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Earlier Initiation of Antiretroviral Therapy Results in Better Neurocognitive Functioning
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Reported by Jules Levin
CROI 2012
(from jules: this paper suggests evaluating neurocognitive function immediately after HIV diagnosis & starting HAART soon improves neurocognitive function)
T.D. Marcotte1, M. Ghate2, R. Deutsch1, S. Letendre1, R.A. Meyer1, S. Godbole2, A. Risbud2, M. Thakar2, I. Grant1, and S. Mehendale3
1HIV Neurobehavioral Research Program, University of California, San Diego, 2National AIDS Research Institute, Pune, India, 3National Institute of Epidemiology, Chennai, India
HIV+ participants in Pune, Maharashtra, India with a CD4 cell count > 350/mm3 and enrolled in a separate study (HPTN 052) were randomized to immediate (n = 35) or deferred treatment (n = 44). 79 HIV-infected individuals in Pune, India with a CD4 cell count > 350/mm3 were recruited from HPTN 052, a randomized
clinical trial to examine whether early treatment
CONCLUSIONS
· Starting antiretroviral treatment (ART) at higher CD4 cell counts, even when NP dysfunction is mild, appears to be beneficial to the central nervous system
· This finding was present despite 45% of the treated participants starting treatment prior to the baseline assessment (most within two weeks), a conservative bias
· ART was most beneficial for those who demonstrated worse NP performance at baseline, consistent with the notion that ART did not "enhance" performance in individuals without presumed HIV-related brain dysfunction
· Future analyses on larger numbers of patients, and control participants (to examine if early ART might delay NP decline), would generate more robust evidence regarding the possible benefit of early treatment
ABSTRACT
Background: Combination antiretroviral treatment (ART) has significantly reduced the severity of HIV-associated
neurocognitive disorders (HAND), although mild forms of neuropsychological impairment remain common. In many
regions treatment is often initiated only after patients show immunocompromise (e.g., CD4 < 350). The goal of this
study was to determine whether initiating ART at higher CD4 cell counts benefits neurocognitive functioning.
Methods: HIV+ participants in Pune, Maharashtra, India with a CD4 cell count > 350/mm3 and enrolled in a separate study (HPTN 052) were randomized to immediate (n = 35) or deferred treatment (n = 44). All participants completed a full NP battery (translated into Marathi) at baseline and a 1-year follow-up. NP performance was summarized using unadjusted mean scaled scores, a normalized score that puts all scores on the same metric (higher scores indicate better performance).
Results: The two groups were similar with respect to age (~33 years), education (~ 9 years), gender (~ 67% male), and disease stage (~ 84% CDC A), and had comparably high current CD4 cell counts (~ 460/mm3). On average, participants started treatment on the day they were tested (median days between testing and treatment = 0 [-12, 1]). At baseline, the mean scaled score for the deferred treatment group was 9.0 (1.9) vs. 9.8 (1.5) for the treated group (p = .06). All participants in the treated group attained virologic suppression by their second visit. In a multivariable model, improvement in mean scaled score was predicted by its baseline value (p = 0.002) and its interaction with group (p = 0.02). Treated participants with the lowest baseline mean scaled scores demonstrated the most improvement. Whether the participants started treatment prior to baseline was not a significant predictor.
Conclusions: ART initiation at higher CD4 cell counts appears to benefit the central nervous system. This finding was present despite 45% of the treated participants starting treatment prior to the baseline assessment (most within a few weeks), a conservative bias. Future analyses of larger sample sizes of participants with or without HAND will generate more robust evidence regarding the possible cognitive benefit of early ART initiation.
BACKGROUND
· Combination antiretroviral treatment (ART) has resulted in reduced severity of HIV-associated neurocognitive disorders (HAND) (Al-Khindi et al., 2011)
· However, milder forms of HAND remain prevalent, affecting up to 50% of persons with HIV infection (Heaton et al., 2010)
· ART is often initiated only after patients show immunocompromise (e.g., CD4 < 350), particularly in resource-limited settings
· It is not known whether treatment at higher CD4 cell counts might still show cognitive benefits, either by improving cognition in individuals with early, mild impairments, or delaying/preventing the onset of HAND
· The goal of the present study was to determine whether individuals
METHODS
Participants
· 79 HIV-infected individuals in Pune, India with a CD4 cell count > 350/mm3 were recruited from HPTN 052, a randomized
clinical trial to examine whether early treatment might reduce HIV transmission rates to partners (Table 1)
· Exclusion criteria consisted of head injury with loss of consciousness greater than 30 minutes, neurologic disorder not
related to HIV infection, other infections that can affect the CNS, current or past psychotic disorder, significant substance
use, current active infection
Procedures
· Participants were randomly assigned to either the ART (treated) or control (non-treated group as part of their HPTN 052 protocol
· All participants completed a full NP battery, translated into Marathi, at baseline and a 1-year follow-up. NP performance was summarized using unadjusted mean scaled scores, based upon a large normal control sample from Pune
Neuropsychological Test Battery
Abstraction/Executive Functioning (Wisconsin Card Sorting Test (64-item), Color Trails 2, Stroop Color Word Test,
Halstead Category Test); Attention/Working Memory (PASAT, Spatial Span), Learning/Delayed Recall (Hopkins Verbal Learning Test - Revised, Brief Visuospatial Memory Test - Revised), Fluency (Word Sound, Animal, Action), Speed of Information Processing (Digit Symbol, Symbol Search, Trailmaking Part A, Color Trails 1), Motor (Grooved Pegboard)
Statistical Analyses
Mixed model linear regression with subjects treated as a random effect was used to identify estimators of neuropsychological performance. After "forcing" treatment group, time from baseline, and ART exposure at baseline into a model, viral load, baseline CD4, baseline impairment, CDC stage, gender, age, baseline global mean scaled score, and their interaction with the forced variables, were entered individually. Significant and forced variables, including main effects for significant interactions, were combined, and those that remained significant in combination were retained in the final model.
RESULTS
· The two groups were similar with respect to age, education, gender, and disease stage, and had comparably high current CD4 cell counts
· At baseline, the Treated group had a higher mean scaled score than the Untreated group
· On average, participants started treatment on the day they were tested (median days between testing and treatment = 0 [-12, 1])
· At the time of follow-up assessment, participants who started treatment were on 3TC/EFV/ZDV (n = 24), 3TC/D4T/EFV (n= 6), 3TC/ATV/ZDV (n = 3), and EFV/FTC/TFV (n = 2)
· All participants in the Treated group attained virologic suppression by their second visit
· In a multivariable model, improvement in mean scaled score was predicted by its baseline value (p=0.002) and its
interaction with group (p = 0.02)
· Treated participants with the lowest baseline mean scaled scores demonstrated the most improvement (Figure 1)
· For both groups, improvement was greater over longer durations when global mean scaled score is low but remains essentially stable for higher baseline mean scaled scores (p < 0.01)
· Whether the participants in the Treated group started treatment prior to baseline was not a significant predictor
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