高效抗反转录病毒治疗6年的临床疗效、安全性和基因耐药的观察
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摘要
20多年以来,艾滋病(acquired immunodeficiency syndrome,AIDS)给人民的健康和生命造成的危害越来越严重,成为世界各国政府高度重视的重大公共卫生问题。高效抗反转录病毒治疗(highlyactive antiretroviral therapy,HAART)的应用和推广,使得抗艾滋病毒(human immunodeficiency virus,HIV)治疗取得了很好的临床效果,有效地降低了HIV/AIDS的发病率和死亡率、减少了传染性、提高了感染者的生存质量,是艾滋病预防和治疗史上一个重要的里程碑。
近年来我国已有不少关于HAART疗效及安全性的文章和报道,但仅限于短期疗效的观察资料,五年以上的长期抗病毒效果暂未见报道。但HIV的感染是慢性的、长程的,抗HIV治疗需终生服药,因此长期HAART的资料更具有临床价值。研究表明:长期HAART疗效毒副反应及病毒耐药的规律与短期的HAART资料既有联系也有不同的特点。本文就近6年来本研究室开展HAART治疗的抗病毒效果、免疫重建效果和毒副作用进行小结,同时讨论了少量病例耐药基因突变的情况。目前罕见国内类似报道。本研究包括以下二部分:
第一部分高效抗反转录病毒治疗6年的抗病毒效果、免疫重建效果和毒副反应
目的:评估中国的艾滋病患者以奈韦拉平加两个核苷类反转录酶抑制剂组合的长期的抗病毒效果、免疫重建效果和毒副反应。
方法:从2002年10月到2004年5月共对57例HIV-1/AIDS陆续开始了高效抗反转录病毒治疗,定期随访到2008年12月为止。HAART方案主要是两个核苷类反转录酶抑制剂(nucleoside reversetranscriptase inhibitor,NRTI)加一个非核苷类反转录酶抑制剂(nonnucleoside reverse transcriptase inhibitors,NNRTI)奈韦拉平。随访期间定期监测治疗对象的病毒载量和T细胞亚群的变化,记录药物的毒副反应并适当处理,以及追踪血常规、主要生化指标的变化;对治疗出现病毒学失败或严重毒副作用反应的患者及时调整用药方案和对症处理。
结果:57例接受HAART的患者中,40例持续追踪了4年以上。观察显示经过5-6年治疗,超过60%的患者病毒载量<50拷贝/ml。CD4细胞比治疗前平均上升了329个/ul。CD8+细胞平均下降128个/ul,CD4+CD45RA+CD62L童贞细胞和CD4+CD45RO记忆细胞逐渐上升,CD8+CD38+免疫激活细胞逐渐下降。这些变化均以治疗2年内较明显,治疗2年以上的长期趋势变缓,但6年时均未达到正常人的水平。32例(56%)先后出现过各种可能与药物相关的毒副作用,主要为消化道症状、神经系统症状、皮疹和脱发,多发生于治疗开始后24周内;血脂分布异常的躯体表现少见,多发生于2年以后。实验室指标改变主要有:29.8%(17/57)患者出现了GGT的升高,26.3%(15/57)患者血脂升高,其中10.5%(6/57)的患者出现了躯干异常脂肪分布,主要发生于女性患者。有25例患者发生过血象异常、肝功能受损、肾功能变化和淀粉酶升高。3例患者发生过3级毒副反应(2例为外周神经炎,分别于第5、6月;一例怀疑乳酸酸中毒,发生于治疗第8月),1例患者发生Ⅲ级皮疹(第4月)。
结论:首次报道中国HIV/AIDS的HAART治疗6年的前瞻性观察,结果提示奈韦拉平加两个核苷类反转录酶抑制剂的HAART药物组合对大部分患者有效:病毒持续抑制,CD4细胞一直在增加,异常免疫激活逐渐缓解。没有出现意料之外的副作用且可控制,主要的毒副反应和死亡多发生在治疗一年内。显示了两种核苷类药物加一种非核苷类药物的HAART方案对中国HIV/AIDS长期治疗的有效性和安全性。
第二部分HIV耐药基因检测
目的:评估两个核苷类药物和非核苷类药物奈韦拉平三药组合的HAART治疗6年的病毒耐药情况,为更有效的开展高效抗反转录病毒治疗提供参考。
方法:从2002年10月到2004年5月共有57例HIV-1感染者陆续开始了HAART治疗,分别抽取治疗前以及治疗后病毒反弹(RT-PCR≥10~3copies/ml)的标本进行耐药基因(pol基因)检测,并对扩增片段进行核苷酸序列测定分析。标本共64例(治疗前57例,治疗后7例),57例患者治疗前从未使用过抗HIV药物。
结果:分析获得的57例目的基因片段,治疗前52份,治疗后有5份。治疗前52份样本中,未检出蛋白酶抑制剂主要耐药相关突变。存在大量的蛋白酶抑制剂次要耐药相关突变,以M36I、I93L、H69K、L63P为多;有7例(13.5%)出现了核苷类逆转录酶抑制剂耐药突变:分别为L210S、M41L、T215H、A62V、T69S、(T215Y K219R)和K70R,有1例存在非核苷类逆转录酶抑制剂耐药突变,其耐药突变点为V179D。继发性耐药情况:未发现蛋白酶抑制剂的主要耐药突变和次要耐药突变。但发现均同时存在核苷类逆转录酶抑制剂和非核苷类逆转录酶抑制剂耐药突变。
结论:湖南省目前HIV/AIDS的原发性耐药处于低水平状态,仍然需要加强检测。另外NVP为基础的组合抗病毒效果较好,继发性耐药少,基因耐药主要针对逆转录酶区的耐药突变。同时,有必要对即将开始HAART的患者开展病毒耐药的检测,以掌握耐药基因变异的规律,合理使用抗病毒药物,从而制定长期有效的治疗方案。
For more than 20 years,AIDS to people's health and life of the harm caused by the more and more serious,has become government attaches great importance to the major public health problem.Highly effective antiretroviral treatment(HAART) the application and promotion,making antiretroviral therapy achieved good clinical results,effectively reduces HIV-associated morbidity and mortality,improve the survival of the infected persons quality,are AIDS treatment and prevention history of an important milestone.
In recent years,China has about HAART efficacy of many articles and reports,but only short-time of observations,More than four years of long-term antiviral efficacy has not yet reported.However,HIV infection is chronic and that exposure to HAART is likely to be life-long,there is a need to evaluate the long-term effect of HAART in this population.In this paper,we first report the long-term follow-up of 57 antiretroviral(ARV) drug-naive Chinese patients for 6 years.This study includes two parts as follows:
PartⅠ
Evaluation for Six-year's Highly Active Antiretroviral Therapy In Chinese HIV-1 Infected Patients
Objective:To evaluate the long-term efficacy and tolerability of nevirapine(NVP)-based regimens in the treatment of HIV-infected Chinese patients in routing clinical practice.
Design:Six-year follow-up of a study of NVP-based HAART.
Methods:HIV-infected,atiretroviral -naive patients originally received two nucleoside reverse transcriptase inhibitors(NRTIs) and nevirapine had HIV RNA levels,T lymphocyte subsets and safety assessed over 6 years.
Results:Of 57 patients,34 patients participated in long-term follow-up.After 5-6 years,more than 60%of subjects had HIV RNA levels＜50 copies/ul,and the median increase in CD4 cell count from baseline was 329 cells/μl.Gamma-GT increased occurred in seventeen patients(29.8%),Serum cholesterol and triglyceride elevations occurred in fifteen patients(26.3%),six(10.5%) patients developed lipodystrophy, mainly in female patients.Grade 3/4 adverse events occurred in three cases(at month 5,6,8).One subject experienced grade 3 rashes(at month 4).
Conclusions:Antiretroviral therapy with NVP-based regimens suppressed HIV viremia and produced continued CD4 cell increases in a majority of subjects for 6 years.Safety and tolerance were good with no unexpected long-term toxicity.This study demonstrates the durable effects of antiretroviral therapy of Chinese patients.
PartⅡ
Resistance mutations in HIV-infected Chinese patients On NVP-based HAART
Objective:To assess the long-term resistance mutations of nevirapine(NVP)-based regimens in HIV-infected Chinese patients in routing clinical practice.
Methods:From October 2002 through May 2004,57 HIV-infected patients commenced antiretroviral therapy(ART).Genotypic resistance tests on plasma RNA(VL＞1000 copies/ml) were carried out before treatment(n=57).Additionally,patients developing VR(virological rebound) were also tested at rebound(n=5).57 HIV-infected patients are naive for antiretroviral drugs.
Results:Analyze the 57 purpose gene fragment,pre-HAART(n=52), post-HAART(n=5).None had PI Major Resistance Mutations.PI Minor Resistance Mutations were generally existed,including major types of M36I,I93L,H69K and L63P,Seven(13.5%) of the 52 patients showed NRTI -associated mutation[L210S、M41I、T215H、A62V、T69S、(T215Y,K219R) and K70R].one patient showed NNRTI-resistance mutations(V179D).Secondary resistance outcome:the resistance mutation on PI Major Resistance Mutations and PI Minor Resistance Mutations,there are some patients that had many mutations on both of NRTIs and NNRTIs simultaneously.
Conclusion:There were primary and secondary drug resistance in naive HIV-1 infected patients in human province,but the prevalence was low,termly and systematic detection for gene resistance will be necessary before and during treatment by HAART to guide anti-HIV therapy. NVP-based HAART allows maintenance of successful long-term control of HIV replication.VR on NVP-based HAART is characterized by the emergence of NNRTI cross-resistance mutation.
近年来我国已有不少关于HAART疗效及安全性的文章和报道,但仅限于短期疗效的观察资料,五年以上的长期抗病毒效果暂未见报道。但HIV的感染是慢性的、长程的,抗HIV治疗需终生服药,因此长期HAART的资料更具有临床价值。研究表明:长期HAART疗效毒副反应及病毒耐药的规律与短期的HAART资料既有联系也有不同的特点。本文就近6年来本研究室开展HAART治疗的抗病毒效果、免疫重建效果和毒副作用进行小结,同时讨论了少量病例耐药基因突变的情况。目前罕见国内类似报道。本研究包括以下二部分:
第一部分高效抗反转录病毒治疗6年的抗病毒效果、免疫重建效果和毒副反应
目的:评估中国的艾滋病患者以奈韦拉平加两个核苷类反转录酶抑制剂组合的长期的抗病毒效果、免疫重建效果和毒副反应。
方法:从2002年10月到2004年5月共对57例HIV-1/AIDS陆续开始了高效抗反转录病毒治疗,定期随访到2008年12月为止。HAART方案主要是两个核苷类反转录酶抑制剂(nucleoside reversetranscriptase inhibitor,NRTI)加一个非核苷类反转录酶抑制剂(nonnucleoside reverse transcriptase inhibitors,NNRTI)奈韦拉平。随访期间定期监测治疗对象的病毒载量和T细胞亚群的变化,记录药物的毒副反应并适当处理,以及追踪血常规、主要生化指标的变化;对治疗出现病毒学失败或严重毒副作用反应的患者及时调整用药方案和对症处理。
结果:57例接受HAART的患者中,40例持续追踪了4年以上。观察显示经过5-6年治疗,超过60%的患者病毒载量<50拷贝/ml。CD4细胞比治疗前平均上升了329个/ul。CD8+细胞平均下降128个/ul,CD4+CD45RA+CD62L童贞细胞和CD4+CD45RO记忆细胞逐渐上升,CD8+CD38+免疫激活细胞逐渐下降。这些变化均以治疗2年内较明显,治疗2年以上的长期趋势变缓,但6年时均未达到正常人的水平。32例(56%)先后出现过各种可能与药物相关的毒副作用,主要为消化道症状、神经系统症状、皮疹和脱发,多发生于治疗开始后24周内;血脂分布异常的躯体表现少见,多发生于2年以后。实验室指标改变主要有:29.8%(17/57)患者出现了GGT的升高,26.3%(15/57)患者血脂升高,其中10.5%(6/57)的患者出现了躯干异常脂肪分布,主要发生于女性患者。有25例患者发生过血象异常、肝功能受损、肾功能变化和淀粉酶升高。3例患者发生过3级毒副反应(2例为外周神经炎,分别于第5、6月;一例怀疑乳酸酸中毒,发生于治疗第8月),1例患者发生Ⅲ级皮疹(第4月)。
结论:首次报道中国HIV/AIDS的HAART治疗6年的前瞻性观察,结果提示奈韦拉平加两个核苷类反转录酶抑制剂的HAART药物组合对大部分患者有效:病毒持续抑制,CD4细胞一直在增加,异常免疫激活逐渐缓解。没有出现意料之外的副作用且可控制,主要的毒副反应和死亡多发生在治疗一年内。显示了两种核苷类药物加一种非核苷类药物的HAART方案对中国HIV/AIDS长期治疗的有效性和安全性。
第二部分HIV耐药基因检测
目的:评估两个核苷类药物和非核苷类药物奈韦拉平三药组合的HAART治疗6年的病毒耐药情况,为更有效的开展高效抗反转录病毒治疗提供参考。
方法:从2002年10月到2004年5月共有57例HIV-1感染者陆续开始了HAART治疗,分别抽取治疗前以及治疗后病毒反弹(RT-PCR≥10~3copies/ml)的标本进行耐药基因(pol基因)检测,并对扩增片段进行核苷酸序列测定分析。标本共64例(治疗前57例,治疗后7例),57例患者治疗前从未使用过抗HIV药物。
结果:分析获得的57例目的基因片段,治疗前52份,治疗后有5份。治疗前52份样本中,未检出蛋白酶抑制剂主要耐药相关突变。存在大量的蛋白酶抑制剂次要耐药相关突变,以M36I、I93L、H69K、L63P为多;有7例(13.5%)出现了核苷类逆转录酶抑制剂耐药突变:分别为L210S、M41L、T215H、A62V、T69S、(T215Y K219R)和K70R,有1例存在非核苷类逆转录酶抑制剂耐药突变,其耐药突变点为V179D。继发性耐药情况:未发现蛋白酶抑制剂的主要耐药突变和次要耐药突变。但发现均同时存在核苷类逆转录酶抑制剂和非核苷类逆转录酶抑制剂耐药突变。
结论:湖南省目前HIV/AIDS的原发性耐药处于低水平状态,仍然需要加强检测。另外NVP为基础的组合抗病毒效果较好,继发性耐药少,基因耐药主要针对逆转录酶区的耐药突变。同时,有必要对即将开始HAART的患者开展病毒耐药的检测,以掌握耐药基因变异的规律,合理使用抗病毒药物,从而制定长期有效的治疗方案。
For more than 20 years,AIDS to people's health and life of the harm caused by the more and more serious,has become government attaches great importance to the major public health problem.Highly effective antiretroviral treatment(HAART) the application and promotion,making antiretroviral therapy achieved good clinical results,effectively reduces HIV-associated morbidity and mortality,improve the survival of the infected persons quality,are AIDS treatment and prevention history of an important milestone.
In recent years,China has about HAART efficacy of many articles and reports,but only short-time of observations,More than four years of long-term antiviral efficacy has not yet reported.However,HIV infection is chronic and that exposure to HAART is likely to be life-long,there is a need to evaluate the long-term effect of HAART in this population.In this paper,we first report the long-term follow-up of 57 antiretroviral(ARV) drug-naive Chinese patients for 6 years.This study includes two parts as follows:
PartⅠ
Evaluation for Six-year's Highly Active Antiretroviral Therapy In Chinese HIV-1 Infected Patients
Objective:To evaluate the long-term efficacy and tolerability of nevirapine(NVP)-based regimens in the treatment of HIV-infected Chinese patients in routing clinical practice.
Design:Six-year follow-up of a study of NVP-based HAART.
Methods:HIV-infected,atiretroviral -naive patients originally received two nucleoside reverse transcriptase inhibitors(NRTIs) and nevirapine had HIV RNA levels,T lymphocyte subsets and safety assessed over 6 years.
Results:Of 57 patients,34 patients participated in long-term follow-up.After 5-6 years,more than 60%of subjects had HIV RNA levels＜50 copies/ul,and the median increase in CD4 cell count from baseline was 329 cells/μl.Gamma-GT increased occurred in seventeen patients(29.8%),Serum cholesterol and triglyceride elevations occurred in fifteen patients(26.3%),six(10.5%) patients developed lipodystrophy, mainly in female patients.Grade 3/4 adverse events occurred in three cases(at month 5,6,8).One subject experienced grade 3 rashes(at month 4).
Conclusions:Antiretroviral therapy with NVP-based regimens suppressed HIV viremia and produced continued CD4 cell increases in a majority of subjects for 6 years.Safety and tolerance were good with no unexpected long-term toxicity.This study demonstrates the durable effects of antiretroviral therapy of Chinese patients.
PartⅡ
Resistance mutations in HIV-infected Chinese patients On NVP-based HAART
Objective:To assess the long-term resistance mutations of nevirapine(NVP)-based regimens in HIV-infected Chinese patients in routing clinical practice.
Methods:From October 2002 through May 2004,57 HIV-infected patients commenced antiretroviral therapy(ART).Genotypic resistance tests on plasma RNA(VL＞1000 copies/ml) were carried out before treatment(n=57).Additionally,patients developing VR(virological rebound) were also tested at rebound(n=5).57 HIV-infected patients are naive for antiretroviral drugs.
Results:Analyze the 57 purpose gene fragment,pre-HAART(n=52), post-HAART(n=5).None had PI Major Resistance Mutations.PI Minor Resistance Mutations were generally existed,including major types of M36I,I93L,H69K and L63P,Seven(13.5%) of the 52 patients showed NRTI -associated mutation[L210S、M41I、T215H、A62V、T69S、(T215Y,K219R) and K70R].one patient showed NNRTI-resistance mutations(V179D).Secondary resistance outcome:the resistance mutation on PI Major Resistance Mutations and PI Minor Resistance Mutations,there are some patients that had many mutations on both of NRTIs and NNRTIs simultaneously.
Conclusion:There were primary and secondary drug resistance in naive HIV-1 infected patients in human province,but the prevalence was low,termly and systematic detection for gene resistance will be necessary before and during treatment by HAART to guide anti-HIV therapy. NVP-based HAART allows maintenance of successful long-term control of HIV replication.VR on NVP-based HAART is characterized by the emergence of NNRTI cross-resistance mutation.
引文
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[70].中国疾病预防控制中心.国家免费艾滋病抗病毒药物治疗手册[M].中国疾病预防控制中心.2005.2.1