European Workshop on NASH in Clinical Practice Barcelona 22-23th November 2019 NASH in HIV-infected patients Berend van Welzen, MD Infectious Diseases specialist University Medical Center Utrecht, the Netherlands Disclosures No conflicts of interest HIV: a short summary • Opportunistic infections and malignancies • Shift from deadly disease toward manageable, chronic illness • Current focus on comorbidities • Therapy is getting easier (STR, dual therapy) HIV: a short summary (II) • Nucleoside Reverse Transcriptase Inhibitors (Zidovudine, Didanosine, Stavudine, Lamivudine, Abacavir, Tenofovir, Emtricitabine) • Non-Nucleoside Reverse Transcriptase Inhibitors (Nevirapine, Efavirenz, Rilpivirine, Doravirine, Etravirine) • Protease inhibitors (PI) (Saquinavir, Indinavir, Ritonavir, Atazanavir, Darunavir) • Fusion/entry inhibitors (Maraviroc, Enfuvirtide, Ibalizumab) • Integrase inhibitors (INSTI) (Raltegravir, Elvitegravir, Dolutegravir, Bictegravir) Epidemiology Risk factors: High BMI, waist circumference, Type II Diabetes, Hypertension, Triglycerides and high CD4 cell count. Maurice et al. AIDS 2017, 31:1621–1632 ‘Head-to-Head’ Kardashian et al. (2017) Price et al. (2014) • MRI based diagnosis • Liver-spleen attenuation • ̴ 200 study subjects • ̴ 700 male study subjects • Excluding CVD • Women 17 vs 33% • Men 41 vs 33% (ns) • 13% (HIV+) vs 19% (HIV-) • Association with genetic polymorphisms & di- deoxynucleoside exposure Kardashian et al. AIDS 2017 Jan 28;31(3):365-373. Price et al. Am J Gastroenterol. 2014 May;109(5):695-704 Pathophysiology in ‘HIV-associated’ NAFLD Insulin resistance Mitochondrial toxicity Alcohol Genetics Microbiome HCV genotype III Immune Activation & Insulin Resistance • Steatosis present in approximately 60% • Steatogenic effect of HIV itself • HIV is characterized by intense immune activation Lebovics et al. Hepatology. 1985 Mar-Apr;5(2):293-8 Neuheus et al. The Journal of Infectious Diseases 2010 p 201(2)1788-1795 Residual immune activation? • Residual immune activation subject of debate • Is there still an increased risk for insulin resistance? Guihot et al. AIDS. 2016 Jan;30(2):327-30 cART-related insulin resistance? • Eearly generation protease inhibitors • Inhibitors of GLUT4-receptor • Ritonavir – still in use as pharmacological booster • Indinavir – not in use anymore. Hresko et al. PloS One. 2011;6(9):e25237. A more traditional risk factor for IR? • Increasing body mass index at diagnosis Crum-Cianflone et al. PLoS One. 2010 Apr 9;5(4):e10106 Weight gain as a result of antiretrovirals? Bourgi et al. Poster CROI 2019 Mitochondrial dysfunction Peripheral adipose tissue Hepatic mitochondria • Associated with Stavudine (d4T), Didanosine (ddI), Zalcitabine (ddC) http://tmedweb.tulane.edu/pharmwiki/doku.php/hiv_haart Lipodystrophy syndrome • mtDNA depletion in the subcutanous fat tissue • Mitochondrial dysfunction leads to apoptosis • Marked insulin resistance • Hypertriglyceridemia Brinkman et al. Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors. UpToDate Hepatic mitochondrial dysfunction Hepatic mitochondrial dysfunction • Decreased mitochondrial oxidation of fatty acids • Increased esterification triglycerides – less egress from the liver • Lipid accumulation in the liver Brinkman et al. Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors. UpToDate NAFLD treatment in HIV • Comparable to the general population • Early initiation of potent cART • cART with favorable metabolic profile • HCV cure • In the pipeline? • Different aetiology? Drug-drug-interactions? In the pipeline? • GHRH analogue – registered for central lipid accumulation in HIV • RCT (1:1) – tesamorelin vs placebo • Liver biopsy + MRI-assessed hepatic fat fraction at baseline and T=12m • Endpoints: HFF at 12m. Progression in fibrosis. Stanley et al. Lancet HIV. 2019 Oct 11. ePub Outcomes • NASH in approximately 30-35% of the patients • Most patients (50-60%) had no fibrosis In the pipeline? • Cenicriviroc (CVC) – originates from HIV research • Inhibitor of CCR2 & CCR5 receptor Mariana Verdelho Machado Presentation 13th International Workshop on co-infection HIV and Hepatitis (2017) In the pipeline? Take Home Messages • NAFLD is common in HIV – but does it exceed the general prevalence? • Common pathways – but sometimes different aetiology • Early start of treatment with safe antiretrovirals • When damage is done in the past, patients remain at risk for NAFLD • HIV-infected patients are underrepresented in current clinical trials .