Concentrations of HIV protease inhibitors increase with age

Plasma concentrations of protease inhibitors increase with age, investigators from the United Kingdom report in the Journal of Antimicrobial Chemotherapy. Each ten-year increment in age was associated with a significant increase in concentrations of protease inhibitors in plasma. In contrast, there was no association between age and plasma levels of non-nucleoside reverse transcriptase inhibitor (NNRTI) levels.

“We have observed a statistically significant association between standardized plasma drug concentrations and protease inhibitors and age, with greater drug exposure associated with increasing age,” write the authors.

Improvements in treatment and care mean that the prognosis of most people living with HIV in the UK is now excellent. It is known that the way in which the body processes medicines changes as people age. However, relatively little is known about the impact of ageing on plasma concentrations of antiretroviral drugs.

UK investigators therefore designed a study involving 2447 people with HIV who had therapeutic drug monitoring as part of their routine care between 1999-2005 and 2008-10. The impact of age on concentrations of protease inhibitors and NNRTIs was analysed by the researchers. Data concerning  liver function was also studied to see if alterations in drug concentrations were accompanied by an increased risk of toxicities.

A total of 3549 therapeutic drug monitoring samples were available for analysis. The majority of these related to people aged between 35 and 50 years, and the fewest from individuals aged over 50. This age profile reflected the demographics of people receiving HIV care in the UK.

Approximately 4% of patients were co-infected with hepatitis B, 5% had hepatitis C co-infection and 30% of individuals had abnormal liver function.

Overall, 71% of samples were from people taking protease inhibitor therapy, and 29% from people taking an NNRTI. The greatest number of concentrations were assessed for lopinavir (Kaletra, 22%), efavirenz (Sustiva, 19%), atazanavir (Reyataz, 17%) and saquinavir (Invirase, 12%).

As age increased, plasma concentrations of NNRTIs remained largely stable.

Conversely, there was a clear relationship between increasing age and increasing concentrations of protease inhibitors (p = 0.033).

This relationship between age and plasma protease inhibitor concentrations remained significant after adjusting for other factors. Each ten-year increase in age was associated with an increase in protease inhibitor concentrations (p = 0.044).

Of all protease inhibitors, the strongest associations between age and plasma levels were for ritonavir (Norvir, p < 0.001) and saquinavir (p = 0.015).

The authors speculate that the relationship between increasing age and concentrations in protease inhibitors is because they are metabolised using the P450 enzyme. “Strengthening this hypothesis is our observation that a stronger effect of age was observed between standardized plasma concentration of ritonavir measurements compared with other protease inhibitors”, comment the authors,

There was no evidence of a relationship between drug concentrations and liver toxicities. Indeed, older age was associated with increased time to changing treatment for reasons other than virological failure (p < 0.001).

The authors are unsure of the clinical significance of their findings, but believe their results “may assist in the design of future work assessing the effects of lifelong antiretroviral therapy in subjects ageing with HIV infection.”