New Drugs for NASH and HIV Infection: Great Expectations for a Great Need 1 2 3 4 1,5 6 Giovanni Guaraldi , James B

| SPECIAL ARTICLE Hepatology, VOL. 71, NO. 5, 2020

New Drugs for NASH and HIV Infection: Great Expectations for a Great Need 1 2 3 4 1,5 6 Giovanni Guaraldi , James B. Maurice, Catia Marzolini, Kenneth Monteith, Jovana Milic, Emmanuel Tsochatzis , 7 8 9 10,11 12 13,14 Sanjay Bhagani, Caryn G. Morse, Jennifer C. Price, Patrick Ingiliz, Maud Lemoine, and Giada Sebastiani , on behalf of the SHIVER Network

In recent years, there has been an increasing number of clinical trials for the treatment of nonalcoholic steatohepatitis (NASH). People living with human immunodeficiency virus (PLWH) are commonly excluded from these studies, usually due to concerns over drug–drug interactions associated with antiretroviral therapy. The Steatohepatitis in HIV Emerging Research Network, a group of international experts in hepatology and infectious diseases, discusses our current understanding on the interaction between human immunodeficiency virus and NASH, and the issues related to the inclusion of PLWH in NASH clinical trials. Recent trials addressing NASH treatment in PLWH are discussed. The risk of drug–drug interactions between antiretroviral therapy and aramchol, cenicriviroc, elafibranor, obeticholic acid and resmetirom (MGL-3196), which are currently in phase 3 trials for the treatment of NASH, are reviewed. A model for trial design to include PLWH is proposed, strongly advocating for the scientific community to include this group as a subpopulation within studies. (Hepatology 2020;71:1831-1844).

(2) he Steatohepatitis in HIV Emerging leading to progressive hepatocellular injury. NASH (2) Research Network, a group of international affects 3%-7% of the general population, and without experts in hepatology and infectious diseases, interventions can progress to advanced liver fibrosis, cir- convenedT recently for a conference focused on non- rhosis, and related end-stage liver complications such as alcoholic fatty liver disease (NAFLD) in people liv- ascites, hepatic encephalopathy, variceal bleeding, hepa- (1) ing with human immunodeficiency virus (PLWH). tocellular carcinoma, and hepatic failure. In the general NAFLD is defined as fat accumulation in more than population, the disease burden is increasing so fast that 5% hepatocytes without a secondary cause such as currently NASH represents the second most common alcohol consumption, and can be evaluated with non- indication for liver transplantation in North America, invasive diagnostic tools such as ultrasound, transient with projections to become the leading indication over (3) elastography, computed tomography, and magnetic res- the next 10 years. NASH is already the leading indi- (4) onance imaging. Nonalcoholic steatohepatitis (NASH) cation for liver transplantation in women. is a histological diagnosis defined by liver steatosis As PLWH live longer due to effective early treat- with hepatocyte ballooning and lobular inflammation, ment with antiretroviral therapy (ART), chronic

Abbreviations: ART, antiretroviral therapy; BMI, body mass index; DDI, drug–drug interaction; HCV, hepatitis C virus; HIV, human immunodeficiency virus; INSTI, integrase inhibitors; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NICM, noninfectious comorbidities; PLWH, people living with HIV. Received November 21, 2019; accepted January 28, 2020. This study was not funded. G.S. is supported by a Junior 1 and 2 Salary Award from FRQS (#27127 and #267806) and research salary from the Department of Medicine of McGill University. © 2020 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.31177 Potential conflict of interest: Dr. Price received grants from Gilead and Merck. Dr. Guaraldi advises and received grants from Gilead, ViiV, and Merck. He received grants from Janssen. Dr. Maurice consults and received grants from Intercept. Dr. Bhagani advises, is on the speakers’ bureau, and received grants from Gilead. He is on the speakers’ bureau for ViiV. Dr. Morse consults for Theratechnologies. Dr. Ingiliz consults, is on the speakers’

1831 GUARALDI ET AL. Hepatology, May 2020 noninfectious comorbidities (NICM) are an increas- trial design to include PLWH, strongly advocating for ingly important aspect of the medical care in this the scientific community to include this group as a aging population. As a result, there is interest in how subpopulation within studies. chronic HIV infection and long-term drug treatment may affect the trajectory of aging-related conditions, such as liver and cardiovascular disease. Liver disease is a leading cause of non–acquired immune deficiency Link Among NASH, HIV, (5) syndrome–related deaths in PLWH. Although in the past co-infections with hepatitis C virus (HCV) and ART and hepatitis B virus have driven this trend, NAFLD/ The prevalence of NAFLD in HIV mono-infection (7) NASH has become the most frequent liver disease in is about 35%, higher than the global average of (6) (10,11) PLWH. 23%-25%, but highly variable depending on dif- Available data paint a fairly equivocal picture on ferent geographical areas and diagnostic tools. Table 1 the role of HIV and associated drug exposure on the summarizes the prevalence of NAFLD and NASH development and progression of NAFLD/NASH in in PLWH, lists associated risk factors, and specifies PLWH. However, there is also an increasing number diagnostic procedures used to define this condition. It of studies suggesting that metabolic disorders play a should be noted that well-matched studies are lacking, key role in the development of NAFLD/NASH as and there is no conclusive evidence about a different (7-9) observed in patients without HIV. prevalence of NAFLD in PLWH in comparison to The purpose of this article is to discuss the cur- the general population. rent understanding on the interaction between HIV The first NAFLD phenotype related to either HIV and NASH, and the issues related to the inclusion or HCV infection, occasionally defined as “virus- of PLWH in NASH clinical trials. We reviewed in associated fatty liver disease,” was characterized by detail the risk of drug–drug interactions (DDIs) a lean constitution, associated with insulin resis- between ART and NAFLD/NASH agents that are tance (particularly characteristic of HCV-genotype currently in phase 3 trials, and we suggest a model for 3 infection) or central fat redistribution in HIV

bureau, and received grants from Gilead. He consults for ViiV and is on the speakers’ bureau for AbbVie, MSD, and Janssen. Dr. Lemoine advises and received grants from Gilead. She received grants from ViiV. Dr. Sebastiani consults, is on the speakers’ bureau, and received grants from Merck. She consults and is on the speakers’ bureau for Gilead. She consults for Intercept and Novartis, is on the speakers’ bureau for AbbVie and Novo Nordisk, and received grants from Theratechnologies.

ARTICLE INFORMATION: 1 From the Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, 2 3 Italy; Hepatology Unit, Department of Surgery and Cancer, Imperial College London, London, United Kingdom; Division of Infectious 4 Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland; Coalition des Organismes Communautaires Québécois 5 de Lutte Contre le Sida, Montréal, QC, Canada; Clinical and Experimental Medicine PhD Program, University of Modena and Reggio 6 Emilia, Modena, Italy; UCL Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, 7 8 United Kingdom; Royal Free London, NHS Foundation Trust, London, United Kingdom; Wake Forest School of Medicine, Medical 9 10 Center Boulevard, Winston-Salem, NC; Department of Medicine, University of California, San Francisco, CA; Center for 11 Infectiology, Berlin, Germany; Department of Gastroenterology and Hepatology, Charité University Medical Center, Berlin, Germany; 12 13 Department of Surgery and Cancer, Liver Unit, St Mary’s Hospital, Imperial College London, London, United Kingdom; Division of Gastroenterology and Hepatology, McGill University Health Centre, Royal Victoria Hospital - Site Glen, Montréal, QC, Canada; 14 Division of Infectious Diseases, McGill University Health Center, Royal Victoria Hospital–Site Glen, Montréal, QC, Canada.

ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Giovanni Guaraldi, M.D. Modena 41124, Italy Department of Surgical, Medical, Dental and Morphological E-mail: [email protected] Sciences, University of Modena and Reggio Emilia Tel.: +39 059 422 5318, +39 335 333434 Largo del Pozzo, 71

1832 Hepatology, Vol. 71, No. 5, 2020 GUARALDI ET AL. 9 18 15 20 33 N/A N/A N/A N/A N/A N/A N/A N/A N/A (%) 33.3 3.64 28.6 35.7 19.4 Fibrosis Fibrosis Prevalence Prevalence 47 8.2 7.3 N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A 63.6 53.3 57.1 28.6 54.8 11.4 NASH (%) 31 60 36 35 28 13 48 31 40 65 76 N/A 57.1 28.7 64.3 36.9 72.6 53.9 28.75 NAFLD (%) 75 39 NA N/A N/A N/A N/A N/A N/A N/A N/A 100 100 100 100 100 100 100 100 ALT (%) ALT Elevated Elevated N/A N/A N/A N/A N/A N/A N/A 13-18) 3.3-12.5) 1.7-22.8) (years) 7.9 (IQR 7 (4-14) 7 (0-27) 8.3 ± 7.2 13 (7-20) 15 (range 15 (range 12.9 (range 12.9 (range 6.33 ± 3.92 6.33 ± 3.92 12.8 ± 11.1 9 (IQR 6-12) Time Time on ART 11 (IQR 0-26) N/A N/A N/A N/A N/A N/A 2.3-27.8) (years) 8.2 + 4.9 Infection Infection 10 (6-16) 13 (7-20) 12.25 ± 5 19.9 ± 7.4 14.5 ± 8.1 10.5 ± 9.3 17.5 (range 17.5 (range 13 (IQR 9-15) 14 (IQR 6-20) 14 (IQR 2-30) Duration HIV Duration 10.6 (median) 9 (range 0-29) 9 (range 7 0 10 11 11 12 8.2 5.1 9.7 N/A N/A N/A (%) 73.9 18.2 6.67 25.1 13.2 18.29 resistance) Diabetes Diabetes 65 (insulin WH Without Viral Hepatitis in Various Studies WithoutViralWH Various Hepatitis in ) 2 N/A 25.4 25.7 27 ± 6 15.3-47.1) 25 + 4.5 (23.0-28.6) (23.2-29.4) 26.7+4.3 29.8 ± 6.0 27.7 ± 4.5 26.0 ± 4.1 23.0 ± 3.1 27.9 + 4.7 23.0 ± 3.4 29.9 ± 7.4 24 (15-41) 27.6 (range 27.6 (range BMI (kg/m 23.75 + 3.59 A SH in PL 26 (IQR 24-30) 26 (IQR 24-30) 26 (IQR 23-29) D and N biopsy biopsy biopsy H-MRS biopsy Liver Diagnostic Procedure CAP/liver CAP/liver biopsy Liver CT biopsy Liver CAP/liver CAP/liver CAP Ultrasound CAP CAP H-MRS CT CAP Liver biopsy Liver biopsy Liver biopsy Liver biopsy Liver A F L (93.8%) black (37.6) black (27.3) black (15.1) black (32) black (8.0) black (30) Chinese Asian Hispanic (51.5) Ethnicity (%) Black 40.0% Others 18% White (45.2); (45.2); White (47.7); White N/A N/A (82) White N/A (76.3); White East Asian 97.5% (52.1); White Black (53%) Caucasian (53%) Caucasian (55%) 42.0% White N/A (65.0); White Caucasian (66); Caucasian (57) revalence of N 1. P N/A LE 31-58) 17-67) 43 + 11 47 ± 10 45 ± 10 B 51.1 + 9 50 (range 50 (range 44.8 ± 9.4 53.9 ± 8.3 47.5 ± 8.5 49.6 ± 9.5 46 (20-75) 50 (42-56) 43.5 (range 43.5 (range Age (years) 48.43 ± 8.16 41 (IQR 30-46) 54 (IQR 53-65) 45 (IQR 35-52) 51 (IQR 57-57) 52 (IQR 47-57) TA N 30 14 80 62 97 14 33 202 216 225 402 156 289 435 538 395 122 329 300 prospective retrospective prospective retrospective Canada/prospective USA/prospective Italy/prospective France/prospective France/prospective Kingdom/ United Kingdom/ United China/prospective Germany/ USA/prospective Japan/prospective Kingdom/ United Canada/prospective Brazil/prospective USA/prospective USA/prospective USA/prospective USA/prospective Canada/prospective Country/Design (79) (80) (72) (67) (71) (77) (78) (74) (70) (64) (65) (66) (68) (69) (73) (75) (76) (8) (2016) (2018) (16) (2006) (2018) (2017) (2008) (2014) (2010) (2017) Mohr (2018) Prat (2018) Prat Vuille-Lessard Vuille-Lessard Price (2017) Price (2017) (2013) Sterling Morse (2015) Ingiliz (2009)

Author Author and Year of Publication Benmassaoud and categorical as percentages. variablespresented are as mean ± SD or median (interquartile range or range), expressed variables Continuous are Note: - interquar IQR, spectroscopy; magnetic resonance proton H-MRS, tomography; computed CT, parameter; attenuation controlled CAP, alanine aminotransferase; ALT, Abbreviations: not available. N/A, tile range; Lemoine Perazzo Pembroke Pembroke Guaraldi Guaraldi Lemoine (2019) (2015) Vodkin Lui (2016) Nishijima Crum Cianflone Crum Cianflone Lombardi Lombardi

1833 GUARALDI ET AL. Hepatology, May 2020

(central fat accumulation with facial and limb lipo- also the case in the progressive forms of the disease dystrophy). In this setting, pathogenetic mech- with NASH and fibrosis, which are most consistently anisms have been identified including chronic associated with features of the metabolic syndrome immune-activation, gut dysbiosis, oxidative stress, rather than HIV-specific factors such as drug expo- (12,13) (7) and mitochondrial toxicities (Fig. 1). In the sure or CD4 nadir. general population, the prevalence of lean NAFLD This immuno-metabolic phenomenon is often (17) ranges between 7% in the United States to 19% in described as “inflammaging” and is pathogenically (14) (18) (19) Asia, with cohort studies suggesting that it might linked with metabolic syndrome, NICM, func- (15,16) (20) (21) be higher in PLWH. tional decline, and geriatric syndromes. In this More recently, in the changing scenario of HIV context, both NAFLD and HIV infection are mul- clinical presentation and management, the current tisystemic diseases affecting multiple organs that are clinical phenotype of NAFLD closely resembles associated with increased risk of age-related NICMs, patients in the general population. In this setting, the including type 2 diabetes mellitus, cardiovascular dis- metabolic complications of obesity are overwhelm- ease, and chronic kidney disease. In PLWH, NAFLD ingly associated with the disease. Importantly, this is does not merely represent a risk factor, but it is also

Investigated agents for NAFLD/NASH treatment and LEGEND their therapeutic target

Lipid metabolism Effect on lipid - Aramchol metabolism - Elafibranor - Obeticholic acid - Tesamorelin Effect on inflammation - Resmetirom

Effect on fibrosis

Fibrosis Inflammation - decrease over time Additional features involved in - Vitamin E pathogenesis of NAFLD/NASH in - Cenicriviroc - unchanged over time PLWH and their evolution over time - increased over time

VPR gene induced adipocyte hypertrophy ; Insulin resistance ; Lipodystrophy HIV VPR gene induced macrophage recruitment in adipose tissue; GALT depletion induces Kupffer cell activation Chronic inflammation; Immune activation

Boosted PI-induced insulin resistance ; First generation NRTI-induced oxidative stress ; INSTI-induced weight gain ART Mitochondrial toxicity induced by first generation NRTIs Cumulative exposure to d-drugs

Obesity ; Inadequate diet ; Sedentary lifestyle ; Genetic factors HIV patient Obesity ; Genetic factors Genetic factors 1996 1998 2007 2017 Time Pre-Art Early- Lipodystrophy associated Weight gain associated Introduction of INSTI class era ART era with the use of PI and NRTI with INSTI use

FIG. 1. Pathogenesis of NAFLD/NASH in PLWH and relative therapeutic targets for investigated agents for NAFLD/NASH treatment. Therapeutic targets are didactically divided into three groups: lipid metabolism, inflammation, and fibrosis. Additional HIV-related features involved in NAFLD/NASH pathogenesis are grouped according to therapeutic targets. Timeline at the bottom depicts the most important historical time points in HIV and ART that have affected the management of PLWH and their possible association with NAFLD/NASH pathogenesis. Abbreviations: GALT, gut-associated lymphoid tissue; NRTI, nucleoside reverse transcriptase inhibitors; PI, protease inhibitors; VPR, viral protein R.

1834 Hepatology, Vol. 71, No. 5, 2020 GUARALDI ET AL.

(22) involved in pathogenesis of NICMs, suggesting studies in PLWH have shown very variable rates of NAFLD as a barometer of metabolic aging. NASH (see prevalence of NASH in Table 1 in stud- ART-induced hepatotoxicity and significant ies with available liver biopsy), similar to those in the (12) (10) metabolic complications exist. However, these general population. Observational studies with side effects were attributed primarily to D-drugs histologically confirmed disease and outcomes after (didanosine and stavudine), which have been phased 10-15 years are required to understand more clearly out in the last decade due to induced mitochondrial the trajectory of NASH in PLWH. Second, although (23) functional impairment (Fig. 1). the metabolic syndrome is integral to NASH patho- A recent preclinical model has shown a putative genesis, more data are required on the secondary role mechanism linking efavirenz to the development of of ART exposure and HIV chronic inflammation in steatosis through pregnane X receptor activation and this process. the disruption of fatty acid transport and cholesterol NASH treatments that block, possibly in synergis- (24) biosynthesis. tic mechanism, steatosis and fibrosis progression, may Although undoubtedly a subset of patients contin- improve this liver disorder, but also have the potential ues to experience the metabolic effects of lipodystro- to reduce the burden on NICMs, particularly relevant phy even years after discontinuing these drugs, they are in PLWH. now thankfully a small minority of modern cohorts of These issues can begin to be addressed through PLWH, and modern regimens with integrase inhibi- inclusion in clinical trials in which prospective, tors appear to be more metabolically friendly. Indeed, per-protocol paired liver biopsies are included in the in a small randomized controlled trial, the switch to trial design. In the general population, such trials, raltegravir from efavirenz has shown to reduce liver particularly those with negative outcomes, have been (25,26) steatosis. invaluable in deepening our insight into the natural (33) The D:A:D cohort has shown that short-term gain history of NASH. Including PLWH as a sub- in body mass index (BMI) following ART initiation population will also provide an opportunity for well- increases the long-term risk of diabetes, regardless of matched comparisons with HIV-negative subjects. (27) pre-ART BMI, somehow exceeding a simple “return (28) to health” phenomenon. This observation has been characterized more recently in PLWH initiating ART (28) with integrase strand transfer inhibitors (INSTIs). Current Trials for NASH in In a large, well-characterized ART naïve cohort, among 1,152 PLWH, 356 initiated INSTI-based HIV regimens. At all examined study time points, weight Few pilot studies have addressed NASH treatment gain was highest among PLWH starting dolutegravir. in HIV. At 18 months, PLWH on dolutegravir gained 6.0 kg, Lifestyle changes, with particular focus on phys- compared with 2.6 kg for subjects on non–nucleoside ical activity and diet, are the first-line therapy in reverse transcriptase inhibitors (P < 0.05), and 0.5 kg NAFLD/NASH in the general population. Weight (28) for those on elvitegravir (P < 0.05). Similar findings loss of 10% is associated with resolution of steato- were described in experienced PLWH switching to hepatitis and improvement of fibrosis in a substantial (29) (34) INSTIs. Nevertheless, metabolic consequences of number of patients. In PLWH, studies have shown weight gain after INSTI initiation are still controver- that higher intensity of physical exercise is needed to sial, and whether this will affect the risk of NAFLD obtain similar metabolic improvements to the general (30-32) (35) in PLWH is unclear (Fig. 1). population, while the effect on NAFLD/NASH Important unanswered questions remain. First, has not been reported. there are no longitudinal data evaluating long-term In the context of HIV-associated lipodystrophy, the outcomes of PLWH and NASH. Cross-sectional use of pioglitazone, a thiazolidinedione insulin sensi- studies are suboptimal in the assessment of disease tizing agent, has been shown to reduce liver fat and severity and dynamics, while the requirement for a lobular inflammation, but fell short of achieving the liver biopsy and retrospective design of most studies primary endpoint of improvement or resolution of (36) introduce significant selection bias. Therefore, biopsy NASH (Table 3).

1835 GUARALDI ET AL. Hepatology, May 2020

The ARRIVE trial, a double-blind, randomized, alter the exposure of antiretroviral drugs (Table 2). placebo-controlled trial, tested the efficacy of 12 weeks Because tesamorelin induces the secretion of growth of treatment with aramchol versus placebo in 25 HIV- hormone, concerns have been raised that CYP associated NAFLD. Over a 12-week period, hepatic expression and/or activity may be modulated by fat or change in body fat and muscle composition did growth hormone. However, growth hormone was not change as assessed by using the new MRI-based shown to have no significant effect on CYP2D6 and assessment in patients with HIV-associated NAFLD CYP3A4 activity (CYPs contributing the metabo- (37) (Table 3). lism of several antiretroviral drugs) in a randomized, A recently published phase 4 open-label clinical double-blind, placebo-controlled clinical study in trial included 27 mono-infected PLWH with NASH which individuals received injections of growth hor- (41) treated with vitamin E 800 IU daily for 24 weeks. mone or placebo. The study found a decrease in inflammation assessed In a retrospective cohort study, maraviroc, a chemo- with alanine aminotransferase (−27 units/L), steato- kine (C-C motif) receptor 5 (CCR5) antagonist, sis estimated by controlled attenuation parameter showed a potential protective role in reducing the (42) (−22 dB/m), and hepatocyte apoptosis with cytokeratin- incidence of NAFLD in PLWH (Table 3). A cur- 18 (−123 units/L). These results are encouraging, but rent, ongoing, randomized pilot study is assessing its once again treatment with vitamin E did not improve efficacy in an add-on antiretroviral therapy strategy liver fibrosis. At present, vitamin E treatment may be over 48 weeks in HIV-1 mono-infected patients with (43) considered as a bridge therapy only, while waiting for NASH. availability of new drug combinations simultaneously Altogether, these studies are too small to affect clin- (38) addressing steatosis and fibrosis (Table 3). ical practice or guidelines consideration at this stage. A particular case is represented by tesamorelin, a synthetic form of growth hormone–releasing hormone, which is Food and Drug Administration– approved for the treatment of excess abdominal fat Investigational Agents for in HIV-associated lipodystrophy. In a randomized, double-blind, multicenter trial including 61 PLWH NASH and Potential DDIs with NAFLD, Stanley et al. assessed its effect on liver fat and histology. At baseline, liver biopsies in the Context of HIV revealed that 43% of patients had liver fibrosis and As the clinical phenotype of NASH in PLWH 33% had NASH. After 12 months of treatment, increasingly mirrors that of the general population, it liver fat in patients on tesamorelin had decreased could be considered that the treatment of NASH in by 32% from baseline, while it had increased by 5% PLWH would likely have the same etiological targets in placebo patients (P = 0.02), amounting to a 37% as in the general population. An increasing number relative reduction in liver fat. Furthermore, 35% of of agents are being investigated for the treatment of patients in the tesamorelin group returned to liver NASH, and many registrational trials are ongoing. fat values below 5% in comparison to only 4% of In this setting, it is striking that PLWH have con- (39) patients on placebo (P = 0.007). The study also sistently been excluded from these studies. We are concluded that 10.5% of patients in the tesamore- concerned that this may limit therapeutic options for lin group experienced progression of liver fibrosis NASH in PLWH. Pharma and sometimes regulatory compared with 37.5% in patients receiving a pla- agencies justify the exclusion of PLWH due to the (39) cebo (P = 0.04) (Table 3). The DDI potential risk of DDIs associated with concomitant chronic of tesamorelin has been evaluated with simvasta- exposure to ART. tin, a cytochrome P4503A4 (CYP3A4) sensitive This concern can be addressed by conduct- substrate, and the HIV protease inhibitor ritonavir. ing properly designed studies that aim to evaluate Tesamorelin (2 mg, multiple doses) was shown to DDIs between compounds to treat NASH and have a minimal effect on simvastatin (80 mg) and ART. Furthermore, for some of these compounds ritonavir (100 mg) pharmacokinetics in healthy vol- available, pharmacological data allow researchers to (40) unteers, suggesting that tesamorelin is unlikely to predict the likelihood of having DDIs with ART.

1836 Hepatology, Vol. 71, No. 5, 2020 GUARALDI ET AL. ↔ ↔ ↔ ↔ ↔ ↔ TDF ↔ ↔ ↔ ↔ ↔ ↔ TAF ↔ ↔ ↔ ↔ ↔ ↔ 3TC ↔ ↔ ↔ ↔ ↔ ↔ FTC ↔ ↔ ↔ ↔ ↔ ↔ ABC ↔ ↔ ↔ ↔ RAL ↑ ↔ ↔ EVG/c ctions.org (University ctions.org of Liverpool). A SH ↔ ↔ ↔ ntera DTG ↓ 29% reat N reat T ↔ ↔ ↔ ↔ BIC ↔ ↔ ↔ ↔ MVC ↔ ↔ ↔ ↔ RPV ↓ ↔ ↔ ↔ NVP ↓ ↔ ↔ ↔ ETV † ↔ ↔ ↔ EFV ↓ 43% ↔ ↔ ↔ ↔ DOR ↑ ↔ DRV/r ↑ 213% ↑ ↔ ↔ DRV/c otential DDIs Between Selected A ntiretrovirals and Drugs to 2. P ↑ ↔ LE ATV/r ↑ 289% B TA ↑ ↑ ↔ ATV/c III III III III III Clinical trial phase (MGL-3196) acid* Resmetirom Resmetirom Cenicriviroc Aramchol Tesamorelin Obeticholic Elafibranor The limited available data on drugThe limited available data on assessment of the risk metabolism do not allow for DDIs. No clinically No predicted. significant interaction clinically or clinical adjustment dosage monitoring. require that may Potential interaction significant Doubling cenicriviroc dosage allows compensation for the drug allows compensation with efavirenz. dosage Doubling cenicriviroc interaction Potential elevated exposure of the NASH drug. of the NASH elevated exposure ↑ Potential drug. of the NASH exposure decreased ↓ Potential effect. significant ↔ No see http://www.hep-drugi adjustments, data and dosage interaction detailed pharmacokinetic DDIs and for more additional *For NASH drugs † The bold was used for the better visualization of the presented data. The bold was used for the better visualization of the presented darunavir/ritonavir; DRV/r, darunavir/cobicistat; DRV/c, doravirine; DOR, bictegravir; BIC, atazanavir/ritonavir; ATV/r, atazanavir/cobicistat; TAF, rilpivirine; ATV/c, abacavir; ABC, Abbreviations: RPV, raltegravir; RAL, nevirapine; NVP, maraviroc; MVC, emtricitabine; FTC, elvitegravir/cobicistat; EVG/c, etravirine; ETV, efavirenz; EFV, dolutegravir; DTG, lamivudine. 3TC, fumarate; tenofovir disoproxil TDF, tenofovir alafenamide;

1837 GUARALDI ET AL. Hepatology, May 2020 Main Finding patic fat from baseline (15.1%-7.0%) to week 48 week baseline (15.1%-7.0%) to from patic fat of −7.4% with a mean difference (7.6%-3.9%), did not placebo group whereas n = 5), ( P = 0.02, content changes in hepatic fat any show 12 weeks composition over and muscle fat - attenu with controlled steatosis (−27 units/L), and hepatocyte (−22 dB/m), ation parameter with CK-18 (−123 units/L) apoptosis 32% from by had decreased on tesamorelin 5% in placebo, by it increased whereas baseline, 37% by fat liver reducing of NAFLD in PLWH the burden reducing Pioglitazone group had a significant decrease in he - decrease had a significant group Pioglitazone or change body steatosis did not reduce Aramchol ALT assessed with was in inflammation A decrease in patients fat liver 12 months of treatment, After in role protective a potential showed Maraviroc Yes Yes No Yes No Group Control Control A SH treatment in HIV Treatment Pioglitazone Aramchol E Vitamin Tesamorelin Maraviroc D/N A F L for NAFLD/NASH for patients with HIV- NAFLD associated ≥ 248 based on CAP dB/m and CK-18 > 130.5 U/L CT assessed by Diagnostic Method MRS imaging in MRI technique NASH diagnosis was MRS imaging ratio Liver-to-spleen hat E xamined N T verview of Studies 3. O Study Design LE B TA placebo-controlled trial placebo-controlled trial placebo-controlled gator-initiated, arm trial multicenter 48-week, randomized, double-blind, double-blind, randomized, 48-week, - investi randomized, double-blind, 12-week, single open-label, single-center, 24-week, double-blind, randomized, 48-week, Retrospective HCV coinfection infection patients infected Country/Sample Size USA/13 subjects with HIV/ USA/50 subjects with HIV Canada/27 HIV-mono- USA/61 PLWH PLWH Italy/312 (39) (37) (42) (36) (38) (2015) ARRIVE Trial (2019) Matthews Matthews spectroscopy. magnetic resonance MRS, tomography; computed CT, alanine transaminase; ALT, Abbreviations: Author Author and Year of Publication Ajmera (2019) Ajmera Sebastiani (2019) Stanely Piconi (2019)

1838 Hepatology, Vol. 71, No. 5, 2020 GUARALDI ET AL.

The DDI profiles of these compounds can be sum- currently unclear whether this decrease in exposure marized in tables, thereby providing an overview of would require a dosage adjustment of cenicrivi- the DDI risk within a therapeutic class, similarly roc. The coadministration with atazanavir/ritonavir to what has been done with other drugs to treat (300/100 mg once daily) increased cenicriviroc (50 mg NICMs (www.hiv-druginteractions.org; www.hep- once daily) exposure by 289%. Hyperbilirubinemia was druginteractions.org). observed following coadministration of atazanavir/ This section explores potential DDIs between ritonavir with cenicriviroc. Similarly, coadministra- ART and five drugs in the pipeline that are in phase tion with darunavir/ritonavir (800/100 mg once daily) 3 trials for NASH, thus being the most likely candi- increased cenicriviroc (50 mg once daily) exposure dates to be approved for clinical use in the near future: by 213%, although no clinically relevant laboratory (48) aramchol, cenicriviroc, elafibranor, obeticholic acid, abnormalities were observed. Finally, coadminis- and resmetirom (MGL-3196). tration with efavirenz (600 mg once daily) reduced cenicriviroc (200 mg once daily) exposure by 43%, ARAMCHOL although cenicriviroc exposure was not significantly reduced when doubling cenicriviroc dose (400 mg (49) Aramchol is a fatty acid–bile acid conjugate– once daily). inhibiting stearoyl coenzyme A desaturase 1 (SCD1), an enzyme that plays a role in lipid metabolism. The ELAFIBRANOR inhibition of this DDI results in decreasing synthesis of fatty acids, with consequent decrease in storage tri- Peroxisome proliferator-activated receptors (PPARs) glycerides and other esters of fatty acids. This reduces are transcription factors involved in lipid metabo- liver fat, including triglycerides and free fatty acids, lism. PPARs are implicated in fatty acid catabolism. (44) resulting in an improvement in insulin resistance. Elafibranor is a PPAR-alpha/PPAR-delta agonist. Information on the potential of aramchol to cause PPAR-alpha activation increases lipolysis cellular lipid DDIs is currently not available, although there is uptake. In animal models, PPAR-delta activation leads an ongoing trial evaluating CYP3A4 inhibition of to fatty acid consumption in skeletal muscle and adi- (45) (44) by-aramchol. Thus, the risk for DDIs with drugs pose tissue. undergoing primarily hepatic metabolism cannot be Information on the metabolic pathway of ela- established currently. fibranor is not available from the public domain, except the fact that elafibranor is metabolized to (50) CENICRIVIROC GFT1007. Cenicriviroc is a CCR5 and CCR2 CCR5/CCR2 OBETICHOLIC ACID antagonist. CCR5 and CCR2 are chemokine receptors expressed on circulating monocytes as well as on Obeticholic acid (Ocaliva) is a bile acid analogue Kupffer cells. Activation of these receptors induces that is conjugated with glycine or taurine in the liver (44) migration of macrophages into the liver. It was ini- and secreted into the bile. Obeticholic acid is a semi- (46) tially developed as an HIV drug, but it was shown synthetic farnesoid X nuclear receptor (FXR) agonist. to reduce the rates of hepatic fibrosis. Farnesoid X nuclear receptor is a bile acid receptor Cenicriviroc is currently investigated in patients that regulates lipid and glucose metabolism, and its with NASH due to its anti-inflammatory and antifi- activation leads to reduction in serum and hepatic tri- (44) brotic potential at an oral dosage of 150 mg daily. glyceride levels. Cenicriviroc is metabolized by CYP3A4 and Concomitant medications to obeticholic acid that CYP2C28 and is a substrate of P-glycoprotein. inhibit canalicular membrane bile acid transporters, Cenicriviroc is devoid of strong inhibitory or induc- such as bile salt export pump, may exacerbate accu- ing effects on drug metabolizing enzymes. DDI stud- mulation of conjugated bile salts including taurine ies with dolutegravir (50 mg once daily) showed no conjugate of obeticholic acid in the liver, which may significant effect on dolutegravir exposure, whereas cause clinical symptoms. Thus, in case of coadmin- (47) (51) cenicriviroc exposure was reduced by 29%. It is istration with bile salt export pump inhibitors,

1839 GUARALDI ET AL. Hepatology, May 2020 serum transaminases and bilirubin should be moni- hypothesized that treatment with statins may have tored (Ocaliva product label). Although obeticholic beneficial effects on NAFLD and its liver-related acid was shown to inhibit CYP3A4 in vitro, a DDI complications, exerting systemic pleiotropic mech- study has demonstrated no clinically significant inhi- anisms that collectively may concur in improving bition of CYP3A4 at the doses of obeticholic acid in steatosis, sterile inflammation, fibrosis and tum- (52) clinical use. Obeticholic acid is not expected to sig- origenesis; nevertheless, these evidences are still (58) nificantly inhibit or induce other cytochromes or drug lacking. transporters (Ocaliva product label).

RESMETIROM (MGL-3196) Lessons from Direct-Acting Resmetirom is an agonist of the thyroid hormone (53) receptor-β. There is no information on the meta- Antiviral Trials in HIV/ bolic pathway of resmetirom, except that it is taken into the liver by hepatic transporters. Thus, poten- HCV Co-infection tial DDIs with boosted ART regimens cannot be So, how do we move forward toward the safe excluded. DDI studies have shown no significant inclusion of PLWH into NASH trials? The phe- effect of resmetirom on statins exposure, suggesting nomenally successful development of safe and effec- (54) that resmetirom is unlikely to affect ART. tive drugs against the HCV that included HCV/ Table 2 summarizes the predicted risk of DDIs HIV co-infection could provide a helpful paradigm between selected antiretrovirals and drugs to treat from which to draw lessons to inform our approach NASH. to NASH in PLWH. In the absence of randomized clinical studies, The natural history of HCV/HIV co-infection it is difficult to predict which therapeutic strat- was known to behave differently than HCV mono- egies would be more suitable in PLWH. From a infection, characterized by more rapid fibrosis (59) theoretical point of view, it can be hypothesized progression. In the early studies on pegylated inter- that lean NAFLD associated with d-drug exposure feron and ribavirin, response rates were much lower in would benefit more from a drug strategy focused on PLWH, perhaps, among other mechanisms, linked to anti-oxidative stress aiming to improve mitochon- the significant immune dysregulation in patients with (60) drial dysfunction. On the other side, the pathogen- advanced and inadequately treated HIV. Therefore, esis and thus therapeutic target for NAFLD/NASH the registration trials for pegylated interferon only in PLWH with obesity and/or diabetes mellitus, occurred some years after the trials, leading to its may be similar to the general population. With this licensing in HCV mono-infection. regard, a number of studies of animal models and The early trials in the direct-acting antiviral era human trials have evaluated the effects of glucagon- with the protease inhibitors boceprevir and telaprevir like peptide-1 receptor agonist on liver fat content responded to this uncertainty over response and dos- and suggest that the treatment could represent a new ing, following the experience with pegylated interferon (55) alternative for NAFLD management. However, in designing trials of longer duration with the same (61) the hypothesis that such treatments have a direct doses. However, ribavirin/sofosbuvir studies set the effect on hepatocytes is still questionable and there benchmark for designing trials that continued to sepa- is no evidence that the positive effect of glucagon- rate patients with HIV co-infection but used the same (62) like peptide-1 receptor agonists is linked to the duration and dosing as in trials on mono-infection. presence of glucagon-like peptide-1 receptor on This has remained the most common approach, expe- (56) hepatocytes. In HIV setting, there is an ongoing diting registration trials in HCV/HIV co-infection randomized double-blinded, placebo-controlled trial and demonstrating the diminished influence of ART to assess effect of semaglutide on visceral and ecto- or HIV itself on treatment safety and efficacy. (57) pic fat in HIV-associated lipohypertrophy. Taking it one step further, the Zepatier com- With regard to dyslipidaemia, frequently PLWH bination (elbasvir and grazoprevir) included sub- with NAFLD are qualified for statin therapy. It is jects with HCV/HIV co-infection within the main

1840 Hepatology, Vol. 71, No. 5, 2020 GUARALDI ET AL. registration trial, and built in an a priori analysis of pathophysiology and efficacy of new drugs in HIV- the subgroup with HIV when designing the power associated NASH, while expediting the licensing of (63) of the study. new therapies in this population. Therefore, as the quality of the drugs available improved, the relevance of HIV in the delivery or efficacy of the interventions diminished such that there Conclusions was much closer alignment with this population in NASH is a common problem in aging popula- the introduction of DAAs for HCV. tions of PLWH treated with antiretrovirals. The predominating pathophysiological mechanisms are likely to be similar to the general population and closely related to the metabolic complications of obesity. PLWH are likely to benefit from the ther- A Way Forward for PLWH apeutic targets investigated in current trials, and in NASH Trials where there is adequate knowledge of DDIs, they should be included as a prespecified subpopula- How can these lessons inform trial design for tion to improve the generalizability of the results NASH in HIV? As in HCV/HIV, there are some and expedite the introduction of therapies in this data to support additional pathophysiological mech- population. Clinical trial data will also help address anisms in HIV-associated NASH, including ART current gaps in the disease mechanisms and natural effects on lipid metabolism, particularly, but not history of HIV-associated NASH. exclusively, with respect to those patients subjected to now-obsolete drugs strongly associated with lipo- Author Contributions: G.G., J.B.M., and G.S. conceptu- dystrophy. However, because the clinical phenotype alized the study and drafted the manuscript. C.M. con- is so strongly associated with the metabolic syn- tributed an expert opinion. G.G., J.B.M., J.M., K.M., drome, the pathways leading to liver injury, NASH, C.M., S.B., and G.S. wrote and revised the manuscript. and fibrosis (e.g., insulin resistance, adipose-derived G.G., J.B.M., T.E., and G.S. supervised the study and inflammation, and impaired lipid metabolism) the final version of the manuscript. All authors con- remain those targeted by many current therapies tributed to discussion and revised the manuscript. under investigation. It would therefore be reason- able to expect similar response rates between those REFERENCES with and without HIV. 1) The First International Workshop Network, Steatohepatitis in Therefore, for drugs for which there is a low prob- HIV Emerging Research (SHIVER). https://www.fourwav.es/ ability of DDIs, PLWH may be included as a pre- view/1167/info/. Accessed December 30, 2019. 2) Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella specified subgroup within a trial population. To allay M, et al. The diagnosis and management of nonalcoholic fatty concerns from the pharmaceutical industry about liver disease: practice guidance from the American Association for delays in licensing for the general population, PLWH the Study of Liver Diseases. Hepatology 2018;67:328-357. 3) Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, can then be excluded from the interim analysis, much Younossi ZM, et al. Nonalcoholic steatohepatitis is the second lead- like other trials have included F1 fibrosis stage as a ing etiology of liver disease among adults awaiting liver transplan- group of interest but focused on F2/3 in the interim tation in the United States. Gastroenterology 2015;148:547-555. 4) Noureddin M, Vipani A, Bresee C, Todo T, Kim IK, Alkhouri N, analysis. Where significant uncertainty exists over et al. NASH leading cause of liver transplant in women: updated potential DDIs, driven primarily by booster-containing analysis of indications for liver transplant and ethnic and gender regimens, small exploratory studies can be readily variances. Am J Gastroenterol 2018;113:1649-1659. 5) Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, et al. conducted to answer this question before proceeding Trends in underlying causes of death in people with HIV from to inclusion in larger trials. 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet This approach, in contrast to separate trials on 2014;384:241-248. 6) Verna EC. Non-alcoholic fatty liver disease and non-alcoholic ste- HIV-associated NASH, is particularly important, as atohepatitis in patients with HIV. Lancet Gastroenterol Hepatol the requirement for a liver biopsy makes it very diffi- 2017;2:211-223. cult to recruit into adequately powered trials. A pre- 7) Maurice JB, Patel A, Scott AJ, Patel K, Thursz M, Lemoine M. Prevalence and risk factors of nonalcoholic fatty liver disease in specified subanalysis within a larger trial would enable HIV-monoinfection. AIDS 2017;31:1621-1632. exploration into some unanswered questions on the

1841 GUARALDI ET AL. Hepatology, May 2020

8) Vuille-Lessard É, Lebouché B, Lennox L, Routy J-P, Costiniuk 26) Calza L, Colangeli V, Borderi M, Coladonato S, Tazza B, Fornaro CT, Pexos C, et al. Nonalcoholic fatty liver disease diagnosed G, et al. Improvement in liver steatosis after the switch from a by transient elastography with controlled attenuation parame- ritonavir-boosted protease inhibitor to raltegravir in HIV-infected ter in unselected HIV monoinfected patients. AIDS 2016;30: patients with non-alcoholic fatty liver disease. Infect Dis (London, 2635-2643. England) 2019;51:593-601. 9) Lemoine M, Lacombe K, Bastard JP, Sébire M, Fonquernie 27) Achhra AC, Sabin C, Ryom L, Hatleberg C, Antonella d’Aminio L, Valin N, et al. Metabolic syndrome and obesity are the cor- M, de Wit S, et al. Body mass index and the risk of serious non- nerstones of liver fibrosis in HIV-monoinfected patients. AIDS AIDS events and all-cause mortality in treated HIV-positive in- 2017;31:1955-1964. dividuals: D: A: D cohort analysis. J Acquir Immune Defic Syndr 10) Younossi ZM, Blissett D, Blissett R, Henry L, Stepanova M, 2018;78:579-588. Younossi Y, et al. The economic and clinical burden of non- 28) Bourgi K, Rebeiro PF, Turner M, Castilho JL, Hulgan T, Raffanti alcoholic fatty liver disease in the United States and Europe. SP, et al. Greater weight gain in treatment naive persons start- Hepatology 2016;64:1577-1586. ing dolutegravir-based antiretroviral therapy. Clin Infect Dis 11) Rinella M, Charlton M. The globalization of nonalcoholic fatty 2019May 17. https://doi.org/10.1093/cid/ciz407. [Epub ahead of liver disease: prevalence and impact on world health. Hepatology print] PubMed PMID: 31100116. 2016;64:19-22. 29) Norwood J, Turner M, Bofill C, Rebeiro P, Shepherd B, Bebawy 12) Guaraldi G, Lonardo A, Maia L, Palella FJ. Metabolic concerns in S, et al. Brief report: weight gain in persons with HIV switched aging HIV-infected persons. AIDS 2017;31:S147-S156. from efavirenz-based to integrase strand transfer inhibitor-based 13) Guaraldi G, Lonardo A, Ballestri S, Zona S, Stentarelli C, Orlando regimens. J Acquir Immune Defic Syndr 2017;76:527-531. G, et al. Human immunodeficiency virus is the major determinant 30) Kouanfack C, Mpoudi-Etame M, Omgba Bassega P, Eymard- of steatosis and hepatitis C virus of insulin resistance in virus-as- Duvernay S, Leroy S, Boyer S, et al. Dolutegravir-based or low- sociated fatty liver disease. Arch Med Res 2011;42:690-697. dose efavirenz-based regimen for the treatment of HIV-1. N Engl 14) VanWagner LB, Armstrong MJ. Lean NAFLD: a not so benign J Med 2019;381:816-826. condition? Hepatol Commun 2018;2:5-8. 31) Venter WDF, Moorhouse M, Sokhela S, Fairlie L, Mashabane 15) Lombardi R, Sambatakou H, Mariolis I, Cokkinos D, N, Masenya M, et al. Dolutegravir plus two different prodrugs of Papatheodoridis GV, Tsochatzis EA. Prevalence and predictors of tenofovir to treat HIV. N Engl J Med 2019;381:803-815. liver steatosis and fibrosis in unselected patients with HIV mono- 32) Sax PE, Erlandson KM, Lake JE, Mccomsey GA, Orkin C, Esser infection. Dig Liver Dis 2016;48:1471-1477. S, et al. Weight gain following initiation of antiretroviral ther- 16) Lemoine M, Assoumou L, De Wit S, Girard P-M, Valantin apy: risk factors in randomized comparative clinical trials. Clin MA, Katlama C, et al. Diagnostic accuracy of noninvasive mark- Infect Dis 2019 Oct 14. 10.1093/cid/ciz999. [Epub ahead of ers of steatosis, NASH, and liver fibrosis in HIV-monoinfected print] individuals at risk of nonalcoholic fatty liver disease (NAFLD): 33) Sanyal AJ, Harrison SA, Ratziu V, Abdelmalek MF, Diehl AM, results from the ECHAM study. J Acquir Immune Defic Syndr Caldwell S, et al. The natural history of advanced fibrosis due to 2019;80:e86-e94. nonalcoholic steatohepatitis: data from the simtuzumab trials. 17) Fulop T, Herbein G, Cossarizza A, Witkowski JM, Frost E, Hepatology 2019;70:1913-1927. Dupuis G, et al. Cellular senescence, immunosenescence and HIV. 34) Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres- Interdiscip Top Gerontol Geriatr 2017;42:28-46. Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight 18) Martin-Iguacel R, Negredo E, Peck R, Friis-Moller N. loss through lifestyle modification significantly reduces features Hypertension is a key feature of the metabolic syndrome in sub- of nonalcoholic steatohepatitis. Gastroenterology 2015; 149:367- jects aging with HIV. Curr Hypertens Rep 2016;18:46. 378.e5. 19) Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi 35) Erlandson KM, MaWhinney S, Wilson M, Gross L, McCandless E, et al. Premature age-related comorbidities among HIV-infected SA, Campbell TB, et al. Physical function improvements with persons compared with the general population. Clin Infect Dis moderate or high-intensity exercise among older adults with or 2011;53:1120-1126. without HIV infection. AIDS 2018;32:2317-2326. 20) Erlandson KM, Allshouse AA, Jankowski CM, Lee EJ, Rufner 36) Matthews L, Kleiner DE, Chairez C, McManus M, Nettles MJ, KM, Palmer BE, et al. Association of functional impairment Zemanick K, et al. Pioglitazone for hepatic steatosis in HIV/ with inflammation and immune activation in HIV type 1-in- hepatitis C virus coinfection. AIDS Res Hum Retroviruses fected adults receiving effective antiretroviral therapy. J Infect Dis 2015;31:961-966. 2013;208:249-259. 37) Ajmera VH, Cachay E, Ramers C, Vodkin I, Bassirian S, Singh 21) Guaraldi G, Palella FJ. Clinical implications of aging with HIV S, et al. MRI assessment of treatment response in HIV-associated infection: perspectives and the future medical care agenda. AIDS NAFLD: a randomized trial of a stearoyl-coenzyme-A- 2017;31:S129-S135. desaturase-1 inhibitor (ARRIVE trial). Hepatology 2019;70: 22) Byrne CD, Targher GNAFLD. A multisystem disease. J Hepatol 1531-1545. 2015;62:S47-S64. 38) Sebastiani G, Saeed S, Lebouche B, de Pokomandy A, Szabo J, 23) Cossarizza A, Moyle G. Antiretroviral nucleoside and nucleotide Haraoui L-P, et al. Vitamin E is an effective treatment for non- analogues and mitochondria. AIDS 2004;18:137-151. alcoholic steatohepatitis in HIV mono-infected patients. AIDS 24) Gwag T, Meng Z, Sui Y, Helsley RN, Park S-H, Wang S, et al. 2020;34:237-244. Non-nucleoside reverse transcriptase inhibitor efavirenz acti- 39) Stanley TL, Fourman LT, Feldpausch MN, Purdy J, Zheng I, vates PXR to induce hypercholesterolemia and hepatic steatosis. Pan CS, et al. Effects of tesamorelin on non-alcoholic fatty liver J Hepatol 2019;70:930-940. disease in HIV: a randomised, double-blind, multicentre trial. 25) Macias J, Mancebo M, Merino D, Téllez F, Montes-Ramírez ML, Lancet HIV 2019;6:e821-e830. Pulido F, et al. Changes in liver steatosis after switching from 40) Teng S, Potvin D, Mamputu J-C, Vincent G, Zoltowska M, Morin efavirenz to raltegravir among human immunodeficiency virus- J, et al. Impact of tesamorelin, a growth hormone-releasing factor infected patients with nonalcoholic fatty liver disease. Clin Infect (GRF) analogue, on the pharmacokinetics of simvastatin and ritona- Dis 2017;65:1012-1019. vir in healthy volunteers. Clin Pharmacol drug Dev 2013;2:237-245.

1842 Hepatology, Vol. 71, No. 5, 2020 GUARALDI ET AL.

41) Jurgens G, Lange KHW, Reuther LO, Rasmussen BB, Brosen 58) Nascimbeni F, Pellegrini E, Lugari S, Mondelli A, Bursi S, K, Christensen HR. Effect of growth hormone on hepatic cy- Onfiani G, et al. Statins and nonalcoholic fatty liver disease in the tochrome P450 activity in healthy elderly men. Clin Pharmacol era of precision medicine: more friends than foes. Atherosclerosis Ther 2002;71:162-168. 2019;284:66-74. 42) Piconi S, Foschi A, Malagoli A, Carli F, Zona S, Milic J, et al. 59) Thein H-H, Yi Q, Dore GJ, Krahn MD. Natural history of hepa- Impact of prolonged maraviroc treatment on non-AIDS-related titis C virus infection in HIV-infected individuals and the impact comorbidities in HIV-positive patients: a retrospective cohort of HIV in the era of highly active antiretroviral therapy: a meta- study. J Antimicrob Chemother 2019;74:2723-2731. analysis. AIDS 2008;22:1979-1991. 43) Maraviroc add-on therapy for steatohepatitis in HIV—the 60) Shire NJ, Welge JA, Sherman KE. Response rates to pegylated MASH study. https://www.clinicaltr ialsr egist er.eu/ctr-searc h/searc interferon and ribavirin in HCV/HIV coinfection: a research syn- h?query=Maraviroc+Add-On+therapy+for+steatohepatitis+in- thesis. J Viral Hepat 2007;14:239-248. +HIV. Accessed December 30, 2019. 61) Wilby KJ, Partovi N, Ford JAE, Greanya ED, Yoshida EM. 44) Connolly JJ, Ooka K, Lim JK. Future pharmacotherapy for Review of boceprevir and telaprevir for the treatment of chronic non-alcoholic steatohepatitis (NASH): review of phase 2 and 3 hepatitis C. Can J Gastroenterol 2012;26:205-210. trials. J Clin Transl Hepatol 2018;6:264-275. 62) Sulkowski MS, Naggie S, Lalezari J, Fessel WJ, Mounzer K, 45) Study of Potential for Drug Interactions Mediated by CYP3A4 Shuhart M, et al. Sofosbuvir and ribavirin for hepatitis C in pa- Inhibition With Aramchol in Healthy Volunteers. https://clinical- tients with HIV coinfection. JAMA 2014;312:353-361. trials.gov/ct2/show/NCT03760848. Accessed February 29, 2020. 63) Morikawa K, Nakamura A, Shimazaki T, Sakamoto N. Safety and 46) Sherman KE, Abdel-Hameed E, Rouster SD, Shata MTM, efficacy of elbasvir/grazoprevir for the treatment of chronic hepati- Blackard JT, Safaie P, et al. Improvement in hepatic fibro- tis C: current evidence. Drug Des Devel Ther 2018;12:2749-2756. sis biomarkers associated with chemokine receptor inactiva- 64) Benmassaoud A, Ghali P, Cox J, Wong P, Szabo J, Deschenes M, tion through mutation or therapeutic blockade. Clin Infect Dis et al. Screening for nonalcoholic steatohepatitis by using cytoker- 2019;68:1911-1918. atin 18 and transient elastography in HIV mono-infection. PLoS 47) Lefebvre E, Enejosa J, Chang W, Jenkins H, Martinez A, Willett ONE 2018;13:1-13. M, Griffith SP. Pharmacokinetic interactions between cenicrivi- 65) Crum-Cianflone N, Collins G, Medina S, Asher D, Campin R, roc and dolutegravir. In Proceedings of the 14th European AIDS Bavaro M, et al. Prevalence and factors associated with liver test Conference, Brussels, Belgium, 2013.Abstract PE10/8. abnormalities among human immunodeficiency virus-infected 48) Lefebvre E, Enejosa J, Chang W, Jenkins H, Martínez A, Willett persons. Clin Gastroenterol Hepatol 2010;8:183-191. M. Pharmacokinetics of cenicriviroc when administered with 66) Guaraldi G, Squillace N, Stentarelli C, Orlando G, D’Amico R, and without ritonavir, darunavir/ritonavir or atazanavir/ritonavir. Ligabue G, et al. Nonalcoholic fatty liver disease in HIV-infected In Proceedings of the 14th International Workshop on Clinical patients referred to a metabolic clinic: prevalence, characteristics, Pharmacology of HIV Therapy, Amsterdam, Netherlands, 2013. and predictors. Clin Infect Dis 2008;47:250-257. Abstract O_09A. 67) Ingiliz P, Valantin M-A, Duvivier C, Medja F, Dominguez S, 49) Lefebvre E, Enejosa J, Chang W, Jenkins H, Martínez A, Willett Charlotte F, et al. Liver damage underlying unexplained transami- M. Pharmacokinetic interactions between cenicriviroc and efa- nase elevation in human immunodeficiency virus-1 mono-infected virenz. In Proceedings of the 14th International Workshop on patients on antiretroviral therapy. Hepatology 2009;49:436-442. Clinical Pharmacology of HIV Therapy (abstract O_09A), 68) Lemoine M, Barbu V, Girard PM, Kim M, Bastard JP, Wendum Amsterdam, Netherlands, 2013.Abstract O_09A. D, et al. Altered hepatic expression of SREBP-1 and PPARgamma 50) Botta M, Audano M, Sahebkar A, Sirtori CR, Mitro N, Ruscica is associated with liver injury in insulin-resistant lipodystrophic M. PPAR agonists and metabolic syndrome: an established role? HIV-infected patients. AIDS 2006;20:387-395. Int J Mol Sci 2018;19. https://doi.org/10.3390/ijms19041197. 69) Lombardi R, Lever R, Smith C, Marshall N, Rodger A, Bhagani 51) Pedersen JM, Matsson P, Bergstrom CAS, Hoogstraate J, Norén S, et al. Liver test abnormalities in patients with HIV mono- A, LeCluyse EL, et al. Early identification of clinically relevant infection: assessment with simple noninvasive fibrosis markers. drug interactions with the human bile salt export pump (BSEP/ Ann Gastroenterol 2017;30:349-356. ABCB11). Toxicol Sci 2013;136:328-343. 70) Lui G, Wong VWS, Wong GLH, Chu WC-W, Wong C-K, Yung 52) Edwards JE, Eliot L, Parkinson A, Karan S, MacConell L. IMH, et al. Liver fibrosis and fatty liver in Asian HIV-infected Assessment of pharmacokinetic interactions between obeticholic patients. Aliment Pharmacol Ther 2016;44:411-421. acid and caffeine, midazolam, warfarin, dextromethorphan, ome- 71) Mohr R, Boesecke C, Dold L, Schierwagen R, Schwarze-Zander prazole, rosuvastatin, and digoxin in phase 1 studies in healthy C, Wasmuth J-C, et al. Return-to-health effect of modern com- subjects. Adv Ther 2017;34:2120-2138. bined antiretroviral therapy potentially predisposes HIV patients 53) Taub R, Chiang E, Chabot-blanchet M, Kelly MJ, Reeves RA, to hepatic steatosis. Med (Baltimore) 2018;97:e0462. https://doi. Guertin MC, et al. Lipid lowering in healthy volunteers treated org/10.1097/MD.0000000000010462. with multiple doses of MGL-3196, a liver-targeted thyroid hor- 72) Morse CG, McLaughlin M, Matthews L, Proschan M, Thomas mone receptor-b agonist. Atherosclerosis 2013;230:373-380. F, Gharib AM, et al. Nonalcoholic steatohepatitis and hepatic 54) MGL-3196. https://www.madrigalph arma.com/ourap proac h/ fibrosis in HIV-1-monoinfected adults with elevated ami- mgl3196/. Accessed July 24, 2019. notransferase levels on antiretroviral therapy. Clin Infect Dis 55) Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, 2015;60:1569-1578. et al. Liraglutide safety and efficacy in patients with non-alcoholic 73) Nishijima T, Gatanaga H, Shimbo T, Komatsu H, Nozaki Y, steatohepatitis (LEAN): a multicentre, double-blind, randomised, Nagata N, et al. Traditional but not HIV-related factors are asso- placebo-controlled phase 2 study. Lancet (London, England) ciated with nonalcoholic fatty liver disease in Asian patients with 2016;387:679-690. HIV-1 infection. PLoS One 2014;9:1-6. 56) Petit J-M, Verges B. GLP-1 receptor agonists in NAFLD. 74) Iogna Prat L, Roccarina D, Lever R, Rodger A, Hall A, Bhagani Diabetes Metab 2017; 43(Suppl. 1):2S28-2S33. S, et al. Aetiology and severity of liver disease in HIV posi- 57) Effects of semaglutide in HIV-associated lipohypertrophy. https:// tive patients with suspected NAFLD: lessons from a cohort clinicaltr ials.gov/ct2/show/NCT04 019197. Accessed January 13, with available liver biopsies. J Acquir Immune Defic Syndr 2020. 2018;68:S572-S573.

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75) Pembroke T, Deschenes M, Lebouché B, Benmassaoud A, 78) Price JC, Wang R, Seaberg EC, Budoff MJ, Kingsley LA, Palella Sewitch M, Ghali P, et al. Hepatic steatosis progresses faster in FJ, et al. The association of inflammatory markers with nonalco- HIV mono-infected than HIV/HCV co-infected patients and is holic fatty liver disease differs by human immunodeficiency virus associated with liver fibrosis. J Hepatol 2017;67:801-808. serostatus. Open Forum Infect Dis 2017;4:1-9. 76) Perazzo H, Cardoso SW, Yanavich C, Nunes EP, Morata M, 79) Sterling RK, Smith PG, Brunt EM. Hepatic steatosis in human Gorni N, et al. Predictive factors associated with liver fibrosis and immunodeficiency virus: a prospective study in patients without steatosis by transient elastography in patients with HIV mono- viral hepatitis, diabetes, or alcohol abuse. J Clin Gastroenterol infection under long-term combined antiretroviral therapy. J Int 2013;47:182-187. AIDS Soc 2018;21:1-9. 80) Vodkin I, Valasek MA, Bettencourt R, Cachay E, Loomba R. 77) Price JC, Ma Y, Scherzer R, Korn N, Tillinghast K, Peters MG, Clinical, biochemical and histological differences between HIV- et al. Human immunodeficiency virus-infected and uninfected associated NAFLD and primary NAFLD: a case-control study. adults with non-genotype 3 hepatitis C virus have less he- Aliment Pharmacol Ther 2015;41:368-378. patic steatosis than adults with neither infection. Hepatology 2017;65:853-863. Author names in bold designate shared co-first authorship.

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