Renal adverse events and fractures proved rare among people taking tenofovir disoproxil fumarate (TDF) as part of a single-tablet regimen in a large U.S. database of insured patients. Rates of renal problems and fracture were lower with coformulated efavirenz/TDF/emtricitabine (Atripla) than with elvitegravir/cobicistat/emtricitabine/TDF (Stribild, E/C/F/TDF), according to the study.
TDF is well known for its potentially adverse impact on kidneys and bone. The magnitude of these side effects may be related to tenofovir plasma concentrations, which vary from one TDF regimen to the next. To gain a better understanding of between-regimen differences in renal and bone outcomes, Bristol-Myers Squibb researchers compared these outcomes in patients taking the single-tablet regimens efavirenz/TDF/emtricitabine, E/C/F/TDF or rilpivirine/emtricitabine/TDF (Complera, R/F/TDF).
This retrospective analysis relied on 2008-2014 data from a large commercial insurance claims database including Medicare recipients. Follow-up continued from first use of efavirenz/TDF/emtricitabine, E/C/F/TDF or R/F/TDF until a renal or bone outcome, end of single-tablet regimen use, end of insurance plan enrollment or end of the study period. All participants were adults enrolled in the plan for at least six months before starting one of the three single-tablet regimens. Primary outcomes included exposure-adjusted incidence rate (IR) for renal and bone adverse outcomes defined by ICD-9 codes and incidence rate differences (IRDs) between pairs of the three regimens.
The renal analysis included 8107 people taking efavirenz/TDF/emtricitabine, 1017 taking R/F/TDF and 752 taking E/C/F/TDF. Age averaged around 43 years across the three groups, and approximately 86% of participants were men. IRs per 1000 person-years were lower for efavirenz/TDF/emtricitabine (9.7), R/F/TDF (10.5) and E/C/F/TDF (13.6) than for all HIV patients in the database (18.0). Among all participants taking a single-tablet regimen, risk factors for renal adverse outcomes by multivariate analysis were older age, hypertension, cardiovascular disease, diabetes, hepatitis C infection and hospitalization. In adjusted analysis, renal adverse events proved significantly less frequent with efavirenz/TDF/emtricitabine than with E/C/F/TDF (IRD -1.78, 95% confidence interval [CI] -2.19 to -1.50) but did not differ significantly between efavirenz/TDF/emtricitabine and R/F/TDF (IRD -1.05, 95% CI -2.90 to 0.53).
The fracture analysis included 7797 people taking efavirenz/TDF/emtricitabine, 1262 taking R/F/TDF and 1324 taking E/C/F/TDF. Age averaged around 43 years across the three groups, and about 86% of participants were men. Fracture incidence rates per 1000 person-years were 4.4 for all HIV patients in the database, 3.4 for those taking efavirenz/TDF/emtricitabine, 3.6 for those taking R/F/TDF and 7.2 for those taking E/C/F/TDF. Univariate analysis identified older age and substance abuse history as predictors of fracture; multivariate analysis could not be performed because of the low number of fractures. Univariate analysis determined that fracture incidence was significantly lower with efavirenz/TDF/emtricitabine than with E/C/F/TDF (IRD -3.85, 95% CI -5.02 to -2.78) but did not differ significantly between efavirenz/TDF/emtricitabine and R/F/TDF (IRD -0.25, 95% CI -1.02 to 0.44).
The researchers note that follow-up during efavirenz/TDF/emtricitabine therapy was much longer than during treatment with the other single-tablet regimens. As a result, they may have overestimated renal and bone adverse events with efavirenz/TDF/emtricitabine. They observe that the lower renal event rate with efavirenz/TDF/emtricitabine than with E/C/F/TDF reflects findings in a randomized double-blind trial.