From Weight Gain to Heart Strain: HIV Antiretroviral Adverse Effect Management in Primary Care

Abstract

Background:

More than 40 years after discovering HIV, the prognosis has transformed from an acute, fatal illness, to an average life expectancy approximating that of the general population. Correspondingly, new concerns regarding the management of older adults with HIV and multimorbidity are beginning to emerge. To support the HIV care continuum, people with HIV benefit from having a primary care medical home to address multimorbidity associated with age, genetic disposition, chronic HIV, and/or antiretroviral adverse effects. The interplay between HIV, antiretrovirals, and metabolic conditions is complex and is under study. It is imperative that primary care clinicians and medical team members are aware of how HIV and antiretrovirals can impact a person’s comorbidities and corresponding mitigation strategies.

Objective:

The goal of this commentary is to raise awareness of the metabolic consequences of modern antiretrovirals so that interdisciplinary teams caring for people with HIV can better coordinate the management of related conditions such as obesity, diabetes, and cardiovascular disease.

Introduction

More than 40 years after its discovery, the prognosis for human immunodeficiency virus (HIV) has transformed from that of an acute, fatal illness, to a chronic, manageable condition.^1-3 Newer, more efficacious medications combined with simpler dosing regimens, including single pill combinations and long-acting injectables, have also facilitated medication adherence and contributed to the normalization of HIV treatment. ⁴ The average life expectancy of a young adult with a new HIV diagnosis who is adherent to antiretroviral therapy (ART) now approximates that of the general population extending into the eighth decade of life. ⁵

New concerns regarding the management of HIV in older adults and multimorbidity management are beginning to emerge.^2,6,7 People with HIV (PWH), much like the general population, greatly benefit from a medical home to comprehensively address comorbidities associated with age, genetic disposition, chronic HIV, and/or ART side effects.^6-12 This includes deciphering the evolving literature on the contribution of ART to metabolic conditions such as weight gain, diabetes mellitus (DM), and cardiovascular disease (CVD). Primary care clinicians are experts in managing these chronic conditions that are increasingly prevalent in PWH, prompting the 2024 updates to the primary care guidelines for this population.^2,9,10,13 Now more than ever, PWH deserve a healthcare paradigm that integrates primary and specialty care. The goal of this commentary is to review the metabolic consequences of modern ART and the role they may play in primary care management for PWH with the increasingly common comorbidities of obesity, DM, and CVD.

ART Associated Weight Gain

Historical perceptions of HIV are associated with the emaciation of acquired immunodeficiency syndrome (AIDS) wasting syndrome, but this no longer holds true for the modern population of PWH on ART.^14,15 Koethe et al compared PWH from the North America AIDS Cohort Collaboration on Research and Design study to matched controls and found an increase in the prevalence of obesity and overweight in PWH from 1998 to 2010. ¹⁶ Other studies have found not only a growing incidence of overweight and obesity at HIV diagnosis but a general increase in both conditions in PWH over time. A complex interplay of factors may increase the risk of weight gain in PWH. Identified facilitators for weight gain in PWH include age ≤35 years, lower baseline BMI, black race, female sex, CD4 counts <200 cells/mm³, HIV viral loads >100 000 copies/mL, the absence of injection drug use, and select ART.^16-19

Current ART medications under significant scrutiny for potential weight-associated side effects are tenofovir alafenamide (TAF) and integrase strand transfer inhibitors (INSTIs) such as dolutegravir.^19,20 Pooled analyses of eight randomized controlled trials associated TAF with a 4.25 kg (95% CI = 3.94-4.56) weight gain compared to 2.07 kg from tenofovir disoproxil fumarate (TDF; 95% CI = 1.84-2.3), and had a higher odds of participants experiencing ≥10% weight gain (OR = 1.47, 95% CI = 1.14-1.9). ¹⁹ However, not all studies find dramatic increases in weight between TDF and TAF; the multicenter Spanish AIDS Research Network found that switching from TDF to TAF in virologically suppressed PWH was associated with a mean weight increase of +0.5 kg at 144 weeks. ²¹ Data regarding weight gain with INSTIs also continues to emerge. One retrospective cohort study of ART naïve PWH seen in an infectious diseases clinic in the US found no statistically significant increase in weight gain based on INSTI initiation. However, when differentiated by sex, the adjusted multivariate analysis found females had an absolute weight gain of 6.66 kg (95% CI = 2.51-10.82). ²² Of the INSTIs, dolutegravir and bictegravir appear to have the highest association with weight gain of approximately 4 kg.^1,19,23 Initial data suggest that cabotegravir is more likely to be weight neutral. ²⁴

ART strategies that are weight neutral, associated with less weight gain, or promote weight loss are actively being investigated. ²⁵ For example, an analysis of the Swiss HIV Cohort Study found that switching from TAF to TDF was associated with a 1.84 kg weight loss (95% CI = −2.72 to −0.97), but the statistically significant benefit was not sustained when switching to ART regimens without tenofovir within 1 year. ²⁶ Also, the use of newer non-nucleoside reverse transcriptase inhibitors, such as doravirine, are being investigated as a potentially weight neutral ART options.^18,19,27 While switch strategies are still being investigated, the 2024 primary care guidelines for PWH recommend against switching ART regimens solely because of weight gain due to a lack of conclusive evidence of benefit. ²

In addition to shared decision making around ART selection, it is imperative that when PWH are starting or switching ART, all care providers consider the above noted risk factors associated with weight gain. Current guidelines recommend measuring weight at every visit and annual measurements of waist circumference. ² Primary care teams can also consider integrating general weight mitigation strategies such as caloric-deficit diets and physical exercise into the management plans for persons at the highest risk of weight gain. ²⁸ Data on newer anti-obesity medications in PWH are evolving and various review articles have synthesized current evidence for different obesity management strategies in PWH.^29,30 Notably, an observational study in the Centers for AIDS Research Network of Integrated Clinical Systems cohort found semaglutide was associated with an average weight loss of 6.47 kg (95% CI = −7.67 kg to −5.18 kg) at 1 year among PWH. ³¹ The SLIM LIVER study also found a 2.77 kg/m² decrease in the BMI of PWH when using semaglutide for non-alcoholic fatty liver disease. ³² A small observational study of canagliflozin use in eight virologically suppressed PWH with a BMI >27 kg/m² and uncontrolled DM saw a 6.12 kg weight loss and two point reduction in BMI. ³³ Primary care clinicians should be aware of the risks for weight gain, and strategies to mitigate those risks or promote weight loss in PWH.

Modern ART and DM

Epidemiologic data suggest a significantly growing prevalence of PWH with DM, with one estimate documenting the prevalence of DM to be 3.8% higher in PWH than in the general population (95% CI = 1.8%-5.8%).^34-36 An evaluation of the use of traditional tools to evaluate risk for developing DM in PWH in the Swiss HIV Cohort Study suggests that risk scores may be applicable to this population and could help the primary care clinician with stratifying risks. ³⁷ Additionally, potential associations between HIV infection and glucose dysregulation are being investigated, along with the potential role of select ART.^35,36,38-40

In addition to their association with weight gain, TAF and INSTIs are increasingly being investigated for a potential association with the development of DM.^1,41 Research to understand the linkages, metabolic mechanisms, and clinical impact of INSTI on the risk of DM has resulted in discordant data with unclear implications.^22,42-45 The prevailing theory for the mechanisms of INSTI-associated DM suggests a cascade of treatment-emergent obesity, increased insulin resistance, and other metabolic syndromes, especially when INSTIs are used in combination with TAF.^39,46 A review of an FDA adverse event reporting system suggests INSTI therapy may increase the risk for the development of DM and new onset hyperglycemia. ⁴⁴ Risk appears to vary between INSTIs, with elvitegravir (HR = 1.54) at the highest risk, followed by dolutegravir (HR = 1.28), bictegravir (HR = 1.20), and raltegravir as the lowest risk (HR = 1.19). Of note, as with weight gain, cabotegravir was not evaluated in this analysis.^44,45 Interestingly, a recent meta-analysis of pooled results from 16 studies suggests the DM-related risk of INSTIs may be overestimated. ⁴⁷ However, subgroup analyses indicate that certain populations may be at a higher risk, such as PWH of African origin (RR = 2.99, 95% CI = 2.53-3.54). ⁴²

Implications for primary care include the need for ongoing risk assessment, diagnostics, and therapeutic management of DM in PWH. Risk stratification should include an assessment of traditional risk factors as well as accounting for certain populations at an increased risk of DM, such as women and African American PWH, especially when taking INSTIs.^42,43 Contributing risk factors such as weight gain or obesity at ART initiation should also be considered by the primary care team. Additionally, it is important to note that fasting blood glucose is the preferred diagnostic test given the hemoglobin A1c predilection to underestimate glucose levels in PWH.^1,2 Other than the differences in screening, PWH are typically treated according to standard DM guidelines used in the general population. Notably, bictegravir and dolutegravir interact with metformin causing a higher metformin exposure which should prompt additional monitoring for gastrointestinal toxicity.^48,49 Canagliflozin and semaglutide both have evidence suggesting an approximate 1% improvement in hemoglobin A1c.^31,33 Liraglutide, dulaglutide, and injectable semaglutide have demonstrated an atherosclerotic CVD (ASCVD) benefit and weight loss in the general population that could extend to PWH.^48,49 With the increasing need for expertise in DM prevention and management in PWH, it is important that primary care team members be aware of the evolving literature related to ART-associated risks for DM.

HIV and ART Related CVD Risk

The prevalence of HIV-related CVD has increased from 0.36% (95% CI = 0.21%-0.56%) to 0.92% (95% CI = 0.55%-1.41%) globally and is responsible for 2.6 million disability-adjusted life-years annually. ⁵⁰ HIV infection is associated with an increased risk of CVD encompassing myocardial infarction, thrombosis, and heart failure mediated by chronic immune activation, inflammation, and cardiomyopathy.^51,52 Recent literature has demonstrated that CVD risk is not entirely eliminated with virologic suppression and it is unknown to what degree ART side effects may actually contribute to a PWH’s CVD risk. ⁵³

Increased CVD risk is more classically associated with older ART therapies, such as protease inhibitors and abacavir, as opposed to modern ART.^54-57 Despite other metabolic side effects associated with INSTIs, current evidence does not suggest increased CVD risk with INSTIs.^58,59 A retrospective cohort analysis found that among 20,242 PWH newly initiating ART, PWH on INSTI-based regimens were 21% less likely (HR = 0.79, 95% CI = 0.64-0.96) to experience major cardiac events compared to PWH on non-INSTI-based regimens. ⁵⁸ Corroborating this is a Swiss cohort study with a median follow-up of 5 years where INSTIs were not associated with an increased risk for CVD events (adjHR = 0.8, 95% CI = 0.46-1.39). ⁵⁹ However, the RESPOND trial reported that INSTI use had a temporal CVD risk that was highest in the first 6 months of exposure (adjIRR = 1.85, 95% CI = 1.44-2.39) that then normalized after 24 months on INSTI therapy (adjIRR = 0.89, 95% CI = 0.62-1.29). ⁶⁰ The various time intervals of follow-up in studies, heterogeneous patient populations, and the different INSTI regimens being evaluated hinder understanding of and effective management of INSTI-related CVD risk mitigation.

Multidisciplinary teams are central to minimizing CVD morbidity in PWH. In addition to the management of HIV and ART, it is important to encourage CVD prevention strategies addressing traditional risk factors like total cholesterol, hypertension, and smoking. ⁶¹ The REPRIEVE randomized controlled trial is a landmark trial in PWH on ART demonstrating a significant major cardiac event benefit when using pitavastatin 4 mg once daily compared to placebo (HR = 0.65, 95%CI = 0.48-0.90, P = .002). ⁶² Though the data is less compelling for an ASCVD risk < 5%, based largely on the results of the REPRIEVE trial, current guidelines recommend routine use of at least moderate intensity statins in PWH between 40 and 75 years old, regardless of ASCVD risk for primary prevention.^1,2 As the REPRIEVE trial only included PWH ages 40 to 75 years old, current guidelines do not recommend or recommend against statin therapy for primary prevention in PWH <40 years old. ¹ Due to potential drug interactions between individual statins and ART, therapy selection should be individualized. Additionally, there is ongoing research in the SLIM LIVER study suggesting semaglutide could have a triglyceride benefit in PWH. ³² As the population of PWH ages, ASCVD, metabolic comorbidities such as DM and obesity, and the polypharmacy associated with treatment of these conditions will be a central responsibility for the care teams managing them.

Discussion

There are currently different models for the care of PWH, including whether all disease management is done within primary care, or co-managed by primary care and HIV specialists.^7,10,13 Modern ART drastically improves the lives of PWH with rapid and sustained virologic suppression extending life expectancy to be consistent with the general population.^4,5 Meeting the goals in the HIV care continuum is just part of a PWH’s holistic medical care; and it is important for all clinicians to stay abreast of the evolving understanding of the impact of modern ART on comorbidities. Whether correlated to genetics, ART, or other confounders contributing to the national increase in overweight and obesity conditions, primary care clinicians should be mindful of the potential weight gain with ART and incorporate the recommended weight assessment at every visit. Current guidelines do not recommend switching ART solely because of weight gain due to limited evidence of benefit. Management of overweight and obese adult PWH is similar to that of the general population, with evolving literature supporting the use of newer anti-obesity agents.^2,29-31 The impact of INSTIs on DM is still unclear; all clinicians should be cognizant of the need for appropriate screening and monitoring for persons at higher-risk including that the diagnostic ability of hemoglobin A1c is insensitive in PWH, but the test can be used for disease monitoring. Traditional DM prevention and management methods are applicable to PWH.^{2,31,33,42,47} Mitigating CVD risk in PWH with moderate to high intensity statins is guided by ASCVD risk and the REPRIEVE trial whose study population was PWH ages 40 to 75 years.^1,2,62

Primary care clinicians are not only central to recognizing the interplay between HIV and these chronic conditions: they play a pivotal role in managing them. A multidisciplinary approach led by the primary care teams would be highly beneficial to PWH. Nurse clinicians can advocate for healthy living at home for persons who are aging, while social workers can address important determinants that impede health. Effective polypharmacy management requires strong partnerships with pharmacists, particularly community and ambulatory care pharmacists, who can support adherence, ameliorate inappropriate medication use, and navigate drug interactions. Future research into the biochemical mechanisms of metabolic changes in PWH, the impact of ART, and the involvement of the immune system may guide strategically targeted therapeutics and risk mitigation. Clinicians and industry partners can contribute to research in PWH through clinical trial participation and design. Ensuring adequate representation of PWH in metabolic studies is essential for generating translatable findings. Ultimately, all team members can uniquely contribute to improving the health of the growing and aging population of PWH with multiple chronic conditions. ⁸