TENOFOVIR DISOPROXIL FUMARATE/LAMIVUDINE/DOLUTEGRAVIR

Indications

• HIV infection without resistance to other inhibitors of HIV integrase
• HIV infection in patients with resistance to other inhibitors of HIV integrase (specialist use only)

Dosage

Children: Refer to BNF for Children for appropriate dosing.

Adults: 50 mg once daily.

Mechanism of action

Dolutegravir inhibits the HIV integrase enzyme by binding to its active site, blocking the strand transfer step of retroviral DNA integration into the host cell genome. This step is essential for the replication of HIV, and by preventing this integration, dolutegravir effectively inhibits viral activity and replication.

Pharmacodynamics

Clinical trials have demonstrated that dolutegravir leads to a rapid and dose-dependent reduction of HIV-1 RNA in infected subjects. The antiviral response can be sustained for several days following the last dose, indicating its long half-life and strong binding affinity. This characteristic contributes to a high barrier to the development of resistance, making dolutegravir a potent option in combination therapy regimens.

Pharmacokinetics

Dolutegravir exhibits favorable pharmacokinetics, with a mean elimination half-life of approximately 14 hours. It is well absorbed following oral administration, with food enhancing its bioavailability. The drug is metabolized primarily by UGT1A1 and UGT1A9 enzymatic pathways, and it is excreted mainly via feces. Drug interactions may occur, particularly with medications that induce or inhibit UGT enzymes.

Contra-indications

• Hypersensitivity to dolutegravir or any of its excipients

Adverse effects

• Nausea
• Vomiting
• Drowsiness
• Increased weight
• Skin reactions
• Sleep disorders
• Hepatotoxicity
• Pancreatitis
• Osteonecrosis

Interactions

• Moderate increase in exposure with dopaminergic receptor agonists
• Moderate increase in exposure with pramipexole
• Moderate increase in exposure with metformin
• Moderate increase in exposure with atazanavir
• Unknown decrease in exposure with carbamazepine
• Unknown decrease in exposure with oxcarbazepine
• Unknown decrease in exposure with phenytoin
• Unknown decrease in exposure with primidone
• Unknown increase in exposure with encorafenib
• Unknown increase in concentration with fampridine

Precautions

• Use with caution in patients with HIV-1 subtype A6/A1, or BMI of 30 kg/m2 or more
• Caution in severe hepatic impairment
• Patients or carers should be advised on how to recognize signs of hypersensitivity

Pregnancy

Avoid unless potential benefit outweighs risk, no information available.

Breast-feeding

Avoid; may be present in milk for up to 12 months or longer after last prolonged-release injection.

Storage

Store in a cool, dry place, away from direct light.

Formulations

• Tablets: 50 mg and 30 mg
• Powder and solvent for solution for injection

Indications

• HIV-1 infection
• Chronic hepatitis B virus (HBV) infection

Dosage

Children: Refer to the BNF for

Adults: Refer to the relevant clinical guidelines or BNF for the appropriate dosing recommendations.

Mechanism of action

Disoproxil is converted intracellularly to its active form, tenofovir diphosphate. This active metabolite competes with natural deoxyadenosine triphosphate (dATP) for incorporation into viral DNA by the viral reverse transcriptase enzyme. Once incorporated, it leads to chain termination, thereby inhibiting viral replication. Additionally, tenofovir diphosphate interferes with the activity of HIV reverse transcriptase and HBV polymerase, further contributing to its antiviral effects.

Pharmacodynamics

Disoproxil exhibits a dose-dependent decrease in HIV-1 viral load and improves CD4 cell counts in patients. Its antiviral activity is primarily against HIV-1 and HBV, with a mechanism that does not exhibit cross-resistance with other classes of antiretroviral drugs. The drug has a long half-life, allowing for once-daily dosing, which improves adherence in patients. It is effective in both naïve and treatment-experienced patients.

Pharmacokinetics

Disoproxil is absorbed following oral administration; its bioavailability is approximately 25% when taken without food. The drug is extensively distributed in the body, with a volume of distribution of about 1.3 L/kg. It undergoes renal clearance, with about 70% of the drug eliminated unchanged in the urine. The elimination half-life of disoproxil is around 17 hours, allowing for once-daily dosing. It is not significantly metabolized by the liver, which reduces the risk of drug-drug interactions associated with hepatic metabolism.

Contra-indications

• Hypersensitivity to disoproxil or any component of the formulation
• Severe renal impairment

Adverse effects

• Nausea
• Diarrhea
• Headache
• Fatigue
• Renal toxicity
• Liver function abnormalities
• Bone mineral density loss
• Lactic acidosis

Interactions

• Potential interactions with nephrotoxic drugs
• May interact with other antiviral agents
• Can affect the metabolism of drugs that are substrates of CYP450 enzymes

Precautions

• Monitor renal function regularly during therapy
• Assess bone mineral density before and during treatment
• Use with caution in patients with a history of pancreatitis
• Evaluate liver function before initiation and during treatment

Pregnancy

Disoproxil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data on human use.

Breast-feeding

Disoproxil is excreted in breast milk. A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Storage

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

Formulations

• Oral tablets
• Oral solution

Indications

• HIV-1 infection
• Chronic hepatitis B virus infection

Dosage

Children: For children, dosing of lamivudine

Adults: For adults, the general dosing of lamivudine for HIV is typically 150 mg twice daily or 300 mg once daily. For chronic hepatitis B, the usual dose is 100 mg once daily. Specific doses may vary based on individual patient factors and treatment regimens, so consultation of the latest guidelines or BNF is recommended for precise dosing.

Mechanism of action

Lamivudine is phosphorylated inside the cell to its active form, lamivudine triphosphate, which competes with the natural nucleoside cytidine triphosphate for incorporation into viral DNA. Once incorporated, it leads to chain termination during viral replication, thereby inhibiting the synthesis of viral DNA and halting the replication process of HIV and HBV.

Pharmacodynamics

The pharmacodynamics of lamivudine involve its action against HIV and HBV. It exhibits a dose-dependent inhibition of reverse transcriptase activity. The drug has a high genetic barrier to resistance, meaning that it is less likely to lead to resistant strains of the virus compared to other antiretrovirals. Lamivudine is considered to have a favorable safety profile, with a low incidence of adverse effects, primarily gastrointestinal disturbances.

Pharmacokinetics

Lamivudine is well absorbed after oral administration, with peak plasma concentrations occurring approximately 1 to 2 hours after intake. The drug has a bioavailability of around 80-85%. It is primarily excreted unchanged in the urine, with a half-life of approximately 5 to 7 hours in individuals with normal renal function. Renal impairment can significantly affect the clearance and half-life of the drug, necessitating dose adjustments in patients with renal insufficiency.

Contra-indications

• Hypersensitivity to lamivudine or any of its components
• Severe liver disease

Adverse effects

• Headache
• Dizziness
• Nausea
• Diarrhea
• Fatigue
• Insomnia
• Rash
• Lactic acidosis
• Hepatomegaly

Interactions

• Zidovudine may increase the risk of hematologic toxicity
• Co-administration with other antiretrovirals may require dose adjustments

Precautions

• Regular monitoring of liver function
• Use with caution in patients with renal impairment
• Risk of developing HIV resistance if not taken as prescribed

Pregnancy

Category C. Use only if clearly needed. Consult guidelines for treatment of HIV in pregnancy.

Breast-feeding

Excreted in breast milk. Mothers should discuss the risks and benefits of breastfeeding.

Storage

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

Formulations

• 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

Dolutegravir is an HIV-1 antiviral agent. It inhibits HIV integrase by binding to the active site and blocking the strand transfer step of retroviral DNA integration in the host cell. The strand transfer step is essential in the HIV replication cycle and results in the inhibition of viral activity. Dolutegravir has a mean EC50 value of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.

Pharmacodynamics

HIV-1 infected subjects on dolutegravir monotherapy demonstrated rapid and dose-dependent reduction of antiviral activity with declines of HIV-1 RNA copies per ml. The antiviral response was maintained for 3 to 4 days after the last dose. The sustained response obtained in clinical trials indicates that dolutegravir has a tight binding and longer dissociative half-life providing it a high barrier to resistance. The combination therapy (ripivirine and dolutegravir) presented the same viral suppression found in previous three-drug therapies without integrase strand transfer inhibitor mutations or rilpivirine resistance.

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.