Weight gain among treatment‐naïve persons with HIV starting integrase inhibitors compared to non‐nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada

Bourgi, Kassem; Jenkins, Cathy A.; Rebeiro, Peter F; Palella, Frank J.; Moore, Richard D.; Altoff, Keri; Gill, John; Rabkin, Charles S.; Gange, Stephen J.; Horberg, Michael A.; Margolick, Joseph B.; Li, Jun; Wong, Chung F.; Willig, Amanda L.; Lima, Viviane D.; Crane, Heidi M.; Thorne, Jennifer E.; Silverberg, Michael J.; Kirk, Gregory D.; Mathews, W. Christopher; Sterling, Timothy R.; Lake, Jordan E.; Koethe, John R.

doi:10.1002/jia2.25484

Cited by 161 publications

(145 citation statements)

References 29 publications

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“…Taking an INSTI-based regimen was the single most sensitive predictor for an excessive weight increase in this study. Besides, similar to several previous reports [ 1 , 4 , 9 , 12 ], our findings show that INSTI users had greater weight gain than NNRTI users, even though the most prevalent INSTI in our study was elvitegravir, which was associated with less weight gain than dolutegravir or bictegravir [ 1 , 9 ]. These findings may partly be explained by the effect of efavirenz on weight suppression as efavirenz accounted for 93% of NNRTIs in this study [ 27 , 28 ].…”

Section: Discussionsupporting

confidence: 91%

“…Some experts have considered the return-to-health phenomenon as a major driver, a process by which individuals with reduced weight recover to their pre-illness weight (ie, healthy weight) following ART initiation [ 22 ]. Several studies support the return-to-health phenomenon, including the finding that people with lower CD4 counts and higher HIV RNA levels had more significant weight gain after treatment [ 1 , 12 ]; more weight gain was observed in the first year after ART initiation [ 4 , 15 ]; and weight change in PWH approached HIV-uninfected comparators after 3 years of ART [ 2 ].…”

mentioning

confidence: 99%

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Integrase Strand Transfer Inhibitors Play the Main Role in Greater Weight Gain Among Men With Acute and Early HIV Infection

Anderson

2020

Open Forum Infectious Diseases

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Background The predictors of weight gain remain unclear in people with acute and early HIV infection (AEH). Methods Eligible antiretroviral-naïve men diagnosed with AEH from January 1, 2000, to December 31, 2019, were enrolled in an observational cohort study at the University California, San Diego. The study used multivariable mixed-effect linear regression models to analyze differences in the rate of weight gain over time between participants receiving early vs deferred antiretroviral therapy (ART) treatment, low vs high baseline CD4 count and HIV RNA, and different classes of ART. Results A total of 463 participants were identified, with mean CD4 cell count of 507 cells/μL and log HIV RNA of 5.0 copies/mL at study entry. There was no difference in the rate of weight gain between participants who did and did not receive ART within 96 weeks of incident HIV infection. Neither a baseline CD4 count of <350 cells/μL nor a baseline HIV RNA of >100 000 copies/mL was a predictor of weight gain. Compared with persons taking non-nucleoside reverse transcriptase inhibitor–based regimens, those who received integrase strand transfer inhibitor (INSTI)–based regimens showed greater weight gain over time. Conclusions Neither baseline CD4 count and HIV RNA nor early ART was associated with weight change in the first 96 weeks following incident HIV infection. Use of INSTI-based regimens represented a major driver of weight gain in men who initiated ART with relatively higher CD4 cell counts.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

Integrase Strand Transfer Inhibitors Play the Main Role in Greater Weight Gain Among Men With Acute and Early HIV Infection

Anderson

2020

Open Forum Infectious Diseases

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“…Thus, a greater fat gain both in the peripheral and truncal depots, resulting in generalized fat gain, has been observed in some individuals receiving INSTIs, both in cohort studies and in clinical trials 10,41,[65][66][67][68] . Indeed, in a large analysis of more than 22,000 treatment-naive PLWH in the multi-site NA-ACCORD, individuals who initiated INSTI-based regimens gained an estimated mean 5.9 kg after 5 years of treatment, compared with 3.7 kg among individu als receiving NNRTI-based regimens and 5.5 kg for those receiving PI-based regimens 69 . Smaller observational studies have also reported a greater weight gain in PLWH initiating INSTI-containing regimens than in those initiating NNRTI or PI regimens, which generally has been greater in women, black individuals, and in those with lower weight and CD4 + T cell counts before starting ART 65,66, 68,70 .…”

Section: Generalized Fat Gain and Obesitymentioning

confidence: 99%

HIV and antiretroviral therapy-related fat alterations

Koethe

Lagathu

Lake

et al. 2020

Nat Rev Dis Primers

122

116

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Adipose tissue accounts for ~20-30% of total body weight in non-obese or overweight persons and for up to 50% in individuals with obesity and is a primary energy store with important endocrine and immunomodulatory functions. Most adipose tissue depots are comprised of white fat, which is responsible for energy storage and release in response to food intake and energy demand. In humans, brown and beige fat are minor components of adipose tissue and can dissipate energy as heat. White adipocytes sequester dietary lipids in adipose tissue depots to serve as energy stores during periods of fasting and prevent toxic lipid accumulation in other tissues such as muscle, liver, pancreas and heart 1. In addition, white adipocytes have a role in glucose and lipid metabolism and respond differentially to physiological cues or metabolic stresses by releasing adipokines and lipokines that regulate energy expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation, immune function and tissue repair 2. Although adipose tissue is mainly comprised of adipocytes, it also contains mesenchymal stem cells (which can differentiate into adipocytes, myoblasts, osteoblasts and chondroblasts), immune cells (including M1 and M2 phenotype macrophages, CD4 + T cells and CD8 + T cells) and fibroblasts, in addition to blood vessels and nerves. Fat expands owing to excess energy supply either through hypertrophy (increased size of existing adipocytes) or hyperplasia (the formation of new adipocytes from mesenchymal stem cells in adipose tissue). In obesity, hypertrophic adipocytes have different biochemical properties to smaller adipocytes, including increased lipolysis, inflammatory cytokine production and reduced secretion of anti-inflammatory adipokines, such as adiponectin, that are also involved in insulin sensi tivity 1. Such alterations in fat depots predispose to ectopic lipid accumulation and the development of comorbidities, including type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), sarcopenia, atherosclerosis and heart failure 2. During physiological ageing, fat is lost from lower limbs and increases in the trunk, alongside accumulation of senescent adipocytes that have altered adipogenic potential and increased secretion of proinflammatory cytokines 3. Fat alteration became a major concern in Western countries in the mid-1990s, when people living with HIV (PLWH) receiving combination antiretroviral therapy

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“…Insulin resistance with impaired glucose metabolism has been observed with PIs (indinavir and lopinavir/ritonavir), NRTIs (stavudine, zidovudine, lamivudine, and didanosine), and NNRTIs (efavirenz) [ 14 •]; its underlying mechanisms are not fully understood, but in the case of indinavir, it involves blockade of the insulin-sensitive glucose transporter GLUT4 [ 14 •]. Recently, more weight gain on integrase strand transfer inhibitors (INSTIs) compared with NNRTI-based regimens has been reported [ 23 ]. In this class of INSTIs, dolutegravir and raltegravir induced adipogenesis, lipogenesis, oxidative stress, fibrosis, and insulin resistance in PWH [ 24 ].…”

Section: Role Of Hiv Infection and Art In Metabolic Syndromementioning

confidence: 99%

Hypertension and Metabolic Syndrome in Persons with HIV

et al. 2020

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Purpose of Review With the advent of highly active antiretroviral therapy (ART), the life span of persons with HIV (PWH) has been nearly normalized. With aging, prevalence of the metabolic syndrome (MetS), including hypertension, has increased in the HIV population and exceeds that in the general population in some studies. This is due to a combination of traditional risk factors in addition to the effects attributable to the virus and ART. We review recent findings on the mechanisms contributing to MetS and hypertension in PWH, particularly those specific to the viral infection and to ART. Recent Findings Activation of the renin-angiotensin-aldosterone system (RAAS) and chronic immune activation contribute to the development of MetS and hypertension in PWH. HIV proteins and some ART agents alter adipocyte health contributing to dyslipidemias, weight gain, and insulin resistance. HIV infection also contributes to hypertension by direct effects on the RAAS that intertwine with inflammation by the RAAS also contributing to T cell activation. Summary Recent data suggest that in addition to current ART, therapeutic targeting of the MetS and hypertension in PWH, by interfering with the RAAS, treating insulin resistance directly or by use of immunomodulators that dampen inflammation, may be critical for preventing or treating these risk factors and to improve overall cardiovascular complications in the HIV-infected aging population.

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Weight gain among treatment‐naïve persons with HIV starting integrase inhibitors compared to non‐nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada

Cited by 161 publications

References 29 publications

Integrase Strand Transfer Inhibitors Play the Main Role in Greater Weight Gain Among Men With Acute and Early HIV Infection

Integrase Strand Transfer Inhibitors Play the Main Role in Greater Weight Gain Among Men With Acute and Early HIV Infection

HIV and antiretroviral therapy-related fat alterations

Hypertension and Metabolic Syndrome in Persons with HIV

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