TreatmentUpdate
235

January 2020 

An analysis of randomized clinical trials and weight gain

In studies reviewed earlier in this issue of TreatmentUpdate, we examine data captured from as early as a few years after the introduction of potent HIV treatment (ART) to about 2010. In that era, commonly used drugs used to anchor a regimen were non-nukes (such as efavirenz and nevirapine) and protease inhibitors (such as ritonavir, indinavir, saquinavir, nelfinavir, lopinavir and atazanavir). However, analyses from that era have shown that obesity was occurring among some HIV-positive people even before they initiated ART. Furthermore, obesity increased after initiation of ART. Note that issues such as being overweight and obesity are also increasing in the population of HIV-negative people.

In the current era, many people who initiate ART in Canada and other high-income countries are most likely to have a regimen anchored by an integrase inhibitor. Today, that is most commonly bictegravir (in Biktarvy) or dolutegravir (Tivicay and in Dovato, Juluca and Triumeq). A new once-daily formulation of the integrase inhibitor raltegravir (Isentress HD) is available in high-income countries. However, it is not commonly used because it is not co-formulated with other drugs.  

In a paper in press in the journal Clinical Infectious Diseases, a team of scientists with the pharmaceutical company Gilead Sciences along with some physicians in Europe and the United States reviewed data from randomized clinical trials in which ART was initiated in more than 5,000 people between 2003 and 2015. They found that, overall, weight gain occurred in all clinical trials and with nearly all drugs used. However, the team stated that “weight gain was greater in more recent [clinical] trials and with use of newer ART regimens.”

Factors prior to ART initiation that played a role in subsequent weight gain were as follows:

  • lower CD4+ cell counts
  • higher viral loads
  • not injecting street drugs
  • being female
  • being black

We now report on comparisons among different regimens and classes of anti-HIV drugs done by the team.

Study details

The study team focused on regimens that were in the final stage of clinical trials (phase III) prior to licensure. All participants were monitored for about two years.

At the start of the studies, the distribution by weight of participants was as follows:

  • normal weight – 52%
  • overweight – 31%
  • obese – 16%

(Numbers do not total 100 due to rounding.)

Results

Overall trends were as follows:

  • People who entered the more recent trials tended to be heavier and have higher CD4+ cell counts prior to initiating ART.
  • Weight gain occurred regardless of the regimen used.
  • Weight gain was greater in more recent clinical trials (these tended to have newer drugs).
  • Newer regimens were associated with greater weight gain than older regimens.
  • On average, people gained about 2 kg of weight.
  • The greatest weight gain tended to occur within the first year of the study.

Risk factors for weight gain

CD4+ cell count

As with other large analyses, participants who entered the Gilead studies with less than 200 CD4+ cells/mm3 gained more weight (nearly 3 kg) than participants who entered the study with a CD4+ count greater than 200 cells/mm3.

Viral load

People who entered a study with a viral load greater than 100,000 copies/mL gained about 1 kg more than people who had a lower viral load at study entry.

Symptoms and AIDS

People who had symptoms of AIDS or symptoms of immune deficiency gained half a kilogram more than symptom-free people.

Not injecting street drugs

People who did not inject street drugs gained 1.4 kg more than people who injected street drugs.

Race/ethnicity

Black people generally gained about 1 kg more in weight compared to non-Black people.

Gender

Women gained more weight than men. The greatest weight gain occurred among women who were black. The second-greatest weight gain was seen among men who were black.

Types of ART

All major classes of ART were associated with weight gain, as follows:

  • integrase inhibitors – 3.24 kg
  • non-nukes – 1.93 kg
  • protease inhibitors – 1.72 kg

These differences in weight gain were statistically significant when comparing weight gain with integrase inhibitors to other classes of ART.

Integrase inhibitors

Weight gain was greatest among integrase inhibitors:

  • bictegravir – 4.2 kg
  • dolutegravir – 4.07 kg
  • elvitegravir – 2.72 kg

Non-nukes (NNRTI)

Among non-nukes, participants who took rilpivirine (in Complera and Odefsey) gained more weight than people who took efavirenz:

  • rilpivirine – 3.01 kg
  • efavirenz – 1.7 kg

Nucleoside analogues (nukes)

Compared to the oldest nuke (AZT, zidovudine, Retrovir and in Combivir and Trizivir), participants who took other nukes more commonly used today gained substantially more weight as follows:

  • tenofovir alafenamide (TAF, the newer and safer form of tenofovir) + FTC – 4.25 kg
  • abacavir (often this is co-formulated with 3TC) – 3.08 kg
  • tenofovir disoproxil fumarate (TDF, the older formulation of tenofovir) + FTC – 2.08 kg

People who took AZT generally gained about 0.39 kg.

Risk factors for gaining 10% or more of baseline body weight

The team focused on the 10% figure because this is usually clinically significant; they called such weight gain “extreme.” Such an increase occurred in nearly 13% of participants.

Factors at the start of the study that were associated with an increase of 10% or more of body weight were as follows:

  • lower CD4+ cell count
  • higher viral load
  • having a normal body mass index (BMI) vs. being overweight or obese
  • being female
  • being black

Comparing different drugs and an increase in body weight of 10% or more

The team used the non-nuke efavirenz (in Atripla and Sustiva, Stocrin) as a reference when comparing the impact of other drugs on weight gain of 10% or more and found that initiating a regimen containing any of the following drugs was associated with an increased risk for a large degree of weight gain:

  • bictegravir
  • dolutegravir
  • elvitegravir
  • rilpivirine

However, the use of atazanavir with a small dose of ritonavir (this is called “boosted atazanavir”) in a regimen was not associated with a large increase in weight.

Among nukes, the scientists found that initiating a regimen containing TAF (this is usually co-formulated with FTC) was associated with a significantly increased risk of gaining 10% or more of body weight. In contrast, the following nukes were not associated with such a risk for weight gain:

  • TDF (this is usually co-formulated with FTC)
  • abacavir (this is usually co-formulated with 3TC)

Metabolic issues—Good and bad news

In general, the team did not find clinically significant increases in measures of fasting blood sugar or blood pressure during the study. Increased weight was not associated with an increased risk for type 2 diabetes. However, participants in phase III clinical trials (of HIV treatment or non-HIV treatment) tend to be relatively healthier than the average person with the same condition in the community. Also, participants were monitored for about two years. This is both good and bad news. The good news is that the findings likely mean that in the short-term (two years) the increase in weight does not generally cause metabolic problems. However, the bad news is that studies among HIV-negative people have generally found that weight gain over the long-term is associated with a range of health problems.

Note well

The present studies were not designed primarily to assess weight gain. The studies were meant to assess the effectiveness and general safety of ART. Yet, their findings about weight gain concur with what leading physicians are seeing in their clinics with some patients and with reports from other randomized and observational studies. Additional clinical trials with a focus on weight, metabolic and cardiovascular issues are now needed to monitor ART users over the long term and to help find ways to safely lose weight if necessary. Although all modern HIV regimens are generally associated with some degree of weight gain, the good news is that most people who use ART do not become obese. In the short-term (two years), the increased weight was usually a few kilograms.

—Sean R. Hosein

REFERENCES:

  1. 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.
  2. Bares SH. Is modern antiretroviral therapy causing weight gain? 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. Havlir DV, Doherty MC. Global HIV treatment - Turning headwinds to tailwinds. New England Journal of Medicine. 2019 Aug 29;381(9):873-874.