Hepatic steatosis after switching to integrase inhibitor-based regimens does not parallel short-term weight gain

Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ “This is a pre-copyedited, author-produced version of an article accepted for publication in AIDS. The published version of record Gonzalez-Serna, Alejandroa,b,c; Macías, Juana,c,d; Rincon, Pilara,c; Arriaza, Maria Josea,c; Corma- Gomez, Anaisa,c; Santos, Martaa,c; Fernandez-Fuertes, Martaa,c; Pineda, Juan Antonioa,c,d,∗; Real, Luis Miguela,c,d,e,∗. Hepatic steatosis after switching to integrase inhibitor-based regimens does not parallel short-term weight gain. AIDS 37(14):p 2259-2262, November 15, 2023. is available online at: https://doi.org/10.1097/QAD.0000000000003673 . 1 Hepatic steatosis after switching to integrase inhibitor-based 1 regimens does not parallel short-term weight gain 2 3 Alejandro GONZALEZ-SERNA1,2,3, Juan MACIAS1,3,4,§, Pilar RINCON1,3, Maria 4 Jose ARRIAZA1,3, Anais CORMA-GOMEZ1,3,, Marta SANTOS1,3, Marta 5 FERNANDEZ-FUERTES1,3, Juan Antonio PINEDA1,3,4*, Luis Miguel REAL1,3,4,5*. 6 7 1. Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen de Valme 8 /CSIC/Universidad de Sevilla. 9 2. Departamento de Fisiología, Facultad de Farmacia, Universidad de Sevilla, 10 Sevilla, Spain. 11 3. Centro de Investigación Biomédica en Red de Enfermedades Infecciosas 12 (CIBERINFEC). 13 4. Departamento de Medicina, Universidad de Sevilla, Sevilla, Spain. 14 5. Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología. 15 Facultad de Medicina, Universidad de Málaga, Málaga, Spain. 16 17 Keywords: Integrase strand transfer inhibitors, weight gain, hepatic steatosis, 18 metabolic complications, HIV, ART. 19 Running title: Hepatic steatosis and INSTI. 20 *These authors contributed equally to this manuscript. 21 §Corresponding author: Juan Macías. Infectious Diseases and Microbiology 22 Unit, Hospital Universitario Virgen de Valme, Avda Bellavista s/n, 41014-Seville, 23 2 Spain. ORCID: 0000-0002-4778-790X. Tel: +34 955015736. Email: 24 [email protected] 25 26 3 Summary 27 28 We studied hepatic steatosis (HS) in people living with HIV (PLWH) who 29 switched to an integrase-inhibitors (INSTI)-based regimen. One hundred fifty-four 30 PLWH were included. After 48 weeks, median (Q1-Q3) weight gain was 1.2(-0.6- 31 3.8) Kg and median (Q1-Q3) controlled attenuation parameter (CAP) change was 32 -4(-33-27) dB/m. Weight gain was weakly correlated with CAP change [R2 (IC 33 95%)=0.144(-0.014, 0.296);p=0.074)]. Changes in HS after switching to INSTI- 34 based regimens do not seem to parallel weight gain after one year. 35 36 4 Clinical trials and large observational studies have confirmed that 37 integrase inhibitors (INSTI) administration is associated with weight gain [1, 2]. In 38 people living with HIV (PLWH), body mass index (BMI) is the main predictor of 39 hepatic steatosis (HS) [3, 4]. The influence that INSTI may have on fat 40 accumulation in the liver needs to be clarified. We evaluated the effect of 41 switching to INSTI on HS, estimated by controlled attenuation parameter (CAP), 42 in PLWH with controlled viremia. 43 In this prospective cohort study were included 154 PLWH who 44 consecutively attended to our hospital (see supplementary figure) with: 1) 45 Absence of active hepatitis C virus (HCV) infection; 2) Undetectable HIV viral 46 load for more than 24 weeks with antiretroviral therapy (ART) based on boosted- 47 protease inhibitor (PI) or non-nucleoside analogue (NNRTI); 3) Not having been 48 previously treated with an INSTI-based regimen; 4) Switching from PI or NNRTI 49 based to INSTI; 5) CAP determinations measured at the date of switching to 50 INSTI and after 48 weeks of follow-up; 6) Self-reported alcohol consumption <50 51 grams/day. A clinical evaluation was obtained every 24 weeks, and liver stiffness 52 and CAP values every 48 weeks. The date of ART switch was considered as the 53 baseline date. Change in CAP value and weight gain, were calculated as the 54 difference between the measurements at the 48-week visit and the baseline 55 measurements. Hepatic steatosis (HS) was defined as CAP ≥248 dB/m. 56 Characteristics of PLWH at baseline are shown in supplementary table 1. Drugs 57 combined with INSTI and before switching are summarized in supplementary 58 table 2. 59 5 Global weight change and weight change for each INSTI are shown in 60 Figure 1a. Overall median (Q1, Q3) weight gain was 1.2 Kg (-0.6, 3.8). Median 61 (Q1, Q3) weight gain for each INSTI is shown in supplementary table 4. Seventy- 62 two PLWH (46.8%) had BMI >25 kg/m2 at baseline and 81 (52.6%) had BMI ≤25 63 kg/m2 after 48 weeks (p=0.012). Nineteen (12.3%) PLWH had BMI >30 kg/m2 at 64 baseline and 23 (14.9%) had BMI >30 kg/m2 after 48 weeks (p=0.219 65 respectively). 66 Global CAP change and CAP change for each INSTI are shown in Figure 67 1b. Overall median (Q1, Q3) CAP change -4 dB/m (-33, 27). Median (Q1, Q3) 68 CAP change for each INSTI is shown in Figure 1b. No significant differences in 69 CAP change associated with any specific drug were observed (Supplementary 70 table 5). Weight gain was weakly correlated with CAP change [R2 (IC 95%) = 71 0.144 (-0.014, 0.296); p=0.074)]. Median (Q1, Q3) CAP change among PLWH 72 who gained weight was 4 dB/m (-32, 33) compared to -13 dB/m (-38, 8) among 73 those who did not (p=0.044). HS was found in 76 (49%) PLWH at baseline and in 74 71 (46%) patients at 48 weeks (p=0.551). Twenty-five (32.9%) out of 76 PLWH 75 with HS at baseline experienced HS resolution after 48 weeks. Twenty (25.6%) 76 out of 78 PLWH without HS at baseline experienced HS after 48 weeks. Among 77 patients who gained weight, 14/55 (25.5%) of them experienced HS resolution 78 after 48 weeks compared to 11/21 (52.4%) among patients who did not gain 79 weight (p=0.025). Among PLWH without HS at baseline, 11/37 (29.7%) of those 80 6 with a weight gain ≥1.2 Kg developed HS after 48 weeks compared to 9/41 (22%) 81 among those with a weight gain < 1.2 Kg (p=0.432). In univariate analyses, no 82 variables were significantly associated with CAP change (supplementary table 3). 83 After multiple linear regression analysis adjusted by sex and age, sex was 84 independently associated with CAP change (supplementary table 3). 85 We found that the emergence of HS, as measured by CAP, one year after 86 switching from PIs or NNRTIs to INSTI-containing regimens did not seem to 87 parallel weight gain experienced in PLWH. Indeed, the overall frequency of 88 PLWH with HS was similar after 48 weeks of switching to INSTI-containing 89 regimens. In a clinical trial we had already found that the change from Efavirenz 90 (EFV) to Raltegravir (RAL) was related to a reduction in steatosis, despite greater 91 weight gain with RAL [5]. It has been reported that past INSTI use was 92 associated with a higher prevalence of steatosis [6]. However, in that study the 93 prevalence of steatosis was very low (8.6%) [6], and not comparable to that 94 reported by other studies like ours (>40%) [5, 7]. Furthermore, our study is 95 longitudinal and prospective, so it is a more suitable design to determine whether 96 the use of INSTI is associated with changes in HS. Therefore, the positive effect 97 on HS of switching to RAL could be regarded as a drug class effect. 98 The lack of relationship between weight and HS in PLWH switching to 99 INSTI could be explained by a lower degree of liver toxicity of INSTI compared 100 with PIs or NNRTIs, a more favorable lipid profile of INSTI, and a positive effect 101 of this drug family on systemic inflammation. Thus, EFV has been related to 102 mitochondrial toxicity and HS, and the interruption of EFV, a regimen which 50 103 7 PLWH in this study were receiving before switching, can lead to reversal in 104 mitochondrial toxicity in the liver [8] and, as a consequence, decreases in CAP 105 values [9], as has been observed in in vitro studies. In addition, the lipid profile 106 after switching to INSTI improves [10-12], and this beneficial effect could also 107 lessen HS. Besides, the intense reduction of inflammation exerted by INSTI could 108 have a positive influence over HS [13-15]. 109 Our follow-up was limited to one year but whether longer periods of 110 observation might be needed to detect increases in HS linked to weight gain 111 among PLWH receiving INSTI is not known. Also, because of the observational 112 nature of our study a randomly selected control group was not available. Finally, 113 the relatively low proportion of women included in this study could also be 114 considered a limitation. 115 In conclusion, HS one year after switching from PIs or NNRTIs to INSTI- 116 containing regimens do not seem to parallel weight gain experienced in PLWH 117 with controlled viremia. These results need confirmation in randomized clinical 118 trials aimed to evaluate the effect of INSTI-based regimens on hepatic steatosis. 119 120 8 References 121 122 1) Bourgi K, Jenkins CA, Rebeiro PF, et al. 2020. Weight Gain Among 123 Treatment-Naïve Persons With HIV Starting Integrase Inhibitors Compared to 124 Non-Nucleoside Reverse Transcriptase Inhibitors or Protease Inhibitors in a 125 Large Observational Cohort in the United States and Canada. J Int AIDS Soc. 126 23:e25484. doi: 10.1002/jia2.25484. 127 128 2) NAMSAL ANRS 12313 Study Group; Kouanfack C, Mpoudi-Etame M, et al. 129 2019. Dolutegravir-Based or Low-Dose Efavirenz-Based Regimen for the 130 Treatment of HIV-1. N Engl J Med. 381:816-826. doi: 10.1056/NEJMoa1904340. 131 132 3) Macías J, Real LM, Rivero-Juárez A, et al. 2016. Changes in liver steatosis 133 evaluated by transient elastography with the controlled attenuation parameter in 134 HIV-infected patients. HIV Med. 17:766-773. doi: 10.1111/hiv.12384. 135 136 4) Macías J, González J, Tural C, et al. 2014. Prevalence and factors associated 137 with liver steatosis as measured by transient elastography with controlled 138 attenuation parameter in HIV-infected patients. AIDS 28:1279-87. doi: 139 10.1097/QAD.0000000000000248. 140 141 5) Macías J, Pineda JA, Real LM. 2017. Non-Alcoholic Fatty Liver Disease in HIV 142 Infection. AIDS Rev. 19:35-46. 143 15 259 Figure 1. a) Median weighs changes one year after switch; b) Median CAP 260 changes one year after switch 261 Figure legend: Integrase inhibitors (INSTI), Dolutegravir (DTG), Raltegravir 262 (RAL), Elvitegravir (EVG), Bictegravir (BIC) 263