Folinic Acid: Supplementation and Therapy
Condition: HIV Infection; HCV Coinfection
MeSH terms: Coinfection
Study type: Interventional
Phase: Phase 3

Summary: 
      Patients infected by HIV or HIV-HCV coinfected have higher survival due to the use of HAART,
      but survival is accompanied by increased morbidity and associated cardiovascular disease
      (CVD). Endothelial dysfunction is an early marker of atherogenesis, acting as an intermediate
      in the causal pathway of CVD. Folinic acid (FA) has been shown to reduce CVD outcomes,
      especially among individuals with hyperhomocisteinemia.

      To date, few studies provided consistent information about efficacy of pharmacological
      interventions that minimize damage to the vascular endothelium in patients infected by HIV or
      HIV-HCV coinfected. The main hypothesis of this study is that FA supplementation protects the
      vascular endothelium, and consequently might prevent subclinical atherosclerosis. Thus, the
      first step is to determine the efficacy of supplementation with FA, and to compare the effect
      between HIV and HIV-HCV coinfected.
    

Detailed description: 
      Study design: This was a randomized placebo-controlled trial, with blinding of health care
      team, participants, and investigators, in which the participants were randomly assigned in a
      1:1 ratio to receive FA or placebo for four weeks.

      Participants: Patients receiving care for HIV, at the outpatient clinic of the Hospital
      Universitario de Santa Maria, in southern Brazil, from October 2012 to September 2013, were
      recruited. Eligible participants: HIV infected or HIV-HCV coinfected patients, 18-50 years,
      men and women, receiving HAART, had undetectable viral load for more than six months.
      Patients were excluded: patients with diabetes mellitus, previous acute myocardial
      infarction, myocardial revascularization, or stroke, creatinine >1.5 mg/dL, clinical
      diagnosis or ultrasound, endoscopic, or laboratory evidence of liver cirrhosis, on treatment
      with statins, fibrates, hormone replacement therapy, sulfonamides, vitamin supplements, or FA
      in the last 30 days, and pregnant women.

      Intervention Patients assigned to the intervention group received FA 5 mg, per oral, once a
      day, in the morning, during four weeks. Patients assigned to the placebo group received the
      same prescription. The trial provided FA and placebo in tablet form, identical in color,
      smell, taste, shape, and size. Both FA and placebo were prepared in a single batch, in an
      independent laboratory, by a pharmacist with no involvement in the trial. They were
      pre-packed in bottles containing 30 tablets each, individually labeled with an alphanumeric
      code and stored.

      Outcomes The primary endpoint were changes in homocysteine, vitamin B12 levels, and brachial
      artery FMD during reactive hyperemia, as measured by Doppler ultrasound, from randomization
      to the end of follow-up. FMD was characterized by the variation in mean arterial flow
      measured as the peak change in vessel diameters relative to the baseline.

      Sample size Sample size was calculated based on the results of a previous RCT,(14) which used
      plethysmography to measure FMD. To detect a difference of at least 6% between intervention
      and placebo groups, with standard deviations ranging from 5% to 7%, we calculated that a
      sample size of at least 17 patients per group, with randomization stratified by HCV
      coinfection status, was required to achieve 80% power and a 95% confidence interval.
    

Intervention name(s): Folinic Acid; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Folinic acid 5 mg, taking in the morning, daily, during four weeks; Placebo capsule received 1 tablet, taking in the morning, during four weeks
Other intervention name(s): FA; Control
Intervention MeSH terms: Leucovorin; Folic Acid; Levoleucovorin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Prevention