In the context of life-long combination antiretroviral therapy (cART) for people living with HIV (PLWH), long-term drug toxicities, adherence, costs and drug–drug interactions have prompted to look for treatment simplification strategies. Recently, specific two-antiretroviral-based regimens (dual therapy) proved to be noninferior compared with three-drugs therapies (triple therapy) in terms of viroimmunological control . Lacking experimental data, concerns regarding immune-activation, resistance-associated mutations (RAMs) selection and viral escape in anatomical reservoirs, such as lymph-nodes and central nervous system (CNS) have been raised [1–4]. HIV replication may persist in tissues of treated patients presenting undetectable viraemia and relates to local lower drug exposure as compared with plasma levels [4–7]. This raises the question whether switching to dual therapy can further increase the risk of virological escapes and impact persistent replicating viral reservoir, leading in turn to higher levels of immune-activation and inflammation-related comorbidities, including HIV-associated neurocognitive disorders (HAND). In this regard, clinical reports alerted about the risk of cerebrospinal fluid (CSF) viral escape (CVE) during dual therapy, but this message could have been distorted by publication bias and by the dual therapy used, which were not always supported by trials results [8,9]. Indeed, providing good adherence, CSF viral suppression seems to persist after switching to dual therapy . Among aviremic patients both AtLaS-M (Atazanavir and Lamivudine for treatment Simplification-Multicentric study) and SALT (Simplification to Atazanavir/Ritonavir + Lamivudine as Maintenance Therapy) trials have demonstrated that, comparing patients switching to dual therapy to those remaining in triple therapy, neurocognitive function is stable and similar up to 144 weeks [11,12]. Data from the neurocognitive sub-study of the NEAT001/ANRS143 trial (European AIDS Treatment Network 001/French National Agency for AIDS Research 143) on viremic patients starting first-line DRV/r + RAL vs. DRV/r + 2 nucleoside reverse transcriptase inhibitors (NRTIs) are awaited. Limitations of these studies were variably the short-term follow-up , the restricted neurocognitive battery adopted  or the significant loss of patients undergoing the neurocognitive evaluation during follow-up . Since HIV-related neuropathogenesis may not relate immediately and solely to uncontrolled viral replication within CNS and may arise after long periods of low-level tissue replication, other tools such as CSF biomarkers may be more accurate in detecting alterations at presymptomatic stages not yet evident at the neurocognitive assessment. On the other hand, archived RAMs and virus evolution in reservoirs during cART coupled with specific pharmacokinetic considerations in brain tissues may indicate that a surprising proportion of PLWH on triple therapy is actually on mono/dual functional therapies [7,13–15], undermining the preconceived superiority of triple therapy over well tailored dual therapy. Therefore, considering the unsolved concerns and the gaps between the ideal world of clinical trials and the reality of clinical settings, we have retrospectively analysed data of our Neuro-AIDS cohort consisting of more than 500 HIV-positive neurologically/neurocognitively symptomatic adult patients undergoing lumbar puncture for clinical and/or research reasons. Specifically, we have compared the virological control within CSF, several biomarkers of CNS functions and the neurocognition of patients presenting suppressed or low-level viraemia (LLV) and no other neurological confounding on dual therapy vs. triple therapy based on 2NRTIs and a third drug. Our primary objective was to assess whether dual therapy hold higher risk of CSF virological failure in such a clinical setting of high-risk adult patients. Our secondary aim was to evaluate whether dual therapy associate with a heavier burden of CSF inflammation, CNS injury and/or poorer neurocognition.
Study design and patients
We performed a retrospective cross-sectional study nested in ongoing prospective studies on HIV-related neurological/neurocognitive disorders (Prospective study on predictors of neurocognitive decline in HIV-positive patients PRODIN, Study of nasal brushing collected olfactory mucosa samples in the diagnosis of human encephalopathies SOLFAMU and Maraviroc-based treatment switch in HIV-positive patients with HAND: consequences of reducing antiretroviral-associated neurotoxicity MARANDX study, all approved by the local Ethics Committee). Data collected from PLWH undergoing lumbar puncture for clinical and/or research reasons at our centre (Infectious Diseases Clinic, Amedeo di Savoia hospital, Torino, Italy) from 2010 to February 2019 were retrospectively analysed. Inclusion criteria were as follows: age at least 18 years; being on any type of dual therapy or 2NRTIs-based triple therapy; being stably on the same cART regimen since at least 3 months before lumbar puncture; plasma HIV-RNA less than 200 copies/ml since at least 6 continuous months before lumbar puncture. Exclusion criteria were as follows: active/previous CNS infective, neoplastic, traumatic, vascular, inflammatory or neurodegenerative disorders; disclosure of substance or alcohol abuse within the last year from lumbar puncture; clinically relevant scores at the Beck Depression Inventory-II (≥30) or at the Hamilton Anxiety Rating Scale (≥25).
The neurocognitive battery consisted of Trail Making Test A for processing speed/reaction time, Trail Making Test B and Stroop Colour test for executive functioning, Digit Span forward, Digit Span backward and Digit Symbol for attention/working memory, Corsi test and Disyllabic Words Serial Repetition test for visuospatial and verbal short-term memory, Free and Cued Selective Reminding, Story Recall and Rey–Osterrieth Complex Figure Delayed Recall tests for verbal long-term memory and learning, Phonemic Verbal Fluency for language skills, Grooved Pegboard for Dominant/Nondominant hand test for motor skills and Rey–Osterrieth Complex Figure Copy test for visuoconstruction ability. Raw scores were converted to age-adjusted, sex-adjusted and education-adjusted normative t-scores in accordance with published manuals. HAND diagnosis was performed according to Frascati's criteria . Daily functioning impairment was assessed by the Instrumental Activities of Daily Living.
Cerebrospinal fluid analysis
Quantitative determination of intrathecal synthesis and blood–brain barrier (BBB) damage markers (CSF-serum albumin ratio CSAR, IgG index, intrathecal synthesis, Tourtelotte and Tibbling indices) were measured by immunoturbidimetric methods (AU5800; Beckman Coulter, Brea, California, USA) and calculated by Reibergram (Behring Nephelometer Analyser, Behringwerke AG, Marburg, Germany), as previously described . Reference values: CSAR less than 6.5 up to 40 years and less than 8.0 in patients aged above; IgG index less than 0.7; intrathecal synthesis 0%. CSF total tau (t-tau), phosphorylated tau (p-tau), β-amyloid1–42 (Aβ1–42), neopterin and S100β were measured by immunoenzymatic methods (Fujirebio diagnostics, Malvern, USA; R&D Systems Europe, Ltd. Abingdon, UK; DRG Diagnostics, Marburg, Germany; Diametra Srl, Spello, Italy). Reference values: t-tau less than 300 pg/ml in patients aged 21–50, less than 450 pg/ml in patients aged 51–70 and less than 500 pg/ml in older; p-tau less than 61 pg/ml; Aβ1–42 more than 500 pg/ml; neopterin less than 1.5 ng/ml; S100β less than 380 pg/ml. HIV-RNA was quantified by the Roche Amplicor assay v2.0 (Hoffman-La Roche, Basel, Switzerland) with a lower limit of quantification of 20 copies/ml. CNS penetration-effectiveness (CPE) score was derived from Letendre et al. and updated with approximation on similarities and preliminary data for newer drugs. CVE was defined as any case of CSF HIV-RNA 0.5 Log10 higher than plasma HIV-RNA or any case of detectable CSF HIV-RNA coupled with undetectable plasma HIV-RNA . Any plasma HIV-RNA determination between 20 and 200 copies/ml was defined as LLV.
Data were analysed using standard nonparametric statistical methods considering the variables distribution (Mann–Whitney, chi-squared and Fisher exact tests). Continuous variables were described as medians (interquartile ranges) and discrete variables were described as absolute number (percentage). The significance threshold to reject the null hypothesis was set at 5% (α = 0.05, two-tailed predictions). Bonferroni correction was applied when appropriate. Data analysis was performed using SPSS software for Windows (version 25.0; IBM Corp., Armonk, New York, USA).
A total of 97 patients met our inclusion criteria and were analysed. A total of 19 patients were on dual therapy and 78 on triple therapy. Dual therapies were as follows: 12 integrase inhibitors (INI) + boosted protease inhibitors (PI) (63.2%), three INI + nNRTI (15.8%), two boosted PI + nNRTI (10.5%) and two boosted PI + NRTI (10.5%). One started dual therapy as naïve, while the others (94.7%) switched from other regimens. Before starting dual therapy, 10 patients (52.6%) showed a plasma HIV-RNA less than 20 copies/ml, being the median plasma HIV-RNA among unsuppressed patients 33 copies/ml (22–690). The median time on dual therapy was 20 months (12–60), while the time spent on previous regimen was 27 months (16–44). Demographic and clinical data of the 19 patients on dual therapy are reported in details in Supplementary Fig. 1, https://links.lww.com/QAD/B773. Among triple therapy, 24 patients (30.8%) were on 2NRTIs + boosted PI and 27 (34.6%) on 2NRTIs + INI and 2NRTIs + nNRTI both. They were on the current triple therapy since 16 months (7–27) and spent 23 months (15–41) on previous regimens (79.5% coming from another triple therapy, 19.2% starting the current triple therapy as naïve and one from DRV/r + RAL).
Indications for lumbar puncture were as follows (the same patient may present more than one): neurological signs or symptoms (dual therapy: 12, 63.2%; triple therapy: 50, 64.1%), neurocognitive complaints (dual therapy: 8, 42.1%; triple therapy: 36, 46.2%), brain MRI abnormalities (dual therapy: 14, 73.7%; triple therapy: 44, 56.4%), other clinical reasons (dual therapy: 1 syphilis and 1 follow-up in previous rebound HIV encephalitis, 10.5%; triple therapy: 2 Non Hodgkin lymphoma prophylaxis, 2 syphilis, 5.1%) and research purposes (dual therapy: 5, 26.3%; triple therapy: 18, 23.1%). No difference was observed between dual therapy vs. triple therapy at the comparison for lumbar puncture indications.
Similarly, after the diagnostic work-up, no significant difference was observed in terms of prevalence of diagnosed clinical conditions. Specifically (multiple diagnoses per individual were recorded): HAND (for patients who underwent the neurocognitive assessment, see below; dual therapy: 10/11, 90.9%; triple therapy: 38/52, 73.1%), CVE (dual therapy: 4, 21.1%; triple therapy: 15, 19.2%), isolated brain MRI abnormalities (dual therapy: 4, 21.1%; triple therapy: 18, 23.1%) and alternative diagnoses excluded (dual therapy: 3, 15.8%; triple therapy: 14, 17.9%). A definitive diagnosis among patients complaining of neurocognitive or neurological signs or symptoms was reached in similar percentage (9/13, 69.2% in dual therapy vs. 34/51, 66.7% in triple therapy; p.86).
No significant differences in terms of demographic and viroimmunological features were observed, as shown in Table 1. Dual therapy showed a trend for a higher proportion of patients with a history of LLV and for a smaller proportion presenting plasma HIV-RNA less than 20 copies/ml at lumbar puncture (Table 1). Furthermore, the groups did not differ in the duration of continuous virological suppression, while the length of time from HIV diagnosis was longer for dual therapy but the difference did not reach the significance threshold and none was diagnosed during primary HIV infection (Table 1).
Cerebrospinal fluid virological suppression
As shown in Table 1, despite the expected lower RAMs-unadjusted CPE score in dual therapy, the amount of CSF HIV-RNA did not differ between the groups: 14 patients on dual therapy (73.7%) presented a CSF HIV-RNA below the detection limit and similarly it was in triple therapy (78.2%; Table 1). Among patients with detectable CSF virus, CSF HIV-RNA was 120 (45–182) and 54 copies/ml (43–77) in dual therapy and triple therapy, respectively (p.1.0; Table 1). Lastly, the prevalence of CVE was similar among the groups: four cases in dual therapy and 15 among triple therapy (21.1 vs. 19.2%; p.86).
A total of 63 patients (64.9%) underwent the neurocognitive assessment: 11 on dual therapy and 52 on triple therapy. As shown in Table 2, the groups did not score differently at the depression and anxiety questionnaires. HAND prevalence did not differ between dual therapy and triple therapy (90.9 vs. 73.1%; p.21), as well as the distribution of HAND grades (Table 2). Comparing the groups, there was no difference in raw or adjusted scores in any neurocognitive tests (data not shown).
Cerebrospinal fluid biomarkers
Comparing patients on dual therapy vs. triple therapy, there was no difference at any tested CSF biomarkers of intrathecal humoral response (intrathecal synthesis, IgG index, Tourtelotte and Tibbling indices), inflammation and monocyte/macrophages activation (cells, proteins, neopterin), BBB integrity (CSAR), astrocytosis (S100β), neuronal injury (tau, p-tau) and amyloid metabolism (Aβ1–42), as shown in Table 2; Fig. 1. Since CSAR and CSF tau have different age-adjusted cut-offs of normality, we also assessed the proportion of patients with altered CSAR and CSF tau. No significant difference was registered between the groups: altered CSF tau levels in 5.9 vs. 2.9% of patients on dual therapy and triple therapy, respectively (p.55); impaired BBB integrity in 5.6 vs. 21.9% of patients on dual therapy and triple therapy, respectively (p.11).
In our cohort of adult PLWH with suppressed or LLV undergoing lumbar puncture due to neurological or neurocognitive issues or neurologically oriented research purposes, dual therapy showed similar efficacy in suppressing viral replication within CSF compared with standard triple therapy.
The study patients represent a clinical group of patients characterized by a high risk of presenting CSF alterations and/or an abundant compartmentalized CNS reservoir, as confirmed by the significantly higher prevalence of observed CVE and HAND than those recently reported [19–22]. Given this, patients on dual therapy did not show greater prevalence of CVE than triple therapy and the amount of quantifiable CSF virus was also similar. As we were not able to calculate for every patient a genotypic susceptibility-adjusted CPE score, which seems to better relate to neurocognitive performance and CVE risk [23,24], we cannot rule out that the observed equivalence in CSF viro-suppression could be partially affected by discrepancies in RAMs between the groups. Among patients with available data (37 triple therapy; 11 dual therapy), those on triple therapy presented a lower prevalence of cumulative genotype testing positive to RAMs compared with dual therapy (reverse transcriptase and protease 37.8 and 31.4% vs. 72.7 and 45.4%). Although the available data for triple therapy may not be representative for the whole group, we can infer that our patients on triple therapy should have a similar or lower RAMs prevalence than those on dual therapy, reliably reducing the risk of a biased nonrejection of the null hypothesis.
Considering also other acknowledged risk factors for CVE [25,26], dual therapy and triple therapy did not differ in terms of CD4+ nadir and duration of cART, while the former were disadvantaged by a trend to significance of more patients with a LLV history and of longer duration of the infection. Nevertheless, both the groups showed an equivalent long-lasting plasma viral suppression, whereby, although these mild unfavourable differences against dual therapy in terms of CVE risk, CVE prevalence in dual therapy and in triple therapy overlapped. In line with this, also the neurocognitive performance and the alterations in all the measured CSF biomarkers were similar between the groups. In contrast to clinical trials reporting neurocognitive data, our sample was larger  or analysed through an extensively wider battery  assessing nine neurocognitive domains. As for trials aviremic patients [11,12], compared with patients on triple therapy, those on dual therapy did not present a higher prevalence of HAND nor reduced performances in specific tasks that may be expected considering recent data on intertwined associations between drug classes/molecules, neurocognitive functions and differential penetration in brain areas [27,28]. This observation has to be interpreted knowing that HAND development timing is not clear and that our neurocognitively tested patients were on dual therapy since a median time of almost 4 years but with a large variability within the sample (minimum 4–maximum 124 months).
Concerning the time of the development of CNS complications, neuropathogenesis may not relate immediately and solely to uncontrolled viral replication within CNS and may arise after long periods of low-level CSF viraemia or even optimal suppression [29,30]. In fact, we have analysed CSF cell-free HIV-RNA only, but both cell-associated HIV-DNA and HIV-RNA have been detected with a significant higher prevalence compared with CSF cell-free HIV-RNA among on cART patients and the presence of the former has been associated with worse neurocognitive outcomes regardless of age and nadir CD4+ cell count prior to the patient's initiation of cART . If available, the assessment of HIV-DNA and RNA within CSF cells may reveal differences between dual therapy and triple therapy that the simple cell-free RNA cannot, especially in cohorts of patients with high prevalence of undetectable CSF HIV-RNA, such as ours.
The absence of any difference in CSF biomarkers of intrathecal humoral response, inflammation, monocyte/macrophages activation, BBB integrity, astrocytosis, neuronal injury and amyloid plaques deposition, already variably associated with viral replication, CVE and with the presence and severity of HAND [26,32–35], once again confirms the equality in safety and effectiveness of dual therapy and triple therapy in our clinical setting.
Significantly, some of the pathways linked to the CSF biomarkers used here have also been associated with cART-related neurotoxicity [36–38]. The lack of any difference in CSF biomarkers in an era in which one of the main driver to dual therapy simplification is the proactive prevention of cART-related toxicity could be disappointing. This conclusion has to be confirmed by larger samples, longer observational periods, alternative biomarkers and analyses and should consider possible legacy effects of previous regimens and treatment holidays as well as the antiretroviral drugs (ARVs) molecules included/excluded from dual therapy. For instance, we found that patients on triple therapy have BBB alterations four times more commonly than those on dual therapy. Despite the difference was not statistically significant, the finding requires further studies since evidence exists on BBB injury caused by some ARVs, primarily efavirenz [37,39], which is not included in any current dual therapy.
Lastly, from a clinical point of view, neurological and neurocognitive issues of patients on dual therapy were similar to those registered among triple therapy, as well as for the results of the diagnostic work-up. Furthermore, among patients complaining of signs or symptoms, a final conclusive diagnosis was reached in identical proportions. Despite preliminary, this observation may also suggest that CNS complications and challenges in clinical management may not be affected by being on a dual therapy instead of a triple therapy.
The subsequent follow-up of the patients allowed us to exclude those with neurological conditions unclear at lumbar puncture but already likely present biasing CSF analysis. Thus, despite retrospective, clinical confounders were limited.
Only one included dual therapy can be considered as a modern dual therapy (DTG-based) and, overall, only seven (36.8%) are currently recommended by guidelines (DTG + RPV; RAL + boosted DRV). Therefore, our dual therapy sample is mostly represented by PI-based or old unconventional non-PI-based dual therapy, presenting possible representativeness issues that require a confirmation in larger samples of modern dual therapy. Considering our sample size and inclusion criteria and the fact that the majority of patients on dual therapy switched from triple therapy, further studies on larger samples of neurologically and neurocognitively asymptomatic PLWH including naïve starting on dual therapy are also warranted to assess our findings in different clinical settings.
Several reasons can explain the observed equality between dual therapy and triple therapy in terms of CNS efficacy and safety. First, it is the result of balancing direct and indirect viral neurotoxicity with cART-related direct and indirect neurotoxicity. Second, taking into account ARVs differential and molecule-specific penetration across BBB, their diffusion and concentration through the several brain areas and cells and their differential intracellular inhibitory potential within the cells types (macrophages/glial cells vs. neurons vs. astrocytes), as well as possible archived RAMs and the established CNS reservoir with its dynamics of decay and evolution under cART [7,13–15,27,40], the residual activity of some triple therapy (actually functional dual therapies) may overlap the one of well patient-tailored dual therapy, but with an addition of toxicity. Lastly, an effective long-lasting and continuous virological suppression in blood, characterising both the groups, may be enough to restore an efficient immune system and this, in turn, may be sufficient for an adequate CNS functioning [12,41].
In conclusion, our retrospective analysis on a small but highly characterized sample suggests that, among symptomatic patients with peripheral virological control, dual therapy can be as effective and safe as triple therapy within the CNS compartment. Further studies on larger samples, different clinical conditions and with long-term prospective design are warranted to confirm that the removal of a drug over three of a standard regimen might not make the difference within CNS in patients with durable virological suppression in blood.
We are grateful to all the patients that took part in PRODIN, SOLFAMU and MARANDX study and to their families that support them. M.T. and A.C. conceived and designed the study, performed the statistical analysis, interpreted the results and wrote the article; W.R., E.B. and G.G. clinically managed the patients and collected the data; D.V. and S.D. performed the neurocognitive evaluation; C.A., M.N. and L.M. performed the laboratory analyses; all the authors helped in interpreting the results and revising the article.
The current work was supported by internal funding of ASL Città di Torino, Torino, Italy and of University of Torino, Department of Medical Sciences, Torino, Italy.
Conflicts of interest
G.D.P. has received honoraria from Abbvie, BMS, Gilead, Janssen-Cilag, MSD, Viiv. A.C. has received honoraria from Abbvie, BMS, Gilead, Janssen-Cilag, MSD, Viiv and he is currently receiving research grants from BMS, Gilead and Viiv. S.B. has received honoraria from Abbvie, BMS, Gilead, Janssen-Cilag, MSD, Viiv. The other authors have no conflict of interest to declare
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