Triumeq®
Dolutegravir 50 mg / Abacavir 600 mg / Lamivudine 300 mg
Fabricant : ViiV Healthcare
1 tablet DIE with or without food. For missed doses, the product monograph recommends the 4 hour interval.
Take the missed dose as soon as possible, unless there are only 4 hours or less left before the next dose. Do not double the dose.
According to the product monograph, not recommended < 12 years and < 40kg
According to DHHS guidelines : 1 tablet DIE with or without food for children or adolescents ≥ 25 kg
It is recommended to monitor the plasma concentrations of antiretrovirals every three months for the pediatric population.
CrCl ≥ 50 mL/min : No adjustment required.
CrCl ≥ 30 mL/min and < 50 mL/min : Monitor for signs of hematological toxicities and adjust lamivudine dose as needed. If a reduction in the dose of lamivudine is necessary, discontinue treatment with Triumeq® and administer each of the drug components separately.
CrCl < 30 mL/min : Administration not recommended (lamivudine adjustment required, use compounds separately).
Child-Pugh A : Administration not recommended (recommended abacavir adjustment, use compounds separately)
Child-Pugh B or C : Administration not recommended
Triumeq® has been studied in treatment-naïve patients as well as in patients undergoing treatment with virological suppression.
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL) |
SINGLE |
DTG + ABC/3TC (N=414) vs EFV/FTC/TDF (N=419) |
Week 96 (Snapshot algorithm) |
ARIA (study in women) |
DTG/ABC/3TC (N=250) vs atazanavir/r + TDF/FTC (N=249) |
Week 48 (Snapshot algorithm) |
FLAMINGO |
DTG + ABC/3TC or TDF/FTC (N=242) vs DRV/r + ABC/3TC or TDF/FTC (N=242) |
Week 96 (Snapshot algorithm) |
GS-US-380-1489 |
DTG/ABC/3TC (N=315) vs BIC/FTC/TAF (N=314) |
Week 96 (Snapshot algorithm) |
Study |
Comparator groups |
Efficacy results (reaching a viral load < 50 copies/mL at 24 weeks) |
Types of patients |
STRIIVING * |
DTG/ABC/3TC (N=275) vs continue current regimen (2 NRTIs with a PI, NNRTI or INI) (N=278) |
Noninferiority of DTG/ABC/3TC (85% vs 88%, 95% CI -9.1% to 2.4%) |
Virological suppression since ≥ 6 months; without hepatitis B infection and not requiring treatment for hepatitis C, not carrying the HLA-B*5701 allele. |
* Patients with a history of mono or dual NRTI therapy were excluded from the study.
In studies in patients who have never received antiretrovirals or in a therapy modification in the presence of virological suppression, Triumeq® has been shown to be very effective provided that dolutegravir and at least one of the two NRTIs which accompany it are active. In contrast, functional monotherapy with dolutegravir was associated with a significant risk of resistance.
The most common integrase inhibitor resistance mutations in people with VF on a regimen containing dolutegravir were R263K, G118R, N155H and Q148H/R, with the predominant R263K and G118R mutations in people previously naive to integrase inhibitors. The R263K mutation reduced the sensitivity to dolutegravir by approximately 2 times, while the G118R mutation generally reduced the sensitivity to dolutegravir by 5 times. The highest levels of reduced sensitivity have occurred in viruses containing Q148 mutations in combination with G140 and/or E138 mutations.
SINGLE ING114467 Study
|
||
DTG + ABC/3TC (N=414) |
EFV/FTC/TDF (N=419) |
|
Insomnia |
3% |
3% |
Depression |
1% |
2% |
Abnormal dreams |
3% |
8% |
Dizziness |
< 1% |
5% |
Headache |
2% |
2% |
Fatigue |
2% |
2% |
Nausea |
< 1% |
3% |
Diarrhea |
< 1% |
2% |
Skin rash |
< 1% |
3% |
Vertiges |
0% |
2% |
GS-US-380-1489 Study
|
||
DTG/ABC/3TC (N=315) |
BIC/FTC/TAF (N=314) |
|
Insomnia |
10% (< 5%) |
7% (< 5%) |
Headache |
16% (5%) |
13% (5%) |
Fatigue |
11% |
9% |
Nausea |
24% (17%) |
11% (6%) |
Diarrhea |
16% |
15% |
Back pain |
10% |
8% |
In these two studies, 2-3% of participants taking Triumeq® dropped out of the study due to adverse effects or mortality (week 96). In the ARIA study, 4% of participants taking Triumeq® dropped out of the study due to adverse effects or mortality (week 48). In the SINGLE study, 12% of participants in the EFV/FTC/TDF group dropped out of the study due to side effects.
Several epidemiological and observational studies have observed a link between the administration of abacavir and a risk of myocardial infarction. For example, the D.A.D Cohort in 2008 found a correlation with abacavir and IMA risk (odds ratio: 1.9). Risk associated with current or recent use (in the last six months) and disappearing when this use stops. Over a longer period, the risk is mitigated (odds ratio: 1.68), but appears to be cumulative.
In contrast, meta-analyzes of randomized controlled trials have not documented an additional risk of myocardial infarction related to abacavir. Although some speculative mechanisms have been advanced, none have been formally retained.
The product monograph states that the available data demonstrate an inconsistency and that a causal relationship between abacavir treatment and the risk of myocardial infarction is inconclusive. Abacavir remains a basic treatment recommended for people who have previously had a negative HLA-B * 5701 test.
As prevention, measures must be taken to minimize all modifiable risk factors (eg, hypertension, hyperlipidemia, type 2 diabetes and smoking) in all HIV-positive patients at risk for coronary artery disease.
Hypersensitivity reactions
Hypersensitivity reactions have been associated with integrase inhibitors. This reaction presents itself by a rash, constitutional symptoms, multi-organ and liver damage.
The product monograph recommends discontinuing Triumeq® immediately in the presence of 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.
For management of adverse effects associated with antiretrovirals, see section adverse effects management.
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.
Creatine phosphokinase abnormalities (CPK) : grade 2 (4%) and grade 3-4 (5%).
In addition, cases of myalgia or myositis coinciding with increases in CPK were reported during the program. Their link to the use of dolutegravir could not be excluded.
Increase in ALT/AST : grade 2 ALT (2%) and AST (3%), grade 3-4 ALT (> 1%) and AST (< 1%)
Integrase inhibitor
Reverse transcriptase inhibitors (by competition with the natural nucleoside)
Abacavir : 83 %
Lamivudine : 80-85 %
Dolutegravir : absorbed in the small intestine and predominantly in the duodenum according to the manufacturer
Abacavir : absorbed in the small intestine, with potentially greater absorption in the duodenum (Mariappan et al, 2007)
Lamivudine : absorbed in the small intestine, with similar absorption in the duodenum, jejunum and ileum
Dolutegravir : 2-3 h
Abacavir : 1.5 h
Lamivudine : 1 h
Dolutegravir : 14 h
Abacavir : 2.6 h
Lamivudine : 18-19 h
Dolutegravir : UGT1A1 (major) and CYP3A (minor 9.7%)
Abacavir : alcohol dehydrogenase and glucuronidation 66%
Lamivudine : not metabolized
Dolutegravir : 17.4 L
Abacavir : 0.8 L/kg
Lamivudine : 1.3 L/kg
Dolutegravir : urinary excretion 31 % (< 1 % unchanged) and in faeces (53 % unchanged)
Abacavir : 83% renal as metabolites and < 2% unchanged
Lamivudine : renal at 70%
Dolutegravir : 99%
Abacavir : ~ 49%
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.
Dolutegravir : According to animal studies, dolutegravir may be present in human breast milk.
Abacavir : Abacavir is excreted in breast milk at concentrations similar to those seen in plasma.
Lamivudine : Lamivudine is excreted in breast milk at concentrations similar to those found in serum.
Because of the risk of HIV-1 transmission and the potential for adverse reactions to infants, HIV-positive mothers should be told 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.
Administration with other antiretrovirals
Patient co-infected with hepatitis B or with hepatic impairment
Patient with impaired renal function
Although this has not been fully studied, Triumeq® can be crushed and added to a small amount of liquid or food for immediate consumption. A study in 22 healthy volunteers (Roskam-Kwint et al, 2017) demonstrated an increase in the maximum concentration of dolutegravir by 26 to 30% when the tablet was crushed compared to taking the tablet intact. Efficiency would therefore not be affected. If necessary, the clinician may choose to have a dolutegravir dosage.
Store the tablets at a maximum temperature of 30° C.
DTG, dolutegravir; ABC, abacavir; 3TC, lamivudine; DIE, once daily; CrCl, creatinine clearance; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; TAF, tenofovir alafenamide; r, ritonavir; DRV, darunavir; BIC, bictegravir; NRTIs, nucleoside and nucleotide reverse transcriptase inhibitors; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; INI, integrase inhibitors; VL, viral load.