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Benefits of low-dose methotrexate in HIV patients unclear
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In a phase 2 trial performed in older HIV-infected adults who have or are at an increased risk for atherosclerotic cardiovascular disease, low-dose methotrexate was associated with a significant decrease in CD8+ T cells in adults but had no effect on endothelial function or inflammatory biomarkers. Low doses of the treatment were also associated with more safety events compared with placebo, but the 15% noninferiority margin was not surpassed, researchers reported.
The results were published in Clinical Infectious Diseases and previously presented at CROI.
“People with HIV on antiretroviral therapy (ART) are at increased risk for atherosclerotic cardiovascular disease (ASCVD), possibly due to inflammation that persists despite virologic suppression,” Priscilla Y. Hsue, MD, professor in the department of medicine at the University of California, San Francisco, and colleagues wrote. “To determine if [low-dose methotrexate (LDMTX)] was safe, tolerable, and had the potential to reduce ASCVD risk in individuals with treated HIV, we performed a randomized, double-blind, placebo-controlled clinical trial.”
The phase 2, multicenter AIDS Clinical Trials Group Study A5314 enrolled 176 participants aged 40 years or older with suppressed or treated HIV from 22 clinical sites. Study participants either had or were at an increased risk for ASCVD and had CD4+ T-cell counts equal to or greater than 400 cells/mm3.
Participants were randomly assigned 1:1 to the LDMTX study arm or to receive placebo. At baseline, they were given 5 mg of LDMTX or placebo for 1 week. If it was well-tolerated, they received 10 mg a week until week 12. The dose was then increased to 15 mg until the conclusion of the study period at week 24. According to the study, participants in both groups received 1 mg of folic acid from baseline through 4 weeks after week 24. The primary end points were brachial artery flow-mediated dilation and safety, which included:
- Confirmed CD4+ T-cell decline;
- Virologic failure;
- New or recurrent CDC category C AIDS-indicator condition;
- HIV-associated infections, such as cytomegalovirus end-organ disease, varicella zoster or Epstein-Barr virus-related clinical disease;
- Confirmed grade 3 or higher toxicity;
- Lymphoproliferative malignancy; or
- Pulmonary toxicity
The study cohort was 90% male, median age was 54 years and 59% (n =103) reported statin use. At weeks 8, 12 and 24, Hsue and colleagues observed an association between LDMTX and decreases in CD8+ T cells. Additionally, at week 24, the study drug was associated with decreases in CD4+ T cells. In the LDMTX group, 12.8% (n = 11) experienced safety events, whereas safety events occurred in 5.6% (n = 5) of participants in the placebo group. Change in artery flow-mediated dilation at week 24 in the LDMTX and placebo study arms was 0.47% and 0.09%, respectively.
Hsue and colleagues reported that although LDMTX was reasonably well-tolerated, the primary and secondary efficacy measurements were unaffected. Furthermore, the LCMTX group had more safety events compared with the placebo group, but the researchers said that serious event rate differences between the study arms was within the 15% noninferiority margin.
“This is an important negative study in HIV and one of the largest clinical trials performed in older HIV-infected adults with or at risk for ASCVD,” the researchers wrote. “The balance of risks and potential benefits of LDMTX on ASCVD risk in the setting of treated and suppressed HIV infection remains unclear and will require additional investigation.” – by Marley Ghizzone
Disclosures: Hsue reports honoraria from Gilead and Merck, outside the submitted work. Please see the study for all other authors’ relevant financial information.
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