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Integrase Inhibitors Tied to Weight Gain, Hepatic Steatosis in Longitudinal Cohort
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Mark Mascolini
A small single-center longitudinal study at Bonn University Hospital linked treatment with the integrase inhibitors dolutegravir or raltegravir to clinically meaningful weight gain and to new hepatic steatosis [1]. The analysis also indicated that a body mass index (BMI) of 23.5 kg/m2--below the overweight/obese range--may be a cutoff for steatosis risk in people with HIV.
With collaborators at other centers, Bonn University researchers aimed to pinpoint factors linked to significant weight gain and to progression to hepatic steatosis in people with HIV. They studied HIV-positive people in the Nonalcoholic Fatty Liver Disease (NAFLD) Cohort Bonn, which began enrollment in January 2013. Participants in this analysis could not have HCV or HBV infection, and they had to make two or more study visits.
The 321 participants had yearly transient elastography and assessments of controlled attenuation parameters (CAP) to detect fibrosis and hepatic steatosis. The study ran from January 2013 through December 2018, and follow-up time averaged 42.1 months (3.5 years). Endpoints were new development of hepatic steatosis, defined as a CAP value of 238 dB/m or greater, and clinically significant weight gain, defined as a 10% or greater increase from baseline body weight. A Fibroscan result of 7.1 or greater kPa indicated fibrosis.
Most study participants were men (77%) and white (76%). Age averaged 45.7 years, body mass index 24.9 kg/m2 (just below the overweight range), CAP 235.7 dB/m, and liver stiffness 5.1 kPa. One in 5 people had arterial hypertension, and 6% had type 2 diabetes. Most people, 95%, were taking antiretroviral therapy, time on treatment averaged 8.1 years, and 86% had an undetectable viral load. Similar proportions took a nonnucleoside (43.7%) or a protease inhibitor (43.4%), while 20.3% took an integrase inhibitor.
At the baseline measure, 91.7% of participants did not have fibrosis (below 7 kPa), 6.8% had F1-F3 fibrosis (7.1 to 12.4 kPa), and 1.5% had F4 fibrosis (kPa 12.5+). Baseline CAP indicated that 54% did not have steatosis (237 dB/m or lower), 14% had S1 steatosis (238 to 259 dB/m), 14% had S2 steatosis (260 to 291 dB/M), and 18% had S3 steatosis (292+ dB/m). During follow-up, steatosis developed in 22% of participants, and 7% had progression to a higher level of steatosis.
Weight averaged 68.4 kg in people without steatosis and 77.6 kg in those with new steatosis, a highly significant difference (P < 0.001). Binary multivariable logistic regression linked higher weight to new steatosis (beta 0.2, P = 0.003). ROC curve analysis indicated that a nonoverweight/nonobese baseline BMI, 23.5 kg/m2, predicted new hepatic steatosis in these people.
The new-steatosis analysis focused on 52 people taking a protease inhibitor--30 on darunavir/ritonavir, 12 on atazanavir/ritonavir, and 10 on lopinavir/ritonavir. Rates of no steatosis versus new steatosis did not differ with any of these three regimens. Seventeen people took an integrase inhibitor--7 on raltegravir, 7 on dolutegravir, and 3 on elvitegravir. Rates of new steatosis versus no steatosis were higher with each of these integrase inhibitors: 11.5% versus 1.3% for raltegravir, 9.6% versus 1.3% for dolutegravir, and 3.8% versus 2.6% for elvitegravir (P = 0.02 overall).
Among 32 people with more than a 10% weight gain during follow-up, liver stiffness averaged 5.9 kPa, compared with 5.0 kPa in 233 people with less than a 10% weight gain (P = 0.03). Variables that did not differ significantly between people with more than or less than a 10% weight gain were sex, age, BMI, nadir CD4 count, viral load below 40 copies, CAP, HbA1c (a diabetes marker), and antiretroviral therapy switch.
Weight gain greater than 10% occurred in higher proportions of people taking dolutegravir (18.8%) or raltegravir (18.8%) than taking bictegravir (9.4%), elvitegravir (0%), darunavir/ritonavir (9.4%), or atazanavir/ritonavir (3.1%) (P = 0.008 for integrase inhibitor comparison).
The Bonn team concluded that clinically significant weight gains occur more often in antiretroviral-treated people taking dolutegravir or raltegravir than other integrase inhibitors or protease inhibitors. They proposed that dolutegravir and raltegravir "seem to impact development of hepatic steatosis in HIV-monoinfected individuals." At this point, however, these conclusions rest on small numbers of people taking integrase inhibitors. If larger studies confirm these findings, they would begin to answer the question whether integrase inhibitor-associated weight gains have a clinical impact.
Reference
1. Bischoff J, Schwarze-Zander C, Boesecke C, et al. Hepatic steatosis in HIV monoinfected individuals: which impact has baseline BMI and treatment with integrase inhibitors? 17th European AIDS Conference, November 6-9, 2019, Basel. Abstract PS12/6.
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