By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved tenofovir alafenamide (TAF), a prodrug for tenofovir (TFV). TFV is a nucleoside analog reverse transcriptase inhibitor, previously approved for HIV infection, which now is approved for the treatment of chronic hepatitis B virus infections (HBV) with compensated liver disease. This provides an alternative to tenofovir disoproxil fumarate (TDF). TAF is marketed as Vemlidy.
INDICATIONS
TAF is indicated for the treatment of chronic HBV with compensated liver disease.1
DOSAGE
The recommended dose is 25 mg once daily with food.1 Patients should be tested for HIV infection prior to initiation of therapy. TAF is available as 25 mg tablets.
POTENTIAL ADVANTAGES
TAF provides a more efficient delivery of TFV to the liver, requiring one-tenth of the dose of TDF.2 It is also less likely to affect bone mineral density and cause decline in renal function.1
POTENTIAL DISADVANTAGES
Glycosuria (≥ 3+) and elevation of LDL-cholesterol (> 190 mg/dL) were numerically higher with TAF (5% vs. 1% and 4% vs. < 1%) compared to TDF.
COMMENTS
TFV, as a chemical entity, exhibits poor membrane permeability; thus, it is unable to be converted intracellularly to active tenofovir diphosphate (TFV-DP). TDF was the first approved prodrug for TFV. It is metabolized intracellularly to TFV and subsequently to TFV-DP. However, it has been associated with reduced renal function and decreased bone mineral density due to high system exposure. TAF, a new prodrug, has improved passive permeability and is actively transported into the liver cells, providing pharmacologically active TFV-DP at one-tenth the oral dose and 90% lower systemic exposure.2 The efficacy and safety of TAF were evaluated in two randomized, double-blind, active-controlled, non-inferiority, 48-week studies.1 Subjects (n = 1298) were treatment-naïve and treatment-experienced adults presenting with chronic HBV with compensated liver disease. Study one included subjects who were HBeAg-negative who were randomized 2:1 to TAF 25 mg (n = 285) or TDF 300 mg (n = 140). Study two included subjects who were HBeAg-positive (n = 581, n = 292). Twenty-one percent were treatment-experienced in study one and 26% in study two. The primary efficacy endpoint was the proportion of subjects with plasma HBV DNA levels < 29 IU/MmL. Secondary endpoints were proportion of subjects with ALT normalization, HBeAg loss, and seroconversion in study one and HBeAg loss and seroconversion in study two. Treatment successes were 94% vs. 93% in study one and 64% vs. 67% in study two, and noninferiority criteria was met. Numerically, normalization of ALT and serological improvements (loss of HBeAg and seroconversion) were higher for TAF. Common adverse reactions, such as headache, abdominal pain, fatigue, cough, nausea, and back pain, were similar between TAF and TDF. Changes in estimated glomerular filtration rate showed a median decrease from baseline of 1.2 mL/min for TAF vs. 5.4 mL/min. BMD declines of ≥ 5% at the lumbar spine occurred in the TAF arm compared to 20% for the TDF arm. Switching from TDF to TAF showed improvement in BMD and renal function in HIV subjects.3 Seven of 866 subjects on TAF experienced elevated amylase levels and associated symptoms (e.g., nausea, biliary pancreatitis, pancreatitis), but none were associated with TDF. The wholesale cost for TAF and TDF is the same — $978 per 30-day supply.
CLINICAL IMPLICATIONS
Chronic hepatitis B affects up to 2.2 million people in the United States. The American Association for the Study of Liver Diseases recommends pegylated interferon, entecavir, or TFV as preferred initial therapy for adults suffering from immune-active chronic hepatitis B.4 TAF provides an effective and potentially safer option than TDF for the treatment of hepatitis B. Long-term safety in terms of fracture risk and renal toxicity has not been established.
REFERENCES
- Vemlidy prescribing information. Gilead Sciences, Inc. November 2016.
- Murakami E, et al. Antimicrob Agents Chemother 2015;59:3563-3569.
- Mills A, et al. Lancet Infect Dis 2016;16:43-52.
- Agency for Healthcare Research and Quality. AASLD guidelines for treatment of chronic hepatitis B. Available at: http://bit.ly/2jp7Ow8.
Vemlidy is indicated for the treatment of chronic hepatitis B virus with compensated liver disease.
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