Increase in visceral adipose tissue in a woman living with HIV after introduction of integrase strand transfer inhibitor

Introduction

Integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy is recommended as first-line treatment for HIV infection, ¹ due to high virologic efficacy and improved tolerability. However, studies have shown that the use of INSTIs, especially dolutegravir, is associated with greater body weight gain compared to other antiretroviral classes.^2–5

We have observed several patients, followed at the Outpatient Clinic of the Infectious and Tropical Disease Unit, Verona University Hospital, who gained considerable weight after starting, or being switched to, a dolutegravir-based regimen. One recent study confirmed the association between dolutegravir treatment and body weight gain in a small cohort of patients on dolutegravir monotherapy; ⁶ however, no patients developed hypertension or diabetes over one year and no one started cholesterol-lowering therapy.

We now report the case of a woman living with HIV who experienced an important increase in weight, with accumulation of visceral adipose tissue, following a switch to dolutegravir monotherapy.

Case presentation

A 60-year-old, post-menopausal woman since the age of 52 years, was diagnosed with HIV infection (CDC stage A2) in 1990. Her nadir CD4 lymphocyte count was 268 cells/µL and her zenith plasma HIV-RNA 54,600 copies/mL. Two years after HIV diagnosis, ART was initiated with two nucleoside reverse transcriptase inhibitors (NRTIs) only (zidovudine and lamivudine, then stavudine and didanosine). In 2010, the patient developed non-cirrhotic portal hypertension, likely related to didanosine treatment, ⁷ and was put on a protease inhibitor-based therapy with indinavir (subsequently replaced by fosamprenavir), lamivudine and abacavir. In December 2014, to avoid NRTI toxicity, ART was changed to maraviroc and raltegravir. In September 2015, to reduce pill burden, the patient was switched to dolutegravir monotherapy. She never experienced virologic failure and her weight remained stable in the years before the latter switch, at which time the patient weighed 62 Kg and had a BMI of 24.22 Kg/m². A substantial increment in weight (5.5 Kg) and BMI (2.15 Kg/m²) was observed in the first year after the switch, with abdominal and cervico-dorsal fat accumulation. The patient had not changed her diet or physical activity, had not used concomitant medications and had no socio-psychological conditions that may have caused weight gain. The weight gain was neither associated with metabolic abnormalities nor with the development of cardiovascular diseases or diabetes: both the Tyg index and the HSI index remained broadly unchanged (4.3 vs 4.25 and 30.9 vs 32.9 respectively).

In May 2017, a computed tomography (CT) scan was performed and targeted to the evaluation of adipose tissue accumulation and distribution. Visceral and subcutaneous lipid amount of abdominal, liver and pancreas fat were appreciable through the CT investigation (Figure 1(a) and (b)). In the following years, the patient remained on dolutegravir monotherapy; her weight continued to increase, although less markedly than in the first year post-switch. After one year and eight months, the weight gained was 7.3 Kg, while BMI was 2.85 Kg/m². Lipidic and glycemic profile remained unaltered.

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Figure 1.

(a,b) MRI scan images in 2017 show the accumulation of adipose tissue, particularly in the cervical region with a thickness of 35 mm, and at the thoracic level. (c) Unenhanced CT in 2013 (before the treatment). The liver density is 19 HU greater than the spleen. HUs are indicated in the circles. (d) Unenhanced CT after 4 years of INSTI treatment. The liver density is 4 HU greater than the spleen as for lipid accumulation. HUs are indicated in the circles. The 3d reconstruction shows the increase in weight and waist circumference before (e) and after therapy (f).

The patient died in 2018, at the age of 63, as a result of massive brain hemorrhage due to rupture of a brain aneurysm.

To determine if dolutegravir monotherapy was linked to the accumulation of visceral adipose tissue, we matched images of her CT performed in 2017 (age of patient: 62 years old) and in 2013 (age of patient: 58 years old). Adipose tissue quality can be indirectly assessed by quantifying adipose density (in Hounsfield units, HU) on CT; ⁸ a decreased adipose tissue density has been associated with cardiovascular risk, independently of adipose tissue quantity. ⁹ CT diagnostic criteria for steatosis are liver attenuation at least 10 HU less than the spleen, or absolute liver attenuation of less than 40 HU; unenhanced CT has a 43–95% sensitivity and a 90–100% specificity for steatosis. With contrast-enhanced CT, a difference of 18.5 HU between liver and spleen attenuation had a sensitivity of 93%, a specificity of 93%, and a receiving operating curve of 0.98. The sensitivity and specificity of unenhanced CT are similar to those of ultrasound (SN 84.8%, SP 93.6%) and magnetic resonance imaging (MRI). ¹⁰ In 2013, the liver density was 19 HU greater than the spleen (Figure 1(c)); four years later, liver density was 4 HU greater than the spleen (Figure 1(d)). The 3d reconstruction highlights the increase in weight and waist circumference before and after the switch to dolutegravir monotherapy (Figure 1(e) and (f)).

Discussion and conclusions

The effects of INSTIs on body composition and metabolism are an ongoing research area. Several studies have already stressed a link between weight gain and dolutegravir-based regimens, both in treatment-naïve and treatment-experienced patients.

While the weight gain observed in many patients shortly after ART initiation is thought to be due, at least partly, to the “return to health” phenomenon (nutritional rehabilitation following weight loss due to advanced disease), the etiology of weight gain in virologically-suppressed patients who modify their ART regimen is unclear. A plausible hypothesis includes a possible dolutegravir effect on systems regulating energy homeostasis and food intake; in vitro, dolutegravir inhibits the binding of melanocyte-stimulating hormone to melanocortin 4 receptor, ¹¹ which is involved in the regulation of energy homeostasis and caloric intake.

Evidence was presented at the 17th European AIDS Conference, that dolutegravir and raltegravir exposure is associated with larger adipocytes and larger lipid droplets in adipocytes. ¹² Recently, Debroy and colleagues confirmed this observation after raltegravir exposure, and reported a relationship between changes in adipose tissue density and metabolic abnormalities linked to an increased cardiovascular risk. ¹³ A cardiovascular and metabolic derangement as a consequent of INSTI use has also been described by Galdamez and colleagues, represented by BMI and systolic blood pressure increases. ¹⁴

Our case suggests a link between INSTI use and decreased adipose tissue density and is an interesting addition to the data available because the patient was on monotherapy. Larger studies are needed to determine if the INSTI class is indeed linked to an indirect increase of cardiovascular and metabolic risks.