Tenofovir Alafenamide

Tenofovir alafenamide is an oral phosphonoamidate prodrug of tenofovir that delivers the active drug into lymphocytes and hepatocytes at plasma tenofovir levels about 90% lower than tenofovir disoproxil fumarate. It is used for chronic hepatitis B as a single tablet and for HIV-1 infection and pre-exposure prophylaxis only as part of fixed-dose combinations. It causes less kidney tubular injury and bone loss than the disoproxil salt, but more weight gain and lipid rise. It carries a boxed warning for severe hepatitis B flares on stopping.

Class. Nucleotide reverse transcriptase inhibitor; nucleotide analogue antiviral; prodrug.

Mechanism. Hydrolysed in cells by cathepsin A (lymphocytes) and carboxylesterase 1 (hepatocytes) to tenofovir, then phosphorylated to tenofovir diphosphate, which terminates viral DNA synthesis. The K65R mutation reduces susceptibility.

Pharmacokinetics. Absorbed orally and improved by food. Plasma half life of the prodrug about 30 minutes; intracellular tenofovir diphosphate half life over 150 hours. It is a P-glycoprotein substrate, so inducers lower levels.

Chronic hepatitis B (adults and children 6 years and over weighing 25 kg or more). 25 mg orally once daily with food, usually for years or indefinitely.

HIV-1 infection. Given only in fixed-dose tablets with other antiretrovirals: emtricitabine 200 mg with tenofovir alafenamide 25 mg once daily when the third drug is not boosted (for example dolutegravir), or emtricitabine 200 mg with tenofovir alafenamide 10 mg once daily when the third drug is boosted with ritonavir or cobicistat.

Pre-exposure prophylaxis against HIV. Emtricitabine 200 mg with tenofovir alafenamide 25 mg once daily in men and transgender women who have sex with men; not established for receptive vaginal sex.

Dose adjustment for kidney function. - Hepatitis B single tablet: no adjustment at CrCl 15 mL/min or more; on haemodialysis give after dialysis; not advised under 15 mL/min without dialysis. - Combination tablets: use at CrCl 30 mL/min or more; in haemodialysis for HIV treatment only, given after dialysis.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 25 mg daily.

Main alternative. Tenofovir disoproxil fumarate 300 mg once daily, which is cheaper and has more data in pregnancy.

Contraindications. Hypersensitivity; co-prescription with strong P-glycoprotein inducers (rifampicin, rifabutin, rifapentine, carbamazepine, phenytoin, phenobarbital, St John’s wort).

Serious adverse effects. Severe acute exacerbation of hepatitis B after stopping, lactic acidosis with hepatic steatosis (rare), new or worse kidney impairment (less than with the disoproxil salt), and immune reconstitution syndrome.

Common adverse effects. Nausea, headache, fatigue, weight gain, and rises in total and LDL cholesterol and triglycerides.

Interactions. - Rifampicin lowers tenofovir alafenamide exposure to a degree that makes combination unreliable; use a tenofovir disoproxil fumarate regimen during tuberculosis treatment. - Anticonvulsant inducers lower levels. - Boosted protease inhibitors and cobicistat raise levels, which is why the 10 mg dose is used with them.

Common prescribing errors. Using it with rifampicin, stopping it without covering hepatitis B, and giving the hepatitis B tablet alone for HIV.

Special groups.

• Pregnancy: data are growing and reassuring for HIV treatment; for prevention of hepatitis B transmission, the disoproxil salt has more evidence.
• Breastfeeding: limited data; considered compatible.
• Children: 25 mg for hepatitis B from 6 years and 25 kg; HIV combinations are weight-banded.
• Older adults: lower kidney and bone risk than the disoproxil salt.
• Kidney impairment: no adjustment at CrCl 30 mL/min or more; limited data under 30.
• Liver impairment: no adjustment in compensated disease; not advised in decompensated cirrhosis for the single tablet.

Regional points. In East Africa the disoproxil salt in a fixed-dose combination with lamivudine and dolutegravir is the usual first-line drug, so tenofovir alafenamide is used mainly in people with kidney disease or low bone density and where programmes supply it. Tuberculosis co-treatment is common, and rifampicin rules out the alafenamide salt.

Formulations. Tablet 25 mg; fixed-dose tablets with emtricitabine (200 mg with 10 mg or 25 mg), with dolutegravir or bictegravir, and others.

Administration. Once daily with food (the hepatitis B tablet).

Baseline. Hepatitis B surface antigen, HIV test (for prophylaxis), creatinine and eGFR, urinalysis, lipids, weight, pregnancy test.

Monitoring. Creatinine, urinalysis and phosphate at 4 weeks and then every 6 to 12 months; lipids and weight yearly; HBV DNA and ALT every 3 to 6 months in hepatitis B; HIV test every 3 months in prophylaxis.

Stopping thresholds. Stop only with a plan for hepatitis B: monitor ALT and HBV DNA for at least 6 months after stopping; stop for eGFR under 15 mL/min without dialysis, or for anaphylaxis.

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