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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0000000000000016

Can antiretroviral therapy prevent HIV-associated cognitive disorders?

Winston, Alana , b; Vera, Jaime H.a , b

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aFaculty of Medicine, Department of Medicine, Imperial College London, St Mary's Hospital Campus

bDepartment of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust, London, UK

Correspondence to Dr Alan Winston, Clinical Reader and Consultant Physician, Clinical Trials, Ground Floor Winston-Churchill Wing, St. Mary's Hospital, Praed Street, London W2 1NY, UK. Tel: +44 203 312 1603; fax: +44 203 312 6123; e-mail:

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Purpose of review: In general, the initiation of combination antiretroviral (cART) is associated with improvement in cognitive function. However, the impact of cART has on cognitive function in neurologically asymptomatic HIV-infected individuals initiating therapy at high CD4+ lymphocyte cell counts is unknown.

Recent findings: Cognitive function impairment remains prevalent despite effective cART. Several clinical risk factors for this condition have been described, including low nadir CD4+ lymphocyte cell count which may be associated with greater neuroinflammatory process, a potential pathogenic mechanism underlying this cognitive impairment. The earlier initiation of antiretroviral therapy could theoretically avoid this risk factor and limit the degree of neuroinflammation. On the converse, the earlier initiation of cART may be associated with the development of neuronal toxicities.

Summary: This review article highlights the recent literature and arguments for and against the earlier initiation of cART with regards to cognitive function.

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The advent of effective combination antiretroviral (cART) therapy has led to dramatic reductions in the incidence and prevalence of HIV-associated central-nervous-system (CNS) opportunistic-infections [1] and other AIDS-defining illnesses such as HIV-encephalopathy [2]. With the development of cART regimens with reduced toxicity and increased tolerability, the incidence of these conditions continues to decline [3].

Despite these advances, milder forms of HIV-associated cognitive impairment are reported to persist. Clinically significant cognitive function impairment has been reported in approximately 10–15% of effectively treated HIV-infected individual within cohorts worldwide [4–6]. Although higher prevalence rates of cognitive impairment in up to 50% of individuals has been described in recent times [7,8], these reports may be overestimations because of the analysis of cohorts including individuals not receiving effective cART and cohorts which included individuals who were otherwise asymptomatic who under-performed on formal cognitive testing wherein control data-sets were unavailable to interpret such findings [9,10]. Incidence rates are also high with the onset of de-novo cognitive symptomatology reported in 22% of individuals with clinical risk factors annually [11].

This cognitive decline is of clinical relevance. Typically, the domains of memory, attention and information processing are affected with the clinical consequences being reduced quality of life [12], reduced functioning on activities of daily living [13] and even increased mortality [14]. Furthermore, HIV-associated cognitive impairment may undermine sustained adherence to lifelong cART, jeopardizing both the long-term effectiveness of treatment for the individual and the prevention of onward HIV transmission.

Several underlying pathogenic mechanisms for this condition have been proposed, and many clinical risk factors have been identified. One important clinical risk factor is an individual's CD4+ lymphocyte count at nadir [15]. This had led to the hypothesis that the avoidance of low nadir CD4+ lymphocyte count, by commencing cART at an earlier stage of HIV-disease, could lead to a reduced incidence of HIV-associated cognitive impairment. In this review article, we firstly summarize some of the proposed pathogenic mechanisms that may underlie this condition with the associated clinical risk factors, and then in detail outline the impact of antiretroviral therapy in differing stages of HIV-disease.

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Numerous pathogenic mechanisms have been implicated with the development of cognitive impairment in the cART era. These include on-going neuroinflammation despite effective cART, antiretroviral factors and general patient factors such as other comorbidities, coinfections and lifestyle factors Table 1.

Table 1
Table 1
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The main effectors of immune responses and inflammatory processes with the CNS are microglia, which constitutes approximately 10% of the entire brain cell population. Compelling evidence exists suggesting that activation of microglial cells which leads to neuroinflammation plays an important role in HIV-associated brain disease.

Prior to the advent of effective cART, in individuals with frank HIV-encephalopathy, increased microglial activation was demonstrated on postmortem examination [16] and utilizing PET imaging in which ligands which bind to activated microglial cells can be visualized in vivo [17]. More recently, microglial activation has also been reported in cART era, again both on postmortem examination in in vivo. The ‘Edinburgh Brain Banks’ group have described microglial activation to be present in effectively treated HIV-infected individuals deceased from non-AIDS and non-CNS-related diseases suggesting neuroinflammation is on-going despite cART [18]. PET imaging supports these findings with increased binding of PET-ligands which adhere to activated microglial cells in effectively treated HIV-infected individuals with mild forms of cognitive impairment and in those without any evidence of cognitive disease [19].

Furthermore, cerebrospinal-fluid (CSF) biomarker studies measuring concentrations of inflammatory markers produced by activated microglia have revealed that despite a reduction in the level of intrathecal immune activation observed with cART, significant on-going inflammation activity is evident [20]. Letendre et al. [21] measured the concentration of three inflammatory chemokines macrophage inflammatory protein-1α (MIP-1α), RANTES (regulated on activation, normal T cell expressed and secreted) and MIP-β in 73 HIV-infected individuals and reported increased concentrations of all three biomarkers in the CSF of individuals with HIV-associated cognitive impairment compared with individuals without cognitive impairment. A prospective study looking at the effects of 12 weeks of cART on changes in immune-markers in 12 patients with cognitive impairment, demonstrated a reduction in MIP-1α and RANTES following the initiation of cART [22]. Other markers studied include IP-10 [23] and S100β [24] in which increased concentrations in HIV-infected individuals with either more advanced or more rapidly progressive cognitive impairment have been reported. The literature in this field includes many studies reporting differences in both blood CSF biomarkers in HIV-infected individuals on effective cART compared with HIV-uninfected individuals and differences in such biomarkers in HIV-infected individuals with cognitive impairment. Overall, the data suggest that patients with HIV-associated cognitive disorders tend to have higher levels of inflammatory blood and CSF biomarkers.

An individual's CD4+ lymphocyte count nadir is a marker of historical HIV-disease progression and a well described risk factor for the presence of cognitive impairment in many cohorts [4,10,15,25]. On the converse, for individuals on effective antiretroviral therapy, current CD4+ lymphocyte count has not been reported to be a strong risk factor for the presence of cognitive impairment. This may be due to HIV-disease progression, whereby as HIV-disease progresses, increased peripheral and CNS immune activation occurs. It is possible this process may persist despite effective cART and be a potential explanation for the strong clinical correlation observed between nadir CD4+ lymphocyte count and cognitive function, in which individuals with lower nadir CD4+ lymphocyte counts are more likely to display poorer cognitive function, despite higher CD4+ lymphocyte counts after effective cART.

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Many comorbidities and lifestyle factors have been associated with higher rates of cognitive impairment. Comorbidities such as cardiovascular disease and diabetes [26,27] are among the strongest predictors of cognitive function impairment within the Strategic Management of ART study, one of the largest HIV-treatment studies to date. Such noncommunicable comorbidities are reported to be highly prevalent in treated HIV-infected individuals and may potentially increase prematurely with ageing [28]. Therefore, within ageing HIV-infected populations, the presence of cognitive impairment could increase exponentially over time.

Coinfections are also important risk factors for cognitive impairment. HIV-infected individuals coinfected with chronic viral hepatitis-C infection have an increased risk of cognitive impairment compared to those infected with HIV alone [29]. Similarly, poorer cognitive function has been described in HIV-infected individuals with higher cytomegalovirus antibody concentrations and those with past history of syphilis infection [30,31]. It is possible that these coinfections are associated with increased neuroinflammatory responses and nervous system injury.

Lifestyle factors such as cigarette smoking, recreational drug and alcohol use are also reported to be highly prevalent in HIV-disease as are diagnoses of depressive symptoms, which may further fuel the incidence of this condition. Not only may these clinical risk factors themselves directly affect cognitive function (for instance, recreational drug-use), these may also contribute to the pathogenesis of other diseases leading to cognitive decline (for instance, cardiovascular disease contributing to vascular dementia). Moreover, the presence of these conditions may also lead to increased peripheral inflammatory responses [32], which could in turn also lead to neuroinflammation [33].

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On a population level, there is compelling evidence to suggest cART is beneficial with regards to cognitive function. The incidence of severe HIV-associated brain disease fell dramatically with the advent of effective cART and continues to decline with the development of regimens with reduced toxicity [3], and moreover cognitive function improves in HIV-infected individuals commencing cART for the first time [34,35].

A further hypothesis underlying the observed cognitive impairment in the cART era is inadequate of antiretroviral agents in the CNS compartment. A great amount of recent attention has focused on this hypothesis, which assumes that although cART regimens may suppress HIV-viraemia in the plasma compartment, the efficacy of viral suppression in the CNS compartment may not be optimal. This thinking has led to scorning systems, whereby antiretroviral agents are graded based on their pharmacokinetic properties with agents with greater potential exposure in the CNS having greater scores [36]. However, there is no conclusive evidence that different cART regimens with different pharmacokinetic properties are associated with differences in cognitive function [37]. Separate consideration should be given to cases of ‘cerebro-spinal-fluid (CSF) viral escape’, in which suppressive control of HIV RNA in the CNS is lost. This rare condition, distinct from HIV-associated cognitive impairment, is often promptly diagnosed, as symptoms are overt and generally responds to modifying cART following HIV-resistance testing [38].

On the converse, cerebral toxicities may ensue after the initiation of cART, which may cause cognitive decline. Laboratory studies suggest that many of the antiretroviral agents in current clinical use may have neuronal toxicities, even at the concentrations one would expect to observe in the CNS during general clinical usage [39]. In this study, cultured rat cortical neurones were challenged with several antiretroviral agents in current clinical use such as abacavir, efavirenz, etravirine, nevirapine and atazanavir within the range of concentrations one would expect to observe in plasma and CSF with standard clinical dosing. The study described a considerable loss of neurones caused by alterations of the neuronal calcium homeostasis and mitochondrial membrane potentials suggesting one possible mechanism for neuronal injury may be due to antiretroviral therapy itself.

Clinical data describing cerebral toxicities from antiretroviral therapy are sparse, however, knowledge in this field is expanding [40]. Cerebral imaging studies suggest toxicities may be present and are associated with the duration [41] or number [42] of nucleoside-reverse-transcriptase-inhibitor agents used within a cART regimen, which may be markers of mitochondrial toxicity. Clinical data regarding specific drug-toxicities are also starting to emerge. Within cohort studies, efavirenz use has been associated with poorer cognitive function [43] and switching from this agent associated with improvements in CNS-symptomatology [44].

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Current guidelines recommend the initiation of antiretroviral therapy in all HIV-infected individuals with clinically overt cognitive-symptomatology, which is considered related to HIV-disease regardless of CD4+ lymphocyte count [45].

However, could the early initiation of antiretroviral therapy, prior to current guidelines recommendation based on CD4+ lymphocyte count be beneficial to cognitive function in cognitively asymptomatic HIV-infected individuals? When considering this, several of the above principles should be taken into consideration.

First, the earlier initiation of antiretroviral therapy would avoid HIV-infected individuals obtaining low nadir CD4+ lymphocyte, and therefore avoiding this risk factor. However, one also needs to consider that this is a risk factor described within clinical cohorts and although this may be linked to increased neuroinflammation and other pathogenic mechanisms associated with the development of cognitive impairment, cohort biases should also be taken into consideration. If one considers two HIV-infected individuals, one with a very low nadir CD4+ lymphocyte count and one with a high nadir CD4+ lymphocyte count then these individuals general phenotypes could be quite different. The underlying reasons that one individual has developed a low nadir CD4+ lymphocyte may include late HIV-disease presentation, greater risk-taking behaviour and general poorer engagement with healthcare services. Therefore, this individual may inherently have poorer cognitive function rather than this being directly related to HIV-disease, and as such the earlier initiation of antiretroviral therapy may have little if any impact on cognitive function.

Secondly, the earlier initiation of antiretroviral therapy would allow individuals to benefit from the effects of cART on cognitive function at an earlier stage. However, again on the converse, such a strategy would expose individuals to the potential cerebral toxicities of antiretroviral therapy for a longer duration of time and from an earlier stage of HIV-disease.

Therefore, there remains equipoise regarding the role of commencing cART in neurologically asymptomatic individuals with high CD4+ lymphocyte counts. A neurology sub-study with the Strategic Timing of Antiretroviral Therapy study; Identifier NCT00867048 is assessing the impact of the earlier initiation of cART on cognitive function. In this study, individuals with CD4+ lymphocyte counts above 500 cells/ul are randomized to immediate cART or deferred cART (until CD4+ lymphocyte counts falls below 350 cells/ul) with prospective cognitive function assessed during the study period. Results from this study may definitively answer the above conundrum regarding the impact of the earlier initiation of cART on cerebral function.

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Since the advent of effective cART, controversy has existed regarding the optimal timing for initiation of this therapy. This controversy continues, with the impact of cART on comorbidities, an important current consideration. With regards to cognitive function impairment, although cART has shown beneficial effects in individuals with symptomatic cognitive decline and in individuals commencing cART for the first time, the impact of cART has on cognitive function in asymptomatic individuals with high CD4+ lymphocyte counts remains unknown.

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All authors are grateful to the NIHR Biomedical Facility at Imperial College London for infrastructure support.

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Conflicts of interest

A.W. holds grants from the British Medical Research Council and the European Union (Framework 7).

A.W. has received honoraria or research grants, or been a consultant or investigator, in clinical trials sponsored by Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Cilag, Roche, Pfizer and ViiV Healthcare.

J.H.V. is a recipient of a Wellcome Trust Translational Medicine and Therapeutics Fellowship.

J.H.V. has received honoraria by Merck, Janssen Cilag and sponsorship to attend scientific conferences from Janssen Cilag and Gilead Sciences and AbbVie.

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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1. d’Arminio Monforte A, Cinque P, Mocroft A, et al. Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol 2004; 55:320–328.

2. Dore GJ, Correll PK, Li Y, et al. Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 1999; 13:1249–1253.

3. Garvey L, Winston A, Walsh J, et al. HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era. Eur J Neurol 2011; 18:527–534.

4. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 2010; 24:1243–1250.

5. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69:1789–1799.

6. Dore GJ, McDonald A, Li Y, et al. Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 2003; 17:1539–1545.

7. Heaton RK, Franklin DR, Ellis RJ, et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 2011; 17:3–16.

8. Robertson KR, Smurzynski M, Parsons TD, et al. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 2007; 21:1915–1921.

9. Gisslen M, Price RW, Nilsson S. The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence? BMC Infect Dis 2011; 11:356.

10. Garvey L, Surendrakumar V, Winston A. Low rates of neurocognitive impairment are observed in neuro-asymptomatic HIV-infected subjects on effective antiretroviral therapy. HIV Clin Trials 2011; 12:333–338.

11. Heaton R, Franklin D, Woods S, et al. Asymptomatic Mild HIV-associated Neurocognitive Disorder Increases Risk for Future Symptomatic Decline: A CHARTER Longitudinal Study In: 19th Conference on Retroviruses and Opportunistic Infections. Seattle, WA: 2012. p. abstract 77.

12. Tozzi V, Balestra P, Galgani S, et al. Neurocognitive performance and quality of life in patients with HIV infection. AIDS Res Hum Retroviruses 2003; 19:643–652.

13. Morgan EE, Woods SP, Grant I. Intra-individual neurocognitive variability confers risk of dependence in activities of daily living among HIV-seropositive individuals without HIV-associated neurocognitive disorders. Arch Clin Neuropsychol 2012; 27:293–303.

14. Tozzi V, Balestra P, Serraino D, et al. Neurocognitive impairment and survival in a cohort of HIV-infected patients treated with HAART. AIDS Res Hum Retroviruses 2005; 21:706–713.

15. Ellis RJ, Badiee J, Vaida F, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 2011; 25:1747–1751.

16. Fischer-Smith T, Croul S, Adeniyi A, et al. Macrophage/microglial accumulation and proliferating cell nuclear antigen expression in the central nervous system in human immunodeficiency virus encephalopathy. Am J Pathol 2004; 164:2089–2099.

17. Hammoud DA, Endres CJ, Chander AR, et al. Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS. J Neurovirol 2005; 11:346–355.

18. Anthony IC, Ramage SN, Carnie FW, et al. Influence of HAART on HIV-related CNS disease and neuroinflammation. J Neuropathol Exp Neurol 2005; 64:529–536.

19. Garvey LJ, Pavese N, Politis M, et al. Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART; An 11C-PK11195 PET study. AIDS 2013; [Epub ahead of print].

20. Cinque P, Vago L, Mengozzi M, et al. Elevated cerebrospinal fluid levels of monocyte chemotactic protein-1 correlate with HIV-1 encephalitis and local viral replication. AIDS 1998; 12:1327–1332.

21. Letendre SL, Lanier ER, McCutchan JA. Cerebrospinal fluid beta chemokine concentrations in neurocognitively impaired individuals infected with human immunodeficiency virus type 1. J Infect Dis 1999; 180:310–319.

22. Monteiro de Almeida S, Letendre S, Zimmerman J, et al. Dynamics of monocyte chemoattractant protein type one (MCP-1) and HIV viral load in human cerebrospinal fluid and plasma. J Neuroimmunol 2005; 169:144–152.

23. Kolb SA, Sporer B, Lahrtz F, et al. Identification of a T cell chemotactic factor in the cerebrospinal fluid of HIV-1-infected individuals as interferon-gamma inducible protein 10. J Neuroimmunol 1999; 93:172–181.

24. Pemberton LA, Brew BJ. Cerebrospinal fluid S-100beta and its relationship with AIDS dementia complex. J Clin Virol 2001; 22:249–253.

25. Cysique LA, Letendre SL, Ake C, et al. Incidence and nature of cognitive decline over 1 year among HIV-infected former plasma donors in China. AIDS 2010; 24:983–990.

26. Fabbiani M, Ciccarelli N, Tana M, et al. Cardiovascular risk factors and carotid intima-media thickness are associated with lower cognitive performance in HIV-infected patients. HIV Med 2013; 14:136–144.

27. Wright EJ, Grund B, Robertson K, et al. Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. Neurology 2010; 75:864–873.

28. Negin J, Martiniuk A, Cumming RG, et al. Prevalence of HIV and chronic comorbidities among older adults. AIDS 2012; 26 (Suppl 1):S55–63.

29. Sun B, Abadjian L, Rempel H, et al. Differential cognitive impairment in HCV coinfected men with controlled HIV compared to HCV monoinfection. J Acquir Immune Defic Syndr 2013; 62:190–196.

30. Wallace MR, Heaton RK, McCutchan JA, et al. Neurocognitive impairment in human immunodeficiency virus infection is correlated with sexually transmitted disease history. Sex Transm Dis 1997; 24:398–401.

31. Gow AJ, Firth CM, Harrison R, et al. Cytomegalovirus infection and cognitive abilities in old age. Neurobiol Aging 2013; 34:1846–1852.

32. Duprez DA, Neuhaus J, Kuller LH, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One 2012; 7:e44454.

33. Hannestad J, Gallezot JD, Schafbauer T, et al. Endotoxin-induced systemic inflammation activates microglia: [(11)C]PBR28 positron emission tomography in nonhuman primates. Neuroimage 2012; 63:232–239.

34. Cysique LA, Vaida F, Letendre S, et al. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology 2009; 73:342–348.

35. Winston A, Puls R, Kerr SJ, et al. Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: a randomized, controlled study. HIV Med 2012; 13:245–251.

36. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 2008; 65:65–70.

37. Marra CM, Zhao Y, Clifford DB, et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 2009; 23:1359–1366.

38. Canestri A, Lescure FX, Jaureguiberry S, et al. Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis 2010; 50:773–778.

39. Robertson K, Liner J, Meeker RB. Antiretroviral neurotoxicity. J Neurovirol 2012; 18:388–399.

40. Kahouadji Y, Dumurgier J, Sellier P, et al. Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score. HIV Med 2013; 14:311–315.

41. Schweinsburg BC, Taylor MJ, Alhassoon OM, et al. Brain mitochondrial injury in human immunodeficiency virus-seropositive (HIV+) individuals taking nucleoside reverse transcriptase inhibitors. J Neurovirol 2005; 11:356–364.

42. Winston A, Duncombe C, Li PC, et al. Does choice of combination antiretroviral therapy (cART) alter changes in cerebral function testing after 48 weeks in treatment-naive, HIV-1-infected individuals commencing cART? A randomized, controlled study. Clin Infect Dis 2010; 50:920–929.

43. Ciccarelli N, Fabbiani M, Di Giambenedetto S, et al. Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology 2011; 76:1403–1409.

44. Waters L, Fisher M, Winston A, et al. A phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine. AIDS 2011; 25:65–71.

45. Williams I, Churchill D, Anderson J, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012. HIV Med 2012; 13 (Suppl 2):1–85.


antiretroviral therapy; antiretroviral toxicity; nadir CD4 cell count; neurocognitive function

© 2014 Lippincott Williams & Wilkins, Inc.


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