PIFELTRO™ (doravirine 100 mg) tablets and DELSTRIGO™ (doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg) tablets

 

Weight change data for PIFELTRO

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  • Primary efficacy end point: Proportion of patients with HIV-1 ≥50 copies/mL: 2% for a doravirine-based FDC (ISG at week 48) vs 1% for baseline regimen (DSG at week 24). Difference (95% CI): 0.7 (-1.3, 2.6).
View DRIVE-SHIFT study design

Participants who completed the week 48 study visit were eligible to enter study extension 1 and continue receiving open-label DOR/3TC/TDF for an additional 96 weeks.

Weight change in virologically suppressed adults

Change in body weight (kg) since switching to a doravirine-based FDC at week 1441,a

144 week pifeltro update corrected(weeks 0-144)nAdjusted Mean ChangeAdjusted Median Change(95% CI)(95% Cl)1.4 kg1.0 kg(0.8, 1.9)(0.4, 1.6)358Immediate Switch Group(weeks 24-144)nAdjusted Mean ChangeAdjusted Median Change(95% CI)(95% Cl)1.2 kg1.2 kg(0.4, 2.0)(0.3, 2.0)177Delayed Switch Group

At week 24 of the DSG, the baseline regimen showed a mean change of -0.32 kg (95% CI: -0.80, 0.16) and a median change of 0.00 kg (Q1, Q3: -1.55, 1.20) prior to switching to a doravirine-based FDC.

A 144-week, retrospective analysis of weight change in virologically suppressed patients who switched to a doravirine-based FDC at either Day 1 in the immediate switch group (ISG) or at week 24 in the delayed switch group (DSG).

Because mean and median changes from baseline in weight were not pre-specified, and because other data related to weight gain were not measured, comparisons between treatment arms of individual trials should not be made. These results should be interpreted with caution.

aBaseline regimen = PI plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI, each administered with 2 NRTIs.

DRIVE-SHIFT study design

A randomized, international, multicenter, open-label study of adults with virologically suppressed HIV-1 for ≥6 months on 2 NRTIs with a PI plus either ritonavir or cobicistat, or elvitegravir plus cobicistat, or an NNRTI, with no history of virologic failure. Patients either immediately switched to a doravirine-based FDC on Day 1 of the study for 48 weeks (ISG [n=447]) or continued on their baseline regimen and switched after 24 weeks to a doravirine-based FDC (DSG [n=223]).

  • Primary efficacy end point: Proportion of patients with HIV-1 ≥50 copies/mL: 2% for a doravirine-based FDC (ISG at week 48) vs 1% for baseline regimen (DSG at week 24). Difference (95% CI): 0.7 (-1.3, 2.6).

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Primary efficacy end point and weight change in treatment-naïve adultsa

  • DRIVE-FORWARD primary end point: Proportion of participants who had plasma HIV-1 RNA <50 copies/mL at week 48: 84% for PIFELTRO + 2 NRTIs (n=383) vs 80% DRV/r + 2 NRTIs (n=383). Difference (95% CI): 3.9 (-1.6, 9.4).
  • A DRIVE-AHEAD primary end point: Proportion of participants who had plasma HIV-1 RNA <50 copies/mL at week 48: 84% for doravirine-based FDC (n=364) vs. 81% EFV/FTC/TDF (n=364). Difference (95% CI): 3.5 (-2.0, 9.0).2

Weight change in treatment-naïve adults

Change in body weight from baseline (kg) through weeks 48 and 96.2

144 week pifeltro update 2 treatment naivenMean ChangeMedian Change(95% CI)(Q1, Q3)1.72 kg1.0 kg(1.35, 2.10)(-1.2, 3.9)7512.37 kg1.5 kg(1.91, 2.83)(-1.0, 4.9)677week 48week 96Combined DORnMean ChangeMedian Change(95% CI)(Q1, Q3)1.35 kg0.6 kg(0.57, 2.13)(-1.9, 3.4)3161.78 kg0.7 kg(0.84, 2.73)(-1.9, 5.1)268week 48week 96DRV/rnMean ChangeMedian Change(95% CI)(Q1, Q3)0.56 kg0.0 kg(-0.13, 1.24)(-2.6, 2.8)4021.58 kg1.0 kg(0.88, 2.28)(-2.2, 4.6)362week 48week 96Combined EFVb

The mean and median changes were from a retrospective data analysis. The data were pooled from 3 doravirine clinical trials in treatment-naïve adults.

Because clinical trials are conducted under widely varying conditions, comparisons should not be made across trials. In addition, because mean and median changes from baseline in weight were not pre-specified, and because other data related to weight gain were not measured, comparisons between treatment arms of individual trials should not be made. These results should be interpreted with caution.

bThese data were pooled from 2 doravirine phase 3 clinical trials (DRIVE-FORWARD and DRIVE-AHEAD) and a doravirine phase 2 trial.

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Study design

DRIVE-FORWARD study design

A randomized, multicenter, double-blind, active-controlled, non-inferior, phase 3 study comparing PIFELTRO 100 mg once daily (n=383) vs DRV 800 mg + ritonavir 100 mg once daily (n=383), each in combination with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator, in treatment-naïve adult patients with HIV-1 RNA ≥1000 copies/mL.3

  • Primary end point: Proportion of participants who had plasma HIV-1 RNA <50 copies/mL at week 48: 84% for PIFELTRO + 2 NRTIs (n=383) vs 80% DRV/r + 2 NRTIs (n=383). Difference (95% CI): 3.9 (-1.6, 9.4).3

DRIVE-AHEAD study design

A randomized, multicenter, double-blind, active-controlled, non-inferior, phase 3 study comparing DOR 100 mg + 3TC 300 mg + TDF 300 mg once daily (n=364) vs EFV 600 mg + FTC 200 mg + TDF 300 mg once daily (n=364) in treatment-naïve adult patients with HIV-1 RNA ≥1000 copies/mL.4

Primary end points:

  • The proportion of participants who had plasma HIV-1 RNA <50 copies/mL at week 484
  • Proportion of participants with three pre-specified neuropsychiatric events (dizziness, sleep disorders/disturbances, and altered sensorium)

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Definitions

  • 3TC, lamivudine; ABC, abacavir; DOR, doravirine; DRV+r; darunavir+ritonavir; EFV, efavirenz; FDC, fixed-dose combination; FTC, emtricitabine; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; TDF, tenofovir disoproxil fumarate.
  • References

    • 1. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package US-DOV-00469.
    • 2. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package US-DOV-00278.
    • 3. Molina JM, Squires K, Sax PE, et al; for the DRIVE-FORWARD Study Group. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5(5):e211-e220. doi:10.1016/S2352-3018(18)30021-3. Epub 2018 March 25.
    • 4. Orkin C, Squires KE, Molina JM, et al; for the DRIVE-AHEAD Study Group. 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;68(4):535-544.

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Indications

PIFELTRO is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to doravirine.

DELSTRIGO is indicated as a complete regimen for the treatment of HIV-1 infection in adult patients with no prior ARV treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DELSTRIGO.

Selected Safety Information

Warning: Posttreatment Acute Exacerbation of Hepatitis B (HBV)

All patients with HIV-1 should be tested for the presence of HBV before initiating ARV therapy. Severe acute exacerbations of HBV have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing lamivudine or tenofovir disoproxil fumarate (TDF), which are components of DELSTRIGO. Patients coinfected with HIV-1 and HBV who discontinue DELSTRIGO should be monitored with both clinical and laboratory follow-up for at least several months after stopping DELSTRIGO. If appropriate, initiation of anti-HBV therapy may be warranted.

Contraindications

PIFELTRO and DELSTRIGO are contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers (including the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin and rifapentine; the cytotoxic agent mitotane; and the herbal product St. John’s wort (Hypericum perforatum)), as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of DELSTRIGO and PIFELTRO.

DELSTRIGO is contraindicated in patients with a previous hypersensitivity reaction to lamivudine.

Warnings and Precautions

Renal Impairment: New or Worsening of Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been reported with the use of TDF. DELSTRIGO should be avoided with concurrent or recent use of a nephrotoxic agent (eg, high-dose or multiple NSAIDs). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in patients with risk factors for renal dysfunction who appeared stable on TDF.

Prior to or when initiating DELSTRIGO, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue DELSTRIGO in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Discontinue DELSTRIGO if estimated creatinine clearance declines below 50 mL/min.

Bone Loss and Mineralization Defects

In clinical trials in HIV-1 infected adults, TDF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher. Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF.

Immune Reconstitution Syndrome

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment.

Drug Interactions

Because DELSTRIGO is a complete regimen, co-administration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.

Co-administration of PIFELTRO with efavirenz, etravirine, or nevirapine is not recommended.

If DELSTRIGO is co-administered with rifabutin, take one tablet of DELSTRIGO once daily, followed by one tablet of doravirine (PIFELTRO) approximately 12 hours after the dose of DELSTRIGO.

If PIFELTRO is co-administered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart).

Consult the full Prescribing Information prior to and during treatment for more information on potential drug-drug interactions.

Dosage and Administration/Special Populations

Renal Impairment

Because DELSTRIGO is a fixed-dose combination tablet and the dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not recommended in patients with estimated creatinine clearance less than 50 mL/min.

Adverse Reactions

The most common adverse reactions with DELSTRIGO (incidence ≥5%, all intensities) were dizziness (7%), nausea (5%), and abnormal dreams (5%). The most common adverse reactions with PIFELTRO (incidence ≥5%, all intensities) were nausea (7%), dizziness (7%), headache (6%), fatigue (6%), diarrhea (6%), abdominal pain (5%), and abnormal dreams (5%).

By Week 96 in DRIVE-FORWARD, 2% of adult subjects in the PIFELTRO group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication.

By Week 96 in DRIVE-AHEAD, 3% of adult subjects in the DELSTRIGO group and 7% in the EFV/FTC/TDF group had adverse events leading to discontinuation of study medication.

In DRIVE-FORWARD, mean changes from baseline at Week 48 in LDL-cholesterol (LDL-C) and non HDL-cholesterol (non-HDL-C) were pre-specified. LDL-C: -4.6 mg/dL in the PIFELTRO group vs 9.5 mg/dL in the DRV+r group. Non-HDL-C: -5.4 mg/dL in the PIFELTRO group vs 13.7 mg/dL in the DRV+r group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-AHEAD, mean changes from baseline at Week 48 in LDL-C and non-HDL-C were prespecified. LDL-C: -2.1 mg/dL in the DELSTRIGO group vs 8.3 mg/dL in the EFV/FTC/TDF group. Non-HDL-C: -4.1 mg/dL in the DELSTRIGO group vs 12.7 mg/dL in the EFV/FTC/TDF group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-SHIFT, mean changes from baseline at Week 48 in LDL-C and non-HDL-C were prespecified. LDL-C: -16.3 mg/dL in the DELSTRIGO group vs -2.6 mg/dL in the PI + ritonavir group. Non-HDL-C: -24.8 mg/dL in the DELSTRIGO group vs -2.1 mg/dL in the PI + ritonavir group. The clinical benefits of these findings have not been demonstrated.

In DRIVE-AHEAD, neuropsychiatric adverse events were reported in the three pre-specified categories of sleep disorders and disturbances, dizziness, and altered sensorium. Twelve percent of adult subjects in the DELSTRIGO group and 26% in the EFV/FTC/TDF group reported neuropsychiatric adverse events of sleep disorders and disturbances; 9% in the DELSTRIGO group and 37% in the EFV/FTC/TDF group reported dizziness; and 4% in the DELSTRIGO group and 8% in the EFV/FTC/TDF group reported altered sensorium.

The safety of DELSTRIGO in virologically-suppressed adults was based on Week 48 data from subjects in the DRIVE-SHIFT trial. Overall, the safety profile in virologically-suppressed adult subjects was similar to that in subjects with no ARV treatment history.

Pregnancy/Breastfeeding

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to PIFELTRO or DELSTRIGO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Mothers infected with HIV-1 should be instructed not to breastfeed if they are receiving PIFELTRO or DELSTRIGO due to the potential for HIV-1 transmission.

Before prescribing PIFELTROTM (doravirine), please read the accompanying Prescribing Information. The Patient Information also is available. Before prescribing DELSTRIGOTM (doravirine/lamivudine/tenofovir disoproxil fumarate), please read the accompanying Prescribing Information, including the Boxed Warning about posttreatment acute exacerbation of Hepatitis B. The Patient Information also is available.

US-DOR-0077402/21