Antiretroviral therapy use, HIV RNA, and CD4+ cell counts through follow-up
Participants were followed for a mean of 3.4 years (range 0.2–5.4 years). By design, ART use differed substantially between treatment groups. In the immediate ART group, 291 (93.1%) of participants started ART within 2 months of randomization, and 92.8% or more used ART at any follow-up visit (Fig. 2a). In the deferred ART group, 11.9, 34.8, 56.7, and 70.8% were using ART at months 12, 24, 36, and 48, respectively (Fig. 2a). ART was used for 94.2% of follow-up time accrued in the immediate group, and for 31.8% in the deferred group (Fig. 2b). During the first year, ART was used for 91.5% of follow-up time in the immediate group compared with 4.4% in the deferred group.
Differences in ART use between the groups were reflected in the HIV RNA and CD4+ levels. For almost all participants, viral load was suppressed while using ART (Fig. 2a). Through follow-up, mean CD4+ cell counts were higher in the immediate ART group, by 226 cells/μl (95% CI 201–250, P < 0.001) (Fig. 2c). Mean CD4+ cell counts at ART commencement were 676 and 411 cells/μl in the immediate and deferred ART groups, respectively.
Neuropsychological test performance through follow-up
The trajectories for mean change in QNPZ-8 in the immediate and deferred ART groups were almost identical; mean QNPZ-8 scores increased substantially from baseline through month 12, by 0.22 and 0.24, respectively (P < 0.001 each for increase), and remained stable afterwards (Fig. 3a, and Supplemental Appendix, Table S2A, http://links.lww.com/QAD/B233). There was no difference between treatment groups in change in QNPZ-8 from baseline through follow-up [estimated difference −0.02 (95% CI −0.06 - 0.03, P = 0.44)], or from baseline to any of the follow-up visits (Fig. 3, and Supplemental Appendix, Table S2A, http://links.lww.com/QAD/B233).
When considering individual tests, we found no difference between treatment groups for seven of the eight tests (P = 0.08–0.94 for comparing mean change in z-scores through follow-up; Fig. 3b, and Supplemental Appendix, Tables S2B-I, http://links.lww.com/QAD/B233). For the Digit Symbol test, while performance increased in both arms, the z-score increase was lower in the immediate ART group, with an estimated treatment difference through follow-up of −0.12 (95% CI −0.21 to −0.04, P = 0.005) favouring the deferred ART group (Supplemental Appendix, Table S2D, http://links.lww.com/QAD/B233).
The pattern of an initial marked increase in z-scores through month 12 in both treatment groups was apparent for the Grooved Pegboard, Color Trails 1 and 2, and WAIS Digit Symbol tests. z-scores for the HVLT-R Learning test also increased over time. For Semantic Verbal Fluency, only the treatment difference, but not the overall increase or decrease from baseline could be estimated because z-scores for this test were standardized to zero at each follow-up visit to account for the different test versions used at different study visits.
Sensitivity analyses showed similar results, when comparing treatment groups through month 12 only (Supplemental Appendix, Tables S2A-I, http://links.lww.com/QAD/B233), and when excluding participants who did not start ART within the first year in the immediate ART group and censoring follow-up at ART initiation in the deferred group (Supplemental Fig. S1, http://links.lww.com/QAD/B234).
The prevalence of NCI (not corrected for practice effect at follow-up) and changes in mean GDS are shown in the Supplemental Appendix, Tables S3 and S4, http://links.lww.com/QAD/B233, respectively; there was no evidence for a difference between treatment groups.
There was no difference between treatment groups regarding change in continuous CES-D scores, estimated difference −0.59 (95% CI −1.63 to 0.45, P = 0.27) for longitudinal comparison (Supplemental Appendix, Table S5, http://links.lww.com/QAD/B233). Depression prevalence (CES-D ≥16) was similar in both groups (P = 0.21; Supplemental Appendix, Table S6, http://links.lww.com/QAD/B233).
Figure 4 illustrates treatment differences for the change in QNPZ-8 across several subgroups; of these, subgroup analyses by age, education, baseline HIV RNA, baseline QNPZ-8, prespecified ART regimens, and CPE score were defined a priori. We analysed 24 subgroup factors, listed in the footnote to Fig. 4.
Among participants whose prespecified regimens included efavirenz, the deferred ART group improved their QNPZ-8 score slightly more than the immediate group, estimated mean difference −0.05 (95% CI −0.10 to −0.00). In contrast, among participants with other prespecified ART, the immediate arm showed greater improvement in their QNPZ-8 scores than the deferred arm, estimated difference 0.11 (95% CI 0.01–0.20; P = 0.004 for heterogeneity of the treatment effect; Fig. 4). Importantly, participants who were prespecified ART without efavirenz differed from those who were prespecified efavirenz in several characteristics that may impact upon neurocognitive test performance, including a higher prevalence of prior psychiatric diagnoses (20.6 versus 4.9%) and depression (CES-D score ≥16, 43.3 versus 28.6%; Supplemental Appendix, Table S7, http://links.lww.com/QAD/B233).
Additionally, the treatment difference between the immediate and deferred groups varied across subgroups by baseline QNPZ-8 scores (P < 0.001 for heterogeneity) and by the baseline global deficit score (P = 0.004). There was no evidence for a difference in mean QNPZ-8 change between the immediate and deferred ART groups within any of the investigated subgroups, however, except for the subgroup of participants who were not prespecified EFV (Fig. 4).
The START Neurology substudy is the largest controlled clinical trial to evaluate the impact of ART on neurocognitive performance among HIV-positive individuals with CD4+ cell counts greater than 500 cells/μl. We found no difference in the change in neuropsychological test performance when comparing immediate versus delayed ART in previously untreated, HIV-positive adults with CD4+ cell counts above 500 cells/μl. Thus, the study's hypothesis that immediate versus delayed ART would have a favourable effect on neurocognitive performance was refuted. As a corollary, we found that early ART neither benefits nor harms neurocognitive performance.
Why was there no beneficial effect of immediate ART on neurocognitive performance, given that benefit has been reported in previous studies [7–9]? This study was well powered to detect a modest treatment difference. There was no difference between the outcomes in the two arms evaluated either by intent-to-treat or in sensitivity analyses. During the first year, ART was used for 91.5% of the follow-up time accrued in the immediate group, compared with 4.4% in the deferred group, and undetectable HIV-RNA levels were observed on ART; therefore, the study's finding could not be explained by ineffective ART, or poor adherence.
It is highly likely that practice effect influenced the sharp, near-identical increase in aggregate test performance (QNPZ-8) in both study arms through month 12. Practice effect occurs following the repeated administration of neuropsychological tests and is well documented [23,24], but often ignored in Neuro-HIV studies . The trajectories we observed are similar to those seen with repeated testing in healthy persons, or in HIV-positive persons who are clinically stable on ART . Of note, participants in both study arms achieved the same incremental improvement in QNPZ-8 from baseline to year 1, and the improvement was orders of magnitude larger than any differences between the immediate and deferred ART groups. In previous Neuro-HIV studies that reported beneficial effects of ART, all participants started ART at study entry, there was no control group of delayed ART, no adjustment for practice effect, and the observed improvement in test performance was attributed to ART [7–9]. Our findings contradict conclusions drawn from uncontrolled prospective studies and underline the importance of a control arm in studies assessing neurocognitive test performance over time.
The likeliest biological explanation for the observed lack of effect of immediate ART is that there was little HIV-induced neural injury in our study population, despite the presumed presence of HIV in CSF and local inflammation within at least some of the participants. Study participants were young, urban, educated, mostly employed, and without rapid immune progression; these factors may have afforded neuropsychological protection against the effect of HIV, and as a result neuropsychological performance was not remediated by immediate ART.
With respect to the possibility that ART may have contributed to CNS toxicity, and hence abrogated any possible benefit of immediate ART, use of ART regimens with high CNS penetration effectiveness scores neither benefitted, nor disadvantaged either treatment group. Similarly, with respect to the potential toxicity from efavirenz, those participants whose prespecified ART regimen did not include efavirenz had slightly greater neuropsychological improvement in the immediate versus the deferred group. However, comparing efavirenz to other ART is based on a nonrandomized analysis that needs to be interpreted cautiously, as those participants who were prespecified efavirenz differed markedly from those prespecified other ART.
It is possible that immediate ART in individuals with high CD4+ cell counts protects neural health in ways that were not captured by the neurocognitive tests used in this study, or that will only manifest in a delayed fashion. For example, early treatment might reduce or stop expansion of the CNS HIV reservoir, potentially resulting in longer-term benefit . Other measures of ongoing neural injury, including CSF or blood biomarkers such as neurofilament light chain (NFL) [28–30] or neuroimaging modalities , may eventually prove to be more sensitive and robust than the neurocognitive test performance. On the other hand, in the absence of confounding conditions, neurocognitive performance has been the evaluation and diagnostic standard for assessing the impact of HIV on CNS functional integrity [32,33], and was not appreciably altered by early compared with delayed therapy in this study.
The study's chief strengths were its randomized design, the large sample size, and the standardized test battery administration. There were several limitations. First, mean follow-up was 3.4 years and, plausibly, an ART effect could emerge after longer treatment duration. Notwithstanding, there was no evidence for a divergence of treatment arms in the study's later years. Second, the test battery was limited to eight neuropsychological tests. However, the battery constitutes tests shown to be highly correlated with cognitive performance on a larger battery . Lastly, we have not measured biomarkers of neural injury or the size of the HIV reservoir in cerebrospinal fluid.
In conclusion, we observed a striking improvement of test performance during the first year in both study arms, which underlines the need for a control group in studies assessing neurocognitive test performance over time. The parent START study showed that immediate ART significantly decreases risk of serious AIDS and non-AIDS conditions, leading to the 2015 WHO recommendation that all HIV-positive individuals should initiate ART irrespective of CD4+ cell counts . However, the START Neurology substudy shows neither benefit, nor harm of early ART with respect to neurocognitive performance in individuals with CD4+ cell counts above 500 cells/μl.
This article is dedicated to the memory of Mollie Poehlman-Roediger, our kind and joyful colleague who worked with us closely on this project and who is greatly missed. Vale.
The authors wish to acknowledge and thank the study participants.
START Neurology Substudy Credit Roster
International Coordinating Centers
Copenhagen: P.O. Jansson.
London: A.G. Babiker, A. Arenas-Pinto, N. B-Atako, E. Dennis, S. Forcat, F. Hudson, B. Jackson, C. Purvis, C. Russell.
Sydney: S. Emery, C. Carey, M. Clewett, S. Jacoby.
Washington: B. Standridge, A. Sanchez, M.J. Vjecha.
Site Investigators by Country by Enrollment (n = number of participants enrolled)
Brazil (n = 169)
Projeto Praça Onze Pesquisa em Saúde (n = 102): S.R. Telles, N.N. Tebet.
Instituto de Infectologia Emílio Ribas – IIER (n = 67): A.C.P. Oliveira, M.R.P. Gascon.
Thailand (n = 89)
Chulalongkorn University Hospital (n = 68): K. Ruxrungtham, S. Gatechompol.
Khon Kaen University, Srinagarind Hospital (n = 21): P. Chetchotisakd, S. Anunnatsiri.
Site Coordinating Center: A. Avihingsanon, P. Rerksirikul.
United States (n = 88)
Denver Public Health (n = 17): J. Scott, E. Gardner.
Regional Center for Infectious Disease (n = 12): K. Epperson, C. Van Dam.
UNC AIDS Clinical Trials Unit (n = 11): M.R. Chicurel-Bayard, D. Currin.
Virginia Commonwealth University (n = 11): V. Watson, D.E. Nixon.
The R & E Group at the Portland VA Research Foundation (n = 8): M.D. Murphy, S.M. Sweek.
Bronx-Lebanon Hospital Center (n = 7): R. Cindrich, M. Vasco.
Naval Medical Center San Diego (n = 7): M.F. Bavaro, S.J. Echols, B.K. Agan.
San Antonio Military Health System (n = 6): J.F. Okulicz, T.J. Sjoberg.
Wayne State University (n = 4): M. Farrough, R. MacArthur.
Wake County Human Services (n = 2): C. Kronk, J. Jackson.
(Closed sites not included)
Belgium (n = 59)
Centre Hospitalier Universitaire St. Pierre (C.H.U. St. Pierre; n = 30): K. Kabeya, V. Lenoir.
Institute of Tropical Medicine (n = 29): M. van Frankenhuijsen, L. van Petersen.
United Kingdom (n = 48)
St. Mary's Hospital (n = 19): B. Mora-Peris, A. DelRosario.
Barts and the Royal London (n = 12): C. Orkin, J. Hand.
Chelsea and Westminster Hospital, London (n = 12): B. Gazzard, C. Higgs.
St. Thomas’ Hospital (n = 5): J. Fox, A. Sharp.
Argentina (n = 46)
FUNCEI (n = 22): G. Lopardo, G.L. Copertari.
Hospital General de Agudos JM Ramos Mejia (n = 15): M.H. Losso, J. Bruguera.
Hospital Rawson (n = 9): D. Daniel, A. Crinejo.
Site Coordinating Center: G.R. Loria, M.L. Doldan, A. Moricz.
Chile (n = 38)
Fundación Arriarán: M. Wolff, G. Allendes.
Germany (n = 24)
Klinik I für Innere Medizin, Klinikum der Universität zu Köln (n = 14): C. Lehman, C. Wyen.
Medizinische Universitätsklinik - Bonn, Immunologische Ambulanz CRS (n = 6): J. Rockstroh, C. Schwarze-Zander.
Johann Wolfgang Goethe - University Hospital, Infektionsambulanz CRS (n = 4): C. Stephan, T. Wolf.
Australia (n = 23)
The Alfred Hospital (n = 11): J. Hoy, J. Costa.
St Vincent's Hospital Sydney (n = 10): D.A. Cooper, K. MacRae.
Sexual Health and HIV Service - Clinic 2 (n = 2): D. Rowling, E. Warzywoda.
Site Coordinating Center: S. Emery, C. Carey, M. Clewett, S. Jacoby.
Switzerland (n = 14)
University Hospital Zurich (n = 9): N. Müller, M. Rizo-Oberholzer.
Bern University Hospital (n = 5): H. Furrer, M. Lacalamita.
Italy (n = 10)
IRCCS San Raffaele, Milan: P. Cinque, F. Ferretti.
The complete list of START investigators can be found at N Engl J Med 2015; 373:795–807.
Research in Context
Evidence before this study: In advanced, untreated Human Immunodeficiency Virus type 1 (HIV-1) infection, 15–20% of individuals develop HIV-associated dementia (HAD). Combination antiretroviral therapy (ART) improves neuropsychological performance in 40–60% of individuals with HAD. In acute HIV-1 infection, mild neurological manifestations occur in up to 50% of individuals and clinical resolution is usually observed with immediate ART. However, it is unclear if such benefit occurs in HIV-positive individuals with high CD4+ cell counts and whether any benefit might be counteracted by potential ART toxicities, which have been reported in individuals receiving ART regimens that have high penetration into the brain.
Added value of this study: We undertook a Neurology substudy within the Strategic Timing of Antiretroviral Treatment (START) study. The START Neurology substudy which enrolled 608 participants is the largest clinical trial to date to evaluate the impact of ART on neurocognitive performance in HIV-positive, ART-naive individuals with greater than 500 cells/μl. Our study found that participants randomized to commence ART immediately versus deferring ART until CD4+ less than 350 cells/μl did not experience either benefit or harm with respect to their neurocognitive performance, during a mean follow-up period of 3.4 years. ART regimens with high brain penetration did not benefit or advantage either treatment group. Importantly, we observed a marked improvement in neurocognitive test performance in both study arms during the first 12 months, strongly suggesting a practice effect.
Implications of all the available evidence: Our finding suggests that there was minimal underlying neurological damage that could be either prevented or reversed by immediate ART in this study population. The START parent study showed that immediate versus deferred ART decreases the risk of serious AIDS and non-AIDS illnesses by 57%. These pivotal findings led to the 2015 World Health Organization recommendation that all HIV-positive individuals should initiate ART irrespective of CD4+ cell counts, and the START Neurology substudy findings support the safety of initiating ART with respect to neurocognitive performance. Our study also underlines the importance of having a control arm in intervention studies that evaluate neurocognitive test performance over time.
Funding: The parent START study was supported by the National Institute of Allergy and Infectious Diseases (United States), Agence Nationale de Recherches sur le SIDA et les Hipatites Virales (France), National Health and Medical Research Council (Australia), National Research Foundation (Denmark), Bundesministerium für Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and the University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Additionally, the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke (United States) specifically funded the START Neurology substudy.
NIH grants: UM1-AI068641 and UM1-AI120197, NINDS/NIMH (funding provided via START NIH grant).
Role of authors: E.J.W., R.W.P., K.R., B.B., and B.G. designed the study, E.J.W., B.G., and R.W.P. wrote the first draft of the manuscript, B.G., G.C., and M.P.R. analyzed the data. E.J.W., K.R., L.C., B.B., M.V., A.P.d.O., B.S., A.A., E.F., J.L., A.A.P., N.M., A.W., L.L., and R.W.P. enrolled participants, performed training, and/or supervised implementation of the study. All co-authors critically reviewed the manuscript.
Conflicts of interest
There are no conflicts of interest.
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