Cerebrospinal Fluid Viral Escape Research Articles

Cerebrospinal Fluid Viral Escape on Highly Active Antiretroviral Therapy: Analysis from Single Tertiary Care Centre.

HIV-infected individuals receiving regular antiretroviral therapy (ART) can present with a high viral load in cerebrospinal fluid (CSF) at times when it is suppressed in blood. This study presents data of HIV-infected patients who had undetectable or low plasma viral load in blood but presented with neurological signs and symptoms and were diagnosed to have CSF HIV viral escape. Records were reviewed for clinical manifestations, details of opportunistic or coinfection, and HIV viral copies in plasma and CSF at time of diagnosis of CSF escape. A total of 10,200 HIV-infected individuals were registered in HIV care till December 31, 2021. Nineteen individuals (14 virologically confirmed and 5 clinically) were diagnosed with high viral copies in CSF from June 2014 to December 2021. Mean age was 41.5 ± 9.2 (median, 39.5; range, 30-62) years. Average duration of antiretroviral treatment received at the time of diagnosis of CSF escape was 10.1 years. Median plasma HIV-viral copies were 2,469.8 (undetectable to 29,418) and in CSF were 12,773.7 (n = 14, range, 1,340-48,530) copies/mL. HIV viral copies in CSF were significantly higher than in plasma at the time of presentation (p = .003). ART regimen switch was done after identification of HIV CSF escape. Seventeen patients were alive with a regular follow-up of average 35 (range 7-66) months. All had documented clinical improvement with reversal of neurological impairment after ART switch. There was one death and one lost to follow-up. Early identification and timely intervention in CSF viral escape could revert severe neurological impairment and improves treatment outcome.

Learning from cerebrospinal fluid drug-resistant HIV escape-associated encephalitis: a case report

BackgroundIn the era of antiretroviral therapy (ART), central nervous system (CNS) complications in patients with human immunodeficiency virus (HIV) infection are sometimes associated with cerebrospinal fluid (CSF) viral escape. Here, we reported a case of persistent CNS viral escape with recurrent symptomatic encephalitis, which had ultimate stabilization achieved by a combination of ART adjustment and corticosteroids.Case presentationA 27-year-old man with HIV infection complained of recurrent headaches during the last year. His magnetic resonance imaging (MRI) presented diffused bilateral white matter lesions, and laboratory tests confirmed elevated CSF protein level, lymphocytic pleocytosis, and detectable CSF HIV RNA (774 copies/mL). Plasma HIV RNA was well suppressed with tenofovir, lamivudine, and lopinavir/ritonavir. Prednisone 60 mg once daily was initiated to reduce intracranial inflammation, followed by a good clinical response, with CSF HIV RNA still detectable (31.1 copies/mL). During the gradual tapering of prednisone, his headache relapsed, and booming viral loads were detected in both CSF (4580 copies/mL) and plasma (340 copies/mL) with consistent drug-resistant mutations. Thereupon, prednisone was resumed and the ART regimen was switched to zidovudine, lamivudine, and dolutegravir according to drug resistance tests. Persistent clinical recovery of symptoms, neuroimaging, and laboratory abnormalities were observed in the follow-up visits.ConclusionCSF and plasma HIV RNA and further drug resistance tests should be monitored in HIV-infected patients with neurologic symptoms, as opportunistic infections or tumors can be ruled out. ART optimization using a sensitive regimen may be crucial for addressing CSF viral escape and the related encephalitis.

Cerebrospinal fluid viral escape can provide clues for the management of HIV-associated neurologic complications: Highlights from the 2023 American Academy of Neurology Annual Meeting, Boston.

Cerebrospinal fluid viral escape can provide clues for the management of HIV-associated neurologic complications: Highlights from the 2023 American Academy of Neurology Annual Meeting, Boston.

Cohort profile: InfCareHIV, a prospective registry-based cohort study of people with diagnosed HIV in Sweden

PurposeThe Swedish InfCareHIV cohort was established in 2003 to ensure equal and effective care of people living with HIV (PLHIV) and enable long-term follow-up. InfCareHIV functions equally as a decision...

Reversal of CSF HIV-1 Escape during Treatment of HIV-Associated Cryptococcal Meningitis in Botswana.

Cerebrospinal fluid (CSF) viral escape has been poorly described among people with HIV-associated cryptococcal meningitis. We determined the prevalence of CSF viral escape and HIV-1 viral load (VL) trajectories in individuals treated for HIV-associated cryptococcal meningitis. A retrospective longitudinal study was performed using paired CSF and plasma collected prior to and during the antifungal treatment of 83 participants recruited at the Botswana site of the phase-3 AMBITION-cm trial (2018–2021). HIV-1 RNA levels were quantified then CSF viral escape (CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma) and HIV-1 VL trajectories were assessed. CSF viral escape occurred in 20/62 (32.3%; 95% confidence interval [CI]: 21.9–44.6%), 13/52 (25.0%; 95% CI: 15.2–38.2%) and 1/33 (3.0%; 95% CI: 0.16–15.3%) participants at days 1, 7 and 14 respectively. CSF viral escape was significantly lower on day 14 compared to days 1 and 7, p = 0.003 and p = 0.02, respectively. HIV-1 VL decreased significantly from day 1 to day 14 post antifungal therapy in the CSF but not in the plasma (β = −0.47; 95% CI: −0.69 to −0.25; p < 0.001). CSF viral escape is high among individuals presenting with HIV-associated cryptococcal meningitis; however, antifungal therapy may reverse this, highlighting the importance of rapid initiation of antifungal therapy in these patients.

CNS infections in HIV.

Central nervous system (CNS) infections associated with HIV remain significant contributors to morbidity and mortality, particularly among people living with HIV (PLWH) in resource-limited settings worldwide. In this review, we discuss several recent important scientific discoveries in the prevention, diagnosis, and management around two of the major causes of CNS opportunistic infections-tuberculous meningitis (TBM) and cryptococcal meningitis including immune reconstitution syndrome (IRIS) associated with cryptococcal meningitis. We also discuss the CNS as a possible viral reservoir, highlighting Cerebrospinal fluid viral escape. CNS infections in HIV-positive people in sub-Saharan Africa contribute to 15-25% of AIDS-related deaths. Morbidity and mortality in those is associated with delays in HIV diagnosis, lack of availability for antimicrobial treatment, and risk of CNS IRIS. The CNS may serve as a reservoir for replication, though it is unclear whether this can impact peripheral immunosuppression. Significant diagnostic and treatment advances for TBM and cryptococcal meningitis have yet to impact overall morbidity and mortality according to recent data. Lack of early diagnosis and treatment initiation, and also maintenance on combined antiretroviral treatment are the main drivers of the ongoing burden of CNS opportunistic infections. The CNS as a viral reservoir has major potential implications for HIV eradication strategies, and also control of CNS opportunistic infections.

Cerebrospinal fluid pleocytosis as a predictive factor for CSF and plasma HIV RNA discordance and escape.

The aims of this study were to investigate the frequency of HIV-1 RNA level discordance between the cerebrospinal fluid (CSF) and plasma and of CSF viral escape (CVE) in patients with HIV-1 subtype C on antiretroviral therapy, and evaluate the CSF white blood cell (WBC) performance characteristics in predicting CSF discordance in HIV+ group and the frequency of cognitive impairment in individuals with CSF HIV discordance or escape. HIV-1 RNA levels were assessed in plasma and CSF samples from 68 HIV+ participants without opportunistic infection. CSF discordance was found in 7.4% and CVE in 10%, with comparable frequencies between HIV-1B and C. Twenty samples (29%) showed increased CSF WBC counts. This group had higher CSF and plasma HIV-1 RNA levels than the group with normal WBC counts (p < 0.0001 and 0.006, respectively). The odds of CSF discordance were 18 times higher for a person with CSF WBC count of > 5cells/mm3 than the group with normal CSF WBC count. CSF WBC counts (cut-off of 15cells/mm3) showed high-performance characteristics as a predictive biomarker of CSF discordance (AUC the ROC curve 0.98). The frequency of cognitive impairment for CSF escape or discordance was 83% and 80%. The odds of cognitive impairment in these groups were 19 and 15 times higher than those for an HIV(-) person. Viral discordance or escape in the CNS occurs at a comparable frequency for HIV-1C and HIV-1B. The CSF WBC count was effective as a predictive biomarker of CSF and plasma discordance.

Recall Responses from Brain-Resident Memory CD8+ T Cells (bTRM) Induce Reactive Gliosis.

SummaryHIV-associated neurocognitive disorders (HAND) persist even during effective combination antiretroviral therapy (cART). Although the cause of HAND is unknown, studies link chronic immune activation, neuroinflammation, and cerebrospinal fluid viral escape to disease progression. In this study, we tested the hypothesis that specific, recall immune responses from brain-resident memory T cells (bTRM) could activate glia and induce neurotoxic mediators. To address this question, we developed a heterologous prime-central nervous system (CNS) boost strategy in mice. We observed that the murine brain became populated with long-lived CD8+ bTRM, some being specific for an immunodominant Gag epitope. Recall stimulation using HIV-1 AI9 peptide administered in vivo resulted in microglia displaying elevated levels of major histocompatibility complex class II and programmed death-ligand 1, and demonstrating tissue-wide reactive gliosis. Immunostaining further confirmed this glial activation. Taken together, these results indicate that specific, adaptive recall responses from bTRM can induce reactive gliosis and production of neurotoxic mediators.

Cerebrospinal fluid viral escape in aviremic HIV-infected patients receiving antiretroviral therapy: prevalence, risk factors and neurocognitive effects.

During antiretroviral therapy, HIV RNA can be detected in cerebrospinal fluid (CSF) when it is undetectable in plasma, a condition termed 'CSF viral escape'. The aim of the current study was to determine the prevalence and risk factors for CSF viral escape in two large cohorts in the USA. A total of 1264 HIV-infected volunteers enrolled in two US cohorts at their most recent visit between 2003 and 2011 were included in this cross-sectional analysis if their HIV RNA level in plasma was less than 50 copies/ml while receiving stable antiretroviral therapy (ART) (>6 months) and if they had HIV RNA measured in CSF at their most recent visit between 2003 and 2011. Potential risk factors were identified using univariable and multivariable regression. CSF viral escape was detected in 55 adults (4.4%; 95% CI: 3.4-5.6), who had a median CSF HIV RNA of 155 copies/ml [interquartile range (IQR: 80-283)]. Patients with or without CSF viral escape had similar rates of neurocognitive impairment (38.2 vs. 37.7%; P = 0.91). CSF viral escape was independently associated with the use of ritonavir-boosted protease inhibitors [odds ratio (OR): 2.0; 95% CI: 1.1-3.8] or unboosted atazanavir (OR: 5.1; 95% CI: 1.3-16.1), CSF pleocytosis (OR: 7.6; 95% CI: 4.2-13.7) and abnormal CSF total protein (OR: 2.1; 95% CI: 1.1-3.7). In this large study of aviremic patients receiving ART, CSF viral escape was uncommon and was linked to evidence of central nervous system inflammation and the use of protease inhibitors, but not with worse neurocognitive performance.

Impact of Antiretroviral Regimens on Cerebrospinal Fluid Viral Escape in a Prospective Multicohort Study of Antiretroviral Therapy-Experienced Human Immunodeficiency Virus-1-Infected Adults in the United States.

Cerebrospinal fluid (CSF) viral escape occurs in 4%-20% of human immunodeficiency virus (HIV)-infected adults, yet the impact of antiretroviral therapy (ART) on CSF escape is unclear. A prospective study of 1063 participants with baseline plasma viral load (VL) ≤400 copies/mL between 2005 and 2016. The odds ratio (OR) for ART regimens (protease inhibitor with nucleoside reverse transcriptase inhibitor [PI + NRTI] vs other ART) and CSF escape was estimated using mixed-effects models. Baseline mean age was 46 years, median plasma VL, and CD4 count were 50 copies/mL, and 424 cells/μL, respectively. During median follow-up of 4.4 years, CSF escape occurred in 77 participants (7.2%). PI + NRTI use was an independent predictor of CSF escape (OR, 3.1; 95% confidence interval, 1.8-5.0) in adjusted analyses and models restricted to plasma VL ≤50 copies/mL (P < .001). Regimens that contained atazanavir (ATV) were a stronger predictor of CSF viral escape than non-ATV PI + NRTI regimens. Plasma and CSF M184V/I combined with thymidine-analog mutations were more frequent in CSF escape vs no escape (23% vs 2.3%). Genotypic susceptibility score-adjusted central nervous system (CNS) penetration-effectiveness (CPE) values were calculated for CSF escape with M184V/I mutations (n = 34). Adjusted CPE values were low (<5) for CSF in 27 (79%), indicating suboptimal CNS drug availability. PI + NRTI regimens are independent predictors of CSF escape in HIV-infected adults. Reduced CNS ART bioavailability may predispose to CSF escape in patients with M184V/I mutations.

Cerebrospinal fluid HIV RNA in persons living with HIV.

Despite adequate suppression of plasma HIV RNA, viral escape in cerebrospinal fluid (CSF) is widely reported. Rates of CSF HIV RNA escape vary in the literature. In persons living with HIV (PLWH) undergoing lumbar puncture examination for clinical reasons, we assessed rates of CSF HIV RNA escape. Persons living with HIV attending a designated HIV neurology service undergoing CSF assessment for clinical reasons between January 2015 and April 2017 were included in the study. CSF HIV RNA escape was defined as HIV RNA ≥0.5 log10 HIV-1 RNA copies/mL higher than plasma HIV RNA or detectable CSF HIV RNA when plasma HIV RNA was <20 copies/mL. Clinical factors associated with CSF HIV RNA were assessed using logistic regression modelling. Of 38 individuals, 35 were receiving antiretroviral therapy, 30 were male and their mean age was 51years. Clinical reasons for CSF assessment included investigation for cognitive decline (n=25), early syphilis (n=4) and other central nervous system (CNS) conditions (n=9). HIV RNA was detectable in plasma and CSF in seven and six individuals, respectively, with two individuals (5.3%) meeting the definition of CSF escape. Detectable CSF HIV RNA was associated with a detectable plasma HIV RNA (P<0.001) and a history of known antiretroviral drug resistance mutations (P=0.021). The prevalence of CSF viral escape in PLWH undergoing lumbar puncture examination for clinical reasons is lower than previously reported.

Temporal Patterns and Drug Resistance in CSF Viral Escape Among ART-Experienced HIV-1 Infected Adults.

Cerebrospinal fluid (CSF) viral escape is an increasingly recognized clinical event among HIV-1-infected adults. We analyzed longitudinal data and drug-resistance mutations to characterize profiles of HIV-1-infected patients on antiretroviral therapy with discordant CSF and plasma HIV-1 RNA levels. Forty-one cases of CSF escape defined as detectable CSF HIV-1 RNA when plasma levels were undetectable, or HIV-1 RNA >0.5-log higher in CSF than plasma were identified from Boston Hospitals and National NeuroAIDS Tissue Consortium (NNTC) from 2005 to 2016. Estimated prevalence of CSF escape in Boston and NNTC cohorts was 6.0% and 6.8%, respectively; median age was 50, duration of HIV-1 infection 17 years, CD4 count 329 cells/mm and CD4 nadir 21 cells/mm. Neurological symptoms were present in 30 cases; 4 had repeat episodes of CSF escape. Cases were classified into subtypes based plasma HIV-1 RNA levels in the preceding 24 months: high-level viremia (1000 copies/mL), low-level viremia (LLV: 51-999 copies/mL), and plasma suppression with CSF blip or escape (CSF RNA <200 or ≥200 copies/mL). High-level viremia cases reported more substance abuse, whereas LLV or plasma suppression cases were more neurosymptomatic (81% vs. 53%); 75% of repeat CSF escape cases were classified LLV. M184V/I mutations were identified in 74% of CSF samples when plasma levels were ≤50 copies per milliliter. Characteristics frequently observed in CSF escape include HIV-1 infection >15 years, previous LLV, and M184V/I mutations in CSF. Classification based on preceding plasma HIV RNA levels provides a useful conceptual framework to identify causal factors and test therapeutics.

PP 4.3 - Asymptomatic cerebrospinal fluid viral escape during ART is associated with increased intrathecal immune activation

PP 4.3 - Asymptomatic cerebrospinal fluid viral escape during ART is associated with increased intrathecal immune activation

Cerebrospinal fluid and plasma lopinavir concentrations and viral response in virologically suppressed patients switching to lopinavir/ritonavir monotherapy once daily.

Lopinavir/ritonavir (LPV/r) monotherapy is used in selected virologically suppressed HIV-infected patients. Some would prefer a once-daily (OD) dose instead of the usual twice-daily dose to favour adherence. However, trough concentrations of the drug in blood and particularly in cerebrospinal fluid (CSF) may not be adequate to maintain viral suppression. Prospective, open-label pilot study to evaluate the efficacy and safety of LPV/r monotherapy OD. HIV-1-infected patients, virologically suppressed for at least 6 months were enrolled. HIV viral load (VL) was determined at baseline and at weeks 4, 8, 12, 16, 24, 36 and 48. Lumbar puncture was performed in a subgroup of patients to evaluate CSF VL and CSF LPV concentrations. A total of 21 patients were included. At week 48, 85.7% (n=18) showed viral suppression (VL<40 copies/ml). Two patients had viral failure (9.5%) and a third was withdrawn from the study because of gastrointestinal symptoms. Nine patients were enrolled in the substudy. CSF VL was <40 copies/ml in all cases. Median (range) LPV concentration was 9.78 ng/ml (1.93-78.3) in CSF and 1,970 (154-16,700) ng/ml in plasma; the CSF/plasma ratio was 0.004 (0.001-0.186). In this small pilot study, LPV/r monotherapy OD maintained plasma HIV RNA suppression at 48 weeks in most patients, with no cases of CSF viral escape. However, CSF LPV concentrations were close to the 50% inhibitory concentration threshold in several patients; hence, this intervention should be avoided in patients with advanced immune suppression and/or those individuals presenting with significant comorbidities such as hepatitis C coinfection.

Cerebrospinal Fluid HIV Escape from Antiretroviral Therapy.

CNS infection is a nearly constant facet of systemic CNS infection and is generally well controlled by suppressive systemic antiretroviral therapy (ART). However, there are instances when HIV can be detected in the cerebrospinal fluid (CSF) despite suppression of plasma viruses below the clinical limits of measurement. We review three types of CSF viral escape: asymptomatic, neuro-symptomatic, and secondary. The first, asymptomatic CSF escape, is seemingly benign and characterized by lack of discernable neurological deterioration or subsequent CNS disease progression. Neuro-symptomatic CSF escape is an uncommon, but important, entity characterized by new or progressive CNS disease that is critical to recognize clinically because of its management implications. Finally, secondary CSF escape, which may be even more uncommon, is defined by an increase of CSF HIV replication in association with a concomitant non-HIV infection, as a consequence of the local inflammatory response. Understanding these CSF escape settings not only is important for clinical diagnosis and management but also may provide insight into the CNS HIV reservoir.

Efficacy of PI monotherapy versus triple therapy for 1964 patients in 10 randomised trials.

IntroductionThe efficacy of protease inhibitor monotherapy has been analyzed with different endpoints: initial HIV-1 RNA rebound, long-term HIV-1 RNA suppression after re-intensification, treatment-emergent drug resistance, neurocognitive testing and HIV-1 RNA in the cerebrospinal fluid (CSF).MethodsA PUBMED search identified nine randomised trials of PI monotherapy versus triple therapy in patients with HIV RNA<50 copies/mL at baseline. Results from the recently completed PROTEA trial were also included. The percentage of patients with HIV RNA suppression <50 copies/mL was analyzed using switch equals failure and intensification included endpoints (ITT). The number of patients with new drug resistance mutations, HIV RNA in the CSF or change in neurocognitive function was analyzed by treatment arm.ResultsFour trials evaluated darunavir/r monotherapy (n=785: MONET, MONOI, MONARCH, PROTEA), five evaluated lopinavir/r monotherapy (n=592: OK-04, KalMo, KALESOLO, KRETA, MOST) and one evaluated both (MRC PIVOT, n=587). HIV-1 RNA suppression rates tended to be lower on PI monotherapy than triple therapy in “switch equals failure” analysis (76% vs 82%), but not when the outcome of intensification was included (87% vs 85%). There were small numbers of patients taking PI monotherapy with detectable HIV-1 RNA in the CSF, in three trials: PROTEA (n=2), MONOI (n=2) and MOST (n=5), but only two cases of CSF viral escape (MONOI). In two trials, there was no difference in neurocognitive test results between PI monotherapy and triple therapy, based on z-scores from five domains (in PROTEA, mean change in NPZ-5 score=0.0 for DRV/r monotherapy vs −0.10 for triple therapy); similar results were observed in the MRC PIVOT trial. The risk of treatment emergent NRTI or PI resistance (Table 1) was 11/973 (1.1%) for patients on PI monotherapy, versus 7/991 (0.7%) for patients on triple therapy.ConclusionsIn 10 randomised trials of 1964 patients with HIV-1 RNA suppression at baseline, PI monotherapy showed a higher risk of HIV RNA elevations, and small numbers with HIV RNA detectable in CSF and concomitantly in the plasma. However there was no increased risk of treatment-emergent drug resistance, neurocognitive endpoints were not different between the arms and HIV-1 RNA suppression rates after intensification were similar between PI monotherapy and triple therapy.

Factors associated with cerebrospinal fluid HIV RNA in HIV infected subjects undergoing lumbar puncture examination in a clinical setting

Cerebrospinal fluid (CSF) HIV RNA load may be associated with central nervous system (CNS) disease in HIV infected subjects. We investigated parameters associated with CSF HIV RNA within a large clinical cohort. All HIV infected subjects undergoing CSF examination including assessment of CSF HIV RNA at St. Mary's Hospital, London, UK between January 2008 and October 2010 were included. Parameters associated with a detectable CSF HIV RNA load were assessed using linear regression modelling. CSF viral escape was defined as CSF RNA >0.5 log(10) copies/mL greater than plasma HIV RNA and >200 copies/mL where plasma HIV RNA <50 copies/mL. Of 142 subjects, 99 were receiving antiretroviral therapy (ART). Plasma HIV RNA was <50 copies/mL in 69 subjects. CSF examination was performed for investigation of presumed HIV encephalopathy (IxHE, n = 57), other CNS diseases considered HIV related (n = 39), syphilis (n = 20) and CNS presentations not considered HIV related (n = 26). CSF viral escape was present in 30/142 (21%) subjects overall and in 9/69 (13%) of those on ART with undetectable plasma HIV RNA. Overall, plasma HIV RNA load was significantly associated with detectable CSF HIV RNA (p ≤ 0.001). In subjects with plasma HIV RNA <50 copies/mL, only CNS penetration effectiveness (CPE, 2008) score of <2 was significantly associated with detectable CSF HIV RNA (p = 0.044). In patients undergoing LP for IxHE both plasma HIV RNA and CPE scores were independently associated with detectable CSF HIV RNA (p = 0.019 & 0.003 respectively) which was not observed in subjects undergoing CSF examination for other medical reasons. In a clinical setting, CSF viral escape is observed frequently in 21% of subjects and is associated with different parameters depending on the clinical scenario.

Reply to Seligman

TO THE EDITOR—We appreciate the suggestions made by Dr Seligman in relation to our work on cerebrospinal fluid (CSF) viral escape. As noted, the detection of low-level viremia in blood samples from patients receiving successful suppressive therapy may result from occasional nonadherence. Because of the limited penetration of some antiretroviral drugs into the central nervous system (CNS), adherence may potentially be even more crucial in the treatment of HIV-1 in the CNS. However, we would argue that the detection of low-level viral load in CSF is indeed of potential importance. Because of limitations in accessibility, residual virus in CSF during suppressive antiretroviral therapy is, if at all present, less well characterized than in blood. However, viral load in the CSF compartment during antiretroviral therapy is usually substantially lower than that in blood in neurologically asymptomatic patients [1, 2]. Previously, detection of selective viral escape in the CSF compartment was rare. Even in patients with systemic treatment failure, the level of HIV-1 RNA is frequently substantially lower in the CSF compartment [2]. However, we fully agree that compartmentalized viral resistance in the CNS remains an important factor to investigate. As suggested by Dr. Seligman, we are currently studying this issue. To increase the sensitivity of the analysis, ultra-centrifugation of CSF samples is implemented for improved HIV-1 RNA yield, followed by polymerase chain reaction amplification, sequencing, and genotypic resistance testing. Using these analyses, we hope to further characterize selective viral resistance as a possible factor in relation to the CSF viral escape found in 10% of patients included in the present study [3].

HIV‐1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment

Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank. Sixty-nine neurologically asymptomatic subjects treated with antiretroviral therapy >6 months and plasma HIV-1 RNA <50 copies/mL were cross-sectionally included in the analysis. Antiretroviral therapy regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir, or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analyzed with real-time polymerase chain reaction assays. Neopterin was analyzed by enzyme-linked immunosorbent assay. Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median 121 copies/mL (interquartile range, 54-213 copies/mL). Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. Central nervous system penetration effectiveness rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Viral escape in CSF is more common than previously reported, suggesting that low-grade central nervous system infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice.