Clinicians must identify when additional pounds cross the line of diminishing return.
Weight gain after life-saving antiretroviral therapy (ART) is common. Some of this weight gain early after ART initiation often represents effective viral suppression leading to restoration of healthy preinfection weight known as the “return-to-health” phenomenon. However, excessive clinically undesirable weight gain that places an individual in the overweight or obese category has been noted.
There is growing evidence supporting greater weight gain when patients start or are switched off a stable regimen to integrase strand transfer inhibitors (INSTIs) compared with existing agents. This finding is clinically important, as INSTI-based regimens are now recommended first-line ART, and patients living with HIV (PLWH) are at an increasing risk for obesity, metabolic comorbidities, and cardiovascular disease.1
Separating weight gain due to improved health status from weight gain due to an undesired effect of therapy, understanding the pathogenesis of weight gain, and its health repercussions are of paramount importance.
The pathophysiology of such excessive weight gain among PLWH following ART is multifactorial in nature (FIGURE)2 and is governed by the interplay between demographic factors, HIV-related factors, the composition of ART regimens, and our current obesogenic environment. The mechanisms by which certain ART agents differentially contribute to weight gain remain unknown. Some clinical investigators speculate that INSTIs could interfere with central nervous system appetite regulation (melanocortin-4 receptor), insulin signaling, or may have a better penetration of adipose tissue where they could exert a direct impact on adipose tissue adipogenesis,3 fibrosis, and insulin resistance.
The magnitude of weight gain and body fat distribution associated with ART contribute to the growing metabolic and cardiovascular disease burden in PLWH. Results from a Veterans Affairs study showed that a 5% increase in weight gain in PLWH relates to a 14% increase in risk for developing diabetes mellitus compared with 8% of vets without HIV.4
More importantly, central adiposity associated with an increased waist circumference coupled with reduced muscle mass has been independently associated with an increased 5-year mortality rate in PLWH. Ectopic fat deposition known as visceral fat is 1 of the most important factors predisposing individuals to cardiometabolic complications (ie, diabetes mellitus, coronary artery disease, and fatty liver) and other comorbidities. Visceral fat is hard to evaluate, not routinely measured in our clinics, and may or may not be associated with central obesity.5
Both longitudinal prospective randomized studies and observational cohort studies showed a significant weight gain associated with INSTI-based regimens. Most of these studies were conducted in ART-naïve populations where some of the weight gain could be primarily driven by return to health. More importantly, however, many of these studies did not account for numerous confounding contributors to weight gain such as concomitant medications, diet, physical activity, marijuana use, or smoking, making it harder to fully assess the direct impact of each ART agent on weight gain. In addition, it is important to note that the majority of these observational studies examined dolutegravir (DTG) association to weight gain, but few included bictegravir (BIC), as it was approved in February 2018 and has little longitudinal follow-up time.
PROSPECTIVE RANDOMIZED STUDIES THAT EXAMINED WEIGHT GAIN IN NAÏVE PATIENTS
ACTG 5257 randomized 1809 ART-naïve patients to atazanavir/ritonavir/tenofovir disoproxil fumarate/emtricitabine (ATV/r/TDF/FTC), darunavir/ritonavir/tenofovir disoproxil fumarate/emtricitabine (DRV/r/TDF/FTC), or raltegravir/ tenofovir disoproxil fumarate/emtricitabine (RAL/TDF/FTC). Weight increased on average by 3.8 kg and body mass index (BMI) by 1.3 kg/m2 over 96 weeks. Compared with RAL, patients prescribed ATV/r were less likely to experience a severe weight increase, and those prescribed DRV/r were less likely to experience a significant BMI increase.6
The ADVANCE trial conducted in South Africa recruited 1053 patients and compared 3 first-line regimens in PLWH starting 1 of the following current first-line regimens: TAF/ FTC/DTG versus TDF/FTC/DTG, as compared with TDF/ FTC (or lamivudine)/efavirenz [EFV]) (comparator arm). At week 96, absolute weight gain and the percentage of patients in whom obesity emerged during treatment were highest in the TAF-based group (7.7 kg, 27% new obesity), but the values in the TDF-based group (4.2 kg, 17% new obesity) were also higher than those in the standard-care group (2.1 kg, 11% new obesity). The respective proportions of women who gained more than 10% of weight through 96 weeks, on these 3 regimens, were 51%, 32%, and 23%, and proportions of men totaled 42%, 27%, and 18%, respectively.7
In the NAMSAL study, conducted in adults PLWH in Cameroon, more weight gain was observed in the DTG group than those in the-low dose efavirenz group ( a 400-mg dose, known as, EFV400) (median weight gain, 5.0 kg vs 3.0 kg; incidence of obesity, 12.3% vs 5.4%).Weight gain of at least 10% was observed in more women than men and in more participants who had a low BMI at baseline than participants who were in other BMI categories at baseline. A significantly greater increase in the cholesterol level in both groups, as well as a greater increase in the glucose level in the DTG group, was observed in participants who had weight gain of at least 10% compared with participants who did not.8
A recent pooled analysis of weight gain in 8 randomized controlled, phase 3 clinical trials in naïve patients and follow-up duration of 96 weeks or more, encompassed more than 5000 participants and 10,000 person-years of follow-up. This study conducted between 2013 and 2015 revealed that INSTI-containing regimens were associated with more weight gain than protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), with DTG and BIC associated with more weight gain than elvitegravir/cobicistat (EVG/c). Among the NNRTIs, rilpivirine (RPV) was associated with more weight gain than efavirenz. A multivariate modeling analysis identified these baseline factors to be associated with incident obesity: lower CD4 count (most important single factor), higher viral load, female patients, and black race. Tenofovir alafenamide was associated with more weight gain than TDF, abacavir, or zidovudine. Interestingly, this pooled analysis did not show a significant difference in fasting glucose levels between participants with ≥10% or <10% weight gain.9
OBSERVATIONAL COHORT STUDIES THAT EXAMINED WEIGHT GAIN
Treatment Naïve PLWH
NORTH AMERICAN ACCORD: In this large, multiethnic, North American cohort of 21,886 adult, ART-naïve participants, the initiation of an INSTI-based regimen was associated with the highest and statistically significant weight gain of 4.4 and 5.8 kg compared with NNRTIs at 3.3 and 4.1 kg at 2 and 5 years, respectively. This weight gain was not statistically significant when comparing INSTI-based with protease inhibitor—based ART. DTG- and RAL-based regimens were associated with the higher risk of weight gain compared with older NNRTI class regimens, but EVG/c-based ART demonstrated a different pattern. Of interest, > 80% of the total 3-year weight gain occurred within the first 12 months.10
There have been few studies looking at weight/ BMI changes associated with ART regimens among treatment-experienced, virologically suppressed patients living with HIV, where return to health has been accomplished. One of these retrospective studies was derived from the OPERA cohort, a longitudinal EMR-based database that comprises > 100,000 patients (approximately 8% of the total population of PLWHV in the United States), and its main objective was to compare changes in BMI among ART-experienced virologically suppressed PLWH (n = 10,653 patients) after switching to a DGV/EVG/c-, RGV-, RPV-, or bDRV-based regimen. This must be the patient’s first exposure to these agents. This study was adjusted for TAF and other drugs associated with weight gain. When looking at unadjusted changes in BMI since the regimen switch, patients taking DTG, EVG, and RPV experienced the greatest weight gains, but an upward trend in weight gain over time was noted across all groups. At 12 months, most patients who had a normal BMI at baseline maintained their normal category; only around 20% transitioned to an overweight category, and <0.5% became obese or underweight. These changes were not as pronounced as the BMI changes encountered in treatment-naïve patients following ART. After adjustment for important confounders, compared with DTG, only bDRV was associated with a smaller increase in BMI at 12 months.11
Few prospective studies examined body fat composition associated with INSTI-based therapies, as this entails standardized and centrally read abdominal CT scans and whole-body dual-energy absorptiometry scans, both not commonly used in clinical practice.
ACTG 5260, a substudy of ACTG 5257, involved 328 antiretroviral-naïve patients without cardiovascular disease or diabetes. No one was taking lipid-lowering drugs. At study week 96, trunk fat and lean mass increased significantly in all study arms and did not differ with RAL versus ATZ or DRV. This was an eye-opener, as it was the first study to incriminate INSTI with weight gain and central adiposity.6
In the most recent ADVANCE trial, increases in trunk and limb fat measured by dual-energy absorptiometry scan were higher in both DTG arms and increased further from week 48 to week 96. These changes were considerably higher in women in the TAF/FTC+DTG arm, but it is worth noting that many women were missing end points between 48 and 96 weeks (451 down to 263). Increases in lean mass, both limb and trunk, were also higher in the DTG arms than with the EFV group. Using the International Diabetes Federation definition of metabolic syndrome (central obesity plus any 2 of the following: raised triglycerides, reduced high-density lipoprotein cholesterol, raised blood pressure, and raised fasting glucose), the researchers found that 9% randomized to TAF/ FTC+DTG, 5% randomized to TDF/FTC+DTG, and 3% randomized to TDF/FTC+EFV had metabolic syndrome at week 96.7
The association of weight gain with INSTI is unequivocal and represents more than simply an improvement in health. Knowing the predisposing factors for weight gain (ART-naïve patients, diet and other life style factors, genetic predisposition, black race, female sex, age, low CD4 count, high viral load, and persons with baseline obesity) will help clinicians inform their patients before initiating ART to be on the lookout for undesirable weight gain. It is important for clinicians to identify when such gain becomes detrimental. In general, 80% of weight gain observed in the first 3 years occurs during the first 12 months following ART initiation. However, when a patient has a weight gain greater than 5% over the first 6 months, especially if coupled with truncal adiposity (a likely surrogate of visceral fat deposition), this can increase the likelihood of downstream cardiovascular and other metabolic complications. To further complicate the situation, weight and BMI do not accurately estimate visceral and abdominal adiposity. Hence, there is a need for large-scale longitudinal prospective studies with more rigorous data to better characterize lean body mass gain and fat distribution associated with weight gain following INSTI-based ART, in order to better understand the significance of these changes and their relationship with subsequent cardiometabolic complications. Pending further evidence, clinicians should remain cognizant of the life-saving value of ART and not reflexively alter their practice. Weight gain in PLWH should be approached the same way as for any individuals with obesity. Weight, waist-to-hip ratio, and waist circumference should be monitored in a standardized manner. Although the reversibility of weight gain post switch remains unknown at this time, it is reasonable to consider early treatment modification in those patients on an INSTI-based regimen who are on an extreme weight gain trajectory.
Mounzer is the chief medical officer of Philadelphia FIGHT, a federally qualified health center (www.fight.org), and the medical director of the Jonathan Lax Treatment Center (the largest, community-based Philadelphia HIV program). He is involved with many clinical trials focusing on drug development and better understanding of HIV immunopathogenesis with the Wistar Institute. He serves as a clinical professor of medicine and continues to participate in inpatient care and educational programs in the Infectious Disease Division at Penn Presbyterian Medical Center.
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