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Inflammation in Chronic HIV Infection: What can we do? Author findings suggest integrase inhibitors have benefits
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"Hileman, et al. found that in the context of a double-blind randomized trial, 48 weeks of co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir-DF produced a significantly greater reduction in soluble CD14, hsCRP, and Lp-PLA2 compared to a co-formulated efavirenz/emtricitabine/tenofovir-DF regimen in antiretroviral-naïve adults.......These findings are similar to those reported in prior switch studies with raltegravir, a different integrase strand transfer inhibitor, where a change to raltegravir from enfuvirtide decreased IL-6, hs-CRP, and d-dimer [38]; a change from a protease inhibitor or nonnucleoside reverse transcriptase inhibitor decreased soluble CD14 [39]; and a change from efavirenz decreased soluble CD14 and hs-CRP [40]. .......authors demonstrate the potential benefit on inflammation and immune activation of a fixed dose, single-tablet integrase inhibitor-based regimen for the initial treatment regimen in antiretroviral-naïve individuals, independent of virologic suppression or immune recovery"
(see below full text of original article)
Journal of Infectious Diseases Advance Access published January 12, 2015
Kristine M. Erlandson and Thomas B. Campbell
University of Colorado; Department of Medicine, Division of Infectious Diseases
"HIV-infected persons have persistent, low grade inflammation and immune activation [1] that are strongly associated with a heightened risk for cardiovascular disease [2-4], osteoporosis [5], anemia [6], physical function impairments and frailty [7], among other non-AIDS events and mortality......Multiple factors likely contribute to the chronic inflammation and immune activation found in HIV-infected persons on antiretroviral therapy, but the independent role of each factor is difficult to discern. HIV-infected persons with residual HIV-1 replication, immune depletion, or with hepatitis B or C co-infection, especially among those with underlying fibrosis, exhibit higher levels of inflammation and immune activation.....Lifestyle changes, including exercise, can also reduce inflammation [31-33] and have proven clinical benefits beyond just a reduction in inflammatory biomarkers......Hileman, et al. found that in the context of a double-blind randomized trial, 48 weeks of co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir-DF produced a significantly greater reduction in soluble CD14, hsCRP, and Lp-PLA2 compared to a co-formulated efavirenz/emtricitabine/tenofovir-DF regimen in antiretroviral-naïve adults......authors demonstrate the potential benefit on inflammation and immune activation of a fixed dose, single-tablet integrase inhibitor-based regimen for the initial treatment regimen in antiretroviral-naïve individuals, independent of virologic suppression or immune recovery........authors hypothesize that the effect could be due to a greater concentration of integrase inhibitors in the gut.....The study reported by Hileman, et al. is another contribution supporting integrate inhibitors as a preferred component of initial antiretroviral regimens [48], although care should be taken to avoid over-generalization of these results.....Longer-term follow-up from the study by Hileman, et al. will help determine whether these effects on inflammation and activation are sustained, but larger trials will be needed to determine if these effects are clinically meaningful......specific biomarkers are associated with adverse clinical events in prior studies, whether a greater reduction in biomarker concentration with either of the single-tablet regimens tested by Hileman, et al. would result in an improvement in clinical outcomes has not yet been shown."
Effective antiretroviral therapy has dramatically improved the life expectancy of persons living with human immunodeficiency virus (HIV). However, even with long-term, effective antiretroviral therapy, HIV-infected persons have persistent, low grade inflammation and immune activation [1] that are strongly associated with a heightened risk for cardiovascular disease [2-4], osteoporosis [5], anemia [6], physical function impairments and frailty [7], among other non-AIDS events and mortality [8,9]. For example, a recent analysis in the Multicenter AIDS Cohort Study found that levels of soluble CD14, a marker of monocyte activation, were significantly higher in HIV-infected compared to HIV-uninfected men, but did not differ between HIV-infected men with or without effective antiretroviral therapy and changed very little in the years following antiretroviral initiation [10]. Given the long-term consequences of chronic inflammation, there is an urgent need to better understand the causes and to develop interventions that attenuate the effects of inflammation and immune activation in people living with HIV infection. The study by Hileman, et al in this issue of the Journal of Infectious Diseases, offers insight into how the choice of the initial antiretroviral regimen affects subsequent changes in inflammation and immune activation markers.
Multiple factors likely contribute to the chronic inflammation and immune activation found in HIV-infected persons on antiretroviral therapy, but the independent role of each factor is difficult to discern. HIV-infected persons with residual HIV-1 replication, immune depletion, or with hepatitis B or C co-infection, especially among those with underlying fibrosis, exhibit higher levels of inflammation and immune activation Other chronic viral co-infections are similarly associated with inflammation or immune activation: greater high sensitivity C-reactive protein (hs-CRP) and T-cell activation (%CD38 HLA-DR expression) were seen in subjects with HIV and human herpesvirus 8 co-infection [13], and elevated interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were associated with higher quantitative cytomegalovirus immunoglobulin in older, HIV-uninfected populations [14]. Microbial translocation persists to some degree despite suppressive antiretroviral therapy, and is associated with both immune activation and inflammation [15,16]. Lifestyle factors (e.g.., smoking, sedentary habits, or intravenous drug use) can further increase immune activation and inflammation: HIV-infected smokers had higher T-cell activation, soluble CD14 and lipopolysaccharide compared to HIV-infected non-smokers, [17]; increased injection drug frequency in a cohort with or at risk for HIV was associated with higher IL-6 and CRP [18]. Whether concomitant comorbidities are the consequence or cause is a matter of debate, but heightened inflammation and immune activation during HIV infection are associated with several diseases including depression [19], obesity [20], and diabetes [21].
In previous studies, interventions to attenuate inflammation and immune activation have targeted some of the inflammation-associated factors mentioned above. For instance, treatment with valganclovir, which has broad antiviral activity against herpesviruses including CMV, led to a decrease in CD8+ T-cell activation (%CD38 HLA-DR expression), but not other markers of inflammation [22], whereas acyclovir, which does not have activity against CMV, had no effect on markers of inflammation or activation [23]. Attempts to decrease inflammation by decreasing microbial translocation from the intestine with sevalamer or rifaximin have not proven successful [24,25], whereas 12 weeks of the probiotic Saccharomyces boulardii produced significant reductions in systemic IL-6 and lipopolysaccharide binding protein (LBP) [26]. Treatment with vitamin D, omega-3 fatty acids, and statins have reduced CD38 expression on CD8 T-cells [27], decreased IL-6 and TNF-alpha [28], and decreased lipoprotein-associated phospholipase A2 (Lp-PLA2) [29], respectively, among HIV-infected, antiretroviral-suppressed individuals. A recent observational study found that initiation of antiretroviral therapy together with rosuvastatin was associated with significantly greater decreases in both hs-CRP and TNFalpha compared to antiretrovirals alone [30]. Lifestyle changes, including exercise, can also reduce inflammation [31-33] and have proven clinical benefits beyond just a reduction in inflammatory biomarkers.
Over the past 27 years, the United States Food and Drug Administration has approved 25 antiretroviral drugs for treatment of HIV-1 infection [34]. Many well designed clinical trials have compared the efficacy and safety of various antiretroviral combinations, but relatively little is known about the impact of contemporary antiretroviral regimens on markers of inflammation or activation, outside of a possible adverse effect of abacavir on cardiovascular disease risk markers [35-37]. Could certain antiretroviral therapy regimens be associated with a greater decline in inflammation or immune activation? The article by Hileman, et al. provides interesting results to address this question. Hileman, et al. found that in the context of a double-blind randomized trial, 48 weeks of co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir-DF produced a significantly greater reduction in soluble CD14, hsCRP, and Lp-PLA2 compared to a co-formulated efavirenz/emtricitabine/tenofovir-DF regimen in antiretroviral-naïve adults. It is well known that integrase strand transfer inhibitors, such as elvitegravir, produce a more rapid phase of initial plasma HIV-1 RNA decay; however, the CD4+ lymphocyte count and plasma HIV-1 viral load responses were not significantly different between study arms. Moreover, the efavirenz/emtricitabine/tenofovir-DF arm actually had increased soluble CD14, hs-CRP, and Lp-PLA2 from week 0 to week 24 that failed to decline by week 48. These findings are similar to those reported in prior switch studies with raltegravir, a different integrase strand transfer inhibitor, where a change to raltegravir from enfuvirtide decreased IL-6, hs-CRP, and d-dimer [38]; a change from a protease inhibitor or nonnucleoside reverse transcriptase inhibitor decreased soluble CD14 [39]; and a change from efavirenz decreased soluble CD14 and hs-CRP [40]. Thus, the authors demonstrate the potential benefit on inflammation and immune activation of a fixed dose, single-tablet integrase inhibitor-based regimen for the initial treatment regimen in antiretroviral-naïve individuals, independent of virologic suppression or immune recovery.
Why might this be? The authors hypothesize that the effect could be due to a greater concentration of integrase inhibitors in the gut. Supporting this, a previous study showed that the integrase inhibitor raltegravir achieves higher gut tissue levels than other antiretrovirals, with the highest exposure following a single dose achieved in the terminal ileum compared to other gut sites [41]. Similarly, intensification with raltegravir decreased unspliced HIV RNA in the ileum, but not in other small or large bowel sites [42]. Although raltegravir intensification has been extensively tested to further decrease virologic replication, findings have primarily demonstrated a rapid increase followed by a decrease of 2-long terminal repeat circles, but no further reduction in HIV single-copy RNA or DNA proviral levels [42-47].
The study reported by Hileman, et al. is another contribution supporting integrate inhibitors as a preferred component of initial antiretroviral regimens [48], although care should be taken to avoid over-generalization of these results. First, soluble CD14, hs-CRP, and Lp-PLA2 are measures of immune activation and inflammation that serve as markers for clinical outcomes. Although these specific biomarkers are associated with adverse clinical events in prior studies, whether a greater reduction in biomarker concentration with either of the single-tablet regimens tested by Hileman, et al. would result in an improvement in clinical outcomes has not yet been shown. Depending on the clinical context, changes in biomarker levels might be interpreted quite differently. For example, elevated Lp-PLA2 (also known as platelet-activating factor acetylhydrolase or PAF-AH) is associated with increased cardiovascular disease risk in both HIV-infected and uninfected adults, and Lp-PLA2 inhibitors are currently under investigation to improve outcomes following cardiovascular events, thus far with limited mortality improvement [49]. In contrast, in the setting of septic shock, markedly low levels of Lp-PLA2 in multi organ failure [50] prompted a Phase III clinical trial of recombinant Lp-PLA2 to increase systemic Lp PLA2 levels, but was stopped early due to a lack of efficacy [51]. Thus, whether there is actual clinical benefit with reduction of these markers is unknown, and improvement in clinical outcomes should be demonstrated before clinical care is altered. A second key point in
interpreting the finding of Hileman, et al. is that the results are specific to the comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir-DF to efavirenz/emtricitabine/tenofovir-DF. Whether similar effects would be demonstrated with alternate integrase inhibitor-based regimens is unknown. The two regimens compared by Hileman, et al. also differed by inclusion of the cytochrome P450 inhibitor cobicistat in the formulation with greater effects on inflammation and immune activation markers. Thus, whether elvitegravir or cobicistat affected the immune activation and inflammation markers is not proven.
In clinical practice, when considering the low transmitted resistance, similar barrier to development of resistance, availability of a single-tablet once-daily regimen, and the exceptional tolerability, for many patients initiating antiretroviral therapy without contraindications, elvitegravir/cobicistat/emtricitabine/tenofovir-DF is among the preferred first-line regimens [48], regardless of additional benefits on inflammation or immune activation. Longer-term follow-up from the study by Hileman, et al. will help determine whether these effects on inflammation and activation are sustained, but larger trials will be needed to determine if these effects are clinically meaningful.
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Associations of Inflammatory Markers With AIDS and Non-AIDS Clinical Events After Initiation of Antiretroviral Therapy: AIDS Clinical Trials Group A5224s, a Substudy of ACTG A5202........http://www.natap.org/2014/HIV/012114_02.htm
"In summary, we showed that higher levels of several inflammatory biomarkers were associated independently of CD4 with increased risk of AIDS or non-AIDS events. Larger and longer studies should investigate the use of these markers as predictors of clinical end points, especially during long-term viral suppression on ART.......higher pre-ART and on-ART levels of several inflammatory biomarkers were associated independently of CD4 count with increased risk of progression to AIDS and/or non-AIDS events......we found that higher baseline hsCRP is associated with increased rate of progression to a non-AIDS event.....Baseline hsCRP was significantly associated with developing a non-AIDS event, and there was a trend for an association with IL-6. When we combined progression to AIDS and non-AIDS events, baseline hsCRP and IL-6 were associated with increased risk of clinical progression......non-AIDS-defining events (including cardiovascular disease, non-AIDS-defining malignancies, diabetes, liver disease, serious infection that does not fit CDC category C clinical event) and bone fractures"
"Thus far, several studies have linked a single measurement of an inflammatory marker to subsequent mortality,10-12 myocardial infarction risk,13 and increased intima media thickness14,15 (a marker of vascular disease). In contrast, very limited data exist on the association between either pre-ART or on-ART biomarker values to clinical events. To our knowledge, our study is the largest and longest study to use such an approach to assess this association in a randomized ART-initiation clinical trial""
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[CROI 2012] Changes in Inflammation and Endothelial Activation Markers in ARV-naïve Subjects Randomized to Abacavir/Lamivudine or Tenofovir/Emtricitabine along with Efavirenz or Atazanavir/ritonavir: AIDS Clinical Trials Group A5224s, a Sub-study of ACTG A5202.......http://www.natap.org/2012/CROI/croi_102.htm
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Differential Reduction in Monocyte Activation and Vascular Inflammation with Integrase Inhibitor-Based Initial Antiretroviral Therapy
Journal of Infectious Diseases Advance Access published January 12, 2015
Corrilynn O. Hileman1,2, Bruce Kinley3, Valeska Scharen-Guivel4, Kathy Melbourne4,
Javier Szwarcberg4, Janet Robinson1, Michael M. Lederman1,3, Grace A. McComsey1,3
1Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
2MetroHealth Medical Center, Cleveland, Ohio, USA
3University Hospitals Case Medical Center, Cleveland, Ohio, USA
4Gilead Sciences, Foster City, California, USA
"To our knowledge, this is the first study to compare the effects of ART initiation with an integrase
inhibitor (elvitegravir)- and a non-nucleoside reverse transcriptase inhibitor (NNRTI) (efavirenz)-
based regimen on markers of monocyte activation, systemic and vascular inflammation. We
show here that over 48 weeks, changes in sCD14, hsCRP and Lp-PLA2 favor EVG/c/FTC/TDF
over EFV/FTC/TDF."
"At baseline, markers of monocyte activation, systemic and vascular inflammation were similar
between-groups. Baseline, week 24, week 48 and absolute changes from baseline to week 24
and to week 48 in all markers are shown in Table 2. Within the EVG/c/FTC/TDF group, all
markers decreased significantly relative to baseline by week 48 with the exception of Lp-PLA2
which neared significance (p=0.06 within-group). In the EFV/FTC/TDF group, the changes were
mixed. Over 48 weeks, sCD163, sTNF-RI and IL-6 decreased significantly; however, Lp-PLA2
increased, and sCD14 and hsCRP did not change significantly.
Within-group analyses evaluating percent change in the markers were
similar to the absolute changes except, within the EVG/c/FTC/TDF group, change in hsCRP
was not statistically significant; and, in the EFV/FTC/TDF group, increases in sCD14 and
hsCRP were significant at both week 24 and 48.
Absolute and percent changes from baseline to week 24 and from baseline to week 48 were significantly different for sCD14, hsCRP (absolute
change only) and Lp-PLA2 with changes favoring the EVG/c/FTC/TDF group. Changes were
similar between groups for sCD163, sTNF-RI and IL-6. After adjustment for percent changes
from baseline to week 48 in weight, CD4+ cell count, hemoglobin level, eGFR, glucose level
and lipoprotein levels, percent change from baseline to week 48 in sCD14 and Lp-PLA2
remained significantly different between groups with changes favoring EVG/c/FTC/TDF (data
not shown)."
Abstract
Background. Little is known about how different antiretrovirals effect inflammation and monocyte activation in HIV infection.
Methods. We examined plasma obtained during a randomized, double-blind trial in ART-naïve HIV-infected adults comparing efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/c/FTC/TDF) and efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). From a random sample achieving HIV-1 RNA<50 copies/mL by week 48, changes over 24 and 48 weeks in biomarkers of monocyte activation (sCD14, sCD163), systemic (sTNF-RI, IL-6, hsCRP) and vascular inflammation (Lp-PLA2) were compared. Multivariable linear regression was employed.
Results. 200 participants were included. Significant differences favoring EVG/c/FTC/TDF were noted for changes in sCD14, hsCRP and Lp-PLA2. Factors independently associated with larger sCD14 decrease included randomization to EVG/c/FTC/TDF, higher baseline sCD14, and larger decreases in hsCRP and sCD163; and of larger Lp-PLA2 decrease included higher baseline Lp-PLA2 and IL-6, smaller increases in total cholesterol and triglycerides, larger decrease in sCD14, and smaller decrease in sCD163.
Conclusions. Antiretroviral initiation with EVG/c/FTC/TDF led to greater decreases in sCD14, hsCRP and Lp-PLA2 compared with EFV/FTC/TDF. Randomization group independently predicted change in sCD14, and changes in monocyte activation independently predicted change in Lp-PLA2. There appears to be a more favorable effect of the integrase inhibitor EVG over EFV on immune activation which may affect vascular inflammation.
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