TRIVIRO-LNS COMBINATION PRODUCT TABLET

Indications

• HIV infection in combination with other antiretroviral drugs
• Chronic hepatitis B infection with evidence of viral replication and active liver inflammation or fibrosis

Dosage

Children: For children aged 3 months to

Adults: For HIV infection, the adult dose is 150 mg every 12 hours or alternatively 300 mg once daily. For chronic hepatitis B, the recommended dose is 300 mg once daily.

Mechanism of action

Lamivudine is phosphorylated intracellularly to its active form, lamivudine triphosphate (L-TP). This active metabolite is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, leading to DNA chain termination. Lamivudine competes with deoxycytidine triphosphate for binding to reverse transcriptase, and its incorporation into DNA results in the disruption of DNA synthesis due to the absence of a 3'-OH group necessary for chain elongation.

Pharmacodynamics

As a nucleoside reverse transcriptase inhibitor (NRTI), lamivudine disrupts the viral DNA synthesis pathway, particularly for HIV-1 and HBV. The active metabolite formed competes with natural nucleotides and incorporates into the growing viral DNA chain, ultimately leading to chain termination. This action inhibits the replication of the virus, thereby reducing viral load in infected individuals.

Pharmacokinetics

Lamivudine is absorbed via passive diffusion and is rapidly phosphorylated to its active triphosphate form within cells. Its bioavailability is approximately 80-85% when taken orally. The drug has a half-life of about 5-7 hours in plasma and is primarily eliminated via the kidneys through glomerular filtration and active tubular secretion. Renal impairment necessitates dose adjustments, particularly in patients with creatinine clearance below 50 mL/min.

Contra-indications

• Severe hypersensitivity to lamivudine or any of its excipients
• Patients with decompensated liver disease when used for chronic hepatitis B

Adverse effects

• Peripheral neuropathy
• Headache
• Nausea
• Diarrhea
• Fatigue
• Insomnia
• Malaise
• Cough
• Pharyngitis
• Respiratory tract infections
• Alopecia
• Arthralgia

Interactions

• Trimethoprim may increase exposure to lamivudine
• Concomitant use with other antiretroviral drugs should be evaluated for cross-resistance

Precautions

• Monitor liver function tests every 3 months in patients with chronic hepatitis B
• Recurrent hepatitis may occur upon discontinuation in chronic hepatitis B patients
• Use with caution in renal impairment; dose adjustments may be necessary if creatinine clearance is less than 50 mL/min

Pregnancy

Lamivudine is classified as category B, indicating that there are no known risks in humans, but caution should be exercised. It may be used during pregnancy if deemed necessary by the healthcare provider.

Breast-feeding

Lamivudine can be used with caution while breastfeeding, provided adequate measures are taken to prevent hepatitis B infection in infants.

Storage

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

Formulations

• Lamivudine 150 mg tablets
• Lamivudine 300 mg tablets
• Epivir oral solution

Indications

• HIV infection in antiretroviral treatment-experienced adults
• HIV infection in antiretroviral treatment-experienced paediatric patients from 2 years of age

Dosage

Children: For children aged 3–17 years: 200 mg once daily for body surface area 0.

Adults: Initially 200 mg once daily for the first 14 days, followed by 200 mg twice daily. If treatment is interrupted for more than 7 days, restart with 200 mg once daily for 14 days.

Mechanism of action

Nevirapine binds directly to reverse transcriptase (RT) and inhibits its RNA-dependent and DNA-dependent DNA polymerase activities by disrupting the enzyme's catalytic site. This binding occurs in a deep pocket on the enzyme, affecting the alignment of essential components for the chemical reaction necessary for viral DNA synthesis, which ultimately hinders HIV replication.

Pharmacodynamics

As a non-nucleoside reverse transcriptase inhibitor, nevirapine exhibits selective activity against HIV-1, showing no inhibitory effects on HIV-2 RT or human DNA polymerases. It is generally prescribed when the immune system is compromised and in the presence of opportunistic infections. Nevirapine is effective only when used in combination with other antiretroviral agents, as monotherapy can lead to the development of drug resistance.

Pharmacokinetics

Nevirapine is well absorbed after oral administration, with peak plasma concentrations typically occurring within 4 hours. It undergoes extensive hepatic metabolism primarily via the cytochrome P450 system, particularly CYP3A4. The elimination half-life of nevirapine ranges from 25 to 30 hours, allowing for less frequent dosing. It is primarily excreted in urine as metabolites, with minimal unchanged drug excreted.

Contra-indications

• Acute porphyrias

Adverse effects

• Hypersensitivity reactions
• Rash
• Eosinophilia
• Fever
• General malaise
• Myalgia
• Arthralgia
• Blistering
• Oral lesions
• Conjunctivitis
• Hepatitis
• Diarrhoea
• Drowsiness
• Dry mouth
• Dyslipidaemia
• Dyspnoea
• Gastrointestinal discomfort
• Headache
• Hyperglycaemia
• Hypertension
• Memory loss
• Myocardial infarction
• Nausea
• Peripheral neuropathy
• Renal failure
• Abnormal skin reactions
• Sleep disorders
• Angina pectoris
• Angioedema
• Atrial fibrillation
• Bronchospasm
• Concentration impaired
• Confusion
• Gynaecomastia
• Haematemesis
• Hepatic disorders
• Inflammatory syndrome
• Pancreatitis
• Seizure
• Syncope
• Tremor
• Vertigo
• Weight increased
• Osteonecrosis

Interactions

• Nevirapine + ketoconazole: Severe (decreases exposure)
• Nevirapine + voriconazole: Moderate (decreases exposure)
• Nevirapine + midazolam: Moderate (decreases concentration)
• Nevirapine + caspofungin: Moderate (decreases concentration)
• Nevirapine + antiepileptics: Unknown (decreases concentration)
• Nevirapine + carbamazepine: Unknown (decreases concentration)
• Nevirapine + fosphenytoin: Unknown (decreases concentration)
• Nevirapine + phenobarbital: Unknown (decreases concentration)
• Nevirapine + phenytoin: Unknown (decreases concentration)
• Nevirapine + primidone: Unknown (decreases concentration)

Precautions

• C

Indications

• HIV infection
• AIDS

Dosage

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

Adults: Refer to the BNF for specific dosing guidelines.

Mechanism of action

Stavudine is phosphorylated to its active triphosphate form, stavudine-5'-triphosphate, which competes with natural deoxyribonucleoside triphosphates for incorporation into viral DNA. Once incorporated, it causes chain termination during viral DNA synthesis due to the absence of a 3'-hydroxyl group, thereby inhibiting further elongation of the DNA strand and preventing replication of HIV.

Pharmacodynamics

Stavudine exhibits dose-dependent inhibition of HIV-1 reverse transcriptase activity. The drug's effectiveness can be influenced by the presence of thymidine analog mutations in the viral genome, which may confer resistance. Clinical studies have shown that stavudine contributes to a significant reduction in HIV viral load, improves immunological markers, and enhances overall clinical outcomes in HIV-infected individuals.

Pharmacokinetics

Stavudine is rapidly absorbed after oral administration, with peak plasma concentrations occurring approximately 1 to 2 hours post-dose. It has a bioavailability of about 85%. The drug is primarily eliminated via renal excretion, with a half-life of approximately 1.5 hours in individuals with normal renal function. Renal impairment may necessitate dosage adjustments due to decreased clearance. Stavudine does not significantly bind to plasma proteins, which enhances its availability in tissues.

Contra-indications

• Hypersensitivity to stavudine or any component of the formulation
• Severe hepatic impairment
• Concurrent use with other nucleoside reverse transcriptase inhibitors (NRTIs) that may cause similar toxicities

Adverse effects

• Lactic acidosis
• Hepatotoxicity
• Peripheral neuropathy
• Pancreatitis
• Lipodystrophy
• Anemia
• Nausea
• Vomiting
• Diarrhea
• Headache

Interactions

• Other drugs that may cause peripheral neuropathy or pancreatitis should be used with caution
• Didanosine: increased risk of pancreatitis
• Zidovudine: potential additive hematological toxicity
• Ribavirin: may increase the risk of hemolytic anemia

Precautions

• Monitor for signs of lactic acidosis and hepatic dysfunction
• Assess for peripheral neuropathy prior to and during treatment
• Use with caution in patients with a history of pancreatitis
• Consider dosage adjustment in renal impairment

Pregnancy

Stavudine is classified as Category C. It should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Stavudine is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Protect from light.

Formulations

• Capsules: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg
• Oral solution: 1 mg/mL

Mechanism of action

Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination. Lamivudine enters cells by passive diffusion and is phosphorylated to its active metabolite, lamivudine triphosphate. Lamivudine triphosphate competes with deoxycytidine triphosphate for binding to reverse transcriptase, and incorporation into DNA results in chain termination. Lamivudine has very low affinity for human alpha and omega DNA polymerases, moderate affinity for beta DNA polymerase, and higher affinity for gamma DNA polymerase.

Pharmacodynamics

Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1) and hepatitis B (HBV) to disrupt viral DNA synthesis. When phosphorylated, lamivudine can form active metabolites that compete for incorporation into viral DNA. Via DNA incorporation, lamivudine metabolites competitively inhibit the activity of the HIV reverse transcriptase enzyme and act as a chain terminator of DNA synthesis. Due to the lack of a 3'-OH group, incorporated nucleoside analogues prevent the formation of a 5' to 3' phosphodiester linkage that is essential for DNA chain elongation.

Mechanism of action

Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. The binding site for nevirapine on HIV-1 reverse transcriptase is near, but not at the proposed site of active polymerization, in a deep pocket lying between the beta sheets of the palm and at the base of the thumb subdomains of the enzyme's p66 subunit. In the absence of nevirapine, the binding of deoxynucleoside triphosphate to the reverse transcriptase-template complex results in a change in the conformation of reverse transcriptase. This conformational change is followed by a magnesium-dependent chemical reaction in which deoxynucleoside triphosphate is incorporated into the newly forming viral DNA; the conformational change appears to be the rate-limiting step of the reverse transcriptase catalysis of viral DNA formation. Nevirapine appears to have no appreciable effect on the rate of or equilibrium constant for the conformational change but may slow the chemical reaction, which then becomes the rate-limiting step in the catalytic sequence. When nevirapine binds to the reverse transcriptase-template complex, changes may occur in the position of aspartic acid carboxyl groups in reverse transcriptase so that magnesium ions are not in proper alignment for the chemical reaction to occur efficiently, and the reaction is slowed. Therefore, although the nevirapine-reverse transcriptase-template complex may continue to bind deoxynucleoside triphosphate and to catalyze its incorporation into the newly forming viral DNA, it appears to do so at a slower rate. The mechanism of action of nevirapine differs from that of nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine). Nucleoside antiretroviral agents require intracellular conversion to triphosphate metabolites, which then compete with naturally occurring deoxynucleoside triphosphates for incorporation into viral DNA by reverse transcriptase and cause premature viral DNA chain termination by preventing further 5 to 3 phosphodiester linkages. Nevirapine, however, is noncompetitive with respect to primer-template or nucleoside triphosphate binding and is specific for HIV-1 reverse transcriptase. The drug binds directly to heterodimeric HIV-1 reverse transcriptase and appears to inhibit viral RNA- and DNA-dependent DNA polymerase activities by disrupting the catalytic site of the enzyme. Nevirapine diffuses into the cell and binds to reverse transcriptase adjacent to the catalytic site. This induces conformational changes that inactivate the enzyme. Resistance develops rapidly in cells exposed to nevirapine. High-level resistance is associated with mutations at reverse transcriptase codons 101, 103, 106,108, 135, 181, 188, and 190. A single mutation at either codon 103 or 181 decreases susceptibility more than 100 fold. Cross-resistance may extend to all FDA-approved nonnucleoside reverse transcriptase inhibitors, especially with the codon 103 mutation. Nevirapine is a highly specific inhibitor of HIV-1 reverse transcriptase, and results of in vitro studies indicate that nevirapine does not appear to inhibit cellular DNA polymerases, including human alpha-, beta-, Gamma-, or Delta-polymerases.

Pharmacodynamics

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (nNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases alpha, beta, or sigma) are not inhibited by nevirapine. Nevirapine is, in general, only prescribed after the immune system has declined and infections have become evident. It is always taken with at least one other HIV medication such as Retrovir or Videx. The virus can develop resistance to nevirapine if the drug is taken alone, although even if used properly, nevirapine is effective for only a limited time.