Dolutegravir (DTG) + Abacavir (ABC) + Lamivudine (3TC)

DOSAGE

Adult or adolescent dosage ≥ 12 years et ≥ 40 kg

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.

Pediatric dosage

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.

Adjustment in renal impairment

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).

Adjustment in hepatic impairment

Child-Pugh A : Administration not recommended (recommended abacavir adjustment, use compounds separately)

Child-Pugh B or C : Administration not recommended

COMPARATIVE EFFICIENCY

Triumeq^® has been studied in treatment-naïve patients as well as in patients undergoing treatment with virological suppression.

Studies in patients who have never received antiretrovirals

Study in patients with virological suppression

* Patients with a history of mono or dual NRTI therapy were excluded from the study.

RESISTANCE

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.

ADVERSE REACTIONS

In short

• Nausea
• Headache
• Insomnia
• Fatigue
• Diarrhea
• Weight gain observed in retrospective cohorts and especially in black women

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.

Cardiac toxicity with abacavir

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.

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 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.

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.

Bilirubine 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.

Impacts on liver enzymes and CPK observed in the SINGLE study at week 96

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%)

MECHANISM OF ACTION

Dolutegravir

Integrase inhibitor

Abacavir and lamivudine

Reverse transcriptase inhibitors (by competition with the natural nucleoside)

PHARMACOKINETICS

Bioavailability

Abacavir : 83 %
Lamivudine : 80-85 %

Absorption

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

Tmax

Dolutegravir : 2-3 h
Abacavir : 1.5 h
Lamivudine : 1 h

Elimination T½ (plasma)

Dolutegravir : 14 h
Abacavir : 2.6 h
Lamivudine : 18-19 h

Metabolism

Dolutegravir : UGT1A1 (major) and CYP3A (minor 9.7%)
Abacavir : alcohol dehydrogenase and glucuronidation 66%
Lamivudine : not metabolized

Distribution volume

Dolutegravir : 17.4 L
Abacavir : 0.8 L/kg
Lamivudine : 1.3 L/kg

Elimination

Dolutegravir : urinary excretion 31 % (< 1 % unchanged) and in faeces (53 % unchanged)
Abacavir : 83% renal as metabolites and < 2% unchanged
Lamivudine : renal at 70%

Binding to plasma proteins

Dolutegravir : 99%
Abacavir : ~ 49%
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.

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

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.

PRECAUTIONS AND CONTRAINDICATIONS

Contrandications

• Hypersensitivity to the active or inactive molecules contained in the tablet.

• Carriers of the HLA-B*5701 allele and patients who have already had a hypersensitivity reaction to abacavir or to products containing abacavir whether or not they carry the HLA-B*5701 allele.

• Concomitant administration with drugs transported by OCT2 and with a narrow therapeutic index such as dofetilide and fampridine.(See in the interactions module for additional details).

Precautions

Drugs interactions

• Co-administration with potent CYP3A4 inducers such as rifampin, carbamazepine, oxcarbazepine, phenytoin, phenobarbital 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 Triumeq^®.

• 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.

Administration with other antiretrovirals

• Triumeq^® should not be coadministered with other antiretrovirals that contain abacavir, lamivudine or emtricitabine (Atripla, Combivir, Complera, Delstrigo, Descovy, Dovato, Emtriva, Epivir, Heptovir, Genvoya, Kivexa, Odefsey, Symtuza, Stribild, Trizivir, Truvada)

Patient co-infected with hepatitis B or with hepatic impairment

• Patients who are co-infected with HBV and who require treatment should not be treated with Triumeq^®. Combines with tenofovir and emtricitabine are the antiretrovirals of choice for HIV and HBV co-infection and should be preferred. Treatment of hepatitis B with lamivudine is associated with a high resistance rate.

• If Triumeq^® has been started in a patient co-infected with hepatitis B and in need of treatment, caution should be exercised if treatment is discontinued. Indeed, severe acute exacerbations of hepatitis B (eg, hepatic decompensation and hepatic impairment) have been observed in patients co-infected with HBV and HIV-1. Therefore, discontinuing treatment with Triumeq^® without initiating an alternative hepatitis B treatment is not recommended.

• Not recommended for moderate or severe hepatic impairment (Child-Pugh B or C).

Patient with impaired renal function

• Triumeq^® is a fixed dose tablet, it should not be prescribed to patients whose CrCl is less than 30 mL/min. Dolutegravir, abacavir, and lamivudine should be used separately.

FURTHER INFORMATION

Administration for patients with swallowing difficulties

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.

Storage

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

REFERENCES

• Dolutegravir/Abacavir/Lamivudine (Triumeq), ViiVHealthcare, Quebec, Canada, Nov 22, 2021.

• Fischetti B, Shah K, Taft DR, Berkowitz L, Bakshi A et al. Real-world experience with higher-than-recommended doses of lamivudine in patients with varying degrees of renal impairment. Open Forum Infect Dis. 2018 Sep 10; 5(10): ofy225.

• Mounzer K, Brunet L, Wyatt CM, Fusco JS, Vannappagari V et al. To dose-adjust or not to dose-adjust: lamivudine dose in kidney impairment. AIDS. 2021 Jul 1; 35(8): 1201-1208.

• Wood B and AL Pozniak. Dosing lamivudine or emtricitabine in renal impairment: new data confirm it’s time for updated guidance! AIDS. 2021 Jul 1; 35(8): 1305-1307.

• 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). Antiretroviral Dosing Recommendations in Patients with Renal or Hepatic Insufficiency. Publié le 10 juillet 2019. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/44/arv-dosing-for-renal-or-hepatic-insufficiency Consulté le 30 novembre 2019.

• U.S. Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Publié le 10 juillet 2019. https://aidsinfo.nih.gov/guidelines/html/2/pediatric-arv/0 Consulté le 30 novembre 2019.

• Roskam-Kwint M, Bollen P, Colbers A, Duisenberg-van Essenberg M, Harbers V et al. Crushing dolutegravir-combination tablets increases dolutegravir exposure. CROI 2017, Seattle, WA USA, February 13-16 2017. Abstract P-429.

• Foisy M, Pharm.D., AAHIVP, Northern Alberta Program, Royal Alexandra Hospital Site, Edmonton, C. Hughes, Pharm.D., AAHIVP, Northern Alberta Program, KEC Site,Edmonton, Alberta, Sarah Lamb, PharmD Student (2017 updates), and A. Tseng, Pharm.D, AAHIVP, Toronto General Hospital. ORAL ANTIRETROVIRAL ADMINISTRATION: INFORMATION ON CRUSHING AND LIQUID DRUG FORMULATIONS

• Walmsley S, Baumgarten A, Berenguer J et al. Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96-144 result from SINGLE randomized clinical trial. J Acquir Immune Defic Syndr 2015; 70: 515-519.

• RosKam-Kwint Marieke, Bollen P, Colbers A et al. Crushing of dolutegravir fixed-dose combination tablets increases dolutegravir exposure. J Antimicrob Chemother 2018; 73: 2430-2434.

• La pharmacométrie clinique des antirétroviraux et l’individualisation de la thérapie antirétrovirale chez les adultes et les enfants vivant avec le VIH – Guide pour les professionnels de la santé du Québec: https://publications.msss.gouv.qc.ca/msss/fichiers/2013/13-308-06W.pdf

• Trottier B, Lake JE and Logue K. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label Phase IIIb study. Antiviral Therapy 2017; 22: 295–305.

• Orrell C, Hagins DP, Belonosova E, Porteiro N, Walmsley S, Falcó V et al. Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study. The Lancet HIV, 4(12), e536-e546.

• Mariappan TT, Singh S. Gastrointestinal permeability studies using combinations of rifampicin and nucleoside analogue reverse transcriptase inhibitors in rats. Indian Journal of Pharmacology. 2007; 39(6): 284-290.

• Molina JM, Clotet B, van Lunzen J and FLAMINGO study team. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015 Apr; 2(4): e127-36.

• Rhee, SY, Grand Pm, Tzou PL et al. A systematic review of the genetic mechanisms of dolutegravir resistance.
  J Antimicrob Chemother. 2019 Nov 1; 74(11): 3135-3149.

• EACS Guidelines version 11.0. Treatment of Pregnant Women Living with HIV or Women Considering Pregnancy. Published in october 2021. https://eacs.sanfordguide.com/art/pregnancy-and-hiv Consulted on October 14, 2022.

• 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 March 17, 2022.
  https://clinicalinfo.hiv.gov/en/guidelines/perinatal/whats-new-guidelines Consulted on October 14, 2022.

ABBREVIATIONS

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.