Clinicians face new challenge in HIV: Obesity

Studies have shown associations between ART and fat gain in patients living with HIV, and experts are suggesting options that range from preventive care to medical treatment to keep patients’ weight under control and avoid obesity.

ART has greatly increased the lifespan of patients with the virus, and now the negative health consequences of excessive fat gain that plague the general population have been added to the list of comorbidities that patients with HIV face.

Photo by Geri Davis, UAB

“It is ironic for those who have been in the field a long time, who were used to seeing the wasted AIDS patients who typified our clinical population, that now obesity is such a prevalent concern in HIV patients,” David B. Clifford, MD, a Melba and Forest Seay professor of neuropharmacology at Washington University in St. Louis, told Infectious Disease News.

Clifford said unhealthy fat gain in patients with HIV is a problem that deserves attention.

“The risks of secondary morbidity driven by excess fat are, if anything, increased in the HIV population and thus of great importance,” he explained. “Indeed, as we look for ways we can help improve the health and prognosis of our patients already benefiting from highly effective HIV therapies, this area is ripe for improved care and management.”

Infectious Disease News spoke with leading experts about the growing problem of obesity in patients with HIV and the different approaches to maintaining healthy weights in this patient population.

An ‘underestimated’ problem

In a consensus paper published in Clinical Infectious Diseases in February, researchers assessed the associations between ART and unhealthy fat gain.

“I think ART–associated obesity is probably underestimated,” Jordan E. Lake, MD, an infectious diseases and internal medicine specialist at McGovern Medical School in Houston and a co-author of the consensus article, told Infectious Disease News. “We have made efforts to combat the perception that obesity is not an issue at all in HIV infection.”

Researchers have found that non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and integrase strand transfer inhibitors (INSTI) are generally associated with fat gain, Lake and colleagues wrote in the consensus paper. However, they have not assessed the effects of the newer INSTIs like Vitekta (elvitegravir, Gilead Sciences) and Tivicay (dolutegravir, ViiV Healthcare).

“Similarly, randomized switch studies have not shown a benefit of switching from a PI,” the authors wrote.

Body of evidence

In a meta-analysis of 60 studies on ART and fat gain, researchers found associations between ART and increases in four fat-related factors. The meta-analysis, published in 2016 in AIDS Reviews, included data from 53,199 patients with HIV.

The researchers found that ART was associated with increases in BMI (standard mean deviation [SMD], 0.17 kg/m2; 95% CI, 0.07-0.26), waist circumference (SMD, 0.20 cm; 95% CI, 0.07-0.33), overweight/obesity (borderline significance, OR = 1.36; 95% CI, 0.99-1.86) and abdominal obesity (OR = 1.49; 95% CI, 1.16-1.90).

ART was also associated with what the researchers called “significant increases” in BMI, overweight/obesity and abdominal obesity among patients with a CD4 cell count of less than 350 cells/mm3 compared with those with a higher CD4 cell count.

In a study published in AIDS Research and Human Retroviruses, researchers assessed ART effects on 14,084 patients with HIV who started treatment between 1998 and 2010. They found that, of those patients who had a normal BMI at the start of ART, 20% were overweight after 1 year. Similarly, 15% of those who had been overweight at the start of treatment were obese after 1 year. After 3 years on ART, 22% of HIV patients who had a normal BMI at the start of treatment were overweight, and 18% of those who had been overweight at the start of treatment were obese.

In a study published in Clinical Infectious Diseases involving 328 patients, researchers tested the effects of three ART regimens. Patients were randomly assigned to receive tenofovir–emtricitabine plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r) or raltegravir (RAL) for 96 weeks. At week 96 of therapy, the overall mean increase in trunk fat was 18%. The increases were 14% in patients on ATV/r, 20.8% for those on DRV/r and 19.4% for those on RAL (P < .001). All three study arms also experienced similar increases in visceral adipose tissue (VAT). The overall mean increase in VAT was 25.8%. The changes were 21.9% in patients receiving ATV/r, 26.5% for RAL and 29% for DRV/r (P < .001).

Lake said ART initially helps patients gain a healthy amount of weight.

“There is obviously the concept of the return-to-health phenomenon, where once a person is not in a catabolic state from having uncontrolled HIV replication in their blood, they do not need as many calories and so they are able to gain weight just because they do not have virus essentially burning calories for them,” she said.

But, she added, weight gain for patients on ART often can go beyond what is healthy.

“I think we definitely see many patients go way past return to health and into BMI categories in which we become worried about their metabolic health, diabetes risk and heart disease risk.”

Lake said she would not yet single out certain ART regimens as being more likely than others to cause unhealthy weight gain. She did suggest developing ART drugs that do not negatively impact patients’ weight.

“I think we need to continue efforts to optimize ART and come up with newer agents,” she said. “If we can figure out the mechanism of how exactly some of the ART agents contribute to the metabolic abnormalities, we could have rational drug design in the future.”

Taking on the obesity trend

In their consensus paper, Lake and colleagues outlined possible approaches to maintaining healthy weights in patients with HIV. The options for confronting excess weight gain in patients undergoing ART vary, they said. They began with nonmedical approaches.

“Body weight and BMI should be tracked at least yearly, and weight gain addressed, as prevention and early intervention are likely more effective than reversing fat accumulation,” they wrote.

Because lower muscle mass can decrease total BMI, they recommended measuring waist circumference (WC) yearly. According to the International Diabetes Foundation, WC cutoffs for increased metabolic risk are 94 cm for men and 80 cm for women.

“However, the WC cutoffs for metabolic risk and elevated VAT have not been validated in HIV–infected populations,” they wrote.

Other recommendations by Lake and colleagues included measuring fasting lipids and glucose yearly and within 3 months of an ART regimen change, as well as blood pressure and glycemic control and smoking cessation, among others.

Measures preventing unhealthy fat gain and obesity are as important for patients undergoing ART as they are for those not infected with HIV, Kristine M. Erlandson, MD, one of the consensus article’s authors and an assistant professor of medicine and infectious diseases at the University of Colorado Anschutz Medical Campus told Infectious Disease News.

“Establishing a healthy lifestyle even prior to ART initiation is important, with regular physical activity and plenty of vegetables and fruits, lean proteins and limited or no sweets, saturated fats or alcohol — these are recommendations that we can make to all patients, with or without HIV,” she said.

There is not a standout plan for patients on ART that has been widely validated, Erlandson explained.

“We can extrapolate on nutrition and exercise guidelines from the obesity guidelines, as there are limited data to support a specific diet or exercise strategy that may be unique for HIV–infected patients,” she said. “Adjuvant behavioral interventions may improve the long-term durability of dietary and exercise changes.”

The consensus paper authors suggested that medical treatment is possible for patients without isolated central lipohypertrophy and with comorbidity and a BMI of at least 27 kg/m2, or those without comorbidity and a BMI greater than 30 kg/m2. Behavioral changes like diet and exercise would accompany medication.

The authors listed the five medications and combinations approved in the United States to treat obesity in the general population — orlistat; Qsymia (phentermine/topiramate, Vivus), Belviq (lorcaserin, Eisai), Contrave (naltrexone/bupropion, Orexigen) and liraglutide. They noted, however, that none has proven to be a first-line therapy.

Clinicians can also turn to medications for patients with diabetes. Options include glucagon-like peptide-1 receptor agonists, which are used to treat type 2 diabetes.

For patients with cardiovascular disease or uncontrolled hypertension, sympathomimetics — drugs that promote activation of the body’s sympathetic nervous system — should not be considered an option, the authors wrote.

Egrifta (tesamorelin, Theratechnologies) is the only drug approved in certain countries for treatment of excess VAT in HIV patients, they added. Tesamorelin can reduce VAT by about 15% within 6 months in male patients with a waist circumference of at least 95 cm and female patients with at least 94 cm, the authors said. However, VAT returns to its initial level, on average, 6 months after discontinuation of the drug.

Although medications can help, researchers must learn more about their effects, Amanda L. Willig, PhD, RD, assistant professor in the division of infectious diseases at the University of Alabama at Birmingham School of Medicine, told Infectious Disease News.

“If someone is dealing with strong food cravings or a heavy appetite, some medications can reduce these cravings when used with a lifestyle, including nutrition and an exercise program,” she said. “Drugs like lorcaserin and liraglutide can help with fat loss without interacting with antiretroviral drugs, but weight loss medications can cause side effects such as dry mouth, nausea or stomach problems ... We need more studies to learn which weight loss medications are the safest and most effective for people with HIV.”

Willig was similarly cautious about surgery options.

“There is very limited research on bariatric surgery outcomes with HIV, but more surgeons are willing to provide this service for people with HIV,” she said.

She noted that patients who undergo bariatric surgery would need guidance from dietitians for months before and after the procedure and take lifelong supplements.

Certain weight management strategies have proven to be effective for patients on ART, Willig said.

“Aerobic and strength training are both helpful, and high-intensity interval training is shown to be effective for overall health in those with HIV,” she explained.

However, researchers have more to learn about a comprehensive approach, she added.

“We know exercise works for people with HIV to prevent weight gain,” Willig said. “We know far less about which nutrition strategies are best to lose or maintain weight when you have HIV ... The Mediterranean diet has been studied the most in HIV and may work for weight control, and the dietary approaches to stop hypertension (DASH) diet can help with weight control and blood pressure control. Both of these programs are higher in fiber with lots of vegetables and fruit.”

A multidisciplinary approach

Lake said managing fat levels in ART patients should be a multidisciplinary effort.

“I know there are some providers who only treat HIV and only prescribe ART and send the patients back to their primary care doctors for management of all other disease states, and if that is the way a patient is receiving care, if there is not close communication between the primary care provider and the HIV care provider, it is harder to keep an eye on things,” she said.

Civil authorities can help make coordinated care easier as well by eliminating red tape, according to Ann C. Collier, MD, professor of medicine and director of the AIDS Clinical Trials Unit at the University of Washington School of Medicine’s Harborview Medical Center.

“Some states have laws that allow sharing of medical information between medical organizations and medical care providers taking care of the same patient without having a specific consent form between the two [parties],” she said. “In Washington, some of the larger medical care providers that have electronic medical record systems are part of a system called Care Everywhere, which allows providers to access information from another organization about a specific person if they have authorization to access the person’s records electronically at their institution.”

That is not what Collier called “wholesale access to records,” and there are restrictions, she said. Regardless of who is retrieving records, however, coordination is central to the care of patients with HIV and others.

“When multiple physicians are involved with the care of the same patient, coordination is always needed, regardless of what medical conditions a person has,” Collier said. “Generally, other health care professionals — including dietitians, nutritionists, physical therapists and diabetic educators — work in conjunction with physicians, so the situation with diet and exercise in persons living with HIV is not different from that in patients with many other conditions,” she said.

Weight management in patients with HIV can include nonmedical caregivers like trainers and exercise counselors, who can handle facets of care that physicians cannot, Collier explained.

“Physicians tend to defer to these other experts, since we often don’t have as much time with patients as would be ideal to counsel them about all issues in-depth,” she said. “This way, we can stick to the management of issues where we will be most likely to optimize a patient’s health. We may introduce the idea that other issues are important but that they will be managed by someone other than us.”

The breadth of treatment options offered by an institution can make a difference as well.

“Because I practice in a setting that has many more resources than some community settings — we have dietitians, diabetic educators, etc. — often I may end up orchestrating services that the patient’s primary care provider can’t readily access for their patients,” Collier said.

The complexity of obesity-related problems is another factor that makes teamwork among specialists so important, Willig said.

“Obesity that causes other health problems is a disease,” she said, “and weight management is much more complex than people want to believe. If it was easy, no one would have a problem with it.”

Willig offered advice to anyone with HIV who is trying to reach a healthy weight.

“It is very important to work with your physician and registered dietitian-nutritionist on a plan that you can follow for years, not just for weeks,” she said. “You will be more successful if a plan for weight loss and maintenance is tailored to your needs and considers your ART regimen.” – by Joe Green

• References:
• Koethe JR, et al. AIDS Res Hum Retroviruses. 2016;doi:10.1089/aid.2015.0147.
• Lake JE, et al. Clin Infect Dis. 2017;doi:10.1093/cid/cix178.
• McComsey GA, et al. Clin Infect Dis. 2016;doi:10.1093/cid/ciw017.
• Nduka CU, et al. AIDS Rev. 2016;18:198-211.

• For more information:
• David B. Clifford, MD, can be reached at the Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110; email: clifforddb@wustl.edu.
• Ann C. Collier, MD, can be reached at the University of Washington School of Medicine’s Harborview Medical Center, 325 Ninth Ave., Seattle, WA 98104; email: acollier@u.washington.edu.
• Kristine M. Erlandson, MD, can be reached at the University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave, Autota, CO 80045; email: Kristine.Erlandson@ucdenver.edu.
• Jordan E. Lake, MD, can be reached at the McGovern Medical School, 6411 Fannin St., Houston, TX 77030; email: Jordan.E.Lake@uth.tmc.edu.
• Amanda L. Willig, PhD, RD, can be reached at the University of Alabama at Birmingham, 1720 2nd Ave. South, Birmingham, AL 35294; email: awillig@uabmc.edu.

Disclosures: Clifford and Willig report no relevant financial disclosures. Collier reports serving on a data safety-monitoring board for Merck-sponsored studies and previously receiving research funding, through her institution, from Roche Molecular Systems, Merck and Bristol-Myers Squibb. Erlandson reports receiving research funding to her institution from Gilead Sciences and serving as a consultant to Theratechnologies. Lake reports receiving research funding through her institution from Gilead Sciences and serving as a consultant to Gilead and GlaxoSmithKline. Willig reports no relevant financial disclosures.