Maraviroc and metformin fail to control NAFLD in people living with HIV

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 to 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 runs a liver clinic in England for people living with HIV, are coming back to the only intervention that has been proven to work. “So far the only thing proven to have a very positive effect is weight loss,” said Gilleece, who heads the clinic at Brighton and Sussex University Hospital in Brighton. drugs, especially this combination, easily. MAVMET has really shown that in reality it is not effective and it is not particularly beneficial for patients.

Data from the MAVMET trial were presented at the 18th European AIDS Conference,

There was good reason to believe that maraviroc might work. A 2018 study in Hepatology found that one of the molecular cousins ​​of maraviroc, cenicriviroc, significantly reduced fibrosis in people with NAFLD. Gilleece is a co-investigator of another study of maraviroc in NAFLD, the HEPMARC trial, which is now ending. In addition to these studies, there are other potential treatments in ongoing trials, including semaglutide, which is being investigated in the United States as the SLIM LIVER study.

MAVMET recruited 90 people living with HIV from six clinical sites in London who were 35 years of age or older and had at least one marker of NAFLD, such as abnormal laboratory results of the liver. But 70% qualified via NAFLD confirmed by imaging and / or biopsy. Almost all of the participants (93%) were male and 81% were Caucasian. The trial excluded people who are pregnant or breastfeeding. The median age was 52 and participants met criteria for overweight but not obesity, with a median BMI of 28.

In other words, participants generally had fatty liver disease without the inflammation that characterizes the more aggressive non-alcoholic steatohepatitis (NASH). Clinicians cannot yet tell the difference between those who will continue to have asymptomatic fatty liver disease and those who will progress to NASH and potentially need a liver transplant.

All of the people living with HIV in the trial had undetectable viral loads and were on HIV treatment. Almost 1 in 5 people (19%) were using a regimen containing tenofovir alafenamide (TAF), which has been associated with weight gain. Almost half were on integrase strand inhibitors.

The investigators divided the participants into four groups: 24 people remained on anti-HIV treatment and did not add anything else; 23 people took only maraviroc; 21 took only metformin; and the last group took both maraviroc and metformin. In all groups, baseline liver fat was 8.9% and 78% had mild fatty liver disease.

After taking the drugs for 48 weeks, participants returned to the clinic to be scanned via Proton Density Fat Fraction MRI (MRI-PDFF), which was found to successfully measure liver fat. . However, due to the COVID-19 pandemic, 20 of the 83 people who returned to the clinic arrived more than 48 weeks after the start of the trial.

When investigators looked at the results, they didn’t see what they assumed, said Sarah Pett, professor of infectious diseases at University College London: any additional treatment sometimes lost more liver fat than those under processing. In fact, the mean percentage of hepatic fat increased by 2.2% in the maraviroc group, by 1.3% in the metformin group and by 0.8% in the combination group. The control group saw a 1.4% increase, meaning there was no difference in the change in fat between people on treatment and those who were not.

Additionally, those who delayed scans – and continued 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 pretty low, but we still weren’t expecting this,” she said. “This is not explained by the containment weight gain, although we still have to examine in detail how alcohol consumption may have contributed to it.”

There were also some limitations to what the design of this particular trial could tell researchers. For example, almost half of the participants in the maraviroc group, one-third of the people in the metformin group, and 36% of those in the combined group had degrees of fatty liver disease of 0, which means their liver was healthy. And the IRM-PDFF becomes less reliable at this level.

“One of the regrets is that maybe we should have done FibroScan [ultrasound], as well, “Pett said. The implication is that the study may have underestimated the fat level using MRI-PFDD.

“This suggests that the surrogate markers for NAFLD used in MAVMET were not very sensitive to those with a higher fat percentage,” Pett said during his presentation. “We were really trying to be pragmatic and not need an MRI when screening.”

Either way, she said the failure of this particular treatment only underscores the growing need to take a more serious and collaborative look at fat and liver health in people living with HIV.

“We really need to focus on building large cohorts of people living with HIV to rigorously examine weight gain, waistline changes, ectopic fat, capture hepatic steatosis index scores and cardiovascular risk, to acquire longitudinal data, “she said. “And [we need to] Join our fellow researchers in the medicine and hepatology of overweight and obesity to ensure people living with HIV are included in new treatments for NASH, as several large RCTs have ruled out [people living with HIV]. “

From Gilleece’s perspective, this also indicates how far the field needs to go to identify people with asymptomatic fatty liver disease from those who will progress to fibrosis and potentially need a liver transplant.

“MAVMET shows the difficulty of managing NAFLD,” she said. “It sounds like a pretty harmless disease, because for the majority of people it won’t be a problem in their lifetime. But the reality is that for some it will, and we don’t really know how to treat it. . “

Gilleece did not disclose any relevant financial relationship. Pett said he received funding for trials from Gilead Sciences and Janssen-Cilag. ViiV Healthcare funded the MAVMET trial.

18th European AIDS Conference: Best BPD3 / 4 Poster. 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, was released in 2014.

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