Canakinumab in HIV reduces inflammation
As mentioned earlier in this issue of TreatmentUpdate, chronic HIV infection is associated with inflammation. Initiating HIV treatment (ART) and achieving and maintaining an undetectable viral load helps to partially reduce but not eliminate excess inflammation. Researchers think that HIV-related inflammation may gradually increase the risk for health complications over the long-term.
In a pilot study, researchers in San Francisco tested a single injection of canakinumab 150 mg under the skin of HIV-positive people taking ART. They found that the drug significantly reduced inflammation and did not cause harm, at least in the short term. A larger and longer study of canakinumab in this population is now underway.
Researchers enrolled 10 participants (nine men, one woman) who were between 55 and 65 years old. The average profile of participants upon entering the study was as follows:
- current smoker – 20%
- higher-than-normal blood pressure – 90%
- abnormal cholesterol levels – 80%
- history of heart attack and/or stroke – 30%
- history of heart attack among parents or siblings – 40%
- taking medicines to lower cholesterol levels – 80%
- CD4+ count – 638 cells/mm3
- lowest-ever CD4+ count – 238 cells/mm3
- viral load – less than 50 copies/mL in all participants
- history of hepatitis C co-infection – 20%
All participants received a single subcutaneous injection of canakinumab 150 mg and subsequently underwent close clinical and laboratory monitoring.
The drug was well tolerated by participants.
Canakinumab caused a significant decrease in the levels of neutrophils (cells needed to fight infections) in the blood at two and three weeks after the injection. At those time points the decrease in neutrophil levels was 30%. However, four weeks after receiving the canakinumab injection, neutrophil levels began to enter the normal range.
One person developed shingles (herpes zoster) during the study. It is unclear if this was related to canakinumab, as there were no changes in CD4+ counts or HIV viral load prior to the episode of shingles. It subsequently resolved without complications.
Across all participants there were no significant changes in CD4+ counts and no change in CD4/CD8 ratio. During the first week of the study, CD8+ cell counts decreased by an average of 17% in participants but this resolved the following week.
Viral load did not rise above the 200-copy/mL mark in any participants during the study.
Changes in inflammation
Elevated levels of the chemical signals IL-6 (interleukin-6) and high-sensitivity C-reactive protein (hsCRP) are seen in inflammatory conditions such as HIV infection.
In the present study, a single dose of canakinumab gradually and significantly reduced IL-6 levels in the blood—by 24% at the fourth week of the study, and by a total of 30% by the eighth week of the study.
The drug also reduced hsCRP levels by 61% at the eighth week of the study.
No significant changes in the proportion of activated T cells in the blood were detected. However, there was a significant reduction in a subgroup of cells called monocytes. The specific subgroup of monocytes that were diminished were ones that displayed the HIV co-receptor CCR5 on their surface.
Participants underwent FDG PET/CT scans. In these scans, a small amount of radioactive sugar (FDG-glucose) is given to the person via intravenous infusion and researchers wait for some time (up to two hours) for this sugar to be taken up by active tissues. In this case, inflammation was taking place in the lymph nodes and arteries. The PET (positron emission tomography) scan detects the radioactive material and its location, while the CT (computer tomography) scan helps to form detailed images of the tissues being scanned. The researchers found that canakinumab caused a significant decrease in inflammation—10% in the arteries and 11% in the bone marrow—compared to pre-study levels.
A larger (100-person) and longer randomized, placebo-controlled study is underway with canakinumab in which two doses of the drug will be given to ART users. Participants are randomized in a 2:1 ratio, so about 67% will receive canakinumab. This study will provide more information about the short- and medium-term safety of canakinumab in HIV-positive people.
—Sean R. Hosein
- Hsue P, Deeks SG, Ishai AE, et al. IL-1β inhibition significantly reduces atherosclerotic inflammation in treated HIV in treated HIV. In: Program and abstracts of the Conference on Retroviruses and Opportunistic Infections, Seattle, Washington, 13-17 February 2016. Abstract 126.
- Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory therapy with canakinumab for atherosclerotic disease. New England Journal of Medicine. 2017 Sep 21;377(12):1119-1131.
- Ridker PM, MacFadyen JG, Everett BM, et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2017 Nov 13. pii: S0140-6736(17)32814-3.