1、Towards an HIV cure,Reporter : Fang Zhao Ph.D.&M.D.,Definition HIV cure,a sterilizing cure: the elimination of all HIV-infected cells. a functional cure: the generation of effective host immunity to HIV that would result in lifelong control of the virus in the absence of therapy, despite not achievi
2、ng the complete eradication of HIV.,cured following an allogeneic CCR532/32 haematopoietic stem cell transplant has sparked interest in studying curative interventions in the clinic,“Berlin Patient”, Timothy Brown,a baby and 14 adults are “functionally cured.“,“A Mississippi baby” born with HIV more
3、 than two years ago appears to be the first documented case of a childs being cured of the virus. * VISCONTI cohort: 14 patients who began ART within 10 weeks after the start of infection and continued for up to 3 years were more likely to control HIV replication without medications after subsequent
4、 treatment discontinuation.(PLoS Pathogens, DOI: 10.1371/journal.ppat.1003211),“Very early antiretroviral treatment”,i) further reduce residual viral replication ii) accelerate immune restoration iii) preserve innate immunity and T band B cell functions iv) limit viral diversity and viral reservoirs
5、,Resting memory CD4+ T cells monocytes dendritic cells macrophages haematopoietic stem cells,viral reservoirs,Short-Course Antiretroviral Therapy in Primary HIV Infection,The SPARTAC Trial Investigators* *(Short Pulse Anti-Retroviral Therapy at Seroconversion )N Engl J Med 2013; 368:207-217January 1
6、7, 2013DOI: 10.1056/NEJMoa1110039,Immunologic damage after HIV acquisition occurs rapidly. a short course of ART during primary HIV infection preserve immune function, decrease viral evolutionlimit the viral reservoir,Back ground,Primary HIV infection defined,Definitive Criterion:1. a positive HIV-a
7、ntibody test within 6 months after a negative test; 2. a negative HIV-antibody test with a positive reverse-transcriptionpolymerase-chain-reaction assay for HIV RNA,Presumptive Critrion,3. a low level of HIV antibodies (optical density units OD, 0.6) according to a serologic testing algorithm for re
8、cent infection (subtype B strain only) 4. an equivocal HIV-antibody test with a repeat test within 2 weeks showing an increase in the level of HIV antibodies 5. clinical manifestations of symptomatic HIV seroconversion illness supported by antigen positivity and less than 4 positive bands on Western
9、 blot analysis.,Study design,366 primary HIV infection from August 2003 through July 2007 in eight countries. the first 6 months after HIV infection (median 3 months) A majority (60%) were men the median age was 32 years the median CD4 count at study entry was approximately 560 cells/mm3 About 60% s
10、aid they had experienced symptoms of acute retroviral infection/seroconversion. People who needed immediate ART due to low CD4 count or clinical symptoms of AIDS were excluded.,Study design,Participants were randomly assigned, in a 1:1:1 ratio, to receive ART for 48 weeks, ART for 12 weeks, or no th
11、erapy (standard of care); Two nucleoside reverse-transcriptase inhibitors (NRTIs) plus a ritonavir-boosted protease inhibitor were recommended Clinic visits were scheduled at weeks 0, 4, 12,16, and 24, and every 12 weeks thereafter. Follow-up continued for a mean 4.2 years. The primary endpoints wer
12、e reaching a CD4 count less than 350 cells/mm3 - a previous threshold for treatment initiation - or starting long-term ART.,Study design,Study design,Study design,Results,50% of participants in the 48-week ART arm reached the primary endpoints, compared with 61% in both the 12-week ART group and the
13、 standard-of-care group.The hazard ratio was 0.63 for 48-week ART versus the standard of care, a significant difference (P=0.01).The hazard ratio was 0.93 for 12-week ART versus the standard of care, which did not reach statistical significance (P=0.67).,28% of patients in the 48-week ART group saw
14、their CD4 count fall below 350 cells/mm3 compared with 40% both the 12-week ART and standard-of-care groups.,The proportion of people who started long-term treatment was similar in all 3 groups: 22%, 21%, and 22%, respectively.,A post hoc analysis found a trend toward a longer interval between ART i
15、nitiation and the primary endpoints when therapy was started closer to the time of seroconversion.,48-week ART was associated with a 0.44 log reduction in HIV viral load at 60 weeks after completing short-course therapy.,others,There were no significant differences between the groups with regard to
16、progression to AIDS, death, or serious adverse events.,conclusion,A 48-week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment,“ There was no evidence of adverse effects of ART interruption on the cli
17、nical outcome.,Enhanced CD4+ T-Cell Recovery with Earlier HIV-1 Antiretroviral Therapy,Tuan Le, M.D., Dr.P.H., Edwina J. Wright, M.D., Davey M. Smith, M.D., Weijing He, M.D., Gabriel Catano, M.D., Jason F. Okulicz, M.D., Jason A. Young, Ph.D., Robert A. Clark, M.D., Douglas D. Richman, M.D., Susan J
18、. Little, M.D., and Sunil K. Ahuja, M.D.N Engl J Med 2013; 368:218-230January 17, 2013DOI: 10.1056/NEJMoa1110187,Background,The relationship between the timing of the initiation of antiretroviral therapy (ART) after infection with HIV-1and the recovery of CD4+ T-cell counts is unknown.the restorativ
19、e time window:The interval between the estimated date of infection and the peak CD4+ count in participants who were not receiving therapy. Earlier ART was defined as the initiation of ART within the restorative time window. Viral-load suppression was defined as the documentation of at least two cons
20、ecutive undetectable plasma HIV viral loads(75 copies per milliliter),Follow-up times: study set 1 as 48 months from the estimated date of infection or until participants began to receive ART; study set 2 as 48 months from the date of ART initiation, until discontinuation of ART or loss to follow-up
21、, or until loss of viral-load suppression.,Table 1. Characteristics of Study Participants in Study Sets 1 and 2.*,ART denotes antiretroviral therapy, and EDI estimated date of infection.,Results,Among participants who were not receiving ART, the median CD4+ count at study entry were 495 cells/mm3.CD
22、4 counts reached a peak within approximately 4 months after the estimated date of infection, at a median 763 cells/mm3.After this point, however, CD4 counts progressively declined.,Results,Among participants who started ART (study set 2), the median CD4+ count before treatment initiation was 451 cel
23、ls per cubic millimeter. ART was associated with a rapid gain of approximately 200 CD4+ T cells and then a slower, sustained increase,CD4+ counts crested at approximately 900 cells per cubic millimeter at approximately 4 months after the initiation of ART and then plateaued,Despite this modest diffe
24、rence, CD4+ counts increased more quickly among those starting ART earlier, irrespective of whether ART was initiated when the CD4+ counts were higher or lower,conclusion,A transient, spontaneous restoration of CD4+ T-cell counts occurs in the 4-month time window after HIV-1 infection. The initiatio
25、n of ART within this early restorative time window, when the host immune system is poised for recovery, greatly accelerates the pace and augments the extent of CD4+ T-cell recovery. Even a fairly short deferral of ART after closure of this time window may come at the expense of compromised CD4+ T-ce
26、ll recovery, irrespective of the CD4+ count at the time of treatment initiation.,Some promblems,In clinical practice, it is difficult to identify persons at early stages of HIV infection because of limitations in diagnostic technology. earlier therapy might provide additional benefit for example, by
27、 limiting damage to the immune system and reducing the extent of viral reservoirs persons who receive a diagnosis shortly after infection may also have a better chance of responding to “cure” strategies.,Prospective,Treatment of infected partners clearly decreases the risk of subsequent infection to others.-treatment as prevention(higher viral loads during primary infection)-early treatment during acute infection. when to initiate ART remains a difficult one, particularly in resource-limited settings,
