HIV-Associated Inflammation: Do the drugs matter? Jun 15, 2018 Darrell H. S. Tan MD FRCPC PhD

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1 HIV-Associated Inflammation: Do the drugs matter? Jun 15, 2018 Darrell H. S. Tan MD FRCPC PhD

2 Faculty/Presenter Disclosure Faculty: Darrell H. S. Tan Relationships with financial sponsors / potential for conflicts of interest: Grants/Research Support: Gilead Sciences Inc., Viiv Healthcare Other: Site PI for clinical trials sponsored by Glaxo Smith Kline

3 Objectives 1. Why worry about inflammation in HIV? 2. What is the impact of different antiretroviral drugs on inflammation? 3. What other strategies might help reduce systemic inflammation?

4 Objectives 1. Why worry about inflammation in HIV? 2. What is the impact of different antiretroviral drugs on inflammation? 3. What other strategies might help reduce systemic inflammation?

5 5472 HIV+ pts with CD4>350 randomized to: Continuous therapy ( viral suppression, VS) Episodic therapy ( drug conservation, DC) ie. stop if CD4>350, restart if CD4<250 HR=2.6 (95%CI=1.9, 3.7) for death/oi HR=1.7 (95%CI=1.1, 2.5) for major CV/renal/hepatic NEJM 2006;355:2283

6 1. Nested case-control study Compared plasma inflammatory markers in n=85 pts who died vs. two matched controls/death Two timepoints: baseline, last value before death 2. Random sample of VS vs DC participants Compared biomarker changes in n=250 participants/arm 1 month post-randomization PLoS Med 2008;5:e203

7 Nested case-control study Pts who died had higher baseline hscrp, IL-6, D-dimer OR for death, comparing highest vs lowest quartile: hscrp: OR=2.0 (1.0,4.1) aor=3.1 (1.2, 8.0) IL-6: OR=8.3 (3.3,20.8) aor=12.4 (3.6, 42.0) D-dimer: OR=12.4 (4.2, 37.0) aor=41.2 (7.5, 225.6) PLoS Med 2008;5:e203

8 Comparing VS & DC arms at 1mo Drug conservation arm had greater increases in IL-6 & D-dimer after 1mo PLoS Med 2008;5:e203

9 Greater increase in VL associated with greater increase in D-dimer PLoS Med 2008;5:e203

10 Greater increase in VL associated with greater increase in IL-6 PLoS Med 2008;5:e203

11 Inflammatory markers remain higher than in HIV-negative controls despite suppressive ART Baseline biomarker levels in SMART participants with VL 400 and % difference compared to two general population cohorts (CARDIA, MESA) JID 2010;201;1788

12 HIV-related inflammation is associated with many forms of end-organ disease HIV-associated neurocognitive disorder AIDS 2013;27:1387 Malignancy AIDS 2013;27:1433 Cardiovascular disease PLoS One 2012;7:e44454 Chronic obstructive pulmonary disease Chest 2014;146:1543 Incident diabetes Diabetes Care 2010;33:2244 Osteoporosis J Infect Dis 2015;212:1241 Frailty J Infect Dis 2017;215:228

13 Multidimensional nature of HIVassociated inflammation Curr Op HIV/AIDS 2014;9:80

14 Objectives 1. Why worry about inflammation in HIV? 2. What is the impact of different antiretroviral drugs on inflammation? 3. What other strategies might help reduce systemic inflammation?

15 ACTG 5257: Open-Label ATV/RTV vs RAL vs DRV/RTV in First-line ART Stratified by HIV-1 RNA < or 100,000 c/ml, participation in metabolic substudy, CV risk Wk 96 after last patient enrolled ART-naive patients with HIV-1 RNA 1000 c/ml (N = 1809) ATV/RTV 300/100 mg QD + TDF/FTC (n = 605) RAL 400 mg BID + TDF/FTC (n = 603) Primary endpoints DRV/RTV 800/100 mg QD + TDF/FTC (n = 601) Virologic failure: time to VL>1000 (at Wk 16-24) or >200 (at/after Wk 24) Tolerability failure: time to discontinuation for toxicity Nested substudy of inflammation & immune activation

16 CID 2015;61:651

17 No consistent pattern in differences in biomarkers emerged that favoured any of the ART regimens CID 2015;61:651

18 RCT comparing TDF/FTC/ELV/cobi vs TDF/FTC/EFV Nested substudy of n=200 participants achieving VL<50 at week 48 JID 2015;212:345

19 JID 2015;212:345

20 Switch studies Trial n Switch Systemic inflammation SPIRAL 233 PI RAL hscrp IL-6 TNF ANRS 138 JID 2013;208: T20 RAL hscrp IL-6 Coagulation D-dimer D-dimer Monocyte activation Gupta et al. JAIDS 2013;64: EFV RAL hscrp scd14 scd163 Women, Integrase & Fat Accumulation Trial HIV Med2014;15: PI or NNRTI RAL hscrp IL-6 scd14

21 RAL intensification associated with decreased CD8 T-cell activation in immunodiscordant pts AIDS 2012;26:2285

22 RAL intensification associated with D-dimer declines in those on PI but not NNRTI regimens PLoS One 2014;9:e114142

23 Challenges in interpretation Statistical vs. clinical significance Adjustments for multiple comparisons Greater variability among participants than between drugs Class effect or drug effect?

24 Objectives 1. Why worry about inflammation in HIV? 2. What is the impact of different antiretroviral drugs on inflammation? 3. What other strategies might help reduce systemic inflammation?

25 RCT in N=30 CMV/HIV+ pts with CD4<350 on ART JID 2011;203:1474

26 Adjunctive strategies to treat inflammation in HIV Valganciclovir 900 mg/d (n=30) S boulardii (n=44) Rosuvastatin 10 mg/d (n=147) Rifaximin (n=65) Omega-3 FA 3.6g/d (n=48) Decreased T-cell activation Decreased IL-6, LPS-binding protein Decreased scd14, CD14 dim CD16+TF+ monocytes Less CD8+ T-cell activation Decreased IL-6, TNFa Unsuccessful Valacyclovir, aspirin, sevelamer, hydroxychloroquine, isotretinoin Forthcoming Pitavastatin, losartan, metformin, canakinumab, ruxolitinib, edoxaban, vorapaxar

27 Summary Many inflammatory pathways are upregulated in HIV & associated with mortality and endorgan disease ART is associated with incomplete decrease in this inflammation Small trials have shown modest differences between specific ARVs in some inflammatory markers Emerging literature on adjunctive therapies

28 The End