CATIE News

• Metformin, a compound found in French lilac, has long been used to treat diabetes
• Canadian researchers studied the impact of metformin on people living with HIV
• The study found modest reductions in weight and indicators of reduced inflammation

The power of combination HIV treatment (ART) is so tremendous that scientists increasingly expect that many ART users will have near-normal life expectancy.

However, ART is only able to partially reverse some of the immunological injury arising from chronic HIV infection. That is, scientists have found that despite the use of ART, HIV-positive people have excess immunological activation and inflammation. The cause of these issues is uncertain but may be related to a number of factors, including the following:

• proteins produced by residual HIV-infected cells deep within lymph nodes, lymphoid organs and the brain may continue to stimulate and injure the immune system
• co-infection with a member of the herpes virus family—CMV (cytomegalovirus)
• injury to the gut occurs early in the course of HIV infection, and this injury does not heal and allows harmful bacteria to cross the intestines and gain entry to the blood; these unfriendly bacteria shift the overall profile of bacteria that live in the body to one that favours inflammation

The immune system

Cells of the immune system are widely distributed throughout different organs and tissues of the body where they patrol for the presence of germs and tumours. As these cells rove around the body, they release chemical signals that incite inflammation. Thus, it is plausible that an immune system that is experiencing excess activation and inflammation can pass on inflammation to vital organs and tissues such as the brain, bones, cardiovascular system, kidneys, lungs and so on. Elevated levels of chronic inflammation likely contribute to diseases that affect these organs and tissues, perhaps accelerating their aging.

Scientists are studying different interventions to try to thwart excess immunological activation and inflammation.

In Canada

A team of scientists in Montreal and Ottawa have been testing an old drug called metformin, which is normally used to help control blood sugar in people with diabetes. However, experiments in animals and HIV-negative people suggest that metformin has the potential to do much more. The scientists conducted a short pilot study of metformin in HIV-positive people who did not have diabetes and who were taking ART. They found that participants lost a modest amount of weight over the course of the study and the balance of bacteria in the gut shifted to one that was anti-inflammatory.

From French lilac to metformin

For several hundred years, doctors in Europe prescribed French lilac to help relieve the excessive urination that accompanies what is now called type 2 diabetes, though they did not know how the herb worked. Beginning in the late 19^th century, the drug metformin was synthesized several times, based on compounds in French lilac, but it was then abandoned and forgotten. In the 1950s it was rediscovered and subsequently shown to have potent effects in people with type 2 diabetes. Metformin seems to have anti-inflammatory activity in general, and in another pilot study it caused subtle improvements in the immune systems of HIV-positive people by decreasing excess activation.

Metformin is widely used today to help control type 2 diabetes in HIV-negative people and is generally safe and well tolerated at lower doses.

The Canadian study

Based on the potential effects of metformin, scientists in Montreal and Ottawa enrolled non-diabetic HIV-positive people to assess its ability to affect the immune system. All participants had low CD4/CD8 ratios, suggestive of a relatively weak immune system, and had been taking ART for several years with a suppressed viral load during that time. Metformin was taken orally at a dose of 800 mg twice daily. The dose was reduced to 500 mg twice daily in instances where participants were taking dolutegravir as part of ART, as there is an interaction between the two drugs.

Blood and stool samples were collected at the start of the study and at weeks 12 and 24. Participants took metformin for 12 weeks.

The average profile of participants was as follows:

• 21 men and 2 women
• age – 56 years
• ethno-racial groups: 15 were White and 8 were of African descent
• CD4+ count – 435 cells/mm³
• CD8+ count – 729 cells/mm³
• CD4/CD8 ratio – 0.6 (a normal ratio is 1.0 or greater)
• HIV viral load – less than 50 copies/mL

During the study none of the participants were treated with antibiotics or changed their HIV regimen.

Results

Metformin did not affect CD4+ or CD8+ cell counts or the CD4/CD8 ratio. All participants continued to have a suppressed viral load during the study.

Weight

On average, participants lost 1.6 kg during the time they took metformin. This weight loss occurred regardless of age, gender or the type of ART used. However, three months after discontinuing metformin, participants’ weight returned to its pre-metformin levels. Metformin did not cause a change in waist size or blood sugar.

Gut bugs

Metformin caused complex changes to the bacterial population in the gut. Overall, there was a shift in favour of bacteria that are anti-inflammatory.

Inflammation

One of the many proteins, or markers, in the blood used to assess inflammation is called sCD14 (soluble CD14). Levels of this protein rise during bacterial infections and inflammatory conditions. Levels of sCD14 are usually elevated in HIV infection despite the use of ART. During the study, levels of sCD14 fell modestly at first but then continued to fall after the cessation of metformin.

Possible explanations

The scientists are uncertain why people lost weight in this study. It is possible that the reduction in inflammation, perhaps brought about by a more favourable balance of bacteria, might be responsible. Another possibility is that metformin stimulated cells in the body to produce a protein called GDF-15 (growth differentiation factor-15). This protein has many functions, one of which is to regulate appetite.

Whatever the precise ways that metformin appeared to cause beneficial changes, it seems that this old drug has a future in HIV research. The findings from this pilot study should be viewed as preliminary and exploratory. A larger and longer study, ideally with a placebo, is needed to find out more about metformin’s long-term effects on the health of HIV-positive people who do not have diabetes. Such a future study should explore different doses of metformin, including lower ones. In the first two weeks of the present study, one person developed a cluster of symptoms that seemed like metformin-related side effects—stomach cramps, muscle aches and loose stools—and had to prematurely leave the study.

Bear in mind

In the past several years, reports have emerged of some HIV-positive people experiencing weight gain when they initiated ART that contained integrase inhibitors. It is possible that metformin could be tested in clinical trials for its ability to blunt unwanted increases in weight in this population. Clinical trials are necessary because although metformin has a long history of generally safe use (for the treatment of diabetes), its experimental use in HIV-positive people who do not have diabetes requires clinical and laboratory monitoring so that its potential for side effects is understood.

—Sean R. Hosein

Resources

Weight issues in HIV – TreatmentUpdate 235

REFERENCES:

1. Isnard S, Lin J, Fombuena B, et al. Repurposing metformin in non-diabetic people living with HIV: Influence on weight and gut microbiota. Open Forum Infectious Diseases. 2020; in press.
2. Witters LA. The blooming of the French lilac. Journal of Clinical Investigation. 2001;108(8):1105-1107.
3. Ouyang J, Lin J, Isnard S, et al. The bacterium Akkermansia muciniphila: A sentinel for gut permeability and its relevance to HIV-related inflammation. Frontiers in Immunology. 2020;11:645.
4. Depommier C, Everard A, Druart C, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nature Medicine. 2019;25(7):1096-1103.
5. Shikuma CM, Chew GM, Kohorn L, et al. Short Communication: Metformin reduces CD4 T cell exhaustion in HIV-infected adults on suppressive antiretroviral therapy. AIDS Research and Human Retroviruses. 2020;36(4):303-305.
6. Ouyang J, Isnard S, Lin J, et al. Daily variations of gut microbial translocation markers in ART-treated HIV-infected people. AIDS Research and Therapy. 2020;17(1):15.
7. Tsai VWW, Husaini Y, Sainsbury A, Brown DA, Breit SN. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: Implications for obesity, cachexia, and other associated diseases. Cell Metabolism. 2018;28(3):353-368.
8. Wada NI, Jacobson LP, Margolick JB, et al. The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation. AIDS. 2015;29(4):463-471.
9. Castillo-Mancilla JR, Brown TT, Palella FJ Jr, et al. Partial normalization of biomarkers of inflammation and immune activation among virally suppressed men with HIV infection and high ART adherence. Open Forum Infectious Diseases. 2020;7(4):ofaa099.
10. Gantner P, Pagliuzza A, Pardons M, et al. Single-cell TCR sequencing reveals phenotypically diverse clonally expanded cells harboring inducible HIV proviruses during ART. Nature Communications. 2020;11(1):4089.
11. Dufour C, Gantner P, Fromentin R, Chomont N. The multifaceted nature of HIV latency. Journal of Clinical Investigation. 2020;130(7):3381-3390.
12. Jiang, C., Lian, X., Gao, C. et al. Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Nature. 2020; in press.
13. Estes JD, Kityo C, Ssali F, et al. Defining total-body AIDS-virus burden with implications for curative strategies. Nature Medicine. 2017;23(11):1271-1276.
14. Rothenberger M, Nganou-Makamdop K, Kityo C, et al. Impact of Integrase Inhibition Compared With Nonnucleoside Inhibition on HIV Reservoirs in Lymphoid Tissues. Journal of Acquired Immune Deficiency Syndromes. 2019;81(3):355-360.
15. Lorenzo-Redondo R, Fryer HR, Bedford T, et al. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature. 2016;530(7588):51-56.
16. Chaillon A, Nakazawa M, Rawlings SA, et al. Subclinical CMV and EBV Shedding is associated with increasing HIV DNA Molecular Diversity in Peripheral Blood during Suppressive Antiretroviral Therapy. Journal of Virology. 2020; in press.
17. J Heath J, D Grant M. The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence. Cells. 2020;9(3):766.
18. Leng SX, Margolick JB. Aging, sex, inflammation, frailty, and CMV and HIV infections. Cellular Immunology. 2020;348:104024.
19. Ramendra R, Isnard S, Lin J, et al. CMV seropositivity is associated with increased microbial translocation in people living with HIV and uninfected controls. Clinical Infectious Diseases. 2020; in press.