efavirenz/lamivudine/tenofovir DF

Action and Spectrum

Actions and Spectrum: 

efavirenz/lamivudine/tenofovir DF is a combination of antiretroviral therapy used to treat HIV infection. Each component of this regimen plays a crucial role in suppressing the replication of HIV and reducing its detrimental effects on the immune system. 

efavirenz is a NNRTI (non-nucleoside reverse transcriptase inhibitor) that specifically targets the reverse transcriptase enzyme of HIV. By binding to the enzyme, efavirenz prevents the conversion of the viral RNA into DNA, thereby inhibiting viral replication. It effectively lowers the viral load, allowing the immune system to regain strength and reducing the progression of HIV-related complications. 

lamivudine and tenofovir DF are nucleoside reverse transcriptase inhibitors (NRTIs) that work by blocking the action of the reverse transcriptase enzyme. lamivudine hampers the replication of the viral DNA chain, while tenofovir DF inhibits viral DNA synthesis. Together, they enhance the antiviral effects of efavirenz, making the drug combination more potent against HIV. Additionally, tenofovir DF has the added benefit of targeting HIV at different stages of its replication cycle, providing a broader spectrum of activity. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Pain (13%) 

Rash (18%) 

Diarrhea (11%) 

Depression (11%) 

Headache (14%) 

1-10% 

Peripheral neuropathy (1%) 

Abdominal pain (7%) 

Myalgia (3%) 

Asthenia (6%) 

Arthralgia (5%) 

Fever (8%) 

Insomnia (5%) 

Lipodystrophy (1%) 

Anxiety (6%) 

Pneumonia (5%) 

Dizziness (3%) 

Black Box Warning

Black Box Warning: 

• Lactic Acidosis/Severe Hepatomegaly with Steatosis: efavirenz/lamivudine/tenofovir DF and other nucleoside analogs have been associated with the risk of developing lactic acidosis and severe hepatomegaly with steatosis. The black box warning emphasizes the need for careful monitoring of liver function. It warns against using the drug combination in patients with pre-existing liver disease or those at risk of liver dysfunction. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication 

• Hypersensitivity: The drug combination should not be used in individuals who have previously exhibited hypersensitivity or an allergic reaction to any of the components, including efavirenz, lamivudine, or tenofovir DF.  
• Severe Hepatic Impairment: efavirenz/lamivudine/tenofovir DF is contraindicated in individuals with severe liver disease or significant liver impairment. This is because the metabolism of the drugs primarily occurs in the liver, and severe liver dysfunction can alter drug levels and increase the risk of adverse effects. 
• Pregnancy: The combination therapy should be used cautiously during pregnancy, as efavirenz has been associated with potential risks to the developing fetus. However, the specific recommendations may vary depending on individual circumstances, and the potential benefits and risks should be carefully evaluated and discussed with the healthcare provider. 
• Concomitant Use with Certain Medications: efavirenz/lamivudine/tenofovir DF may interact with other medications, including those metabolized by the cytochrome P450 system.  

Caution 

• Central Nervous System (CNS) Effects: efavirenz, one of the components in this regimen, can cause CNS-related side effects, including dizziness, confusion, impaired concentration, abnormal dreams, and sleep disturbances. Patients should be cautious when performing activities that require mental alertness, like the driving or operating machinery until they know how the medication affects them. Additionally, individuals with a history of psychiatric disorders may be at an increased risk of experiencing psychiatric symptoms while taking efavirenz. 
• Renal Impairment: tenofovir DF, another component of this combination therapy, can affect kidney function. It is vital to assess renal function before treatment and periodically monitor kidney function during therapy. Dose adjustments may be necessary in patients with impaired renal function to prevent the accumulation of tenofovir DF and minimize the risk of renal toxicity. 
• Bone Health: tenofovir DF has been associated with a potential risk of decreased bone mineral density and osteoporosis, especially with long-term use. This caution is significant for individuals with existing risk factors for bone loss, such as older age, a history of fractures, or prolonged use of corticosteroids. Regular monitoring of bone health may be recommended, and appropriate interventions, such as calcium and vitamin D supplementation or medication adjustments, may be considered. 
• Hepatitis B Coinfection: lamivudine, one of the components of this combination therapy, is also used to treat hepatitis B virus (HBV) infection. However, suppose efavirenz/lamivudine/tenofovir DF is used solely to treat HIV in individuals with HBV coinfection. In that case, it is essential to closely monitor liver function and consider additional antiviral treatment for the HBV infection if necessary. Sudden discontinuation of the medication may result in exacerbation of HBV infection. 

Pregnancy / Lactation

Pregnancy consideration:  

US FDA pregnancy category: Not assigned. 

Lactation:   

Excreted into human milk: Yes. 

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    
• Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

efavirenz/lamivudine/tenofovir DF combines antiretroviral therapy (ART) for treating HIV infection. The three components of this regimen act through different mechanisms to suppress the replication of HIV. efavirenz is a NNRTI (non-nucleoside reverse transcriptase inhibitor) that binds to and inhibits the reverse transcriptase enzyme, preventing the conversion of viral RNA into DNA.

lamivudine and tenofovir DF are nucleoside reverse transcriptase inhibitors (NRTIs) that interfere with viral DNA synthesis. lamivudine inhibits the viral DNA chain elongation, while tenofovir DF inhibits viral DNA synthesis by acting as a nucleotide analog. This combination therapy provides a potent and synergistic effect, reducing the viral load, preserving immune function, and improving the overall health outcomes of individuals living with HIV. 

Pharmacodynamics: 

Mechanism of action: efavirenz/lamivudine/tenofovir DF is a combination of antiretroviral therapy (ART) used in the treatment of HIV infection. Each component of this regimen works through different mechanisms to suppress the replication of the HIV: 

• efavirenz (Non-Nucleoside Reverse Transcriptase Inhibitor – NNRTI): efavirenz inhibits the reverse transcriptase enzyme of HIV. It binds directly to the enzyme, explicitly targeting the catalytic site, and prevents the conversion of viral RNA into DNA. efavirenz blocks the essential step in the viral replication cycle by inhibiting reverse transcription, ultimately reducing viral load and replication. 
• lamivudine (Nucleoside Reverse Transcriptase Inhibitor – NRTI): lamivudine is a nucleoside analog incorporated into the growing viral DNA chain by the reverse transcriptase enzyme. Once incorporated, lamivudine acts as a faulty building block, leading to premature termination of the viral DNA chain. This inhibits viral replication and reduces the production of new infectious viral particles. 
• tenofovir DF (Nucleotide Reverse Transcriptase Inhibitor – NRTI): tenofovir DF is converted into its active form, tenofovir, within the body. tenofovir is a nucleotide analog that competes with the natural building blocks of viral DNA. The reverse transcriptase enzyme incorporates it into the viral DNA chain, causing premature chain termination and inhibiting further viral replication. 

By combining efavirenz, lamivudine, and tenofovir DF, the triple therapy regimen targets multiple steps in the HIV replication cycle. This comprehensive approach helps prevent the virus from multiplying, reduce the viral load, preserve immune function, and slow disease progression in individuals living with HIV. The combination therapy’s effectiveness and ability to target different stages of viral replication make it a cornerstone of HIV treatment. 

Pharmacokinetics: 

Absorption 

efavirenz is well absorbed orally, with peak plasma concentrations reached within 3-5 hours after administration. It is recommended to take efavirenz on an empty stomach to enhance absorption. 

lamivudine is rapidly and extensively absorbed after oral administration, with peak plasma concentrations achieved within 1-2 hours. It can be taken with or without food. 

tenofovir DF is a prodrug of tenofovir and is rapidly absorbed from the GIT (gastrointestinal tract) following oral administration. It is well absorbed, and food does not significantly affect its absorption. 

Distribution 

efavirenz has a high protein binding capacity (approximately 99%) and distributes widely into tissues, including the central nervous system (CNS). 

lamivudine has a small volume of distribution and readily distributes into various body tissues, including the CNS. 

tenofovir is distributed into various body tissues, including the kidneys, liver, and lymphoid tissues. 

Metabolism 

efavirenz undergoes extensive metabolism primarily by the liver enzyme cytochrome P450 2B6 (CYP2B6). It is converted into several metabolites, with the most active metabolite being 8-hydroxyefavirenz. 

lamivudine is not extensively metabolized in the body. It undergoes minimal hepatic metabolism and is primarily excreted unchanged. 

tenofovir DF is rapidly converted to its active form, tenofovir, by hydrolysis in the body. tenofovir does not undergo significant hepatic metabolism. 

Elimination and Excretion 

The elimination of efavirenz occurs mainly through hepatic metabolism, and the metabolites are predominantly eliminated in the feces. Only a tiny portion (less than 1%) of the drug is generally excreted unchanged in the urine. 

Most lamivudine is eliminated unchanged through renal excretion via glomerular filtration and active tubular secretion. 

tenofovir is eliminated primarily through renal excretion, glomerular filtration, and active tubular secretion. A small amount is also excreted in feces. 

Adminstartion

Administration: 

Oral administration 

efavirenz/lamivudine/tenofovir DF is typically a fixed-dose combination tablet. The dosing and administration instructions may vary based on factors such as renal function, concomitant medications, and treatment history. Following the prescribing healthcare professional’s instructions and the medication package insert is essential.  

• Dosage: The tablet should be taken orally with food to enhance absorption and reduce the likelihood of gastrointestinal side effects. 
• Timing: Taking efavirenz/lamivudine/tenofovir DF at the same time each day can help maintain consistent drug levels in the body. Establishing a routine for medication administration can assist in adherence to the treatment regimen. 
• Renal Impairment: In individuals with impaired renal function (creatinine clearance less than 50 mL/min), dosage adjustments may be necessary. Consultation with a healthcare professional is crucial to determine the appropriate dosage modifications based on renal function. 
• Concomitant Medications: It is essential to review all concomitant medications with a healthcare professional to identify potential drug interactions. Certain medications may require dosage adjustments or careful monitoring when combined with efavirenz/lamivudine/tenofovir DF. 
• Pregnancy Considerations: If the medication is being used during pregnancy, it is essential to follow the specific recommendations the healthcare professional provides. Dosage adjustments or alternative treatment options may be considered to optimize both maternal health and fetal outcomes. 
• Missed Dose: If a dose is missed, taking it as soon as possible is generally recommended. However, if the next scheduled dose is missed, it should be skipped and the following dose should be taken at the appropriate time. It is important to avoid taking a double dose of the medication to compensate for the missed dose.

Patient Information Leaflet

Patient information leaflet 

Generic Name: efavirenz/lamivudine/tenofovir DF 

Pronounced: [ ef-AV-ir-enz, la-MIV-ue-deen, and-ten-OF-oh-vir ] 

Why do we use efavirenz/lamivudine/tenofovir DF? 

efavirenz/lamivudine/tenofovir DF is primarily used to treat HIV-1 infection in adults and adolescents (aged 12 years and older) who weigh nearly 40 kg. This combination therapy is indicated for both treatment-naïve patients (those initiating HIV treatment for the first time) and treatment-experienced patients (those who have previously received antiretroviral therapy). 

• HIV Treatment: The combination therapy is effective in suppressing HIV replication, reducing the viral load, and preserving immune function. It helps slow disease progression, delay the onset of opportunistic infections, and improve the quality of life in individuals with HIV. 
• First-Line Therapy: efavirenz/lamivudine/tenofovir DF is commonly used as a first-line treatment option for HIV.  
• Combination Tablet: The fixed-dose combination of efavirenz/lamivudine/tenofovir DF simplifies treatment by combining three active antiretroviral drugs into a single tablet. This reduces the pill burden and helps improve adherence to the medication regimen, which is critical for successful HIV treatment outcomes. 
• Resistance Management: The three components of efavirenz/lamivudine/tenofovir DF belong to different antiretroviral drug classes (NNRTI and NRTIs), which helps minimize the development of drug resistance. The combination therapy is effective against a broad range of HIV strains and can be used to manage drug-resistant HIV infections in some instances.