Cette page a été mise à jour le 30 November 2020

FORMULATION(s)

Fabricant : ViiV Healthcare

DOSAGE

Adult dosage or adolescent ≥ 40 kg and ≥ 12 years of age

1 tablet DIE with or without food For missed doses, the product monograph recommends an interval of 4 hours.

Take the missed dose as soon as possible, unless there are only 4 hours or less before the next dose. Do not double the dose.

Pediatric dosage

According to product monograph : safety and efficacy have not been established in pediatric population (< 12 years of age and < 40 kg)

Adjustment in renal impairment

CrCl ≥ 50 mL/min :  No adjustment required

CrCl < 50 mL/min :  Administration not recommended (lamivudine adjustment to be made, use the compounds separately)

Adjustment in hepatic impairment

Child-Pugh A or B : No adjustment required

Child-Pugh C : Administration not recommended (not studied in this population)

COMPARATIVE EFFICIENCY

Dovato® has been studied in treatment-naive patients as well as in patients undergoing treatment with virological suppression.

Studies in patients who have never received antiretrovirals
(Without major resistance to NRTIs or PIs, without hepatitis B infection and not requiring treatment for hepatitis C)

Study

Comparator groups

Efficacy results (reaching a viral load < 50 copies/mL)

GEMINI 1 and GEMINI 2

DTG + 3TC (N=716) vs DTG + FTC/TDF (N=717)

Week 48
Noninferiority of DTG + 3TC (91%) vs DTG + FTC/TDF (93%).
Lack of response (VL > 50 copies/mL) observed in 3% vs 2%.

Week 96
Noninferiority of DTG + 3TC (86%) vs DTG + FTC/TDF (90%).
Lack of response (VL > 50 copies/mL) observed in 3% vs 2%.

Study in patients with virological suppression
(Without resistance to NRTIs or INIs, without hepatitis B infection and not requiring treatment for hepatitis C)

Study

Comparator groups

Efficacy results (reaching a viral load < 50 copies/mL at 48 weeks)

Types of patients

TANGO

DTG + 3TC  (N=369) vs antiretroviral therapy with TAF (Genvoya, Odefsey, Prezcobix or Prezista/r + Descovy) (N=372)

Noninferiority of DTG + 3TC (93.2%) vs (93.0%) antiretroviral therapy with TAF.
Lack of response (VL > 50 copies/mL) observed in 0.3% vs 0.5%.

Virologic suppression for ≥ 6 months; majority with CD4+ ≥ 350 cells/μL.

RESISTANCE

High resistance barrier. No mutations in reverse transcriptase or integrase were observed in participants with virological failures.
Dovato® should not be used in patients with known or possible resistance to dolutegravir or lamivudine.

ADVERSE REACTIONS

In short

  • Headache
  • Digestive effects like diarrhea and nausea
  • Neuropsychiatric effects like anxiety or insomnia
  • Fatigue
  • Diarrhea
  • Potential weight gain (observed in retrospective cohort studies)

GEMINI 1 and GEMINI 2 studies
(Pooled analyses, Week 48)
Adverse reactions reported in (all grades) in ≥ 1% of participants

DTG + 3TC
(N=716)
DTG + FTC/TDF
(N=717)

Headache

3%

4%

Drowsiness

1%

< 1%

Dizziness

1%

2%

Nausea

2%

5%

Diarrhea

2%

3%

Insomnia

2%

3%

Fatigue

1%

< 1%

At week 48, among the adverse reactions of all grades, those of grade 1 were the most represented (except for headache). 2% of patients in each group had to discontinue treatment due to adverse effects related to the study drugs. A disturbance of renal and bone parameters was observed in the DTG + FTC/TDF group compared to DTG + 3TC.

At week 96, 20% vs 25% of the adverse effects observed were considered to be related to medication. As in week 48, headaches occurred in more than 1% of patients and could be of grade 2 to 5.

3% of patients in each group had to discontinue treatment due to adverse effects related to the study drugs. The effects that motivated the discontinuation of the medication are neuropsychiatric effects in each of the groups. Discontinuation due to renal and bone effects has also been seen in patients on DTG + FTC/TDF.

TANGO study
(Week 48)
Adverse effects (grades 2-5) related to drug

DTG/3TC
(N=369)
ART with TAF*
(N=372)

Insomnia

1%

0%

Constipation

1%

< 1%

Flatulence

1%

0%

Headache

1%

0%

* Antiretroviral therapy with TAF (Genvoya, Odefsey, Prezcobix or Prezista/r + Descovy)

At week 48, grade 2 to 5 adverse reactions were observed in 5% of patients with DTG + 3TC vs 1% in the groups maintaining antiretroviral therapy with TAF. 2% vs < 1% for each group had to discontinue treatment due to adverse events related to the study drugs. The main side effects that caused the treatment to stop were anxiety, insomnia, weight gain and fatigue.

For management of adverse reactions associated with antiretrovirals, see section management of adverse reactions.

Rarer but reported adverse effects with dolutegravir in studies or post-marketing

Hypersensitivity reactions

Hypersensitivity reactions have been associated with integrase inhibitors. This reaction presents with a rash, constitutional symptoms, multi-organ and liver damage.

The product monograph recommends that Dovato® be discontinued immediately if there are signs or symptoms that may suggest a hypersensitivity reaction (severe rash or accompanied by fever, general malaise, fatigue, muscle or joint pain, vesicles, mouth sores, conjunctivitis, facial edema , hepatitis, eosinophilia or angioedema) and closely monitor the patient’s clinical condition.

Hepatotoxicity

Acute hepatitis has been reported in patients who had no pre-existing liver disease, or other identifiable risk factors. With Triumeq®, an antiretroviral containing dolutegravir, a liver transplant was required in one patient. Therefore, it is recommended to monitor the appearance of hepatotoxicity during treatment.

Immune reconstitution inflammatory syndrome (IRIS)

This effect can be seen with any antiretroviral therapy. An inflammatory response to poorly progressive or residual opportunistic infections (e.g. Mycobacterium avium complex, cytomegalovirus, Pneumocystis jerovinci pneumonia or tuberculosis) which may require treatment. Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been observed.

IMPACT ON LABORATORY

Creatinine increase

Dolutegravir increases the serum concentration of creatinine via an inhibition of tubular secretion. This should not be interpreted as an impairment of kidney function. The increase usually occurs within the first four weeks of treatment and is, on average, around 10 μmol/L. This should be taken into account when estimating a patient’s kidney function. Some will subtract the serum creatinine observed when adding dolutegravir before calculating the estimated glomerular filtration rate.

Bilirubin increase

A slight increase in total bilirubin (without clinical jaundice) has been observed due to competition between dolutegravir and unconjugated bilirubin for UGT1A1. This variation would not be clinically significant.

MECHANISM OF ACTION

Dolutegravir

Integrase inhibitor

Lamivudine

Nucleoside reverse transcriptase inhibitor (by competition with the natural nucleoside)

PHARMACOKINETICS

Bioavailability

Lamivudine : 80-85 %

Tmax

Dolutegravir : 2.5 h
Lamivudine : 1 h

Elimination T½ (plasma)

Dolutegravir : 14 h
Lamivudine : 18-19 h

Metabolism

Dolutegravir : UGT1A1 (major) and CYP3A (minor, 9.7% of the total dose)
Lamivudine : not metabolized

Effects on transporters

Dolutegravir : inhibitor of the OCT2 transporter and inhibits tubular secretion of creatinine and excretion of drugs that depend of OCT2 (dofetilide, fampridine and metformin); also MATE1 transporter inhibitor

Distribution volume

Dolutegravir : 17.4 L

Elimination

Dolutegravir : urinary excretion 31 % (< 1 % unchanged) and in faeces (53 % unchanged)
Lamivudine : renal at 70 %

Binding to plasma proteins

Dolutegravir : 99 %
Lamivudine : < 36 %

PREGNANCY AND BREAST FEEDING

Pregnancy

Dolutegravir has been associated with neural tube defects in a Boswana follow-up cohort (Tsepamo study), and current data recommend avoiding dolutegravir during conception and early pregnancy. Indeed, the risk of neural tube defect is slightly increased compared to other antiretrovirals, but according to the latest analyzes it is less important than the risk presented initially. The abnormalities are said to have occurred at a rate of 0.3% when pregnant women were taking dolutegravir during periconception, while the overall prevalence during the periconception period was 0.1% for all antiretroviral therapy and 0.08% for all deliveries. Another retrospective study in Brazil (second largest surveillance cohort) and pregnancy registers did not observe neural tube defects.

In this same study when looking at women who started dolutegravir during pregnancy, only one case of neural tube defect was reported, 0.03% (N = 3840), compared to 0.05% (N = 59 520). No causal link has been established with the use of dolutegravir.

The risk in the general population would be 0.5-1 cases per 1000 live births.

Since the risk is low and dolutegravir is an antiretroviral that has the advantage of being given once a day, with few side effects and an ability to rapidly decrease viral load, the DHHS guidelines recommend dolutegravir as a preferred agent for pregnant women at all trimesters and as an alternative (after discussion of low risk) for women who are planning to become pregnant.

The DHHS guidelines have posted an appendix to guide healthcare professionals in their consultation with patients regarding dolutegravir.

Since neural tube defects occur during the first four weeks of fetal development, patients of childbearing potential should therefore be informed of the potential low risk before pregnancy. If necessary, contraception or the use of an alternative antiretroviral solution can be discussed.

Professionals are encouraged to discuss the risk of neural tube defect and to make the decision with the person concerned based on the risk observed in the literature to date. Professionals are also encouraged to report pregnancy cases with a view to adding them to the register:
www.apregistry.com/  Telephone : 1-800-258-4263 Fax : 1-800-800-1052.

See also the pharmacokinetics section.

Breastfeeding

According to animal studies, dolutegravir may be present in human breast milk and lamivudine is known to be found in levels comparable to plasma levels. For reasons of risk of HIV transmission, women are advised not to breastfeed.

PRECAUTIONS AND CONTRAINDICATIONS

Contraindications

  • Hypersensitivity to the active or inactive molecules contained in the tablet.
  • Concomitant administration with drugs transported by OCT2 and with a narrow therapeutic index such as dofetilide and fampridine (dalfampridine). (See in the interactions module for additional details).

Precautions

Drugs interactions

  • Co-administration with potent CYP3A4 inducers such as rifampin, carbamazepine, oxcarbazepine, phenobarbital, phenytoin and St. John’s wort may decrease the concentration of dolutegravir and compromise efficacy. The dosage of dolutegravir should be adjusted to 50 mg twice a day. The additional 50 mg dose of dolutegravir should be taken 12 hours apart from Dovato®
  • The use of cations like calcium or iron can decrease the absorption of dolutegravir.
  • Also, dolutegravir may increase the plasma concentration of metformin.

For a safer use of these drugs used in combination with dolutegravir, consult the product monograph or the drug interactions section.

Patient co-infected with hepatitis B

  • The efficacy and safety of lamivudine have not been established in the presence of chronic hepatitis B infection in HIV+ patients. Resistance to lamivudine has been observed in HIV+ patients who have received lamivudine as antiretroviral therapy. This is why additional treatment or an alternative should be considered in patients with chronic hepatitis B infection.
  • Indeed, the combinations with tenofovir and emtricitabine are the antiretrovirals of choice during HIV and HBV co-infection and should be preferred. Treatment of hepatitis B with lamivudine is associated with a resistance rate compared to the combination of tenofovir/emtricitabine.
  • On the other hand, if Dovato® has been initiated in a patient co-infected with hepatitis B and requiring treatment, care should be taken if the latter is interrupted. Indeed, severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been observed in patients co-infected with HBV and HIV-1. Therefore, discontinuation of treatment with Dovato® without initiation of alternative hepatitis B therapy is not recommended.

Virus with documented or suspected resistance

  • Dovato® should not be prescribed for patients with documented or suspected viral resistance to dolutegravir or lamivudine.

Patient with impaired renal function

  • Dovato® is a fixed dose tablet, it should not be prescribed to patients whose CrCl is less than 50 mL/min.

FURTHER INFORMATION

Administration

The tablet should be swallowed whole.

According to the company, for patients who cannot swallow, the tablet could be halved or crushed and added to a small amount of semi-solid or liquid food and the contents should be consumed whole and immediately.

Storage

Store the tablets at a maximum temperature of 30° C.

REFERENCES

  • Dolutegravir/Lamivudine (Dovato), ViiV Healthcare, Quebec, Canada, September 29, 2020.
  • Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. The Lancet, Jan 2019, 393 (10167): 143-145.
  • Cahn P, Madero JS, Arribas JR et al. Durable Efficacy of dolutegravir (DTG) plus lamivudine (3TC) in antiretroviral treatment–naive adults with HIV-1 infection: 96-week results from the Gemini studies. IAS 2019; Mexico City, Mexico. Slides WEAB0404LB.
  • Van Wyk J, Ajana F, Bishop F et al. Switching to DTG/3TC fixed-dose combination (FDC) is non-inferior to continuing a TAF-based regimen in maintaining virologic suppression through 48 weeks (Tango study). IAS 2019; Mexico City, Mexico. Slides WEAB0403LB.
  • Mofenson LM, Vannappagari V, Scheuerle AE, et al. Periconceptional antiretroviral exposure and central nervous system (CNS) and neural tube birth defects–data from Antiretroviral Pregnancy Registry (APR). 10th IAS Conference on HIV Science (IAS 2019), July 21-24, 2019, Mexico City. Abstract TUAB0101.
  • U.S. Department of Health and Human Services (DHHS). Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. Published on december 7, 2018.
    https://aidsinfo.nih.gov/guidelines/html/3/perinatal/0 Consulted on november 30, 2019.

ABBREVIATIONS

DTG, dolutegravir; 3TC, lamivudine; DIE, once daily; CrCl, creatinine clearance; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; TAF, tenofovir alafenamide; r, ritonavir; NRTIs, nucleoside and nucleotide reverse transcriptase inhibitors; PIs, protease inhibitors; INIs, integrase inhibitors; VL, viral load.

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