Dovato®
Dolutegravir 50 mg / Lamivudine 300 mg
Fabricant : ViiV Healthcare
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.
According to product monograph : safety and efficacy have not been established in pediatric population (< 12 years of age and < 40 kg)
CrCl ≥ 50 mL/min : No adjustment required
CrCl ≥ 30 mL/min and < 50 mL/min : Monitor for signs of hematological toxicities and adjust the lamivudine dose as needed. If a reduction in the dose of lamivudine is necessary, discontinue treatment with Dovato® and administer each of the drug components separately.
CrCl < 30 mL/min : Administration not recommended (lamivudine adjustment necessary, use the compounds separately). A retrospective review suggests that dual therapy with dolutegravir and lamivudine, with dose adjustment for renal function, could be effective in controlling viral load in older patients with comorbidities.
Child-Pugh A or B : No adjustment required
Child-Pugh C : Administration not recommended (not studied in this population)
Dovato® has been studied in treatment-naive patients as well as in patients undergoing treatment with virological suppression.
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL) |
Type of patients |
GEMINI 1 and GEMINI 2 |
DTG + 3TC (N=716) vs DTG + FTC/TDF (N=717) |
Week 48 Week 96 |
Median age 33 years, 85% male, 69% white, 80% viral load < 100 000 copies/mL, 92% CD4+ ≥ 200 cells/mm3. |
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. |
Patients on tenofovir AF-based antiretroviral therapy with no history of previous virologic failure. No resistance conferring resistance to reverse transcriptase inhibitors or integrase inhibitors. Virologic suppression for ≥ 6 months. Patients not requiring treatment for hepatitis B. Median age 39 years, 92% male, 79% white, 98% CD4+ ≥ 200 cells/mm3. |
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.
GEMINI 1 and GEMINI 2 studies
|
||
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
|
||
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.
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.
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.
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.
Integrase inhibitor
Nucleoside reverse transcriptase inhibitor (by competition with the natural nucleoside)
Lamivudine : 80-85 %
Dolutegravir : 2.5 h
Lamivudine : 1 h
Dolutegravir : 14 h
Lamivudine : 18-19 h
Dolutegravir : UGT1A1 (major) and CYP3A (minor, 9.7% of the total dose)
Lamivudine : not metabolized
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
Dolutegravir : 17.4 L
Dolutegravir : urinary excretion 31 % (< 1 % unchanged) and in faeces (53 % unchanged)
Lamivudine : renal at 70 %
Dolutegravir : 99 %
Lamivudine : < 36 %
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.
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.
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.
Drugs interactions
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
Virus with documented or suspected resistance
Patient with impaired renal function
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.
Store the tablets at a maximum temperature of 30° C.
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.