Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate is an oral prodrug of tenofovir, a nucleotide reverse transcriptase inhibitor with activity against HIV-1 and hepatitis B virus. It is a backbone of first-line HIV treatment, a first-line drug for chronic hepatitis B, and used for pre-exposure prophylaxis and prevention of mother-to-child transmission of hepatitis B. Proximal renal tubular injury and loss of bone mineral density are the main long-term toxicities, and stopping it can cause severe hepatitis B flares (boxed warning).

Class. Nucleotide reverse transcriptase inhibitor; nucleotide analogue antiviral.

Mechanism. Hydrolysed to tenofovir, phosphorylated to tenofovir diphosphate, which competes with deoxyadenosine triphosphate and terminates viral DNA synthesis. The K65R mutation reduces susceptibility.

Pharmacokinetics. Oral bioavailability about 25%, increased by a high-fat meal. Plasma half life about 17 hours; intracellular half life of tenofovir diphosphate longer than 60 hours. Excreted unchanged by glomerular filtration and tubular secretion.

HIV-1 infection (adults and adolescents 35 kg or more). 300 mg orally once daily, combined with lamivudine or emtricitabine and a third active drug (for example dolutegravir). Duration: lifelong.

Chronic hepatitis B (adults and adolescents 12 years and over, 35 kg or more). 300 mg once daily, usually for years or indefinitely, with stopping considered only in selected patients under specialist supervision.

Pre-exposure prophylaxis against HIV. 300 mg with emtricitabine 200 mg once daily; event-driven dosing (two tablets 2 to 24 hours before sex, then one at 24 and 48 hours) is used in some settings for men who have sex with men.

Prevention of mother-to-child transmission of hepatitis B. 300 mg once daily from 28 to 32 weeks of pregnancy until delivery or up to 4 to 12 weeks postpartum, for women with high viral load (HBV DNA over 200,000 IU/mL) or HBeAg positivity.

Children (2 years and over). 8 mg/kg once daily using weight-banded granules or tablets; 35 kg or more: 300 mg.

Dose adjustment for kidney function (adults). - CrCl 30 to 49 mL/min: 300 mg every 48 hours. - CrCl 10 to 29: 300 mg every 72 to 96 hours. - Haemodialysis: 300 mg every 7 days or after about 12 hours of dialysis. - CrCl under 10 mL/min not on dialysis: no dosing established; use alternative.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 300 mg daily.

Main alternative. Tenofovir alafenamide, with less renal and bone toxicity, in kidney impairment or osteoporosis.

Contraindications. Hypersensitivity, and use for pre-exposure prophylaxis in people with unknown or positive HIV status.

Serious adverse effects. Renal tubular injury (Fanconi syndrome), acute kidney injury, reduced bone mineral density and osteomalacia, lactic acidosis with hepatic steatosis (rare), and severe acute exacerbation of hepatitis B after discontinuation.

Common adverse effects. Nausea, diarrhoea, headache, dizziness and fatigue.

Interactions. - Nephrotoxins (NSAIDs, aminoglycosides, amphotericin B, high-dose cidofovir, foscarnet, ciclosporin) increase renal risk. - Didanosine levels rise (avoid). - Atazanavir and lopinavir interact: boost and monitor kidney function. - Sofosbuvir-velpatasvir with boosted regimens raises tenofovir exposure.

Common prescribing errors. No baseline hepatitis B test before stopping, no kidney monitoring, full dose in kidney impairment, and stopping the drug abruptly in hepatitis B co-infection.

Special groups. - Pregnancy: safe and widely used in HIV and for preventing hepatitis B transmission. - Breastfeeding: compatible. - Children: weight-banded dosing from 2 years; monitor growth and bone health. - Older adults: greater risk of kidney and bone toxicity; monitor. - Kidney impairment: 300 mg every 48 hours at CrCl 30 to 49 mL/min and every 72 to 96 hours at CrCl 10 to 29; avoid if CrCl is under 10 mL/min without dialysis. - Liver impairment: no dose adjustment; monitor for hepatitis B flares.

Regional points. In East Africa fixed-dose combinations of tenofovir disoproxil fumarate, lamivudine and dolutegravir are widely used as first-line HIV treatment, and hepatitis B co-infection means treatment must never be stopped without a plan to cover the hepatitis.

Formulations. Tablets 300 mg; fixed-dose combinations with lamivudine, emtricitabine, efavirenz, dolutegravir or others; oral granules for children.

Administration. Once daily with or without food; a meal improves absorption.

Baseline. HIV test (for pre-exposure prophylaxis), hepatitis B surface antigen, creatinine and eGFR, phosphate, urinalysis for protein and glucose, pregnancy test, hepatitis C status.

Monitoring. Creatinine, phosphate and urinalysis at 4 weeks, then every 3 to 6 months; HBV DNA and ALT every 3 to 6 months in hepatitis B; HIV test every 3 months in pre-exposure prophylaxis; bone density in risk groups.

Stopping thresholds. Switch to tenofovir alafenamide or another agent for eGFR under 50 mL/min, proximal tubulopathy or osteoporosis; if stopping in hepatitis B, monitor liver tests and viral load for at least 6 months.

Referral and escalation. Specialist review for decompensated cirrhosis, hepatitis flare, kidney injury, or hepatitis B with HIV co-infection.