Why are some people with HIV becoming heavier?

As reported earlier in this issue of TreatmentUpdate, initiating HIV treatment (ART) is generally associated with an increase in weight. We now explore possible reasons for this.

Some of the risk factors for weight gain prior to initiating ART that were reported earlier in this issue were immunological (having a low CD4+ count) or virological (having a high viral load). These findings, also reported in earlier studies, point to an additional benefit for starting HIV treatment long before immune deficiency has developed.

History

Looking back on the history of HIV treatment, most of the early pivotal clinical trials of ART have occurred in white men in high-income countries. Such studies did not generally have sufficient numbers of women and people of colour to make meaningful statistical comparisons of weight differences between genders or ethno-racial groups. Furthermore, most, if not all, of these studies were not primarily designed to assess changes in weight and body mass index (BMI) among regimens. In recent years, phase III clinical trials have included more women and people of colour.

The good news

It is important to note that most people who took ART in pivotal clinical trials did not become obese. However, the findings from recent studies of ART initiation that analysed weight suggest that both healthcare providers and patients need to become more vigilant about monitoring weight and need to intervene quickly when excess weight gain occurs.

Choosing regimens

In general, newer HIV treatment regimens are better tolerated and more effective than older regimens. Newer treatments, particularly integrase inhibitors, tend to have the fewest potential drug interactions. It is very unlikely that doctors and patients will return to using older regimens due to the issue of weight gain.

Not only are older drugs less powerful, they have distinct disadvantages. Long-term use of AZT has been associated with an increased risk for loss of muscle mass and abnormal changes in body shape (the lipodystrophy syndrome). Efavirenz is associated with an increased risk for neuro-psychiatric effects, including dizziness, depression and subtle paranoia in both the short- and long-term. This drug also is associated with an increased risk of thoughts of suicide and attempts at suicide. Despite these issues, some people who initiated efavirenz-based treatment years ago seem to tolerate it well.

Rather than avoid initiating treatment with integrase inhibitors (such as bictegravir, dolutegravir, elvitegravir and raltegravir) and nucleotide analogues such as TAF solely because of concerns about potential weight gain, it may be useful for healthcare providers and patients to check trends in weight prior to and after starting or switching regimens. It may also be useful for healthcare professionals to discuss with patients issues that have the potential to impact weight gain, such as the following:

Physical activity

Are people with HIV getting enough daily physical activity, including walking and climbing stairs? Can they begin a program of exercise? See this article in TreatmentUpdate 234 about different forms of physical activity: Exercise as medicine

Sleeping problems

Rest and sleep quality are sometimes overlooked aspects of health. A large observational study in HIV-negative people found that people who have sleeping problems tend to gain weight. Assessing sleep problems in patients who are unexpectedly gaining weight may be useful.

Emotional and mental health

Are there factors in a person’s life that can affect how they respond to stressful events? For instance, when stressed, some people eat more fat and carbohydrate-rich foods as a source of comfort. Repeated engagement in excessive intake of carbohydrates and fatty food can lead to weight gain over time. Depression can affect appetite—some people gain weight, others lose weight. Is a person who is gaining weight experiencing depression and/or anxiety?

Metabolic conditions, hormones and arthritis

Some conditions and life-stages are associated with weight gain, including the following:

• diabetes
• problems with the thyroid gland and its hormones
• women who are post-menopausal
• arthritis

Diet

Not everyone follows a diet that is informed by dietary guidelines. If subsidized access to dietary counselling is available (sometimes this is provided in large hospitals and clinics), consultation with a registered dietitian may prove fruitful. Registered dietitians can assess the quality and quantity of meals, and if necessary, provide helpful advice about making healthy changes.

Substance use

Alcohol contains calories. Is excess consumption of alcohol an issue? Excess consumption of alcoholic beverages could suggest unaddressed mental health and emotional issues.

Healthcare professionals, including pharmacists, can review the non-HIV medicines a patient is taking to assess their potential impact on weight.

Focus on HIV treatment in weight gain

How might ART play a role in excess weight gain in some people? At this time there are no definitive answers, though some scientists have theories that relate to the following issues/drugs:

Integrase inhibitors

One theory is that dolutegravir (and possibly bictegravir and other integrase inhibitors) interacts with a receptor called MC4R (melanocortin 4 receptor). This receptor is found on cells in the brain and plays a role in maintaining energy balance. MC4R can affect appetite and weight. It is possible that integrase inhibitors interact with MC4R in a way that leads to increased appetite and weight gain. However, research with HIV-positive people and MC4R has not been undertaken. It is likely that scientists would first conduct experiments with cells, HIV, integrase inhibitors and this hormone. If there is a signal that MC4R is affected by integrase inhibitors, then perhaps the next step might be experiments with monkeys infected with SIV (simian immunodeficiency virus). This virus causes an AIDS-like condition in susceptible monkeys and is closely related to HIV.

Setmelanotide

Studies with HIV-negative people have found that some experimental drugs that interfere with MC4R can result in reduced appetite and cause people to lose weight.

One candidate drug that interferes with MC4R is called setmelanotide. It has completed pivotal clinical trials in people with obesity linked to certain genes. In these trials, significant reductions in appetite and weight occurred. Preliminary results suggest that the drug is generally safe, though darkening of the skin and hair can occur. The FDA is currently reviewing an application for approval of setmelanotide by Rhythm Pharmaceuticals and hopefully will approve the drug in 2020. However, setmelanotide needs to be tested in general cases of excess weight and obesity. It has been granted orphan drug status by the FDA. The designation of orphan drug is given to medicines that are used for a relatively small market. Drugs that have this designation are usually very expensive, though at this time a price for setmelanotide has not been made publicly available.

Against the theory that integrase inhibitors interfering with MC4R is the sole cause of weight gain in HIV-positive people who use this class of drug are these observations:

• As mentioned earlier in this this issue of TreatmentUpdate, studies have found that some HIV-positive people appeared to be gaining weight even before they began to use ART.
• Increases in weight have been reported with different classes of ART, though the latest anti-HIV drugs, such as dolutegravir, bictegravir and TAF seem to have the greatest association.

Gut bugs

Scientists use the term microbiome to describe the collection of bacteria, fungi and viruses that live in the body. The intestines of HIV-positive people have been found to contain imbalances in the population of bacteria and fungi that naturally live there. Initiating ART and continuing to take it can only partially correct this imbalance, and clinical trials with supplements of friendly gut bacteria are underway. Such clinical trials could assess possible changes in weight as an outcome.

Inflammation

HIV infection is associated with excessive levels of inflammation and activation of the immune system. Initiating ART and achieving and maintaining an undetectable viral load helps to significantly reduce but not eliminate the excess inflammation and immune activation associated with HIV. Studies in HIV-negative people suggest that chronic inflammation can contribute to gaining excess weight. It is therefore possible that HIV-associated chronic inflammation and immune activation may contribute to excess weight in some people.

Other reasons

There may be other, as yet unknown reasons, that ART is associated with substantial weight gain in some people. One important point to bear in mind is that, in general, HIV-negative people are becoming heavier and the reasons for this are not clear. The factors driving weight gain in HIV-negative people are likely also affecting HIV-positive people. Some scientists think that these days people are generally eating more food, possibly more highly processed food, and, perhaps in some cases, getting less physical activity than they did decades ago. The study in Italy reported earlier in this issue of TreatmentUpdate found that nearly 50% of about 2,600 HIV-positive people were getting no or minimal levels of daily exercise. This shows that among some people a lack of physical activity is a major issue. Other scientists suspect that contaminants in the environment may contribute to the risk of gaining weight. Whatever the cause, much research on weight gain in general and in some ART users lies ahead. Such research will take time.

For the future

Medical doctor Sara Bares at the Nebraska Medical Center has reviewed the analysis of randomized clinical trials by Gilead Sciences. She raised the following questions that need to be answered in future research:

• “What do we do for patients who experience severe weight gain following ART initiation?”
• “How long does this weight gain persist?”
• “Will a switch to an alternative regimen reverse or attenuate some of this weight gain? If so, what regimen should they choose?”
• “Is an adjustment in both the backbone and anchor agent needed?” The term anchor agent refers to the most potent drug in a regimen. The nucleoside analogues (nukes) that usually accompany a regimen are referred to as the backbone by doctors and scientists.
• “Will adjustment in the route of administration alter the side effect profile (i.e. will long-acting injectable therapy be associated with similar amounts of weight gain)?”

These questions can help guide some future research on weight gain in HIV-positive people.

—Sean R. Hosein

REFERENCES:

1. Bares SH. Is modern antiretroviral therapy causing weight gain? Clinical Infectious Diseases. 2020; in press.
2. Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral therapy: Risk factors in randomized comparative clinical trials. Clinical Infectious Diseases. 2020; in press.
3. Kühnen P, Krude H, Biebermann H. Melanocortin-4 Receptor Signalling: Importance for weight regulation and obesity treatment. Trends in Molecular Medicine. 2019 Feb;25(2):136-148.
4. Hall KD, Ayuketah A, Brychta R, et al. Ultra-processed diets cause excess calorie intake and weight gain: An inpatient randomized controlled trial of ad libitum food intake. Cell Metabolism. 2019 Jul 2;30(1):67-77.e3.
5. Moubarac JC, Batal M, Louzada ML, et al. Consumption of ultra-processed foods predicts diet quality in Canada. Appetite. 2017 Jan 1;108:512-520.
6. Gimeno-Ferrer F, Albuquerque D, García Banacloy A, et al. Genetic screening for MC4R gene identifies three novel mutations associated with severe familiar obesity in a cohort of Spanish individuals. Gene. 2019 Jul 1;704:74-79.
7. Lucas N, Legrand R, Bôle-Feysot C, et al. Immunoglobulin G modulation of the melanocortin 4 receptor signaling in obesity and eating disorders. Translational Psychiatry. 2019 Feb 12;9(1):87
8. Clément K, Biebermann H, Farooqi IS, et al. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nature Medicine. 2018 May;24(5):551-555.
9. Kappel BA, Federici M. Gut microbiome and cardiometabolic risk. Reviews in Endocrine & Metabolic Disorders. 2020; in press.
10. Moyle G. Toxicity of antiretroviral nucleoside and nucleotide analogues: is mitochondrial toxicity the only mechanism? Drug Safety. 2000 Dec;23(6):467-481.
11. Moyle GJ, Sabin CA, Cartledge J, et al. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS. 2006 Oct 24;20(16):2043-2050.
12. Lapadula G, Bernasconi DP, Bai F, et al. Switching from efavirenz to rilpivirine improves sleep quality and self-perceived cognition but has no impact on neurocognitive performances. AIDS. 2020 Jan 1;34(1):53-61.
13. Fumaz CR, Muñoz-Moreno JA, Moltó J, et al. Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. Journal of Acquired Immune Deficiency Syndromes. 2005 Apr 15;38(5):560-565.
14. Arenas-Pinto A, Grund B, Sharma S, et al. Risk of suicidal behavior with use of efavirenz: Results from the Strategic Timing of Antiretroviral Treatment Trial. Clinical Infectious Diseases. 2018 Jul 18;67(3):420-429.
15. Mollan KR, Smurzynski M, Eron JJ, et al. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Annals of Internal Medicine. 2014 Jul 1;161(1):1-10.
16. Ma Q, Vaida F, Wong J, et al. Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. Journal of NeuroVirology. 2016 Apr;22(2):170-178.
17. Kapoor E, Collazo-Clavell ML, Faubion SS. Weight gain in women at midlife: A concise review of the pathophysiology and strategies for management. Mayo Clinic Proceedings. 2017 Oct;92(10):1552-1558.