Delstrigo®
Doravirine 100 mg + Lamivudine 300 mg + Tenofovir DF 300 mg
Fabricant : Merck
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.
Safety and efficacy have not been established in pediatric population (< 18 years of age).
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.
Child-Pugh A ou B : No adjustment required
Child-Pugh C : Administration not recommended (not studied in this population)
Delstrigo® has been studied in treatment-naive patients as well as in patients undergoing treatment with virologic suppression.
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 |
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 |
Patients who may have received antiretroviral therapy but have not had previous virologic failure. |
* 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
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.
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
|
||
| 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
|
||
| 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.
Low baseline CD4+ T-cell count and high baseline HIV-1 RNA were significant factors for at least 10% weight gain at weeks 48 and 96 (all P < 0.001) and for BMI class increase at week 48 (P¼ 0.002 and 0.016, respectively) and week 96 (P¼ 0.002 and 0.010, respectively). We did not find significant associations between treatment group, demographic characteristics (sex, race, age), or other baseline characteristics (weight, BMI, region) and at least 10% weight gain or BMI class increase in the multivariate model. However, mean weight gain was numerically higher in women than in men, and in black participants compared with nonblack participants, in all treatment groups at both time points. Similarly, the proportion of participants with weight gain at least 10% was numerically higher in women than in men in all treatment groups at both time points, and in black participants compared with nonblack participants except in the DRV/r group at week 96.
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.
Non-nucleoside reverse transcriptase inhibitor (NNRTI) derived from pyridinone; it blocks the replication of HIV by the non-competitive inhibition of reverse transcriptase.
Reverse transcriptase inhibitors
Doravirine : 64 %
Lamivudine : 80-85 %
Tenofovir DF : 25 % (with an empty stomach)
Doravirine : 15 h
Lamivudine : 18-19 h
Tenofovir DF : 17 h
Doravirine : 2 h
Lamivudine : 1 h
Ténofovir DF : 1 h
Doravirine : CYP3A4
Lamivudine : Not metabolized
Tenofovir DF : Not metabolized
Tenofovir DF : OAT1, OAT3 and MRP4
Doravirine: 60.5 L
Lamivudine : 1.3 L/kg
Tenofovir DF : 0.8 L/kg
Doravirine : Unchanged urinary excretion is minor (6 %) and bile secretion is not expected to be significant.
Lamivudine : Renal 70 %
Tenofovir DF : Renal 70-80 %
Doravirine : 76 %
Lamivudine : < 36 %
Tenofovir DF : < 0.7 %
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.
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.
Drugs interactions
For safer use with drugs used concomitantly Delstrigo®, consult the product monograph or the section on drugs interactions.
Patient co-infected with hepatitis B
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.
Store the tablets at room temperature (15° C to 30° C).
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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