 |
|
|
| |
Is modern antiretroviral therapy causing weight gain?
|
| |
| |
Download the PDF here
"We assessed the association between the specific third agent drug and ≥10% weight gain (Table 5). Compared to EFV, the initiation of BIC or DTG (OR 1.82, 95% CI 1.24-2.66, p=0.002), EVG/c (OR 1.36, 95% CI 1.04-1.78, p=0.026), RPV (OR 1.51, 95% CI 1.03-2.20, p=0.035), but not ATV/r, were associated with an increased risk of ≥10% weight gain. Among the NRTIs, TAF (OR 1.75, 95% CI 1.04-2.95, p=0.034), but not ABC or TDF, were associated with increased risk for ≥10% weight gain compared to AZT. TAF was also associated with an increased risk of ≥10% weight gain compared to ABC (OR 1.90, 95% CI 1.25-2.88, p = 0.003) and TDF (OR 1.47, 95% CI 1.14-1.90, p = 0.003)...... Black race and female sex were associated with weight gain, consistent with other studies.2,5-6,13,15 This association was particularly notable among black females, who gained approximately twice as much weight as non-black women"
"Our analyses revealed several important associations between weight gain and ART at the class and drug level. Examining the clinical trials individually, we observe greater weight gain in newer investigational regimens relative to the comparator, consistent with the findings reported by others.2,24 In our pooled analyses, INSTI-containing regimens were associated with more weight gain than NNRTI or PI-based regimens, with DTG and BIC associated with more weight gain than EVG/c. Among NNRTIs, RPV was associated with more weight gain than EFV. Among NRTI pairs, TAF/emtricitabine (FTC) was associated with the most weight gain, ABC/lamivudine (3TC) and TDF/FTC with slightly less weight gain, and AZT/3TC with weight stability. These findings are similar to the ADVANCE trial, in which DTG and TAF were associated with treatment-emergent obesity, while TDF/FTC/EFV was associated with treatment-emergent underweight status and a higher rate of treatment discontinuation.25 Altogether, these findings establish a pattern of more weight gain with newer ART regimens, possibly reflecting better tolerated, easier to take regimens.26
Black race and female sex were associated with weight gain, consistent with other studies.2,5-6,13,15 This association was particularly notable among black females, who gained approximately twice as much weight as non-black women......Individuals with ≥10% weight gain were more likely to be female or black, have a lower baseline weight or BMI, have lower baseline CD4 count, and higher baseline HIV-1 RNA (Table 4).....Female sex and black race were associated with ≥10% weight gain (female vs. male OR 1.54 [95% CI 1.21-1.96, p<0.001], and black vs. non-black OR 1.32 [95% CI 1.10-1.59, p = 0.003]). More black women experienced ≥10% weight gain than non-black women (19.7% vs 12.4%, p<0.001).....(Table 5). Compared to EFV, the initiation of BIC or DTG (OR 1.82, 95% CI 1.24-2.66,
p=0.002), EVG/c (OR 1.36, 95% CI 1.04-1.78, p=0.026), RPV (OR 1.51, 95% CI 1.03-2.20, p=0.035), but not ATV/r, were associated with an increased risk of ≥10% weight gain. Among the NRTIs, TAF (OR 1.75, 95% CI 1.04-2.95, p=0.034), but not ABC or TDF, were associated with increased risk for ≥10% weight gain compared to AZT. TAF was also associated with an increased risk of ≥10% weight gain compared to ABC (OR 1.90, 95% CI 1.25-2.88, p = 0.003) and TDF (OR 1.47, 95% CI 1.14-1.90, p = 0.003). .....We observed strong associations between weight gain and HIV disease characteristics. Disease stage, as reflected by low baseline CD4 count, and high baseline HIV RNA correlated with weight gain in our models of any weight gain and ≥10% weight gain, similar to other reports.2,4-6,15 These findings support a contribution of the return-to-health phenomenon to weight gain in PWH initiating ART. This effect may be desirable in some individuals, but could also contribute to excess weight gain in individuals with early stage HIV disease and those with normal or above-normal BMI. "
----------------------------
Editorial- Is modern antiretroviral therapy causing weight gain?
CID Oct 2019 - Author: Sara H. Bares MD, University of Nebraska Medical Center, Division of Infectious Diseases, Omaha, NE
Weight gain following the initiation of antiretroviral therapy (ART) has been reported across multiple settings and study populations. While this weight gain often represents a return to health among those who are underweight at the time of ART initiation [1], weight gain among those in the normal and overweight categories prior to the initiation of ART has been associated with an increased risk of metabolic and cardiovascular disease [2-4]. The observational nature of many of the studies published to date limits the interpretation of the findings due to potential confounding by HIV-specific, demographic, and environmental factors that contribute to weight gain.
In this issue of Clinical Infectious Diseases, Sax et al [5] examined weight data from eight randomized comparative trials of ART in 5680 treatment-naïve participants. This pooled analysis offers a unique opportunity to evaluate the changes in weight in those initiating ART in the context of numerous rigorously conducted randomized trials, which, by design, eliminate the possibility of confounding by indication.
Although Gilead Sciences sponsored all of the parent trials, the transparency in the authors' presentation of the results was welcome and there were several important findings from this work. First, the authors observed strong associations between weight gain and HIV disease characteristics. The correlation between low baseline CD4 cell count and high baseline HIV RNA levels and weight gain has been reported by others [6, 7] and supports the notion that some of the observed weight gain signals a return to health. For providers, this finding raises questions regarding the clinical significance of this weight gain. In this analysis, the authors found that over one third of participants in these trials experienced a greater than 5% increase in weight and nearly one fifth experienced a 10% or greater increase in weight. Although the absolute numbers are marked, the fact that some component of the weight gain noted in this analysis represents a return to health complicates any conclusions regarding the clinical significance.
Similar analyses of weight gain in different study populations will help to shed light on some of the confounding. Weight analysis in switch trials, particularly among participants with virologic suppression at the time of switch, avoid confounding by the return to health phenomenon and such studies have demonstrated similar findings [8-10]. Additionally, evaluations of weight changes in pre-exposure prophylaxis trials may help avoid confounding by HIV disease factors. It is imperative that analysis of weight gain be done in ongoing and future pre-exposure prophylaxis trials.
The second major finding is the association between weight gain with black race and female sex. In this analysis, black women gained twice as much weight as non-black women in the 96 weeks following ART initiation. This finding was statistically significant in spite of the fact that women made up only 11.7% of the study population and black women only 5.5%. While this pooled analysis included contributions from sites in predominantly resource-rich countries, notably without any study sites in the African continent, the findings are corroborated by the recently published ADVANCE and NAMSAL efficacy trials of DTG conducted in Africa. These studies were comprised of over 50% women and DTG was unequivocally associated with excess weight gain as compared to efavirenz, particularly with tenofovir alafenamide-emtricitabine [11, 12].
Why are certain demographic groups more affected by this weight gain than others? These findings are particularly concerning given the disproportionate burden of HIV and obesity in the black and female population in the United States [13, 14]. The mechanism is unclear, but a number of factors including environmental and genetic factors may play a role.
Genome-wide association studies have found multiple genes associated with obesity in the general population [15], and functions of proteins that are pharmacodynamic antiretroviral targets may be affected by genetic variants. Sax et al discuss the potential role of off-target interactions such as the interaction between DTG and melanocortin 4 receptor (MC4R). In vitro, DTG inhibits the binding of radiolabelled α-melanocyte- stimulating hormone (MSH) to MC4R [16]. This is a plausible mechanism because MC4R is involved in the regulation of energy homeostasis and caloric intake, and deficiency in MC4R is associated with obesity. It is unknown whether other INSTIs interact with MC4R, but this is also a proposed mechanism for the weight gain associated with antipsychotics and merits further study with DTG and other modern antiretrovirals.
Additionally, a retrospective study found that CYP2B6 EFV slow-metabolizers gained more weight than others after a switch from EFV to INSTI. This finding varied based on racial characteristics (associations present in white but not black participants) and specific INSTI (associations seen in EVG and RAL groups but not DTG) [17]. While these data suggest that pharmacogenetics may be playing a role (Leonard et al hypothesize that those with high EFV exposure have subclinical intolerance that resolves after the switch), the associations seen in this retrospective data do not mirror the findings noted in the study by Sax et al. In summary, large gaps in our understanding remain.
The third major finding is the absence of a clinically significant metabolic impact of the observed weight gain, as measured by fasting glucose and investigator reported adverse effects (AEs). Though there are limitations to this finding, such as limited duration of follow-up, small number of total reported AEs, and lack of more sensitive measures of glucose tolerance, these results are of particular interest for clinicians on the front lines who are concerned about the clinical implications of the observed weight gain. In other words, is this a metabolically neutral weight gain (suggesting a return to health) or is this weight gain associated with metabolic sequelae? This question is particularly relevant in light of the data from ACTG 5260s which demonstrated a significant increase in insulin resistance after 4 weeks of ART initiation that was similar between recipients of RAL, DRV and ATV [18], as well as multiple case reports of new onset hyperglycemia and diabetes following switch to INSTI-containing regimens [19, 20]. The results of this analysis offer some reassurance in terms of changes in fasting glucose, but lipid changes were more nuanced. Lipid changes were small but statistically significant. Although the clinical significance of the lipid changes are unknown, these changes raise questions about the possible synergistic role of weight gain with TAF-containing regimens versus TDF-containing regimens, given the well-described attenuated decreases in LDL and triglycerides with TAF as compared to TDF [21]. Additional analysis is warranted in both treatment initiation and switch studies before inferences regarding the metabolic consequences of weight gain following ART initiation can be made.
The last, and perhaps most novel, finding was the association between weight gain and type of ART. Importantly, associations were found at both the class (INSTIs > NNRTI > PI) and specific ART level (BIC and DTG > EVG/c; RPV > EFV; TAF> ABC > TDF > AZT). Overall, greater weight gain was observed among newer antiretroviral agents relative to the comparators.
These data answer some questions and substantiate many of the findings from cohort studies of weight gain following ART initiation, but also raise a number of additional important questions, especially as these newer regimens are expanded to populations in need. The follow-up questions clinicians are undoubtedly asking are: what do we do for patients who experience severe weight gain following initiation of ART? How long does this weight gain persist? Will a switch to an alternative regimen reverse or attenuate some of this weight gain? If so, what regimen should they choose? Is an adjustment in both the backbone and anchor agent needed? Will adjustment in the route of administration alter the side effect profile (i.e. will long acting injectable therapy be associated with similar amounts of weight gain)?
What other mechanisms might be contributing to this observed weight gain? Sax et al hypothesize that improved gastrointestinal tolerability of the newer ART regimens may be contributing. This is a plausible mechanism and could explain the weight gain noted in both treatment naïve and switch studies as participants who feel better subsequently consume more calories. Data regarding caloric intake and energy expenditure was not collected in this analysis but could help substantiate this hypothesis if collected in future studies.
While this study is not without limitations (raltegravir and darunavir were not included in the analysis and the parent trials were not designed to compare weight changes), it is an elegant analysis that adds to the collection of evidence demonstrating that INSTIs, and, more broadly, modern ART regimens, are associated with more weight gain than older ART regimens, especially in those with more advanced disease and particularly among those of black race and female sex. The challenge for the clinician is to translate these findings into clinical practice at a time when many questions remain about the clinical implications of this weight gain. Awaiting additional data to provide clinical guidance, I concur with the advice given by Havlir, Doherty and Wood in recently published editorial commentaries [22, 23]: we must incorporate counseling and anticipatory guidance regarding potential weight changes when initiating ART and continue research to evaluate the mechanisms, consequences, management and prevention of weight gain following ART initiation and switch. Finally, I view these findings as a call to arms. As we continue to investigate the causes, consequences and management of weight gain following ART initiation (and switch), we must strive to enroll sufficient numbers of women from diverse racial and ethnic backgrounds in order to allow for sex and race-stratified analysis.
-------------------
Weight Gain Following Initiation of Antiretroviral Therapy: Risk Factors in Randomized Comparative Clinical Trials
Paul E. Sax, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Kristine M. Erlandson, University of Colorado School of Medicine, Aurora, CO, USA; Jordan E. Lake, The University of Texas Health Science Center, Houston, TX, USA; Grace A. McComsey, University Hospitals Cleveland Medical Center and Case Western University, Cleveland, Ohio, USA; Chloe Orkin, Barts Health NHS Trust, London, UK; Stefan Esser, University Hospital Essen, Essen, DE; Todd T. Brown, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Jürgen K. Rockstroh, University Hospital Bonn, Bonn, DE; Xuelian Wei, Gilead Sciences, Inc., Foster City, CA, USA; Christoph C. Carter, Gilead Sciences, Inc., Foster City, CA, USA; Lijie Zhong, Gilead Sciences, Inc., Foster City, CA, USA; Diana M. Brainard, Gilead Sciences, Inc., Foster City, CA, USA; Kathleen Melbourne, Gilead Sciences, Inc., Foster City, CA, USA; Moupali Das, Gilead Sciences, Inc., Foster City, CA, USA; Hans-Jürgen Stellbrink, Infectious Disease Medical Center, Hamburg, DE; Frank A. Post, King's College Hospital NHS Foundation Trust, London, UK; Laura Waters, Mortimer Market Center, London, UK; John R. Koethe, Vanderbilt University Medical Center, Nashville, TN, USA;
Summary: In this report, we use pooled data from randomized clinical trials to identify demographic-, HIV disease-, and antiretroviral therapy (ART)-related risk factors for weight gain after the initiation of ART, highlighting the multifactorial nature of ART-associated weight gain.
Abstract
Background
Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation.
Methods
We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naïve people with HIV (PWH) initiating ART between 2003-2015, comprising over 5,000 participants and 10,000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation.
Findings
Weight gain was greater in more recent trials and with the use of newer ART regimens.
Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4, higher HIV-1 RNA, no injection drug use, female sex and black race.
Integrase strand transfer inhibitors (INSTIs) were associated with more weight gain than protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTI), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat.
Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz.
Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine.
Interpretation
Weight gain is ubiquitous in clinical trials of ART initiation, and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens contributing. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.
Introduction
Excess weight and obesity are an escalating global healthconcern, affecting an estimated 600 million adults and contributing to substantial morbidity and mortality through an increased risk of cardiovascular disease, diabetes, chronic kidney disease,non-alcoholic steatohepatitis (NASH), and cancer.An Increasing prevalence of overweight and obesity has also been reported in people with HIV (PWH), among whom initiation of antiretroviral therapy (ART) often leads to weight gain.1-7
While this weight gain may be apositive prognostic indicator in PWH who are underweight at the time of ART initiation,6,8,9 among those in normal or overweight categories weight gain may increasethe risk of cardiovascular and metabolic diseases.7,10,11
Possible mechanisms for ART-associated weight gain include a return-to-health phenomenon, especially in those with advanced HIV disease, with weight returning to a pre-illness baseline. The mechanism underlying the return-to-health phenomenon is incompletely understood, but likely results from the alleviation of HIV-associated inflammation and accelerated catabolism.12 Treatment of HIV may also hasten resolution of opportunistic infections and gastrointestinal dysfunction that could adversely affect appetite and nutrient absorption. Additional factors associated with weight gain among PWH include both demographic and HIV-specific characteristics, with greater weight gain observed in black people, women, and in those with high pre-treatment HIV RNA or low CD4 cell counts.2,4-6,13-15 Specific ART regimens or drug classes have also been implicated in weight gain, with integrase strand transfer inhibitors (INSTIs) cited in two randomized studies15,16and several retrospective cohort studies.2,17,18 In order to further explore the demographic-, HIV-, and treatment-related contributors to weight gain, we conducted a pooled analysis of eight randomized comparative clinical trials of initial ART. We also explored whether weight changes were associated with adverse metabolic effects.
Weight gain in participants initiating ART
In pooled analyses, the 96-week median weight gain was 2.0 kg (IQR -1.0, 5.8), with the greatest rate of weight gain occurring during the initial 48 weeks (Figure 1C). Through 96 weeks, 48.6%, 36.6% and 17.3% of participants had at least 3%, 5%, and 10% weight increase from baseline, respectively. Weight gain was not observed in all participants; 30.2% lost weight. The proportion of participants in overweight and obese BMI categories increased over time (Figure 1D).
Risk factors for any weight gain in participants initiating ART
Baseline CD4 count had the strongest association with weight gain in multivariate models; participants with a baseline CD4 count of <200/μL gained on average 2.97 kg more than participants with baseline CD4 ≥200/μL (95% CI 2.81-3.13, p <0.001)(Table 3). Furthermore, increases in CD4 count and weight over time were closely correlated (Supplementary Figure 3). Higher baseline HIV RNA (>100,000 c/mL) was associated with a mean 0.96 kg greater weight gain (95% CI 0.84-1.08, p<0.001); participants with symptomatic HIV or AIDS gained 0.51 kg more than those with asymptomatic HIV (95% CI 0.36 - 0.65, p<0.001). Participants who did not inject drugs at baseline gained 1.41 kg more than those who did (95% CI 0.97-1.85, p<0.001). Black race was associated with weight gain, with a mean 0.99 kg greater weight gain compared to non-black participants (95% CI 0.87-1.11, p<0.001). Female sex, age <50 years and persons with baseline obesity had smaller but statistically significant correlations with weight gain (Table 3).
We further explored these findings by using longitudinal models to study the relationship between sex, race, and weight gain. Female participants gained more weight than male participants, and black participants gained significantly more weight than non-black participants (Figure 2A-B and Supplementary Table 3). Stratification by both sex and race revealed the greatest weight gain among black female participants, followed by black male participants (96-week difference between black females and black males 1.12 kg 95% CI 0.25-1.99, p=0.011; Figure 2C and Supplementary Table 3).
Association of antiretroviral regimen components with any weight gain
Longitudinal modeling of weight gain and ART third agent class (INSTI, NNRTI or PI) revealed weight gain in all three classes (96-week least squares [LS] mean weight gain: INSTI, 3.24 kg [95% CI 3.02-3.46]; NNRTI, 1.93 kg [95% CI 1.58-2.28]; PI, 1.72 kg [95% CI 1.01-2.43]) (Error! Reference source not found.3A). Participants taking INSTIs experienced the most weight gain (Figure 3A and Supplementary Table 4). Weight gain was similar between the NNRTI and PI treatment groups. Absolute weight followed a similar trend (Figure 3B and Supplementary Table 4).
We next assessed the association between weight gain and the specific INSTI used. Participants taking bictegravir (BIC) or dolutegravir (DTG) demonstrated similar weight gain, both greater than that in PWH taking cobicistat-boosted elvitegravir (EVG/c) (96-week LS mean weight gain: BIC, 4.24 kg [95% CI 3.71-4.78]; DTG, 4.07 kg [95% CI 3.51-4.62]; EVG/c, 2.72 kg [95% CI 2.45-3.0]). We observed a similar trend when the analysis was performed using absolute weight (Figure 3C-D and Supplementary Table 4).
Among participants taking NNRTI-containing regimens, those taking rilpivirine (RPV) gained more weight compared to those taking efavirenz (EFV) (96-week LS mean weight gain: RPV, 3.01 kg [95% CI 2.35-3.68]; EFV, 1.7 kg [95% CI 1.31-2.09]). Absolute weights were similar after an initial rapid increase in participants taking RPV (Figure 3E-F and Supplementary Table 4).
Finally, we assessed whether specific NRTIs were differentially associated with weight gain, using zidovudine (AZT) as a reference. At 96 weeks, mean weight gains by NRTI are: tenofovir alafenamide (TAF), 4.25 kg [95% CI 3.94-4.56]; abacavir (ABC), 3.08 kg [95% CI 2.36-3.81]; tenofovir disoproxil fumarate (TDF), 2.07 kg [95% CI 1.84-2.30]), as compared to AZT 0.39 kg [95%CI -0.57-1.34]. Absolute weight followed a similar trend (Figure 3G-H and Supplementary Table 4).
Weight gain in participants initiating ART
In pooled analyses, the 96-week median weight gain was 2.0 kg (IQR -1.0, 5.8), with the greatest rate of weight gain occurring during the initial 48 weeks (Figure 1C). Through 96 weeks, 48.6%, 36.6% and 17.3% of participants had at least 3%, 5%, and 10% weight increase from baseline, respectively. Weight gain was not observed in all participants; 30.2% lost weight. The proportion of participants in overweight and obese BMI categories increased over time
Risk factors for ≥10% weight increase in participants initiating ART
To understand factors associated with more extreme weight gain, we stratified the pooled trial data into individuals who gained ≥10% body weight over 48 weeks (12.8% of participants) versus those who did not. Individuals with ≥10% weight gain were more likely to be female or black, have a lower baseline weight or BMI, have lower baseline CD4 count, and higher baseline HIV-1 RNA (Table 4).
In multivariate regression models (Table 5), lower CD4 count and higher HIV-1 RNA were associated with greater odds of ≥10% weight gain (OR 4.4; 95% CI 3.60-5.27, p<0.001, and OR 2.0; 95% CI 1.65-2.37, p<0.001, respectively). Normal baseline BMI was associated with ≥10% weight gain when compared to individuals with overweight or obese baseline BMIs (normal vs. overweight OR 1.54 [95% CI 1.27-1.87 p<0.001], normal vs. obese OR 1.66 [95% CI 1.29-2.15]). Female sex and black race were associated with ≥10% weight gain (female vs. male OR 1.54 [95% CI 1.21-1.96, p<0.001], and black vs. non-black OR 1.32 [95% CI 1.10-1.59, p = 0.003]). More black women experienced ≥10% weight gain than non-black women (19.7% vs 12.4%, p<0.001).
We assessed the association between the specific third agent drug and ≥10% weight gain (Table 5). Compared to EFV, the initiation of BIC or DTG (OR 1.82, 95% CI 1.24-2.66, p=0.002), EVG/c (OR 1.36, 95% CI 1.04-1.78, p=0.026), RPV (OR 1.51, 95% CI 1.03-2.20, p=0.035), but not ATV/r, were associated with an increased risk of ≥10% weight gain. Among the NRTIs, TAF (OR 1.75, 95% CI 1.04-2.95, p=0.034), but not ABC or TDF, were associated with increased risk for ≥10% weight gain compared to AZT. TAF was also associated with an increased risk of ≥10% weight gain compared to ABC (OR 1.90, 95% CI 1.25-2.88, p = 0.003) and TDF (OR 1.47, 95% CI 1.14-1.90, p = 0.003).
Metabolic impacts of significant weight increase
Next, we evaluated whether ≥10% weight gain was associated with subsequent changes in fasting glucose or the incidence of treatment-emergent AEs related to diabetes or hyperglycemia. We found no significant difference in fasting glucose change between participants with ≥10% or <10% weight gain (96-week mean fasting glucose change for both groups was 3 mg/dL, 95% CI 1.01-4.99 mg/dL and 2.39-3.61 mg/dL respectively, Supplementary Figure 2A). The incidence rate of diabetes-/hyperglycemia-related AEs was higher in individuals with ≥10% weight gain versus those without, although this difference was not statistically significant (1.01 per 100 person-years [PY] [95% CI 0.59, 1.74] and 0.67 per 100 PY [95% CI 0.53, 0.85] respectively, p = 0.18). LDL and triglycerides had similar small increases in both groups, whereas HDL had a small but significant increase in participants with <10% weight increase compared to those with ≥10% weight increase (Supplementary Figure 2B-D). Total cholesterol-to-HDL ratio was slightly higher in the ≥10% weight gain group (week 96 median [IQR] 3.7 [2.9, 4.6] vs 3.5 [2.9, 4.4] p = 0.027). Blood pressure data are available for three trials (264-0110, 380-1489, and 380-1490); no clinically significant changes were observed (week 96 weighted mean change from baseline in systolic and diastolic blood pressure are 2.2 and 1.5 mmHg respectively).
Discussion
In our pooled analysis of eight ART-naïve randomized clinical trials ranging from 2003 to 2019, we found that PWH are initiating ART at higher baseline weight and many gain significant amounts of weight during the first two years of therapy. A mix of demographic, HIV disease-specific, and ART-specific factors were associated with weight increase from baseline and with more extreme (≥10%) weight gain.
Similar to other reports, we observed higher baseline weight in more recent ART-naïve studies, with median baseline BMIs at or near the overweight category.1-4 Weight gain was common following ART initiation: about half of participants gained at least 3% body weight with a median weight gain of 2.0 kg over nearly 2 years of follow-up. This degree of weight gain mirrors the obesity trend observed in the NHANES CARDIA study, where the average American aged 20-40 gained nearly one kilogram per year.19 Accordingly, the distribution of BMI classes in trial participants shifted toward overweight and obese categories by trial conclusion, approaching the distribution seen in recent HIV cohort studies and in the general population (approximately 1/3 overweight, 1/3 obese).4,5,19-21
We did not observe a clinically significant metabolic impact of weight gain in our trials as measured by fasting glucose and investigator reported AEs, however this analysis is limited by duration of follow-up, a relatively small number of reported AEs, and the absence of more sensitive markers of glucose tolerance.
Black race and female sex were associated with weight gain, consistent with other studies.2,5-6,13,15 This association was particularly notable among black females, who gained approximately twice as much weight as non-black women. The mechanism underlying this observation is unknown, but it mirrors the disproportionately high prevalence of obesity in black women in the US,22 and both may be affected by similar factors. These findings are similar to prior studies reporting a concurrence of HIV and obesity risk in the black population23, and highlight the need for increased obesity awareness, monitoring and clinical intervention in this high-risk population.
We observed strong associations between weight gain and HIV disease characteristics. Disease stage, as reflected by low baseline CD4 count, and high baseline HIV RNA correlated with weight gain in our models of any weight gain and ≥10% weight gain, similar to other reports.2,4-6,15 These findings support a contribution of the return-to-health phenomenon to weight gain in PWH initiating ART. This effect may be desirable in some individuals, but could also contribute to excess weight gain in individuals with early stage HIV disease and those with normal or above-normal BMI.
Our analyses revealed several important associations between weight gain and ART at the class and drug level. Examining the clinical trials individually, we observe greater weight gain in newer investigational regimens relative to the comparator, consistent with the findings reported by others.2,24 In our pooled analyses, INSTI-containing regimens were associated with more weight gain than NNRTI or PI-based regimens, with DTG and BIC associated with more weight gain than EVG/c. Among NNRTIs, RPV was associated with more weight gain than EFV. Among NRTI pairs, TAF/emtricitabine (FTC) was associated with the most weight gain, ABC/lamivudine (3TC) and TDF/FTC with slightly less weight gain, and AZT/3TC with weight stability. These findings are similar to the ADVANCE trial, in which DTG and TAF were associated with treatment-emergent obesity, while TDF/FTC/EFV was associated with treatment-emergent underweight status and a higher rate of treatment discontinuation.25 Altogether, these findings establish a pattern of more weight gain with newer ART regimens, possibly reflecting better tolerated, easier to take regimens.26
The hypothesis that improved tolerability may contribute to weight gain in PWH initiating ART is supported by clinical trial data comparing the gastrointestinal (GI) tolerability of HIV regimens. INSTIs such as DTG, BIC, and RAL do not require boosting with cobicistat, which has been associated with nausea and diarrhea.27 Among NNRTIs, RPV is better tolerated than EFV, and should be taken with food which may result in higher caloric intake.28 In the case of NRTIs, early trials demonstrated more GI toxicity with AZT compared to newer NRTIs, including ABC and TDF.29 There is also evidence that TAF may be associated with better GI tolerability than ABC; in a study comparing BIC/FTC/TAF vs. ABC/DTG/3TC, there was a lower incidence of nausea in the TAF-containing arm, a difference not observed in a study comparing BIC with DTG, both with TAF/FTC.30-31
If individual agents contribute to weight gain aside from tolerability, the mechanisms by which they do so is not known. For treatment-naïve PWH, some of the association between weight gain and INSTI-containing regimens could be their faster virologic control compared to older regimens.32 Another explanation for drug-specific effects on weight could be off-target biological interactions. One such example is the observed interaction between DTG and melanocortin 4 receptor (MC4R), a receptor involved in the regulation of caloric intake by modulating leptin signaling in the central nervous system.33-34 This finding is intriguing since mutations in MC4R are associated with heritable obesity.34 This potential mechanism requires further validation, and it remains unknown whether other INSTIs interact similarly.
Evaluating the effect of ART drugs on weight gain is confounded by HIV disease factors such as return-to-health; some of these limitations may be avoided by studying weight changes in pre-exposure prophylaxis (PrEP) trials. In the iPrEx study comparing TDF/FTC to placebo, the TDF/FTC arm gained less weight than placebo, suggesting TDF/FTC may have a mild weight suppressive effect.35 In the DISCOVER trial of TDF/FTC vs. TAF/FTC for PrEP, weight gain at week 48 was 1.1 kg in the TAF/FTC arm with no change in the TDF/FTC arm.36 Finally, in a phase 2 placebo controlled trial of cabotegravir for PrEP, both arms experienced about 1kg of weight gain over 41 weeks, with no significant difference between arms.37 Together these findings suggest that heathy participants taking TAF or an INSTI likely experience weight gain much like the general population, which contrasts with the weight-suppressive effect of TDF.
There are several limitations to our analyses. We do not have body composition data, so we cannot determine the anatomical distribution of the observed weight gain. However, data from recent studies suggest that ART-associated weight gain is generalized, with increases in subcutaneous fat, visceral fat, and lean mass.38 Additionally, our assessment of GI tolerability relied solely on investigator-reported AEs, as more detailed and sensitive participant-reported outcome data are only available in more recent trials.30-31 Our analyses did not evaluate other potential contributors to weight gain such as psychiatric comorbidities, concomitant medications, diet, physical activity, or smoking. In the included trials, newer third agents were generally co-administered with newer NRTIs, making it challenging to completely disentangle the independent associations of individual agents with weight gain, and thus these associations should be interpreted with some caution. Finally, while we report two-year data, the duration of follow-up may not be long enough to capture longer-term metabolic consequences of weight gain.
Collectively our results suggest that there are demographic-, HIV- and treatment-related contributors to weight gain in PWH. Our findings raise the possibility that modern ART regimens with improved tolerability and potency may lead to weight gain in some PWH, necessitating increased clinical attention to the maintenance of healthy body weight, lifestyle modification, and exercise at ART initiation.39-40 Ongoing studies including the analysis of weight gain in ART switch trials may provide important insights by avoiding the contribution of return-to-health effects. Additional important areas for investigation include the magnitude, clinical significance, and biologic mechanisms of ART-related weight gain.
|
| |
|
|
|
|
|
