Lack of an association between clinical INSTI-related body weight gain and direct interference with MC4 receptor (MC4R), a key central regulator of body weight

McMahon, Carrie; Trevaskis, James L.; Carter, Christoph; Holsapple, Kevin; White, Kirsten; Das, Moupali; Collins, Sean E; Martin, Hal; Burns‐Naas, Leigh Ann

doi:10.1371/journal.pone.0229617

Cited by 27 publications

(21 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, the results of the CoRIS cohort study support our findings that TAF itself is associated with weight gain by showing significantly greater weight gain with TAF in patients newly commencing treatment with TAF or TDF. [31] Various other explanations for different observations in weight changes related to cART include a return-to-health effect in the first years after therapy initiation, altered regulation of appetite, and interactions with the MC4 receptor [ 19 , 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Stratifying the risk of NAFLD in patients with HIV under combination antiretroviral therapy (cART)

Bischoff

Schwarze‐Zander

et al. 2021

EClinicalMedicine

View full text Add to dashboard Cite

Background De novo steatosis is the main criteria for non-alcoholic fatty liver disease (NAFLD), which is becoming a clinically relevant comorbidity in HIV-infected patients. This may be due to the HIV virus itself, as well as long-term toxicities deriving from antiretroviral therapy. Therefore, HIV infected patients require prevention and monitoring regarding NAFLD. Methods This study investigated the differential role of body mass index (BMI) and combination antiretroviral treatment (cART) drugs on NAFLD progression. This single center prospective longitudinal observational study enrolled HIV monoinfected individuals between August 2013 to December 2018 with yearly visits. Each visit included liver stiffness and steatosis [defined as controlled attenuation parameter (CAP)>237 dB/m] assessment by annually transient elastography using an M- or XL-probe of FibroScan, and calculation of the novel FibroScan-AST (FAST) score. Risk factors for denovo/progressed steatosis and tripling of FAST-score increase were investigated using Cox regression model with time-dependent covariates. Findings 319 monoinfected HIV positive patients with at least two visits were included into the study, of which 301 patients had at least two valid CAP measurements. 51·5%(155) patients did not have steatosis at first assessment, of which 45%(69) developed steatosis during follow-up. A BMI>23 kg/m 2 (OR: 4·238, 95% CI: 2·078–8·938; p < 0·0001), tenofovir-alafenamid (TAF) (OR: 5·073, 95% CI: 2·362–10·899); p < 0·0001) and integrase strand transfer inhibitors (INSTI) (OR: 2·354, 95% CI: 1·370–4·048; p = 0·002), as well as type 2 diabetes mellitus (OR: 7·605, 95% CI: 2·315–24·981; p < 0·0001) were independent predictors of de novo steatosis in multivariable analysis. Tenofovir disoproxilfumarate (TDF) was associated with a lower risk for weight gain and steatosis progression/onset using CAP value (HR: 0·28, 95% CI: 0·12–0·64; p = 0·003) and FAST scores (HR: 0·31, 95% CI: 0·101–0·945; p = 0·04). Interpretation Steatosis can develop despite non-obese BMI in patients with HIV monoinfection under cART, especially in male patients with BMI over 23 kg/m 2 . While TAF and INSTI increase the risk of progression of steatosis, TDF was found to be independently associated with a lower risk of a clinically significant weight gain and thereby, might slow down development and progression of steatosis. Funding There was no additional funding received for this project. All funders mentioned in the ‘declaration of interests’ section had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript.

show abstract

Section: Discussionmentioning

confidence: 99%

Stratifying the risk of NAFLD in patients with HIV under combination antiretroviral therapy (cART)

Bischoff

Schwarze‐Zander

et al. 2021

EClinicalMedicine

View full text Add to dashboard Cite

show abstract

“…The authors present an elegant description and figure detailing potential ways (at least 4) by which this could occur. However, another group tested and refuted this theory [ 73 ]. They evaluated the effects of INSTIs on MC4R in an in vitro cell-based assay and found that INSTIs indeed antagonize MC4R, but only at supratherapeutic concentrations, and thus concluded that this is unlikely to explain INSTI-induced weight gain.…”

Section: Integrase Strand Transfer Inhibitorsmentioning

confidence: 99%

Excess Weight Gain With Integrase Inhibitors and Tenofovir Alafenamide: What Is the Mechanism and Does It Matter?

Wood

Huhn

2021

Open Forum Infectious Diseases

View full text Add to dashboard Cite

Numerous studies have detected a greater likelihood of excess weight gain with specific antiretrovirals (ARVs), particularly tenofovir alafenamide and integrase inhibitors, as compared with other agents and classes. The long-term implications and potential reversibility for individuals who have experienced substantial ARV-associated weight accumulation remain poorly understood. Furthermore, the underlying mechanism remains controversial: Is the explanation mitochondrial toxicity and weight suppression from the older agents or direct effects of the newer drugs on appetite, adipocytes, or other unintended targets? This review discusses proposed mechanisms and evidence to date and argues that the question about mechanism is highly clinically relevant because it carries significant implications for ARV management. The existing literature suggests that older ARVs, such as tenofovir disoproxil fumarate and efavirenz, suppress weight gain, but also that integrase inhibitors may stimulate excess weight gain through several plausible biologic pathways. Confirming the mechanisms of ARV-associated excess weight gain should be high priority for future research.

show abstract

“…It has been shown that DTG inhibits the binding of amelanocyte-stimulating hormone (aMSH) and melanocortin 4 receptor (MC4R) in the hypothalamus; this might promote hyperphagia (147,148). However, the serum DTG levels in patients are much lower than those required for hyperphagia (149).…”

Section: Local Effectsmentioning

confidence: 99%

Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment

et al. 2021

View full text Add to dashboard Cite

White adipose tissue (AT) contributes significantly to inflammation – especially in the context of obesity. Several of AT’s intrinsic features favor its key role in local and systemic inflammation: (i) large distribution throughout the body, (ii) major endocrine activity, and (iii) presence of metabolic and immune cells in close proximity. In obesity, the concomitant pro-inflammatory signals produced by immune cells, adipocytes and adipose stem cells help to drive local inflammation in a vicious circle. Although the secretion of adipokines by AT is a prime contributor to systemic inflammation, the lipotoxicity associated with AT dysfunction might also be involved and could affect distant organs. In HIV-infected patients, the AT is targeted by both HIV infection and antiretroviral therapy (ART). During the primary phase of infection, the virus targets AT directly (by infecting AT CD4 T cells) and indirectly (via viral protein release, inflammatory signals, and gut disruption). The initiation of ART drastically changes the picture: ART reduces viral load, restores (at least partially) the CD4 T cell count, and dampens inflammatory processes on the whole-body level but also within the AT. However, ART induces AT dysfunction and metabolic side effects, which are highly dependent on the individual molecules and the combination used. First generation thymidine reverse transcriptase inhibitors predominantly target mitochondrial DNA and induce oxidative stress and adipocyte death. Protease inhibitors predominantly affect metabolic pathways (affecting adipogenesis and adipocyte homeostasis) resulting in insulin resistance. Recently marketed integrase strand transfer inhibitors induce both adipocyte adipogenesis, hypertrophy and fibrosis. It is challenging to distinguish between the respective effects of viral persistence, persistent immune defects and ART toxicity on the inflammatory profile present in ART-controlled HIV-infected patients. The host metabolic status, the size of the pre-established viral reservoir, the quality of the immune restoration, and the natural ageing with associated comorbidities may mitigate and/or reinforce the contribution of antiretrovirals (ARVs) toxicity to the development of low-grade inflammation in HIV-infected patients. Protecting AT functions appears highly relevant in ART-controlled HIV-infected patients. It requires lifestyle habits improvement in the absence of effective anti-inflammatory treatment. Besides, reducing ART toxicities remains a crucial therapeutic goal.

show abstract

Lack of an association between clinical INSTI-related body weight gain and direct interference with MC4 receptor (MC4R), a key central regulator of body weight

Cited by 27 publications

References 25 publications

Stratifying the risk of NAFLD in patients with HIV under combination antiretroviral therapy (cART)

Stratifying the risk of NAFLD in patients with HIV under combination antiretroviral therapy (cART)

Excess Weight Gain With Integrase Inhibitors and Tenofovir Alafenamide: What Is the Mechanism and Does It Matter?

Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment

Contact Info

Product

Resources

About