After 24 weeks, no statistically significant differences in any AT parameter were observed between women switching to RAL versus continued PI or NNRTI, although a slight decrease in VAT (3.6%) was observed in the RAL group compared to a 1.9% increase in subjects continuing PI or NNRTI.
In the SPIRAL study, subjects on a suppressive, ritonavir-boosted, PI-based regimen were randomized to switch to RAL versus continued PI. After 48 weeks, PI-treated patients experienced significant increases in CT-quantified total abdominal and visceral AT, whereas RAL-treated subjects experienced no significant AT changes. Similar to our study, no statistically significant between-arm changes were observed.28
The 48-week follow-up of our participants will allow us to observe whether significant within-group AT changes will emerge in the immediate-switch group. While an observed benefit on VAT would be an important positive finding, failure to show a significant VAT improvement will also be important to our understanding of the possible contribution of ART classes to lipohypertrophy, and would be consistent with findings from the SPIRAL study.
Body image impact measures improved in subjects switched to RAL. While sample size limited our ability to detect between-group differences, within-group improvements in body image and body distress (with a focus on belly distress) were observed in the immediate- but not delayed-switch groups after 24 weeks. Importantly, changes in VAT volume correlated significantly with improvements in belly size and distress after controlling for baseline VAT and PRO scores, possibly suggesting the improvements observed in the RAL-treated group reflected an underlying change in clinical status rather than an unrelated subjective assessment.
In this study, statistically significant improvements in median total and LDL cholesterol were observed in subjects switching to RAL, with the effect size dominated by subjects switching from a PI to RAL. These results are in keeping with those observed in the SWITCHMRK and SPIRAL trials,23,29
although statistically significant improvements in triglyceride levels were not seen in our study. Importantly, more women in our study were on atazanavir (predominantly ritonavir-boosted) than PIs more commonly associated with lipid abnormalities (such as lopinavir/ritonavir), highlighting the potential benefit of switching to RAL from any PI.
Most importantly, switch to RAL was safe in this cohort of women, and was not associated with an increased risk of virologic failure or emergence of new adverse events. Although women at risk for underlying ART resistance were excluded from participation in this study, our findings reinforce the virologic safety of RAL in patients with minimal treatment experience.
Our study has several important limitations. First, the high prevalence of generalized obesity in this cohort (median BMI 32 kg/m2
) likely limited our ability to see the desired treatment effect, an improvement in HIV-related lipohypertrophy, and the study was not powered to observe smaller improvements in VAT in the number of women with BMI less than 30 (n
=14/37). This limitation is the result of having a minimum waist circumference and/or waist-to-hip ratio as an entry criterion (designed to target subjects with isolated abdominal adiposity) without defining a maximum BMI to prevent the inclusion of subjects with generalized obesity. The severity of obesity in our cohort is apparent in the baseline VAT:SAT ratio (immediate-switch group: mean 0.29±0.17, Delayed-switch group: mean 0.31±0.16, means and standard deviations provided for comparison with growth hormone releasing factor data), which differs drastically from that in the studies of growth hormone releasing factor (tesamorelin group: mean 1.27±1.61, placebo group: mean 1.18±1.58).26
Second, due to the small sample size and relatively short length of follow-up, targeting a 10% between-group difference in VAT over 24 weeks may have been overly ambitious. Accordingly, an overall between-group VAT difference of 5.4% was observed after 24 weeks, and it is possible that longer follow-up would have allowed for greater between-group differences to emerge. However, due to the delayed-start design of this study, no control group exists beyond 24 weeks, and 48-week follow-up will only allow for additional information on continued RAL in the immediate-switch group.
Third, this study was not designed to assess the potential contribution of NRTIs to lipohypertrophy, nor can we exclude the NRTI backbone as a confounding factor. Fourth, the PRO results observed in the immediate-switch group could have been influenced by the open label study design. We acknowledge that self-reported assessments are subject to bias, and while the validated Phase V Technologies PRO assessment tool is designed to minimize the introduction of biases, we cannot rule out this possibility. Similarly, we cannot rule a potential influence of the open-label design on patient behavior, as subjects did not keep diet and exercise diaries (although no significant change in weight or BMI was observed).
Finally, safety concerns following closure of the SWITCHMRK protocols obligated us to limit inclusion to women with the lowest risk of virologic failure following a switch to RAL. These restrictions may limit the generalizability of our results to the larger population of women on ART with lipohypertrophy, and may have excluded some women with lipohypertrophy secondary to prolonged antiretroviral exposure.
Switching to RAL was safe and well tolerated. No statistically significant improvement in VAT or other AT parameters was seen 24 weeks following a switch to RAL versus continued PI or NNRTI in virologically suppressed, HIV-infected women with lipohypertrophy. Significant improvements in total and LDL cholesterol were observed, mainly in subjects switching from a PI to RAL. The planned 48-week follow-up will help determine whether additional metabolic or AT changes can occur with continued RAL therapy in this group of HIV-infected women.