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Recent research has associated integrase inhibitors, female gender, and non-White race to unwanted weight gain in persons with HIV (PWH) receiving contemporary ART. The underlying potential mechanisms linking INSTIs to weight gain still remain undetermined, with direct effects on adipocytes or interference in adipocyte differentiation, affected glucose, lipid, or appetite metabolic pathways, and reduced insulin sensitivity via magnesium chelation properties all under exploration.1 Yet clinically, what’s perhaps most important to providers and patients is how we counsel patients regarding the risk for weight gain. Researchers at Ohio State University conducted a single-center, retrospective cohort study of adults receiving ART for at least 3 months to identify factors associated with weight gain, defined as a ≥5 kg increase in weight during the study period from 2015- 2019.2 Using mixed linear and logistic regression analyses adjusted for age, gender, and weight at study entry, and years on study, the investigators evaluated demographic factors, comorbidities, and ART medications.
Of importance, they evaluated the influence of diet, a factor that was unique because studies have not yet drilled down to the dietary influences that can lead to or attenuate weight gain. Diet was defined as “any change a patient made in their oral intake to improve consumption of nutrient-dense foods in efforts to maintain or lose weight.” Healthcare professionals counseled patients on diet, then recorded patient-reported subjective improvements in diet since the last office visit.
The results showed an average weight gain of 2.12% in relative weight and 1.64 kg after a mean follow-up of 1.86 years.2 Dieting resulted in a 30% decreased risk for weight gain. Male gender was also a protective factor, lowering the odds of weight gain by approximately 40%, and every 10 years of age reducing the odds by approximately 23%. Every year of continuing on the same ART regimen increased the odds of experiencing a weight gain of at least 5 kg by approximately 40%.
Three treatments were associated with a greater chance of gaining at least 5 kg: tenofovir alafenamide (TAF)/emtricitabine (FTC), dolutegravir (DTG), and any integrase inhibitor.
There were also 3 treatments associated with a lower chance of experiencing weight gain of at least 5 kg: tenofovir disoproxil fumarate (TDF)/FTC, darunavir (DRV)/ritonavir (RTV), and efavirenz (EFV).
The investigators believe this to be the first study highlighting the potentially crucial role of diet in weight changes among PWH receiving current ART regimens, and they emphasized that these findings underline the role of diet in helping to address weight gain during scheduled office visits. This study reinforces previous findings that linked integrase inhibitors and TAF to weight gain, but it also highlights that that weight gain in the current ART era can be multifactorial, involving demographic, behavioral, and ART-related inputs. Of importance, the study did not examine the phenomenon of switching from TDF to TAF, which has been proposed as a mechanism to reverse the potential suppressive effects of TDF on adipogenesis.
A meta-analysis of TDF and weight changes among HIV-negative individuals receiving pre-exposure prophylaxis (PrEP) for prevention of HIV was reported at IDWeek 2021.3 Seven PrEP trials, 6 comparing either TDF or TDF/FTC with placebo and 1 comparing TDF/FTC with CAB, were included in the analysis. The analysis included some of the landmark trials for PrEP that led to licensing of FTC/TDF as the first agent for HIV PrEP.4 Also included was HPTN 084, with TDF as the standard of care vs the newer agent CAB, positioned to be licensed for PrEP, in 2022 through data from HPTN 083 and 084.
The meta-analysis determined that TDF use as PrEP among HIV-negative participants produced greater weight loss vs control.3 To account for substantial heterogeneity among the 7 trials, investigators used the Mantel-Haenszel test with random effects modeling for calculating the odds ratios and 95% CI. The results suggest that there are suppressive effects for TDF within this population.
The investigators also evaluated GI adverse events (AEs) across the 7 trials and found that patients receiving TDF experienced significantly higher rates of vomiting than patients receiving placebo.3 Rates of other GI AEs, including nausea, diarrhea, and loss of appetite, were similar between patients receiving TDF and those who received placebo. Overall, TDF was well tolerated, with an expected acclimation period for those patients on PrEP.
Weight gain in patients receiving ART is well documented and associated with many factors, including gender, race, comorbidities, use of integrase inhibitors, and disease-related factors (such as HIV-1 RNA and CD4+ cell count). The Denver Health Weight Gain Study is a retrospective analysis of PWH initiating first-line ART through the Denver Health Clinic from 2005 to 2019.5 The goal of the study was to use a real-world clinic cohort to isolate factors linked to excessive weight gain and to assess the ability of early weight gain to predict excessive weight gain, defined as the top 20% of weight gainers among participants who experienced weight gain.
Participants were adults with at least 2 years of follow-up on stable ART and were virologically suppressed from 6 months after ART initiation through the 2-year follow-up period. Pregnant women and persons with missing weight measurements were excluded.
Median weight at baseline was 163 lb (interquartile range [IQR]: 142-182) and at 2 months was 163 lb (IQR: 146-181), rising to 170 lb (IQR: 151-192) at 1 year and then to 173 lb (IQR: 151-196) at the end of 2 years.5 These translate into a 4% weight gain in 2 years. Excessive weight gainers added more than 13% of their baseline body weight in the 2-year follow-up period, with 70% of weight gain occurring during the first year of therapy. BMI climbed from 23.7 kg/m2 (21.4-27.0) at baseline to 25.2 (22.3-29.1) at 2 years, just into the overweight range. A large percentage of patients experienced excessive weight gain by year 2 following suppressive ART initiation (89%). Participants who gained less than 2% of their body weight by 2 months had a very low likelihood of excessive weight gain at 2 years (8%). However, a gain of ≥5% by 2 months increased the risk of excessive weight gain at 2 years to 55%. The largest weight gain in 2 years was seen in the group of participants starting a protease inhibitor (PI) (145-166 lb). Baseline to 2-year median weight rose from 168 lb to 178 lb among those on integrase inhibitors and from 165 lb to 173 lb in the nonnucleos(t)ide reverse transcriptase inhibitor (NNRTI) group.
Multivariate analysis independently linked only 2 factors—a lower baseline CD4+ cell count and a higher baseline HIV-1 RNA—with excessive weight gain after 2 years on first-line ART.5 For every 100-cell higher increase from the initial CD4+ cell count cutpoint, the chances of excessive weight gain were 30%, and for every 1 log increase in initial HIV-1 RNA, this tripled the chances of excessive weight gain; that adjusted odds ratio was 3.2. There were also trends toward associations between younger age and female gender in excessive weight gain. Of importance, the individual antiretroviral (ARV) agents and classes including integrase strand transfer inhibitor (INSTI), NNRTIs, abacavir (ABC), or TAF did not predict excessive weight gain.
The authors stress that these lower pretreatment CD4+ cell counts and higher pretreatment HIV-1 RNA can predict excessive weight gain, and that patients should be counseled. When weight gain is not linked to TAF or integrase inhibitors but more to immunologic or virologic factors, it throws a little controversy into the puzzlement of weight gain that we have seen in the past couple of years, since this was first uncovered in patients switching from EFV/FTC/TDF (first documented in observations at Vanderbilt and then worldwide).
Later in this program, we will look at some of the ADVANCE trial data for switching onto an integrase inhibitor-based regimen, recently updated at EACS 2021. I think it adds a bit more nuance to the conversations that we need to have with patients regarding what to expect. If you have a lower CD4+ cell count or a higher HIV-1 RNA, you should potentially be on the lookout for a “return to health phenomenon,” regardless of which ART is started.
EuroSIDA is prospective, observational cohort study initiated in 1994 and now including data from more than 23,000 PWH.6-8 It is a collaboration of more than 100 clinics in 35 European countries, spanning all the regions of Europe as well as Israel and Argentina.7 EuroSIDA is the largest pan-European longitudinal study since its inception in 1994, so these are big data, which is often quite informative.
The current study evaluated patients with substantial exposure to integrase inhibitors to assess long-term clinical outcomes—including cardiovascular disease (CVD), malignancy, and all-cause mortality—in relationship to BMI changes after the initiation of contemporary ART.9 This cohort comprised PWH from EuroSIDA who had initiated a new ART regimen during the 10-year period from 2010 through 2019, and multivariate regression analysis was used to assess the effect of BMI changes over time with at least 1 year of follow-up assessment on incident clinical outcomes.9
The 6721 study participants represented 31,420 person-years of follow-up.9 During the study period, 26% of participants experienced a BMI increase and 16% experienced a BMI decrease. The distribution of BMI categories remained similar over time. However, a trend toward increased BMI over time was noted, and there were fewer participants in the healthy weight category (BMI 18-24 kg/m2) by the end of the study.
The authors noted that the power of the study is limited, as shown by relatively low clinical event rates. There were 100 CVD events, 149 malignancies, 144 diabetes mellitus events, and 257 deaths with incidence rates of 4.4, 6.8, 6.6, and 10.6 per 1000 patient-years of follow-up, respectively.
Results were adjusted for age, gender, and potential confounders, including previous ARV regimens and other comorbidities. A sensitivity analysis excluding participants with the potential to experience a “return to health phenomenon,” that is, those in the underweight category at baseline (BMI <18.5 kg/m2), which constituted approximately 5% of the cohort, produced consistent findings.
The investigators identified a significant increase in the incidence of diabetes following increase in BMI and an increase in mortality following a decrease in BMI, compared with those whose BMI remained stable. Of interest, the differences in incident CVD and malignancies were not statistically significant.
It is not surprising that emerging diabetes was associated with weight gain, and this finding is consistent with observations in the general populations. The association of mortality with weight loss likely reflects other debilitating origins driving both weight loss and mortality, such that the weight changes had no impact on other important clinical outcomes of CVD or malignancy. The results highlight the need for more information and counseling for patients regarding the risk of weight gain linked to metabolic syndromes and diabetes. With the lower power of this study, longer-term follow-up is likely needed to confirm these results.
Of note, another large cohort study from NA-ACCORD, recently published in October 2021, showed that ART-naive PWH who initiated either a PI- or INSTI-based regimen, particularly if raltegravir (RAL)-based, had an increased risk for incident diabetes as compared with PWH initiating NNRTIs, and that these patients should be monitored.10 This increased risk was not entirely explained by weight gain, so we still need to sort out if diabetes is linked to weight gain or to any individual ARV agent. This is an evolving picture, and we certainly will see more data from these large cohort settings.