Lenacapavir: A Novel Long-Acting Capsid Inhibitor for HIV.

OBJECTIVE: To review the efficacy, safety, and role of lenacapavir (LEN) in the treatment of HIV-1 infection. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (through March 2023) with the search term LEN and GS-6207. Other resources included abstracts presented at recent conferences, the manufacturer's Web site, and prescribing information. STUDY SELECTION AND DATA EXTRACTION: All relevant articles, trial updates, and conference abstracts in the English language were included. DATA SYNTHESIS: Lenacapavir represents a new class of antiretrovirals (ARVs) with a novel mechanism of action as a capsid inhibitor and a unique twice-a-year subcutaneous administration schedule. Lenacapavir when combined with other ARVs has proven to benefit heavily treatment-experienced (HTE) patients with HIV-1 infection in achieving viral suppression and immune restoration. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Lenacapavir is a new treatment option that patients who are HTE can consider adding as part of an ARV regimen. CONCLUSIONS: Lenacapavir is an effective and well-tolerated option for HTE patients which is a valuable addition to the arsenal of ARVs.

Predictors of Inappropriately Rapid Coronary Lesion Progression in Patients Undergoing Percutaneous Coronary Interventions.

Background: Patients undergoing percutaneous coronary intervention (PCI) may experience rapid atherosclerotic plaque progression in nontreated vessels that is unlikely to result from natural de novo atherosclerosis. We hypothesize that intra-lesion bleeding plays a central role in this process. The aim of this study is to investigate the factors that may contribute to accelerated narrowing in coronary diameter. Methods: We reviewed 65 interventional procedures and their consequent staged PCIs and mapped the coronary tree into 16 segments (as divided by the American Heart Association), grading the percentage of stenosis in each segment and spotting the rapidly progressing lesions. Demographic, procedural, and laboratory data were recorded and analyzed. Results: For the lesions that progressed rapidly in the time period between angiographies, the administration of eptifibatide intra-procedurally was associated with rapid progression of coronary lesions. Moreover, an increased white blood cell count prior to the index procedure was also associated with a trend toward rapid plaque progression. Conclusions: In this hypothesis-generating study, treatment with a IIb/IIIa inhibitor in the index PCI was associated with an accelerated short-term progression of some of the nontreated lesions, suggesting that this mode of anti-aggregation therapy could facilitate plaque hemorrhage and consequent acceleration of coronary atherosclerosis in eroded plaques.

Contexte: Les patients qui subissent une intervention coronarienne percutanée (ICP) peuvent présenter une progression rapide de plaques d'athérosclérose dans des vaisseaux non traités, phénomène qui n'est probablement pas le résultat d'une athérosclérose de novo naturelle. Nous formulons l'hypothèse qu'un saignement intralésionnel jouerait un rôle central dans ce processus. Cette étude vise à explorer les facteurs qui pourraient contribuer à l'accélération de la réduction du diamètre coronarien. Méthodologie: Nous avons étudié 65 interventions et les ICP en plusieurs étapes qui s'en étaient suivies, ainsi que divisé l'arbre coronarien en 16 segments (conformément à la segmentation de l'American Heart Association), afin d'évaluer le pourcentage de sténose dans chaque segment et de repérer les lésions qui progressaient rapidement. Les données démographiques et celles relatives aux interventions et aux résultats de laboratoire ont été consignées et analysées. Résultats: En ce qui concerne les lésions qui avaient progressé rapidement durant l'intervalle entre les angiographies, l'administration d'éptifibatide lors de l'intervention semblait être un facteur contributif. De plus, un nombre accru de leucocytes avant l'intervention initiale a également été associé à une évolution rapide des plaques. Conclusions: Dans le cadre de cette étude servant à émettre une hypothèse, le traitement par un inhibiteur de la glycoprotéine IIb-IIIa lors de l'ICP initiale a été associé à une accélération de la progression à court terme de certaines lésions non traitées, ce qui laisse croire que ce mode de traitement antiagrégant pourrait favoriser les hémorragies intraplaques et l'accélération de l'athérosclérose coronarienne dans les plaques érodées.

HIV: how to manage heavily treatment-experienced patients.

Although decreasing in prevalence, heavily treatment-experienced (HTE) persons with limited options for HIV treatment present unique complexities, even amongst experienced providers, as there is no single approach to successful management. HTE patients are described as those having two or less antiretroviral (ARV) classes available for use with limited fully active ARV agents within each class. A detailed understanding of the underlying processes that caused previous treatment failures, diagnostics to define resistance, resistance mechanisms and ARV pharmacology should all function in tandem to determine the next steps of clinical care. This narrative review provides an overview of the clinician approach to care, including diagnostics, approaches to regimen creation, relevant resources, and a broad array of both currently available and upcoming ARVs that may be used in regimens for HTE patients.

Crushing and Splitting Direct-Acting Antivirals for Hepatitis C Virus Treatment: A Case Series and Literature Review.

Limited data exist regarding the use of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) in patients who are unable to swallow tablets. This case series describes HCV treatment in patients requiring tablet manipulation, providing evidence for safety and effectiveness of HCV DAA tablet manipulation.

Characteristics, Comorbidities, and Outcomes in a Multicenter Registry of Patients With Human Immunodeficiency Virus and Coronavirus Disease 2019.

BACKGROUND: People living with human immunodeficiency virus (HIV) may have numerous risk factors for acquiring coronavirus disease 2019 (COVID-19) and developing severe outcomes, but current data are conflicting. METHODS: Health-care providers enrolled consecutively, by nonrandom sampling, people living with HIV (PWH) with lab-confirmed COVID-19, diagnosed at their facilities between 1 April and 1 July 2020. Deidentified data were entered into an electronic Research Electronic Data Capture (REDCap) system. The primary endpoint was a severe outcome, defined as a composite endpoint of intensive care unit (ICU) admission, mechanical ventilation, or death. The secondary outcome was the need for hospitalization. RESULTS: There were 286 patients included; the mean age was 51.4 years (standard deviation, 14.4), 25.9% were female, and 75.4% were African American or Hispanic. Most patients (94.3%) were on antiretroviral therapy, 88.7% had HIV virologic suppression, and 80.8% had comorbidities. Within 30 days of testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 164 (57.3%) patients were hospitalized, and 47 (16.5%) required ICU admission. Mortality rates were 9.4% (27/286) overall, 16.5% (27/164) among those hospitalized, and 51.5% (24/47) among those admitted to an ICU. The primary composite endpoint occurred in 17.5% (50/286) of all patients and 30.5% (50/164) of hospitalized patients. Older age, chronic lung disease, and hypertension were associated with severe outcomes. A lower CD4 count (<200 cells/mm3) was associated with the primary and secondary endpoints. There were no associations between the ART regimen or lack of viral suppression and the predefined outcomes. CONCLUSIONS: Severe clinical outcomes occurred commonly in PWH with COVID-19. The risks for poor outcomes were higher in those with comorbidities and lower CD4 cell counts, despite HIV viral suppression. CLINICAL TRIALS REGISTRATION: NCT04333953.

Fostemsavir: A Novel Attachment Inhibitor for Patients With Multidrug-Resistant HIV-1 Infection.

OBJECTIVE: To review the efficacy and safety of fostemsavir (FTR) for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults who are failing their current antiretroviral regimen. DATA SOURCES: Clinical trials and review articles were obtained through PubMed (2015 to July 2020) using the search terms fostemsavir, BMS-663068, and GSK3684934. STUDY SELECTION AND DATA EXTRACTION: All relevant articles, trials, and abstracts in the English language were included. DATA SYNTHESIS: FTR demonstrates a novel mechanism of action, preventing virus attachment to the host CD4 receptor. FTR extended-release 600-mg tablets every 12 hours orally has proven beneficial in obtaining viral suppression for heavily treatment-experienced patients with multidrug-resistant infection refractory to other agents, as indicated in phase 3 trials. Treatment courses were evaluated to 96 weeks with significant viral load reductions noted within the first 24 weeks. Adverse events commonly reported include nausea, vomiting, diarrhea, fatigue, and headache. Serious events and fatality were not attributed to FTR and occurred because of advancement of HIV or other acute infection. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: FTR presents a new treatment option for patients with multidrug resistance and intolerability to other medications. The favorable adverse effect profile of FTR alongside the limited drug interaction profile makes it a viable option in a salvage regimen. CONCLUSIONS: FTR provides an alternative agent when composing a regimen for patients with multidrug-resistant HIV-1 infection. It is generally well tolerated, with few significant interactions, and neither renal nor hepatic dose adjustments are required.

Predicting Treatment Failure for Initiators of Hepatitis C Virus Treatment in the era of Direct-Acting Antiviral Therapy.

Introduction: Hepatitis C virus (HCV), the leading cause of advanced liver disease, has enormous economic burden. Identification of patients at risk of treatment failure could lead to interventions that improve cure rates. Objectives: Our goal was to develop and evaluate a prediction model for HCV treatment failure. Methods: We analyzed HCV patients initiating direct-acting antiviral therapy at four United States institutions. Treatment failure was determined by lack of sustained virologic response (SVR) 12 weeks after treatment completion. From 20 patient-level variables collected before treatment initiation, we identified a subset associated with treatment failure in bivariate analyses. In a derivation set, separate predictive models were developed from 100 bootstrap samples using logistic regression. From the 100 models, variables were ranked by frequency of selection as predictors to create four final candidate models, using cutoffs of ≥80%, ≥50%, ≥40%, and all variables. In a validation set, predictive performance was compared across models using area under the receiver operating characteristic curve. Results: In 1,253 HCV patients, overall SVR rate was 86.1% (95% CI = 84.1%, 88.0%). The AUCs of the four final candidate models were: ≥80% = 0.576; ≥50% = 0.605; ≥40% = 0.684; all = 0.681. The best performing model (≥40%) had significantly better predictive ability than the ≥50% (p = 0.03) and ≥80% models (p = 0.02). Strongest predictors of treatment failure were older age, history of hepatocellular carcinoma, and private (vs. government) insurance. Conclusion: This study highlighted baseline factors associated with HCV treatment failure. Treatment failure prediction may facilitate development of data-driven clinical tools to identify patients who would benefit from interventions to improve SVR rates.

Perceptions of Long-Acting Injectable Antiretroviral Treatment Regimens in a United States Urban Academic Medical Center.

Patient acceptance of long-acting injectable antiretroviral (LAI-ARV) HIV-1 regimens will determine uptake. Although previous literature reports high satisfaction, these data stem from clinical trials subject to selection bias. This cross-sectional survey from the HIV practices of an urban academic medical center assessed perceptions and preferences using Likert scales toward overall acceptability, proposed frequencies, injection-site reaction durations, and distribution venue. 59% of surveys were completed resulting 202 respondents. 60% were male, 72% black, and the median age was 49 (IQR 36-58). 93% reported a once daily tablet frequency, 69% reported single tablet regimens, and 59% reported missing zero doses in the prior 30 days. Patients self-categorized as likely (57%) or unlikely (43%) to accept LAI-ARV. Both decreasing frequencies between injections and durations of injection-site reactions resulted higher acceptability scores. 57% of respondents preferred receiving an injectable from their clinician's office over other potential options. These data demonstrate positive LAI-ARV acceptance potential.

A Call to Action: The Role of Antiretroviral Stewardship in Inpatient Practice, a Joint Policy Paper of the Infectious Diseases Society of America, HIV Medicine Association, and American Academy of HIV Medicine.

Persons living with human immunodeficiency virus (HIV) and others receiving antiretrovirals are at risk for medication errors during hospitalization and at transitions of care. These errors may result in adverse effects or viral resistance, limiting future treatment options. A range of interventions is described in the literature to decrease the occurrence or duration of medication errors, including review of electronic health records, clinical checklists at care transitions, and daily review of medication lists. To reduce the risk of medication-related errors, antiretroviral stewardship programs (ARVSPs) are needed to enhance patient safety. This call to action, endorsed by the Infectious Diseases Society of America, the HIV Medicine Association, and the American Academy of HIV Medicine, is modeled upon the success of antimicrobial stewardship programs now mandated by the Joint Commission. Herein, we propose definitions of ARVSPs, suggest resources for ARVSP leadership, and provide a summary of published, successful strategies for ARVSP that healthcare facilities may use to develop locally appropriate programs.

Expanding Hepatitis C Virus Care and Cure: National Experience Using a Clinical Pharmacist-Driven Model.

BACKGROUND: The US National Viral Hepatitis Action Plan depends on additional providers to expand hepatitis C virus (HCV) treatment capacity in order to achieve elimination goals. Clinical pharmacists manage treatment and medication within interdisciplinary teams. The study's objective was to determine sustained virologic response (SVR) rates for clinical pharmacist-delivered HCV therapy in an open medical system. METHODS: Investigators conducted a multicenter retrospective cohort study of patients initiating direct-acting antivirals from January 1, 2014, through March 12, 2018. Data included demographics, comorbidities, treatment, and clinical outcomes. The primary outcome of SVR was determined for patients initiating (intent-to-treat) and those who completed (per-protocol) treatment. Chi-square tests were conducted to identify associations between SVR and adverse reactions, drug-drug interactions, and adherence. RESULTS: A total of 1253 patients initiated treatment; 95 were lost to follow-up, and 24 discontinued therapy. SVR rates were 95.1% (1079/1134) per protocol and 86.1% (1079/1253) intent to treat. The mean age (SD) was 57.4 (10.1) years, the mean body mass index (SD) was 28.7 (6.2) kg/m2, 63.9% were male, 53.7% were black, 40.3% were cirrhotic, 88.4% were genotype 1, and 81.6% were treatment-naïve. Patients missing ≥1 dose had an SVR of 74.9%; full adherence yielded 90% (P < .0001). CONCLUSIONS: HCV treatment by clinical pharmacists in an open medical system resulted in high SVR rates comparable to real-world studies with specialists and nonspecialists. These findings demonstrate the success of a clinical pharmacist-delivered method for HCV treatment expansion and elimination.

Impact of an Antiretroviral Stewardship Team on the Care of Patients With Human Immunodeficiency Virus Infection Admitted to an Academic Medical Center.

BACKGROUND: Interdisciplinary antiretroviral stewardship teams, comprising a human immunodeficiency virus pharmacist specialist, an infectious diseases physician, and associated learners, have the ability to assist in identification and correction of inpatient antiretroviral-related errors. METHODS: Electronic medical records of patients with antiretroviral orders admitted to our hospital were evaluated for the number of interventions made by the stewardship team, number of admissions with errors identified, risk factors for occurrence of errors, and cost savings. Risk factors were analyzed by means of multivariable logistic regression. Cost savings were estimated by the documentation system Clinical Measures. RESULTS: A total of 567 admissions were included for analysis in a 1-year study period. Forty-three percent of admissions (245 of 567) had ≥1 intervention, with 336 interventions in total. The following were identified as risk factors for error: multitablet inpatient regimen (odds ratio, 1.834; 95% confidence interval, 1.160-2.899; P = .009), admission to the intensive care unit (2.803; 1.280-6.136; P = .01), care provided by a surgery service (1.762; 1.082-2.868; P = .02), increased number of days reviewed (1.061; 1.008-1.117; P = .02), and noninstitutional outpatient provider (1.375; .972-1.946; P = .07). The 1-year cost savings were estimated to be $263 428. CONCLUSIONS: Antiretroviral stewardship teams optimize patient care through identification and correction of antiretroviral-related errors. Errors may be more common in patients with multitablet inpatient regimens, admission to the intensive care unit, care provided by a surgery service, and increased number of hospital days reviewed. Once antiretroviral-related errors are identified, the ability to correct them provides cost savings.

The Pharmacist's Expanding Role in HIV Pre-Exposure Prophylaxis.

The efficacy of pre-exposure prophylaxis (PrEP) to prevent HIV has been firmly established; however, the success of PrEP largely depends on access to care as well as high levels of medication adherence. One of the key areas of focus for the National HIV/AIDS Strategy for 2020 in the United States calls for full access to comprehensive PrEP services where appropriate and desired, with support for medication adherence. Despite advances and advocacy for PrEP since approval for adults in 2012, large rates of prescribing disparity exist among gender and race/ethnicity. In 2016, only 3.7% of all PrEP users were women and only 11.2% were black. As one of the most widely accessible health care resources, pharmacists are well positioned to improve patient understanding, promote medication adherence, provide key risk reduction counseling, and enhance PrEP efficacy. Pharmacists' knowledge and accessibility in nearly every urban and rural community can be leveraged as part of a comprehensive HIV prevention strategy to expand access to care and improve population health. As trusted health care professionals, pharmacists develop a strong rapport with patients and may be the key to address current disparities in PrEP prescribing patterns as well as serve as an essential liaison between patients and other members of the multi-disciplinary care team. The purpose of this review is to summarize available data on pharmacist involvement in various models of care providing PrEP services and to identify opportunities to maximize and expand the role of the pharmacist to improve access to PrEP.

Hepatitis C Update and Expanding the Role of Primary Care.

Primary care physicians (PCPs) are increasing their role in the fight against the Hepatitis C Virus (HCV). Approximately 3.5 million Americans currently live with chronic HCV with rising incidence among young persons, especially those affected by the opioid epidemic. Online guidelines and drug interaction checkers streamline treatment and increase accessibility for both patients and providers. Although treatment with new Direct Acting Antiviral agents ensure cure rates that routinely exceed 95%, as well as cause fewer adverse effects than previously available interferon-based regimens, some states still restrict access to HCV treatment, including by mandating which providers can prescribe and treat HCV. This special communication reviews HCV treatment resources, discusses data demonstrating similar cure rates between PCPs and specialists, and argues that capacity-building among PCPs will be necessary to control the HCV epidemic.

GABA release selectively regulates synapse development at distinct inputs on direction-selective retinal ganglion cells.

Synaptic inhibition controls a neuron's output via functionally distinct inputs at two subcellular compartments, the cell body and the dendrites. It is unclear whether the assembly of these distinct inhibitory inputs can be regulated independently by neurotransmission. In the mammalian retina, γ-aminobutyric acid (GABA) release from starburst amacrine cells (SACs) onto the dendrites of on-off direction-selective ganglion cells (ooDSGCs) is essential for directionally selective responses. We found that ooDSGCs also receive GABAergic input on their somata from other amacrine cells (ACs), including ACs containing the vasoactive intestinal peptide (VIP). When net GABAergic transmission is reduced, somatic, but not dendritic, GABAA receptor clusters on the ooDSGC increased in number and size. Correlative fluorescence imaging and serial electron microscopy revealed that these enlarged somatic receptor clusters are localized to synapses. By contrast, selectively blocking vesicular GABA release from either SACs or VIP ACs did not alter dendritic or somatic receptor distributions on the ooDSGCs, showing that neither SAC nor VIP AC GABA release alone is required for the development of inhibitory synapses in ooDSGCs. Furthermore, a reduction in net GABAergic transmission, but not a selective reduction from SACs, increased excitatory drive onto ooDSGCs. This increased excitation may drive a homeostatic increase in ooDSGC somatic GABAA receptors. Differential regulation of GABAA receptors on the ooDSGC's soma and dendrites could facilitate homeostatic control of the ooDSGC's output while enabling the assembly of the GABAergic connectivity underlying direction selectivity to be indifferent to altered transmission.

HIV Pre-Exposure Prophylaxis and Women: Survey of the Knowledge, Attitudes, and Beliefs in an Urban Obstetrics/Gynecology Clinic.

Uptake of HIV pre-exposure prophylaxis (PrEP) is low among women at risk for HIV acquisition. Of 468,000 women, whom the United States Centers for Disease Control and Prevention estimates to be eligible for PrEP, only 10,000 unique women have begun therapy through the third quarter of 2015. These data suggest insufficient HIV prevention efforts. This study, conducted at the site of an urban academic medical center with an emergency department HIV prevalence rate of 4%, assesses the knowledge, attitudes, and beliefs of women toward PrEP. A self-administered survey was conducted among women at a family planning obstetrics/gynecology clinic at Temple University Hospital (Philadelphia, PA). Participants assessed their HIV acquisition risk and answered eight questions regarding knowledge, attitudes, and beliefs toward PrEP. Three hundred eighty-nine surveys met inclusion criteria. Sixty-five percent of women were black, and 73% were between 18 and 33 years of age. The median self-perceived risk score was 0 (interquartile range = 2) using a Likert scale. Thirty-three percent of women believed that PrEP could work, and 27% knew that such a regimen existed. Concerns existed toward cost (44%) and side effects (39%). Fifty-seven percent of women surveyed stated that they would take a medication to prevent HIV, and 64% felt comfortable discussing the subject with her doctor. Our data demonstrate a lack of PrEP knowledge, although willingness for uptake among women at risk for HIV acquisition, and a need for directed education and outreach.

Ibalizumab.

PURPOSE OF REVIEW: Antiretroviral options for patients infected with multiclass resistant HIV-1 warrant the development of new agents with unique mechanisms of action and modes of delivery. Here we review one such agent, ibalizumab, a parenteral CD4 postattachment inhibitor that has demonstrated efficacy as part of combination antiretroviral therapy in the treatment of HIV-1. RECENT FINDINGS: In a phase III clinical trial in HIV-infected participants with multiclass antiretroviral drug resistance, the intravenous administration of ibalizumab led to declines in plasma HIV-1 RNA more than 0.5 log in 83% of participants at 1 week. An optimized background antiretroviral regimen was then added, and plasma HIV-1 RNA became less than 50 copies/ml in 43% of participants at 24 weeks. Adverse effects of ibalizumab were uncommon and generally low grade. Ibalizumab was approved by the US Food and Drug Administration on March 16, 2018, under the trade name Trogarzo. SUMMARY: Ibalizumab has demonstrated both safety and efficacy in the treatment of HIV-1 infection. Its primary use will be in the setting of multidrug resistant virus as part of combination antiretroviral therapy. Further enhancements of ibalizumab to prolong its clearance and broaden its activity are in development.

Cross-compartmental Modulation of Dendritic Signals for Retinal Direction Selectivity.

Compartmentalized signaling in dendritic subdomains is critical for the function of many central neurons. In the retina, individual dendritic sectors of a starburst amacrine cell (SAC) are preferentially activated by different directions of linear motion, indicating limited signal propagation between the sectors. However, the mechanism that regulates this propagation is poorly understood. Here, we find that metabotropic glutamate receptor 2 (mGluR2) signaling, which acts on voltage-gated calcium channels in SACs, selectively restricts cross-sector signal propagation in SACs, but does not affect local dendritic computation within individual sectors. mGluR2 signaling ensures sufficient electrotonic isolation of dendritic sectors to prevent their depolarization during non-preferred motion, yet enables controlled multicompartmental signal integration that enhances responses to preferred motion. Furthermore, mGluR2-mediated dendritic compartmentalization in SACs is important for the functional output of direction-selective ganglion cells (DSGCs). Therefore, our results directly link modulation of dendritic compartmentalization to circuit-level encoding of motion direction in the retina.

Retinal origin of direction selectivity in the superior colliculus.

Detecting visual features in the environment, such as motion direction, is crucial for survival. The circuit mechanisms that give rise to direction selectivity in a major visual center, the superior colliculus (SC), are entirely unknown. We optogenetically isolate the retinal inputs that individual direction-selective SC neurons receive and find that they are already selective as a result of precisely converging inputs from similarly tuned retinal ganglion cells. The direction-selective retinal input is linearly amplified by intracollicular circuits without changing its preferred direction or level of selectivity. Finally, using two-photon calcium imaging, we show that SC direction selectivity is dramatically reduced in transgenic mice that have decreased retinal selectivity. Together, our studies demonstrate a retinal origin of direction selectivity in the SC and reveal a central visual deficit as a consequence of altered feature selectivity in the retina.

Stimulus-dependent recruitment of lateral inhibition underlies retinal direction selectivity.

The dendrites of starburst amacrine cells (SACs) in the mammalian retina are preferentially activated by motion in the centrifugal direction, a property that is important for generating direction selectivity in direction selective ganglion cells (DSGCs). A candidate mechanism underlying the centrifugal direction selectivity of SAC dendrites is synaptic inhibition onto SACs. Here we disrupted this inhibition by perturbing distinct sets of GABAergic inputs onto SACs - removing either GABA release or GABA receptors from SACs. We found that lateral inhibition onto Off SACs from non-SAC amacrine cells is required for optimal direction selectivity of the Off pathway. In contrast, lateral inhibition onto On SACs is not necessary for direction selectivity of the On pathway when the moving object is on a homogenous background, but is required when the background is noisy. These results demonstrate that distinct sets of inhibitory mechanisms are recruited to generate direction selectivity under different visual conditions.