Raltegravir increases waist circumference more than boosted PIs: greater with use of later ART

1 October 2016. Related: Conference reports, Side effects, Lipodystrophy Workshop (IWADRH) 18 New York 2016.

Simon Collins, HIV i-Base

A large US ACTG study reported significantly different body changes with raltegravir compared to combinations using a boosted PI. [1]

While the results presented at the 18th International Workshop on Comorbidities and Adverse Drug Reactions in HIV were not associated with different clinical outcomes, this could reduce quality of life for people who are trying to reduce weight and conversely have advantages for people with low BMI who are looking to gain weight.

As all participants used the same background NRTIs and randomisation should have balanced lifestyle and environmental factors equally, this suggests the results might be real. The results are surprising given boosted PIs need to be taken with food and that raltegravir has a lipid neutral side effect profile.

ACTG A5257 randomised more than 1800 treatment-naive adults 1:1:1 to raltegravir, atazanavir/r or darunavir/r with 96-week follow-up, running from 2009 to 2013. All participants also used tenofovir-DF/emtricitabine. Results from the main study were presented at CROI 2014, and results from a DEXA substudy (ACTG 5260) that showed no difference in body composition changes between groups, published earlier this year. [2, 3]

This analysis reported change in waist circumference (WC) from baseline to week 96 using standardised measurements across study sites. Previous studies have supported a strong associated between changes in WC to increases in visceral adipose tissue (VAT) confirmed by DEXA results.

The study looked for predictors of weight gain that included demographics (race/ethnicity, sex and age) and baseline characteristics (BMI, CD4 and viral load) in three models that presented ITT analyses and also adjusted for potential confounding factors (smoking, drug use, income and health insurance status).

Baseline demographics include approximately 75% men; mean age 37; ethnicity: black 42%, white 34%, Hispanic 22%; median WC and BMI were 90 cm and 26 kg/m2 respectively.

Between week 0 and 96, WC increased by a mean of 3.4 cms (SD 8.1) in the study overall and showed steady increases in all three treatment arms: +4.0, +3.5 and +2.8 cm in the rategravir, atazanavir and darunavir arms respectively.

Results were different by sex and race with the much larger increases with raltegravir in black women. The mean increases in women were +5.9, +2.7 and +2.9 cm and in men were +3.7, +3.7 and 2.8 cm, in raltegravir, atazanavir and darunavir groups respectively. The results by race were +5.8, +4.0 and +2.3 for black participants compared to +3.7, +2.4 and +3.2 in non-black participants, again in raltegravir, atazanavir and darunavir groups respectively. These treatment effects continued after adjustment for lower CD4 and higher viral load at baseline which were both significantly associated with higher increases in WC (p<0.0001)

However, in the fully adjusted model which also corrected for multiple comparisons, only treatment group and baseline CD4 and viral load remained as predictors, with race and sex dropping out.

Comment

The results for raltegravir are surprising and difficult to understand given the DEXA substudy from the same study found no differences between treatment groups.

It would be interesting to know whether other analyses from the extensive ACTG research archive could see whether similar findings for raltegravir, integrase inhibitors or other individual drugs.

The overall association with lower baseline CD4 and higher viral load suggest that later use of ART is a higher risk for fat accumulation and that earlier use of ART might reduce incidence of fat accumulation.

References:

1. Bhagwat P et al. Raltegravir is associated with greater abdominal fat increases after antiretroviral therapy initiation compared to protease inhibitors. 18th International Workshop on Comorbidities and Adverse Drug Reactions in HIV, 12-13 September 2016, New York. Oral abstract O7.
2. Landovitz RJ et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. 21st CROI, 3-6 March 2014, Boston. Oral abstract 85.
   http://www.croiwebcasts.org/console/player/22165
   Also published in Ann. Intern. Med.. 2014;161(7):461-71. DOI 10.7326/M14-1084.
   http://annals.org/article.aspx?articleid=1911116
3. McComsey GA et al. Body Composition changes after initiation of raltegravir or protease inhibitors: ACTG A5260s. Clin Infect Dis (2016) 62(7): 853-62. (1 April 2016). DOI 10.1093/cid/ciw017. (20 January 2016).
   http://cid.oxfordjournals.org/content/62/7/853