Author: Liclican, Albert ; Singer, Eric ; Xu, Lianhong ; Yu, Helen ; Ahmadyar, Shekeba ; Cihlar, Tomas ; Gonzalez, Ana ; Lee, Michael ; Aoyama, Ron ; Stafford, Brian ; Brumshtein, Boris ; Mulato, Andrew ; Voigt, Johannes ; Wang, Ruth ; Schultz, Brian ; Yant, Stephen R ; Lee, Johnny ; Murray, Bernard ; Marchand, Bruno ; Lee, Gary ; Chan, Julie ; Cho, Aesop ; Schmitz, Uli ; Xu, Yili ; Lansdon, Eric ; Gong, Ruoyu ; 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: Graham, Simon M. ; Laubscher, Maritz ; MacPherson, Peter ; Lalloo, David G. ; Harrison, William J. ; Maqungo, Sithombo ; Ferreira, Nando ; Held, Michael ; Simpson, A. Hamish

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 2019·Current Infectious Disease ReportsQ3 · MEDICINE

Simplifying ARV Therapy in the Setting of Resistance

Q3 · MEDICINE

Review

Author: Badowski, Melissa E ; Pallotta, Andrea M ; Michienzi, Sarah M ; Pandit, Neha Sheth ; Chastain, Daniel B ; Huesgen, Emily C

PURPOSE OF REVIEWHIV treatment simplification is typically indicated for virologically suppressed patients with no baseline resistance-associated mutations (RAMs) or prior virologic failure (VF) to the simplification regimen. Simplification can occur to minimize pill burden, toxicities, drug-drug interactions, or costs. As most studies for treatment simplification excluded patients with baseline RAMs or prior VF, this review is aimed to critically analyze data regarding treatment simplification in treatment-experienced patients.RECENT FINDINGSAntiretroviral (ARV) regimens containing three-, two-, and one-drug(s) have been scarcely studied to assess virologic efficacy in treatment-experienced patients. Three-drug regimens with the most data and highest efficacy are with integrase strand transfer inhibitors (INSTIs). Regimens including dolutegravir (DTG) and bictegravir have been shown to maintain efficacy in patients with certain baseline RAMs. Dual therapy regimens include the use of DTG plus either lamivudine (3TC), rilpivirine (RPV), or other ARVs. None of these studies evaluated patients with baseline DTG resistance. Baseline RAMs to 3TC were not a predictor of VF in patients on DTG/3TC. Efficacy was seen with DTG/RPV; however, studies showed high rates of discontinuation. DTG plus boosted-protease inhibitors were studied in smaller but promising studies. Two small studies assessed the use of monotherapy with boosted darunavir or DTG, both showing virologic efficacy. Currently, three- and two-drug ARV regimens may be considered in this population with most studies evaluating the use of DTG and bictegravir without baseline INSTI RAMs. Future studies should include heavily treatment-experienced patients with a variety of baseline RAMs and a larger sample size.

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