课件：抗病毒治疗.ppt

艾滋病抗病毒治疗,中国疾病预防控制中心 性病艾滋病预防控制中心 治疗与关怀室 赵 燕,HIV感染的自然史 抗病毒治疗药物 药品及作用机理 治疗目的 抗病毒治疗前准备 治疗时机、方案 治疗效果 依从性 耐药,ART ARV HAART NNRTI NRTI PI Adherence IRIS DR,临床表现（HIV感染的自然史）,急性期 无症状期(临床潜伏期) 临床期（艾滋病期）,急性HIV感染期,50%-70%以上的患者在感染后2周到2个月出现。 主要表现为传染性单核细胞增多症样表现 通常在2-4周内自行缓解。,无症状期(临床潜伏期),5%-15%的无症状期患者在2-3年发展为艾滋病称快速进展者。 5%的无症状期患者可以维持正常免疫12年以上称长期存活者。 一般6-10年。,AIDS期,此期具有以下基本特点 体质性疾病 严重的细胞免疫缺陷 发生各种病原感染、多脏器多系统的性机会性感染 发生各种机会性肿瘤,诊断标准（艾滋病期）, 原因不明的38以上持续不规则发热，1个月； 慢性腹泻次数多于3次/日，1个月； 6个月之内体重下降10以上； 反复发作的口腔白念珠菌感染； 反复发作的单纯疱疹病毒感染或带状疱疹病毒感染； 肺孢子虫肺炎； 反复发生的细菌性肺炎； 活动性结核或非结核分枝杆菌病；,诊断标准, 深部真菌感染； 中枢神经系统占位性病变； 中青年人出现痴呆； 活动性巨细胞病毒感染； 弓形虫脑病； 青霉菌感染； 反复发生的败血症； 皮肤黏膜或内脏的卡波氏肉瘤、淋巴瘤。 (17)CD4小于200/l,HIV/AIDS实验室诊断,诊断性检测,初筛实验：IFA、ELISA:1985 确认实验：Western blot,预后判定性检测,T细胞亚群检测：流式细胞仪技术 HIV RNA检测,HIV耐药检测,表型耐药：细胞培养技术 基因型耐药：序列测定，杂交技术,RT,Provirus,Proteins,RNA,DNA,RNA,DNA,DNA,RT,Viral protease,Reverse transcriptase,RNA,RNA,DNA,DNA,DNA,(Fusion and entry),HIV Life Cycle,RT,Provirus,Proteins,RNA,RNA,RT,Viral maturation,Reverse transcriptase,RNA,RNA,DNA,DNA,DNA,Current antiretroviral targets and agents,ZDV, ddI, ddC, d4T, 3TC, ABC, TDF, FTC DLV, NVP, EFV, TMC125, R278,SQV RTV IDV NFV APV LPV FOS ATZ TPV TMC114 BCV PL-100,Fusion,Integration,Viral protease,PA-457,MK-0518 GS-9137,T-20 TRI-1144,Entry inhibitors,Maraviroc Vicriviroc TNX-355,Timeline of ARV Development,AIDS 1st reported,Eliza,WB, blood screening program,ZDV,ddI,ddC,d4T,3TC, SAQ,RTV, IDV, NVP,NFV, DLV, COM, SAQ-gc,EFV, ABC,APV,Viral load Amplicor 1.0,1981,1984,1994,1992,1991,1985,1987,1995,1996,1997,1999,1998,2000,2001,2002,2003,2005,HIV isolated,Resistance Testing TruGene,Amplicor 1.5,NEJM, Pallela et al.,LPV/r, ddI-EC, TZV,TDF,EFV-600, 3TC-300,ENF NFV-625 ATV FTC FPV,EPV-ABC TDF-FTC TPV,Current Antiretroviral Medications,NRTI Abacavir ABC Didanosine DDI Emtricitabine FTC Lamivudine 3TC Stavudine D4T Zidovudine ZDV Tenofovir TDF NNRTI Delavirdine DLV Efavirenz EFV Nevirapine NVP,PI Amprenavir APV Atazanavir ATV Darunavir DRV Fosamprenavir FPV Indinavir IDV Lopinavir LPV Nelfinavir NFV Ritonavir RTV Saquinavir SQV hard gel HGC tablet INV Tipranavir TPV Fusion Inhibitor Enfuvirtide T-20,目前我国所有的抗病毒药物,核苷类：DDI，D4T，3TC，AZT，ABC ，（TDF ？） 非核苷类：EFV ，NVP 蛋白酶：IDV，ATV ，LPV/RTV,New Antiretrovirals in Development,NRTIs/NtRTIs Amdoxovir (DAPD) Apricitabine (AVX754) Compound X Dexelvucitabine (D-d4FC) Racivir ( FTC) SN1212 Protease inhibitors Brecanavir (GW640385) Darunavir (TMC114) P-1946,Entry inhibitors BMS-488043 Maraviroc NB-2, NB-64 PRO140 TNX-355 Vicriviroc KRH-3955 KRH-3140 TRI-999 TRI-1144,NNRTIs BILR 355 BS CSIC DAPY/DATA Etravirine (TMC125) TMC120 (microbicide) TMC278 UC781 Integrase inhibitors GS-9137 MK-0518 Maturation inhibitors PA-457,J. Gallant CCO 2005,AIDS-related Mortality in the USA,1995 1996 1997 1998 1999 2000 2001,Year,Deaths per 100 person-years,Therapy with a PI (% of patient-days),Deaths,Use of PIs,Palella et al. 8th CROI, 2001,40 35 30 25 20 15 10 5 0,100 75 50 25 0,Impact of Protease Inhibitors on AIDS Mortality,Palella F. et al., New Engl J Med 1998; 338:853-860,HAART Impacted on AIDS progression and/or death in Hong Kong,Wong et al CID 2004,N=303,N=278,1984-1996,1997-mid 2003,HAART era,Pre-HAART,抗逆转录病毒治疗的目的,抑制病毒的复制 病毒载量最大程度的下降 免疫重建 防止耐药的出现 存活 疾病进展 传染性,Goals of Therapy & Tools to Achieve Goals,Improvement of quality of life Reduction of HIV-related morbidity and mortality Restoration and/or preservation of immunologic function Maximal and durable suppression of viral load,Selection of ARV regimen Preservation of future treatment options Rational sequencing of therapy Maximizing adherence Use of resistance testing in selected clinical settings,推迟治疗的潜在益处 避免药物治疗带来的对于生活质量的负面影响及药物毒副反应。 保留治疗选择 推迟药物耐药的发生 患者有更多时间充分理解治疗需求 减少总的服药时间 有机会等待效力更强、毒副反应更少的药物及更好药物组合的出现 推迟治疗的潜在风险 由于没有及时接受治疗对免疫系统造成不可逆转的损害 增加进展为艾滋病的可能性 由于没有接受治疗，增加了传播HIV的危险,Initial Treatment: Preferred Components,*Avoid in pregnant women and women with significant pregnancy potential. *Emtricitabine can be used in place of lamivudine and vice versa.,OR,NNRTI Option,PI Options,Tenofovir + emtricitabine* Zidovudine + lamivudine*,+,NRTI Options,Initial Treatment: Alternative Components,*Nevirapine should not be initiated in women with CD4 counts 250 cells/mm3 or men with CD4 counts 400 cells/mm3 *Atazanavir must be boosted with ritonavir if used in combination with tenofovir,OR,NNRTI Option,PI Options,Abacavir + lamivudine Didanosine + (emtricitabine or lamivudine),NRTI Options,Initial Treatment: Other Possible Options,Rationale,ARV drugs or regimens,These are considered acceptable but inferior to preferred or alternative components. They may be used in special circumstances.,Antiretroviral Components in Initial Therapy: NNRTIs,ADVANTAGES Less dyslipidemia and fat maldistribution than in PI-based regimens PI options preserved for future use,DISADVANTAGES Resistance - single mutation Cross-resistance among NNRTIs Rash; hepatotoxicity Potential drug interactions (CYP450),Antiretroviral Components in Initial Therapy: PIs,ADVANTAGES Longest prospective data NNRTI options preserved for future use,DISADVANTAGES Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance) Greater potential for drug interactions (CYP450), especially with ritonavir,Antiretroviral Components in Initial Therapy: NRTIs,ADVANTAGES Established backbone of combination therapy Minimal drug interactions PI and NNRTI preserved for future use,DISADVANTAGES Lactic acidosis and hepatic steatosis reported with most NRTIs (rare) Triple NRTI regimens show inferior virologic response compared with efavirenz- and indinavir-based regimens*,* Triple NRTI regimen of abacavir + lamivudine + zidovudine to be used only when a preferred or alternative NNRTI- or PI-based regimen cannot or should not be used as first-line therapy.,98% 61%,Week,LPV/r + d4T + 3TC in treatment-nave adults HIV-1 RNA 400 (50) copies/mL through Week 360,N: 100 86 72 63 62,Murphy R. et al., 10th EACS, Dublin, Ireland, November 2005, #P7.9/3 Study 720,(95%) (59%),HIV RNA 400 (50) copies/ml on Kaletra+d4T/3TC,Week,Mean change in CD4 Cell Count Through 7 years,+501 cells/mm3 (n=60),Murphy R. et al., 10th EACS, Dublin, Ireland, November 2005, #P7.9/3 Study 720,Mean absolute value at year 7 = 776 cells/mm3,Subjects with Values at Week 360 (n=15) (n=12) (n=11) (n=11) (n=11),Bartlett JA, et al. AIDS. 2006. In press., 65% VL 50 疗效药物( 48周),在48周VL 50百分比,Boosted PI,NNRTI,40,COMBINE (NVP + ZDV/3TC) 2NN (NVP BID + d4T + 3TC) ZODIAC (EFV + ABC QD + 3TC) M98-863 (LPV/RTV + d4T + 3TC) ZODIAC (EFV + ABC + 3TC) CNA30024 (EFV + ZDV + 3TC) 2NN (NVP QD + d4T + 3TC) 2NN (EFV + d4T + 3TC) CNA30024 (EFV + ABC + 3TC) M02-418 (LPV/RTV + FTC + TDF QD) FTC301 (EFV + FTC + ddI QD) DMP266-043 (EFV + D4T + 3TC) CLASS (EFV + ABC + 3TC) ANRS 12-04 (EFV + ddI + 3TC) M97-720 (LPV/RTV +d 4T + 3TC) Dart 1 (EFV + ddI EC + 3TC) GS903 (EFV + d4T + 3TC) GS903 (EFV + TDF + 3TC) ANRS 091 (EFV + ddI + FTC),50,60,70,80,90,100,30,Treatment-Experienced Patients: ARV Treatment Failure,Causes of treatment failure include: Patient factors (CD4 nadir, VL, comorbidities, etc) Suboptimal adherence ARV toxicity and intolerance Pharmacokinetic problems Suboptimal drug potency Viral resistance,Immune Reconstitution Inflammatory Syndrome (IRIS),Lipoatrophy (fat loss),ARV的毒性包括,线粒体的毒性 代谢异常 肝脏毒性 超敏反应 不同药物的副作用,0,Time (days),Drug Concentration,IC50,2,4,6,8,10,12,14,16,- NNRTI - NRTIs,How to stop ARV,Definitions,Genotype Virus nucleotide sequence from which a proteins amino acids can be deduced Mutations reported as change in the deduced amino acid sequence, e.g., Met184Val Specific mutations confer phenotypic resistance The phenotype is always derived from the genotype Phenotype Relative growth of the virus in the presence of different drug concentrations Usually reported as the drug concentration that inhibits virus replication by 50% (IC50), or the fold increase in IC50,Clinical characteristics Primary HIV infection Established HIV infection First regimen failure Multiple regimen failures Pregnancy,Recommendation Consider testing Consider testing Recommend testing Recommend testing Recommend testing,Rationale Detect transmission of drug- resistant virus; modify therapy to optimize response and maintain HIV-specific immune responses Detect prior transmission of drug- resistant HIV although this may not always be possible with current tests Document drug(s) to which