Obesity Among People Living With HIV: Strategies for Maintaining Healthy Weight

Given that the prevalence of obesity is increasing among people living with HIV infection in the United States, what are best evidence-based strategies to help these patients maintain a healthy weight? To help answer this question, Infectious Diseases Consultant spoke with Michael Reid, MD, an assistant professor of infectious diseases at the University of California, San Francisco, and a clinical provider of HIV care at Zuckerberg San Francisco General Hospital and Trauma Center.

Dr Reid discusses the epidemiology of obesity among people living with HIV and the factors that influence the development of obesity in this population, and he explores the question of whether obesity influences HIV outcomes and vice versa. He also summarizes practical strategies, based on evidence from the latest clinical trials, for weight loss in people living with HIV.

Infectious Diseases Consultant: What do we know about the epidemiology of obesity?

Michael Reid: In the general population, approximately 36% of adult Americans are obese. We know that non-Hispanic blacks have the highest rates of obesity, followed by Hispanics, and we know that the health care financial burden that is associated with obesity in the general population is tremendous. It has been estimated that there will be more than 164 million obese Americans by 2030,¹ and this is likely to cost the US health economy $147 billion per year,¹ in addition to existing health care costs, as more people with obesity are likely to develop sequelae of obesity such as diabetes and cardiovascular disease.

We also know that the prevalence of obesity is increasing among people living with HIV. Data from the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) cohorts have clearly demonstrated that the proportion of individuals with obesity who are starting antiretroviral therapy (ART) has doubled over the past 10 years or so—9% of individuals starting ART were obese compared with 18% starting ART 12 years later.² While this proportion is smaller than the proportion of people in the general population who are obese, the relative increase in the proportion of people living with HIV who are obese is certainly increasing more than the proportion in the general population over the past decade.

ID CON: What are the factors associated with the development of obesity in people living with HIV?

MR: Numerous studies have looked at this question. For example, from a cohort of HIV-infected individuals starting ART in a study by researchers at Duke University in Durham, North Carolina,³ we know that the relative increase in obesity is greater in individuals who have a low CD4 cell count of less than 200/mm³. Those who are on protease inhibitor (PI) based regimens and women starting ART also are more likely to develop obesity.

More recently, a subanalysis of the TEMPRANO (Early Antiretroviral Treatment and/or Early Isoniazid Prophylaxis Against Tuberculosis in HIV-infected Adults) trial, a study based in Ivory Coast in sub-Saharan Africa investigating the best time to initiate ART in people living with HIV, researchers found that the initiation of ART was associated with increased body mass index (BMI) even at high baseline CD4 cell counts.⁴ People with HIV who were already overweight were at the greatest risk of becoming obese after 24 months on treatment in that study.

What is the role of antiviral medication?

ID CON: Do we know whether certain antiretrovirals are associated with more weight gain than others?

MR: A number of studies have looked at this question. For example, AIDS Clinical Trials Group (ACTG) 5224s, which was a study exploring efavirenz vs atazanavir-ritonavir with different nucleoside reverse-transcriptase inhibitor (NRTI) backbones, demonstrated that there was no difference in increase in BMI associated with an abacavir backbone compared with a tenofovir backbone.⁵ But there was a small but significant increase in BMI of 0.88 kg/m² associated with being on an atazanavir-ritonavir regimen compared with the efavirenz regimen.

Is there a difference between NRTIs like efavirenz and integrase strand transfer inhibitors like raltegravir? This question was addressed in the STARTMRK trial.⁶ The investigators found that there was no difference in BMI between being on a raltegravir regimen and an efavirenz regimen after 5 years of therapy. However, in a different study, ACTG 5257, exploring raltegravir vs darunavir vs atazanavir, all with a emtricitabine-tenofovir backbone, it was noted that raltegravir was associated with the biggest increase in waist circumference compared with PIs, particularly in women.⁷ This study looked at waist circumference rather than BMI, but it does seem to demonstrate a significant difference with raltegravir.

In summary, the role of antiretrovirals in the development of obesity is certainly unclear. Raltegravir is associated with an increase in waist circumference in one study but not BMI in another. We know that a higher BMI is associated with an increased risk of obesity after ART initiation. But certainly, more research is necessary in evaluating the impact of antiretrovirals on weight gain, particularly since so many more people are on potent drugs such as dolutegravir.

ID CON: Does obesity influence immune recovery in people living with HIV?

MR: This is an interesting question that I am particularly fascinated by. Certainly, older data from the pre-ART era, from studies out of Miami and the Bronx, demonstrated that individuals who were obese at the time of HIV diagnosis were less likely to advance to full-blown AIDS, and in that sense, obesity was protective against AIDS development. It remains unclear whether the patients in these studies had a lower rate of advancement toward AIDS because of nutritional reserves that were protective against the stresses associated with advancing HIV, and to some extent, these data are inconsequential now that we are obviously trying to get people on to treatment as quickly as possible.

More recently, observational data from NA-ACCORD, which includes 17 different cohorts, illustrated that higher BMI was associated with improved CD4 cell recovery after ART initiation. In this study—83% of participants were male, and 45% were on PI-based regimens—the mean CD4 cell recovery after 5 years was 34% higher if the BMI was greater than 40 kg/m² and 22% higher if the BMI was greater than 30 kg/m² compared with individuals with a normal BMI.⁸

Why this effect? It is unclear, but it may reflect qualitative differences in T-cell functional responses. Alternatively, it may reflect the fact that adipose tissue has an independent effect on immune recovery. Certainly, a higher BMI is associated with a slower HIV disease course in pre-ART patients, body composition seems to affect peripheral CD4 cell recovery, and adipose tissue hormones alter lymphocyte function and alter immune recovery in persons with HIV. But without doubt, more research is necessary to better understand the role of adipose tissue in immune recovery.

ID CON: Does obesity influence non-HIV outcomes in people living with HIV?

MR: There is a tremendous amount of data demonstrating that increased BMI appears to be bad for one’s health, and certainly obesity is bad for one’s health regardless of HIV status. We know, for example, that obesity is associated with a relative risk of diabetes of between 42 and 61. Hypertension is 1.7 times more likely for every 5 kg in weight gain. Dementia is also more prevalent in people with obesity. Hepatobiliary disease is twice as common in obese men and nearly 3 times as common in obese women. And there are also numerous psychosocial sequelae of sustained obesity including stigma, depression, and unemployment.

What are the non-AIDS associated sequelae of obesity in individuals living with HIV? The researchers involved with the large D:A:D study (Data Collection on Adverse Events of Anti-HIV Drugs) cohort explored the impact of change in BMI after ART initiation on cardiovascular disease and diabetes in a subset of participants.^9,10 They found that for each 1-unit gain in BMI after ART initiation, there was a 20% increased risk in cardiovascular disease if pre-ART BMI was normal and a 12% increased risk of diabetes regardless of pre-ART BMI but higher in individuals who were overweight or obese at the time of ART initiation. The take-home message from this study is that gaining more weight in the first year of ART increases the risk of diabetes and cardiovascular disease. Although the mechanism for that increased risk is unclear based on these observational data, it probably relates to an increase in inflammation related to weight gain.

A number of other studies have demonstrated that gaining weight in the first 48 weeks after ART initiation leads to an increase in serological blood levels of certain markers of inflammation. Data from the ACTG PEARLS (Prospective Evaluation of Anti-retroviral Combinations for Treatment Naive, HIV Infected Persons in Resource-limited Settings) study, where individuals were randomly assigned to 1 of 3 different drug regimens, found that weight gain in individuals that were already overweight or obese on ART was associated with an increased level of soluble CD14, suggesting that gaining weight is associated with increased levels of inflammation.

Data from another observational cohort study, the FRAM (Fat Redistribution and Metabolic Change in HIV Infection) study, demonstrated that increased adiposity was associated with increased inflammation in those individuals that were the most obese.¹² In this population of HIV-infected individuals in North America, every doubling of visceral adiposity was associated with a 17% increase in the level of C-reactive protein, a proinflammatory marker that is associated with adverse cardiovascular outcomes. It seems to suggest that in this patient population, being more obese is likely to lead to an increased risk of cardiovascular disease associated or mediated by adiposity.

In summary, we know that adiposity leads to inflammation, which in turn leads to increased adverse outcomes. Higher serum inflammatory biomarkers are associated with adiposity, and some HIV proteins—particularly Tat and Vpr—promote adipocyte expression of inflammatory mediators. There are sufficient data to demonstrate that obesity is increasing in prevalence among people living with HIV, and adiposity and obesity are associated with an increased risk of adverse non-HIV associated outcomes. Overall, obesity is probably bad news for people living with HIV, but more research is warranted to understand the mechanisms by which inflammation leads to metabolic sequelae in this patient population.

How can we help people living with HIV lose weight?

ID CON: What strategies can we employ in to help patients with HIV lose weight?

MR: Are there any data to suggest particular weight loss strategies that are likely to have good effect in people living with HIV? Well, the answer is no, not really. There is not a great deal of HIV-specific data on what weight loss strategies are likely to be most effective.

In a randomized controlled trial published in 2012, Fitch and colleagues¹³ randomly assigned individuals with prediabetes or metabolic syndrome to 1 of 4 different interventions: lifestyle changes (exercise and diet), lifestyle changes plus metformin, metformin alone, or neither lifestyle changes nor metformin. The authors found that in HIV-infected individuals with metabolic syndrome or prediabetes, metformin was associated with an improvement in some cardiovascular outcomes (coronary artery calcification on computed tomography scan) but no effect on weight loss overall. The summary of that study is that metformin in this prediabetic group did have some impact on coronary artery calcification scores but had no effect in terms of weight loss strategies.

Can we learn anything from the general population? A huge number of studies have looked at the best ways to help patients lose weight. One is the Look AHEAD (Action for Health in Diabetes) trial,¹⁴ in which investigators randomly assigned individuals to support and education 3 times a year for 4 years in the control arm or a calorie-restricted diet of 1200 to 1800 calories a day and exercise in the intervention arm. The take-home study from this trial was that there was an initial weight loss at 2 months that was predictive of sustained weight loss, but overall, weight loss was hard to achieve and hard to sustain with diet and exercise. And, in fact, the results did not demonstrate a clear effect on cardiovascular events at the end of the study period. Nonetheless, I think it is appropriate that all obese patients should be recommended to try and adhere to diet, exercise, and behavioral changes, and referral to nutritional counseling services is appropriate in almost all circumstances. I think it’s also germane for providers to recognize that weight loss is very hard, and patients need to be supported in an individualized way, acknowledging that sometimes issues such as food insecurity and housing have a tremendous impact on their ability to lose weight and maintain healthy weight.

ID CON: Does bariatric surgery have a role?

MR: We know that evidence supports the role of bariatric surgery in patients with a BMI greater than 40 kg/m² without coexisting medical problems and in patients with a BMI greater than 35 kg/m² with at least one other severe obesity-related complication such as diabetes, hypertension, or obstructive sleep apnea. There are a number of small case series evaluating whether such surgeries work in HIV-infected individuals, and those data do seem to suggest that weight loss surgeries can lead to diabetes remission and sustained weight loss in people living with HIV. But the number of individuals in these case series is very small, and I would be cautious about extrapolating the findings to populations at large.

In summary, the prevalence of obesity is increasing among people living with HIV in North America. We know that obesity is associated with a number of adverse outcomes including inflammation and metabolic complications. Unfortunately, there remains a paucity of data exploring the best evidence-based strategies for weight loss among people living with HIV. It is worth recognizing that losing weight is hard regardless of HIV status, and providers need to employ an individualized approach to support patients as they try to lose weight or try to maintain a healthy weight.

References:

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