1 Cocktail therapy 2 Combination therapy 3 HAART
抗病毒治疗概念 • 1. Cocktail therapy 鸡尾酒疗法 • 2. Combination therapy 联合疗法 • 3. HAART (Highly Active Anti. Retroviral Therapy) 高效抗逆转录病 毒治�
Why NOT to use dual and monotherapy % of patients progressing Progression to AIDS/Death No therapy Mono-therapy Dual-therapy Triple therapy Months JAMA 1998 & CMAJ 1999
Reduced morbidity and mortality related to AIDS since HAART % 40 Deaths MAC CMV Pneumoc. 30 20 10 1994 1995 1996 1997 from Palella, 98
Antiretroviral Drugs 2004 Ns. RTI NNRTI PI zidovudine (ZDV) didanosine (dd. I) zalcitabine (dd. C) stavudine (d 4 T) nevirapine (NVP) efavirenz (EFV) delavirdine (DLV) saquinavir (SQV) ritonavir (RTV) indinavir (IDV) nelfinavir (NFV) lamivudine (3 TC) abacavir (ABC) FTC Tenofovir (TFV) enfuvirtide (T 20) Entry inhibitor amprenavir (APV) lopinavir/r (LPV/r) atazanavir (ATV) Fosamprenavir
• 核苷类逆转录酶抑制剂NRTIs: 通用名 注册名 中文名 • Zidovudine (ZDV或AZT) Retrovir 立妥威 • Didanosine (dd. I) Videx 惠妥滋 • Zalcitabine (dd. C) HIVID • Stavudine (d 4 T) Zerit 赛瑞特 • Lamivudine (3 TC) Epivir 益平维 • Abacavir (ABC) Ziagen 赛进 • Combivir (AZT+3 TC) Combivir 双汰芝 • Trizivir (AZT+3 TC+ABC) Trizivir 三协维 • Tenofovir (TNV) Viread
非核苷类逆转录酶抑制剂NNRTIs: 通用名 注册名 中文名 • Nevirapine(NVP) Viramune 维乐命 • Delavirdine Resciptor • Efavirenz (EFV) Stocrin 施多宁
• 蛋白酶抑制剂PIs : • • • 通用名 注册名 中文名 Saquinavir Fortovas (软胶囊) 沙奎那维 Invirase (硬胶囊) 沙奎那维 Indinavir Crixivan 佳息患 Ritonavir Norvir Nelfinavir Viracept Amprenavir Agenerase Lopinavir/Ritonavir Kaletra Atazanavir
融合抑制剂(Fusion Inhibitor) 通用名 注册名 Enfuvirtide Fuzeon 90 mg/1 ml,皮下注射,每日 2次
何时开始治疗? HIV RNA load Clinically latent period CD 4 lymphocytes 1996 6– 24 weeks Infection with HIV 0. 5– 15 (? ) years 2001 1987 2– 3 years Clinical symptoms
Indication of antiretroviral treatment CD 4 count Symptomatic Recommanded Asymptomatic Differ if stable any value Treatement Recommanded CD 4 < 350/mm 3 CD 4 : 350 - 500/mm 3 CD 4 > 500/mm 3 No treatment.
药物组合原则 2 NRTIs+1 NNRTI 2 NRTIs+1 PI 3 NRTIs (A few regimes) NRTI: Nucleoside reverse transcriptase inhibitors NNRTI : Non-nucleoside reverse transcriptase inhibitors PI: Protease inhibitors
以PI为基础的组合 • 每天服药粒数 • 首选 Kaletra+3 TC+(TNF or AZT or d 4 T) 8– 10 • 次选 14 • 10 • 12 APV+RTV+3 TC(AZT or d 4 T) 12– IDV+3 TC+(AZT or d 4 T) 8– IDV+RTV+3 TC+(AZT or d 4 T) 8–
AIDS 合并TB感染时的HAART
多种治疗方案的病毒抑制作用 91% 82% 67% 周 Ref: K. Squire et al. IATEC, 1999
患者VL低于400拷贝的百分比 依从性与治疗成功的关系 70% 70 -80% 80 -90% 90 -95% >95% 依从性的百分比 From Peterson et al, 6 th Conf ROI 1999 abstr #92
Hypersensitivity reactionmoderate
Hypersensitivity reactionsevere (Stevens-Johnson syndrome )
Steven-Johnson 综合征
Potential new targets Binding, fusion and entry Viral zinc-finger nucleocapsid proteins Viral protease RNA Reverse transcriptase RNA Proteins RT RNA DNA RT Viral regulatory proteins DNA Viral integrase Provirus
Entry Inhibitors Overview Inhibitor CD 4 Attachment Pro-542 (Progenics) FP-21399 (Lexigen) BMS Entry Inhibitors CCR-5/CXCR 4 Binding SCH-C ( Schering) PRO-140 ( Progenics) AMD-3465 ( Anor. MED) Fusion T-1249 ( Trimeris) Molecule Target ROA Status s. CD 4 -Ig. G 2 bis-azo cmpd Aza-indole Viral SCH-351125 Mab Cyclam CCR-5 CXCR 4 Oral Injectable Phase II Yes No Maybe 39 aa peptide Viral Injectable Phase II Yes Injectable Phase II Oral Preclinical POC Yes No
- Slides: 65