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Weight Gain and Metabolic Complications with ART: Data from AIDS 2020

Over the past few years, numerous studies have examined weight gain in people with HIV who start or change antiretroviral therapy (ART). While it is clear that some people gain excessive amounts of weight after starting (and sometimes upon changing) ART, the roles of specific antiretroviral (ARV) agents or classes are not entirely clear, nor the mechanisms responsible. Emerging data have been incomplete and contradictory, but concern has been particularly focused on the effects of integrase inhibitors (INSTIs) and of tenofovir alafenamide (TAF). At the 2020 International AIDS Conference (virtual) conference, several studies added to our growing knowledge of the effects of integrase inhibitors and TAF on weight gain and metabolic parameters. These include the following studies in initial and subsequent ART:

Initial Therapy: The ADVANCE Study

The primary results from the phase 3 ADVANCE study of three initial ART regimens in South Africa (n=1053), published in 2019, showed that the all of the regimens resulted in high (and not significantly different) rates of viral suppression at 48 weeks, but that the group that received dolutegravir (DTG) plus either TAF/emtricitabine (FTC) or tenofovir disoproxil fumarate (TDF)/FTC gained more weight than the group that received efavirenz (EFV)/TDF/FTC . Further, weight gain was greatest in the DTG + TAF/FTC group, and was especially pronounced in women.

At AIDS 2020 virtual, researchers presented 96-week results of the study. Rates of viral suppression continued to be similar in the three groups (79% in DTG + TAF/FTC vs 78% DTG + TDF/FTC vs 74% in EFV/TDF/FTC). In the few people who experienced virologic failure on DTG (28/702), there was no emergent integrase resistance (two people in the DTG + TDF/FTC study arm developed NRTI resistance). The groups treated with DTG, especially in combination with TAF, continued to have striking weight increases to week 96 (and to 144 weeks in patients who had reached that time point):

Table 1. Mean weight gain from baseline: Women

 

TAF/FTC+DTG

TDF/FTC+DTG

TDF/FTC/EFV

Week 48

6.4 kg

3.2 kg

1.7 kg

Week 96

8.2 kg

4.6 kg

3.2 kg

Week 144

12.3 kg

7.4 kg

5.5 kg

Table 2. Mean weight gain from baseline: Men

 

TAF/FTC+DTG

TDF/FTC+DTG

TDF/FTC/EFV

Week 48

4.7 kg

3.0 kg

0.5 kg

Week 96

5.2 kg

3.6 kg

1.4 kg

Week 144

7.2 kg

5.5 kg

2.6 kg

Dexa scans performed on a subset of participants showed that weight gain was mostly caused by increases in fat in the trunk and limbs, not by increases in lean body weight.

Additionally, by week 96, metabolic syndrome occurred in 8.4% of people on DTG + TAF/FTC compared with 5.9% of those on DTG + TDF/FTC, and 3.9% of those on EFV/TDF/FTC; emergent metabolic syndrome was more common in women than men.

Switch to TAF +/- INSTI-containing ART, OPERA Cohort

OPERA is a large longitudinal multisite cohort comprised of people with HIV in the United States and Puerto Rico, with data collected prospectively from electronic health records. An analysis presented at AIDS 2020 focused on weight changes in persons with viral suppression (VL <200 copies/mL) taking 3-drug TDF-containing ART regimens who switched from TDF to TAF while maintaining other ART components (n=5479). Another analysis evaluated those who switched both from TDF to TAF and from a nonnucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) anchor drug to an INSTI (n=1423). Approximately 80% of this study population were male, 40% were black, and 25% Hispanic. About 60% were on an INSTI at baseline, and 85% of these were on elvitegravir/cobicistat (EVG/c).

Researchers modeled weight changes and rates of weight change from 60 months before the change from TDF to TAF to up to 48 months after, adjusting for factors such as age, sex, race, body mass index, CD4 count, and presence of endocrine conditions. They found that weight increased modestly in the 60 months before the switch to TAF, jumped rapidly in the 9 months after the switch to TAF, and then leveled out. Weight gains in the 9 months after switch were greater in the group on INSTIs, followed by NNRTIs and boosted PIs: 

Table 3: Estimated mean weight gain with switch from TDF to TAF, continuing other ARVs, according to class of anchor drug

 

-60 months to start of TAF

0-9 months after switch

>= 9 months after switch

INSTI

0.42 kg/yr

2.64 kg/yr

0.29 kg/yr

NNRTI

0.66 kg/yr

2.25 kg/yr

0.20 kg/yr

PI (boosted)

0.31 kg/yr

1.98 kg/yr

-0.11 kg/yr

Of those who were on an INSTI at baseline and continued the same INSTI, persons on EVG/c or dolutegravir (DTG) gained more in the first 9 months after the change from TDF to TAF (2.51 kg and 2.38 kg respectively) than those on raltegravir (1.80 kg); no comparable data on bictegravir (BIC) were available.

In the group that switched from a NNRTI or PI to an INSTI at the time they also switched from TDF to TAF, 78% switched to EVG/c, 12% and 9% to DTG and BIC, respectively.

More weight gain occurred in the DTG and BIC groups in first 9 months than in EVG/c group (3.09 kg/year, 4.47 kg/year, and 2.55 kg/year), though the BIC group appeared to lose weight after 9 months.

Table 4: Estimated mean weight gain with switch from TDF to TAF and to INSTI from NNRTI or boosted PI, according to INSTI agent

 

-60 months to start of TAF and INSTI

0-9 months after switch

>= 9 months after switch

EVG/c

0.24 kg/yr

2.55 kg/yr

0.26 kg/yr

DTG

0.22 kg/yr

3.09 kg/yr

-0.23 kg/yr

BIC

0.01 kg/yr

4.47 kg/yr

-9.97 kg/yr

Switch to DTG/3TC from TAF-based ART, TANGO Study

TANGO is a randomized open-label study in which subjects with virologic suppression on 3- or 4-drug TAF-based ART either switched to the 2-drug regimen of DTG/lamivudine (3TC) (Dovato) (n = 369) or continued their baseline ART (n = 372). Previously published data showed no significant difference between the regimens in viral suppression at 48 weeks. This post hoc analysis looked at selected metabolic effects of switching from standard ART containing TAF to DTG/3TC. The study population was 90% male, 80% white, and the median age was 40; 78% were on an INSTI at baseline (66% were on EVG/c), and 74% were on a pharmacokinetic (PK) booster (in combination with EVG or a PI). Subjects had been on ART a median of 34 months, and on TAF for a median of 18 months. At baseline, the groups had roughly similar metabolic parameters.

Key findings of the study are that at week 48:

  • Weight changes were not significantly different in the two groups: +0.81 kg after switch to DTG/3TC vs +0.76 kg with continued TAF-based ART
  • Total and low-density lipoprotein (LDL) cholesterol, triglycerides, and total cholesterol (TC)/high-density lipoprotein (HDL) ratio values improved in the DTG/3TC group (-4.5%, -5.5%, -11.2%, -3.3% respectively), while they worsened in the comparator group (2.3%, 2.2%, 6.0%, 0.5%). These differences were statistically significant.
  • Fasting glucose and HbA1c were not significantly different in the two groups, but fasting insulin was lower in the DTG/3TC switch group, as was the risk of insulin resistance (adjusted OR: 0.59; P = .008).
  • Metabolic syndrome: there was no significant difference in the proportions of subjects who developed metabolic syndrome

Improvements in lipid parameters and in insulin resistance were greater in subjects that switched from TAF-containing boosted regimens (EVG/c or boosted PIs) to DTG/3TC.

Clinical bottom line

These data, from both naive and switch studies, reinforce and extend concerns about the possible adverse effects of TAF and INSTIs on weight and metabolic outcomes. Many questions require further study including risk factors for development of these effects, causative mechanisms, relative contributions of ARV components (e.g., specific INSTIs) or combinations of agents (e.g., PK-boosted ARVs with TAF), and whether the changes can be reversed, e.g. by switching off problematic ARVs.

Meanwhile, based on efficacy and tolerability, INSTIs and TAF remain recommended components of initial therapy in the guidelines of the U.S. Department of Health and Human Services and the International Antiviral Society-USA (IAS-USA).

References

  • Venter F, Moorhouse M, Sokhela S, et al. The ADVANCE trial: Phase 3, randomised comparison of TAF/FTC+DTG, TDF/FTC+DTG or TDF/FTC/EFV for first-line treatment of HIV-1 infection. AIDS 2020: 23rd International AIDS Conference Virtual. July 6-10, 2020. Abstract OAXLB0104.
  • Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. N Engl J Med. 2019;381:803-815. doi: 10.1056/NEJMoa1902824
  • Mallon P, Brunet L, Hsu R, et al. Weight gain before and after switch from TDF to TAF. AIDS 2020: 23rd International AIDS Conference Virtual. July 6-10, 2020. Abstract OAB0604.
  • van Wyk J, Ajana F, Bisshop F, et al. Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose Two-Drug Regimen Versus Continuing a Tenofovir Alafenamide-Based Three- or Four-Drug Regimen for Maintenance of Virologic Suppression in Adults With HIV-1: Phase 3, Randomized, Non-inferiority TANGO Study [published online ahead of print, 2020 Jan 6]. Clin Infect Dis. 2020;ciz1243. doi:10.1093/cid/ciz1243
  • van Wyk J, Ait-Khaled M, Santos J, et al. Improved metabolic parameters after switching from TAF-based 3- or 4-drug regimen to the 2-drug regimen of DTG/3TC (dolutegravir/lamivudine): The TANGO study. AIDS 2020: 23rd International AIDS Conference Virtual. July 6-10, 2020. Abstract OAB0606.