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Can Low-Dose Ritonavir Help Preserve Body Shape?

April 1, 2009

The widespread availability of highly active antiretroviral therapy (HAART) in high-income countries has greatly reduced deaths related to AIDS. HAART's benefits are so immense that researchers in these countries increasingly expect HIV positive people who do not have serious co-existing health conditions and who are engaged in their care and treatment to have near-normal life spans.

One potential side effect of some anti-HIV treatments is the loss of the fatty layer (subcutaneous fat) just under the skin -- a problem called lipoatrophy. This can affect any part of the body. However, lipoatrophy of the face can be particularly distressing because it can drastically change one's appearance. Although reparative therapy is possible, it is expensive and not generally subsidized by health care systems in high-income countries, with the exception of France and the UK.

Results from clinical trials in the late 1990s and early part of this century suggested that lipoatrophy was mostly linked to the use of a group of anti-HIV agents called thymidine analogues, especially d4T (stavudine, Zerit) and, to a lesser extent, AZT (zidovudine, Retrovir).

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More recently, two studies suggest that the anti-HIV drug efavirenz (Stocrin, Sustiva and in Atripla) also appears to have this negative effect. In these trials, efavirenz was compared to combinations of lopinavir-ritonavir (Kaletra). Both efavirenz and lopinavir-ritonavir were taken with two nucleoside analogues, AZT and 3TC (Combivir). After reviewing those two trials, some researchers theorized that perhaps exposure to low doses of ritonavir might have somehow protected users from fat wasting.

Now news comes from a third clinical trial that has found that exposure to ritonavir reduces the chance of fat wasting. The news from this study will likely spur more research with low-dose ritonavir to explore its impact on fat wasting.


Study Details

Researchers in 10 countries in North America, South America, Europe and Africa recruited and randomly assigned 200 HIV positive volunteers to the following combinations of drugs:

  • 95 people -- atazanavir-ritonavir (300/100 mg), 3TC (300 mg) and an experimental formulation of extended-release d4T called d4T-XR (100 mg)
  • 105 people -- atazanavir (400 mg), 3TC and d4T-XR (these two drugs were taken at the same doses as listed above)

All medicines were taken once daily by all study volunteers. None of the participants had previously used anti-HIV drugs and all of them knew which drugs they were receiving.

The average profile of participants at the start of the study was as follows:

  • 30% female, 70% male
  • age -- 35 years
  • viral load -- 80,000 copies
  • CD4+ count -- 200 cells

Major ethno-racial grouping as described by the researchers was as follows:

  • White people -- 55%
  • Black people -- 26%
  • other people -- 19%

The study lasted for two years. In addition to the routine assessment of blood samples, the researchers also took CAT and DEXA scans (low-dose X-rays) to help them determine the proportion of fat in the bodies of participants.


Results -- Effectiveness and Safety

Both combinations used in the study were generally safe and effective.

There were three cases in people taking atazanavir-ritonavir in which the virus developed resistance to treatment vs. 10 cases in people taking atazanavir 400 mg.

Eight participants who were taking atazanavir-ritonavir and one who was taking atazanavir 400 mg left the study because of side effects -- mostly because of higher-than-normal levels of bilirubin in the blood. Bilirubin is a waste product that can discolour the skin and whites of the eyes when it builds up. Once bilirubin levels fall, this discolouration effect clears.


Results -- Changes in Body Shape

In total, 129 participants had DEXA scans taken at the start and end of the study two years later, divided as follows:

  • atazanavir-ritonavir -- 60 people
  • atazanavir 400 mg -- 69 people

When reading these results, it is useful to bear in mind that all participants in this study received d4T -- notorious for its fat-wasting effect.

On average, scans reveled that the fatty layer under the skin had increased in thickness at the end of the study compared to pre-study levels as follows:

  • atazanavir-ritonavir: + 8%
  • atazanavir 400 mg: + 2%

However, a different analysis reveals differences in gender -- women were more likely than men to have changes in their body fat. For instance, the average percent change in subcutaneous fat by gender in people who received atazanavir-ritonavir was as follows:

  • females: +29%
  • males: +2%

The equivalent figures for people who received atazanavir 400 mg were as follows:

  • females: +11%
  • males: -2%


Belly Fat

The fat that is deep within the abdomen and wrapped around vital organs is called visceral fat. The quantity of this fat increased in both groups of the study by about 33%.


Focus on the Limbs

When the skin's fatty layer disappears in the arms and legs, limbs can appear skinnier and veins seem to bulge. Limb fat decreased to a significant degree only in people who received atazanavir 400 mg.

Another way to assess changes in limb fat is to look at changes that are large, such as a decrease of 20% or more. Using this metric, over the course of the study the team found the following:

  • atazanavir-ritonavir -- 30% of participants lost 20% or more of their limb fat
  • atazanavir 400 mg -- 50% of participants lost 20% or more of their limb fat

This difference between study arms was statistically significant.


Why the Differences?

The intriguing finding from this study is that exposure to ritonavir apparently decreased the chance of losing subcutaneous fat. Moreover, people who took ritonavir and who lost fat lost less fat than people not taking ritonavir.

This is now the third clinical trial to find that ritonavir exposure may protect from fat loss.

The combination of nukes used in this study -- d4T and 3TC -- is not commonly used in high-income countries today chiefly because d4T is notorious for causing nerve damage, changes to body shape and abnormal lipid levels in blood. Instead, other combinations that have not been shown to cause fat wasting are used, such as:

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

It is possible that people using either of the above nuke combinations together with a protease inhibitor and ritonavir might be less likely to experience fat wasting than seen in studies where d4T was used, but this needs to be confirmed. Further research needs to be done to try to answer the following questions:

  • Why does ritonavir have this effect on subcutaneous fat?
  • Are there some people who are less likely to lose fat when given ritonavir?
  • Which combinations of anti-HIV drugs are effective, safe and least likely to be associated with fat wasting?

This latter question is particularly important, as HIV positive people will have to take HAART for many years, perhaps decades.


References

  1. Lohse N, Hansen AB, Pedersen G, et al. Survival of persons with and without HIV infection in Denmark, 1995-2005. Annals of Internal Medicine. 2007 Jan 16;146(2):87-95.
  2. van der Valk M, Gisolf EH, Reiss P, et al. Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS. 2001 May 4;15(7):847-55.
  3. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA. 2002 Jul 10;288(2):207-15.
  4. McComsey GA, Ward DJ, Hessenthaler SM, et al. Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study. Clinical Infectious Diseases. 2004 Jan 15;38(2):263-70.
  5. Tebas P, Zhang J, Hafner R, et al. Peripheral and visceral fat changes following a treatment switch to a non-thymidine analogue or a nucleoside-sparing regimen in HIV-infected subjects with peripheral lipoatrophy: results of ACTG A5110. Journal of Antimicrobial Chemotherapy. 2009; in press.
  6. Haubrich RH, Riddler S, DiRienzo G, et al. Metabolic outcomes of ACTG 5142: a prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI-sparing regimens for initial treatment of HIV-1 infection. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections, February 25-28, 2007, Los Angeles, USA. Abstract 38.
  7. Cameron DW, da Silva B, Arribas J, et al. Significant sparing of peripheral lipoatrophy by HIV treatment with LPV/r + ZDV/3TC induction followed by LPV/r monotherapy compared with EFV + ZDV/3TC. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections, February 25-28, 2007, Los Angeles, USA. Abstract 44LB.
  8. El Hadri K, Glorian M, Monsempes C, et al. In vitro suppression of the lipogenic pathway by the non-nucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes. Journal of Biological Chemistry. 2004 April 9;279(15):15130-15141.
  9. Nguyen AT, Gagnon A, Angel JB, et al. Ritonavir increases the level of active ADD-1/SREBP-1 protein during adipogenesis. AIDS. 2000 Nov 10; 14(16):2467-73.
  10. McComsey G, Rightmire A, Wirtz V, et al. Changes in Body Composition with Ritonavir-Boosted and Unboosted Atazanavir Treatment in Combination with Lamivudine and Stavudine: A 96-Week Randomized, Controlled Study. Clinical Infectious Diseases. 2009; in press.



This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication CATIE News. Visit CATIE's Web site to find out more about their activities, publications and services.
 

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