TreatmentUpdate
235

January 2020 

From wasting to obesity—the changing issue of weight in HIV

In the early 1980s, medical records indicated that a new syndrome had suddenly and simultaneously appeared mostly among gay and bisexual men in North America and Western Europe, and among heterosexual people in parts of Central and East Africa. In parts of East Africa, people coined the name “slim” or “slim disease” to describe the effect of the new syndrome. It was initially associated with severe and relentless weight loss, fever, persistent oral yeast infections and sometimes other low-level but persistent infections.

Eventually severe, life-threatening infections would develop. By 1983, scientists at the Pasteur Institute in Paris had isolated a virus, now called HIV, that would eventually be linked to the cause of the syndrome seen around the world in different populations. In the early years of the AIDS pandemic, the wasting associated with the syndrome could become life threatening.

Today, thanks to the widespread availability of HIV testing and treatment (ART) in Canada and other high-income countries, AIDS-related conditions, including wasting, are now rare compared to the time before ART was available.

In the 21st century, weight continues to be an issue among HIV-positive people in high-income countries but in a different way than it was in the 1980s and early 1990s. Today there are increasing concerns among doctors and scientists that more HIV-positive people are becoming overweight or obese.

It should be noted that compared to earlier decades, more HIV-negative people have become overweight or obese.

Carrying excess weight has long-term implications for HIV-negative people, including an increased risk for pre-diabetes and diabetes, abnormal cholesterol levels and higher-than-normal blood pressure—all of which add to the risk of heart attack and stroke.

The larger society

It is not clear why obesity is a growing problem among HIV-negative people than in the past. Scientists suspect that at least several factors may contribute to a risk for excessive weight including the following:

  • insufficient exercise
  • less access to healthy food and/or eating more processed food
  • eating large portions of food
  • taking certain prescribed medicines

It is plausible that there may also be environmental factors, such as chemical contaminants in food that may play a role in weight gain.

Back to HIV

When people with HIV initiate ART, over the course of the first year or two they usually experience an increase in weight. Weight gain, particularly in people who were thin or underweight, is normal and signals a return to health. However, when the increased weight contributes to being overweight or obese, this can pave the way for health problems.

Different treatments, different effects

Protease inhibitors

At the dawn of effective HIV treatment in 1996 and for many years after, regimens that came into use were anchored by a class of drugs called protease inhibitors. Over time, one protease inhibitor would be replaced by a more effective and sometimes better-tolerated protease inhibitor. However, between 1996 and 2006, most protease inhibitors tended to cause some degree of diarrhea or frequent bowel movements, particularly treatments such as nelfinavir (Viracept) and lopinavir-ritonavir (Kaletra). Although these drugs were associated with weight gain, reports of obesity were not common in the late 1990s or early 2000s among HIV-positive people.

Nucleosides

A group of older anti-HIV drugs called nucleoside analogues (commonly called “nukes”) was widely used before and immediately after 1996. These older drugs included the following:

  • d4T (stavudine, Zerit)
  • AZT (zidovudine, Retrovir)

Both of these drugs are called thymidine analogues. The use of d4T and to a lesser extent AZT was associated with strange changes in body shape, including the accumulation of fat in the belly. As a result, leading guidelines do not recommend that they be used today. Instead, commonly used nukes nowadays are as follows:

  • tenofovir DF + FTC (sold in a pill called Truvada and also available in generic formulations)
  • abacavir + 3TC (sold in a pill called Kivexa and also combined with another drug and sold in a pill called Triumeq)

These nukes are generally well tolerated and do not cause changes in body shape, though tenofovir DF (TDF) is associated with an increased risk for kidney injury and bone loss.  Abacavir is associated with an increased risk for heart attack among a minority of people in some studies. 3TC and FTC tend to be very well tolerated and are not by themselves associated with weight gain.

A newer formulation of tenofovir, called tenofovir alafenamide (TAF), is increasingly being used. This formulation of tenofovir is generally safer than the older one (TDF). A pill containing TAF + FTC is sold under the brand name Descovy. TAF is also co-formulated with other medicines in a single pill and sold under brand names such as Biktarvy, Genvoya and Odefsey. We will have more to say about TAF; in some studies it was associated with weight gain.

Non-nukes

Another group of drugs that were widely used starting in 2000 were non-nukes (NNRTIs), such as efavirenz (Sustiva and in Atripla) and nevirapine (Viramune). These drugs did not generally cause diarrhea but, especially in the case of efavirenz, could have a range of side effects on the brain and mood. They were generally not associated with reports of obesity, though efavirenz sometimes could cause abnormal cholesterol levels. The commonly used non-nuke rilpivirine (Edurant and in Complera and Odefsey) is discussed later in this issue of TreatmentUpdate.

Finally, there is a new non-nuke called doravirine (Pifeltro and in Delstrigo). Detailed data about its impact on weight will be released over the coming months. Preliminary analysis suggests that it has a modest impact on weight.

Both non-nukes and protease inhibitors have additional drawbacks—they can interact with other drugs that HIV-positive people need, either raising or lowering the levels of these drugs in the body. Some drug interactions with these classes of medicines can be dangerous. Modern non-nukes, such as rilpivirine and doravirine, are generally well tolerated, though they all carry the potential of drug interactions.

Integrase inhibitors

In 2007, the first integrase inhibitor, raltegravir (Isentress, twice daily) was introduced. In general, integrase inhibitors have few drug interactions and are well tolerated. Furthermore, integrase inhibitors are very powerful and when used as part of ART can usually quickly reduce the amount of HIV in the blood to very low levels commonly called “undetectable.” As a result, leading treatment guidelines in the U.S. and other high-income countries privilege the use of integrase inhibitors.

The leading integrase inhibitors are dolutegravir (in Dovato, Juluca, Tivicay and Triumeq) and bictegravir (in Biktarvy). A new formulation of raltegravir that can be taken once daily has recently become available.

An older integrase inhibitor, elvitegravir (co-formulated with other drugs and sold in pills called Genvoya and Stribild), is still used by some people. However, this drug must be taken with a small dose of the booster cobicistat. This latter drug is similar to a protease inhibitor and, like all protease inhibitors, cobicistat can cause gastrointestinal issues and interact with many other drugs.

ART, integrase inhibitors and weight gain

Over the past several years, reports have emerged that some people who have used integrase inhibitors have gained weight. In most cases the increased weight is probably associated with a return to health. However, in a minority of cases, there have been substantial increases in weight. Many of the reports associated with weight gain and the use of ART are from study designs that could not yield definitive results—they were retrospective; they looked back on data previously collected for one reason and then re-analysed for another reason. Other studies were cross-sectional in nature—they only looked at data captured at one point in time. Both retrospective and cross-sectional studies are relatively cheap to conduct and can serve as a starting point for exploring an issue. However, interpreting the results from such studies can inadvertently increase the risk of drawing biased conclusions about the cause of an issue; in this case, weight gain. Trials of a more robust statistical design are expensive and time consuming. When randomized trials were done, weight was not always assessed or monitored as the main outcome of the study.

In this issue of TreatmentUpdate, we review studies that explore the issue of weight and body composition in HIV-positive people. When interpreting the data from such studies, bear in mind the following:

  • Changes in the broader population – being overweight and obesity now appear to be more common among HIV-negative people than they were decades ago. This suggests that some of the factors that are driving weight gain in HIV-negative people are also possibly driving weight gain in HIV-positive people.
  • HIV causes chronic and excess inflammation and activation of the immune system – taking ART and achieving and maintaining a suppressed viral load significantly reduces but does not normalize inflammation and immune activation. Among HIV-negative people, chronic inflammation contributes to an increased risk for many conditions, including obesity. It is plausible that the chronic inflammation seen in HIV infection also plays a role in increasing the risk for weight gain and obesity over the long term.
  • Clinical trials of ART did not usually compare the physical activity and diet of participants. So the effect of these factors on weight gain/loss is not known.

—Sean R. Hosein

REFERENCES:

  1. Serwadda D, Mugerwa RD, Sewankambo NK, et al. Slim disease: a new disease in Uganda and its association with HTLV-III infection. Lancet. 1985 Oct 19;2(8460):849-852.
  2. Centers for Disease Control. Update on acquired immune deficiency syndrome (AIDS)--United States. Morbidity and Mortality Weekly Report. 1982 Sep 24;31(37):507-8, 513-514.
  3. Barré-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983 May 20;220(4599):868-871.
  4. Worobey M, Watts TD, McKay RA, et al. 1970s and 'Patient 0' HIV-1 genomes illuminate early HIV/AIDS history in North America. Nature. 2016 Nov 3;539(7627):98-101.
  5. Worobey M, Gemmel M, Teuwen DE, et al. Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature. 2008 Oct 2;455(7213):661-664.
  6. Gilbert MT, Rambaut A, Wlasiuk G, et al. The emergence of HIV/AIDS in the Americas and beyond. Proceedings of the National Academy of Sciences USA. 2007 Nov 20;104(47):18566-18570.
  7. Shor-Posner G, Campa A, Zhang G, et al. When obesity is desirable: a longitudinal study of the Miami HIV-1-infected drug abusers (MIDAS) cohort. Journal of Acquired Immune Deficiency Syndromes. 2000 Jan 1;23(1):81-88.
  8. Crum-Cianflone N, Roediger MP, Eberly L, et al. Increasing rates of obesity among HIV-infected persons during the HIV epidemic. PloS One. 2010 Apr 9;5(4):e10106.
  9. Lakey W, Yang LY, Yancy W, et al. Short communication: from wasting to obesity: initial antiretroviral therapy and weight gain in HIV-infected persons. AIDS Research and Human Retroviruses. 2013 Mar;29(3):435-440.
  10. Koethe JR, Heimburger DC, PrayGod G, et al. From wasting to obesity: The contribution of nutritional status to immune activation. Journal of Infectious Diseases. 2016 Oct 1;214 Suppl 2:S75-S82.
  11. Godfrey C, Bremer A, Alba D, et al. Obesity and Fat metabolism in human immunodeficiency virus-infected individuals: Immunopathogenic mechanisms and clinical implications. Journal of Infectious Diseases. 2019 Jul 2;220(3):420-431.
  12. Koethe JR, Jenkins CA, Furch BD, et al. Brief Report: Circulating markers of immunologic activity reflect adiposity in persons with HIV on antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes. 2018 Sep 1;79(1):135-140.
  13. Koethe JR, Jenkins CA, Lau B, et al. Rising obesity prevalence and weight gain among adults starting antiretroviral therapy in the United States and Canada. AIDS Research and Human Retroviruses. 2016 Jan;32(1):50-58.
  14. Bares SH, Smeaton LM, Xu A, et al. HIV-Infected Women Gain More Weight than HIV-Infected Men Following the Initiation of Antiretroviral Therapy. Journal of Women’s Health. 2018 Sep;27(9):1162-1169.
  15. Cook RR, Fulcher JA, Tobin NH, et al. Combined effects of HIV and obesity on the gastrointestinal microbiome of young men who have sex with men. HIV Medicine. 2020; in press.
  16. Gogokhia L, Taur Y, Juluru K, et al. Intestinal dysbiosis and markers of systemic inflammation in viscerally and generally obese persons living with HIV. Journal of Acquired Immune Deficiency Syndromes. 2020 Jan 1;83(1):81-89.
  17. Glesby MJ, Hanna DB, Hoover DR, et al. Abdominal fat depots, insulin resistance, and incident diabetes mellitus in women with and without HIV infection. AIDS. 2018 Jul 31;32(12):1643-1650.
  18. Taramasso L, Ricci E, Menzaghi B, et al. Weight gain: a possible side effect of all antiretrovirals. Open Forum Infectious Diseases. 2017 Nov 3;4(4):ofx239.
  19. Norwood J, Turner M, Bofill C, et al. Weight gain in persons with HIV switched from efavirenz-based to integrase strand transfer inhibitor-based regimens. Journal of Acquired Immune Deficiency Syndromes. 2017 Dec 15;76(5):527-531.
  20. Debroy P, Sim M, Erlandson KM, et al. Progressive increases in fat mass occur in adults living with HIV on antiretroviral therapy, but patterns differ by sex and anatomic depot. Journal of Antimicrobial Chemotherapy. 2019 Apr 1;74(4):1028-1034.
  21. Tate T, Willig AL, Willig JH, et al. HIV infection and obesity: where did all the wasting go? Antiviral Therapy. 2012;17(7):1281-1289.
  22. Lagathu C, Béréziat V, Gorwood J, et al. Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment. Expert Opinion on Drug Safety. 2019 Sep;18(9):829-840
  23. Blüher M. Obesity: Global epidemiology and pathogenesis. Nature Reviews Endocrinology. 2019 May;15(5):288-298.
  24. Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and management of obesity. New England Journal of Medicine. 2017 Apr 13;376(15):1492.
  25. Sonnenburg JL, Sonnenburg ED. Vulnerability of the industrialized microbiota. Science. 2019 Oct 25;366(6464). pii: eaaw9255.
  26. Couturier J, Winchester LC, Suliburk JW, et al. Adipocytes impair efficacy of antiretroviral therapy. Antiviral Research. 2018 Jun;154:140-148.
  27. Gorwood J, Bourgeois C, Mantecon M, et al. Impact of HIV/simian immunodeficiency virus infection and viral proteins on adipose tissue fibrosis and adipogenesis. AIDS. 2019 May 1;33(6):953-964.
  28. Dirajlal-Fargo S, Moser C, Rodriguez K, et al. Changes in the Fungal marker β-D-glucan after antiretroviral therapy and association with adiposity. Open Forum Infectious Diseases. 2019 Nov 11;6(11):ofz434.000
  29. Landovitz RJ, Zangeneh SZ, Chau G, et al. Cabotegravir is not associated with weight gain in HIV-uninfected individuals in HPTN 077. Clinical Infectious Diseases. 2020; in press.
  30. Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different prodrugs of tenofovir to Treat HIV. New England Journal of Medicine. 2019 Aug 29;381(9):803-815.
  31. NAMSAL ANRS 12313 Study Group, Kouanfack C, Mpoudi-Etame M, Omgba Bassega P, et al. Dolutegravir-based or low-dose efavirenz-based regimen for the treatment of HIV-1. New England Journal of Medicine. 2019 Aug 29;381(9):816-826.
  32. Havlir DV, Doherty MC. Global HIV treatment - Turning headwinds to tailwinds. New England Journal of Medicine. 2019 Aug 29;381(9):873-874
  33. Debroy P, Lake JE, Sim M, et al. Lean mass declines consistently over 10 years in people living with HIV on antiretroviral therapy, with patterns differing by sex. Antiviral Therapy. 2019;24(5):383-387.
  34. Bhagwat P, Ofotokun I, McComsey GA, et al. Changes in waist circumference in HIV-infected individuals initiating a raltegravir or protease inhibitor regimen: Effects of sex and race. Open Forum Infectious Diseases. 2018 Nov 16;5(11):ofy201.
  35. Bares SH. Is modern antiretroviral therapy causing weight gain? Clinical Infectious Diseases. 2020; in press.
  36. 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.
  37. 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.
  38. Lisan Q, Tafflet M, Thomas F, et al. Body silhouette trajectories over the lifespan and insomnia symptoms: The Paris Prospective Study 3. Scientific Reports. 2019 Feb 7;9(1):1581.
  39. Gafoor R, Booth HP, Gulliford MC. Antidepressant utilisation and incidence of weight gain during 10 years' follow-up: population based cohort study. BMJ. 2018 May 23;361:k1951.
  40. 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.
  41. Verhaegen AA, Van Gaal LF. Drug-induced obesity and its metabolic consequences: a review with a focus on mechanisms and possible therapeutic options. Journal of Endocrinological Investigation. 2017 Nov;40(11):1165-1174.
  42. Ford ND, Patel SA, Narayan KM. Obesity in Low- and Middle-Income Countries: Burden, Drivers, and Emerging Challenges. Annual Review of Public Health. 2017 Mar 20;38:145-164.
  43. McLachlan JA. Environmental signaling: from environmental estrogens to endocrine-disrupting chemicals and beyond. Andrology. 2016 Jul;4(4):684-694.
  44. Lauretta R, Sansone A, Sansone M, et al. Endocrine Disrupting Chemicals: Effects on Endocrine Glands. Frontiers in Endocrinology. 2019 Mar 21;10:178.