral therapy. J Pharmacol Sci 2019; 139(4): 275-9.
[] [PMID: 30928089]
Shikuma CM, Kohorn L, Paul R, et al. Sleep and neuropsychological performance in HIV+ subjects on efavirenz-based therapy and response to switch in therapy. HIV Clin Trials 2018; 19(4): 139-47.
Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS 2013; 27(9): 1403-12.
[] [PMID: 23343913]
Avihingsanon A, Maek-A-Nantawat W, Gatechompol S, et al. Efficacy and safety of a once-daily single-tablet regimen of tenofovir, lamivudine, and efavirenz assessed at 144 weeks among antiretroviral-naïve and experienced HIV-1-infected Thai adults. Int J Infect Dis 2017; 61: 89-96.
[] [PMID: 28627427]
Larru B, Eby J, Lowenthal ED. Antiretroviral treatment in HIV-1 infected pediatric patients: focus on efavirenz. Pediatric Health Med Ther 2014; 5: 29-42.
[PMID: 25937791]
Kiselinova M, Geretti AM, Malatinkova E, et al. HIV-1 RNA and HIV-1 DNA persistence during suppressive ART with PI-based or nevirapine-based regimens. J Antimicrob Chemother 2015; 70(12): 3311-6.
[] [PMID: 26324076]
Ruan Y, Liang S, Zhu J, et al. Gender and ethnic disparities of HIV and syphilis seroconversions in a 4-year cohort of injection drug users. Southeast Asian J Trop Med Public Health 2013; 44(5): 842-53.
[PMID: 24437319]
Qian HZ, Schumacher JE, Chen HT, Ruan YH. Injection drug use and HIV/AIDS in China: review of current situation, prevention and policy implications. Harm Reduct J 2006; 3: 4.
[] [PMID: 16451717]
Mungati M, Mhangara M, Gonese E, et al. Pre-treatment drug resistance among patients initiating antiretroviral therapy (ART) in Zimbabwe: 2008-2010. BMC Res Notes 2016; 9: 302.
[] [PMID: 27287672]
Hunt GM, Coovadia A, Abrams EJ, et al. HIV-1 drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine. AIDS 2011; 25(12): 1461-9.
[] [PMID: 21633285]
Su L, Liang S, Hou X, et al. Impact of worker emigration on HIV epidemics in labour export areas: a molecular epidemiology investigation in Guangyuan, China. Sci Rep 2018; 8(1): 16046.
[] [PMID: 30375405]
Li X, Gao R, Zhu K, et al. Genetic transmission networks reveal the transmission patterns of HIV-1 CRF01_AE in China. Sex Transm Infect 2018; 94(2): 111-6.
[] [PMID: 28784618]
Liu S, Wang QX, Nan L, et al. The changing trends of HIV/AIDS in an ethnic minority region of China: modeling the epidemic in Liangshan prefecture, Sichuan Province. Biomed Environ Sci 2013; 26(7): 562-70.
[PMID: 23895701]
Yang Y, Luan RS, Liu P, Wu CL, Zhou Y, Chen W. Casual sex and concurrent sexual partnerships among young people from an Yi community with a high prevalence of HIV in China. Asian J Androl 2012; 14(5): 758-65.
[] [PMID: 22683999]
Wang X, Liu X, Li F, et al. Epidemiological surveillance of HIV-1 transmitted drug resistance among newly diagnosed individuals in Shijiazhuang, northern China, 2014-2015.[J]. PLoS One 2018; 13(6) e0198005
[] [PMID: 29870534]
Pollicita M, Surdo M, Di Santo F, et al. Comparative replication capacity of raltegravir-resistant strains and antiviral activity of the new-generation integrase inhibitor dolutegravir in human primary macrophages and lymphocytes. J Antimicrob Chemother 2014; 69(9): 2412-9.
[] [PMID: 24860155]
Buckheit RW Jr. Understanding HIV resistance, fitness, replication capacity and compensation: targeting viral fitness as a therapeutic strategy. Expert Opin Investig Drugs 2004; 13(8): 933-58.
[] [PMID: 15268633]
Hofstra LM, Nijhuis M, Pingen M, et al. Evolution and viral characteristics of a long-term circulating resistant HIV-1 strain in a cluster of treatment-naive patients. J Antimicrob Chemother 2013; 68(6): 1246-50.
[] [PMID: 23467175]
Castro H, Pillay D, Cane P, et al. UK Collaborative Group on HIV Drug Resistance. Persistence of HIV-1 transmitted drug resistance mutations. J Infect Dis 2013; 208(9): 1459-63.
[] [PMID: 23904291]
Tambuyzer L, Nijs S, Daems B, Picchio G, Vingerhoets J. Effect of mutations at position E138 in HIV-1 reverse transcriptase on phenotypic susceptibility and virologic response to etravirine. J Acquir Immune Defic Syndr 2011; 58(1): 18-22.
[] [PMID: 21637112]
Meng Z, Xin R, Abubakar YF, et al. Five new CRF07_BC near full-length sequences isolated from Sichuan, China. AIDS Res Hum Retroviruses 2013; 29(1): 191-7.
[] [PMID: 22931113]
Ma Ye LZ, Zhang KX. Identification of HIV infection among drug users in China. Zhonghua Liu Xing Bing Xue Za Zhi 1990; 11: 184-5.
Ragonnet-Cronin M, Lee BE, Plitt SS, et al. Baseline clinical HIV genotypes are a valid measure of transmitted drug resistance within the treatment-naive population. J Acquir Immune Defic Syndr 2013; 64(5): 443-7.
[] [PMID: 24231785]

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