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Blockbuster obesity drug leads to better health in people with HIV

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Light micrograph of white adipose tissue, or fat, stained with haematoxylin and eosin.

Long-term use of antiretroviral drugs can cause abnormal fat accumulation in people with HIV.Credit: Jose Calvo/SPL

People with HIV are the latest group to benefit from the new generation of anti-obesity drugs. If early data about the treatments’ effects are confirmed, the drugs could become key to controlling the metabolic problems often caused by anti-HIV medications.

Studies presented last week at the Conference on Retroviruses and Opportunistic Infections in Denver, Colorado, suggest that the anti-obesity drug semaglutide not only helps people with HIV to lose weight but also reduces certain conditions associated with fat accumulation that are especially common in people infected with the virus.

The number of people who are overweight or have obesity is increasing among those with HIV, driving interest among both affected individuals and medical providers in medications such as semaglutide, says Daniel Lee, a physician at the University of California San Diego Medical Center. At his clinic, which treats people with metabolic complications of HIV therapies, around 20% of patients already receive semaglutide or other drugs of the same class.

“For the most part, we’ve had very good experiences with these medications,” Lee says. But, so far, few studies have looked at the effect of the blockbuster anti-obesity drugs on people with HIV.

Unwanted side effects

Although the increasing incidence of obesity in people with HIV is similar to the trend in the general population, certain antiretroviral medications used to suppress HIV could contribute further to weight gain and weight-related conditions in these individuals1,2.

Semaglutide, marketed as Wegovy for obesity and Ozempic for diabetes, mimics a hormone called glucagon-like peptide 1, which helps to lower blood sugar levels and control appetite. In people who are overweight or have obesity, the drug promotes substantial weight loss3.

In a talk on 4 March, researchers at the Centers for AIDS Research Network of Integrated Clinical Systems, a group of HIV clinics across the United States, described their analysis of semaglutide use by 222 individuals receiving HIV care. The drug was associated with an average weight loss of 6.5 kilograms in around one year, or 5.7% of initial body weight.

Helping a fatty liver

Antiretroviral therapies have also been associated with abnormal fat accumulation. One condition affecting 30–40% of people with HIV is metabolic dysfunction-associated steatotic liver disease, which is characterized by the build-up of fat in the liver. As the condition progresses, it can result in liver failure and cardiovascular disease. “We do know that people with HIV have a more aggressive form of fatty liver disease,” says Jordan Lake, an infectious-disease physician at the University of Texas Health Science Center at Houston. But there is currently no approved medication to treat the condition.

She and her colleagues evaluated the use of a weekly injection of semaglutide for around six months in people with both HIV and metabolic dysfunction-associated steatotic liver disease. The results, presented on 5 March, demonstrated that 29% of participants had a complete resolution of the liver disease. “What we saw were really great clinically significant reductions in liver fat even over that short period of time,” Lake said at the conference.

But data from the same study show that participants taking semaglutide lost muscle volume, an effect also observed in other people taking the drug. Individuals who were 60 years of age or older were affected the most. Lee notes that older individuals with HIV are especially vulnerable to semaglutide-linked muscle loss and should be followed closely by health-care providers.

Taming inflammation

Another talk at the conference examined the use of semaglutide for a condition called lipohypertrophy in people with HIV. Characterized by the accumulation of abdominal fat, it “is associated with increased inflammation and carries an increased cardiometabolic risk”, says Allison Eckard, an infectious-disease paediatrician at the Medical University of South Carolina in Charleston. “We have currently few treatments and those treatments often show ineffective response rates.”

In an earlier clinical trial, Eckard and her colleagues scanned the bodies of people with HIV and lipohypertrophy and found that semaglutide helped to reduce abdominal fat. They had presented results from that study in October at IDWeek, a meeting of infectious-disease specialists and epidemiologists in Boston, Massachusetts. And at the conference in Denver, the team showed that a blood marker of inflammation called C-reactive protein fell by almost 40% in study participants who took semaglutide compared with those who did not.

That could be an important effect, because even well-controlled HIV leads to a chronic state of inflammation, Lee says. And, he says, “if there’s increased inflammation, it can lead to end-organ disease of all sorts, including certainly cardiovascular outcomes, but also liver, kidney, brain, cognitive function, you name it”.

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Children surpass a year of HIV remission after treatment pause

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Four children have remained free of detectable HIV for more than one year after their antiretroviral therapy (ART) was paused to see if they could achieve HIV remission, according to a presentation today at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) in Denver. The children, who acquired HIV before birth, were enrolled in a clinical trial funded by the National Institutes of Health in which an ART regimen was started within 48 hours of birth and then closely monitored for drug safety and HIV viral suppression. The outcomes reported today follow planned ART interruptions once the children met predefined virological and immunological criteria.

“These findings are clear evidence that very early treatment enables unique features of the neonatal immune system to limit HIV reservoir development, which increases the prospect of HIV remission,” said NIAID Director Jeanne Marrazzo, M.D., M.P.H. “The promising signals from this study are a beacon for future HIV remission science and underscore the indispensable roles of the global network of clinicians and study staff who implement pediatric HIV research with the utmost care.”

Advances in ART have significantly reduced perinatal HIV transmission, when a child acquires HIV while in the uterus, during birth, or through consumption of milk from a lactating person. If transmission does occur, children must take lifelong ART to control replication of the virus and protect their immune systems from life-threatening complications. Typically, interruption in treatment will lead to rapid resumption of HIV replication and detectable virus in the blood within weeks. However, in 2013, a case report described an infant born with HIV in Mississippi who initiated treatment at 30 hours of life, was taken off their ART at 18 months of age and remained in remission with no evidence of detectable HIV for 27 months.

Building on the observation that very early ART initiation may limit HIV’s ability to establish reservoirs of dormant virus in infants researchers began an early-stage proof-of-concept study of very early ART in infants conducted in Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, the United States, Zambia, and Zimbabwe. Previous publications from the clinical study showed that ART initiated within hours of birth was safe and effective at achieving and maintaining HIV suppression. A small subset of children achieved sustained HIV suppression and met other predefined study criteria for interrupting ART. These criteria include a durable absence of HIV replication from 48 weeks of ART initiation onward, no detectable antibodies near the time of ART interruption, and having a CD4+ T-cell count (the main immune cell target of HIV) similar to those of a child without HIV. Children who met these criteria, were older than 2 years and had stopped consuming human milk were eligible to interrupt ART.

Data presented at CROI summarized the experience of six children, all aged 5 years, who were eligible for ART interruption with close health and safety monitoring. Four of the six children experienced HIV remission, defined as the absence of replicating virus for at least 48 weeks off ART. One of them experienced remission for 80 weeks, but then their HIV rebounded to detectable levels. Three others have been and remain in remission for 48, 52 and 64 weeks, respectively. However, two children did not experience remission, and their HIV became detectable within three and eight weeks after ART interruption, respectively. The two children whose HIV returned at eight and 80 weeks experienced mild acute retroviral syndrome (ARS) with symptoms including headache, fever, rash, swollen lymph nodes, tonsillitis, diarrhea, nausea and vomiting. One child had markedly low white blood cells, which are a type of immune cell. Both the ARS and white blood deficiency resolved either prior to or soon after restarting ART. The three children who experienced viral rebound resumed HIV suppression within six, eight and 20 weeks of restarting ART.

“This is the first study to rigorously replicate and expand upon the outcomes observed in the Mississippi case report,” said lead study virologist Deborah Persaud, M.D., professor of pediatrics at the Johns Hopkins University School of Medicine, and director of the Division of Pediatric Infectious Diseases at Johns Hopkins Children’s Center, Baltimore. “These results are groundbreaking for HIV remission and cure research, and they also point to the necessity of immediate neonatal testing and treatment initiation in health care settings for all infants potentially exposed to HIV in utero.”

The latest findings show that very early ART initiation has varying but favorable outcomes on control of HIV. While ARS was generally mild and resolved in both cases, the authors cautioned that close monitoring for this potential event is needed in ongoing and future HIV remission research involving ART interruption. The children participating in this study took ART regimens with medicines that have been part of standard first-line therapy for decades. Further research is planned or underway to understand how these observations could differ in children receiving newer, more potent generations of antiretroviral drugs, and to identify biomarkers to predict the likelihood of HIV remission or rebound following ART interruption. Additional studies are also needed to understand the mechanisms by which neonatal immunity and very early ART initiation limited the formation of HIV reservoirs and contributed to the remission observed in this study.

“ART shifted the HIV care paradigm, but treatment is a long road, especially for children as lifetime HIV survivors” said Adeodata Kekitiinwa, MBChB, MMed, emeritus clinical associate professor in the Department of Pediatrics at Baylor College of Medicine, study investigator of record and clinical research site leader in Kampala, Uganda. “This trial takes us a step closer to realizing another paradigm shift in which our approach to ART could be so effective that it might be used for a season of life, rather than its entirety.”

This ongoing research is being conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network, which is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH).

The research was led by study co-chairs Ellen Chadwick, M.D., professor of pediatrics at Northwestern University Feinberg School of Medicine, and Yvonne Bryson, M.D., professor of pediatrics at the David Geffen School of Medicine and Mattel Children’s Hospital at UCLA, and director of the Los Angeles Brazil AIDS Consortium. Dr. Kekitiinwa, Boniface Njau, M.S., study coordinator at Kilimanjaro Christian Medical Centre in Tanzania and Teacler Nematadzira, MBChB, site investigator at the University of Zimbabwe-University of California San Francisco Collaborative Research Program continue to lead the study teams overseeing care of children who experienced HIV remission. Jennifer Jao, M.D., M.P.H., professor of pediatrics at Northwestern University Feinberg School of Medicine has since assumed a study co-chair role with Dr. Chadwick. The full IMPAACT P1115 study team consists of hundreds of staff across 30 NIAID- and NICHD-supported sites in the 11 study countries.

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