Papers on weight gain associated with integrase inhibitor treatment

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More evidence that HIV integrase inhibitor treatment is associated with weight gain, and that people gain more weight after beginning treatment with an integrase inhibitor than people taking other drug classes, was presented this week at the Conference on Retroviruses and Opportunistic Infections (CROI 2019) in Seattle.

Weight gain on integrase inhibitor treatment was first flagged up in late 2018 and, since the first reports, other research groups have been looking at weight gain in a wider range of patient groups.

The form of weight gain seen in people starting integrase inhibitor treatment is not the same as the fat redistribution syndrome, or lipodystrophy, observed when the first generation of protease inhibitors was used in combination with nucleoside reverse transcriptase inhibitors (NRTIs) or when non-nucleoside reverse transcriptase inhibitors (NNRTIs) were used in combination with older NRTIs, especially stavudine (d4T).

Whereas lipodystrophy involved accumulation of central abdominal or visceral fat, and loss of subcutaneous fat, weight gain on modern antiretroviral treatment consists of general fat gain – both subcutaneous and central fat – with an increase in waist circumference.

Weight gain after starting antiretroviral treatment is a common event; gaining a modest amount of weight is normal, especially in people with more advanced HIV disease or low body mass prior to treatment. It’s been dubbed ‘return to health’ weight gain.
However, what has been seen with some drug regimens – not just integrase inhibitors, but some protease inhibitors too – is more substantial weight gain. Some clinicians have raised concerns that weight gain might eventually increase cardiovascular disease risks, blood pressure and type 2 diabetes in populations which already have a high prevalence of obesity and other risk factors for cardiovascular disease. The VACS study showed that gaining five pounds (2.26kg) after starting treatment increased the risk of diabetes by 14%, while the D:A:D cohort found that every unit of body mass increase after starting antiretroviral treatment raised the risk of diabetes by 13%.

But is this weight gain caused by antiretroviral drugs or is it a product of environments that encourage people to eat unhealthily and be physically inactive? Moderating a discussion on weight gain after starting treatment, Jane O’Halloran of Washington University in St Louis, pointed out that up to half of adults starting antiretroviral therapy in the US may already be obese. Weight gain after starting treatment may be occurring in adults who already have diets and lifestyles that predispose them to further weight gain.

On the other hand, asked Carl Fichtenbaum of University of Cincinnati, what if weight gain on regimens other than integrase inhibitors is being blunted by effects of certain drugs on fat deposits?

Studies presented at CROI attempted to shed more light on the problem, specifically: whether integrase inhibitors cause more weight gain than other drugs; how much weight is being gained and over what period; who might be at greater risk; and whether there is any difference between integrase inhibitors. Are integrase inhibitors associated with greater weight gain than other drugs?

The largest study to report on this question, the North American AIDS Cohort Collaboration, found that among people starting treatment for the first time, treatment with dolutegravir or raltegravir was associated with greater weight gain than treatment with NNRTI-based treatment. The cohort analysis looked at 24,001 people who started treatment between 2007 and 2015. During that period, 4740 people started treatment with an integrase inhibitor (1681 raltegravir, 2124 elvitegravir and 935 dolutegravir).
After five years on treatment, people taking an integrase inhibitor had gained a median of 6kg, compared to 4.3kg for people who started an NNRTI (p < 0.001). There was no difference in weight gain between people who started an integrase inhibitor or a protease inhibitor. (Bourgi) The Women’s Interagency Health Study examined its cohort of 1118 women who had undetectable viral loads between 2008 and 2017 on treatment, 234 of whom switched to an integrase inhibitor during that period. This cohort had a high prevalence of obesity and a mean body mass index of just over 30 at baseline. There was no significant difference in body weight by demographics or by drug regimen at baseline, with mean weight of approximately 80kg. Women who switched to an integrase inhibitor gained 2.14kg more than women who did not switch. (Kerchberger)

Dallas Parkland Hospital looked at 4,048 patients who started treatment between 2009 and 2017, with median exposure to antiretroviral treatment of 6.7 years. They looked at differences in changes in body mass index after starting treatment between people who started regimens based on an NNRTI, a protease inhibitor or an integrase inhibitor. The median increase in body mass index was greatest in the integrase inhibitor group (+0.32/m2 per year) and smallest in the NNRTI group (+0.22/mm2 per year). (Bedimo)

In summary, most studies did find an association between integrase inhibitor treatment and weight gain, in previously untreated people and in people switching from another regimen. One study did not find an association. An analysis of clinic databases in 21 US states, covering 3,468 people with suppressed viral load for at least one year, looked at weight gain between 2013 and 2018. They found that patients gained an average of 3% a year in weight, but in a discussion on weight gain research Grace McComsey at Case Western Reserve University, Cleveland, Ohio, pointed out that most people are not gaining substantial weight – “only 30% gained more than 3%”. Regression analysis failed to show an association between integrase inhibitor treatment and weight gain. Instead, significant predictors of weight gain in this population were low body mass index at baseline, being overweight at baseline, hypogonadism (low testosterone), protease inhibitor treatment, and psychiatric disorder. (McComsey)

The HIV prevention study HPTN 077 looked at weight gain in 199 HIV-negative people who received oral induction treatment and subsequent injectable cabotegravir. Weight was measured at each study visit to week 41 and no difference in weight gain was seen between those who received cabotegravir or placebo – both groups gained around 1kg. The investigators commented that an interaction between HIV infection and integrase inhibitor treatment may be an important contributor to weight gain on antiretroviral treatment. (Landovitz)

Are some people at greater risk of weight gain on integrase inhibitor treatment? A review of 972 people who switched to an integrase inhibitor in AIDS Clinical Trials Group studies found that in the two years after switching, white or black race, age 60 or over, or a pre-switching body mass index of 30 or above (obese) were associated with greater weight gain in women. In men, only age over 60 was associated with weight gain. Dolutegravir was associated with the greatest weight gain and the gains in weight after starting treatment were larger than those expected for a person’s age. (Lake)

A review of 437 patients in the HIV Outpatients Study found that among patients who switched to integrase inhibitor-based treatment after viral suppression on another regimen, weight gain was significantly greater in non-Hispanic black patients and in people with no prior history of nucleoside reverse transcriptase inhibitor use. (Palella)

Are there differences between integrase inhibitors in weight gain? In the NACCORD study, researchers looked at weight gain after two years on each integrase inhibitor and compared this with weight gained by people starting treatment with an NNRTI or a protease inhibitor. Taking into account that fewer people received dolutegravir because it was licensed after raltegravir and elvitegravir, the investigators found that patients on raltegravir or dolutegravir gained significantly more weight than people taking NNRTI treatment, while people taking elvitegravir gained less weight than people taking a protease inhibitor.

In the Parkland study discussed in a previous section, women gained more weight than men on dolutegravir and raltegravir, but not on elvitegravir. Black people gained more than other ethnic groups on dolutegravir, but not on other integrase inhibitors. In the entire cohort, people taking elvitegravir gained more weight than people taking dolutegravir or raltegravir. (Bedimo)

In summary, no clear pattern emerged from the research presented at CROI regarding the effects of various integrase inhibitors.

 

Abstract 1
While older protease inhibitors (PI) were more frequently associated with central fat accumulation, initiation of currently used ART regimens has been associated with increases in body mass index (BMI), particularly in women and with integrase strand transfer inhibitors (INSTI). The goal of this study was to analyze the differential effect of individual PIs and INSTIs on changes in BMI by sex and race in a large urban HIV clinic.
All patients initiating ART at the Parkland Health and Hospital System in Dallas, TX from 2009 to 2017 were included in the analysis. Exposure to ART was defined as concurrent receipt of at least two nucleoside reverse transcriptase inhibitors (NRTI) and at least one PI, Non-nucleoside reverse transcriptase inhibitor (NNRTI) or INSTI. In regression analysis, we compared yearly change in BMI (kg/m2) between men and women and between Blacks, Hispanics and Non-Hispanic Whites following initiation of PIs (Atazanavir [ATV], Darunavir [DRV] or Lopinavir [LPV]) or INSTI (Raltegravir [RAL], Elvitegravir [EVG] or Dolutegravir [DTG]). We controlled for year of HAART initiation, baseline CD4 count and HIV-1 RNA, and whether patients achieved virologic suppression on HAART.
We included 4,048 patients, 69% male, 53% Black, 28% Hispanic, and 16% non-Hispanic Whites. Mean age was 46.3 years (SD 11.9). Mean baseline BMI was 27.0 kg/m2 (6.4). Median follow-up time on HAART was 6.7 years (IQR 2.8 – 11.2). Cumulative exposure to NNRTI, PI, and INSTI-based HAART were 3546, 6184, and 3090 person-years, respectively. The BMI slope per year on NNRTI, PI and INSTI were 0.22, 0.24 and 0.32, respectively. BMI slopes for individual PI- and INSTI-based regimens by sex, race and ethnicity are presented in Table 1. There was no significant interaction between sex and race/ethnicity on BMI gains. Proportion of overweight /obese (BMI, ≥ 25) increased from 51% at HAART initiation to 65% at year 3 (pWe observed a differential effect of individual INSTI and PI-based HAART regimens on BMI changes by sex. All PIs were associated with greater BMI gain in women than in men, but with no difference by race/ethnicity. LPV-based ART was associated with relatively smaller BMI gains. Among INSTIs, while EVG appeared to be associated with greater BMI gains overall, the effect did not vary or by sex or race/ethnicity. DTG and RAL are associated with greater BMI gains in women, and DTG with greater gains in Blacks & Hispanics.

Authors
Roger Bedimo, Xilong Li, Beverley Adams-Huet, Jordan E Lake, Barbara S Taylor, Deborah Kim, Pablo Tebas, Amneris Luque

Abstract 2
Obesity among persons living with HIV (PLWH) has steadily increased in the era of combination antiretroviral therapy (ART), and some PLWH experience substantial weight gain after initiating ART that may lead to metabolic comorbidities and poorer survival. To assess the influence of antiretroviral class and integrase strand transfer inhibitors (INSTI) on this phenomenon, we compared weight changes after initiating ART among treatment-naïve PLWH in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).
Adult, treatment-naïve PLWH in NA-ACCORD initiating INSTI, protease inhibitor (PI), and non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART regimens after 01/01/2007 were included and followed through 12/31/2015. We used multivariate linear mixed effects models to generate marginal predictions of weights over time, adjusting for age, sex, race, cohort site, HIV acquisition mode, ART initiation year, and baseline weight, HIV-1 RNA, and CD4+ cell count. We used restricted cubic splines to relax linearity assumptions, multiple imputation for missing values, and bootstrapping to generate 95% confidence intervals. Predicted weights by ART class were reported at years 2 and 5. Due to shorter follow-up for newer INSTI drugs, predicted weights for raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) were reported at years 1 and 2.
Among 21,886 participants, 4,112 initiated INSTI-based regimens (2106 RAL, 1510 EVG and 477 DTG), 87% were male, and 43% were white. At ART initiation median age was 42 years, BMI was 25 kg/m², and CD4+ count was 303 cells/mm³. Weight gain was highest among PLWH starting INSTI (Figure1, A). At 2 and 5 years, PLWH on INSTI gained 4.4 and 5.8 kg, respectively, compared to 3.3 and 4.1 kg for NNRTI (pTreatment-naïve PLWH starting INSTI, especially DTG and RAL, are at higher risk of weight gain compared to older NNRTI-class regimens. This is clinically important as INSTI-based regimens are now recommended first line ART and PLWH are at increasing risk for obesity, metabolic comorbidities, and cardiovascular disease.

Authors
Kassem Bourgi, Cathy Jenkins, Peter F Rebeiro, Jordan E Lake, Richard D Moore, WC Mathews, Michael A Horberg, Amanda Willig, Michelle Floris-Moore, Michael John Gill, Angel M Mayor, Ronald Bosch, Timothy R Sterling, John R Koethe

Abstract 3
Integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) is recommended first line for HIV treatment. Studies have suggested individuals who switch to INSTI-ART experience increase in body weight. These changes may be more prominent in women. We evaluated the effect of INSTI use on body weight and measurements in HIV+ women.
Data were collected from 2008-2017 from HIV+ women enrolled in the Women’s Interagency HIV Study (WIHS) with viral load 1118 WIHS participants (884 STAY and 234 SWAD) were followed for average 2.0 (+/- 0.1) years; mean baseline age was 48.8 (+/- 8.8) years, 61% were Black, and mean CD4 669 (+/- 294) cells/mm3. At baseline, women in SWAD group were more likely to be on protease inhibitor-ART but did not differ from STAY by demographics or body measurements. Compared to the STAY group, the SWAD group experienced 2.14 kg greater increase in weight, 0.78 kg/m² greater increase in BMI, 1.35% greater increase in PBF, and 2.05, 1.87, 0.58, and 0.98 cm greater increases in waist, hip, arm, and thigh circumference, respectively (Table 1). Women in SWAD also had 2.24 and 1.17 mmHg greater change in systolic and diastolic BP. New-onset DM occurred in 4.5% (n=8) in SWAD and 2.2% (n=15) in STAY, p=0.11. No significant differences in outcomes were observed by INSTI type.
In a longitudinal study of HIV+ women on ART, a switch to INSTI was associated with significant increases in body weight and measurements, body fat, and blood pressure compared to those remaining on non-INSTI ART. Further research is urgently needed for prevention and management of metabolic effects with INSTI use.

Authors
Anne Marie Kerchberger, Anandi N Sheth, Christine D Angert, Cyra Christina Mehta, Nathan A Summers, Igho Ofotokun, Deborah Gustafson, Sheri Weiser, Seble Kassaye, Deborah Konkle-Parker, Anjali Sharma, Adaora Adimora, Hector Bolivar, Cecile D Lahiri

Abstract 4
Weight gain following antiretroviral therapy (ART) initiation occurs with all modern regimens. Recent real-world reports from small studies suggest that integrase strand transfer inhibitor (INSTI)-based ART may be associated with excess weight gain. We assessed weight gain following switch to INSTI-based ART among AIDS Clinical Trials Group (ACTG) participants in ACTG protocols A5001 and A5322, which provided long-term observational follow-up of individuals enrolled in randomized interventional trials.
A5001 and A5322 participants in follow-up from 1997-2017 who switched to INSTI were included. Within-person weight and waist circumference trajectories were generated, allowing participants to serve as their own controls for estimation of background/age-related weight gain. Piecewise linear mixed effects models adjusting for age, sex, race/ethnicity, parent study baseline BMI and their interactions, nadir CD4+ T cell count, smoking, diabetes and percent follow-up time with suppressed (Adults (n=972) who switched to INSTI (68% from PI, 31% NNRTI, 2% other non-INSTI at median 7.8 years after parent trial entry) were 81% male and 50% non-white. Median age at switch was 50 years, CD4+ T cell count 511 cells/μL and BMI 26.4 kg/m2; 539 switched to RAL, 222 to EVG and 211 to DTG. When restricted to persons with suppressed HIV-1 RNA at switch (n=691), women, blacks and persons age ≥60 experienced significantly greater weight gain in the 2 years following switch to INSTI vs 2 years prior to switch; men and persons age Yearly weight gain increased following switch to INSTI. These increases were particularly significant for women, blacks and persons age ≥60. When compared to pre-switch weight changes on stable suppressive ART and given concomitant increases in waist circumference, these data suggest increases in weight/fat mass greater than expected for age. The cardiometabolic implications of increased weight gain following switch to INSTI need to be established.

Authors
Jordan E Lake, Kunling Wu, Kristine M Erlandson, Sara H Bares, Paula Debroy, Catherine Godfrey, John R Koethe, Grace A McComsey, Frank J Palella, Katherine Tassiopoulos

Abstract 5
In people living with HIV, ART treatment with regimens containing integrase inhibitors (INIs) has been associated with weight gain and increased waist circumference, raising concerns about possible future risk for metabolic and cardiovascular disease. These changes have been associated with female sex, non-white individuals, and those with higher baseline BMI. HPTN 077, a Phase 2a randomized placebo-controlled study of two dose/dose-interval regimens of cabotegravir, enrolled HIV-uninfected participants from 8 sites in the US (4), Brazil (1), and sub-Saharan Africa (3). 199 participants were enrolled and randomized 3:1 to active CAB or placebo and received oral CAB 30mg or placebo (PBO) QD x 4 weeks, a one-week washout, and then sequential injections of CAB LA or 0.9% saline PBO from Week (W) 5 through W41.
We measured weight at study entry (W0), during oral study product administration (W2, W4) and during injectable study product administration (W5, 17, 19, 29/33, and 41). Age, race/ethnicity, sex at birth, injectable dosing cohort, smoking status, and BMI were assessed at baseline. Longitudinal models fitted via generalized estimating equations (GEE) were used to assess marginal effects of study arm on weight over time. Wilcoxon rank sum tests were used to compare medians of numeric variables and chi-square tests were used to compare frequencies of categorical variables.
The Table shows median weights at W0 and W41 overall, and changes from baseline (W0-W41) by covariates of interest. Median weight change over 41 weeks was +1.1 kg (IQR -0.9, 3.0) in the CAB arm and +1.0 kg (IQR -1.2, 3.2) in the PBO arm (p=.66). In longitudinal statistical analyses, no statistically significant differences were found in change in weight from W0 to 41 in CAB vs. PBO treated participants in aggregate, by sex, dosing cohort, age, race/ethnicity, smoking status, BMI, nor by baseline BMI category. No differences in weight change for CAB vs. PBO were seen for W0-4 and W5-41 separately.
In this moderately sized global cohort of 199 HIV-uninfected males and females, there was no difference in weight change for participants receiving CAB compared to PBO-treated participants. Although structurally similar to dolutegravir, CAB may have different effects on weight/weight gain, or the interaction b

Authors
Raphael J Landovit, Sahar Z Zangeneh, Gordon Chau, Beatriz Grinsztejn, Joseph J Eron, Halima Dawood, Manya Magnus, Albert Y Liu, Ravindre Panchia, Mina C Hosseinipour, David A Margolis, Adeola Adeyeye, Marybeth McCauley, Myron S Cohen, Judith S Currier

Abstract 6
Weight gain is a known complication of HIV treatment. However, the specific risk factors and magnitude are not well understood, especially after the initial treatment period. The objectives of this study were (1) to describe the demographic, clinical, and treatment characteristics of treatment-experienced adults with virally-suppressed HIV that had ≥3% annual weight gain in recent years (2013 to 2018) and (2) to identify variables independently associated with such gain.
EMR and prescription data were collected for the most recent ART exceeding 1 year in length for 3,468 previously-treated adult patients with continued HIV suppression. Patients resided in 21 States + DC and were in care at 6 HIV treatment centers. Data inclusion required ≥1 BMI at ARV prescription and ≥1 BMI during treatment but after 365 days up to 730 days. The resultant observation window was Aug 2013 to Aug 2018 and represented 5,459 patient years. Bivariate comparisons were made using chi-square or Fisher’s tests followed by independent variable assessment via logistic regression (LR).
Among the 3,468 adults, annualized weight gain was ≥3% for 1,045 (30%). Compared to those with Weight gain in the treatment-experienced population with continued HIV suppression was primarily associated with lower BMI, reduced proportion of hypogonadism, increased proportion of psychiatric disorders, and non-PI-containing regimens. The association between InSTI-based ART and weight gain, which reached significance in bivariate analyses, did not remain significant in LR, suggesting that in this population, weight changes are primarily driven by other factors.

Authors
Grace A McComsey, Joseph J Eron, Steven Santiago, Karam Mounzer, Graeme Moyle, Thanes Vanig, Paul E Sax, Keri N Althoff, Scott Milligan, Michael Marks, Richard Haubrich, Richard A Elion

Abstract 7
INSTI-associated weight gain has been described among ART-naïve persons initiating INSTI-containing ART, but not among virally suppressed (VS) persons whose first INSTI exposure is via a switch regimen. We evaluated changes in weight (CW) among such persons in the HIV Outpatient Study (HOPS).
We analyzed medical record data of patients from nine United States HIV clinics who were INSTI-naive and VS for >1 year on non-INSTI-based ART, and switched to INSTI-based ART and remained VS. Participants received INSTI-based ART for >6 months, had >2 weights recorded in the year prior to switch and >1 after. We evaluated CW over time, overall and stratified by demographics, pre-switch body mass index (BMI) and ART use, CD4 at ART start, and INSTI received. We used multivariable random regression mixed model to estimate factors associated with CW.
Among 437 patients (median age 51 years, interquartile range 44.5, 57.5), 86 (19.6%) were women, 107 (24.5%) were non-Hispanic Black (NHB). Pre-INSTI regimens often included an NNRTI (193 [44.1%]) or PI (185 [42.0%]) with >1 NRTI (402 [91.5%]). INSTI regimens included raltegravir (236 [54.0%]), elvitegravir (89 [20.4%]), or dolutegravir (112 [25.6%]). Mean CW in the year prior to INSTI was -0.2 kg (95% confidence interval [CI]: -0.6, 0.2). Mean duration of INSTI use was 2.9 years (max=9.7 years). Mean CW on INSTI was 1.2 kg (CI 0.6, 1.9), did not differ by INSTI drug used (p>0.2) and was greater for persons with pre-INSTI BMI 30 (0.4 kg, CI -1.7, 2.6), p=0.03; NHB than Non-Hispanic whites, 2.7 kg (CI 1.3, 4.1) vs 1.0 kg (CI 0.2, 1.7), p=0.02; and persons whose pre-INSTI ART did not include an NRTI vs those whose did, 4.5 kg (CI 1.8, 7.3) vs. 0.9 kg (CI 0.3, 1.6), pWe observed weight gain among VS persons who switched to INSTI-based ART that was associated with NHB race, no pre-INSTI NRTI use, and lower pre-INSTI BMI .These findings of differential risk for INSTI-related weight gain require further evaluation.

Authors
Frank J Palella, Nabil Rayeed, Jun Li, Douglas Ward, Jack Fuhrer, Stacey Purinton, Ellen Tedaldi, Richard Novak, Kate Buchacz

 

Aidsmap material
CROI 2019 abstract 1
CROI 2019 abstract 2
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