Changes in functional connectivity in people with HIV switching antiretroviral therapy

We assessed changes in functional connectivity by fMRI (functional magnetic resonance imaging) and cognitive measures in otherwise neurologically asymptomatic people with HIV (PWH) switching combination antiretroviral therapy (cART). In a prospective study (baseline and follow-up after at least 4 months), virologically suppressed PWH switched non-nuclease reverse-transcriptase inhibitors (NNRTI; tenofovir-DF/emtricitabine with efavirenz to rilpivirine) and integrase-strand-transfer inhibitors (INSTI; tenofovir-DF/emtricitabine with raltegravir to dolutegravir). PWH were assessed by resting-state fMRI and stop-signal reaction time (SSRT) task fMRI as well as with a cognitive battery (CogState™) at baseline and follow-up. Switching from efavirenz to rilpivirine (n = 10) was associated with increased functional connectivity in the dorsal attention network (DAN) and a reduction in SSRTs (p = 0.025) that positively correlated with the time previously on efavirenz (mean = 4.8 years, p = 0.02). Switching from raltegravir to dolutegravir (n = 12) was associated with increased connectivity in the left DAN and bilateral sensory-motor and associative visual networks. In the NNRTI study, significant improvements in the cognitive domains of executive function, working memory and speed of visual processing were observed, whereas no significant changes in cognitive function were observed in the INSTI study. Changes in fMRI are evident in PWH without perceived neuropsychiatric complaints switching cART. fMRI may be a useful tool in assisting to elucidate the underlying pathogenic mechanisms of cART-related neuropsychiatric effects

Cerebral function parameters in people with HIV switching integrase inhibitors: a randomized controlled trial

Background: Different antiretroviral therapies (ARTs) may have differing effects on central nervous system (CNS) function. We assessed CNS pharmacodynamic effects of switching integrase inhibitors in people-with-HIV (PWH). Methods: PWH on tenofovir-DF/emtricitabine plus raltegravir 400 mg twice daily with suppressed plasma HIV RNA and without overt neuropsychiatric symptoms were randomly allocated on a 1:2 basis to remain on raltegravir or switch to dolutegravir 50 mg once daily for 120 days. Pharmacodynamic parameters assessed included cognitive function (z-score of 7 domains), patient-reported outcome measures (PROMs; PHQ-9 and Beck’s depression questionnaires), cerebral metabolite ratios measured by proton magnetic resonance spectroscopy (H1-MRS) and plasma and cerebrospinal fluid (CSF) HIV RNA. Pharmacokinetic parameters were also assessed in plasma and CSF. Changes and factors associated with changes in pharmacodynamics parameters were assessed. Results: In 20 subjects (19 male, 14 white ethnicity, median age 43 years (IQR: 11.5) and CD4 + count 717 (SD: 298) cells/µL), over 120 days there were no statistically significant changes in cognitive function [mean z-score difference (95%CI) −0.004 (−0.38/0.37); p = 0.98], PROMs [PHQ-9 median score change: 0 in control arm, −0.5 switch arm (p = 0.57); Beck’s depression questionnaire: −1.5 control arm, −1.0 switch arm (p = 0.38)], nor cerebral metabolite ratios between study arms. CSF HIV RNA was <5 copies/mL at baseline and day 120 in all subjects. Geometric mean pre-dose CSF dolutegravir concentration was 7.6 ng/mL (95% CI: 5.2–11.1). Conclusions: Switching integrase inhibitor in virologically suppressed PWH without overt neuropsychiatric symptoms resulted in no significant changes in an extensive panel of CNS pharmacodynamics parameters

In vitro models as surrogates of in vivo antiretroviral efficacy in central nervous system of HIV-1 infected subjects

HIV-associated cognitive disorders persist despite combination antiretroviral therapy (cART). The pathogenesis of HIV-associated cognitive disorders has been attributed to factors including the presence of co-morbidities, neuro-inflammation, central nervous system (CNS) antiretroviral toxicity and sub-optimal CNS penetration of antiretroviral drugs. With regards to cART activity in the CNS compartment, attempts have been made to develop pharmacokinetic scoring systems in order to assess CNS antiretroviral efficacy. However, the evidence regarding their clinical validity is non-conclusive. I aimed to establish a novel scoring system to assess antiretroviral efficacy in CNS models. Neurologic cell line-based infectivity assays were developed using brain-derived HIV-1 isolates to calculate CNS anti-retroviral (CAR) scores. CSF samples were collected from HIV-positive neuro-asymptomatic patients receiving cART within clinical studies which also evaluated cerebral parameters including CSF pharmacokinetic parameters, CSF soluble biomarkers, cerebral metabolites measured via magnetic resonance spectroscopy (MRS) and cognitive testing. I hypothesised that greater in vitro CSF CAR scores are associated with greater CSF concentrations of antiretroviral drugs and higher indices of cerebral function parameters. I identified significant differences between CSF CAR scores of patients on differing cART regimens alongside significant correlations between the CSF CAR scores and CSF antiretroviral concentrations of all third antiretroviral drugs in such regimens. Higher CSF CAR scores were associated with higher markers of neuronal integrity (MRS) in patients on a maraviroc containing cART regimen but with higher levels of neuronal toxicity biomarkers in an efavirenz containing regimen. These data highlight that antiretrovirals with known immunomodulatory or toxic effects may have such effects on the CNS. I did not observe any associations between CSF CAR scores and cognitive function. CSF CAR scores are a novel research tool able to discriminate the CNS effects of differing cART regimens and may have a future role in research programmes when utilised with other markers of CNS function.Open Acces

Evolution of changes in cognitive function after the initiation of antiretroviral therapy.

BACKGROUND Cognitive function is reported to improve after the initiation of combination antiretroviral therapy (cART). Data on the evolution of such changes are limited. We assessed the dynamics of changes in cognitive parameters, in HIV-positive subjects initiating cART. METHODS Cognitive function in seven domains was evaluated for HIV-infected patients without clinically significant cognitive impairment prior to the initiation of cART, and 24 and 48 weeks after. Cognitive scores were transformed using standardised z-scores according to the pooled baseline standard deviation. Global, speed, and accuracy composite z-scores were calculated with changes calculated using a paired t test. RESULTS In 14 subjects, change in global cognitive z-scores from baseline was by 0.08 at week 24 (p = 0.59) and 0.15 at week 48 (p = 0.43). Change in composite speed and accuracy z-scores from baseline at weeks 24/48 were 0.07/0.05 (p = 0.45/0.82) and 0.13/0.23 (p = 0.47/0.45), respectively. In two of the cognitive domains assessing speed (learning and monitoring time), a continued improvement from baseline to weeks 24 and 48 was observed (changes of 0.06-0.08 and 0.10-0.19, respectively), whereas in two domains (detection and identification) an initial improvement at week 24 (changes of -0.10 and 0.04 from baseline, respectively) was followed by a deterioration in score at week 48 (changes of -0.12 and -0.08 from baseline, respectively). None of these changes were statistically significant. CONCLUSIONS A trend for improvement in cognitive function was observed in naïve HIV-positive patients starting cART. The dynamics of this improvement differed both between cognitive domains and the time-points assessed

Community transmission of monkeypox in the United Kingdom, April to May 2022.

Between 7 and 25 May, 86 monkeypox cases were confirmed in the United Kingdom (UK). Only one case is known to have travelled to a monkeypox virus (MPXV) endemic country. Seventy-nine cases with information were male and 66 reported being gay, bisexual, or other men who have sex with men. This is the first reported sustained MPXV transmission in the UK, with human-to-human transmission through close contacts, including in sexual networks. Improving case ascertainment and onward-transmission preventive measures are ongoing