Juluca

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections, combinations.‍‍‍‍‍‍​​​‍​​​​​​ ATC code: J05AR25 Mechanism of action Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Lamivudine, via its active metabolite 5'-triphosphates (TP) (an analogue for cytidine), inhibits reverse transcriptase of HIV-1 and HIV-2 through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Lamivudine triphosphate shows significantly less affinity for host cell DNA polymerases. Pharmacodynamic effects Antiviral activity in cell culture Dolutegravir and lamivudine have been shown to inhibit replication of lab-strains and clinical isolates of HIV in a number of cell types, including transformed T cell lines, monocyte/macrophage derived lines and primary cultures of activated peripheral blood mononuclear cells (PMBCs) and monocyte/macrophages. The concentration of active substance necessary to effect viral replication by 50% (IC 50 - half maximal inhibitory concentration) varied according to virus and host cell type. The IC 50 for dolutegravir in various lab-strains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC 50 s were seen for clinical isolates without any major difference between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC 50 value was 0.2 nM (range 0.02-2.14). The mean IC 50 for 3 HIV-2 isolates was 0.18 nM (range 0.09‑0.61). The median or mean IC 50 values for lamivudine against lab-strains of HIV-1 ranged from 0.007 to 2.3 μM. The mean IC 50 against lab-strains of HIV-2 (LAV2 and EHO) ranged from 0.16 to 0.51 μM for lamivudine. The IC 50 values of lamivudine against HIV-1 subtypes (A-G) ranged from 0.001 to 0.170 μM, against Group O from 0.030 to 0.160 μM and against HIV-2 isolates from 0.002 to 0.120 μM in peripheral blood mononuclear cells. HIV-1 isolates (CRF01_AE, n=12; CRF02_AG, n=12; and Subtype C or CRF_AC, n=13) from 37 untreated patients in Africa and Asia were susceptible to lamivudine (IC 50 fold changes < 3.0). Group O isolates from antiviral naïve patients tested for lamivudine activity were highly sensitive. Effect of human serum In 100% human serum, the mean fold shift for dolutegravir activity was 75 fold, resulting in protein adjusted IC 90 of 0.064 μg/mL. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%). Resistance Dovato is indicated in the absence of documented or suspected resistance to the integrase inhibitor class and to lamivudine (see section 4.1). For information around in vitro resistance, and cross resistance to other agents of the integrase- and NRTI class, please refer to the SmPCs of dolutegravir and lamivudine. None of the twelve subjects in the dolutegravir plus lamivudine group or the nine subjects in the dolutegravir plus tenofovir disoproxil/emtricitabine FDC group that met virological withdrawal criteria through Week 144 across the GEMINI-1 (204861) and GEMINI-2 (205543) studies had treatment emergent integrase inhibitor or NRTI class resistance. In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase inhibitor class, or to the NRTI class was seen (n=1118 follow-up of 48‑96 weeks). Effects on electrocardiogram No relevant effects were seen with dolutegravir on the QTc interval, with doses exceeding the clinical dose by approximately three fold. A similar study was not conducted with lamivudine. Clinical efficacy and safety Antiretroviral naïve subjects The efficacy of Dovato is supported by data from 2 identical 148-week, Phase III, randomised, double-blind, multicentre, parallel-group, non-inferiority controlled trials GEMINI-1 (204861) and GEMINI-2 (205543). A total of 1433 HIV-1 infected antiretroviral treatment-naïve adult subjects received treatment in the trials. Subjects were enrolled with a screening plasma HIV-1 RNA of 1000 c/mL to ≤500,000 c/mL. Subjects were randomised to a two-drug regimen of dolutegravir 50 mg plus lamivudine 300 mg once daily or dolutegravir 50 mg plus tenofovir disoproxil/emtricitabine 245/200 mg once daily. The primary efficacy endpoint for each GEMINI trial was the proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48 (Snapshot algorithm for the ITT-E population). Double blind therapy will continue up to week 96, followed by open label therapy up to week 148. At baseline, in the pooled analysis, the median age of subjects was 33 years, 15% were female, 69% were white, 9% were CDC Stage 3 (AIDS), 20% had HIV-1 RNA >100,000 copies/mL, and 8% had CD4+ cell count less than 200 cells per mm 3 ; these characteristics were similar between studies and treatment arms. In the primary week 48 analysis, dolutegravir plus lamivudine was non-inferior to dolutegravir plus tenofovir disoproxil/emtricitabine FDC in GEMINI-1 and GEMINI-2 studies. This was supported by the pooled analysis, see Table 3. Table 3 Virologic Outcomes of Randomised Treatment of GEMINI at Week 48 (Snapshot algorithm) GEMINI-1 and GEMINI-2 Pooled Data * DTG + 3TC N=716 DTG + TDF/FTC N=717 HIV-1 RNA <50 copies/mL 91% 93% Treatment Difference † (95% confidence intervals) -1.7 (-4.4, 1.1) Virologic non response 3% 2% Reasons Data in window and ≥50 copies/mL 1% <1% Discontinued for lack of efficacy <1% <1% Discontinued for other reasons and ≥50 copies/mL <1% <1% Change in ART <1% <1% No virologic data at Week 48 window 6% 5% Reasons Discontinued study due to adverse event or death 1% 2% Discontinued study for other reasons 4% 3% Missing data during window but on study <1% 0% HIV-1 RNA <50 copies/mL by baseline covariates n/N (%) n/N (%) Baseline Plasma Viral Load (copies/mL) ≤100,000 >100,000 526 / 576 (91%) 129 / 140 (92%) 531 / 564 (94%) 138 / 153 (90%) Baseline CD4+ (cells/ mm 3 ) ≤200 50 / 63 (79%) 51 / 55 (93%) >200 605 / 653 (93%) 618 / 662 (93%) HIV-1 subtype B 424 / 467 (91%) 452 / 488 (93%) A 84 / 86 (98%) 74 / 78 (95%) Other 147 / 163 (90%) 143 / 151 (95%) Gender Male 555 / 603 (92%) 580 / 619 (94%) Female 100 / 113 (88%) 89 / 98 (91%) Race White 451 / 484 (93%) 473 / 499 (95%) African-American/African Heritage/Other 204 / 232 (88%) 196 / 218 (90%) * The results of the pooled analysis are in line with those of the individual studies, for which the primary endpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at Week 48 based on the Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil /emtricitabine FDC) was met. The adjusted difference was -2.6 (95% CI: -6.7; 1.5) for GEMINI-1 and -0.7 (95% CI: -4.3; 2.9) for GEMINI-2 with a prespecified non-inferiority margin of 10%. † Based on CMH-stratified analysis adjusting for the following baseline stratification factors: Plasma HIV-1 RNA (≤100,000 c/mL vs. >100,000 c/mL) and CD4+ cell count (≤200 cells/mm 3 vs. >200 cells/mm 3 ). Pooled analysis also stratified by study. Assessed using a non‑inferiority margin of 10%. N = Number of subjects in each treatment group At 96 weeks and at 144 weeks in the GEMINI studies, the lower bound of the 95% confidence interval for the adjusted treatment difference of proportion of subjects with HIV-1 RNA <50 copies/mL (Snapshot) was greater than the non-inferiority margin of -10%, for the individual studies as well as pooled analysis, see Table 4. Table 4 Virologic Outcomes of Randomised Treatment of GEMINI at Weeks 96 and 144 (Snapshot algorithm) GEMINI-1 and GEMINI-2 Pooled Data * DTG + 3TC N=716 DTG + TDF/FTC N=717 DTG + 3TC N=716 DTG + TDF/FTC N=717 Week 96 Week 144 HIV-1 RNA <50 copies/mL 86% 90% 82% 84% Treatment Difference † (95% confidence intervals) -3.4% (-6.7, 0.0) -1.8% (-5.8; 2.1) Virologic non response 3% 2% 3% 3% Reasons Data in window, ≥50 cps/mL <1% <1% <1% <1% Discontinued, lack of efficacy 1% <1% 1% <1% Discontinued, other reasons, ≥50 cps/mL <1% <1% <1% 2% Change in ART <1% <1% <1% <1% No virologic data at Week 96/Week 144 window Reasons Discontinued study due to AE or death Discontinued study for other reasons Loss to follow-up Withdrew consent Protocol deviations Physicians decision Missing data in window, on study 11% 3% 8% 3% 3% 1% 1% 0% 9% 3% 5% 1% 2% 1% <1% <1% 15% 4% 11% 3% 4% 2% 2% <1% 14% 4% 9% 3% 3% 1% 1% <1% * The results of the pooled analysis are in line with those of the individual studies. † Based on CMH-stratified analysis adjusting for the following baseline stratification factors: Plasma HIV-1 RNA (≤100,000 c/mL vs. >100,000 c/mL) and CD4+ cell count (≤200 cells/mm 3 vs. >200 cells/mm 3 ). Pooled analysis also stratified by study. Assessed using a non‑inferiority margin of 10%. N = Number of subjects in each treatment group The mean increase in CD4+ T-cell counts through week 144 was 302 cells/mm 3 in the dolutegravir plus lamivudine arm and 300 cells/mm 3 in the dolutegravir plus tenofovir/emtricitabine arm. Virologically suppressed subjects The efficacy of dolutegravir/lamivudine in virologically suppressed subjects is supported by data from a randomised, open-label, trial (TANGO [204862]). A total of 741 adult HIV-1 infected subjects, without any evidence of resistance to the NRTI or integrase inhibitor (INSTI) class and who were on a stable suppressive tenofovir alafenamide based regimen (TBR) received treatment in the studies. Subjects were randomised in a 1:1 ratio to receive dolutegravir/lamivudine FDC or continue with TBR for up to 200 weeks. Randomisation was stratified by baseline core agent class (protease inhibitor [PI], INSTI, or non-nucleoside reverse transcriptase inhibitor [NNRTI]). The primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNA ≥50 c/mL (virologic non-response) as per the FDA Snapshot category at Week 48 (adjusted for randomisation stratification factor). At baseline the median age of subjects was 39 years, 8% were female and 21% non-white, 5% were CDC Class C (AIDS) and 98% subjects had Baseline CD4+ cell count ≥200 cells/mm 3 ; these characteristics were similar between treatment arms. Subjects had been on ART for a median of around 3 years prior to Day 1 Around 80% were on INSTI-based TBR (mainly elvitegravir/c) at baseline. In the primary 48 week analysis dolutegravir/lamivudine was non-inferior to TBR, with <1% of subjects in both arms experiencing virologic failure (HIV-1 RNA ≥50 c/mL)(Table 5). Table 5 Virologic Outcomes of Randomised Treatment of TANGO at Week 48 (Snapshot algorithm) DTG/3TC N=369 TBR N=372 HIV-1 RNA <50 copies/mL* 93% 93% Virologic non response (≥50 copies/mL) ** <1% <1% Treatment Difference † (95% confidence intervals) -0.3 (-1.2, 0.7) Reasons for virologic non response: Data in window and ≥50 copies/mL 0% 0% Discontinued for lack of efficacy 0% <1% Discontinued for other reasons and ≥50 copies/mL <1% 0% Change in ART 0% 0% No virologic data at Week 48 window 7% 6% Reasons Discontinued study due to adverse event or death 3% <1% Discontinued study for other reasons 3% 6% Missing data during window but on study 0% <1% *Based on an 8% non-inferiority margin, DTG/3TC is non-inferior to TBR at Week 48 in the secondary analysis (proportion of subjects achieving <50 copies/mL plasma HIV-1 RNA). **Based on a 4% non-inferiority margin, DTG/3TC is non-inferior to TBR at Week 48 in the primary analysis (proportion of subjects with plasma HIV-1 RNA ≥50 c/mL). †Based on CMH-stratified analysis adjusting for Baseline third agent class (PI, NNRTI, INSTI). N = Number of subjects in each treatment group; TBR = tenofovir alafenamide based regimen. Treatment outcomes between treatment arms at week 48 were similar across the stratification factor, baseline third agent class and across subgroups by age, sex, race, baseline CD4+ cell count, CDC HIV disease stage, and countries. The median change from baseline in CD4+ count at Week 48 was 22.5 cells per mm 3 in subjects who switched to dolutegravir/lamivudine and 11.0 cells per mm 3 in subjects who stayed on TBR. At 96 weeks in the TANGO study, the proportion of subjects with HIV-1 RNA ≥50 c/mL (Snapshot) was 0.3% and 1.1% in the dolutegravir/lamivudine and TBR groups, respectively. Based on a non-inferiority margin of 4%, dolutegravir/lamivudine remained non-inferior to TBR, as the upper bound of the 95% CI for the adjusted treatment difference (-2.0%; 0.4%) was less than 4% for the ITT E Population. The median change from baseline in CD4+ T-cell counts at week 96 was 61 cells/mm 3 in the dolutegravir/lamivudine arm and 45 cells/mm 3 in the TBR arm. Paediatric population The efficacy of Dovato, or the dual combination of dolutegravir plus lamivudine (as single entities) has not been studied in children or adolescents. The European Medicines Agency has deferred the obligation to submit the results of studies with Dovato in one or more subsets of the paediatric population in the treatment of HIV infection.