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No Neuropsych Test Difference Between Early and Delayed ART in START
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Effects of immediate versus deferred initiation of antiretroviral therapy on bone mineral density: a substudyof the INSIGHT Strategic Timing of Antiretroviral Therapy (START) study - (10/23/15)
EACS: Immediate ART in START Linked to Bigger Bone Loss Over 3 Years - written Mark Mascolini (10/23/15)
15th European AIDS Conference, October 21-24, 2015, Barcelona
Mark Mascolini
Through 3.3 years of follow-up, people randomized to immediate antiretroviral therapy (ART) in the international START trial had neuropsychological (NP) test results similar to people in the delayed-ART arm [1]. Everyone in this young study group entered the trial with a CD4 count above 500, and percentage of time on ART was 93% in the early arm versus 34% in the delayed arm.
START randomized 4600 asymptomatic antiretroviral-naive people with a CD4 count above 500 to immediate ART or to defer treatment until the CD4 count fell to 350 or clinical AIDS developed [1]. After 3 years of follow-up, researchers unblended the trial when significantly more people in the deferred arm met the composite primary endpoint of any serious AIDS or non-AIDS disease or death from any cause.
A neurology substudy aimed to compare NP test results in the immediate and deferred arms over the course of the study. START investigators proposed that early ART may have a neurocognitive impact because HIV enters the central nervous system (CNS) early in the course of infection, overt CNS disease has been reported during primary HIV infection, and cognitive impairment reaches a high prevalence during chronic infection. On the other hand, ART may be neurotoxic.
Neurology substudy participants completed 8 NP tests when entering the study then after 4, 8, and 12 months and annually after that. Researchers standardized test scores to Z scores and figured the average of 8 Z scores, or QNPZ-8. The analysis involved 291 people in the early ART arm and 301 in the deferred arm with follow-up data.
The neurology substudy group had a young median age of 34 years (interquartile range [IQR] 27 to 42), and 11% were women. While 47% were white, 16% were Asian, 16% Hispanic, and 15% black. The highest proportion of participants came from Brazil (28%), followed by European countries (17%), Thailand (15%), the United States (15%), Argentina or Chile (14%), and the UK or Australia (11%). More than half (55%) had at least some college education, and three quarters had a job. The two treatment arms did not differ significantly by any of these measures. Nor did they differ by known duration of HIV infection (median 0.9 year), CD4 count (629), or viral load (about 16,000 copies). Fewer than 1% of participants injected drugs. While 8.3% had a psychiatric diagnosis, 5.2% reported alcohol or substance dependence.
The early ART group spent 93% of follow-up time on treatment, compared with 34% in the deferred arm. Half of deferred arm participants started ART by follow-up year 3. Three years after randomization, average CD4 count rose by about 200 in the early ART arm while remaining unchanged in the deferred arm.
Through an average 3.3 years of follow-up, QNPZ-8 rose to similar degrees in the two study arms. Estimated difference between the immediate and deferred arms at the end of follow-up was negligible (-0.01, 95% confidence interval -0.06 to 0.03, P = 0.63). Statistical adjustment for age, race, sex, education, geographic region, viral load, CD4 count, and CD4/CD8 ratio had little impact on this outcome.
The START team concluded that there is "no overall neurocognitive advantage (or disadvantage) for immediate ART initiation in asymptomatic treatment-naive individuals with high CD4 counts." The researchers believe their results suggest low prevalence of early neurocognitive impairment that ART can reverse and low incidence of neurocognitive decline that ART can prevent. At the same time, the young age, good health, and high educational attainment of the study group may explain why early ART had no neurocognitive advantage.
Brain Markers of Inflammation Drop to Normal With Early ART.....http://www.natap.org/2014/CROI/croi_31.htm
HIV Affects Brain Immediately After Infection with HIV RNA in the CSF & Inflammation & Brain Injury Continues Unfolding During Chronic Infection & There is a Need for Routine Monitoring.......http://www.natap.org/2011/CROI/croi_123.htm
........"Acute HIV infection is associated with detectable virus in CSF as early as 5 days post exposure.......
CROI: Rates of Non-confounded HIV-Associated Neurocognitive Disorder after Early cART..... "Our findings suggest substantial neuroprotective benefit of initiating cART during primary infection" - (03/03/15)........http://www.natap.org/2015/CROI/croi_177.htm
Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection - process of brain cell inflammation and injury begins very early after infection, worsen over time & in the absence of ART, findings suggest early ART initiation reduces inflammation & neurologic injury.........
http://www.natap.org/2014/HIV/112514_01.htm.........."Our findings suggest that inflammation and gliosis, the presumed substrates of later neurologic injury, initially manifest during the first year of HIV infection and worsen during early infection in the absence of treatment. In addition, our findings suggest that initiation of ART can alter this trajectory such that markers of inflammatory changes are no longer increasing, possibly limiting the extent of neurologic injury"
CROI: New Study Reports HIV in Brain Very Early but other studies in the past few years have found HIV gets into the brain very soon after infection....AND studies report very early ART, as soon as possible, within days, is the best way to limit HIV's bad affect on the brain......
http://www.natap.org/2015/HIV/040815_01.htm
EARLY ART Reduces SYSTEMIC HIV & INFLAMMATION IN RESERVOIRS: colon, blood, HIV DNA, PBMCs- ART in Acute Infection, Inflammation/Activation "Largely Disappear"......
http://natap.org/2015/CROI/croi_162.htm
CROI: Inflammation Persists Despite Early ART in Acute HIV - (03/16/15)
In this interesting study they found biomarker of enterocyte death, microbial translocation, inflammation, coagulation & fibrosis increase early in acute HIV infection, that very early ART, within days of infection, decreased inflammation & activation markers but inflammation & activation still persists, and compared to those who started ART in chronic infection inflammation/activation markers were often lower for those who started during early acute infection, and mostly the markers were elevated compared to HIV-uninfected, but D-Dimer normalized for patients treated during acute infection in this study; IL-6 was the lowest for those treated during stage 1 of infection. Authors said: "most biomarkers of microbial translocation, inflammation, coagulation & fibrosis decrease during early ART treatment to lower levels during following chronic infection compared to patients who start ART during chronic infection.....IFABP, biomarkers for intestinal damage/microbial translocation increase & remain elevated during infection despite suppressive ART suggesting ongoing enterocyte damage". Subjects were diagnosed with acute HIV infection and initiated ART within 0-5 days per RV254 protocol. Twenty subjects were diagnosed in 4th generation (4thG) stage 1 (median 12 days post-acquisition), 15 in stage 2 (16 days) and 43 in stage 3 (18 days). All week 0 biomarker levels were significantly higher in HIV+ than HIV- subjects (see table)
References
1. Wright E, Grund B, Robertson K, et al. No difference between the effects of immediate versus deferred ART on neuropsychological test performance in HIV-positive adults with CD4+ cell counts above 500 cells/µl: the Strategic Timing of Anti Retroviral Treatment (START) Neurology Substudy. 15th European AIDS Conference, October 21-24, 2015, Barcelona. Abstract PS10/6.
2. The INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795-807. http://www.nejm.org/doi/full/10.1056/NEJMoa1506816
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