AIDS2013sha网络稿1

Acquired Immunodeficiency Syndrome (AIDS),Sha XinpingDepartment of Infectious DiseasesXiangya HospitalCentral South University,Luc Montagnier,Robert C. Gallo,2012.12.125th World Aids Day,GET TO ZERO 中国艾滋病日的宣传主题 “行动起来，向零艾滋迈进”，副标题 “全民参与，全力投入，全面预防 ”,I. Definition Acquired immunodeficiency syndrome(AIDS), a fatal and epidemic retroviral disease, caused by human immunodeficiency virus(HIV).,The clinical consequences of whole bodys immune deficiency are a variety of unusual opportunistic infections and neoplasia.,Its transmitted mainly through sexual contact (heterosexual or homosexual) transfusion with HIV-contaminated blood, drug injection mother-to-child transmission,II. Etiology / pathogen,HIV, types 1 and 2, a RNA virus . HIV-1, major cause of AIDS worldwide. HIV-2, spreads epidemically in West AfricaPeripheral particle, diameter 90-140 nm , retrovirus（反转录病毒）, lentivirusVirion contain 2 copies of a single-stranded RNA genome, products of the viral genes env (glycoprotein gp 160, gp120, gp41), gag (p24, p17, p7, p9) and pol (p32, p66, p51, p11),The major targets of HIV infection: CD4+T lymphocyte, macrophage and others CD4+ cells. (B lymphocyte, dendritic cell, stem cell from bone marrow ). 1996, scientists found there were some chemokine receptors (for example, CCR5 and CXCR4) supporting HIV fusion and entry to cell.,Chemokines and corecepters of HIV-1 infection,CD8+T cells and other CD4+ cells may secrete chemokines, which inhibit HIV infected macrophage and T lymphocyte. CCR5 ligands MIP-1a, MIP-1b and RNATES block M-tropic strains of HIVs entry, and CXCR4 ligand SDF-1 blocks T tropic strain of HIVs entry.,release virions,target CD4 cell,attach,CD4 molecule and CCR5 or CXCR4 receptor,fusion with cell Membrane,uncoating,enter cell,Reverse transcription,double-stranded DNA,to nucleus,integrated into host cell genome,latency 2-10 years,translate to mRNA and viral proteins,viral replication,HIV,gp120,gp41,HIV-1 virions released from T cell,III. Epidemiology,HIV infection was originally found in United States in 1981, now spreads throughout the world.,Fast facts on HIV/AIDSSource: WHO 2012,2.5 million people were newly infected with HIV worldwide in 2011.1.7 million people died of AIDS-related illnesses worldwide in 2011.5.25 million HIV-positive people had access to ART in low- and middle-income countries in 2011.69% of all people living with HIV are in sub-Saharan Africa.26% of pregnant women were tested for HIV in low- and middle-income countries in 2011.34.0 million people were living with HIV worldwide in 2011.,Katherine Jenkins出席于伦敦 Bond Street万宝龙店46664手镯的开售仪式,克林顿与宋鹏飞,China, by the end of Oct. 2011 43.4万 HIV 感染者/艾滋病 8.8万 deaths reportedExperts estimated there are more than 700,000 persons living with HIV/AIDS in China.,2012 年中国HIV感染者分布示意图,B Routes of transmission,A Sources of infection,AIDS patients and HIV carriers HIV mainly exists in blood and semen and other body fluid .,Sexual behavior: bisexual or homosexual, influential factors: Multiple sexual partners High viral load or advanced AIDS in partner Receptive anal intercourse Sex during menstruation Presence of other STDs Blood products contamination,Intravenous drug abuse, needle sharing,Vertical transmission Delivery or breast-feeding Depended on viral load and CD4+ cell level,Injection-associated nosocomial infection, occupational exposure,C susceptible population,People with multiple sexual partners, male homosexual Commercial sexual workersIntravenous drug users Contaminated transfusion receivers Children of HIV/AIDS mother,IV. Pathogenesis,attach CCR5, CXCR4,Cellular immune dysfunction,Host immunosuppression,Opportunistic infections, neoplasmas, and other life-threatening manifestations.,CD4+ T cell and CD4+ cells,HIV,B Monocyte / macrophages dysfunction and damage,A CD4+T lymphocytes dysfunction, both quantitative and qualitative, hallmark of HIV infection.,C CD4+ B cells and NK cells damages, humoral immune dysfunction CD 8+ T cells damages ,antiviral capacity decrease,D Immune responses against HIV:,Neutralizing antibody.Anti-HIV cytotoxic T lymphocyte (CTL)NK cell-depended cytotoxicity.Bystander killing,Major pathologic responses: inflammation and carcinogenesis in lymph nodes and thymus.,V. Clinical Manifestations,1986, CDC defined HIV infection into 4 clinical phases:Phase I -Acute infection (retroviral syndrome): fever, rash, headache, nausea, diarrhea, lymphadenopathy, serum HIV RNA(+) and P24 antigen (+), last 3-16 days.,Phase II Asymptomatic infection with serum HIV RNA(+) and GP120, GP41, P24 antibodies(+), last 2-10 years.,Phase III Persistent generalized lymphadenopathy (PGL), lymph nodes are palpable in more than two locations last 1-2 years.,Phase IV -Symptomatic AIDS disease, divided into 5 groups:,Group A no special constitutional symptoms, Group B nervous system disease, Group C severe opportunistic infections, Group D carcinoma,Group E other AIDS manifestations.,Constitutional disease:,Pulmonary manifestations:,Gastrointestinal manifestations:,Fever, cough,dyspnea caused by TB, CMV, streptococci, fungi or pneumoncystis jiroveci pneumoncystis pneumonia, PCP,Thrush, nausea, dysphagia, esophageal discomfort and diarrhea frequently caused by Canadida, EBV,CMV infection and Kaposis sarcoma,Fever, rash, headache, weight loss and lymphadenopathy,Bacterial or fungal infectionCNS lymphoma toxoplasma or cryptococcus infectionmental changes: delirium and psychosis, decreased consciousnessmultifocal leukoencephalopathy,Neurological manifestations:,Cutaneous manifestations:,Kaposis sarcoma, fungal or viral infection,haemophilia （19y),耶氏肺孢子菌肺炎(PCP),toxoplasma encephalopathy弓形虫脑病,马尔尼菲青霉菌,VI. Lab examination,C. Pathogen tests,A. Blood routine: WBC RBC PLT,T cell count,CD4/CD81,Northern blot for HIV RNA RT-PCR,ELISA for antibodies (anti-gp24, gp120),B. Immune tests:,CD4+ count,E other examinations,Chest X ray for TB infection , PCP, fungal pneumonia Sputum smear or culture , bronchoscopy Blood culture and bone marrow culture CSF analysis for neurological infection Lymph node biopsy or lesion biopsy for kaposis sarcoma(KS) and neoplasma Endoscopy MRI, CT , Ultrasonic,VII. Diagnosis,A. Epidemiologic history:,B. Clinical manifestation,WBC,HIV-Ab(+) or HIV RNA(+), etc,C. Evidences in laboratory,CD4+/CD8+,T lymphocyte,homosexual behavior, intravenous drug use, contaminated blood transfusion, etc,D. Special examinations,show as above,Persons with following conditions should be highly suspected,A. high risk behavior + clinical manifestation + laboratorys evidencesB. high risk behavior + any two symptoms as belowWeight loss more than 10%Cough or diarrhea 10 months Fever 1 month Persistent generalized lymphadenopathy(PGL)Chronic herpes virus infectionOral cavity mycosis,VIII. Treatment,A. General treatmentsupportive and symptomatic treatment,B. Antiretrovirus therapy,The major goals of treatment:To suppress viremia and prevent immunodeficiency Antiviral therapy are necessary for all patients with symptoms,规范化疗法：1998年第12届艾滋病大会提出，即称“高效抗逆转录病毒疗法”（Highly Active Anti-Retroviral Therapy, HAART）。药物：即反转录酶抑制剂+蛋白酶抑制剂+融合抑制剂。疗程：可能需要终身用药！,Antiviral therapy may be started for some asymptomatic HIV persons,For early control HIV replicationDecrease possibility of mutationDecrease viral load (Viremia)Prevent immunodeficiency and re-establish immunityRetard progression to AIDS,The side effect:,Drug resistance The life quality reduction and toxicity,Three categories of anti-HIV drugs,Nucleaside reverse transcriptase inhibitors (NRTI) To inhibit HIV RT and viral replication To delay AIDS progressionNonnucleaside reverse transcriptase inhibitors (NNRTI) To inhibit HIV RT by a different way than NRTI, but easily produce drug resistanceProtease inhibitors (PI) To inhibit HIV protease and interfere with viral maturation and assembly,NRTI,Drug Dose Side effects,Zidovudine 300mg, Bid Nausea, headache, fatigue;(AZT,ZDV) Anemia, neuropathy,myopathy,Lamivudine 150mg,Bid rare ( 3TC ),Didanosine 200mg,Bid Peripheral neuropathy, pancreatitis ( ddI ),Zalcitabine 0.75mg/kg,Tid Peripheral neuropathy ( ddC ),Stavudine (d4T) 40mg, Bid,Abacavir( ABC ) 300mg,Bid,NNRTI,Drug Dose Side effects,Delavirdine 400mg, Tid Transient rashEfavirenz 600mg, QN Transient rash, dizzinessNevirapine 200mg, QDx14 Transient rash, hepatitis 200mg, Bid,PI,Drug Dose Side effect,Amprenavir 1.2g, Bid Rash, diarrhea, nauseaIndinavir 0.8g, Q8h Urinary calculus, nauseaLopinavir 1.25g, Bid Diarrhea, nauseaRitonavir 0.6g, Bid Nausea, diarrhea, hepatitisSaquinavir SGC 1.6g, Bid or 1.2g, Tid,Combination Therapy,Goals:To enhance inhibition of viral replicationTo reduce or delay HIV mutation and drug resistanceTo reduce drug toxicities and side-effect.High active antiretroviral therapy, HAARTAvailable for adults, children, pregnant women HIV/AIDS persons.Recommended combination is two NRTI-one PI, or two NRTI-one NNRTI.,Summary of initial treatment,Column A Column BEfavirenz d4T + ddIIndinavir d4T + 3TCNelfinavir AZT + ddIRitonavir/Indinavir AZT + 3TCRitonavir/LopinavirRitonavir/Saquinavir,Summary of alternative initial treatment,Column A Column BAbacavir ddI + 3TCAmprenavir AZT + ddCDelavirdine Nevirapine/SaquinavirRitonavirSaquinavir-SGC,C.Immune therapy and gene therapy,Interleukins (IL-2, IL-16), interferon or , and other cytokine (GM-CSF, globulin)Ribozyme,D. Treatment for opportunistic infections,Thrush(oral Candidiasis)- Fluconazole 100mg p.o. TidCMV,HSV and EBV infection-Ganciclovir 0.3 drip, BidPCP-TMP 20mg/kgd + SMZ 100mg/ kgd p.o. Tid x7-14dCryptococcus meningitis-Fluconazole 100mg p.o. TidToxoplasmiasis-Rovamycin or clindamycin 0.5 p.o. TidKS-Combination Therapy of Vincristine(VCR), Doxorubin(ADR) and Bleomycin, or AZT and IFN- ,IX. Principles of prevention,A. Control source of infectionIsolation of HIV/AIDS personBlood donor screening Powerful sterilization of HIV contaminated blood and excrementB. Protect susceptible populationPregnancy is not recommended in HIV(+) womenVaccine is not availableEducate hig