Tenofovir: Action against HIV and Hepatitis B

Tenofovir is a nucleotide analog reverse transcriptase inhibitor used in antiretroviral therapy for HIV infection and treatment of chronic hepatitis B. In Germany, two prodrug forms are available: Tenofovir Disoproxil (TDF, brand name Viread) and Tenofovir Alafenamide (TAF, brand name Vemlidy or as a component of combination preparations). TAF is the newer variant and better tolerated with respect to bone and kidney. Tenofovir is part of standard HIV therapy in combination with other antiretroviral substances and is an important active ingredient in pre-exposure prophylaxis (PrEP).

Tenofovir was introduced in the early 2000s and significantly improved HIV therapy because it offered high antiviral efficacy with once-daily dosing and comparatively good tolerability. Further development into TAF resulted in significantly lower systemic plasma concentrations while maintaining high intracellular activity, which reduces the typical side effects of TDF on bone and kidney. In the treatment of chronic hepatitis B, tenofovir alongside entecavir is a first-line agent.

Mechanism of Action

Tenofovir is phosphorylated in the cell to tenofovir diphosphate, the pharmacologically active form. This competitively inhibits HIV reverse transcriptase and hepatitis B virus DNA polymerase. By incorporation into the growing viral DNA chain, chain synthesis is terminated (chain terminator) because the missing 3 hydroxyl group prevents further elongation. This results in inhibition of viral replication.

Tenofovir Disoproxil and Tenofovir Alafenamide are prodrugs of active tenofovir. TDF is hydrolyzed to tenofovir in plasma and then enters the cell. TAF is transported more stably in plasma and activated only in target cells (lymphocytes, hepatocytes). This results in different pharmacokinetic profiles: TDF has higher plasma levels, leading to more kidney and bone toxicity; TAF achieves similar or higher concentrations in target cells with lower systemic exposure.

Pharmacokinetically, TDF is rapidly absorbed after oral administration with bioavailability of approximately 25 percent (fasting) or 40 percent (with food). The elimination half-life is approximately 17 hours. Tenofovir is primarily renally eliminated, which explains the need for dose adjustment in renal insufficiency. TAF has a shorter plasma half-life (approximately 0.5 hours), but the intracellular half-life is significantly longer.

Areas of Application

• HIV 1 Infection in combination with other antiretroviral substances, usually as part of a combination preparation such as Truvada (TDF + emtricitabine), Descovy (TAF + emtricitabine), or integrated single tablet regimens
• Chronic Hepatitis B Infection in adults and from age 12 years, oral monotherapy
• Pre-exposure Prophylaxis (PrEP) in HIV-negative individuals with high risk of infection (Truvada or Descovy)
• Post-exposure Prophylaxis (PEP) after possible HIV exposure as part of a 28-day regimen
• HIV 2 Infection in specific indications with varying efficacy

Selection between TDF and TAF is based on individual profile: TAF preferred in patients with kidney or osteoporosis risk profile, TDF in low-income countries due to better availability and lower costs.

Dosage and Administration

HIV TDF: 245 mg once daily orally, in combination with additional antiretroviral substances.

HIV TAF: 25 mg once daily orally, in combination with emtricitabine and a third agent; in individual indications 10 mg.

Hepatitis B TDF: 245 mg once daily orally.

Hepatitis B TAF: 25 mg once daily orally.

PrEP TDF: 245 mg plus emtricitabine 200 mg once daily, alternatively "on-demand" regimen in MSM (2 tablets 2 to 24 hours before sex, then one tablet each 24 and 48 hours thereafter).

PrEP TAF: 25 mg plus emtricitabine 200 mg daily.

Pediatric: from 2 years TDF, from 6 years TAF, weight-adjusted dosing.

Administration: take with water, TDF with a meal for better bioavailability, TAF independent of meals.

Renal Insufficiency: TDF requires dose interval extension when creatinine clearance is below 50 ml per minute, contraindicated below 10 ml per minute. TAF is approved down to creatinine clearance of 30 ml per minute, therefore generally more suitable with reduced kidney function. Hepatic Insufficiency: generally no adjustment required.

Side Effects

Very Common (TDF): headache, dizziness, nausea, diarrhea, fatigue, rash, elevated liver values.

Common: abdominal pain, vomiting, bloating, asthenia.

TDF Specific: decreasing bone density with risk of osteopenia and fractures, tubulopathy with Fanconi syndrome, acute kidney failure, long-term progressive renal insufficiency, hypophosphatemia, proximal renal tubular acidosis. In hepatitis B patients with decompensated liver disease, caution is advised.

TAF: kidney and bone friendly, however more frequent lipid metabolism changes with LDL and triglyceride elevation, weight gain.

Rare to Very Rare: lactic acidosis, severe hepatomegaly with steatosis (rare), severe skin reactions such as Lyell syndrome (very rare), pancreatitis, rhabdomyolysis.

Upon Discontinuation of Hepatitis B Therapy: risk of severe hepatitis reactivation. Therapy discontinuation only under close monitoring.

Drug Interactions

• Other Nephrotoxic Medications (aminoglycosides, vancomycin, cidofovir, ciclosporin, high-dose NSAIDs): increased nephrotoxicity.
• Didanosine (ddI): increased didanosine levels, risk of pancreatitis and peripheral neuropathy. Combination to be avoided.
• Atazanavir, Lopinavir/Ritonavir: increased tenofovir levels with increased toxicity risk in TDF.
• Probenecid: inhibits renal tubular secretion of tenofovir, increases plasma levels.
• NSAIDs: increased risk of tubulopathy in TDF, particularly with continuous use.
• Ledipasvir, Sofosbuvir (Hepatitis C therapy): increased TDF levels, possible therapy adjustment.

Special Notes

Pregnancy: TDF is well-studied and considered safe for HIV therapy in pregnant women. TAF in pregnancy has fewer data available, but is increasingly established. Breastfeeding: if HIV-positive, do not breastfeed due to transmission risk, in low-income countries with breastfeeding recommendation continue tenofovir therapy.

Children: approved from 2 years (TDF) or 6 years (TAF), weight-adjusted dosing in pediatric consultation.

Hepatitis B / C Co-infection in HIV: Tenofovir acts against HBV, therefore preferred in co-infection. With HCV therapy, individual adjustment.

Before Therapy: hepatitis B and C serology, HIV resistance test, kidney function (creatinine clearance, urine status with glucose and phosphate), bone density measurement in risk profile, pregnancy status.

During Therapy: kidney function (creatinine, phosphate in serum, glucose and protein in urine) every 3 to 6 months, liver values regularly, lipid status with TAF, virological monitoring, adherence counseling.

Lifestyle: medication adherence is crucial because therapy interruptions favor resistance development. Regular intake at the same time of day is recommended.

Fitness to Drive: with dizziness or vision disturbances, caution is advised, otherwise generally not impaired.

You May Also Be Interested In

• Emtricitabine, combination partner with tenofovir
• Dolutegravir, integrase inhibitor in HIV combination therapy
• Efavirenz, NNRTI in HIV therapy
• Entecavir, antiviral agent for hepatitis B
• Lamivudine, antiviral agent for HIV and hepatitis B

Frequently Asked Questions

Sources

• Gelbe Liste, Tenofovir Active Ingredient Profile
• BfArM, Federal Institute for Drugs and Medical Devices
• German AIDS Society (DAIG)
• AWMF Guidelines for HIV Therapy and Chronic Hepatitis B
• European Medicines Agency, EPAR Viread and Vemlidy