Changes in inflammatory biomarkers in SWORD-1 and SWORD-2 studies - Authors' reply.

Change from baseline is a commonly used and accepted format to show change in parameters over time in clinical studies. The statistical analysis of changes in biomarkers from baseline to week 48, comparing patients switching to the two-drug regimen dolutegravir plus rilpivirine from a standard antiretroviral regimen on day 1 (early-switch group) with those continuing their three-drug current antiretroviral regimen (CAR), and the associated p values, are a valid and appropriate analysis of data generated in the controlled portion of the SWORD studies. The method used for this statistical analysis is stated in the footnote to table S3 in the appendix of our previous paper.1Aboud M Orkin C Podzamczer D et al.Efficacy and safety of dolutegravir-rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies.Lancet HIV. 2019; 6: e576-e587Summary Full Text Full Text PDF Scopus (33) Google Scholar The statistical analysis for the markers of inflammation showed a significantly greater increase in the concentration of sCD14 from baseline to week 48 in the three-drug CAR group compared with the early-switch group. This difference might be viewed as suggesting the presence of increased inflammation in participants who remained on the three-drug regimen compared with those receiving dolutegravir plus rilpivirine. However, we did not make this claim, because two other biomarkers of inflammation, interleukin 6 and sCD163, did not show a significant difference in the change from baseline to week 48 between the early-switch group and the three-drug CAR group. Regarding the biomarkers of atherogenesis, our analysis showed significantly greater reduction from baseline to week 48 in fatty acid binding protein 2 in the early-switch group compared with the three-drug CAR group. Greater reductions in this biomarker might be associated with improved cardiovascular outcomes.2Carlsson M Orho-Melander M Hedenbro J Almgren P Groop LC The T 54 allele of the intestinal fatty acid-binding protein 2 is associated with a parental history of stroke.J Clin Endocrinol Metab. 2000; 85: 2801-2804Crossref PubMed Scopus (56) Google Scholar, 3Makowski L Hotamisligil GS The role of fatty acid binding proteins in metabolic syndrome and atherosclerosis.Curr Opin Lipidol. 2005; 16: 543-548Crossref PubMed Scopus (150) Google Scholar However, the analysis did not identify a significant difference in the change from baseline to week 48 between the early-switch and the three-drug CAR groups for two other markers of atherogenesis, soluble vascular adhesion molecule 1 and D-dimer. These data, together with the heterogeneity in changes in multiple biomarkers from baseline or late-switch baseline, observed longitudinally through to week 100 across the early-switch and late-switch treatment groups, led us to state that together, these biomarker data showed that there was an absence of a consistent, reproducible pattern of change over time. Serrano-Villar and Moreno suggest that the data presented in our paper in table S3 for sCD14, sCD163, and interleukin 6, differ from that in a previous conference poster.4Hernandez B, Kahl L, Matthews J, et al. Bone, renal, and inflammatory biomarkers up to week 100 post switch to DTG + RPV: the SWORD-1 and SWORD-2 studies. HIV & Hepatitis Nordic Conference; Stockholm, Sweden; Sept 26–28, 2018 (abstr P9).Google Scholar The same values for change from baseline or late-switch baseline in biomarkers were included in table S3 as were included within the figure in the poster. This table also includes biomarker data for participants in the three-drug CAR group through to week 48. We reported longitudinal changes, beyond the controlled part of the study, with associated p values for bone biomarkers. These data were reported because longitudinal changes in these markers in people living with HIV have been reported previously, providing context and assisting data interpretation.5Bloch M Tong WWY Hoy J et al.Switch from tenofovir to raltegravir increases low bone mineral density and decreases markers of bone turnover over 48 weeks.HIV Med. 2014; 15: 373-380Crossref PubMed Scopus (46) Google Scholar, 6McComsey GA Kendall MA Tebas P et al.Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV.AIDS. 2007; 21: 2473-2482Crossref PubMed Scopus (129) Google Scholar, 7Stellbrink H-J Orkin C Arribas JR et al.Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study.Clin Infect Dis. 2010; 51: 963-972Crossref PubMed Scopus (313) Google Scholar To date, similar data providing context have not been produced for the markers of inflammation and atherogenesis, an emerging area of considerable interest in the field of HIV research. Longitudinal studies of these biomarkers have not been routinely done in randomised controlled studies evaluating treatment switches for people living with HIV.8Del Mar Gutierrez M Mateo MG Vidal F Domingo P Does choice of antiretroviral drugs matter for inflammation?.Expert Rev Clin Pharmacol. 2019; 12: 389-396Crossref Scopus (5) Google Scholar We concluded that without the context of a randomised control group beyond week 48, interpretation of statistical testing on these biomarkers is limited. Nevertheless, in the interest of transparency, the figure described by Serrano-Villar and Moreno, and presented in poster format at the HIV & Hepatitis Nordic Conference in 2018, is included as an appendix to this Correspondence. Further to the aforementioned discussion of data presented by us in table S3, on review of this figure it should be noted that the significant increase in sCD163 from baseline to week 48 in participants on the two-drug regimen was not significantly different to the increase in participants in the three-drug CAR group. In addition, the significant increase in sCD14 from baseline to week 48 observed in the two-drug group was found to be significantly lower in magnitude than that in the three-drug CAR group.1Aboud M Orkin C Podzamczer D et al.Efficacy and safety of dolutegravir-rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies.Lancet HIV. 2019; 6: e576-e587Summary Full Text Full Text PDF Scopus (33) Google Scholar Further, both the figure in the appendix and table S3 in our paper show an absence of concordance in the change from baseline compared with the change from the late-switch baseline in the two treatment groups, at 48 weeks following the switch to the dolutegravir plus rilpivirine regimen. These observations, together with the described data of atherogenesis biomarkers, support the conclusion that there is no consistent, reproducible pattern of change over time following the switch to the two-drug dolutegravir plus rilpivirine regimen. Together, these observations highlight the need for caution in the interpretation of longitudinal changes over time in biomarkers of inflammation and atherogenesis in the absence of a control group. To improve clarity and assist interpretation of these data of biomarkers of inflammation and atherogenesis from our SWORD studies, we are preparing a new manuscript that will describe changes in these biomarkers from baseline (day 1) through to week 148. Finally, as the results from the SWORD studies do not show a consistent, reproducible pattern of increased biomarkers of inflammation following the switch to dolutegravir plus rilpivirine, the speculation regarding penetration into lymphoid tissue and effect on inflammation is not supported by these studies. LPK is an employee of ViiV Healthcare and owns stock in GlaxoSmithKline. Download .pdf (.24 MB) Help with pdf files Supplementary appendix Changes in inflammatory biomarkers in SWORD-1 and SWORD-2 studiesWe have read with great interest the manuscript by Aboud and colleagues1 reporting the 100-week safety and efficacy data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies. Full-Text PDF