Ritonavir concentrations not correlated with lipid levels in people with HIV taking boosted atazanavir or boosted darunavir

People taking HIV treatment based on ritonavir-boosted atazanavir and darunavir have comparable long-term increases in lipid levels, investigators from the United States report in the online edition of Clinical Infectious Diseases. Trough concentrations of ritonavir were not associated with lipid levels. This is an important finding.

The authors explain: “The lipid changes experienced with ritonavir boosted PI [protease inhibitor] therapy are speculated to be driven to a larger extent by the ritonavir component of the regimens”. This could be because of the way ritonavir is processed by the body. The present research provided an opportunity to test this theory, but showed “associations between ritonavir exposure and lipid changes over 48 and 96 [weeks] were…not apparent (both overall and within specific PI regimens).”

Thanks to antiretroviral therapy, many people with HIV now have a normal life expectancy. However, several anti-HIV drugs, especially protease inhibitors, have been associated with lipid disturbances. Given that cardiovascular disease is an increasingly important cause of illness and death in people with HIV, it’s important to identify which drugs carry the biggest risk of lipid abnormalities.

Glossary

lipid

Fat or fat-like substances found in the blood and body tissues. Lipids serve as building blocks for cells and as a source of energy for the body. Cholesterol and triglycerides are types of lipids.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

syndrome

A group of symptoms and diseases that together are characteristic of a specific condition. AIDS is the characteristic syndrome of HIV.

 

metabolism

The physical and chemical reactions that produce energy for the body. Metabolism also refers to the breakdown of drugs or other substances within the body, which may occur during digestion or elimination.

protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.

ACTG 5257 was an open-label, phase III, randomised study comparing the safety and efficacy of regimens based on ritonavir-boosted atazanavir, ritonavir-boosted darunavir or the integrase inhibitor raltegravir. All the participants in the study were antiretroviral naive at baseline (had not previously taken treatment when the study started) and were also taking the fixed-dose combination emtricitabine/tenofovir (Truvada).

The study also gave investigators the opportunity to compare long-term changes in lipid profiles, incidence of metabolic syndrome and alterations in body shape according to regimen. Additionally, for people taking the protease inhibitors, the investigators also examined whether trough levels of ritonavir were correlated with lipid changes and if these differed between regimens.

Approximately 1800 people were recruited to the study between 2009 and 2011. A quarter were women, 34% were African American, 42% were white and 21% Hispanic.

A fifth of participants had metabolic syndrome at baseline. Prevalence did not differ by regimen and lipid profiles were also comparable between regimens.

During 96 weeks of follow-up, lipid levels increased with all three regimens. However, these were milder with raltegravir compared to the boosted protease inhibitors (p < 0.001).

Approximately a fifth of participants in each study arm developed metabolic syndrome during follow-up. At week 96, rates of use of lipid-lowering agents were also comparable between the three study medications (9 to 14%). People taking raltegravir experienced a larger increase in waist circumference compared to those treated with ritonavir-darunavir but not ritonavir-atazanavir.

Trough concentrations of ritonavir did not differ between arms, and there was no evidence of a correlation between ritonavir levels and lipid profile.

“Raltegravir produced the most favourable lipid profile compared with the two ritonavir boosted PIs,” comment the authors.

They were concerned by the high prevalence of metabolic syndrome at baseline and also the approximately 20% incidence observed during follow-up.

“The long-term clinical significance of the lipid changes noted with the two ritonavir boosted PI regimens relative to the raltegravir based regimen deserve further evaluation, particularly when initiating antiretroviral therapy in patients with high cardiovascular risk profiles,” conclude the authors.

References

Ofotokun I et al. Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin Infect Dis, online edition, 2015.

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