Lower daily tenofovir dose of 150mg safe and effective in people with moderate renal impairment

A reduced tenofovir (Viread) dose of 150mg daily appears to be a safe and effective treatment for people with HIV who have moderate renal impairment, investigators from Thailand report in the online edition of Clinical Infectious Diseases. The 150mg daily dose provided comparable drug exposure to the currently recommended dose of 300mg every 48 hours. Moreover, treatment with the reduced dose maintained viral suppression.

“This is the first report assessing alternative dosing of TDF [tenofovir] in HIV-infected adults with moderate renal dysfunction. Our data demonstrate that reducing the approved TDF dose of 300mg every 48 hours in adults with a creatinine clearance between 30 to <50ml/min to 150mg once daily provides comparable exposure over a 48 hour period when receiving an NNRTI [non-nucleoside reverse transcriptase inhibitor]- or lopinavir/ritonavir-based regimen,” comment the authors. “The preservation of virological suppression and lack of adverse events was reassuring.”

Tenofovir is a widely used antiretroviral. The standard dose is 300mg once daily, in combination with other anti-HIV drugs. The drug is secreted through the kidneys. A pharmacokinetic study involving HIV-negative people with renal impairment showed that individuals with creatinine clearance below 50ml/min had significantly higher blood levels of tenofovir. It was therefore calculated that a tenofovir dose of 300mg every 48 hours for people with moderate renal impairment – creatinine clearance between 30-49ml/min – would provide similar drug exposure to that observed in people with normal renal function receiving the standard 300mg daily dose.

Glossary

renal

Relating to the kidneys.

creatinine

Breakdown product of creatine phosphate in muscle, usually produced at a fairly constant rate by the body (depending on muscle mass). As a blood test, it is an important indicator of the health of the kidneys because it is an easily measured by-product of muscle metabolism that is excreted unchanged by the kidneys.

virological suppression

Halting of the function or replication of a virus. In HIV, optimal viral suppression is measured as the reduction of viral load (HIV RNA) to undetectable levels and is the goal of antiretroviral therapy.

plasma

The fluid portion of the blood.

serum

Clear, non-cellular portion of the blood, containing antibodies and other proteins and chemicals.

 

But many people find dosing every 48 hours confusing and inconvenient. Lower strength tenofovir pills (150, 200, 250mg) have recently been approved. Investigators hypothesised that, for adults with moderate renal impairment, treatment with 150mg once daily would provide similar drug exposure to the currently recommended dose of 300mg every 48 hours.

They therefore designed a phase I, open label, pharmacokinetic study involving 40 people living with HIV who had creatinine clearance between 30 to <50 ml/min, who were taking a tenofovir dose of 300mg every 48 hours. All were virologically suppressed; half were taking a combination based on an NNRTI, the other 50% a lopinavir/ritonavir-containing regimen.

Tenofovir blood levels were intensively sampled over a 48-hour period, and intracellular tenofovir exposure was also monitored in peripheral blood mononuclear cells. The study participants then switched to the 150mg daily tenofovir dose. After two weeks, the pharmacokinetic analysis was repeated.

The participants had a median age of 56 years and an average weight of 51kg. Median creatinine clearance was 43.9 min/ml, and median serum creatinine was 1.3mg/dl. All had an undetectable viral load and median CD4 count was 502 cells/mm3.

Mean plasma tenofovir concentrations were essentially similar for the 300 and 150mg doses, regardless of whether participants were taking the drug in combination with an NNRTI or ritonavir-boosted lopinavir.

Overall, people taking lopinavir/ritonavir had higher tenofovir levels in plasma than people taking an NNRTI. This was observed with both the 300 and 150mg tenofovir doses.

Intracellular tenofovir concentrations were comparable between the 300 and 150mg doses.

“The data reported demonstrates that switching TDF to 150mg once daily in HIV-infected adults with moderate renal function impairment leads to comparable exposure to the current recommended 300mg, every 48 hours,” conclude the authors. “This daily dose option for this subpopulation of patients may be preferable to simplify their regimen and facilitate drug adherence but renal function should continue to be closely monitored in these patients.”

References

Cressey TR et al. Plasma and intracellular pharmacokinetics of tenofovir disoproxil fumarate (TDF) 300mg every 48 hours versus 150mg daily in HIV-infected adults with moderate renal function impairment. Clin Infect Dis, online edition, 2015.