Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients.

BACKGROUND AND AIMS: People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. METHODS: We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). RESULTS: We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. CONCLUSIONS: Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone.

Identification of hepatitis delta superinfection when investigating transaminitis in HIV/hepatitis B virus co-infection.

Hepatitis delta virus (HDV) is a highly pathogenic virus which can cause rapidly progressive liver disease in individuals with chronic hepatitis B virus and for which treatment options are limited. The incidence of sexually transmitted HDV infection is unknown. Here we report the case of a HDV seronegative man with pre-existent HIV/hepatitis B virus, taking effective tenofovir-containing antiretroviral therapy, who experienced a significant acute transaminitis with HDV antibody seroconversion and viraemia and no other identifiable cause.

Decline in Hepatitis C Virus (HCV) Incidence in Men Who Have Sex With Men Living With Human Immunodeficiency Virus: Progress to HCV Microelimination in the United Kingdom?

BACKGROUND: Modeling of the London hepatitis C virus (HCV) epidemic in men who have sex with men (MSM) and are living with human immunodeficiency virus (HIV) suggested that early access to direct-acting antiviral (DAA) treatment may reduce incidence. With high rates of linkage to care, microelimination of HCV within MSM living with HIV may be realistic ahead of 2030 World Health Organization targets. We examined trends in HCV incidence in the pre- and post-DAA eras for MSM living with HIV in London and Brighton, United Kingdom. METHODS: A retrospective cohort study was conducted at 5 HIV clinics in London and Brighton between 2013 and 2018. Each site reported all acute HCV episodes during the study period. Treatment timing data were collected. Incidence rates and reinfection proportion were calculated. RESULTS: A total of.378 acute HCV infections were identified, comprising 292 first infections and 86 reinfections. Incidence rates of acute HCV in MSM living with HIV peaked at 14.57/1000 person-years of follow-up (PYFU; 95% confidence interval [CI], 10.95-18.20) in 2015. Rates fell to 4.63/1000 PYFU (95% CI, 2.60 to 6.67) by 2018. Time from diagnosis to starting treatment declined from 29.8 (2013) to 3.7 months (2018). CONCLUSIONS: We observed a 78% reduction in the incidence of first HCV episode and a 68% reduction in overall HCV incidence since the epidemic peak in 2015, which coincides with wider access to DAAs in England. Further interventions to reduce transmission, including earlier access to treatment and for reinfection, are likely needed for microelimination to be achieved in this population.

A comparison of two post-processing analysis methods to quantify cerebral metabolites measured via proton magnetic resonance spectroscopy in HIV disease.

OBJECTIVE: Non-invasive biomarkers to monitor cerebral function in treated human immunodeficiency virus (HIV) disease are required. Cerebral metabolite ratios (CMRs) measured by proton-MR spectroscopy ((1)H-MRS) are a potential biomarker. Here, we compare two post-processing software packages to quantify CMRs. METHODS: Cerebral (1)H-MRS data from 11 HIV-positive subjects before and after antiretroviral therapy intensification with maraviroc were quantified using a java-based version of the MR user interface package (jMRUI) and the totally automatic robust quantitation in nuclear MR (TARQUIN). (1)H-MRS data included N-acetylaspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) from three cerebral locations. Differences in quantification and clinical associations of CMRs measured by the two packages were evaluated. RESULTS: Mean CMRs were generally lower when measured by TARQUIN than by jMRUI (NAA/Cr, Cho/Cr, mI/Cr ratios of 1.78, 0.83, 0.81 for jMRUI, and 1.27, 0.25, 0.81 for TARQUIN). Longitudinal changes were observed in CMRs in the basal ganglia voxel although these changes were not statistically significant [+7.1% (p = 0.18), +0.0% (p = 0.91) and -6.6% (p = 0.61) and +14.8% (p = 0.18), +17.9% (p = 0.07) and +34.8% (p = 0.17) for NAA/Cr, Cho/Cr and mI/Cr ratios measured by TARQUIN and jMRUI, respectively]. Plasma maraviroc concentration was associated with a decrease in mI/Cr ratio measured via TARQUIN (p = 0.049). CONCLUSION: Although CMRs differed when quantified by jMRUI vs TARQUIN, these differences were consistently observed across three cerebral locations, and clinical associations were evident by both methods. ADVANCES IN KNOWLEDGE: TARQUIN and jMRUI are viable options to use in the post-processing of cerebral MRS data acquired in HIV disease.

Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART.

BACKGROUND: Neuroinflammation plays an important role in HIV-associated neurological disorders; however, its role prior to the onset of symptomatic disease is unclear. We imaged microglial activation, the hallmark of neuroinflammation, in asymptomatic HIV-infected patients on effective combination ART. METHODS: Seven neurologically and cognitively asymptomatic adults with chronic HIV-infection and nine healthy volunteers were investigated with [11C]-PK11195 PET, a marker of translocator protein (TSPO) expressed by activated microglia. In the HIV-infected patients, cognitive speed, accuracy and executive function were also assessed. Between-group differences in [11C]-PK11195 binding potential were localized throughout the brain with statistical parametric mapping (SPM) and associations between levels of [11C]-PK11195 binding and cognitive performance were interrogated using linear regression modelling. RESULTS: In HIV-infected patients, Statistical parametric mapping detected clusters of significantly increased [11C]-PK11195 binding in corpus callosum (P = 0.001), anterior cingulate (P = 0.001), posterior cingulate (P = 0.008) and temporal (P = 0.026) and frontal (P = 0.038) areas. Cognitive functions were intact in the HIV group, however, a significant association between greater [11C]-PK11195 binding and poorer executive function performance was observed in the anterior cingulate (P = 0.031), corpus callosum and posterior cingulate (P = 0.001). CONCLUSION: Despite effective control of HIV infection, neuroinflammation, as evidenced by the presence of focal cortical areas of activated microglia, occurs in asymptomatic HIV-infected patients and levels correlate with poorer executive performance. Further studies are needed to establish whether detection of activated microglia in HIV-infected patients represents a marker of future neurocognitive decline.

Alterations in cerebrospinal fluid chemokines are associated with maraviroc exposure and in vivo metabolites measurable by magnetic resonance spectroscopy.

BACKGROUND: Cerebrospinal (CSF) fluid biomarkers may be a useful tool for assessing the cerebral effects of antiretroviral therapy. OBJECTIVE: The aim of the study was to investigate the relationship between 4 CSF chemokines with maraviroc exposure and cerebral metabolite ratios (CMR) measured by magnetic resonance spectroscopy (1H-MRS) in HIV-infected individuals following maraviroc intensification. METHODS: CSF concentration of maraviroc and 4 chemokines (MCP-1, IP-10, MCP-4, and MIP-1ß), plasma concentration of maraviroc pre-CSF assessment, and right basal ganglia CMR were assessed in 12 male HIV-infected, neuro-asymptomatic adults after 14 days of antiretroviral therapy intensification with maraviroc 150 mg twice daily. The relationship between CSF analytes with both CMRs and plasma and CSF maraviroc concentrations were examined using Spearman correlation coefficient. RESULTS: Twelve subjects completed study procedures with baseline values as follows: mean (SD) age 42 (8) years, CD4+ cell count 503 (199) cells/µL, and plasma HIV RNA<50 copies/mL in most subjects. Mean (range, pg/mL) chemokine concentrations were IP-10, 1242 (190-8073); MCP-4, 6.52 (1-18); MCP-1, 702 (201-1618); and MIP-1ß, 42 (5-153). IP-10, MCP-4, and MIP-1ß were significantly associated with CMRs in the right basal ganglia with (1) lower concentrations of IP-10 correlating with higher N-acetyl aspartate to creatine ratios (NAA/Cr) and (2) higher concentrations of MCP-4 and MIP-1ß correlating with higher myoinositol to creatine (mI/Cr) ratios. There were no significant associations with MCP-1. Finally lower concentrations of IP-10 were significantly associated with higher maraviroc plasma trough concentration (r=-0.629, P=.028) but not CSF concentration (r=-0.308, P=.331). CONCLUSION: We hypothesize that the relationship between IP-10, MCP-4, and MIP-1ß with maraviroc exposure and CMRs may be associated with a direct cerebral effect of maraviroc.

Acute HCV/HIV coinfection is associated with cognitive dysfunction and cerebral metabolite disturbance, but not increased microglial cell activation.

BACKGROUND: Microglial cell activation and cerebral function impairment are described in both chronic hepatitis C viral (HCV) and Human-Immune-Deficiency viral (HIV) infections. The aim of this study was to investigate the effect of acute HCV infection upon cerebral function and microglial cell activation in HIV-infected individuals. METHODS: A case-control study was conducted. Subjects with acute HCV and chronic HIV coinfection (aHCV) were compared to matched controls with chronic HIV monoinfection (HIVmono). aHCV was defined as a new positive plasma HCV RNA within 12 months of a negative RNA test. Subjects underwent neuro-cognitive testing (NCT), cerebral proton magnetic resonance spectroscopy ((1)H-MRS) and positron emission tomography (PET) using a (11)C-radiolabeled ligand (PK11195), which is highly specific for translocator protein 18 kDA receptors on activated microglial cells. Differences between cases and controls were assessed using linear regression modelling. RESULTS: Twenty-four aHCV cases completed NCT and (1)H-MRS, 8 underwent PET. Of 57 HIVmono controls completing NCT, 12 underwent (1)H-MRS and 8 PET. Subjects with aHCV demonstrated on NCT, significantly poorer executive function (mean (SD) error rate 26.50(17.87) versus 19.09(8.12), p = 0.001) and on (1)H-MRS increased myo-inositol/creatine ratios (mI/Cr, a marker of cerebral inflammation) in the basal ganglia (ratio of 0.71(0.22) versus 0.55(0.23), p = 0.03), compared to subjects with HIVmono. On PET imaging, no difference in (11)C-PK11195 binding potential (BP) was observed between study groups (p>0.10 all cerebral locations), however lower BPs were associated with combination antiretroviral therapy (cART) use in the parietal (p = 0.01) and frontal (p = 0.03) cerebral locations. DISCUSSION: Poorer cognitive performance and disturbance of cerebral metabolites are observed in subjects with aHC,V compared to subjects with HIVmono. Higher (11)C-PK11195 BP was not observed in subjects with aHCV, but was observed in subjects not on cART.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Correlations between computerized battery testing and a memory questionnaire for identification of neurocognitive impairment in HIV type 1-infected subjects on stable antiretroviral therapy.

Neurocognitive impairment (NCI) remains prevalent in the highly active antiretroviral therapy (HAART) era. Memory function is commonly affected. There is a need for a rapid, but sensitive screening tool. This study compares the Prospective and Retrospective Memory Questionnaire (PRMQ) and a computerised battery cognitive assessment to establish if the questionnaire has potential as a rapid screening tool for HIV-associated NCI. Neurologically asymptomatic patients with an undetectable HIV viral load on stable HAART were eligible to participate. Asymptomatic NCI (aNCI) was defined as a performance score more than 1SD below the normative mean in at least two domains of the computerised test. Memory impairment (MI) was defined as a t-score more than 1 SD below the normative mean using the PRMQ. Forty-five subjects participated. The mean age was 48 years (SD 11), the mean CD4 count was 546 cells/mul (SD 271), and 84% were male. Of subjects, 14/45 (24%) had NCI and 15/45 (33%) had MI. Two subjects had both types of impairment. No significant association was found between the presence of aNCI and MI (p = 0.229, r = 0.18, 95% CI -1.2, 0.23). aNCI was statistically significantly associated with younger age (p = 0.38, r = 0.31, 95% CI -0.02, 0.001). MI was statistically significantly associated with the set-shifting cognitive domain of the computerized battery (p = 0.04, r = 0.326) and time elapsed since HIV diagnosis (p = 0.035, r = 0.316). High rates of asymptomatic NCI were observed in this cohort, especially in younger individuals. The memory questionnaire did not reliably identify HIV-associated NCI other than executive function deficits and based on our data should therefore not be used as a rapid screening tool for this purpose.