Paraskevis Dimitrios, Zavitsanou Assimina, Magiorkinis Emmanouil, Gargalianos Panagiotis, Xylomenos Georgios, Lazanas Marios, Chini Maria, Skoutelis Athanasios, Papastamopoulos Vasileios, Antoniadou Anastasia, Papadopoulos Antonios, Psichogiou Mina, Daikos Georgios, Vassilakis Alexis, Chrysos Georgios, Paparizos Vasilis, Kourkounti Sofia, Sambatakou Helen, Kordossis Theodoros, Koratzanis Georgios, Panagopoulos Periklis, Maltezos Evangelos, Drimis Stylianos, Hatzakis Angelos
Hygiene Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece.
Department of Internal Medicine, G. Gennimatas General Hospital, Athens, Greece.
J Int AIDS Soc. 2014 Nov 2;17(4 Suppl 3):19742. doi: 10.7448/IAS.17.4.19742. eCollection 2014.
The prevalence of drug resistance is approximately 10% in Europe and North America among newly infected patients. We aim to investigate the temporal patterns of resistance among drug naive HIV-infected individuals in Greece and also to determine transmission networking among those with resistant strains.
Protease (PR) and partial reverse transcriptase (RT) sequences were determined from 2499 newly diagnosed HIV-1 patients, in Greece, during 2003-2013. Genotypic drug resistance was estimated using the HIVdb: Genotypic Resistance Interpretation Algorithm. We identified transmission clusters of resistant strains on the basis of a large collection of HIV-1 sequences from 4024 seropositives in Greece. Phylodynamic analysis was performed using a Bayesian method.
We estimated drug resistance levels among naïve patients on the basis of all resistance mutations in PR and partial RT. The overall prevalence of resistance was 19.6% (490/2499). Resistance to NNRTIs was the most common (397/2499, 15.9%) followed by PIs (116/2499, 4.6%) and NRTIs (79/2499, 3.2%). We found a significant trend for decreasing resistance to NRTIs over time (6.7%-1.6%). There was no time trend for the overall PI and NNRTI resistance. The most frequently observed major resistant sites in PR were V82 (2.0%) and L90 (1.8%). In RT, we found E138 (58.6%), K103 (13.1%), V179 (8.4%) and T215 (7.1%), M41 (4.7%) associated with resistance to NNRTIs and NRTIs, respectively. The prevalence of K103N and E138Q were significantly increased during 2003-2013. Crucially, we found that both K103N, E138Q are associated with transmission networking within men having sex with men (MSM) and intravenous drug user (IDU) local networks. The K103N network included seropositives across Greece, while the latter only from the recent IDU outbreak in Athens metropolitan area (1). Phylodynamic analyses revealed that the exponential growth for K103N network started in 2009 (Figure 1) and for the E138Q in 2010.
The overall resistance has been stable in Greece over time; however, specific NNRTI resistance patterns are increasing. Notably, they are associated with local transmission networking, thus suggesting that this is the cause for the increased patterns of NNRTI resistance and not multiple transmissions of resistant strains from different sources among treated individuals. Our study highlights the advance of molecular epidemiology for understanding the dynamics of resistance.
在欧洲和北美，新感染患者中耐药性的流行率约为10%。我们旨在调查希腊初治HIV感染者的耐药时间模式，并确定耐药毒株感染者之间的传播网络。
2003年至2013年期间，从希腊2499例新诊断的HIV-1患者中测定蛋白酶（PR）和部分逆转录酶（RT）序列。使用HIVdb：基因型耐药性解释算法估计基因型耐药性。我们根据来自希腊4024例血清阳性患者的大量HIV-1序列，确定了耐药毒株的传播簇。采用贝叶斯方法进行系统动力学分析。
我们根据PR和部分RT中的所有耐药突变估计了初治患者的耐药水平。总体耐药率为19.6%（490/2499）。对非核苷类逆转录酶抑制剂（NNRTIs）的耐药最为常见（397/2499，15.9%），其次是蛋白酶抑制剂（PIs，116/2499，4.6%）和核苷类逆转录酶抑制剂（NRTIs，79/2499，3.2%）。我们发现随着时间推移，对NRTIs的耐药性有显著下降趋势（从6.7%降至1.6%）。PI和NNRTI总体耐药性没有时间趋势。PR中最常观察到的主要耐药位点是V82（2.0%）和L90（1.8%）。在RT中，我们发现E138（58.6%）、K103（13.1%）、V179（8.4%）和T215（7.1%）、M41（4.7%）分别与对NNRTIs和NRTIs的耐药相关。在2003年至2013年期间，K103N和E138Q的流行率显著增加。至关重要的是，我们发现K103N和E138Q都与男男性行为者（MSM）和静脉吸毒者（IDU）本地网络内的传播网络有关。K103N网络包括希腊各地的血清阳性者，而后者仅来自雅典大都市区近期的IDU疫情（1）。系统动力学分析显示，K103N网络的指数增长始于2009年（图1），E138Q网络的指数增长始于2010年。
随着时间推移，希腊的总体耐药性一直稳定；然而，特定的NNRTI耐药模式正在增加。值得注意的是，它们与本地传播网络有关，因此表明这是NNRTI耐药模式增加导致的，而非耐药毒株从不同来源在接受治疗个体中的多次传播。我们的研究突出了分子流行病学在理解耐药动态方面的进展。
