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Weight gain after switching to integrase inhibitor treatment is small in Dutch and Swiss cohorts

People with suppressed viral load who switched to an integrase inhibitor-based regimen experienced only small gains in weight and do not appear to gain more weight than HIV-negative people or people who continued taking other regimens, two large cohort studies presented at the 17th European AIDS Conference (EACS 2019) reported.

However, the Swiss HIV Cohort reported that people of African origin gained more weight after switching to dolutegravir, as did women, while a Dutch cohort study by researchers at the Amsterdam University Medical Centres, University of Amsterdam, Amsterdam Institute for Global Health and Development, Amsterdam Infection and Immunity Institute and Amsterdam Public Health Research Institute, HIV Monitoring Foundation-Amsterdam and the Public Health Service of Amsterdam, found that 24% of people who switched to an integrase inhibitor gained at least 5% of body weight. Substantial weight gain after switching was more likely in black women, although the number of black women in the cohort was small.

A recently published meta-analysis of eight large clinical trials found that weight gain after starting antiretroviral treatment was most strongly associated with a low CD4 count before starting treatment. The authors of that study suggested that more evidence from studies of switching treatment was needed to investigate immunological and antiretroviral predictors of weight gain. However, white men tend to be over-represented in switching studies.

Two observational cohort studies of weight changes after switching treatment were presented at the conference. Both studies looked at the effects of switching to an integrase inhibitor-based regimen.

AGEhIV Cohort is a large observational cohort that monitors the long-term health of people over the age of 45 on antiretroviral treatment in the Netherlands in comparison to a control group of HIV-negative people.

To examine the impact of integrase inhibitors on body weight, the cohort investigators designed a prospective observational study in which changes in body weight were monitored in people who switched to an integrase inhibitor-containing regimen. Each person was matched with two people who remained on non-integrase inhibitor treatment and two HIV-negative people. In each case, they were matched according to age, gender, ethnicity and body mass index.

The investigators also simulated a switch point for the controls, by identifying the point during pre-switch follow-up where the control participant most closely resembled the switch participant in characteristics including weight. They then used the time to switching treatment to define a simulated switch time in the control participants and monitored weight before and after 'switch' for the control participants.

The HIV cohort consisted of 598 people and the HIV-negative cohort of 550 people. One hundred and nineteen people switched to an integrase inhibitor-containing regimen (53% dolutegravir; 35% elvitegravir; 13% raltegravir).

The switch group was 89% white and 87% male, had been on antiretroviral treatment for a median of 12 years, had a median age of 55 years and a median body mass index of 24. As the two control groups were matched, proportions were similar in each group. Body weight was measured twice a year, before and after switching. Throughout the follow-up period there was no significant difference in body weight changes between people who switched to an integrase inhibitor-containing regimen and matched HIV-positive and HIV-negative controls. The mean annual weight gain after switching to an integrase inhibitor was 0.17kg a year.

However, 24% of people who switched to an integrase inhibitor gained at least 5% in body weight compared with 13% of the HIV-positive control group (p = 0.012) and 12% of the HIV-negative control group (p = 0.004). Weight gain of 10% or more after switching to an integrase inhibitor occurred more frequently in black women than in other demographic groups, although the number of black women in the study cohort was small.

The Swiss HIV Cohort Study by researchers at Bern University Hospital, University of Bern, Geneva University Hospital, University Hospital Zurich, Kantonsspital Baselland, University of Basel, Lausanne University Hospital, University of Lausanne, Cantonal Hospital St Gallen and Regional Hospital Lugano, is a large observational cohort of people living with HIV receiving treatment at HIV clinics in Switzerland. Weight is measured at six-monthly clinic visits in all cohort members. Investigators analysed weight changes in people who had been virally suppressed for at least 18 months before switching to a dolutegravir-containing regimen, and who had at least 18 months of follow-up after switching.

In this cohort, 2186 people switched to dolutegravir and were eligible for analysis. (Women who were pregnant at the time of switching were excluded.) The switch population was predominantly male (75%) and white (81%), had been on antiretroviral therapy for a median of 11 years and had a median body mass index of 24 at time of switching.

In the 18 months preceding the switch, participants gained a median of 0.47kg (95% confidence interval 0.34-0.61). In the 18 months after switching, they gained a median of 0.72kg (95% CI 0.58-0.86), a significant difference (p < 0.029). Whereas women showed no difference in the rate of weight gain after switching, men gained significantly more weight (p = 0.009), although the amount gained (+0.81kg) remained modest.

Ethnicity did not affect average weight gain, but when the researchers calculated the risk of gaining more than 5% in body weight after switching, they found that women, black people and current smokers had approximately 50% greater likelihood of substantial weight gain. People who were obese at the time of switching were less likely to have substantial weight gain.

The findings of both studies suggest that looking at averages or medians in switch studies may be less useful than looking at risk factors for clinically relevant weight gain of greater than 5kg, especially in cohorts that are predominantly white and male.

Abstract 1
Purpose: We assessed changes in weight and BMI after switching to Dolutegravir (DTG) containing antiretroviral therapy (ART) among patients with suppressed HIV viremia in the Swiss HIV Cohort Study (SHCS).
Methods: Weight, other demographic and clinical characteristics were prospectively collected at 6‐monthly follow‐up visits. Switching was defined as changing to a DTG containing regimen after being at least 18 months on a triple‐drug ART regimen. We excluded pregnant women and patients not virally suppressed 6 months before switching. We assessed weight change within a window of 18 months of DTG start by comparing pre‐ and post‐switch changes using t‐tests and interrupted time series analysis. Risk factors for disproportionate weight gain were identified using logistic regression comparing the top quartile of weight gainers to the rest.

Results: 2,215 patients met the inclusion criteria. Patients were predominantly white males (66%). At time of switch, median age was 51 (interquartile range (IQR) 44 ‐ 56), median BMI 24.0 (IQR 21.7 ‐ 26.8), and median time on ART 11 years (IQR 6 ‐ 17). The Figure shows weight change before and after switching to DTG. Mean weight change over 18 months was 0.5 kg (95% confidence interval (CI) 0.3 ‐ 0.7) before switching, and 1.0 kg (95% CI 0.8 ‐ 1.2) after switching (p<0.001). BMI changed + 0.2 units (95% CI 0.1 to 0.2) before and + 0.3 units (95% CI 0.3 to 0.4) after switching (p<0.001). Risk factors for disproportionate weight gain included males (adjusted odds ratio (aOR) 1.5 95% CI 1.1 to 2.0) and people of African origin (aOR 1.5 95% CI 1.1 to 2.1).
Conclusion: Among patients on stable ART, switching to DTG was associated with a modest increase in weight compared to the time‐period before switch. Weight gain was more prominent among participants of African origin and males.

Authors
C Mugglin, A Calmy, H Günthard, P Tarr, A Atkinson, A Scherrer, M Cavassini, C Marzolini, P Schmid, E Bernasconi, D Braun, G Wandeler, A Rauch, Swiss HIV Cohort Study

Abstract 2
Purpose: Recently, several cohorts reported above‐average weight gain in people with suppressed HIV‐viremia after switching to an integrase inhibitor (INSTI) containing antiretroviral regimen. We evaluated similar changes in standardized bodyweight measurements from HIV‐positive and HIV‐negative AGEhIV cohort participants.

Methods: In 598 HIV‐positive and 550 HIV‐negative AGEhIV participants bodyweight was measured biennially. Virally‐suppressed HIV‐positive participants switching to an INSTI‐containing antiretroviral regimen were matched 1:2:2 with (1) HIV‐positive participants not changing antiretroviral regimen and (2) HIV‐negative participants, using time‐dependent propensity scores based on gender, ethnicity, age and BMI. In all matched controls a hypothetical moment of switch was determined, at which matched controls most resembled propensity scores of the index‐participant at INSTI‐switch. Average yearly bodyweight changes before and after (hypothetical) switch within and between study groups were compared using linear mixed‐effects models. The frequencies of>5% and>10% weight gain were compared using logistic regression.
Results: 119 HIV‐positive participants switched to an INSTI‐containing regimen (53% dolutegravir; 35% elvitegravir; 13% raltegravir) and had a bodyweight measured≥1 times before and after switch. In 49% the NRTI‐backbone was simultaneously modified, the majority from tenofovir disoproxil/emtricitabine to tenofovir alafenamide/emtricitabine (18%) or abacavir/lamivudine (11%). There were no significant differences in yearly mean changes in bodyweight within and between the groups before and after (hypothetical) switch.
Reported results were calculated from a linear mixed‐effects model with bodyweight as the outcome, and the 3‐way interaction‐term study grouptimebefore/after switch as predictor variable.
A>5% increase in bodyweight occurred in 28 (23.5%) HIV‐positive participants after INSTI initiation, and in 31 (13%, p=0.013) non‐switching HIV‐positives, and in 28 (11.8%, p=0.005) HIV‐negative controls, after their hypothetical moment of switch. A>10% increase in bodyweight occurred in 6 (5.0%), 7 (2.9%, p=0.3) and in 6 (2.5%, p=0.2) respectively.
Frequency distributions of proportional weight changes; first post‐ vs. last pre‐switch measurements

Conclusions: We found no evidence for above‐average weight gain in virologically suppressed patients switching to an INSTI‐containing regimen. However, clinically relevant weight gain upon switching to INSTI may be a relatively rare phenomenon deserving further investigation.

Authors
S Verboeket, A Boyd, F Wit, E Verheij, M Schim van der Loeff, N Kootstra, M van der Valk, P Reiss, AGEhIV Cohort Study

[link url="http://www.aidsmap.com/news/nov-2019/weight-gain-after-switching-integrase-inhibitor-treatment-small-dutch-and-swiss"]Aidsmap material[/link]

[link url="https://onlinelibrary.wiley.com/doi/full/10.1111/hiv.12814"]EACS 2019 abstract book[/link]

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