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Changes in Inflammatory and Atherogenesis Biomarkers With the 2-Drug Regimen Dolutegravir Plus Lamivudine in Antiretroviral Therapy-Experienced, Virologically Suppressed People With HIV-1: A Systematic Literature Review
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10 February 2022
SWITCHING TO THE 2-DRUG REGIMEN OF DOLUTEGRAVIR/LAMIVUDINE (DTG/3TC) FIXED-DOSE COMBINATION IS NON-INFERIOR TO CONTINUING A 3-DRUG REGIMEN THROUGH 48 WEEKS IN A RANDOMIZED CLINICAL TRIAL (SALSA)
Switching to DTG/3TC fixed-dose combination (FDC) is non-inferior to continuing a TAF-based regimen in maintaining virologic suppression through 144 weeks (TANGO Study)
Conclusions
Results show that dolutegravir plus lamivudine has a comparable impact on inflammatory and atherogenesis biomarkers vs 3/4DRs, with no consistent pattern of change after switch in virologically suppressed PWH.
In conclusion, switching to the 2DR dolutegravir plus lamivudine was not associated with consistent changes in inflammatory or atherogenesis biomarkers in 2 large, randomized, phase 3 trials (TANGO, n = 369; SALSA, n = 246) or in 1 real-world study (N = 67) in PWH who were virologically suppressed. Dolutegravir plus lamivudine has demonstrated durable, noninferior virologic efficacy, with no differences in low-level viremia and viral blips, or virologic control in sanctuary sites and reservoirs vs 3/4DRs. The data suggest a lack of impact of the number of drugs in an ART regimen as long as virologic suppression is maintained. HIV-associated inflammation is multifactorial, with comorbidities, lifestyle factors, coinfections, long-term immune damage, and ongoing viral replication and persistence all contributing to the inflammatory landscape. Although the clinical significance of inflammation in HIV is currently unknown, further studies are warranted to shed light on causes of underlying persistent inflammation in PWH with suppressed viremia and potential mitigation strategies.
Abstract
Background
The 2-drug regimen dolutegravir plus lamivudine has demonstrated long-term noninferior efficacy vs 3-/4-drug regimens (3/4DRs) in phase 3 trials. This systematic literature review summarizes clinical trial and real-world evidence evaluating impact of dolutegravir plus lamivudine on inflammatory and atherogenesis biomarkers in people with human immunodeficiency virus type 1 (PWH).
Methods
Using Ovid MEDLINE, Embase, PubMed, and Cochrane library databases and conference proceedings, we searched for studies published from 1 January 2013 to 14 July 2021, reporting changes in inflammatory and atherogenesis biomarkers with dolutegravir plus lamivudine in antiretroviral therapy-experienced, virologically suppressed PWH aged ≥18 years.
Results
Four records representing 2 randomized controlled trials (RCTs) and 6 records of real-world evidence met eligibility criteria. All real-world studies evaluated CD4+/CD8+ ratio, while only 1 assessed inflammatory biomarkers. Across both RCTs, no consistent pattern of change in biomarkers was observed between dolutegravir/lamivudine and 3/4DR comparators. There were significant changes in soluble CD14 favoring dolutegravir/lamivudine in TANGO at weeks 48 and 144 and SALSA at week 48, and in interleukin-6 favoring the control group in TANGO at weeks 48 and 144. In the real-world study evaluating inflammatory biomarkers, median soluble CD14 significantly decreased 48 weeks postswitch to dolutegravir plus lamivudine (P < .001), while other biomarkers remained stable. In all 6 real-world studies, increases in CD4+/CD8+ ratio were reported after switch to dolutegravir plus lamivudine (follow-up, 12-60 months).
Conclusions
Results show that dolutegravir plus lamivudine has a comparable impact on inflammatory and atherogenesis biomarkers vs 3/4DRs, with no consistent pattern of change after switch in virologically suppressed PWH.
DISCUSSION
In this systematic literature search of RCTs and real-world evidence, changes in inflammatory and atherogenesis biomarkers were analyzed in virologically suppressed PWH who switched to dolutegravir plus lamivudine 2DR from other ART regimens. Overall, there were no consistent patterns of change from baseline in inflammatory and atherogenesis biomarkers, with minimal changes observed after ART switch. There were significant decreases in sCD14 from baseline after switching to dolutegravir plus lamivudine in both clinical trials [18, 20, 33] and in one study of real-world evidence [29]. Overall changes in IL-6 were small and did not show a consistent trend. The minimal biomarker changes observed are as expected, given similar outcomes in viral replication demonstrated in clinical trials that showed no significant difference in rates of virologic suppression, residual viremia, and viral blips with dolutegravir/lamivudine 2DR vs comparator 3/4DRs [17-20, 22]. The clinical significance of these small fluctuations in inflammatory biomarkers is unknown and data have not demonstrated a difference in AIDS-related or non-AIDS-related clinical endpoints between 3/4DRs and 2DRs [39, 40]. Changes in CD4+/CD8+ ratio were similar between dolutegravir/lamivudine vs comparator postswitch in randomized controlled trials. Consistent increases in CD4+/CD8+ ratios were observed in real-world evidence after switch to dolutegravir plus lamivudine.
These results are consistent with findings in ART-naive PWH. In the phase 3 GEMINI-1 and GEMINI-2 studies comparing first-line ART with dolutegravir plus lamivudine vs the 3DR dolutegravir plus TDF/FTC in ART-naive PWH, there were minimal or no changes from baseline to 144 weeks in median levels of IL-6 (both groups, 0.0 [IQR, 0.0-0.0] ng/L) and CRP (dolutegravir plus lamivudine, 0.0 [IQR, -0.9 to 0.8] mg/L; dolutegravir plus TDF/FTC, −0.2 [IQR, -0.9 to 0.5] mg/L) in both groups [41].
These results are also strengthened by findings from other studies of dolutegravir-based 2DRs that mostly reported data from PWH receiving dolutegravir plus lamivudine but were not eligible for inclusion in this systematic review because they did not separately summarize data for those on dolutegravir plus lamivudine. In a small, randomized, open-label study of virologically suppressed PWH (n = 50; at baseline, 45 PWH were taking dolutegravir plus lamivudine and 5 dolutegravir plus rilpivirine) either continuing the dolutegravir-based 2DR (n = 25) or switching to elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF (n = 25), changes in CRP, IL-6, and D-dimer did not show any significant change with a switch from dolutegravir-based 2DRs to EVG/COBI/FTC/TAF through 96 weeks [42]. In a retrospective analysis of virologically suppressed PWH who switched to any dolutegravir-based 3DR or dolutegravir plus lamivudine 2DR (N = 133; 89 switched to dolutegravir plus lamivudine), plasma levels of sCD14 decreased significantly through 48 weeks after switch (P < .001) when compared with baseline, while changes in IL-6, CRP, and D-dimer were not significant (all P > .2) [43].
A small study nested in a nonrandomized cohort (Spanish HIV Research Network [CoRIS]) assessed changes in inflammatory biomarkers in archived samples over 3 years in suppressed PWH who started ART between 2004 and 2018 and switched to a 2DR (n = 58, 7 on dolutegravir plus lamivudine) or remained on 3-drug ART (n = 90). Increases in CRP and D-dimer were observed in the long-term follow-up modeled trajectories after switch, with no changes in IL-6, sCD14, sCD163, or FABP-2 [28, 40]. However, it is difficult to interpret the validity of this nested study due to several limitations, including small sample size, potential bias, and unmeasured confounders.
Both the randomized clinical trials and real-world evidence suggest an improvement in sCD14 at 48 weeks after switching to dolutegravir plus lamivudine. Soluble CD14 is a marker of monocyte and macrophage activation and a strong predictor of morbidity and mortality as well as cardiovascular disease in PWH [44]. Elevated plasma levels of sCD14 are observed in many chronic diseases associated with inflammation [44, 45]. However, this improvement is not seen in other biomarkers that potentially capture similar mechanisms of underlying inflammation (including CRP and sCD163).
To our knowledge, this is the first systematic literature review investigating the impact of a specific ART regimen on inflammatory and atherogenesis biomarkers in virologically suppressed PWH. The primary strengths of this review are the inclusion of 2 large, phase 3, randomized trials and the sizeable sample of PWH on dolutegravir plus lamivudine analyzed from both real-world evidence (N = 1000) and clinical trials (TANGO, n = 369; SALSA, n = 246). Further, this analysis investigated a wide variety of biomarkers of inflammation and atherogenesis representing multiple underlying pathways, although there are other cellular biomarkers (eg, CD38+) and T-cell subsets (eg, CD8+) that were not investigated in this review. Additionally, there are limitations in the assessment of inflammatory biomarkers with ART. First, the heterogeneity of real-world studies may affect the generalizability of findings, although the data from these studies are fairly consistent (eg, a consistent increase in CD4+/CD8+ ratio postswitch to dolutegravir/lamivudine). Second, although studies have evaluated changes in several markers that have been presumed to be surrogate markers for inflammation or atherogenesis in HIV, the confirmed correlation of these markers with specific clinical events has yet to be clearly established. Third, inflammatory biomarkers are primarily used in a research setting, and their clinical relevance is unknown. Guidelines do not recommend use of biomarkers for monitoring inflammation in clinical practice because there are no determined cutoff values (ie, what defines a meaningful change and how this varies by biomarker) or approved standardized methods for measurement, and biomarkers can significantly fluctuate in PWH due to non-HIV-related factors [46]. Regulatory agencies also do not require biomarker information to support ART approval [47]. Moreover, biomarkers such as CRP and D-dimer are broad, nonspecific indicators of inflammatory response [5, 48, 49]. Finally, most studies assessing changes in inflammatory biomarkers with ART do not account for host characteristics or comorbidities, such as coinfections and lifestyle factors, which may independently induce or modulate inflammation [48]. For example, sex can factor into residual HIV activity, cellular immune activation, and disease outcomes [50-53]. In a recent analysis from the US Women’s Interagency HIV Study, postmenopausal women had higher plasma sCD14 and sCD163 levels compared with premenopausal women after adjusting for relevant baseline covariates, suggesting that menopause (particularly during menopausal transition) may increase innate immune activation [8]. In the present analysis, female participants represented 39% of the overall SALSA study population (44% of dolutegravir/lamivudine participants) but only 8% of the TANGO study population. In the included real-world evidence studies, women represented approximately 25% of each study population. Underrepresentation of women in the existing literature is a common limitation in many studies and underscores the need for increased diversity in HIV studies.
In conclusion, switching to the 2DR dolutegravir plus lamivudine was not associated with consistent changes in inflammatory or atherogenesis biomarkers in 2 large, randomized, phase 3 trials (TANGO, n = 369; SALSA, n = 246) or in 1 real-world study (N = 67) in PWH who were virologically suppressed. Dolutegravir plus lamivudine has demonstrated durable, noninferior virologic efficacy, with no differences in low-level viremia and viral blips, or virologic control in sanctuary sites and reservoirs vs 3/4DRs. The data suggest a lack of impact of the number of drugs in an ART regimen as long as virologic suppression is maintained. HIV-associated inflammation is multifactorial, with comorbidities, lifestyle factors, coinfections, long-term immune damage, and ongoing viral replication and persistence all contributing to the inflammatory landscape. Although the clinical significance of inflammation in HIV is currently unknown, further studies are warranted to shed light on causes of underlying persistent inflammation in PWH with suppressed viremia and potential mitigation strategies.
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