NASH in HIV-Infected Patients

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