TreatmentUpdate
182

2011 January 

Changes in body fat and muscle with lopinavir-ritonavir

In the late 1990s, when potent anti-HIV therapy (commonly called ART or HAART) became available, doctors and their HIV-positive patients reported the emergence of a strange syndrome of changes in body shape—sunken cheeks, temples and limbs, and bulging bellies and breasts (in women). Some people also developed increased fat pads on the back of the neck and shoulders. These changes in body shape were accompanied by unfavourable alterations in levels of lipids (cholesterol and triglycerides), sugar and insulin in the blood. Together, these physical and biochemical changes are called the HIV lipodystrophy syndrome.

The loss of the fatty layer just under the skin (subcutaneous fat) is called lipoatrophy, and the accumulation of fat in the breasts and belly is called lipohypertrophy. In clinical trials, objective assessments of body composition (fat, bone, muscle) are generally done using low-dose X-ray scans called DEXA (dual-energy X-ray absorptiometry) or MRI (magnetic resonance imaging). Because researchers don’t want to expose the brain to needless radiation or other energies, instead of scanning the face for fat loss, DEXA and MRI scans of the limbs are used, as a lot of the fat in the limbs is subcutaneous fat.

Now, many years later, though some progress has been made, the triggering event for lipodystrophy is still not known. What is known is that exposure to two older drugs—d4T (stavudine, Zerit) and, to a lesser extent, AZT (zidouvine, Retrovir; and in Combivir and Trizivir)—can cause lipoatrophy. Note that the simplified chemical names for these drugs (d4T and AZT) both have the letter T, which represents the molecule thymidine. Both of these drugs are called thymidine analogues.

Today the use of d4T is generally shunned in high-income countries. Instead, commonly used nuke combinations are as follows:

  • Kivexa (abacavir + 3TC)
  • Truvada (tenofovir + FTC)

In several clinical trials, the use of Kaletra (lopinavir + ritonavir) has been associated with a limited degree of fat wasting and, in some cases, even an increase in subcutaneous fat. So there is interest in understanding the impact of lopinavir and/or ritonavir on fat, both in lab experiments and in HIV-positive people

Researchers in France, Italy, Poland and Spain recruited HIV-positive people for the Monark study. The purpose of Monark was to assess the safety and efficacy of Kaletra monotherapy. In this clinical trial, participants were randomly assigned to receive one of the following regimens:

  • monotherapy with lopinavir-ritonavir
  • ART (lopinavir-ritonavir + AZT + 3TC)

The results of Monark suggest that participants who received monotherapy with lopinavir-ritonavir had significantly less fat and muscle loss than people who received ART. Monark also found that, in general, lopinavir-ritonavir was not able to consistently suppress HIV levels in most participants, as only 47% had HIV that was less than 50 copies/ml after two years of monotherapy. However, other strategies, such as induction maintenance, where initially ART is used for between six and 12 months and then participants whose viral loads are less than 50 copies/ml are switched to monotherapy (with either lopinavir-ritonavir or darunavir (Prezista)-ritonavir), have been done or are planned or underway. Such trials in very highly adherent participants who do not harbour HIV that is resistant to therapy may prove to have greater efficacy than seen in Monark. For now, monotherapy with lopinavir or darunavir is considered experimental.

Study details

A total of 136 people who had never previously received anti-HIV therapy were enrolled in Monark. A subset of participants had their body composition assessed using DEXA scans both at the start and 48 and 96 weeks into the study. The sub-study focused on the following participants:

  • lopinavir-ritonavir – 41 volunteers
  • ART – 22 volunteers

The approximate profile of sub-study participants was as follows:

  • 33% females, 67% males
  • age – 35 years
  • weight – 70 kg (154 lbs)
  • CD4+ count – 235 cells
  • viral load – 16,000 copies/ml

Results—After 48 weeks

Participants who received lopinavir-ritonavir lost 63 grams of limb fat, while those on ART lost 700 grams (1.5 pounds) of limb fat.

Another way to represent changes in limb fat would be to express it as the proportion of limb fat lost or gained. Using this metric, participants on lopinavir-ritonavir lost about 1% of their limb fat, while those on ART lost 12%.

Lipoatrophy

The study team defined lipoatrophy (fat loss) as the loss of 20% or more of limb fat. Using this definition, the following participants experienced lipoatrophy during the study:

  • lopinavir-ritonavir – 5% of participants
  • ART – 27% of participants

After 48 weeks, participants who took lopinavir-ritonavir monotherapy lost 93 grams of arm muscle compared to a loss of 308 grams of arm muscle in volunteers who took ART.

All of these differences in fat and muscle were statistically significant.

Lipohypertrophy

The study team defined lipohypertrophy as a 20% increase in trunk fat (chest and belly). There were no significant differences between the two study groups in the appearance of lipohypertrophy, with 20% of participants taking lopinavir-ritonavir developing this condition vs. 14% of those who took ART.

Week 96

There was not sufficient data from the sub-study for meaningful conclusions to be drawn about changes in body shape.

Factors affecting fat loss

In a statistical analysis encompassing many factors that could have played a role in the loss of limb fat, only the type of treatment used was found to be important.

Side effects

The following proportions of participants developed serious complications, none of which were due to the anti-HIV treatments used:

  • lopinavir-ritonavir – 12%
  • ART – 7%

Less severe side effects were roughly evenly distributed between the two study groups. Participants who took lopinavir-ritonavir reported less general side effects than participants who took ART. The most common side effects seen in the study were diarrhea and higher-than-normal levels of liver enzymes in the blood.

This analysis of the Monark sub-study, taken together with other studies assessing the impact of lopinavir and/or ritonavir on body composition, suggests that lopinavir and/or ritonavir may have a protective effect on subcutaneous fat. The study team suggests that trials be done with other protease inhibitors to also assess their impact on subcutaneous fat.

REFERENCE:

Kolta S, Flandre P, Van PN, et al. Fat tissue distribution changes in HIV-infected patients treated with lopinavir. Current HIV Research. 2011; in press.