CROI 2024: HIV studies with semaglutide: significant benefits but limited access for treatment and research
10 March 2024. Related: Conference reports, Lipodystrophy and metabolic complications, CROI 2024 Denver.
Simon Collins, HIV i-Base
CROI 2024 included three studies about the GLP-1 receptor agonist semaglutide that was approved in 2017 in the US as a treatment for diabetes, and in 2021 using higher doses as a treatment for weight loss.
The new reports, presented in a poster discussion session, are important because HIV was an exclusion criteria in registrational studies and the manufacturer Novo Nordisk has still not supported any independent studies in people living with HIV.
Despite this optimistically titled session on semaglutide, much of the discussion included the very limited access for either treatment or for research. The drug is so popular that the demand exceeds supply.
Introduction and overview
The introduction to the session by Todd Brown from Johns Hopkins University, Baltimore, included the background to the development of GLP-1 agonists, their mechanisms of action in multiple body sites and reviewed other compounds in this class. [1]
The mechanisms include that GLP-1 receptors in the brain affect appetite and the desire for food, and receptors in the gut delay gut clearance and improve nutrient absorption in the stomach. These drugs regulate functions in the heart and the vascular endothelium, they regulate fat metabolism in brown fat, and regulate pathways of inflammation in T-cells and monocytes.
Early GLP-1 agonists exenatide and liraglutide decreased HbA1c by about 1%, similar to metformin, but with weight loss of approximately 2.5 kg. Dulaglutide and semaglutide approximately doubled this effect with reductions in HbA1c of –1.8% and –2.1% respectively and weight loss of –4.6 and –6.4 kg at the highest doses. Importantly, post-marketing safety studies also showed a reduction in cardiovascular events, increased with semaglutide with 26% reductions.
Tirzepatide, developed by Eli Lilly, was approved in 2022 for diabetes and in 2023 for weight loss. It reduced median HbA1c by –2.3% at the highest (15 mg dose), significantly greater compared to semaglutide at 1 mg dose (p<0.001); with median weight loss of –12.5 kg at 40 weeks – approximately double that with semaglutide 1 mg. Liraglutide is also approved in the US for weight loss (–8 kg with highest 3 mg dose).
Clinical studies also report a percentage of people who are non-responders, defined as less than 5% weight loss in 13%, 12.5% and 46% of participants using semaglutide, tirzepatide and liraglutide, respectively. The reasons for this are not currently understood.
Potential side effects are mainly dose-related nausea and diarrhoea leading to 5-10% of discontinuations, and rare reports of gastroparesis and bowel obstruction. They also include muscle loss and systemic fat loss that can worsen facial lipoatrophy. A signal for severe depression and suicide ideation, independently associated with significant weight loss, was recently refuted. Further research is needed on the increased risk of medullary thyroid cancer reported in rats but not so far in humans.
Semaglutide is now first-line treatment for diabetes in the US, displacing metformin, at least for people able to both access and afford it. In 2023, US guidelines recommended GLP-1 agonists as first-line diabetes treatment in people with any significant cardiovascular risk and in 2024 this was expanded to first-line treatment for everyone. Metformin decreases HbA1c by about 1% and is still widely used because of the lower price and easier access.
Weight loss in people living with HIV
Heidi Crane from the University of Washington, Seattle, presented a retrospective analysis of weight loss after a year in 222 people from 10 clinics across the US who used semaglutide between 2018 and 2022 as part of their clinical care. [2]
Baseline characteristics included 75% male and mean age was 53 years (SD +/– 10). Mean BMI was 35.5 kg/m2, average weight was 108 kg (SD +/– 23), mean HbA1c was 7.7% and 77% had clinical diabetes. Nearly all (97%) were on ART and 89% had undetectable viral load <50 copies/mL. The majority of this cohort (70%, n=87) used low doses (0.25, 0.5 and 1 mg) and 19% (n=24) used higher doses (1.7, 2, and 2.4 mg).
Over one year, in adjusted analyses, overall median weight and percentage losses were 6.5 kg (95% CI: –7.7 to –5.2) and 5.7% (–6.9 to –4.6), respectively. Higher BMI at baseline was associated with greater weight loss, see Table 1.
Table 1: Weight loss at one year by baseline BMI
| BMI (kg/m2) | Median weight loss (kg) (95%: CI) | p |
| 18-5 to 24.1 | –4.1 (–7.9 to –0.2) | 0.04 |
| 25 to 29.9 | −4.6 (−6.9 to −2.3) | < 0.001 |
| 30 to 34.9 | −5.4 (−7.3 to −3.4) | < 0.001 |
| 35 to 39.9 | −7.6 (−9.5 to −5.7) | < 0.001 |
| >40 | −8.8 (−10.9 to −6.7) | < 0.001 |
Weight losses were significantly higher for people with higher BMI at baseline.
Although higher doses were associated with greater weight loss, the study was too small to be powered to adjust for the confounding where diabetes is expected to reduce the effect on weight loss, but will also be associated with using a lower dose.
Impact of semaglutide on inflammation and lipohypertrophy
The second presentation was a double-blind study that randomised 108 non-diabetic participants with HIV-associated lipohypertrophy to either semaglutide (1.0 mg SC) or matching placebo.
Fat accumulation is a metabolic complication first reported during the first years of HIV combination therapies from about 1997 onwards, especially associated with early NRTIs and protease inhibitors, although the aetiology was never explained. The results were presented by Allison Ross Eckard from Medical University of South Carolina. [3]
Behavioural and lifestyle factors were assessed for four weeks before dosing. There was then a titration phase using 0.25 mg for weeks 1 to 4 and 0.5 mg for weeks 5 to 8. The full 24-week study with the 1.0 mg dose ran from weeks 9 to 32. The primary endpoint was changes by week 32 in markers of inflammation and immune activation that are associated with cardiovascular disease.
Baseline demographics included 70% male, 61% Black and 83% were on integrase inhibitor-based ART. Median duration of ART was approximately 12 years (range: 8 to 19 years) and BMI was 33 kg/m2 (range: 28 to 39).
At week 32, significant changes from baseline [geometric mean (+/– SD) within the semaglutide group were reported for IL-6, hsCRP and sCD163, with perhaps a trend for sCD14, see Table 2.
Table 2: Changes in biomarkers on semaglutide (geometric mean +/–SD)
| Biomarker | Baseline | Week 32 | p-value |
| IL-6 (pg/mL) | 2.51 (2.05) | 2.13 (1.85) | 0.016 |
| hsCRP (μg/mL) | 2.98 (2.69) | 1.83 (2.96) | 0.008 |
| sCD163 (μg/mL) | 583 (1.48) | 511 (1.54) | 0.005 |
| sCD14 (μg/mL) | 1694 (1.3) | 1575 (1.28) | 0.085 |
No significant changes were observed for soluble intercellular adhesion molecule-1 (sICAM-1) or TNF-receptor-I/-II or for any markers in the placebo group.
Weight loss reductions in this study were presented at IDWeek 2023. with reported reductions of –8.3% of body weight with semaglutide vs +0.2% with placebo. Approximately 63% of participants achieved >5% reduction in body weight. Total fat and total lean mass reduced by 15% and 5.4%, respectively. [4]
Reductions in both muscle fat and lean muscle
The third presentation looked at semaglutide-related changes in muscle structure in the SLIM Liver study (ACTG A5371), with results presented by Grace Ditzenberger from the University of Colorado. [5]
Although GLP-1 agonists can lead to significant overall weight loss, this can include both fat and lean muscle loss. This was an open-label study in 51 people suppressed on ART, who had metabolic-associated steatotic liver disease (MASLD, previously called NAFLD [non-alcoholic]).
Baseline characteristics included a mean age of 50 (SD: +/–11) years and BMI of 35.5 (SD: +/– 5.6) kg/m2, with 43% women, 33% Black, and 39% Hispanic/Latino.
The primary endpoint of this substudy was changes in the psoas muscle (surrounding the spine and linking to the upper pelvis) which decreased by 9.3% (95% CI: –13.4 to –5.2; p<0.001) with an overall mean weight loss of –7.8 kg (CI: –9.5 to –6.2) over 24 weeks.
Decreases in psoas volume were greatest among those >60 years old (–22.8% [CI: –32.4 to –13.3] vs –7.9% [CI: –12.3 to –3.4]) in 40-60 and –2.4% [CI: –11.9 to – 7.2] in <40). No sex differences were observed. Reductions correlated with decreases in intrahepatic triglycerides (IHTG), p=0.028; BMI: p=0.038; HbA1C: p=0.007, and fasting triglycerides: p=0.027. Indicators of frailty including chair rise time and gait speed modestly improved but this was not statistically significant.
Effect of semaglutide on liver fat
A separate oral presentation on the Slim Liver study also included impressive 24-week results on reducing liver fat (intrahepatic triglycerides). [5]
Semaglutide was well-tolerated, with only 2 possibly related Grade 3 (1 nausea, 1 serotonin syndrome) and no Grade 4 adverse events. Mean baseline (standard deviation) IHTG was 12.7% (6.1%).
Mean (95% CI) absolute and relative declines in IHTG were –4.2% (–5.4 to –3.1) and –31.3% (–39.0 to –23.6), respectively, both p<0.001. MASLD resolved in 29% of participants and 58% had a >30% relative reduction in IHTG. The study also reported significant improvements in weight, waist circumference, fasting glucose and triglyceride concentrations. Improvements in IHTG correlated with weight loss on semaglutide (r=0.54, p<0.0001).
comment
GLP-1 receptor agonists produce such remarkable clinical results that demand currently exceeds supply, including in the US and Europe. Notably, the manufacturer has not supported independent researchers who have asked the company to donate semaglutide.
Of note, the Medicines Patent Pool (MPP) includes GLP-1 agonists on their watch list for new drugs to prioritise. It will be essential for voluntary licensing to enable access in low- and middle-income countries using generic formulations. Nearly half a billion people currently live with diabetes and more than one billion people are living with obesity.
A recent paper in the journal Obesity reported that the price of a 30-day course of semaglutide ranges from $804 in the US to $95 in Turkey, while the estimated minimum price could be as low as $40. This would allow for costs of active pharmaceutical ingredients, excipients, formulation, taxation, and 10% profit margin. [7]
An editorial in SAMJ notably highlighted obesity as a new epidemic in Southern Africa. [8]
Another paper in JAMA Open Network reported: GLP-1 drugs (e.g. Ozempic) are sold at a nearly 40,000% markup in the US, but unavailable in low- and middle-income countries; and treating diabetes using insulin pen devices could be 30% less expensive than using vials and syringes if priced lower. [9]
Apart from the studies above, the only ongoing HIV study listing on clinicaltrials.gov is the SWIFT study being run in Dublin and Liverpool. [10]
The multiple active sites of GLP-1 receptors also suggest other potential indications which currently have limited or no treatments. For example, four ongoing studies are investigating using semaglutide to overcome alcohol disorder.
Just as semaglutide seems to break the reward craving for food that is associated with weight gain, it has anecdotally had a similar impact on the desire and compulsion to drink alcohol.
The discussion at CROI 2024 included references to other addictive conditions including alcohol disorder which is the focus of ongoing studies, and the potential to reduce dependence on crystal meth which currently has no effective drugs to support withdrawal.
This suggests the importance of ongoing and future studies collecting information about behaviour changes to see whether a signal of such benefits supports specific studies.
Novo Nordisk has an estimated net worth of more than US $550 billion.
References
Unless stated otherwise, all references are to the Conference on Retroviruses and Opportunistic Infections, 3–6 March 2024 (CROI 2024), Denver, USA. Abstracts and posters are now available on the online abstract database:
https://www.croiconference.org/search-abstracts
Webcasts for all presentations are restricted to delegates until four weeks after the conference:
https://watch.croiwebcasts.org/croi2024/n/day/all
- Brown T. Is the weight over: GLP-1 receptor agonists are here. CROI 2024, Denver. Themed Discussion-02.
https://www.croiwebcasts.org/console/player/52113 (webcast) - Crane H M et al. Impact of semaglutide on weight change among people with HIV: A stratified analysis by baseline BMI. CROI 2024, Denver. Poster 797.
https://www.croiconference.org/abstract/impact-of-semaglutide-on-weight-change-among-people-with-hiv-a-stratified-analysis-by-baseline-bmi/ (abstract)
https://www.croiwebcasts.org//console/player/52114 (webcast) - McComsey GA et al. Effects of semaglutide on inflammation and immune activation in HIV-associated lipohypertrophy. CROI 2024, Denver. Poster 798.
https://www.croiconference.org/abstract/effects-of-semaglutide-on-inflammation-and-immune-activation-in-hiv-associated-lipohypertrophy/ (abstract)
https://www.croiwebcasts.org/console/player/52115 (webcast) - McComsey GA et al. Effects of semaglutide on inflammation and immune activation in HIV-associated lipohypertrophy. IDWeek 2023.
https://www.natap.org/2023/IDWeek/IDWeek_61.htm - Ditzenberger et al. Effects of semaglutide on muscle structure and function in the SLIM Liver study. CROI 2024, Denver. Poster 799.
https://www.croiconference.org/abstract/effects-of-semaglutide-on-muscle-structure-and-function-in-the-slim-liver-study/ (abstract)
https://www.croiwebcasts.org/console/player/52116 (webcast) - Lake J E et al. Semaglutide reduces metabolic-associated steatotic liver disease in people with HIV: the SLIM Liver study (ACTG A5371). CROI 2023, Denver. Oral abstract O159.
https://www.croiconference.org/abstract/effects-of-semaglutide-on-muscle-structure-and-function-in-the-slim-liver-study/ (abstract)
https://www.croiwebcasts.org/console/player/52201 (webcast) - Levi J et al. Estimated minimum prices and lowest available national prices for antiobesity medications: Improving affordability and access to treatment. Obesity (Silver Spring). 2023 May;31(5):1270-1279. doi: 10.1002/oby.23725. (23 Feb 2023).
https://pubmed.ncbi.nlm.nih.gov/36815242/ - Chandiwana N et al. Obesity is South Africa’s new HIV epidemic. SAMA Journals. DOI: 10.7196/SAMJ.2024.v114i4.1927 (March 2024).
- Barber MJ et al. Estimated sustainable cost-based prices for diabetes medicines. JAMA Netw Open. 2024;7(3):e243474. doi:10.1001/jamanetworkopen.2024.3474
- Semaglutide’s efficacy in achieving weight loss for those with HIV (SWIFT).
https://clinicaltrials.gov/study/NCT04174755