Comparison of DOR and DRV/r in DRIVE-FORWARD Study

DRIVE-FORWARD Study compared the efficacy of doravirine (DOR) with darunavir/ritonavir (DRV/r) in treatment-naive HIV patients. The study aimed to show non-inferiority of DOR based on virologic response at week 48. Results indicated similar virologic response rates between DOR and DRV/r groups, with DOR showing a slight advantage in CD4 cell count increase. Overall, both regimens demonstrated effectiveness in achieving viral suppression.

• HIV treatment
• DRIVE-FORWARD Study
• Doravirine
• Darunavir/ritonavir
• Virologic response

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1. Comparison of NNRTI vs PI/r EFV vs LPV/r vs EFV + LPV/r A5142 Mexican Study NVP vs ATV/r ARTEN EFV vs ATV/r A5202 DOR vs DRV/r DRIVE-FORWARD

2. DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTI Design Randomisation* 1 : 1 Double-blind W48 W96 > 18 years ARV-na ve N = 340 DOR 100 mg QD + DRV/r placebo + 2 NRTI** HIV RNA > 1 000 c/mL Any CD4 cell count eGFR (CG) 50 mL/min No primary resistance to DOR, DRV/r, NRTI DRV/r 800/100 mg QD + DOR placebo + 2 NRTI** N = 340 * Randomisation (DOR vs DRV/r) was stratified by HIV RNA (< or > 100 000 c/mL) at screening and NRTI backbone ** NRTI backbone (TDF/FTC or ABC/3TC if exclusion of the HLA-B*5701 allele) was selected by investigator Objective Non inferiority of DOR at W48: % HIV RNA < 50 c/mL by intention to treat, non completer = failure, snapshot analysis (lower margin of the 95% CI for the difference = - 10%, 90% power) Molina JM, Lancet HIV 2018, March 25 (Epub ahead of print) DRIVE-FORWARD

3. DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTI Baseline characteristics and patient disposition DOR + 2 NRTI (N = 383) DRV/r + 2 NRTI (N = 383) Mean age, years 35 35 Female, % 17 15 AIDS, % 9 10 HIV RNA (log10c/mL), mean HIV RNA > 100 000 c/mL, % 4.4 4.4 22 19 CD4 cell count (/mm3), mean 433 412 CD4 < 200 per mm3, % 11 17 Selected NRTI: TDF/FTC / ABC/3TC, % 87 / 13 88 / 13 Discontinuation at W48, N (%) Lack of efficacy, N Adverse event, N Death, N Lost to follow-up / Consent withdrawal, N Non-compliance / Other, N 56 (15%) 12 4 1 17 / 10 7 / 5 71 (19%) 14 12 0 19 / 13 4 / 9 Molina JM, Lancet HIV 2018, March 25 (Epub ahead of print) DRIVE-FORWARD

4. 58 DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTI Primary endpoint: HIV RNA < 50 c/mL at W48 (ITT, snapshot) % DOR + 2 NRTI (N = 383) DRV/r + 2 NRTI (N = 383) Difference (95 % CI) 100 84 80 DRV/r DOR 80 3.9 60 -1.6 9.4 40 20 13 11 + 10% 10% 0 5 7 0 CD4 increase at W48 (ITT, NC = F) DOR: + 193/mm3 DRV/r: + 186/mm3 Virologic response Virologic non-response No data Molina JM, Lancet HIV 2018, March 25 (Epub ahead of print) DRIVE-FORWARD

5. 59 DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTI HIV RNA < 50 c/mL, observed failure approach * DOR + 2 NRTI DRV/r + 2 NRTI % 100 90.2 88.7 88.9 89.1 89.6 88.286.2 88.0 86.5 83.7 82.9 81.0 76.4 80 72.1 60 40 20 71 364 N = 355 285 282 79 72 41 61 323 294 316 312 48 43 0 5 log10c/mL > 5 log10c/mL > 200/mm3 TDF/FTC ABC/3TC 200/mm3 All participants Baseline HIV RNA Baseline CD4 NRTI backbone * Discontinuation due to lack of efficacy counted as failures, data missing for other reasons excluded Molina JM, Lancet HIV 2018, March 25 (Epub ahead of print) DRIVE-FORWARD

6. 60 DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTI Protocol-defined virologic failures (PDVF) Definition Non response: HIV RNA 200 c/mL at W24 or W36 or confirmed HIV RNA 50 c/mL at W48 Rebound: confirmed HIV RNA 50 c/mL after obtaining HIV RNA < 50 c/mL Resistance tests (genotype and phenotype) performed on confirmatory sample if HIV RNA > 400 c/mL DOR 100 + 2 NRTI (N = 383) 19 (5.0%) 2 7 0 0 0 6 0 DRV/r 800/100 + 2 NRTI (N = 383) 24 (6.3%) 5 8 0 0 0 8 0 Virologic failure, N Non response / Rebound Genotype successfully performed, N Primary NNRTI resistance Primary NRTI resistance Primary PI resistance Phenotype successfully performed, N With any phenotypic drug resistance 17 19 Molina JM, Lancet HIV 2018, March 25 (Epub ahead of print) DRIVE-FORWARD

7. 61 DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTI Emergence of drug resistance in participants with discontinuations DOR 100 + 2 NRTI (N = 383 *) DRV/r 800/100 + 2 NRTI (N = 383) Discontinuation without PDVF, N (%) 40 (10.4%) 53 (13.9%) Genotype successfully performed, N Primary NNRTI resistance Primary NRTI resistance Primary PI resistance 2 * 1 1 0 3 0 0 0 Phenotype successfully performed, N With any phenotypic drug resistance 2 * 2 3 0 * 1 discontinuation for non-compliance at W24, with emergence of resistance to DOR (V106I + H221Y ; > 90 fold increased IC50) and FTC (M184V) ; 1 discontinuation for rash at W2, with increased DOR IC50 2.8 fold WT (resistance cutoff = 2.5 fold), but no genotypic resistance mutations Molina JM, Lancet HIV 2018, March 25 (Epub ahead of print) DRIVE-FORWARD

8. 62 DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTI Adverse events, % DOR 100 + 2 NRTI (N = 383) DRV/r 800/100 + 2 NRTI (N = 383) Serious adverse event Drug-related Discontinuation due to adverse event Drug-related Discontinuation due to serious adverse event Drug-related Adverse event in 10 % in either group Diarrhea Nausea Nasopharyngitis Headache Adverse event of clinical interest Rash Neuropsychiatric 5.0 (N = 19) 0.3 (N = 1) 1.6 (N = 6 *) 1.0 (N = 4) 0.3 (N = 1) 0 6.0 (N = 23) 0.3 (N = 1) 3.1 (N = 12 **) 2.1 (N = 8) 0.5 (N = 2) 0.3 (N = 1) 14.1 10.7 7.8 13.8 22.5 12.0 10.2 10.7 7 11 8 13 * Death = 1, rash = 2, nausea = 2, abdominal pain = 1, kidney injury = 1 ** Abdominal pain = 2, diarrhea = 1, nausea = 1, flatulence = 1, hiatus hernia = 1, ALT and AST increase = 2, hepatitis B or C = 2, peripheral edema = 1, pyrexia = 1, rash = 1, tuberculosis = 2 Molina JM, Lancet HIV 2018, March 25 (Epub ahead of print) DRIVE-FORWARD

9. 63 DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTI Fasting lipids, changes from baseline at W48 (mg/dL) DOR DRV/r 25 22 p < 0.0001 20 17.9 p < 0.0001 13.8 15 9.9 10 4.2 5 3.9 0 - 1.4 - 5 - 3.1 - 4.5 - 5.3 - 10 LDL-C Non HDL-C Total cholesterol Triglycerides HDL-C Molina JM, Lancet HIV 2018, March 25 (Epub ahead of print) DRIVE-FORWARD

10. DRIVE-FORWARD Study: DOR + 2 NRTI vs DRV/r + 2 NRTI Conclusion at Week 48 DOR 100 mg QD, in combination with either TDF/FTC or ABC/3TC Achieved high virologic success at Week 48 And was non-inferior to DRV/r + 2 NRTI regardless of baseline HIV RNA Resistance mutations through 48 weeks None were detected in protocol-defined virologic failures Only 1/383 participants on DOR developed genotypic and phenotypic resistance to DOR + FTC/3TC Adverse events leading to discontinuation occurred with low frequency for both DOR and DRV/r Low rate of discontinuation due to rash or neuropsychiatric adverse events Lipid changes were less pronounced for DOR than for DRV/r Once-daily DOR in combination with fixed-dose NRTIs represents an effective treatment option for HIV-1-infected, treatment-naive patients Molina JM, Lancet HIV 2018, March 25 (Epub ahead of print) DRIVE-FORWARD