VIRADAY

Indications

• HIV-1 infection
• HIV infection in combination with other antiretroviral drugs

Dosage

Children: Refer to the BNF for Children for specific dosing information.

Adults: 600 mg once daily, administered orally, preferably at bedtime to minimize CNS effects.

Mechanism of action

Efavirenz inhibits the activity of viral RNA-directed DNA polymerase, also known as reverse transcriptase. This inhibition interferes with the generation of DNA copies of viral RNA, which are necessary for producing new virions. The drug diffuses into the cell and binds to the reverse transcriptase enzyme, causing a conformational change that results in enzyme inhibition. This process is vital for preventing viral replication, although it does not eliminate HIV from the body.

Pharmacodynamics

As a non-nucleoside reverse transcriptase inhibitor, efavirenz exhibits virustatic properties, meaning it inhibits viral replication without directly killing the virus. Its pharmacodynamic effects are influenced by its intracellular conversion to an active triphosphorylated form. This conversion is variable, depending on the cell type, but ultimately leads to effective inhibition of HIV replication. Efavirenz is often used in conjunction with other antiretrovirals as part of a comprehensive treatment approach for HIV.

Pharmacokinetics

Efavirenz is well-absorbed when administered orally, and its bioavailability is affected by food intake. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes (CYP2B6), leading to the formation of active metabolites. The drug has a long half-life, allowing for once-daily dosing. It is important to monitor liver function due to potential hepatotoxicity, especially in patients with existing liver conditions. The pharmacokinetics may be altered by drug interactions, necessitating dose adjustments in certain situations.

Contra-indications

• Severe hypersensitivity to efavirenz or any component of the formulation
• Acute porphyrias
• History of psychiatric disorders
• History of seizures
• Severe hepatic impairment

Adverse effects

• Rash
• Dizziness
• Nausea
• Vomiting
• Abdominal pain
• Asthenia
• Diarrhoea
• Sleep disorders
• CNS effects (e.g., confusion, hallucinations)
• Fatigue
• Mood alterations
• Suicidal behavior
• Hepatocellular injury
• Seizures
• Stevens-Johnson syndrome

Interactions

• Posaconazole: severe decrease in exposure
• Antimalarials: severe decrease in exposure
• Atovaquone: severe decrease in exposure
• Benzodiazepines: severe interaction affecting effects
• Midazolam: severe interaction affecting effects
• Voriconazole: moderate decrease in exposure
• Caspofungin: moderate decrease in concentration
• Ciclosporin: moderate decrease in concentration
• Coumarins: moderate interaction affecting concentration
• Opioids: moderate decrease in exposure

Precautions

• Caution in patients with history of psychiatric disorders or seizures
• Caution in elderly patients
• Monitor liver function if receiving other hepatotoxic drugs
• Caution in patients with chronic hepatitis B or C
• Driving and skilled tasks may be affected due to CNS effects

Pregnancy

Reports of neural tube defects when used in the first trimester. Manufacturer advises avoiding use during pregnancy.

Breast-feeding

Limited information available; caution is advised.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• 600 mg capsules
• 600 mg tablets

Indications

• HIV infection

Dosage

Children: Child 4 months–17 years (body-weight up to 33 kg): 6 mg/kg once daily. Child 4 months–17 years (body-weight 33 kg and above): 240 mg once daily.

Adults: 200 mg once daily by mouth using capsules or 240 mg once daily by mouth using oral solution.

Mechanism of action

Emtricitabine is a cytidine analog that, when phosphorylated to emtricitabine 5'-triphosphate, competes with deoxycytidine 5'-triphosphate for HIV-1 reverse transcriptase. It incorporates itself into the viral DNA during replication, leading to chain termination. This prevents the incorporation of additional nucleotides and inhibits the transcription of viral RNA into DNA, thereby preventing viral replication.

Pharmacodynamics

Emtricitabine acts by competing with natural substrates of HIV-1 reverse transcriptase, leading to the termination of viral DNA synthesis. It has a long duration of action, allowing for once-daily dosing. Clinicians should monitor for potential side effects, including lactic acidosis and hepatomegaly with steatosis, which can occur with nucleoside analogs.

Pharmacokinetics

Emtricitabine is absorbed well following oral administration, with peak plasma concentrations occurring approximately 1 to 2 hours post-dose. It has a long half-life, allowing for its once-daily administration. Emtricitabine is primarily excreted through the kidneys, and dosage adjustments may be necessary in patients with renal impairment. It is metabolized minimally by the liver.

Contra-indications

• Severe hepatic impairment
• Severe renal impairment (creatinine clearance <30 mL/min)

Adverse effects

• Decreased appetite
• Asthenia
• Constipation
• Diarrhoea
• Dizziness
• Electrolyte imbalance
• Flatulence
• Gastrointestinal discomfort
• Headache
• Abnormal dreams
• Dyspepsia
• Hyperbilirubinaemia
• Hyperglycaemia
• Hypersensitivity reactions
• Hypertriglyceridaemia
• Neutropenia
• Pain
• Rash
• Pustular skin reactions
• Sleep disorders
• Angioedema (uncommon)

Interactions

• Cobicistat and elvitegravir may impact emtricitabine efficacy
• Potential for increased risk of treatment failure in pregnancy when used with elvitegravir
• Monitor for changes in drug levels when co-administered with other antiretrovirals

Precautions

• Caution in patients with hepatic impairment due to increased risk of side effects
• Monitor renal function regularly, particularly in those with existing renal impairment
• Patients should be advised on the risks of lactic acidosis and hepatomegaly with steatosis

Pregnancy

Not recommended for initiation during pregnancy due to risk of treatment failure and maternal-to-child transmission of HIV-1. Women who become pregnant during therapy should be switched to an alternative regimen.

Breast-feeding

Emtricitabine is excreted in human breast milk, caution is advised when administering to breastfeeding mothers.

Storage

Store in the original container, protected from moisture, and keep out of reach of children.

Formulations

• 200 mg capsules
• 240 mg oral solution

Indications

• HIV infection
• Chronic hepatitis B virus infection

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients.

Adults: Refer to the BNF for specific dosing recommendations based on the condition being treated and individual patient factors.

Mechanism of action

Disproxil is converted intracellularly to tenofovir diphosphate, which competes with the natural substrate deoxyadenosine 5'-triphosphate for incorporation into viral DNA by reverse transcriptase. This incorporation leads to premature termination of the viral DNA chain, thereby inhibiting viral replication.

Pharmacodynamics

Disproxil exhibits a potent antiviral effect against HIV and HBV by inhibiting the reverse transcriptase enzyme, which is crucial for the conversion of viral RNA into DNA. The drug demonstrates a high barrier to resistance, making it a preferred option in antiretroviral therapy. Its efficacy is enhanced when used in combination with other antiretrovirals, which can target different stages of the viral life cycle.

Pharmacokinetics

Disproxil is well absorbed after oral administration, with a bioavailability of approximately 25% due to extensive first-pass metabolism. The peak plasma concentration occurs about 1 hour after dosing. It has a half-life of approximately 12-18 hours, allowing for once-daily dosing in most cases. The drug is primarily excreted via the kidneys, with renal clearance being a significant route of elimination. Caution is advised in patients with renal impairment, as dosage adjustments may be necessary.

Adverse effects

• Nausea
• Diarrhea
• Abdominal pain
• Headache
• Fatigue
• Dizziness
• Rash
• Liver function abnormalities
• Renal impairment

Interactions

• Potential interactions with other nephrotoxic drugs
• Antiretroviral medications may alter pharmacokinetics
• Caution with drugs that affect liver enzymes

Precautions

• Monitor renal function regularly
• Assess liver function prior to and during treatment
• Use with caution in patients with pre-existing kidney disease
• Consider potential drug interactions

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult relevant guidelines.

Breast-feeding

Excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablets
• Oral solution

Indications

• HIV infection
• Chronic hepatitis B

Dosage

Children: Refer to BNF for Children for specific pediatric dosing information.

Adults: Refer to BNF for specific dosing information.

Mechanism of action

Once tenofovir is activated by bi-phosphorylation, it functions as an antiviral acyclic nucleoside phosphonate. It inhibits viral reverse transcriptase, exhibiting an inhibitory constant of approximately 0.022 micromolar. Tenofovir competes with deoxyadenosine 5'-triphosphate to generate new viral DNA, leading to chain termination and inhibition of viral replication. Its safety profile is maintained due to its low affinity for cellular DNA polymerases, including mitochondrial DNA polymerase gamma.

Pharmacodynamics

Tenofovir has demonstrated high efficacy in treatment-naive HIV patients, showing comparable effectiveness to efavirenz while exhibiting lower toxicity than some other antiretrovirals, such as stavudine. In patients with hepatitis B, tenofovir treatment has been associated with undetectable viral DNA levels after one year.

Pharmacokinetics

Tenofovir is absorbed after oral administration and is primarily eliminated by the kidneys. It has a half-life that allows for once-daily dosing and achieves therapeutic concentrations in plasma and tissues. The metabolism of tenofovir involves conversion to its active form, which is then incorporated into viral DNA, leading to its antiviral effects.

Contra-indications

• Hypersensitivity to tenofovir or any excipients in the formulation
• Severe renal impairment (CrCl < 30 mL/min) without appropriate dosage adjustment

Adverse effects

• Nausea
• Diarrhea
• Headache
• Fatigue
• Renal impairment
• Bone density loss
• Lactic acidosis

Interactions

• Antiepileptics (carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone) with tenofovir alafenamide: Severe (decreases exposure)
• Tipranavir with tenofovir alafenamide: Severe (decreases exposure)
• Rifamycins with tenofovir alafenamide: Severe (decreases exposure)
• St John’s Wort with tenofovir alafenamide: Severe (decreases exposure)
• Fostemsavir with tenofovir disoproxil: Moderate (increases exposure)
• Fostemsavir with tenofovir alafenamide: Moderate (increases exposure)
• Ciclosporin with tenofovir alafenamide: Unknown (increases exposure)
• Ciclosporin with tenofovir disoproxil: Unknown (increases exposure)
• Eltrombopag with tenofovir alafenamide: Unknown (increases exposure)
• Eltrombopag with tenofovir disoproxil: Unknown (increases exposure)

Precautions

• Monitor renal function regularly during treatment
• Use with caution in patients with a history of renal disease
• Consider bone density monitoring in patients on long-term therapy

Pregnancy

Tenofovir is categorized as a pregnancy category B drug. Animal studies have not shown any harm, but human data is limited. Weigh risks and benefits when prescribing during pregnancy.

Breast-feeding

Tenofovir is excreted in breast milk, but the amount is considered low. The benefits of breastfeeding should be considered against the potential risk of HIV transmission.

Storage

Store at room temperature (20-25°C) in a tightly closed container. Keep away from light and moisture.

Mechanism of action

Similar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity. Efavirenz diffuses into the cell where it binds adjacent to the active site of reverse transcriptase. This produces a conformational change in the enzyme that inhibits function.

Pharmacodynamics

Efavirenz (dideoxyinosine, ddI) is an oral non-nucleoside reverse transcriptase inhibitor (NNRTI). It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine. Efavirenz was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine. Currently, the CDC recommends that Efavirenz be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or efavirenz when treating HIV infection.

Mechanism of action

Emtricitabine is a cytidine analog which, when phosphorylated to emtricitabine 5'-triphosphate, competes with deoxycytidine 5'-triphosphate for HIV-1 reverse transcriptase. As HIV-1 reverse transcriptase incorporates emtricitabine into forming DNA strands, new nucleotides are unable to be incorporated, leading to viral DNA chain termination. Inhibition of reverse transcriptase prevents transcription of viral RNA into DNA, therefore the virus is unable to incorporate its DNA into host DNA and replicate using host cell machinery. This reduces viral load. Emtricitabine, a synthetic nucleoside analog of cytosine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase alpha, beta, epsilon and mitochondrial DNA polymerase gamma.

Pharmacodynamics

Emtricitabine is a cytidine analog that competes with the natural substrate of HIV-1 reverse transcriptase to be incorporated into newly formed DNA, terminating its transcription. It is administered once daily so it has a long duration of action. Patients should be counselled regarding the risk of lactic acidosis and hepatomegaly with steatosis.

Mechanism of action

Once tenofovir is activated by a bi-phosphorylation it acts as an antiviral acyclic nucleoside phosphonate. It is a potent inhibitor of the viral reverse transcriptase with an inhibitory constant of approximately 0.022 micromolar. Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase causing chain termination and the inhibition of viral synthesis. All these activities are attained by its competition with deoxyadenosine 5'-triphosphate in the generation of new viral DNA. Once tenofovir is incorporated in the chain, it induces a chain termination which in order inhibits viral replication. The safety of tenofovir relies on its low affinity towards the cellular DNA polymerase including the mitochondrial DNA polymerase gamma.

Pharmacodynamics

Tenofovir has been shown to be highly effective in patients that have never had an antiretroviral therapy and it seemed to have lower toxicity than other antivirals such as [stavudine]. In phase 3 clinical trials, tenofovir presented a similar efficacy than [efavirenz] in treatment-naive HIV patients. In hepatitis B infected patients, after one year of tenofovir treatment, the viral DNA levels were undetectable.