Tenofovir in HIV Infections: A Comprehensive Review

For Patients:

What Is Tenofovir?

Tenofovir is a type of HIV medicine called an NRTI (nucleotide reverse transcriptase inhibitor), a drug that blocks a key HIV enzyme. It works by targeting an important enzyme that HIV needs to make copies of itself.

HIV is a retrovirus (a virus that turns its RNA (ribonucleic acid) into DNA (deoxyribonucleic acid) inside the body). To do this, it uses an enzyme called reverse transcriptase (a protein that helps HIV convert RNA into DNA).

There are two common forms of Tenofovir used for HIV treatment:

• Tenofovir Disoproxil Fumarate (TDF).

• Tenofovir Alafenamide (TAF).

Once Tenofovir enters the body’s cells, it is changed into its active form called Tenofovir diphosphate (the working version of the drug). This active form competes with the normal building blocks that HIV uses to make new DNA.

When Tenofovir gets added into the viral DNA chain, it stops the chain from growing because it does not have a 3'-hydroxyl group (a small chemical part needed to continue DNA building).

As a result, HIV cannot complete the DNA it needs to multiply. This blocks the virus from making more copies of itself, which helps lower the viral load (the amount of HIV in the blood).

Indications:

• Tenofovir can be used in mixed therapy for both adults and children. It helps prevent the progression of the disease.

• Tenofovir is also used to treat chronic hepatitis B (HBV) infection in adults and pediatric patients. While using Tenofovir for hepatitis, the medicine works by lowering the amount of virus in the body, reducing liver inflammation, and helping improve long-term liver health.

• Tenofovir, in combination with Emtricitabine, is used as a preventive measure in individuals at high risk of acquiring HIV.

Contraindications:

• People who are allergic to Tenofovir or any ingredient in it should not take this medicine.

• Tenofovir is mainly removed from the body through the kidneys. So, people with severe kidney problems or very low creatinine clearance (a test that shows how well the kidneys are working) should not use it. TAF is gentler on the kidneys compared to TDF (TAF and TDF are two forms of Tenofovir).

• Tenofovir may reduce bone mineral density (it can make bones weaker) in some people.

• People with HIV who already have liver disease should avoid taking Tenofovir because the liver helps process this medicine.

• Tenofovir can interact with some other medications. So, make sure to tell your doctor about all the medicines you are taking.

Available doses and dosage forms:

1. Tenofovir disoproxil fumarate (TDF): It is found in 300 mg (milligrams) tablets.

2. Tenofovir alafenamide (TAF): Tablet Tenofovir Alafenamide is available in 25 mg, 10 mg, and 40 mg tablets.

3. Fixed-dose combinations (FDCs): Tenofovir is given along with other antiretroviral drugs in fixed-dose combinations.

Why Is Tenofovir Prescribed For?

• Antiretroviral treatment for HIV: Tenofovir is a critical component of combination antiretroviral therapy (cART) used in the management of HIV. It inhibits the reverse transcriptase enzyme, disrupting the replication of HIV and reducing its ability to spread.

• Pre-exposure prophylaxis (PrEP): Tenofovir PrEP, especially in Tenofovir Disoproxil Fumarate, is used for high-risk individuals.

PrEP involves taking the medication regularly to prevent the acquisition of HIV.

• Tenofovir alafenamide (TAF): TAF is another formulation of Tenofovir used in HIV treatment. TAF is associated with potentially lower risks of certain side effects, making it a preferred choice in some cases.

• Combination therapy: Tenofovir is rarely used as a standalone medication. It is usually prescribed in combination with other antiretroviral drugs to increase efficacy and reduce the risk of developing drug resistance.

• Decreases viral load: It lowers viral load in the blood.

• Controls co-infection: It also assists in controlling co-infections.

• Regular monitoring: Regularly monitoring individuals taking Tenofovir is essential to check for treatment efficacy and side effects.

• Individualized treatment plans: The specific formulation (TDF or TAF) and dosage of Tenofovir can vary based on individual health factors, including kidney function and other medical conditions.

What Special Precautions Should Be Taken?

• Prescription only: Tenofovir is available only by prescription. It should be taken exactly as prescribed by the healthcare provider.

• Regular monitoring: Regular medical check-ups and monitoring of kidney function, bone density, and liver function are typically required during Tenofovir treatment.

• Kidney function: Tenofovir can affect kidney function. If you have a history of kidney problems, inform your healthcare provider, and they may monitor your kidney function regularly.

• Bone health: Some studies have suggested that Tenofovir may be associated with bone density loss. Discuss any concerns about bone health with the healthcare provider, and they may recommend appropriate supplements or lifestyle changes.

• Hepatitis B flare-up: In cases of being treated for chronic hepatitis B, stopping Tenofovir suddenly may cause a severe flare-up of hepatitis. Check with your physician before stopping the medication.

• Adherence to treatment: It is crucial to take Tenofovir consistently and exactly as prescribed. Missing doses or not taking the medication as directed can lead to the development of drug-resistant strains of the virus.

• Interaction with other medications: Inform the healthcare provider about all medications, including over-the-counter drugs, supplements, and herbal products, that are taken. Some medicines may interact with Tenofovir.

• Side effects: Side effects include nausea, vomiting, dizziness, and changes in kidney function. Contact the healthcare provider promptly if you experience any unusual or severe side effects.

What to Do in the Event of an Overdose?

• Give details: Be ready to give details such as the person's age, weight, medication dosage (if known), and any symptoms they may suffer.

• Seek help immediately: Time is vital during an overdose event. Seek medical help before symptoms worsen.

• Follow medical advice: Once emergency medical services arrive, follow their instructions carefully. Depending on the specific circumstances, they may administer appropriate treatments or take other necessary actions.

What Are the Side Effects of Tenofovir?

Tenofovir side effects include the following:

• Nausea: Some people may experience a feeling of sickness or discomfort in the stomach.

• Vomiting: Tenofovir can sometimes cause vomiting as a side effect.

• Diarrhea: Diarrhea is another gastrointestinal side effect that may occur.

• Headache: Some individuals may experience headaches while taking Tenofovir.

• Dizziness: Tenofovir can cause dizziness in some people.

• Fatigue: Feeling tired or fatigued is a common side effect.

• Renal effects: Tenofovir may affect kidney function in some individuals. It can lead to renal impairment, including proximal renal tubulopathy (dysfunction of the proximal tubule) and Fanconi syndrome.

• Liver enzyme changes: Tenofovir may cause liver enzyme changes. Severe liver toxicity is rare.

• Bone density loss: Long-term use may result in bone density loss in some patients.

Storage of Tenofovir:

• Temperature: Store Tenofovir at room temperature, away from extreme heat or cold. As the manufacturer specifies, avoid exposure to temperatures above a certain threshold.

• Humidity: Keep the medication in a dry place. High humidity can affect the stability of pharmaceuticals.

• Light: Some medications are sensitive to light, so it is advisable to store Tenofovir in a container to prevent exposure to light.

• Container: Cover the lid tightly after every use to protect the drug from moisture exposure.

• Expiry date: Avoid using the drug if it has expired.

• Keep out of reach of children: Store medications in a place that is not easily accessible to children.

For Doctors:

What Are the Drug Interactions?

• Didanosine (DDI): Co-administration of Tenofovir with Didanosine should be avoided, as it can increase the concentration of didanosine in the blood, potentially leading to toxicity.

• Adefovir (A related antiretroviral): Concomitant use of Tenofovir and Adefovir should be avoided, as both drugs have similar mechanisms of action and may increase the risk of renal toxicity.

• Other nephrotoxic drugs: Tenofovir can potentially cause renal toxicity. Therefore, caution should be exercised when combining Tenofovir with other drugs that may have nephrotoxic effects.

• Nucleoside reverse transcriptase inhibitors (NRTIs): Tenofovir is often combined with other antiretroviral drugs. Some combinations are preferred over others based on their efficacy and safety profiles.

• Probenecid: Probenecid, a drug used to treat gout, may increase the concentration of Tenofovir in the blood. Caution is advised when these drugs are used together.

• Drugs that affect renal function: Tenofovir is primarily excreted through the kidneys, so drugs that affect renal function may influence Tenofovir levels in the body. Examples include certain diuretics and other medications that impact renal function.

• Cidofovir and other nephrotoxic agents: Co-administration of Tenofovir with Cidofovir or other nephrotoxic agents may increase the risk of renal toxicity.

Pharmacodynamics:

1. Mechanism of action:

• Tenofovir disoproxil fumarate (TDF): Tenofovir Disoproxil Fumarate is metabolized in the body and changed into its functional form, Tenofovir diphosphate. Tenofovir diphosphate is a nucleotide analog that competitively inhibits the activity of HIV reverse transcriptase, an enzyme necessary for the virus's replication. It blocks the lengthening of the viral DNA chain.

• Tenofovir alafenamide (TAF): Tenofovir Alafenamide is also a prodrug, and it is converted to Tenofovir within cells. However, TAF results in higher intracellular levels of the active form of Tenofovir Diphosphate compared to TDF. This allows for similar antiviral efficacy with lower systemic exposure, potentially reducing the risk of side effects.

2. Antiviral activity: In HIV treatment using Tenofovir, this medicine works by stopping the virus from making new copies of itself. The drug interferes with the lengthening of the viral DNA strand and prevents the multiplication of the virus.

3. Spectrum of activity: Tenofovir can work against HIV-1 and HIV-2.

4. Adverse effects: Tenofovir can cause renal (kidney) toxicity, especially TDF, which has been associated with proximal renal tubular dysfunction and bone mineral density loss.

TAF was developed to address some of the renal and bone issues associated with TDF.

5. Combination therapy: Tenofovir is often combined with other ART drugs for treating HIV. Like other antiretroviral drugs, the development of resistance to Tenofovir can occur if the medication is not taken as prescribed.

Pharmacokinetics:

1. Tenofovir Disoproxil Fumarate (TDF):

• Absorption: TDF is administered orally and rapidly converted to its active form, Tenofovir diphosphate, in the body. It is well absorbed from the gastrointestinal tract.

• Distribution: Tenofovir is distributed into various tissues, including the kidneys, liver, and peripheral blood mononuclear cells.

• Metabolism: Tenofovir does not undergo significant metabolism in the liver. The prodrug, TDF, is converted to Tenofovir in the body.

• Elimination: The drug is removed from the body through urine with a half-life of 17 hours.

2. Tenofovir Alafenamide (TAF):

• Absorption: When taken by mouth, TAF is converted into Tenofovir. It stays more stable in the bloodstream than TDF, which allows higher levels of the drug to reach the cells where it is needed.

• Distribution: Once converted, Tenofovir spreads through body tissues in a way similar to TDF.

• Metabolism: Inside the cells, TAF is broken down to form active Tenofovir.

• Elimination: Tenofovir is cleared from the body through both the kidneys and other pathways. Because TAF produces lower Tenofovir levels in the bloodstream compared to TDF, it is considered gentler on the kidneys and bones.

Toxicity:

The common toxicity with Tenofovir is renal toxicity. Constant evaluation of renal function is essential in individuals taking Tenofovir. Furthermore, it also causes bone density loss, and the possibility of osteomalacia is high in individuals who have risk factors for it. It also causes nausea and diarrhea.

Other specifications:

• Tenofovir in pregnant women: Administering Tenofovir in pregnant women prevents the transmission of the virus to the child by reducing the viral load.

• Tenofovir in breastfeeding women: The possibility of drug exposure in infants is high because Tenofovir will be present in breast milk. Data indicate that low levels of Tenofovir will be present in breast milk, and even with that, the adverse effects on the infant appear to be less. However, physicians should weigh the advantages of breastfeeding against potential risks and consider alternative medications.

• Tenofovir in geriatric patients: Tenofovir has been studied in geriatric patients. Geriatric patients may be more susceptible to renal side effects of Tenofovir, such as renal impairment. Adjusting the dosage depending on the individual’s situation is important while prescribing Tenofovir for elderly patients.

• Tenofovir in pediatric patients: Tenofovir is suitable for treating HIV in children. Frequent evaluation of renal function and general safety is critical when prescribing Tenofovir to pediatric patients.