CROI 2019 Abstract eBook
435 MECHANISMS OF WHITE-MATTER LOSS DUE TO HIV INFECTION AND ANTIRETROVIRAL THERAPY Kelly L. Jordan-Sciutto 1 , Lindsay M. Roth 1 , Bassam N. Zidane 1 , Micah Romer 2 , Cagla Akay-Espinoza 1 , Judith B. Grinspan 2 1 University of Pennsylvania, Philadelphia, PA, USA, 2 Children’s Hospital of Philadelphia, Philadelphia, PA, USA Background: White matter pathologies including corpus callosum thinning and disruption of white matter microstructures persist in HIV-positive patients on combination antiretroviral (ARV) therapy (cART). Thinning of the corpus callosum increases with time on cART. Thus, we hypothesized that HIV- infected macrophages and/or antiretroviral compounds alter oligodendrocyte differentiation, function, and/or survival and sought to identify the mechanism underlying this effect. Methods: To model the effect of HIV infection in the CNS on oligodendrocytes, we stimulated primary rat oligodendrocyte precursor cells (OPCs) to differentiate into mature oligodendrocytes in vitro, with concomitant treatment with HIV-infected monocyte-derived macrophage supernatant (HIVMDMS) or ARV compounds from the integrase strand transfer inhibitor class, elvitegravir, raltegravir or cobicistat, the bioavailability boost. To examine the effect of ARV drugs on remyelination, we treated mice with cuprizone, a demyelinating compound, for five weeks and allowed them to recover for three weeks (a time frame that permits remyelination) or treated themwith daily intrajugular injection of elvitegravir and cobicistat during the three-week recovery phase. Brains were harvested, and the corpus collosumwas sectioned and stained for myelin by luxol fast blue, mature oligodendrocytes by ASPA and neuroinflammation by GFAP and Iba1. Results: In our in vitro model, OPC differentiation was inhibited by HIVMDMS and elvitegravir, whereas raltegravir and cobicistat did not affect oligodendrocyte differentiation. The inhibition of OPC differentiation by HIVMDMs and elvitegravir was reversed by inhibiting the integrated stress response using the small molecule trans-ISRIB. Finally, administration of elvitegravir during the recovery phase following cuprizone-induced demyelination resulted in failure of remyelination, indicated by reduced ASPA and luxol fast blue staining. Persistent neuroinflammation was evident in the corpus callosum in elvitegravir-treated mice compared with the untreated controls. Conclusion: These studies suggest that both HIV infection and elvitegravir inhibit OPC differentiation in vitro and in vivo. Further studies of the effects of HIV and/or first-line ARV compounds are warranted to provide insights into the observed persistent white matter changes seen in patients with HIV-associated neurocognitive disorders and their potential contribution to cognitive impairment. 436 SWITCHING TO FTC/TAF FROM ABC/3TC OR FTC/TDF DOES NOT AFFECT CNS HIV-1 INFECTION Aylin Yilmaz 1 , Lars Hagberg 1 , Åsa Mellgren 2 , Dietmar Fuchs 3 , Staffan Nilsson 4 , Kaj Blennow 5 , Henrik Zetterberg 5 , Magnus Gisslén 1 1 Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden, 2 Södra Älvsborg Hospital, Borås, Sweden, 3 Innsbruck Medical University, Innsbrusk, Austria, 4 Chalmers University of Technology, Gothenburg, Sweden, 5 University of Gothenburg, Gothenburg, Sweden Background: Despite suppressive antiretroviral therapy (ART), many HIV- infected individuals have low-level persistent immune activation in the central nervous system (CNS). Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and abacavir/lamivudine (ABC/3TC) have been the most widely used nucleoside analogues for several years. In 2015, when this study was initiated, a new prodrug for tenofovir, tenofovir alafenamide fumarate (TAF), was introduced. One potential concern regarding TAF and its effect in CNS is that TAF is a stronger substrate for P-glycoprotein (P-gp) than TDF, which could theoretically decrease its CNS exposure since substrates for P-gp are subject to active blood-brain barrier efflux. Our aimwas to investigate if switching from FTC/TDF or ABC/3TC to FTC/TAF would lead to changes in residual intrathecal immune activation, viral load, or neurocognitive function. Methods: In this prospective study, we included 20 HIV-infected neuroasymptomatic adults (11 on ABC/3TC and 9 on FTC/TDF) selected from the prospective Gothenburg HIV CSF study cohort who for backward comparison recently had undergone a previous research lumbar puncture when on treatment with the same regimen as on baseline. We performed lumbar punctures, veni punctures, and neurocognitive testing at baseline and
after three and 12 months. At the baseline visit all participants changed their nucleoside analogues to FTC/TAF without any other changes to the ongoing ART regimen. We analysed CSF and plasma HIV RNA, CSF neopterin, CSF β2-microglobulin, IgG index, albumin ratio, and CSF NFL at the pre-study visit, baseline and follow-up. Cognitive function in five domains was assessed by CogState. Results: After three and 12 months of follow-up, there were no significant changes in CSF and plasma HIV RNA, CSF neopterin, CSF β2-microglobulin, IgG index, albumin ratio, CSF NFL, or neurocognitive function in any of the groups (see figure, CSF and plasma HIV RNA and Cogstate results not shown). Conclusion: Switching to FTC/TAF from ABC/3TC or FTC/TDF was neutral on HIV CNS infection and inflammation.
437 POLYPHARMACY IS ASSOCIATED WITH WORSE NEUROCOGNITIVE PERFORMANCE IN AGING ADULTS
Qing Ma 1 , Ronald J. Ellis 2 , Leah H. Rubin 3 , Norman J. Haughey 3 , Donald Franklin 2 , Anne Bang 4 , Rowan Saloner 2 , Mariana Cherner 2 , David J. Moore 2 , Scott L. Letendre 2 1 University at Buffalo, Buffalo, NY, USA, 2 University of California San Diego, San Diego, CA, USA, 3 Johns Hopkins University, Baltimore, MD, USA, 4 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA Background: Persons living with HIV (PLWH) have more aging-related diseases, use more prescribed drugs, and are more likely to have neurocognitive (NC) impairment than the general population. Medical and psychiatric comorbidities increase risk of NC impairment in PLWH but the neurotoxicity of drugs used to treat these diseases remains underinvestigated. Methods: 956 PLWH taking antiretroviral therapy (ART) and enrolled in neuroHIV cohorts underwent NC assessment. Demographically-adjusted T-scores were computed for seven cognitive domains and global performance. The most common classes of concomitant drugs were antidepressants (31.1%), antimicrobials (26.2%), non-steroidal anti-inflammatory drugs (21.0%), opioids (16.0%), gastric acid drugs (15.8%), antipsychotics (12.6%), antihypertensives (11.2%), and anxiolytics (10.9%). Polypharmacy was defined as taking ≥5 concomitant drugs. Psychiatric and substance use diagnoses were available for 719 participants. Stepwise multivariable linear regressions using the Akaike Information Criterion modeled NC performance as a function of concomitant medications, adjusting for age, sex, and HIV disease and treatment characteristics. Results: Participants were generally middle-aged (mean 44.1) white (53.1%) men (86.2%) who had AIDS (56%), viral suppression (71.7%), and immune recovery (median CD4+ count 488/µL). The mean number of concomitant drugs was 3.3 (range 0-24). Overall, PLWH who took more concomitant drugs had worse global performance (r=0.15, p<0.001), as did those who took ≥5 concomitant drugs (d=0.28, p<0.001). Worse global performance was associated with use of anxiolytics (p<0.001), protease inhibitors (p=0.006), opioids (p=0.008), antimicrobials (p=0.009), and antipsychotics (p=0.03) (Model p<0.001). Concomitant drug classes were most frequently associated with worse executive functioning and learning (see Figure). Accounting for psychiatric, medical, and substance use diagnoses and did not significantly weaken the associations between concomitant drugs and global performance. Conclusion: Concomitant drug use is associated with worse NC performance. Distinguishing the effects of concomitant drugs from those of underlying diseases is complex but our analyses support that certain drug classes may cause reversible or irreversible neurotoxicity. Different drug classes were associated with different cognitive patterns, suggesting that they differently affect the neurobiological pathways underlying these abilities.
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