Genetic differences predict triglyceride increase on ritonavir-boosted PI

A single polymorphism, or variation, in one of several genes controlling triglyceride clearance and lipid transport in the body may explain why some individuals suffer more severe lipid elevations when treated with ritonavir-containing drug combinations, according to findings from the Swiss HIV Cohort published online this week in the Journal of Infectious Diseases.

The authors suggest that genetic screening may eventually prove useful in identifying individuals at high risk of serious triglyceride elevations if treated with ritonavir, and note that one of the genetic patterns that increased the risk of hypertriglyceridemia was present in one in six patients in their cohort.

Analysis of the interaction between genes and drugs, known as pharmacogenomics, has begun to highlight a number of genetic contributors to drug activity and side effects, including the risk of hyperbilirubinemia during atazanavir treatment, hypersensitivity during abacavir treatment and central nervous system side effects during efavirenz treatment (Haas 2005).

The Swiss HIV Cohort, which comprises data on HIV-positive patients receiving treatment at Swiss hospitals, collected extensive data on genetic profiles in 329 patients to examine the relationship between polymorphisms in genes known to influence hyperlipidemia and hypertriglyceridemia in the general population, and correlated this information with data on lipid responses to highly active antiretroviral therapy (HAART).

The study evaluated the impact of polymorphisms in the APOE and APOC3 genes associated with hyperlipidemia and hypertriglyceridemia respectively in the general population. The study also looked at the association between lipoatrophy and a polymorphism in the TNF promoter region that has been linked to an increased risk of lipoatrophy in a previous study in HIV-positive people.

The study took lipid measurements gathered during an average follow-up period of 3.2 years and analysed multiple variables, including treatment type, APO genotype, age and sex, to determine which interactions of variables had the most significant impact on lipid levels. Results were compared to a composite female patient with the most common APOE and APOC3 genotypes, aged 43 years, with hypothetical lipid levels of: HDL, 1.25mmol/L, non-HDL cholesterol, 4.87mmol/L, triglycerides, 1.57mmol/L.

The researchers found that only ritonavir-containing regimens were significantly associated with elevations in triglycerides, with a mean change of +1.71mmol/L compared with the reference case when all measurements were averaged across the follow-up period. There was no significant difference in the effect on triglycerides of different ritonavir dosages or of different combinations of ritonavir and other protease inhibitor. A trend towards higher triglyceride levels was also noted amongst patients receiving PI-sparing HAART that contained efavirenz when compared with other PI-sparing regimens.

APOE genotypes other than the most common genotype (&949;3/&949;3) were associated with higher mean triglyceride levels (+0.73mmol/L, p=0.001) in all patients, and were also significantly higher in patients who had all three variant alleles of the APOC3 genotype (+0.57mmol/L, p=0.006).

Patients who had less common APOE genotypes combined with 3 APOC3 variants had significantly higher triglyceride levels regardless of treatment type, and the effect was most marked in those who received ritonavir (+2.23mmol/L, p

Lipoatrophy was not found to be associated with a polymorphism in the TNF promoter region, contradicting findings from a previous smaller study from the University of Liverpool and a larger Australian study, which had suggested an association between carriage of the TNF-238G/A polymorphism and risk of lipoatrophy. However, an association was found between lipoatrophy and carriage of three APOC3 variants (p=0.046).

“The relatively high frequency of variant alleles of APOE and APOC3 might suggest a potential role for genetic testing before initiation of HAART. For example, 27.7% of patients in this study were carriers of variant alleles of APOE, 17.9% were carriers of all 3 variant alleles of APOC3, and 5.8% were carriers of both,” the authors report.

“The genotyping of treatment-naïve patients might be an efficient method to determine the advisability of the administration of of RTV-containing ART. Given the risk of hypertriglceridemia, it might be prudent to select an alternative ART regimen for patients who have unfavourable gentoypes,” the authors conclude. They recommend a larger randomised study to test the value of genetic testing.