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NASH in HIV-infected patients
Berend van Welzen, MD
Infectious Diseases specialist
University Medical Center Utrecht, the Netherlands
European Workshop on NASH in Clinical PracticeBarcelona 22-23th November 2019
Disclosures
No conflicts of interest
• 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
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
Kardashian et al. (2017)
• MRI based diagnosis
• ̴ 200 study subjects
• Women 17 vs 33%
• Men 41 vs 33% (ns)
Price et al. (2014)
• Liver-spleen attenuation
• ̴ 700 male study subjects
• Excluding CVD
• 13% (HIV+) vs 19% (HIV-)
• Association with genetic
polymorphisms & di-
deoxynucleoside exposure
‘Head-to-Head’
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
Microbiome
Genetics
HCV genotype III
Alcohol
• Steatosis present in approximately 60%
• Steatogenic effect of HIV itself
• HIV is characterized by intense immune activation
Immune Activation & Insulin Resistance
Lebovics et al. Hepatology. 1985 Mar-Apr;5(2):293-8Neuheus et al. The Journal of Infectious Diseases 2010 p 201(2)1788-1795
• Residual immune activation subject of debate
• Is there still an increased risk for insulin resistance?
Residual immune activation?
Guihot et al. AIDS. 2016 Jan;30(2):327-30
• Eearly generation protease inhibitors
• Inhibitors of GLUT4-receptor
• Ritonavir – still in use as pharmacological booster
• Indinavir – not in use anymore.
cART-related insulin resistance?
Hresko et al. PloS One. 2011;6(9):e25237.
• Increasing body mass index at diagnosis
A more traditional risk factor for IR?
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
Peripheral adipose tissue Hepatic mitochondria
Mitochondrial dysfunction
• Associated with Stavudine (d4T), Didanosine (ddI), Zalcitabine (ddC)
http://tmedweb.tulane.edu/pharmwiki/doku.php/hiv_haart
• mtDNA depletion in the
subcutanous fat tissue
• Mitochondrial dysfunction
leads to apoptosis
• Marked insulin resistance
• Hypertriglyceridemia
Lipodystrophy syndrome
Brinkman et al. Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors. UpToDate
Hepatic mitochondrial dysfunction
• Decreased mitochondrial oxidation of fatty acids
• Increased esterification triglycerides – less egress from the liver
• Lipid accumulation in the liver
Hepatic mitochondrial dysfunction
Brinkman et al. Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors. UpToDate
• 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?
NAFLD treatment in HIV
• 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.
In the pipeline?
Stanley et al. Lancet HIV. 2019 Oct 11. ePub
• NASH in approximately 30-35% of the patients
• Most patients (50-60%) had no fibrosis
Outcomes
• Cenicriviroc (CVC) – originates from HIV research
• Inhibitor of CCR2 & CCR5 receptor
In the pipeline?
Mariana Verdelho MachadoPresentation 13th International Workshop on co-infection HIV and Hepatitis (2017)
In the pipeline?
• 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
Take Home Messages
