tenofovir disoproxil

Antiretroviral; nucleotide reverse transcriptase inhibitor (NRTI)· Brands: VireadPO

Mechanism of action

Tenofovir disoproxil is an oral prodrug that is hydrolysed to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analogue of adenosine monophosphate. Tenofovir enters cells and is phosphorylated to the active metabolite tenofovir diphosphate. This competes with the natural substrate deoxyadenosine 5'-triphosphate for incorporation into viral DNA by HIV-1 reverse transcriptase. After incorporation, because it lacks a 3'-hydroxyl group, it acts as a chain terminator and inhibits further viral DNA synthesis. It also inhibits hepatitis B virus polymerase. It has no significant activity against human DNA polymerases at therapeutic concentrations, which contributes to a relatively favourable mitochondrial toxicity profile compared with some older nucleoside reverse transcriptase inhibitors.

Pharmacokinetics

Tenofovir disoproxil is rapidly absorbed after oral administration and hydrolysed by esterases to tenofovir; the prodrug is not detected in plasma. Oral bioavailability is approximately 25% in the fasting state and is increased modestly by food, so administration with food may improve exposure. Plasma protein binding of tenofovir is very low (less than 1%). It is widely distributed, with a volume of distribution around 1.3 L/kg. Tenofovir is eliminated mainly unchanged by the kidneys via glomerular filtration and active tubular secretion; the terminal elimination half-life is approximately 17 hours. It is not a substrate or inhibitor of cytochrome P450 enzymes to a clinically important extent, but it is a substrate of renal transporters OAT1, OAT3 and MRP4, which explains interactions with drugs that affect renal secretion. Dose reduction is required in renal impairment.

Indications & dosing

HIV-1 infection, treatment as part of combination antiretroviral therapy

Always combined with at least two other active antiretrovirals; never used as monotherapy for HIV. Dose adjustment needed in renal impairment (reduced frequency or switch to tenofovir alafenamide). Verify against local formulary.

adult · PO: 300 mg once daily · Always combined with at least two other active antiretrovirals; never used as monotherapy for HIV. Dose adjustment needed in renal impairment (reduced frequency or switch to tenofovir alafenamide). Verify against local formulary.

HIV-1 infection, treatment as part of combination antiretroviral therapy

Licensed from 2 years of age using weight bands (for example 150 mg at 17-21 kg rising to 300 mg at 35 kg and above). Weight-based dosing uses 8 mg/kg once daily, capped at 300 mg. Confirm banding against current paediatric formulary.

pediatric · PO: 150–300 mg once daily · Licensed from 2 years of age using weight bands (for example 150 mg at 17-21 kg rising to 300 mg at 35 kg and above). Weight-based dosing uses 8 mg/kg once daily, capped at 300 mg. Confirm banding against current paediatric formulary.

HIV pre-exposure prophylaxis (PrEP) in people at substantial risk of acquiring HIV

Given with or without emtricitabine as fixed-dose combination. Licensed for PrEP in some regions and off-label in others, so licensing status varies. Requires confirmed HIV-negative status before starting, renal monitoring and regular retesting.

adult · PO: 300 mg once daily · Given with or without emtricitabine as fixed-dose combination. Licensed for PrEP in some regions and off-label in others, so licensing status varies. Requires confirmed HIV-negative status before starting, renal monitoring and regular retesting.

Chronic hepatitis B infection with evidence of active replication or liver disease

Preferred long-term option because of its high genetic barrier to resistance. Continue indefinitely in most patients; monitor renal function and consider bone density assessment. Dosing interval extended in renal impairment.

adult · PO: 300 mg once daily · Preferred long-term option because of its high genetic barrier to resistance. Continue indefinitely in most patients; monitor renal function and consider bone density assessment. Dosing interval extended in renal impairment.

Chronic hepatitis B infection, treatment of children and adolescents

Weight-based dosing, typically 8 mg/kg once daily capped at 300 mg, using the same weight bands as for HIV. Age of licensure differs between regions, so check the local label before use.

pediatric · PO: 150–300 mg once daily · Weight-based dosing, typically 8 mg/kg once daily capped at 300 mg, using the same weight bands as for HIV. Age of licensure differs between regions, so check the local label before use.

HIV post-exposure prophylaxis after occupational or sexual exposure

Used as one component of a three-drug regimen started as soon as possible, ideally within hours and no later than 72 hours after exposure, and continued for 28 days. Baseline and follow-up HIV testing and renal monitoring are required.

adult · PO: 300 mg once daily · Used as one component of a three-drug regimen started as soon as possible, ideally within hours and no later than 72 hours after exposure, and continued for 28 days. Baseline and follow-up HIV testing and renal monitoring are required.

Contraindications & precautions

Hypersensitivity to tenofovir disoproxil or any excipient · Discontinue immediately if signs of hypersensitivity occur.
Severe renal impairment (creatinine clearance < 30 mL/min) not on haemodialysis · Dose interval adjustment is required for patients on haemodialysis; use with caution and monitor closely.
Concomitant use with other tenofovir-containing products · Avoid duplicate therapy due to increased risk of tenofovir-related toxicity.
Known or suspected HIV infection when used for pre-exposure prophylaxis (PrEP) · PrEP must only be initiated in confirmed HIV-negative individuals; use in HIV-positive patients can select for resistance.
Monitor renal function (serum creatinine, phosphate, urine glucose and protein) at baseline and periodically. Adjust dose or discontinue if renal impairment develops.
Assess bone mineral density in patients with risk factors for osteoporosis; consider calcium and vitamin D supplementation.
Test all patients for hepatitis B before starting. If positive, monitor liver function closely after discontinuation.
Avoid concomitant use with nephrotoxic agents (e.g., NSAIDs, aminoglycosides, amphotericin B). If unavoidable, monitor renal function closely.
For HIV treatment, use in combination with other antiretrovirals; do not use as monotherapy.
For PrEP, confirm HIV-negative status before initiation and at least every 3 months.

Adverse effects

Nausea, diarrhoea, headache, fatigue
Renal tubular dysfunction (proximal tubulopathy, Fanconi syndrome)serious
Decreased bone mineral density, osteomalacia, fracturesserious
Lactic acidosis with hepatic steatosisserious
Exacerbation of hepatitis B after discontinuationserious
Immune reconstitution inflammatory syndromeserious
Pancreatitisserious
Rash

Renal & hepatic adjustment

eGFR 50+: No dose adjustment: tenofovir disoproxil 300 mg once daily. Many guidelines prefer avoiding tenofovir disoproxil if eGFR is below 60 mL/min/1.73 m2, especially with other risk factors for renal toxicity.
eGFR 30–49: 300 mg every 48 hours.
eGFR 10–29: 300 mg every 72 to 96 hours.
eGFR 0–9: 300 mg every 7 days after haemodialysis; if not on dialysis, avoid unless specialist advises. (avoid)

Monitoring, pregnancy & toxicity

Renal function (serum creatinine, eGFR, urinalysis for protein and glucose) · Baseline, then every 3 to 6 months, or more frequently if risk factors or concomitant nephrotoxic drugs.
Serum phosphate · Baseline, then periodically, especially if renal impairment or bone symptoms.
Bone mineral density · In patients with risk factors for osteoporosis or prolonged therapy.
HIV viral load and CD4 count · Baseline and every 3 to 6 months.
Hepatitis B status and liver enzymes · Baseline; monitor for hepatic flare if tenofovir is discontinued in HBV co-infection.
Lactic acid if symptoms of lactic acidosis · If clinically indicated.
Pregnancy: Tenofovir disoproxil is recommended for use in pregnancy for HIV treatment and prevention of mother-to-child transmission, and for chronic hepatitis B. It is considered safe and effective; no dose adjustment is required. It is a preferred NRTI in many guidelines.
Toxicity: Nephrotoxicity: proximal renal tubulopathy, Fanconi syndrome, acute kidney injury, reduced eGFR. · Monitor renal function; withhold or stop if clinically significant decline; consider alternative antiretroviral; haemodialysis removes tenofovir in overdose or severe renal failure.
Toxicity: Bone toxicity: decreased bone mineral density, osteomalacia, fractures. · Assess bone health; supplement calcium and vitamin D if deficient; consider bone density monitoring in at-risk patients; stop if severe.
Toxicity: Lactic acidosis and severe hepatomegaly with steatosis. · Stop tenofovir if suspected; supportive care; monitor liver enzymes and lactate.
Toxicity: Overdose: no specific antidote; may cause renal toxicity. · Supportive care with monitoring of renal function and electrolytes; haemodialysis may enhance elimination.

Clinical notes

Tenofovir disoproxil is used as part of combination antiretroviral therapy for HIV-1 infection and for pre-exposure prophylaxis (PrEP), usually with emtricitabine. It is also active against hepatitis B virus and is used for chronic hepatitis B. It must not be used as monotherapy for HIV because resistance emerges rapidly. Important adverse effects include renal toxicity, ranging from a modest creatinine rise to proximal tubulopathy and Fanconi syndrome, and reduced bone mineral density. Renal function should be checked before starting and monitored during treatment; tenofovir alafenamide (TAF) is often preferred when renal or bone toxicity is a concern. Discontinuation in hepatitis B co-infection may cause a flare. Tenofovir exposure is increased by some boosted protease inhibitors, cobicistat, ledipasvir/sofosbuvir and nephrotoxic drugs; didanosine levels may rise. Teaching example doses: 300 mg orally once daily for HIV and HBV; 300 mg with emtricitabine 200 mg once daily for PrEP. Practice varies by region and formulary; always verify against local guidance.

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BNF; local formulary; manufacturer's summary of product characteristics; BHIVA guidelines; WHO guidelines