Background:  Tenofovir DF (TDF) was approved for the treatment of HIV infections in 2001 and is widely prescribed. We sought to evaluate the safety profile of TDF over its first 4 years of use.

Methods:  Safety data were evaluated from compassionate use/expanded access programs (EAP) in the United States, Europe, Australia, and Canada, as well as from post-marketing safety reports received through April 30, 2005. Serious adverse events were tabulated, and serious adverse events of clinical importance were characterized. Serum creatinine and phosphates were collected in >1600 patients in the EAP program.

Results:  Data were reviewed from 10,343 patients in EAP programs and spontaneous post-marketing safety reports representing 455,392 patient-years of exposure to TDF. Serious adverse events were reported by 631 patients (6 %) in the EAP programs (211 [2%] serious adverse events related), and no single type of serious adverse event was observed in >1% of patients. In the EAP program, the most common serious adverse events were pneumonia (0.63%), renal (0.57%), pancreatitis (0.47%), fever (0.40%), and bacterial infections (0.26%); related serious adverse events were pancreatitis (0.28%), renal (0.22%), fever (0.15%), pneumonia (0.14%), and diarrhea (0.09%). In the post-marketing safety database, the reporting rates were highest for renal, pancreatitis, lactic acidosis, hepatitis, and diarrhea. Serious renal serious adverse events in the EAP and post-marketing included renal failure (0.3% of patients; 0.50 cases/1000 patient-years, respectively) Fanconi/tubular disorder (0.05%; 0.43), and elevated serum creatinine (0.10%; 0.19). Risk factors for renal serious adverse events included concomitant nephrotoxic medications and low CD4 cell count. Grade 3 or 4 elevations in serum creatinine were reported for 0.3% of 1699 patients in the EAP program. For post-marketing renal serious adverse events with creatinine data, the median maximum serum creatinine was 2.3 mg/dL (IQR 4.0), and median time to resolution to grade 2 or less was 29.0 days (95%CI 17 to 45). Mitochondrial toxicity, neuropathy, and bone fractures were reported infrequently in the EAP (£0.1%) or post-marketing database.

Conclusions:  Safety data received during the first 4 years of TDF use demonstrate that the drug is well tolerated in HIV patients. The pattern of serious adverse events, including renal events, are similar in the post-marketing and EAP databases. The incidence of serious renal serious adverse events was 0.57% among 10,695 patiens in the EAP; risk factors included concomitant nephrotoxic medications and low CD4 cell count. Bone fractures, neuropathy, and mitochondrial toxicity were reported infrequently.