Dolutegravir (Tivicay) is a second-generation HIV integrase strand transfer inhibitor (INSTI). It is used in combination with other antiviral medicines for the treatment of HIV-1 infection.

Dolutegravir (Tivicay) Uses:

• Treatment of HIV-1 infection:

  • Treatment of HIV-1 infection in combination with other antiretroviral agents in adult and pediatric patients weighing at least 30 kg, or in combination with rilpivirine in adults to replace the current antiretroviral regimen in those who are suppressed virologically  (HIV-1 RNA <50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent.

• Off Label Use of Dolutegravir in Adults:

  • HIV-1 nonoccupational postexposure prophylaxis

Adult dose:

Dolutegravir (Tivicay) Dose in the treatment of HIV-1 infection: 

Note: Must be given in combination with other antiretroviral agents.

• Dolutegravir is a component of recommended initial regimens for any antiretroviral therapy (ART)naive adult or adolescent patient (when co-administered with tenofovir plus emtricitabine [or lamivudine]) or for ART-naive adult or adolescent patients who are HLA-B*5701 negative (when co-administered with abacavir plus lamivudine [or emtricitabine]).

• Treatment naive or treatment-experienced integrase strand transfer inhibitor (INSTI)-naive:

  • 50 mg once a day

• Treatment naive or treatment-experienced INSTI-naive when coadministered with carbamazepine, efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin:

  • 50 mg twice a day

• INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance:

  • 50 mg twice a day

• Virologically suppressed (HIV-1 RNA <50 copies/mL) patients switching to dolutegravir plus rilpivirine:

  • 50 mg once a day

Dolutegravir (Tivicay) Dose in the HIV-1 nonoccupational postexposure prophylaxis (nPEP) (off-label):

• Oral: 50 mg once daily for 28 days (in combination with other antiretroviral agents). Initiate therapy within 72 hours of exposure.

Dose in children:

Dolutegravir (Tivicay) Dose in the treatment of HIV-1 infection:

• Children and Adolescents weighing ≥30 kg:

Note: Use in combination with other antiretroviral agents.

• • Treatment-naive or treatment-experienced integrase strand transfer inhibitor (INSTI)naive: Oral:

    • 30 kg to <40 kg: 35 mg once a day
    • ≥40 kg: 50 mg once a day

  • Treatment-naive or treatment-experienced INSTI-naive when coadministered with carbamazepine, efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir or rifampin: Oral:

    • 30 kg to <40 kg: 35 mg twice a day
    • ≥40 kg: 50 mg twice a day

Dolutegravir (Tivicay) Dose in the HIV-1 nonoccupational postexposure prophylaxis (nPEP):

• Adolescents weighing ≥40 kg:

  • Oral: 50 mg once daily for 28 days in combination with other antiretroviral agents.
  • Initiate therapy within 72 hours of exposure.

Dolutegravir Pregnancy Risk Category: B

• Dolutegravir is highly transferable through the human placenta.
• The data from the antiretroviral pregnancy registry do not provide sufficient information to assess human teratogenic risks.
• Preliminary data from observational studies has shown that women who become pregnant while receiving dolutegravir treatment have a higher risk of developing neural tube defects (NTDs). This risk was not seen in women who began treatment before becoming pregnant.
• Although maternal antiretroviral treatment (ART) may increase preterm births, the information available is inconsistent due to variability in maternal factors (disease severity and gestational age at the initiation of therapy),
• Some studies have shown an increased risk of stillbirth and low birth weight in infants.
• Maternal ART is an important treatment option that has clear benefits. Avoid delay if you are concerned about adverse neonatal outcomes.
• All infants who have been exposed to antiretroviral medication should have long-term monitoring. Children with significant organ abnormalities, especially the heart or CNS, that are not of known etiology should be examined for possible mitochondrial dysfunction.
• Dolutegravir is not recommended for use in the first trimester.
• Based on the available data, dolutegravir is considered a preferred integrase-strand transfer inhibitor (ISTI), by the Health and Human Services (HHS), Perinatal HIV Guidelines. It should be used after the first trimester of HIV-infected pregnant women who are both antiretroviral-naive and have acute HIV infection.
• Dolutegravir should be avoided during the first trimester due to the risk of NTDs (14 weeks [upto 13/weeks]; gestational year by last menstrual period).
• The HHS Perinatal HIV Guidelines consider dolutegravir to be a preferred ISTI for HIV-infected pregnant women who have received ART therapy previously but are starting again or need a new regimen due to poor tolerance or poor viral response.
• If dolutegravir therapy is not effective in preventing pregnancy, the patient may continue treatment if they are still in their second or third trimester.
• Discuss the risks and benefits to continuing dolutegravir or changing your ART if pregnancy is detected in the first trimester.
• Dolutegravir's pharmacokinetics may be modified, but no dosage adjustments are necessary during pregnancy.
• HHS Perinatal HIV Guidelines recommend against the use of dolutegravir for patients who are not yet pregnant, but are trying to conceive.
• Assess the pregnancy status of females with reproductive potential. A pregnancy test should be done before starting therapy with dolutegravir.
• Dolutegravir-based regimens should not be prescribed to patients who are pregnant or cannot use contraception.
• When dolutegravir is stopped after delivery, it's important to consider other options for contraception post-partum.
• To keep HIV-positive pregnant women under the control and to reduce the chance of perinatal transmission, it is generally recommended that ART be performed.
• Monitoring during pregnancy is more common than monitoring in adults who are not pregnant.
• All HIV-positive women should continue ART after birth. ART can also be modified once the baby is born.

Dolutegravir use during breastfeeding:

• Breast milk contains Dolutegravir.
• Dolutegravir is recommended as a component of a treatment plan for acute HIV infection in nonpregnant, breastfeeding women.
• If the infection is confirmed, breastfeeding should be stopped and not resumed.
• While waiting for confirmation, milk may be expressed and kept.
• Postnatal HIV transmission is not completely eliminated by infant or maternal antiretroviral treatment.
• The multiclass-resistant virus was also detected in breastfed infants, despite the fact that maternal therapy has not been administered.
• To reduce the possibility of HIV transmission, women with HIV should not breastfeed in the US.

Renal dose:

Dolutegravir (Tivicay) Dose in Kidney disease:

• Treatment-naive or treatment-experienced INSTI-naive:

  • Mild, moderate, or severe impairment:
    • No dosage adjustment necessary.

• INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance:

  • CrCl ≥30 mL/minute:

    • No dosage adjustment is necessary.

  • CrCl <30 mL/minute:

    • There are no dosage adjustments provided in the manufacturer's labeling;
    • Use with caution since the reduction in dolutegravir concentrations may result in loss of therapeutic effect and development of resistance to dolutegravir or other co-administered antiretroviral agents.

  • ESRD including hemodialysis:

    • There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dolutegravir (Tivicay) Dose in Liver disease:

• Mild-to-moderate impairment (Child-Pugh class A or B):

  • No dosage adjustment necessary.

• Severe impairment (Child-Pugh class C):

  • Use is not recommended (has not been studied).

Side effects:

Adverse reactions reported with combination therapy.

Common Side Effects of Dolutegravir (Tivicay):

• Endocrine & Metabolic:

  • Hyperglycemia

• Hepatic:

  • Increased Serum Alanine Aminotransferase

Less Common Side Effects Of Dolutegravir (Tivicay):

• Central Nervous System:

  • Insomnia
  • Fatigue
  • Headache
  • Suicidal Ideation
  • Suicidal Tendencies
  • Depression

• Dermatologic:

  • Pruritus

• Gastrointestinal:

  • Increased Serum Lipase
  • Diarrhea
  • Abdominal Distress
  • Abdominal Pain
  • Flatulence
  • Upper Abdominal Pain
  • Vomiting
  • Nausea

• Hematologic & Oncologic:

  • Neutropenia
  • Leukopenia

• Hepatic:

  • Increased Serum Aspartate Aminotransferase
  • Hyperbilirubinemia
  • Hepatitis

• Hypersensitivity:

  • Hypersensitivity Reaction

• Neuromuscular & Skeletal:

  • Increased Creatine Phosphokinase
  • Myositis

• Renal:

  • Renal Insufficiency

Contraindications to Dolutegravir (Tivicay):

• Hypersensitivity to dolutegravir, or any component of the formulation
• concurrent use with dofetilide

Warnings and precautions

• Hepatotoxicity:

  • Patients without any underlying liver disease or risk factors have reported hepatic adverse events such as elevated serum liver biochemistries, acute liver failure, and hepatitis.
  • Patients with hepatitis B and C could be at greater risk of developing or worsening increased transaminases.
  • Sometimes these increases were consistent either with immune reconstitution syndrome (or hepatitis B activation) (especially when anti-hepatitis treatment was stopped).
  • Dolutegravir, abacavir, and lamivudine have been linked to liver injury due to drug use.
  • Watch out for any signs or symptoms of hepatotoxicity in patients.

• Hypersensitivity reactions

  • Reports have included constitutional findings, rash, and organ dysfunction (eg liver injury).
  • If you notice signs of hypersensitivity, such as severe rash, fever, fatigue, muscle/joint pains, blistering, peeling of skin, oral blisters/lesions or facial edema (e.g., severe rash), immediately discontinue use.
  • Follow up on your clinical condition and liver function to determine if supportive therapy is needed.
  • Dolutegravir therapy should be discontinued if hypersensitivity develops.

• Immune reconstitution syndrome:

  • The immune reconstitution syndrome may occur in patients who have received HIV treatment.
  • This can lead to an inflammatory response to an indolent, residual opportunistic virus, or activation of autoimmune disorders (eg Graves disease or polymysitis) during therapy.
  • Additional evaluation and treatment may still be necessary.

• Hepatic impairment

  • Patients with severe hepatic impairment should not use this product (hasn't been studied).

• Renal impairment

  • Patients with severe renal impairment who are not experienced with integrase-strand transfer inhibitor (INSTI), should be cautious.
  • We observed a decrease in dolutegravir levels, which could lead to a loss of therapeutic effects and resistance to dolutegravir and other antiretroviral drugs.

Dolutegravir: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Pregnancy test prior to initiation of therapy in females of reproductive potential.
• Viral load,
• CD4 count,
• lipid profile;
• liver aminotransferases (baseline and during therapy);
• monitor for hypersensitivity

How to administer Dolutegravir (Tivicay)?

• Administer without regard to meals.
• Administer 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications.
• Alternatively, dolutegravir and supplements containing calcium or iron can be taken together with food.

Mechanism of action of Dolutegravir (Tivicay):

• Binds to the active site of the integrase and blocks the strand transfer step in HIV-1 DNA integration. This is critical for the HIV replication cycle.

Notice: Dolutegravir's pharmacokinetics in HIV-1-infected children weighing >=30kg were comparable to those in HIV-1 infected adults.

Absorption:

• Dolutegravir absorption was slowed by food, which increased its absorption.
• Dolutegravir AUC increased by 33%, 41% and 66% respectively, increased C by 46%-52% and 67% respectively, and extended T to 3, 4 and 5 hours, respectively, from 2 hours in fasted conditions.

Protein binding:

• ≥98.9%

Metabolism:

• Primarily metabolized via UGT1A1 with some contribution from CYP3A

Bioavailability:

• Has not been established

Half-life elimination:

• ~14 hours

Time to peak:

• 2 to 3 hours

Excretion:

• Feces (53% as unchanged drug); urine (31% as metabolites, <1% as unchanged drug)

International Brands of Dolutegravir:

• Tivicay

Dolutegravir Brand Names in Pakistan:

No Brands Available in Pakistan.