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FORMULATION(s)

Fabricant : Merck

DOSAGE

Adult dosage

1 tablet DIE with or without food. For the forgotten doses, the product monograph has no specific data.

It recommends taking the missed dose as soon as possible, unless there is little time before the next dose. Do not double the dose.

Pediatric dosage

Safety and efficacy have not been established in pediatric population (< 18 years of age).

Adjustment in renal impairment

ClCr < 50 mL/min : Administration not recommended since the dosages of lamivudine and tenofovir must be modified. Therefore, each of the compounds should be used separately.

Adjustment in hepatic impairment

Child-Pugh A ou B : No adjustment required

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

COMPARATIVE EFFICIENCY

Delstrigo® has been studied in treatment-naive patients as well as in patients undergoing treatment with virologic suppression.

Study in patients who have never received antiretrovirals

Study

Comparator groups

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

DRIVE-AHEAD

DOR/3TC/TDF (N=364) vs EFV/FTC/TDF (N=364)

Week 48
Noninferiority of DOR/3TC/TDF (84% vs 81%, 95% CI -2.0% à 9.0%)

Study in patients with virological suppression

Study

Comparator groups

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

Types of patients

DRIVE-SHIFT

DOR/3TC/TDF (N=447) vs CAR* (N=223)

Week 24
Noninferiority of DOR/3TC/TDF (91% vs 95%, 95% CI 3.8% (-7.9% to 0.3%)).
Lack of response (VL > 50 copies/mL) observed in 2% of patients in each group.

Patients who may have received antiretroviral therapy but have not had previous virologic failure.
Stable virologic suppression (< 50 copies/mL) since ≥ 6 months.

* CAR : Current initial antiretroviral therapy with 2 NRTIs in combination with a PI boosted by ritonavir or cobicistat, elvitegravir boosted by cobicistat, or a NNRTI

RESISTANCE

The development of resistance to doravirine was observed in 7/30 subjects in the resistance analysis subgroup (CV more than 400 copies/mL at the time of failure or cessation of therapy). Emerging reverse transcriptase substitutions that confer resistance to doravirine included at least one of the following : A98G, V106I, V106A, V106M/T, Y188L, H221Y, P225H, F227C, F227C/R et Y318Y/F.

Among the 7 subjects who acquired resistance to doravirine, 6 had phenotypic resistance to efavirenz and nevirapine, 3 had phenotypic resistance to rilpivirine and 2 had partial resistance to etravirine.

Compared to other agents in the studies (DRIVE-FORWARD and DRIVE-AHEAD) :

DRIVE-FORWARD DRV/r: No resistance to darunavir was observed in the 11 subjects in the resistance analysis subgroup.

DRIVE-AHEAD EFV/FTC/TDF : resistance to efavirenz was observed in 12/24 of the resistance analysis subgroup.

What has been observed for doravirine in all studies :

• Doravirine displays sensitivity in the presence of the K103N, Y181C, G190A, E138K mutations or the double K103N/Y181C mutation, the main mutations associated with NNRTIs.

• Doravirine exhibited a 3-fold smaller variation of IC50 against strains K103N, Y181C and K103N/Y181C.

• Doravirin exhibited a 9-fold smaller variation in IC50 against most single mutant viruses, including A98G,E138A/G/K/Q, G190A, K101E/P, K103N/S, L100I, P236L, V106M, V108I, V197D, V90I, Y181C/V and Y188H/C.

• Substitutions including G190E/S, V106A, Y188L and M230L reduce the sensitivity of doravirine by more than 10 times.

• Substitutions G190S, Y188L and M230L confer 95-fold greater resistance.

ADVERSE REACTIONS

In short

  • Nausea
  • Fatigue, dizziness, drowsiness
  • Headache
  • Insomnia, nightmares

According to clinical studies, doravirine was well tolerated in the majority of patients. Indeed, no moderate or severe side effects with a frequency greater than or equal to 2% were observed.

The most frequently reported adverse reaction was nausea in 6% of patients of all grade.

The product monograph reports serious side effects with a frequency of less than 1% for nausea, vomiting, asthenia, insomnia and nightmares.

DRIVE-FORWARD Study
(Week 48)
Adverse reactions (Grade 1-4)

DOR + 2 NRTIs
(N=383)
DRV/r + 2 NRTIs
(N=383)

Nausea

7%

8%

Vomiting

2%

1%

Diarrhea

5%

3%

Fatigue

5%

2%

Dizziness

3%

2%

Headache

6%

3%

Insomnia

1%

2%

Sleep disorder

2%

< 1%

Drowsiness

0%

< 1%

Strange dreams

1%

< 1%

Nightmares

< 1%

< 1%

Skin rash

< 1%

< 1%

In these clinical studies, all of the side effects observed at week 48 were similar to week 96.

The most common adverse reactions were diarrhea in 5% in the doravirine group and 13% in the darunavir/r group, nausea (7% vs 8%) and headache (6% vs 3%).

Discontinuation of treatment due to adverse reactions was observed in 1.6% of subjects in the doravirine group compared to 3.1% of subjects in the DRV/r group.

DRIVE-AHEAD Study
(Week 48)
Adverse reactions (Grade 1-4)

DOR/3TC/TDF
(N=364)
EFV/FTC/TDF
(N=364)

Nausea

5%

7%

Vomiting

2%

3%

Diarrhea

3%

5%

Fatigue

4%

3%

Dizziness

7%

32%

Headache

4%

4%

Insomnia

4%

5%

Sleep disorder

< 1%

2%

Drowsiness

3%

7%

Strange dreams

5%

9%

Nightmares

2%

4%

Skin rash

2%

9%

The most frequent adverse reactions were dizziness in 8.8% in the doravirine group and 37.1% in the efavirenz group, sleep disturbances (12.1% vs 25.2%) and impaired sensorium (4.4% vs 8.2%).

Discontinuation of treatment related to adverse reactions was observed in 3% of subjects in the doravirine group compared to 6.6% of subjects in the EFV/FTC/TDF group.

For management of side effects associated with antiretrovirals, see section information on adverse drug reactions.

Bone toxicity

Tenofovir DF may be responsible for osteomalacia or osteoporosis. Indeed, cases of osteomalacia associated with proximal renal tubulopathy have been reported.

Renal toxicity

Proximal renal tubulopathy has been reported with tenofovir DF. The risk would be higher in patients with underlying kidney disease or taking nephrotoxic agents.

Lipid profile

Doravirine has the advantage of having a neutral effect on lipids. Compared to DRV/r and EFV, the differences were statistically significant and showed superiority to doravirine. In addition, the DRIVE-SHIFT study shows an improvement in the lipid profile of subjects who switch from a combination of PIs/ritonavir-based antiretroviral therapy to doravirine.

Hypersensitivity reactions

Severe hypersensitivity and skin reactions are possible with the NNRTI class. According to the product monograph, moderate or severe rashes were observed in 0.3% of patients who participated in the DRIVE-FORWARD and DRIVE-AHEAD studies.

If the patient has a skin rash with systemic symptoms, stop taking doravirine immediately.

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.

MECHANISM OF ACTION

Doravirine

Non-nucleoside reverse transcriptase inhibitor (NNRTI) derived from pyridinone; it blocks the replication of HIV by the non-competitive inhibition of reverse transcriptase.

Lamivudine and tenofovir DF

Reverse transcriptase inhibitors

PHARMACOKINETICS

Bioavailability

Doravirine : 64 %
Lamivudine : 80-85 %
Tenofovir DF : 25 % (with an empty stomach)

Elimination T½ (plasma)

Doravirine : 15 h
Lamivudine : 18-19 h
Tenofovir DF : 17 h

Tmax

Doravirine : 2 h
Lamivudine : 1 h
Ténofovir DF : 1 h

Metabolism

Doravirine : CYP3A4
Lamivudine : Not metabolized
Tenofovir DF : Not metabolized

Renal transporters

Tenofovir DF : OAT1, OAT3 and MRP4

Distribution volume

Doravirine: 60.5 L
Lamivudine : 1.3 L/kg
Tenofovir DF : 0.8 L/kg

Elimination

Doravirine : Unchanged urinary excretion is minor (6 %) and bile secretion is not expected to be significant.
Lamivudine : Renal 70 %
Tenofovir DF : Renal 70-80 %

Binding to plasma proteins

Doravirine : 76 %
Lamivudine : < 36 %
Tenofovir DF : < 0.7 %

PREGNANCY AND BREAST FEEDING

Pregnancy

Based on existing data, and due to the lack of studies on the effects of this medication in pregnant or breastfeeding women, it is impossible to comment on the safety of doravirine during pregnancy and breastfeeding.

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.

Breast Feeding

Doravirine : Studies in animals have shown excretion of doravirine in breast milk. It is not excluded that doravirine is also eliminated in breast milk.

Lamivudine : Lamivudine is excreted in breast milk at concentrations similar to those found in serum.

Tenofovir DF : Samples of breast milk taken after delivery have shown that tenofovir is excreted in breast milk. In addition, animal studies have also shown the excretion of tenofovir in breast milk.

Because of the risk of HIV-1 transmission and potential side effects for infants, HIV-positive mothers should be told not to breastfeed.

PRECAUTIONS AND CONTRAINDICATIONS

Contraindications

  • Hypersensitivity to the active or inactive molecules contained in the tablet (see product monograph for additional details).
  • Concomitant administration with strong CYP3A4 inducers: rifampicin, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, enzalutamide, mitotane, St. John’s wort (Hypericum perforatum)  (see the interactions module for further details).

Precautions

Drugs interactions

  • The product monograph makes a recommendation if Delstrigo® is administered with rifabutin (moderate CYP3A4 inducer) and to give doravirine 100 mg tablet (Pifeltro®) approximately 12 hours after the dose of Delstrigo®.
  • Co-administration of Delstrigo® with other moderate CYP3A inducers (eg dabrafenib, bosentan, modafinil) has not been evaluated and should be avoided. If co-administration cannot be avoided, suggest to take a doravirine 100 mg tablet (Pifeltro®) approximately 12 hours after the dose of Delstrigo®

For safer use with drugs used concomitantly Delstrigo®, consult the product monograph or the section on drugs interactions.

Patient co-infected with hepatitis B

  • Patients who are co-infected with HBV and who require treatment should not be treated with Delstrigo®. Indeed, the combined with tenofovir and emtricitabine are the antiretrovirals recommended in the presence of a co-infection HIV and HBV.
  • However, if Delstrigo® is started in a patient co-infected with HBV, care should be taken if the patient is interrupted. In fact, severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been observed after stopping treatment. If discontinuation of Delstrigo® is necessary in a patient co-infected with HIV and HBV, alternative therapy should be provided for the treatment of hepatitis B.

FURTHER INFORMATION

Administration

No data on whether the tablet can be cut or crushed. The company recommends that you do not cut or crush it and swallow it whole.

Storage

Store the tablets at room temperature (15° C to 30° C).

REFERENCES

  • Doravirine/Lamivudine/Tenofovir DF (Delstrigo), Merck, Quebec, Canada, Aug 21, 2019.
  • Milina JM, Squires K, Sax PE et al. Doravirine versus ritonavir-Boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FOWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial. Lancet HIV. 2020 Jan; 7(1): e16-e26.
  • Orkin C, Squires KE, Molina JM et al. Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial.Clin Infect Dis. 2019 Feb 1; 68(4): 535-544.
  • Johnson M, Kumar P, Molina JM et al. Switching to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) Maintains HIV-1 Virologic Suppression Through 48 Weeks: Results of the DRIVE-SHIFT Trial. J Acquir Immune Defic Syndr. 2019 Aug 1; 81(4): 463-472.
  • Pham HT, Xiao MA, Principe MA et al.Pharmaceutical, clinical, and resistance information on doravirine, a novel non-nucleoside reverse transcriptase inhibitor for the treatment of HIV-1 infection. Drugs Context. 2020 Mar: 2019-11-4.
  • Boyle A, Moss CE, Marzolini C et al. Clinical Pharmacodynamics, Pharmacokinetics, and Drug Interaction Profile of Doravirine. Clin Pharmacokinet. 2019 Dec; 58(12): 1553-1565.

ABBREVIATIONS

DOR, doravirine; 3TC, lamivudine; TDF, ténofovir disoproxil fumarate; CrCl, creatinine clearance; DIE, once daily; CAR, current initial ART regimen; NRTIs, nucleoside and nucleotide reverse transcriptase inhibitors; DRV/r, darunavir/ritonavir; EFV, efavirenz; FTC, emtricitabine; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; VL, viral load.

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