GLP-1 agonists for people living with HIV and obesity, is there a potential?

BACKGROUND AND OBJECTIVES: Obesity trends and metabolic dysregulation are rising in people living with HIV using antiretrovirals (ARVs). Underlying causes and preventive strategies are being investigated. Two glucagon like-peptide 1 (GLP-1) agonists, liraglutide and semaglutide, were formerly approved as glucose-lowering drugs and have been recently approved for long-term weight loss in people with obesity. Due to the lack of therapeutic guidelines or clinical trials in people with HIV, we discuss the potential benefits, safety aspects and pharmacological considerations of prescribing liraglutide and semaglutide in people with HIV. RESULTS: Clinical experience is limited to two clinical cases of diabetic people with HIV using liraglutide after which a successful weight loss and glycaemic control were observed. None of the adverse events associated with liraglutide and semaglutide usage indicate an additional risk for people with HIV. Extra caution showed be warranted when initiating GLP-1 agonist therapy in people with HIV taking protease inhibitors who have pre-existing risk factors for heart rate variability to reduce the incidence of RP interval prolongation. GLP-1 agonists are metabolized by endopeptidases, and thus do not generate major drug-drug interactions with most drugs, including ARVs. GLP-s agonists are known to inhibit gastric acid secretion, which warrants caution and close monitoring when combined with atazanavir and oral rilpivirine, two ARVs that require low gastric pH for an optimal absorption. CONCLUSION: Theoretical considerations and a few available clinical observations support semaglutide and liraglutide prescription in people with HIV, with, thus far, no indications of concern regarding efficacy, safety or pharmacological interactions with ARVs.

Exposure and virologic outcomes of dolutegravir combined with ritonavir boosted darunavir in treatment-naïve individuals enrolled in the Netherlands Cohort Study on Acute HIV infection (NOVA).

To the authors' knowledge, there is currently no literature or guidance recommendation regarding whether the dose of dolutegravir (DTG) should be increased when co-administered with darunavir/ritonavir (DRV/r) in patients with acute human immunodeficiency virus infection (AHI). This study assessed the pharmacokinetics (PK) of twice-daily (BID) DTG and once-daily (QD) DRV/r, and compared this with DTG QD without DRV/r in patients with AHI. Forty-six participants initiated antiretroviral therapy within <24 h of enrolment: DTG 50 mg BID, DRV/r 800/100 mg QD, and two nucleoside reverse transcriptase inhibitors (NRTIs) for 4 weeks (Phase I); and DTG 50 mg QD with two NRTIs thereafter (Phase II: reference). Total DTG trough concentration (Ctrough) and area under the concentration-time profile of 0-24 h (AUC0-24h) were predicted using a population PK model. DTG glucuronidation metabolic ratio (MR) and DTG free fraction were determined and compared per treatment phase using geometric mean ratio (GMR) and 90% confidence interval (CI). Participants had a predicted geometric mean steady-state DTG Ctrough of 2.83 [coefficient of variation (CV%) 30.3%] mg/L (Phase I) and 1.28 (CV% 52.4%) mg/L (Phase II), with GMR of 2.20 (90% CI 1.90-2.55). Total exposure during DTG BID increased but did not double [AUC0-24h GMR 1.65 (90% CI 1.50-1.81) h.mg/L]. DTG glucuronidation MR increased by approximately 29% during Phase I. DTG Ctrough was above in-vivo EC90 (0.32 mg/L) during both phases, except in one participant during Phase I. At Week 8, 84% of participants had viral loads ≤40 copies/mL. The drug-drug interaction between DTG (BID) and DRV/r (QD) was due to induced glucuronidation, and is not clinically relevant in patients with AHI.

Outcomes of modern antiretroviral therapy in obese individuals living with HIV.

Obesity is a global epidemic and people living with HIV (PLWH) are showing similar obesity trends to those in the general population. Obesity is manifested by several physiological features that can alter volume of distribution, elimination and metabolism of various medications including ART. Some drugs are increasingly prone to pharmacokinetic alteration during obesity depending on their physicochemical properties and clearance mechanism. These considerations raise concerns of hampered efficacy, development of resistance or increased toxicity of ART in PLWH. Here, we summarize available literature on the exposure and antiviral outcomes of currently available antiretroviral drugs in the context of obesity and provide a panel of recommendations for the clinical management and follow-up in this growing patient population.