Inflammatory Biomarker Reduction With Fostemsavir Over 96 Weeks in Heavily Treatment-Experienced Adults With Multidrug-Resistant HIV-1 in the BRIGHTE Study

Overview

Journal Open Forum Infect Dis

Specialty Infectious Diseases

Date 2024 Sep 5

PMID 39233711

Authors

Andrew Clark

Manyu Prakash

Shiven Chabria

Amy Pierce

Jose R Castillo-Mancilla

Marcia Wang

Fangfang Du

Allan R Tenorio

Affiliations

Soon will be listed here.

Abstract

Background: Fostemsavir, a first-in-class attachment inhibitor that binds to the viral envelope protein gp120, is approved for heavily treatment-experienced persons with HIV-1 with limited treatment options. We explored changes in immunologic and coagulopathy parameters in the BRIGHTE study: a phase 3 trial that evaluated fostemsavir plus optimized background therapy in heavily treatment-experienced adults with multidrug-resistant HIV-1.

Methods: CD4+ T-cell count, CD4+/CD8+ ratio, soluble CD14, soluble CD163, and D-dimer levels were measured through 96 weeks in participants with 1 or 2 fully active antiretroviral agents available at screening. No formal statistical analyses were performed.

Results: Among 272 participants, increases were observed from baseline to week 96 in CD4+ T-cell count (mean increase, +205 cells/mm) and CD4+/CD8+ ratio (mean increase, +0.24). The proportion of observed participants with a CD4+/CD8+ ratio ≥0.45 increased from 9% (25/272) at baseline to 40% (85/213) at week 96. From baseline to week 96, we also observed trends toward decreases in the following (mean [SD] change): soluble CD14, -738.2 (981.8) µg/L; soluble CD163, -138.0 (193.4) µg/L; and D-dimer, -0.099 (0.521) mg/L fibrinogen-equivalent units. Decreases in biomarkers were generally observed among subgroups by baseline disease characteristics, virologic response, and CD4+ T-cell count.

Conclusions: These data suggest that heavily treatment-experienced persons with multidrug-resistant HIV-1 treated with fostemsavir + optimized background therapy may have improvements in immune parameters, including markers of monocyte activation and coagulopathy.

Clinical Trials Registration: NCT02362503 (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02362503).

References

Musinguzi N, Castillo-Mancilla J, Morrow M, Byakwaga H, MaWhinney S, Burdo T . Antiretroviral Therapy Adherence Interruptions Are Associated With Systemic Inflammation Among Ugandans Who Achieved Viral Suppression. J Acquir Immune Defic Syndr. 2019; 82(4):386-391. PMC: 6820698. DOI: 10.1097/QAI.0000000000002148. View

Kuller L, Tracy R, Belloso W, De Wit S, Drummond F, Lane H . Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008; 5(10):e203. PMC: 2570418. DOI: 10.1371/journal.pmed.0050203. View

Hunt P, Lee S, Siedner M . Immunologic Biomarkers, Morbidity, and Mortality in Treated HIV Infection. J Infect Dis. 2016; 214 Suppl 2:S44-50. PMC: 5021241. DOI: 10.1093/infdis/jiw275. View

Kelesidis T, Tran T, Stein J, Brown T, Moser C, Ribaudo H . Changes in Inflammation and Immune Activation With Atazanavir-, Raltegravir-, Darunavir-Based Initial Antiviral Therapy: ACTG 5260s. Clin Infect Dis. 2015; 61(4):651-60. PMC: 4542595. DOI: 10.1093/cid/civ327. View

Sandler N, Wand H, Roque A, Law M, Nason M, Nixon D . Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011; 203(6):780-90. PMC: 3071127. DOI: 10.1093/infdis/jiq118. View

Mussini C, Lorenzini P, Cozzi-Lepri A, Lapadula G, Marchetti G, Nicastri E . CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study. Lancet HIV. 2015; 2(3):e98-106. DOI: 10.1016/S2352-3018(15)00006-5. View

Zicari S, Sessa L, Cotugno N, Ruggiero A, Morrocchi E, Concato C . Immune Activation, Inflammation, and Non-AIDS Co-Morbidities in HIV-Infected Patients under Long-Term ART. Viruses. 2019; 11(3). PMC: 6466530. DOI: 10.3390/v11030200. View

Rychert J, Strick D, Bazner S, Robinson J, Rosenberg E . Detection of HIV gp120 in plasma during early HIV infection is associated with increased proinflammatory and immunoregulatory cytokines. AIDS Res Hum Retroviruses. 2010; 26(10):1139-45. PMC: 2982714. DOI: 10.1089/aid.2009.0290. View

Mani N, Murray J, Gulick R, Josephson F, Miller V, Miele P . Novel clinical trial designs for the development of new antiretroviral agents. AIDS. 2012; 26(8):899-907. PMC: 3343181. DOI: 10.1097/QAD.0b013e3283519371. View

10.

Han W, Apornpong T, Kerr S, Hiransuthikul A, Gatechompol S, Do T . CD4/CD8 ratio normalization rates and low ratio as prognostic marker for non-AIDS defining events among long-term virologically suppressed people living with HIV. AIDS Res Ther. 2018; 15(1):13. PMC: 6158807. DOI: 10.1186/s12981-018-0200-4. View

11.

Harezlak J, Buchthal S, Taylor M, Schifitto G, Zhong J, Daar E . Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS. 2011; 25(5):625-33. PMC: 4326227. DOI: 10.1097/QAD.0b013e3283427da7. View

12.

Appay V, Sauce D . Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol. 2007; 214(2):231-41. DOI: 10.1002/path.2276. View

13.

Borges A, OConnor J, Phillips A, Baker J, Vjecha M, Losso M . Factors associated with D-dimer levels in HIV-infected individuals. PLoS One. 2014; 9(3):e90978. PMC: 3953205. DOI: 10.1371/journal.pone.0090978. View

14.

Attia H, El Nagdy M, Halim R . Preliminary Study of sCD14 and sCD163 as Predictors of Disease Severity and ICU Admission in COVID-19: Relation to Hematological Parameters, Blood Morphological Changes and Inflammatory Biomarkers. Mediterr J Hematol Infect Dis. 2023; 15(1):e2023046. PMC: 10497305. DOI: 10.4084/MJHID.2023.046. View

15.

Freiberg M, Chang C, Kuller L, Skanderson M, Lowy E, Kraemer K . HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013; 173(8):614-22. PMC: 4766798. DOI: 10.1001/jamainternmed.2013.3728. View

16.

Santosuosso M, Righi E, Lindstrom V, Leblanc P, Poznansky M . HIV-1 envelope protein gp120 is present at high concentrations in secondary lymphoid organs of individuals with chronic HIV-1 infection. J Infect Dis. 2009; 200(7):1050-3. DOI: 10.1086/605695. View

17.

Freiberg M, Bebu I, Tracy R, So-Armah K, Okulicz J, Ganesan A . D-Dimer Levels before HIV Seroconversion Remain Elevated Even after Viral Suppression and Are Associated with an Increased Risk of Non-AIDS Events. PLoS One. 2016; 11(4):e0152588. PMC: 4835105. DOI: 10.1371/journal.pone.0152588. View

18.

Gomez-Rial J, Curras-Tuala M, Rivero-Calle I, Gomez-Carballa A, Cebey-Lopez M, Rodriguez-Tenreiro C . Increased Serum Levels of sCD14 and sCD163 Indicate a Preponderant Role for Monocytes in COVID-19 Immunopathology. Front Immunol. 2020; 11:560381. PMC: 7538662. DOI: 10.3389/fimmu.2020.560381. View

19.

Kozal M, Aberg J, Pialoux G, Cahn P, Thompson M, Molina J . Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2020; 382(13):1232-1243. DOI: 10.1056/NEJMoa1902493. View

20.

Llibre J, Aberg J, Walmsley S, Velez J, Zala C, Crabtree Ramirez B . Long-term safety and impact of immune recovery in heavily treatment-experienced adults receiving fostemsavir for up to 5 years in the phase 3 BRIGHTE study. Front Immunol. 2024; 15:1394644. PMC: 11165140. DOI: 10.3389/fimmu.2024.1394644. View