Delstrigo

Pharmacotherapeutic group: Antivirals for systemic use, ATC code: J05AR24 Mechanism of action Doravirine Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV‑1 and inhibits HIV‑1 replication by non-competitive inhibition of HIV‑1 reverse transcriptase (RT). Doravirine does not inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ. Lamivudine Lamivudine is a nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5´‑ triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC‑TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue. Tenofovir disoproxil Tenofovir disoproxil is an acyclic nucleoside phosphonate diester analogue of adenosine monophosphate. Tenofovir disoproxil requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV‑1 RT by competing with the natural substrate deoxyadenosine 5´-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ. Antiviral activity in cell culture Doravirine Doravirine exhibited an EC 50 value of 12.0±4.4 nM against wild-type laboratory strains of HIV‑1 when tested in the presence of 100 % normal human serum using MT4-GFP reporter cells. Doravirine demonstrated antiviral activity against a broad panel of primary HIV‑1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC 50 values ranging from 1.2 nM to 10.0 nM. The antiviral activity of doravirine was not antagonistic when combined with lamivudine and tenofovir disoproxil. Lamivudine The antiviral activity of lamivudine against HIV‑1 was assessed in a number of cell lines including monocytes and peripheral blood mononuclear cells (PBMCs) using standard susceptibility assays. EC 50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 micrograms per mL). The median EC 50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV‑1 clades A‑G and group O viruses (n = 3 except n = 2 for clade B) respectively. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV‑1 activity of lamivudine by 3.5-fold in MT-4 cells. Tenofovir disoproxil The antiviral activity of tenofovir against laboratory and clinical isolates of HIV‑1 was assessed in T lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC 50 values for tenofovir were in the range of 0.04‑8.5 microM. Tenofovir displayed antiviral activity in cell culture against HIV‑1 clades A, B, C, D, E, F, G, and O (EC 50 values ranged from 0.5‑2.2 microM). Resistance In cell culture Doravirine Doravirine-resistant strains were selected in cell culture starting from wild-type HIV‑1 of different origins and subtypes, as well as NNRTI-resistant HIV‑1. Observed emergent amino acid substitutions in RT included: V106A, V106M, V106I, V108I, F227L, F227C, F227I, F227V, H221Y, M230I, L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318F substitutions conferred 3.4-fold to 70-fold reductions in susceptibility to doravirine. Y318F in combination with V106A, V106M, V108I, or F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred a 10-fold reduction in susceptibility to doravirine. Common NNRTI-resistant mutations (K103N, Y181C) were not selected in the in vitro study. V106A (yielding a fold change of around 19) appeared as an initial substitution in subtype B virus, and V106A or M in subtype A and C virus. Subsequently F227(L/C/V) or L234I emerged in addition to V106 substitutions (double mutants yielding a fold change of > 100). Lamivudine Lamivudine-resistant variants of HIV‑1 have been selected in cell culture and in subjects treated with lamivudine. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV‑1 RT at codon 184 changing the methionine to either isoleucine or valine (M184V/I). Tenofovir disoproxil HIV‑1 isolates selected by tenofovir expressed a K65R substitution in HIV‑1 RT and showed a 2‑4 fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV‑1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir. In clinical trials Treatment-naïve adult subjects Doravirine The Phase 3 studies, DRIVE-FORWARD and DRIVE-AHEAD, included previously untreated patients (n = 747) where the following NNRTI substitutions were part of exclusion criteria: L100I, K101E, K101P, K103N, K103S, V106A, V106I, V106M, V108I, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, Y188C, Y188H, Y188L, G190A, G190S, H221Y, L234I, M230I, M230L, P225H, F227C, F227L, F227V. The following de novo resistance was seen in the resistance analysis subset (subjects with HIV‑1 RNA greater than 400 copies per mL at virologic failure or at early study discontinuation and having resistance data). Table 3: Resistance development up to Week 96 in protocol defined virologic failure population + early discontinuation population DRIVE-FORWARD DRIVE-AHEAD DOR + NRTIs* (383) DRV+r + NRTIs* (383) DOR/TDF/3TC (364) EFV/TDF/FTC (364) Successful genotype, n 15 18 32 33 Genotypic resistance to DOR or control (DRV or EFV) 2 (DOR) 0 (DRV) 8 (DOR) 14 (EFV) NRTI backbone M184I/V only K65R only K65R + M184I/V 2 † 2 0 0 0 0 0 0 6 4 1 1 5 4 0 1 *NRTI in DOR arm: FTC/TDF (333) or ABC/3TC (50); NRTI in DRV+r arm: FTC/TDF (335) or ABC/3TC (48) † Subjects received FTC/TDF ABC=abacavir; FTC=emtricitabine; DRV=darunavir; r=ritonavir Emergent doravirine associated resistance substitutions in RT included one or more of the following: A98G, V106I, V106A, V106M/T, Y188L, H221Y, P225H, F227C, F227C/R, and Y318Y/F. Virologically suppressed adult subjects The DRIVE-SHIFT study included virologically suppressed patients (N=670) with no history of treatment failure (see section, Clinical experience). A documented absence of genotypic resistance (prior to starting first therapy) to doravirine, lamivudine, and tenofovir was part of the inclusion criteria for patients who switched from a PI- or INI-based regimen. Exclusionary NNRTI substitutions were those listed above (DRIVE-FORWARD and DRIVE-AHEAD), with the exception of substitutions RT K103N, G190A and Y181C (accepted in DRIVE-SHIFT). Documentation of pre‑treatment resistance genotyping was not required for patients who switched from a NNRTI-based regimen. In the DRIVE-SHIFT clinical trial, no subjects developed genotypic or phenotypic resistance to DOR, 3TC, or TDF during the initial 48 weeks (immediate switch, N=447) or 24 weeks (delayed switch, N=209) of treatment with Delstrigo. One subject developed RT M184M/I mutation and phenotypic resistance to 3TC and FTC during treatment with their baseline regimen. None of the 24 subjects (11 in the immediate switch group, 13 in the delayed switch group) with baseline NNRTI mutations (RT K103N, G190A, or Y181C) experienced virologic failure through Week 48, or at time of discontinuation. Paediatric subjects In the IMPAACT 2014 (Protocol 027) clinical trial, no subject who was virologically suppressed at baseline met the criteria for resistance analysis. One treatment-naïve subject who met the protocol‑defined virologic failure criteria (defined as 2 consecutive plasma HIV-1 RNA test results ≥200 copies/mL at or after Week 24) was evaluated for the development of resistance; no emergence of genotypic or phenotypic resistance to doravirine, lamivudine or tenofovir was detected. Cross-resistance No significant cross-resistance has been demonstrated between doravirine-resistant HIV‑1 variants and lamivudine/emtricitabine or tenofovir or between lamivudine- or tenofovir-resistant variants and doravirine. Doravirine Doravirine has been evaluated in a limited number of patients with NNRTI resistance (K103N n = 7, G190A n = 1); all patients were suppressed to < 40 copies/mL at Week 48. A breakpoint for a reduction in susceptibility, yielded by various NNRTI substitutions, that is associated with a reduction in clinical efficacy has not been established. Laboratory strains of HIV‑1 harbouring the common NNRTI-associated mutations K103N, Y181C, or K103N/Y181C substitutions in RT exhibit less than a 3-fold decrease in susceptibility to doravirine compared to wild-type virus when evaluated in the presence of 100 % normal human serum. In in vitro studies, doravirine was able to suppress the following NNRTI-associated substitutions; K103N, Y181C, and G190A under clinically relevant concentrations. A panel of 96 diverse clinical isolates containing NNRTI-associated mutations was evaluated for susceptibility to doravirine in the presence of 10 % foetal bovine serum. Clinical isolates containing the Y188L substitution or V106 substitutions in combination with A98G, H221Y, P225H, F227C or Y318F showed a greater than 100-fold reduced susceptibility to doravirine. Other substitutions yielded a fold change of 5-10 (G190S (5.7); K103N/P225H (7.9), V108I/Y181C (6.9), Y181V (5.1)). The clinical relevance of a 5-10 fold reduction in susceptibility is unknown. Treatment emergent doravirine resistance associated substitutions may confer cross-resistance to efavirenz, rilpivirine, nevirapine, and etravirine. Of the 8 subjects who developed high level doravirine resistance in the pivotal studies, 6 had phenotypic resistance to EFV and nevirapine, 3 to rilpivirine, and 3 had partial resistance to etravirine based on the Monogram Phenosense assay. Lamivudine Cross-resistance has been observed among NRTIs. The M184I/V lamivudine resistance substitution confers resistance to emtricitabine. Lamivudine-resistant HIV‑1 mutants were also cross resistant to didanosine (ddI). In some subjects treated with zidovudine plus didanosine, isolates resistant to multiple RT inhibitors, including lamivudine, have emerged. Tenofovir disoproxil Cross-resistance has been observed among NRTIs. The K65R substitution in HIV‑1 RT selected by tenofovir is also selected in some HIV‑1 infected patients treated with abacavir or didanosine. HIV‑1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbours the K65R substitution. The K70E substitution selected clinically by tenofovir disoproxil results in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV‑1 isolates from patients (n = 20) whose HIV‑1 expressed a mean of 3 zidovudine associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V RT substitution without zidovudine resistance-associated substitutions (n = 8) had reduced response to tenofovir disoproxil. Limited data are available for patients whose virus expressed a Y115F substitution (n = 3), Q151M substitution (n = 2), or T69 insertion (n = 4) in HIV‑1 RT, all of whom had a reduced response in clinical trials. Clinical experience Treatment-naïve adult subjects The efficacy of doravirine is based on the analyses of 96-week data from two randomised, multicentre, double-blind, active controlled Phase 3 trials, (DRIVE-FORWARD and DRIVE‑AHEAD) in antiretroviral treatment-naïve, HIV‑1 infected subjects (n = 1 494). Refer to Resistance section for NNRTI substitutions that were part of exclusion criteria. In DRIVE-FORWARD, 766 subjects were randomised and received at least 1 dose of either doravirine 100 mg or darunavir + ritonavir 800+100 mg once daily, each in combination with emtricitabine/tenofovir disoproxil (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the median age of subjects was 33 years (range 18 to 69 years), 86 % had CD4 + T cell count greater than 200 cells per mm 3 , 84 % were male, 27 % were non-white, 4 % had hepatitis B and/or C virus co-infection, 10 % had a history of AIDS, 20 % had HIV‑1 RNA greater than 100 000 copies per mL, 13 % received ABC/3TC and 87 % received FTC/TDF; these characteristics were similar between treatment groups. In DRIVE-AHEAD, 728 subjects were randomised and received at least 1 dose of either doravirine/lamivudine/tenofovir disoproxil 100/300/245 mg (DOR/3TC/TDF) or efavirenz/emtricitabine/tenofovir disoproxil (EFV/FTC/TDF) once daily. At baseline, the median age of subjects was 31 years (range 18‑70 years), 85 % were male, 52 % were non-white, 3 % had hepatitis B or C co-infection, 14 % had a history of AIDS, 21 % had HIV‑1 RNA > 100 000 copies per mL, and 12 % had CD4 + T cell count < 200 cells per mm 3 ; these characteristics were similar between treatment groups. Week 48 and 96 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 4. The doravirine-based regimens demonstrated consistent efficacy across demographic and baseline prognostic factors. Table 4: Efficacy response (< 40 copies/mL, Snapshot approach) in the pivotal studies DRIVE-FORWARD DRIVE-AHEAD DOR + 2 NRTIs (383) DRV+r + 2 NRTIs (383) DOR/3TC/TDF (364) EFV/FTC/TDF (364) Week 48 83 % 79 % 84 % 80 % Difference (95 % CI) 4.2 % (-1.4%, 9.7 %) 4.1 % (-1.5 %, 9.7 %) Week 96* 72 % (N=379) 64 % (N=376) 76 % (N=364) 73 % (N=364) Difference (95 % CI) 7.6 % (1.0 %, 14.2 %) 3.3 % (-3.1 %, 9.6 %) Week 48 outcome (< 40 copies/mL) by baseline factors HIV‑1 RNA copies/mL ≤ 100 000 256/285 (90 %) 248/282 (88 %) 251/277 (91 %) 234/258 (91 %) > 100 000 63/79 (80 %) 54/72 (75 %) 54/69 (78 %) 56/73 (77 %) CD4 count, cells/µL ≤ 200 34/41 (83 %) 43/61 (70 %) 27/42 (64 %) 35/43 (81 %) > 200 285/323 (88 %) 260/294 (88 %) 278/304 (91 %) 255/288 (89 %) NRTI background therapy TDF/FTC 276/316 (87 %) 267/312 (86 %) NA ABC/3TC 43/48 (90 %) 36/43 (84 %) NA Viral subtype B 222/254 (87 %) 219/255 (86 %) 194/222 (87 %) 199/226 (88 %) non-B 97/110 (88 %) 84/100 (84 %) 109/122 (89 %) 91/105 (87 %) Mean CD4 change from baseline Week 48 193 186 198 188 Week 96 224 207 238 223 *For Week 96, certain subjects with missing HIV‑1 RNA were excluded from the analysis. Virologically suppressed adult subjects The efficacy of switching from a baseline regimen consisting of two nucleoside reverse transcriptase inhibitors in combination with a ritonavir- or cobicistat-boosted PI, or cobicistat-boosted elvitegravir, or an NNRTI to Delstrigo was evaluated in a randomised, open-label trial (DRIVE-SHIFT), in virologically suppressed HIV-1 infected adults. Subjects must have been virologically suppressed (HIV-1 RNA < 40 copies/mL) on their baseline regimen for at least 6 months prior to trial entry, with no history of virologic failure, and a documented absence of RT substitutions conferring resistance to doravirine, lamivudine and tenofovir (see section, Resistance). Subjects were randomised to either switch to Delstrigo at baseline [N= 447, Immediate Switch Group (ISG)], or stay on their baseline regimen until Week 24, at which point they switched to Delstrigo [N= 223, Delayed Switch Group (DSG)]. At baseline, the median age of subjects was 43 years, 16 % were female, and 24 % were non‑white. In the DRIVE-SHIFT trial, an immediate switch to Delstrigo was demonstrated to be non-inferior at Week 48 compared to continuation of the baseline regimen at Week 24 as assessed by the proportion of subjects with HIV-1 RNA < 40 copies/mL. Treatment results are shown in Table 5. Consistent results were seen for the comparison at study Week 24 in each treatment group. Table 5: Efficacy response (Snapshot approach) in the DRIVE-SHIFT study Outcome Delstrigo Once Daily ISG Week 48 N=447 Baseline Regimen DSG Week 24 N=223 HIV-1 RNA < 40 copies/mL 90 % 93 % ISG-DSG, Difference (95 % CI)* -3.6 % (-8.0 %, 0.9 %) Proportion (%) of Subjects With HIV-1 RNA < 40 copies/mL by Baseline Regimen Received Ritonavir- or Cobicistat- boosted PI 280/316 (89 %) 145/156 (93 %) Cobicistat-boosted elvitegravir 23/25 (92 %) 11/12 (92 %) NNRTI 98/106 (92 %) 52/55 (95 %) Proportion (%) of Subjects With HIV-1 RNA < 40 copies/mL by Baseline CD4 + T cell Count (cells/mm 3 ) < 200 cells/mm 3 10/13 (77 %) 3/4 (75 %) ≥ 200 cells/mm 3 384/426 (90 %) 202/216 (94 %) HIV-1 RNA ≥ 40 copies/mL † 3 % 4 % No Virologic Data Within the Time Window 8 % 3 % Discontinued study due to AE or Death ‡ 3 % 0 Discontinued study for Other Reasons § 4 % 3 % On study but missing data in window 0 0 *The 95 % CI for the treatment difference was calculated using stratum-adjusted Mantel-Haenszel method. † Includes subjects who discontinued study treatment or study before Week 48 for ISG or before Week 24 for DSG for lack or loss of efficacy and subjects with HIV-1 RNA ≥ 40 copies/mL in the Week 48 window for ISG and in the Week 24 window for DSG. ‡ Includes subjects who discontinued because of adverse event (AE) or death if this resulted in no virologic data on treatment during the specified window. § Other reasons include: lost to follow-up, non-compliance with study treatment, physician decision, protocol deviation, withdrawal by subject. Baseline regimen = ritonavir or cobicistat-boosted PI (specifically atazanavir, darunavir, or lopinavir), or cobicistat-boosted elvitegravir, or NNRTI (specifically efavirenz, nevirapine, or rilpivirine), each administered with two NRTIs. Discontinuation due to adverse events In DRIVE-AHEAD, a lower proportion of subjects who discontinued due to an adverse event by Week 48 was seen for the Delstrigo group (3.0 %) compared with the EFV/FTC/TDF group (6.6 %). Paediatric population The efficacy of DOR/3TC/TDF was evaluated in an open-label, single-arm trial in HIV-1 infected paediatric patients 12 to less than 18 years of age (IMPAACT 2014 (Protocol 027)). At baseline, the median age of subjects was 15 years (range: 12 to 17), 58% were female, 78% were Asian and 22% were Black, and the median CD4+ T-cell count was 713 cells per mm 3 (range: 84 to 1,397). After switching to DOR/3TC/TDF, 95% (41/43) of virologically-suppressed subjects remained suppressed (HIV-1 RNA < 50 copies/mL) at Week 24 and 93% (40/43) remained suppressed (HIV-1 RNA < 50 copies/mL) at Week 48. The European Medicines Agency has deferred the obligation to submit the results of studies with Delstrigo in one or more subsets of the paediatric population in treatment of human immunodeficiency virus-1 (HIV‑1) infection. See section 4.2 for information on paediatric use.