Effect on Liver Fat and Metabolic Parameters When Switching a Protease Inhibitor or Efavirenz to Raltegravir

The prevalences of overweight (body-mass-index, BMI 25-30 kg/m2) and obesity (BMI>30 kg/m2) are steadily increasing among HIV-infected patients globally. In parallel, the risk of non-alcoholic fatty liver disease (NAFLD) increases. Clinically alarming are the data which suggest that HIV infected have higher rates of progressive form of NAFLD than non-HIV infected age, gender and BMI matched controls.

As the treatment for HIV is life-long, it is crucial to understand the effects of different antiretroviral therapy (ART) regimens on metabolism. Some antiretroviral agents appear to promote unfavourable changes in metabolism (e.g. in blood lipids) and predispose to trunk fat redistribution and liver fat accumulation.

Raltegravir has been demonstrated to have beneficial impact on some metabolic parameters compared to the protease inhibitor class or efavirenz. In this study, the aim is to investigate whether switching a protease inhibitor or efavirenz to raltegravir reduces liver fat in patients who are overweight or obese and have at least one metabolic syndrome component. For this purpose, the proton magnetic resonance spectroscopy will be used.

In addition, the aim is to clarify the change in the body composition in this study group. For this purpose, the visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volumes will be measured using MRI.

To acquire more knowledge on metabolic effects in adipose tissue level, subcutaneous adipose tissue biopsies will be collected together with blood, saliva and feces samples.

• Raltegravir (Drug), also known as Isentress: The aim of this study is to investigate whether switching a protease inhibitor (PI) or efavirenz to raltegravir has effect on liver fat and metabolism in HIV-infected patients who are overweight or obese and have at least one metabolic syndrome component .

Primary outcomes

• Change in Liver Fat [Baseline and 24 weeks]: 24 week value minus baseline value, liver fat % measured by proton magnetic resonance spectroscopy.

Secondary outcomes

• Change in Subcutaneous and Visceral Adipose Tissue Volume [Baseline and 24 weeks]: 24 week value minus baseline value: change in subcutaneous (SAT) and visceral (VAT) adipose tissue volume (mL) measured by magnetic resonance imaging. Analysis included a series of T1-weighted trans-axial images from 8 cm above to 8 cm below the 4th and 5th lumbar intervertebral disc (16 slices, field of view 375 x 500 mm2, slice thickness 10 mm).
• Change in Body Weight and Total Body Fat [Baseline and 24 weeks]: 24 week value minus baseline value, change in body weight (kg) and total body fat (kg) measured by Bioelectrical Impedance Analysis.

Other outcomes

• Change in Liver Stiffness [Baseline and 24 weeks]: 24 week minus baseline value, change in liver stiffness (kPa) measured by transient elastography (Fibroscan ®).
• Change in Fasting Plasma Glucose [Baseline and 24 weeks]: 24 week value minus baseline value, change in fasting plasma glucose (mg/dL).
• Change in Fasting Serum Lipid Profile [Baseline and 24 weeks]: 24 week value minus baseline value, change in fasting serum lipid profile: LDL and HDL cholesterol, triglyceride (all values in mmol/L)
• Change in Metabolic and Inflammatory Biomarkers: hsCRP [Baseline and 24 weeks]: 24 week value minus baseline value, change in circulating metabolic and inflammatory biomarkers: high sensitivity C-reactive protein (hsCRP mg/L)
• Change in Metabolic and Inflammatory Biomarkers: IL-6 [Baseline and 24 weeks]: 24 week value minus baseline value, change in circulating metabolic and inflammatory biomarkers: interleukin 6 (IL-6 pg/mL)

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Written informed consent (IC) obtained.
* HIV-positive adult (age over 18) subjects currently on stable ART, with no changes in the ART regimens during the past 6 months.
* Current ART includes either a protease inhibitor or efavirenz.
* No documented or suspected resistance to integrase inhibitors or to NRTIs.
* No prior history of virologic failure. Failure is defined as a confirmed plasma viral load > 200 cop/ml measured no less than six months after initiation or modification of therapy.
* Virological blips accepted only if a single viral load measurement has been between 50-200 cop/ml followed by viral load < 50 cop/ml without the need to initiate a change in ART and no blip within 12 month window period prior to screening.
* Documented evidence of at least two HIV viral load < 50 cop/ml measurements during the past 12 months prior to inclusion: one within 6 months prior to screening.
* HIV viral load < 50 cop/ml at screening.
* BMI>25 kg/m2 and one metabolic syndrome condition, which are

  * BP ≥ 130/≥ 85 mmHg or hypertension medication currently in use or
  * fasting glucose ≥ 5.6 mmol/l or B-HbA1C > 42 mmol/mol or diabetes medication currently in use or
  * HDL < 1.0 mmol/l in men and < 1.3 mmol/l in women or triglycerides ≥ 1.7 mmol/l or a cholesterol-lowering regimen currently in use or
  * waist circumference > 94 cm in men and >80 cm in women (or respective cut off values for non-European ethnic groups as defined by International Diabetes Federation). OR
* ultrasound or biopsy proven hepatosteatosis.

Exclusion Criteria:

* Within 12 month window period prior to screening, HIV viral load measurement of >50 cop/ml.
* More than one consecutive HIV viral load measurements of > 50 cop/ml in the treatment history after initial viral suppression with ART.
* Chronic hepatitis B or C.
* Daily alcohol consumption ≥ 30 g for men and ≥ 20 g for women.
* Pregnancy or planned pregnancy during the study period.
* Lipid or glucose lowering regimen or hormonal supplement started within 3 months before the planned study start.
* Psychiatric disorder, which prevents a study subject to understand the study protocol.
* Other serious disease, which prevents a study subject to participate in the study.
* For MRI/spectroscopy imaging: metal objects in the body or claustrophobia.

Participant flow

Outcome results

• Change in Liver Fat (Primary), Median, % hepatic fat fraction: Control (= no Intervention Arm). 0.3 (-0.5 to 2.7); Raltegravir Arm. 0.6 (-0.3 to 1.6)
• Change in Subcutaneous and Visceral Adipose Tissue Volume (Secondary), Median, mL: Control (= no Intervention Arm). -74 (-627 to 202); Raltegravir Arm. 242 (27 to 341)
• Change in Body Weight and Total Body Fat (Secondary), Median, kg: Control (= no Intervention Arm). 0.9 (-1.8 to 4.1); Raltegravir Arm. 2.0 (0.4 to 3.3)
• Change in Liver Stiffness (Other pre specified), Median, kPa: Control (= no Intervention Arm). -0.5 (-1.2 to 0.6); Raltegravir Arm. -0.2 (-1.6 to 0.9)
• Change in Fasting Plasma Glucose (Other pre specified), Median, mg/dL: Control (= no Intervention Arm). 0.0 (-7.2 to 5.4); Raltegravir Arm. -1.8 (-10.8 to 0.0)
• Change in Fasting Serum Lipid Profile (Other pre specified), Median, mmol/L: Control (= no Intervention Arm). 0.1 (-0.4 to 0.4); Raltegravir Arm. -0.5 (-1.0 to -0.1)
• Change in Metabolic and Inflammatory Biomarkers: hsCRP (Other pre specified), Median, mg/L: Control (= no Intervention Arm). 0.66 (-0.07 to 1.45); Raltegravir Arm. -0.06 (-0.59 to 0.22)
• Change in Metabolic and Inflammatory Biomarkers: IL-6 (Other pre specified), Median, pg/mL: Control (= no Intervention Arm). 0.83 (-0.09 to 1.20); Raltegravir Arm. 0.00 (-0.87 to 0.64)

Adverse events

Time frame: 6 months.

Serious adverse events by term

Other adverse events by term

• Results publication: Hanttu AM, Pekkala S, Satokari R, Hartikainen AK, Arkkila P, Pietilainen KH, Sutinen JP. Gut microbiota alterations after switching from a protease inhibitor or efavirenz to raltegravir in a randomized, controlled study. AIDS. 2023 Feb 1;37(2):323-332. doi: 10.1097/QAD.0000000000003419. Epub 2022 Nov 10. PMID 36541643
• Results publication: Hanttu A, Vuoti S, Kivela P, Arkkila P, Lundbom N, Hakkarainen A, Lundbom J, Lehtimaki T, Viskari H, Lehtinen V, Pietilainen KH, Sutinen J. Liver Fat, Adipose Tissue, and Body Composition Changes After Switching from a Protease Inhibitor or Efavirenz to Raltegravir. AIDS Patient Care STDS. 2021 Sep;35(9):335-341. doi: 10.1089/apc.2021.0106. PMID 34524919

• Study Protocol and Statistical Analysis Plan (PDF, 2019-05-28)

• Jussi Sutinen, MD PhD, Principal investigator, Helsinki University Central Hospital