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
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.
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.
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.
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
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