Zaccarelli Mauro, Perno Carlo Federico, Forbici Federica, Cingolani Antonella, Liuzzi Guiseppina, Bertoli Ada, Trotta Maria Paola, Bellocchi Maria Concetta, Di Giambenedetto Simona, Tozzi Valerio, Gori Caterina, D'Arrigo Roberta, De Longis Patrizio, Noto Pasquale, Girardi Enrico, De Luca Andrea, Antinori Andrea
National Institute for Infectious Diseases 'Lazzaro Spallanzani', Rome, Italy.
Antivir Ther. 2003 Feb;8(1):51-6.
M184V/I mutation is associated with high-level phenotypic resistance to lamivudine (3TC). The aim of the present analysis was to correlate the time of appearance/disappearance of M184V/I with duration of 3TC treatment.
Overall, 211 patients were selected from a database of HIV patients undergoing genotypic resistance test after virological failure of HAART regimens in two major reference centres in Rome between 1999 and 2001. At the time of genotyping, 120 of them (56.9%) were failing a 3TC-including HAART, while 91 (43.1%) received 3TC only in previous HAART. Duration of the current 3TC-containing regimen and the time from the end of last 3TC treatment to genotypic resistance test (GRT) were analysed.
Among patients currently undergoing 3TC-containing HAART, the prevalence of M184V/I was 82.5% (78.3/4.2%, respectively) and significantly associated to current 3TC use at GRT. Prevalence of M184V/I was associated to longer history of 3TC (from 47.1% in patients treated with 3TC for <6 months, to 84.0% among those treated for 7-12 months; 100.0% of patients with >42 months of current 3TC carried M184V. At logistic regression analysis, the rate of increase of M184V/I in 3TC-failing patients was statistically significant (OR: 1.066 per month of current 3TC therapy, 95% CI: 1.020-1.114, P<0.01), suggesting a 6.6% monthly increase of probability of M184V/I. Among patients who interrupted 3TC, overall prevalence of M184V/I was 23.1%: proportion of patients carrying the M184V/I dropped from 83.3% among those who interrupted 3TC from < or = 3 months, to 56.3, 20, 10.5 and 0% for those interrupting 3TC from 6, 12, 24 and > or = 24 months, respectively. At logistic regression, the rate of disappearance of M184V/I was also statistically significant (OR: 0.883 per month, 95% CI: 0.804-0.970, P=0.01), indicating a 11.7% monthly decrease of probability of M184V/I after 3TC interruption.
Dynamics of appearance/disappearance of M184V/I mutation is rapid after 3TC failure/interruption, suggesting ease of development of such a mutation, but also suggesting a remarkable growth disadvantage for HIV. From the clinical perspective, recycling of drugs whose antiviral activity is affected by M184V mutation can be successful after appropriate drug wash-out, also in heavily pretreated patients.
M184V/I突变与对拉米夫定（3TC）的高水平表型耐药相关。本分析的目的是将M184V/I出现/消失的时间与3TC治疗持续时间相关联。
总体而言，从1999年至2001年罗马两个主要参考中心接受高效抗逆转录病毒治疗（HAART）方案病毒学失败后进行基因型耐药检测的HIV患者数据库中选取211例患者。在基因分型时，其中120例（56.9%）正在接受含3TC的HAART治疗但治疗失败，而91例（43.1%）仅在之前的HAART治疗中接受过3TC治疗。分析了当前含3TC方案的持续时间以及从上一次3TC治疗结束到基因型耐药检测（GRT）的时间。
在目前正在接受含3TC的HAART治疗的患者中，M184V/I的患病率为82.5%（分别为78.3%/4.2%），并且与GRT时当前使用3TC显著相关。M184V/I的患病率与3TC治疗时间较长相关（从接受3TC治疗<6个月的患者中的47.1%，到接受7 - 12个月治疗的患者中的84.0%；目前接受3TC治疗>42个月的患者中有100.0%携带M184V）。在逻辑回归分析中，3TC治疗失败患者中M184V/I的增加率具有统计学意义（比值比：当前3TC治疗每月1.066，95%置信区间：1.020 - 1.114，P<0.01），表明M184V/I的概率每月增加6.6%。在中断3TC治疗的患者中，M184V/I的总体患病率为23.1%：携带M184V/I的患者比例从3TC治疗中断<或 = 3个月的患者中的83.3%，分别降至中断3TC治疗6、12、24和>或 = 24个月的患者中的56.3%、20%、10.5%和0%。在逻辑回归分析中，M184V/I的消失率也具有统计学意义（比值比：每月0.883，95%置信区间：0.804 - 0.970，P = 0.01），表明3TC中断后M184V/I的概率每月降低11.7%。
3TC治疗失败/中断后，M184V/I突变出现/消失的动态变化迅速，这表明这种突变易于发生，但也表明HIV具有明显的生长劣势。从临床角度来看，对于抗病毒活性受M184V突变影响的药物，在经过适当的药物洗脱后，即使是在经过大量预处理的患者中，药物再利用也可能成功。
