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CROI 2018: Comorbidities and Inflammation
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David H Shepp, MD
Associate Professor of Medicine
Zucker School of Medicine at Hofstra-Northwell
Manhasset, NY
Overview. Contemporary antiretroviral therapy (ART) has increased life expectancy for people with HIV (PWH). As a result, chronic diseases associated with aging now cause the greatest health burden for PWH living in higher income regions. Included are cardiovascular disease (CVD), diabetes, cancer, chronic kidney disease, osteoporosis and cognitive dysfunction, often referred to as non-AIDS co-morbidities (NACs). Traditional risk factors such as smoking, hypertension, and dyslipidemia are highly prevalent in PWH and play a central role in development of NACs. However, chronic inflammation and immune activation also contribute to their pathogenesis.
At CROI 2018, an excellent symposium (S-6: "Life Expectancy at 25") reviewed current information about the intersection between improving life expectancy and NACs. The first talk (Sabin C, abstract 102) showed that life expectancy at age 25 has improved continuously since the mid-1990s, but in most HIV patient subsets still lags behind that of the general population, even in countries with extensive health resources. In resource limited areas, dramatic gains in life expectancy also have been made but the increases are smaller, largely due to high rates of tuberculosis. However, in areas with a low incidence of tuberculosis, those starting ART with CD4 ≥350 and achieving sustained viral suppression have normal life expectancy. Most of the loss of life expectancy occurs in the first 6 months after starting ART. For those surviving this initial period, gains in life expectancy are substantially greater. The burden of many NACs, as well as drug overdoses, accidents and suicide is greater in PWH than in the general population, especially in the first year after ART initiation.
The second talk examined modifiable risk factors for NACs (Althoff KN, abstract 103). Early diagnosis and initiation of ART appears to be the most effective intervention. Reducing smoking, substance abuse, social isolation, obesity, hypertension and hyperlipidemia are also important. For those on ART, smoking reduces life expectancy much more than HIV itself, making effective smoking cessation programs a critical unmet need. The third talk focused on the role of chronic inflammation (Baker JV, abstract 104). Pre-ART biomarkers of inflammation and coagulation have been shown to correlate strongly with subsequent adverse events, both AIDS-related and NACs. IL-6 and d-dimer are the best studied, but other markers also correlate. IL-6 typically declines 10-20% after ART initiation, then plateaus and remains elevated compared to HIV-uninfected controls for extended periods of time. Initiation of ART during very early HIV infection allows the best chance for markers of inflammation and immune activation to normalize.
Causes of Inflammation. Chronic persistent inflammation in those on otherwise successful ART is multifactorial and incompletely understood. Microbial translocation, CMV co-infection, low level HIV replication or expression of viral products, immune dysregulation and toxicity of ART are all potential causes. Several abstracts provided additional insights into the mechanisms of persistent inflammation in HIV.
ART rapidly controls HIV infection in CD4+ T-cells, but sensitive assays may detect viral RNA intermittently at very low levels for extended periods of time, even though very little or no infectious virus can be detected. A likely source is long-lived cells in the macrophage lineage. Two presentations provided laboratory evidence that production of unspliced, intron-containing HIV RNA transcripts are sufficient to cause immune activation in macrophages or dendritic cells, even in the absence of translation of viral proteins. (McCauley S, abstract 21; Akiyama H, poster 216). These studies help explain how non-productively infected cells may still trigger an inflammatory response. Clayton et al presented in-vitro studies showing that HIV-infected macrophages are resistant to killing by cytotoxic T-cells, resulting in persistent but ineffective activation of CD8+ T-cells that produce of cytokines, triggering the inflammatory cascade (Clayton KL, poster 224LB).
Biomarkers of Inflammation and Clinical Events. The human immune response to infection is complex and involves activation and regulation of several independent but closely interrelated cascades. Jason Baker analyzed data from nearly 4000 START trial participants to determine how well the change in IL-6, d-dimer and CD4/CD8 ratio explain the observed reduction in clinical events with immediate vs deferred ART (Baker JV, abstract 74). The percent treatment effect (PTE) explained by each biomarker was calculated as the reduction in the overall hazard ratio (HR) for immediate vs deferred ART after adjustment for the latest biomarker level, as a percentage of the overall HR. For all 3 biomarkers the PTE was around 10, with each providing independent and additive prediction. The finding is consistent with the notion that these 3 biomarkers represent largely separate pathways (innate immunity, coagulation, adaptive immunity) and that multiple pathways each contribute to risk of serious clinical events.
CROI: IL-6, D-dimer or T-cells: which best predict events or explain benefits of early ART? - (03/07/18)
CVD. One of the great success story of modern medicine is the declining death rates due to CVD in the general population, attributable to better management of dyslipidemia, hypertension, declining smoking, improvements in management of acute coronary syndromes. Rates of CVD also are declining in PWH, but remain higher than in the HIV-uninfected population. Post et al presented a large longitudinal study using CT angiography to measure progression of coronary artery plaque in HIV-infected (n=316) and uninfected men (n=235). The average time between scans was 4.5 years. After adjustment for multiple other CVD risk factors, both calcified and non-calcified plaque volume increased significantly more in the HIV-infected participants. The difference was seen only in non-black subjects. HIV was not associated with disease progression in blacks. Among non-blacks, the odds ratios for plaque progression were similar for those with and without sustained viral suppression on ART. Correlations between inflammatory markers and plaque progression will be analyzed but were not presented at this meeting (Post W, abstract 78).
CROI: Progression of Coronary Plaque: The MACS Longitudinal Coronary CT Angiography Study" - (03/07/18)
Peripheral vascular disease (PVD) is part of the spectrum of atherosclerosis and is increased in those with or at risk for CVD in the general population. While many studies have established that CVD risk is greater in HIV-infected than in uninfected controls, there is less data on PVD. Knudsen et al. assessed PVD in 908 HIV-infected individuals and 11,000 matched HIV-uninfected controls in Denmark. PVD was assessed by ankle/brachial blood pressure index. The study population was predominantly white and the HIV-infected participants had very high rates of viral suppression on ART. Before adjustment for other risk factors, PVD was found in 12% of PWH and 6% of controls. After adjustment, HIV was associated with an 80% increase in PVD (odds ratio 1.8), similar to hypertension and exceeded only by current smoking as a risk factor (Knudsen AD, abstract 76).
These two studies provide evidence that both coronary and peripheral vascular disease are increased in PWH and HIV infection is an independent risk factor. The risk associated with HIV persists even in those on effective ART. The lack of effect of HIV on disease progress in black individuals is surprising and requires further study.
Other Disease Associations with Inflammation: The association between chronic inflammation and CVD is well established. An association with many other NACs is likely, but less firm. Several studies provided data linking inflammation to other adverse medical events. Siddiqui et al. compared levels of 24 pre-onset inflammatory markers among 66 HIV-infected MACS cohort participants having a non-AIDS cancer diagnosis and matched controls (Siddiqi M poster 764). Multiple inflammatory markers (IFN-γ IL-6, IL-10, CXCL13, CRP and others) were associated with virus-related non-AIDS cancers (liver, anal oral cancers and Hodgkin's disease), while no biomarkers correlated with cancers that are not virus-related. Decreased small artery elasticity (SAE) has been shown to precede onset of hypertension and CVD in the general population. In a cross-sectional study, Peterson et al. measured SAE using tonometric radial artery waveform and correlated findings with inflammatory markers in 326 participants in the START trial prior to ART initiation (Peterson TE, poster 679). After adjustment for other covariables, higher IL-6 correlated with lower SAE. Since all START participants had a CD4≥500, this study suggests that even in early HIV infection, inflammation causes clinically relevant changes in vascular function that may herald hypertension and CVD. A case-control study of 107 pregnant women in India found an association between sCD14, sCD163 and I-FABP (a marker of gut epithelial injury) levels and pre-term birth (Shivakoti R, poster 835). A cross-sectional study conducted in PWH in rural Uganda, where smoking and firewood smoke exposures were both common, found correlations between pulmonary function (FEV1 and FVC) and the plasma inflammatory markers, hsCRP, IL-6 sCD14, sCD163 (North CM, poster 748).
Statins. Statins have been shown to decrease CVD events in at-risk individuals in the general population. They have anti-inflammatory as well as lipid-lowering properties and a well-characterized safety profile. There are currently no HIV-specific recommendations for statin use, but according to guidelines for the general population, statins are underutilized in PWH. Two large cohort studies reported statin use in PWH receiving care in the US military and the Washington DC area. Only 53% and 56% of eligible patients in these two cohorts, respectively, were receiving statin therapy per the ACC/AHA guidelines (Larson D, poster 705; Levy ME, poster 690).
Even though currently underutilized, there is interest in finding out if even broader use of statins might be beneficial in PWH, because of increased risk of CVD events. The Reprieve trial is a large, ongoing NIH funded randomized clinical end-point trial comparing pitavastatin to placebo in HIV-infected individuals who do not meet the current criteria for statin use. Therefore, the effects of pitavastatin on inflammation is of interest. Twelve Thai patients on ART participated in a placebo-controlled cross-over study of the effect of pitavastatin or placebo on cellular markers of immune activation. Pitavastatin was not associated with lower absolute T-cell or monocyte counts but did lower activation and exhaustion markers for CD4+ T-cells and monocytes (Phuphuakrat A, poster 689). Effects on innate immune and coagulation biomarker such as IL-6 and d-dimer were not reported.
Many cohort studies have found an association between statin use and reduced risk of cancer and/or all-cause mortality. An important limitation of such studies is the possibility of confounding differences between those prescribed and those not prescribed statins that cannot be fully adjusted for in multivariable analysis. Cancer diagnoses and mortality among nearly 100,000 individuals cared for by the VA health system were reported (Bedimo R, abstract 132). HIV-infected and uninfected statin users were matched to non-users by propensity score to try to adjust for confounding by indication. Statin users had large reductions in both AIDS-related and non-AIDS-related cancers in both HIV-infected and uninfected patient subsets. Overall mortality was also lower in statin users. Although this study was large and used propensity scoring to adjust for confounding, there remains a concern that statin users are different from non-users in ways that are not adequately captured by this type of analysis. Although the Reprieve trial is designed to evaluate CVD, it may also provide more reliable data on statins and cancer.
Novel Therapies Targeting Inflammation: The landmark CANTOS trial, conducted in the general population, demonstrated that a purely anti-inflammatory therapy that does not lower cholesterol or blood pressure can reduce CVD events in high risk individuals with an elevated hsCRP. The intervention used was canakinumab, a monoclonal antibody against IL-1ß. Surprisingly, cancers were also reduced but an increased rate of death due to infection cancelled out any potential survival benefit. Use of canakinumab in HIV is being evaluated in a phase 2 trial, but safety concerns may prevent wider use. Low-dose methotrexate (MTX) is an anti-inflammatory therapy with an established safety and efficacy record in inflammatory polyarthropathies. Observational data suggests its use in rheumatoid arthritis is associated with a reduced incidence of CVD events and a controlled trial for CVD prevention in the general population is in progress. Hsue et al. reported the results of a randomized, placebo-controlled trial of 24 weeks of low-dose MTX (maximum 15 mg/week) in 176 ART-treated PWH ≥40 years of age and at increased risk for CVD (Hsue P, abstract 79). The rate of pre-defined key adverse events was 7% higher in MTX recipients, a small enough increase to satisfied the primary outcome of the trial which was safety. The key adverse events included 3 protocol-defined CD4 declines and one fatal case of pneumonia in MTX recipients. CD8+ T-cell number and activation were significantly decreased by MTX at multiple time points. However, endothelial function and multiple biomarkers of innate immune activation were not different been arms. A subset of 28 study participants underwent FDG-PET/CT to measure aortic arterial inflammation (Tawakol A, poster 684LB). More reduction in inflammation was seen in the MTX group but only before adjustment for background. The implications of this trial are unclear. The trial was not designed to assess clinical events. Endothelial function was not improved and even though the protocol-defined primary safety objective was met, some serious adverse events were seen during a relatively short treatment course. Although many lines of evidence have shown an important role for CD8+ T-cells in the pathogenesis of atherosclerosis, in HIV the most robust association with CVD and other NACs have been with markers of innate immunity, such as IL-6, which were not improved.
Understanding how protein kinases deliver intracellular activation signals to regulate growth, and development of drugs to block them, has revolutionized the treatment of certain cancers and rheumatologic disorders. There are many different protein kinases utilized by the major classes of cytokine receptors to deliver intracellular activation signals. All utilize the p38 MAP kinase, although none use it exclusively. Aldovini et al. presented the effects of an investigational p38 MAP kinase inhibitor (PH797804) combined with ART in SIV-infected macaques (Aldovini A, abstract 20). PH79804 added to ART, given either 1 or 6 weeks after infection, yielded greater reductions in many inflammatory markers (IFNα, IFNγ , TNFα , IL-6, CRP,sCD163) and T-cell activation markers than did ART alone. No p38 MAP kinase inhibitors are approved for clinical use, but several are being investigated in other diseases. These studies suggest inhibition or p38 MAP kinase should be explored as an adjunct to ART in HIV.
Microbial translocation (MT) is a cause of chronic inflammation in HIV and results from dysfunction in gut-associated lymphoid tissue, epithelial barrier damage and alterations in the microbiome. Several small pilot studies evaluated adjunctive therapies to restore the normal GI tract microbiome and/or repair epithelial barriers to reduce MT in patients receiving ART. The non-absorbable antibiotic rifaxamin was no more effective than placebo (Ganesan A, poster 313). Two studies using the proprietary pre- and/or probiotics PMT25341 and Visbiome ES, were largely negative (Serrano-Villar S, poster 275, Presti R, poster 274). A third study of 8 weeks of twice daily dosing of Lactobacillus rhamnosus GG found reduced GI tract inflammation as assessed by FDG-PET/MRI but no reduction in the translocation marker LPS in plasma. In a controlled trial, isotretinoin appeared to paradoxically worsen markers of immune activation (Nin NH, poster 219). These mostly negative studies suggest that targeting the microbiome or damaged gut epithelial barriers will not be a simple way to reduce MT and inflammation. The alterations in normal host defenses caused by HIV are complex. Further research is needed to understand how to design effective interventions.
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