Author: Singer, Eric ; Liclican, Albert ; Xu, Lianhong ; Yu, Helen ; Ahmadyar, Shekeba ; Cihlar, Tomas ; Gonzalez, Ana ; Lee, Michael ; Aoyama, Ron ; Stafford, Brian ; Voigt, Johannes ; Mulato, Andrew ; Brumshtein, Boris ; Wang, Ruth ; Schultz, Brian ; Yant, Stephen R ; Lee, Johnny ; Murray, Bernard ; Chan, Julie ; Lee, Gary ; Marchand, Bruno ; Cho, Aesop ; Schmitz, Uli ; Xu, Yili ; Gong, Ruoyu ; Lansdon, Eric ; Stepan, George J

Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no in vitro antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.

15 Aug 2021·JAIDS Journal of Acquired Immune Deficiency Syndromes

Fracture Healing in Patients With HIV in South Africa: A Prospective Cohort Study

Article

Author: Harrison, William J ; Laubscher, Maritz ; MacPherson, Peter ; Simpson, A Hamish ; Lalloo, David G ; Maqungo, Sithombo ; Graham, Simon M ; Held, Michael ; Ferreira, Nando

Background:HIV reduces bone mineral density, mineralization, and turnover and may impair fracture healing.Setting:This prospective cohort study in South Africa investigated whether HIV infection was associated with impaired fracture healing after trauma.Methods:All adults with acute tibia and femur fractures who underwent intermedullary (IM) nailing for fracture fixation between September 2017 and December 2018, at 2 tertiary hospitals, were followed up for a minimum of 12 months postoperatively. The primary outcome was delayed bone union at 6 months (defined by the radiological union scoring system for the tibia score <9), and the secondary outcome was nonunion (defined as radiological union scoring system for the tibia score <9) at 9 months. Multivariable logistic regression models were constructed to investigate the associations between HIV status and impaired fracture healing.Results:In total, 358 participants, who underwent 395 IM nailings, were enrolled in the study and followed up for 12 months. Seventy-one of the 358 (19.8%) participants were HIV-positive [83/395 (21%) IM nailings]. HIV was not associated with delayed fracture healing after IM nailing of the tibia or femur (multivariable odds ratio: 1.06; 95% confidence interval: 0.50 to 2.22). HIV-positive participants had a statistically significant lower odds ratio of nonunion compared with HIV-negative participants (multivariable odds ratio: 0.17; 95% confidence interval: 0.01 to 0.92).Conclusions:Fractures sustained in HIV-positive individuals can undergo surgical fixation as effectively as those in HIV-negative individuals, with no increased risk of delayed union or nonunion.

01 Oct 2020·JAIDS Journal of Acquired Immune Deficiency SyndromesQ3 · MEDICINE

Cerebrospinal Fluid Norepinephrine and Neurocognition in HIV and Methamphetamine Dependence

Q3 · MEDICINE

Article

Author: Heaton, Robert K. ; Iudicello, Jennifer E. ; Ellis, Ronald J. ; Saloner, Rowan ; Cherner, Mariana ; Letendre, Scott L.

Objective:HIV disease and methamphetamine (METH) dependence share overlapping mechanisms of neurotoxicity that preferentially compromise monoamine-rich frontostriatal circuitry. However, norepinephrine (NE) function is poorly understood in HIV and METH dependence. We evaluated associations between cerebrospinal fluid (CSF) NE and HIV, METH dependence, and neurocognition.Methods:Participants included 125 adults, stratified by HIV serostatus (HIV+/HIV−) and recent METH dependence (METH+/METH−), who underwent comprehensive neurocognitive testing and lumbar puncture. CSF NE was assayed using high-performance liquid chromatography. Multivariable regression modelled NE as a function of HIV, METH, and their interaction, adjusting for demographic and clinical factors. Pearson correlations examined relationships between NE and demographically-adjusted neurocognitive domain scores.Results:HIV significantly interacted with METH (P< 0.001) such that compared with HIV−/METH−, CSF NE was markedly elevated in the single risk-groups (HIV+/METH−:d= 0.96; HIV−/METH+:d= 0.79) and modestly elevated in the dual-risk group (HIV+/METH+:d= 0.48). This interaction remained significant after adjustment for lifetime depression, antidepressant use, and race/ethnicity. In the full sample, higher NE levels significantly correlated with worse global function (r= −0.19), learning (r= −0.23), and delayed recall (r= −0.18). Similar relationships between higher NE and worse neurocognition were detected in the METH− groups (ie, HIV−/METH− and HIV+/METH−) and in the virally-suppressed persons HIV+ subgroup, but not in the METH+ groups (ie, HIV−/METH+, HIV+/METH+).Discussion:HIV and METH independently, but not additively, relate to noradrenergic excess in the central nervous system, and perturbations to noradrenergic function may represent a pathophysiological mechanism of HIV-related neurocognitive dysfunction. Consistent with prior reports that noradrenergic excess compromises hippocampal and prefrontal function, higher NE related to worse neurocognition, even among successfully treated persons with HIV. Pharmacological and psychosocial interventions that stabilize NE function may improve neurocognition in persons with HIV.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Preclinical	US	Salus Therapeutics, Inc.	-

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