Tenofovir in HIV Infections: A Comprehensive Review

Overview:

Tenofovir, a potent antiretroviral medication, plays a pivotal role in the management of HIV ((human immunodeficiency virus)infections, significantly contributing to the advancement of HIV or AIDS (acquired immunodeficiency syndrome) treatment. As a nucleotide reverse transcriptase inhibitor (NRTI), Tenofovir works by inhibiting the activity of the HIV enzyme reverse transcriptase, thereby impeding viral replication. Its effectiveness and safety profile have positioned it as a cornerstone in various antiretroviral regimens for treatment-naive and experienced individuals. Tenofovir has demonstrated robust viral suppression, immunological benefits, and a favorable resistance profile, making it a crucial component in the global effort to combat the HIV epidemic. Tenofovir received FDA (Food and Drug Administration) authorization on 26 October 2001.

How Does the Drug Work?

Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI), and it exerts its antiretroviral effects by targeting a key enzyme in the life cycle of the human immunodeficiency virus (HIV). HIV is a retrovirus. Therefore, it can convert its RNA (ribonucleic acid) genome into DNA (deoxyribonucleic acid) within the host cell. The enzyme reverse transcriptase facilitates this conversion. Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF) are two formulations of Tenofovir commonly used to treat HIV.

Once inside the host cell, Tenofovir undergoes phosphorylation to its active form, Tenofovir diphosphate. This active metabolite competes with the natural substrate for reverse transcriptase, incorporating itself into the growing viral DNA chain. However, unlike the natural nucleotides, Tenofovir lacks a 3'-hydroxyl group, which prevents further DNA chain elongation. This disruption inhibits the reverse transcription process, ultimately preventing the formation of a complete, functional viral DNA strand. As a result, Tenofovir hinders the replication of HIV, helping to control its spread and reduce the viral load in the body.

Indications:

• HIV Infection: Tenofovir is used as part of combination therapy for the treatment of HIV infection in both adult and pediatric patients. It helps to reduce viral load, maintain or improve immune function, and delay the progression of HIV-related illnesses.

• Chronic Hepatitis B: Tenofovir is also used to treat chronic hepatitis B (HBV) infection in adults and pediatric patients. It helps to suppress viral replication, reduce liver inflammation, and improve long-term outcomes.

• Pre-Exposure Prophylaxis (PrEP): Tenofovir, in combination with Emtricitabine, is used as a preventive measure in individuals at high risk of acquiring HIV.

Contraindications:

• Hypersensitivity: Individuals with a known hypersensitivity or allergic reaction to Tenofovir or any of its components should not use the drug.

• Renal Impairment: Tenofovir is primarily excreted through the kidneys. Therefore, it is contraindicated in individuals with severe renal impairment or those with a creatinine clearance below a certain threshold. TAF is associated with less renal toxicity compared to TDF.

• Bone Health: Tenofovir, particularly TDF, has been associated with decreased bone mineral density in some individuals. This is a consideration, especially for individuals with pre-existing bone issues or those at risk of osteoporosis.

• Liver Impairment: Individuals with severe liver impairment may require dose adjustments or should avoid Tenofovir, as it is metabolized in the liver.

• Interactions with Other Medications: Tenofovir can interact with other medications, so informing the healthcare provider about all the drugs taken is crucial.

Available Doses and Dosage Forms:

1.Tenofovir Disoproxil Fumarate (TDF):

• Dosage Form: Tablet

• Available Strengths: Tenofovir Disoproxil Fumarate is available in various strengths, such as 300 mg (milligrams) tablets.

2. Tenofovir Alafenamide (TAF):

• Dosage Forms: Tablet

• Available Strengths: Tenofovir Alafenamide has various strengths, such as 25 mg, 10 mg, and 40 mg tablets.

3. Fixed-Dose Combinations (FDCs): Tenofovir is often part of fixed-dose combinations with other antiretroviral drugs. These combinations can simplify treatment regimens and improve adherence.

• Examples include products containing Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide combined with other antiretroviral agents.

For Patients

What Are HIV Infections?

HIV, or Human Immunodeficiency Virus, is a viral infection that attacks the immune system, specifically the CD4 (cluster of differentiation 4) cells (T cells), which play a crucial role in the body's defense against infections. If left untreated, HIV can lead to the disease AIDS (Acquired Immunodeficiency Syndrome). The virus is transmitted through contact with certain body fluids, such as blood, semen, vaginal fluids, rectal fluids, and breast milk, from a person who has HIV. This transmission can occur during unprotected sexual intercourse, sharing of needles or syringes, and from an infected mother to her child during childbirth or breastfeeding. HIV weakens the immune system over time, making it difficult for the body to fight off infections and diseases. While there is no cure for HIV, antiretroviral therapy (ART) can effectively control the virus, allowing individuals with HIV to live healthy and productive lives. Prevention measures, including practicing safe sex, using clean needles, and accessing pre-exposure prophylaxis (PrEP), are crucial in reducing the spread of HIV.

Why Is Tenofovir Prescribed?

• Antiretroviral Treatment for HIV: Tenofovir, in formulations like Tenofovir Disoproxil Fumarate (TDF), 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 the HIV and reducing its ability to spread.

• Pre-Exposure Prophylaxis (PrEP): Tenofovir, especially in the form of Tenofovir Disoproxil Fumarate, is used in PrEP for individuals at high risk of HIV infection.

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.

• Viral Load Suppression: Tenofovir contributes to suppressing the viral load in individuals with HIV, helping to maintain a low level of the virus in the body.

• Management of Co-Infections: In some cases, Tenofovir may be used to manage HIV co-infections, such as chronic hepatitis B (it is a serious liver infection caused by the hepatitis B virus (HBV).

• Regular Monitoring: Patients prescribed Tenofovir need regular medical monitoring to assess the effectiveness of the treatment, manage potential side effects, and adjust the treatment plan as needed.

• 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. Inform the healthcare provider of a history of kidney problems, and they may monitor the 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 case of being treated for chronic hepatitis B, stopping Tenofovir suddenly may cause a severe flare-up of hepatitis. Consult the healthcare provider before discontinuing the medication.

• Adherence to Treatment: Taking Tenofovir consistently and exactly as prescribed is crucial. Missing doses or not taking the medication as directed can lead to developing 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 medications may interact with Tenofovir.

• Side Effects: Be aware of potential side effects of Tenofovir, such as nausea, vomiting, dizziness, and changes in kidney function. If you experience any unusual or severe side effects, contact the healthcare provider promptly.

Side Effects of Tenofovir:

• 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 (it is a defect of the proximal tubule leading to malabsorption of various electrolytes and substances that are usually absorbed by the proximal tubule).

• Bone Density Loss: Long-term use of Tenofovir has been associated with bone density loss in some patients.

• Liver Enzyme Changes: Tenofovir may cause changes in liver enzymes, though severe liver toxicity is rare.

Storage of Tenofovir:

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

• 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 its original packaging or container to protect it from light exposure.

• Container: Close the container tightly after each use to prevent moisture and air from affecting the medication.

• Expiry Date: Always check the expiration date on the medication packaging, and do not use it if it has expired.

• Keep Out of Reach of Children: Store medications in a place that is not easily accessible to children.

What Can Be Done in the Event of an Overdose?

• Provide Information: Be prepared to provide information about the person's age, weight, the amount of medication taken (if known), and any symptoms they may be experiencing.

• Do Not Delay Seeking Help: Time is crucial in the event of an overdose. Do not wait for symptoms to worsen before seeking medical attention.

• Follow Medical Advice: Follow their instructions carefully once emergency medical services arrive. They may administer appropriate treatments or take other necessary actions based on the specific circumstances.

For Doctors:

Pharmacodynamics:

1. Mechanism of Action:

• Tenofovir Disoproxil Fumarate (TDF): Tenofovir Disoproxil Fumarate is a prodrug that gets converted into its active form, Tenofovir diphosphate, after being metabolized in the body. Tenofovir diphosphate is a nucleotide analog that competitively inhibits the activity of HIV reverse transcriptase, an enzyme necessary for the replication of the virus. It acts as a chain terminator, preventing the elongation 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: Tenofovir inhibits the replication of HIV by interfering with the reverse transcription process. It competes with natural nucleotides, incorporating itself into the growing viral DNA chain and causing premature termination.

3. Spectrum of Activity: Tenofovir is active 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 used in combination with other antiretroviral drugs as part of highly active antiretroviral therapy (HAART) for the management of 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 is 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 elimination half-life of Tenofovir is approximately 17 hours. It is primarily excreted unchanged in the urine, with renal clearance being a significant pathway. Dosage adjustments may be necessary in individuals with impaired renal function.

2. Tenofovir Alafenamide (TAF):

• Absorption: TAF is also administered orally and efficiently converted to Tenofovir in the plasma. Unlike TDF, TAF is more stable in plasma, leading to higher intracellular levels of the active drug in target cells.

• Distribution: Tenofovir is distributed into tissues similarly to TDF.

• Metabolism: TAF is primarily metabolized within cells to form Tenofovir.

• Elimination: Tenofovir is eliminated through a combination of renal and non-renal pathways. TAF results in lower plasma concentrations of Tenofovir compared to TDF, which may contribute to a favorable renal and bone safety profile.

Toxicity:

While generally considered safe and effective, like any medication, Tenofovir can be associated with potential toxicities. The most notable concern is renal toxicity, with reports of proximal tubular dysfunction and a decline in kidney function. Regular monitoring of renal function is recommended for individuals taking Tenofovir. Additionally, there have been rare cases of bone density loss and the development of osteomalacia, particularly in patients with pre-existing risk factors. Tenofovir may also cause gastrointestinal symptoms such as nausea and diarrhea. Healthcare providers must assess individual patient characteristics and risk factors when prescribing Tenofovir, balancing the potential benefits of viral suppression with the need to manage and monitor for potential toxicities. Regular medical follow-ups and communication between healthcare providers and patients are essential to manage adverse effects properly.

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.

Other Specifications:

• Tenofovir in Pregnant Women: Tenofovir, an antiretroviral medication, is commonly used in pregnant women with HIV to prevent mother-to-child transmission of the virus. Multiple studies have demonstrated its safety and efficacy, making it a key component of antiretroviral therapy during pregnancy.

• Tenofovir in Breastfeeding Women: Tenofovir, an antiretroviral medication commonly used in the treatment of HIV, can be present in breast milk, raising concerns about potential exposure to breastfeeding infants. Limited data suggest that while low levels of Tenofovir may be detected in breast milk, the overall risk of adverse effects on the infant appears to be low. However, healthcare providers should carefully weigh the benefits of breastfeeding against potential risks and consider alternative antiretroviral medications when possible.

• Tenofovir in Geriatric Patients: Tenofovir, an antiretroviral medication commonly used to treat HIV, has been studied in geriatric patients, and caution is advised due to potential age-related changes in renal function. Geriatric patients may be more susceptible to renal side effects of Tenofovir, such as renal impairment and bone mineral density loss. Monitoring renal function regularly and adjusting the dosage based on individual patient characteristics are essential considerations when prescribing Tenofovir to senior individuals.

• Tenofovir in Pediatric Patients: Tenofovir, an antiretroviral drug used in the treatment of HIV, has been studied in pediatric patients and is considered a key component of pediatric HIV therapy. Its safety and efficacy have been demonstrated in various age groups, and appropriate dosing adjustments are recommended based on the child's age, weight, and renal function. Regular monitoring of renal function and overall safety is crucial when prescribing Tenofovir to pediatric patients.