The MAVMET study, the first randomized controlled trial of maraviroc (Selzentry) with or without metformin, failed to reduce liver fat in people living with HIV and nonalcoholic fatty liver disease compared with placebo — and in some cases, prolonged use actually increased liver fat.
And that means clinicians like Yvonne Gilleece, MB BCh, who was not involved in the study but does run a liver clinic in England for people living with HIV, is returning to the one intervention proven to work. “As yet, the only thing that is proven to have a very positive effect that is published is weight loss,” said Gilleece, who runs the clinic at Brighton and Sussex University Hospital in Brighton. “You don’t put someone on these particular drugs, particularly this combination, easily. MAVMET has really demonstrated that actually it’s not effective and it’s not particularly beneficial to patients.”
The MAVMET trial data was presented at the 18th European AIDS Conference,
There was good reason to think maraviroc might work. A 2018 study in Hepatology found that one of maraviroc’s molecular cousins, cenicriviroc, significantly reduced fibrosis in people with NAFLD. Gilleece is co-investigator of another study of maraviroc in NAFLD, the HEPMARC trial, which is wrapping up now. In addition to those studies, there are other potential treatments in ongoing trials, including semaglutide, which is being studied in the US under the study name SLIM LIVER.
MAVMET enrolled 90 people living with HIV from six clinical sites in London who were at 35 or older and who had at least one marker for NAFLD, such as abnormal liver lab results. But 70% qualified via imaging- and/or biopsy-confirmed NAFLD. Almost all participants (93%) were men and 81% were White. The trial excluded people who were pregnant or breastfeeding. The median age was 52, and the participants met the criteria for overweight but not obesity, with a median BMI of 28.
In other words, participants generally had fatty livers without the inflammation that characterizes the more aggressive nonalcoholic steatohepatitis (NASH). Clinicians can’t yet differentiate between those who will continue to have asymptomatic fatty liver and those who will progress to NASH and potentially need a liver transplant.
All people living with HIV in the trial had undetectable viral loads and were on HIV treatment. Nearly 1 in 5 (19%) were using a treatment regimen containing tenofovir alafenamide (TAF), which has been associated with weight gain. Nearly half were on integrase strand inhibitors.
Investigators divided the participants up into four groups: 24 people stayed on their HIV treatment and added nothing else; 23 people took maraviroc only; 21 took metformin only; and the final group took both maraviroc and metformin. Across groups, liver fat at baseline was 8.9%, and 78% had mild hepatic steatosis.
After taking the medications for 48 weeks, participants returned to clinic to be scanned via MRI proton density fat fraction (MRI-PDFF), which has been found to successfully measure liver fat. However, because of the COVID-19 pandemic, 20 of the 83 people who returned to the clinic came later than 48 weeks after the trial began.
When investigators looked at the results, they didn’t see what they hypothesized, said Sarah Pett, professor of infectious diseases at University College, London: The scatter plot graph of change in weight looked, well, scattershot: People who didn’t take any additional treatment sometimes lost more liver fat than those on treatment. In fact, the mean liver fat percentage rose by 2.2% in the maraviroc group, 1.3% in the metformin group, and 0.8% in the combination group. The control group saw an increase of 1.4% — meaning that there was no difference between the change in fat between those on treatment and those not.
What’s more, those who had delayed scans — and stayed on their treatment for a median of an additional 16 weeks — saw their liver fat increase even more.
In an interview with Medscape Medical News, Pett called the results “disappointing.” “The numbers are quite small, but we still didn’t expect this,” she said. “It’s not explained by lockdown weight gain, although we still have to look in detail at how alcohol consumption could have contributed.”
There were also some limits to what the design of this particular trial could tell the researchers. For instance, nearly half of the participants in the maraviroc group, a third of the people in the metformin group, and 36% of those in the combination group had hepatic steatosis grades of 0, meaning that their livers were healthy. And MRI-PDFF becomes less reliable at that level.
“One of the regrets is that perhaps we should have done FibroScan [ultrasound], as well,” Pett said. The consequence is that the study may have undercounted the fat level by using MRI-PFDD.
“This suggests that the surrogate markers of NAFLD used in MAVMET were not very sensitive to those with a higher percentage of fat,” Pett said during her presentation. “We were really trying to be pragmatic and not require an MRI at screening.”
Whatever the case, she said that the failure of this particular treatment just highlights the growing need to look more seriously, and more collaboratively, at fat and liver health in people living with HIV.
“We need to really focus on setting up large cohorts of people living with HIV to look in a rigorous way at weight gain, changes in waist circumference, ectopic fat, capture fatty liver disease index scores, and cardiovascular risk, to acquire some longitudinal data,” she said. “And [we need to] join with our fellow researchers in overweight and obesity medicine and hepatology to make sure that people living with HIV are included in new treatments for NASH, as several large RCTs have excluded [people living with HIV].”
From Gilleece’s perspective, it also just speaks to how far the field has to go in identifying those with asymptomatic fatty livers from those who will progress to fibrosis and potentially need liver transplants.
“MAVMET shows the difficulty in managing NAFLD,” she said. “It seems quite an innocuous disease, because for the majority of people it’s not going to cause a problem in their lifetime. But the reality is, for some it will, and we don’t really know how to treat it.”
Gilleece has disclosed no relevant financial relationships. Pett reported receiving funding for trials from Gilead Sciences and Janssen-Cilag. ViiV Healthcare funded the MAVMET trial.
18th European AIDS Conference: Best Poster BPD3/4. Presented October 29, 2021.
Heather Boerner is a science journalist based in Pittsburgh, Pennsylvania. Her book, Positively Negative: Love, Pregnancy, and Science’s Surprising Victory Over HIV, came out in 2014.