DESCOVY Film-coated tablet Ref.[10515] Active ingredients: Emtricitabine Emtricitabine and Tenofovir alafenamide Tenofovir alafenamide

Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections, combinations
ATC code: J05AR17

Mechanism of action

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and nucleoside analogue of 2'-deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine triphosphate. Emtricitabine triphosphate inhibits HIV replication through incorporation into viral deoxyribonucleic acid (DNA) by the HIV reverse transcriptase (RT), which results in DNA chain-termination. Emtricitabine has activity against HIV-1, HIV-2, and HBV.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analogue). Tenofovir alafenamide is permeable into cells and due to increased plasma stability and intracellular activation through hydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir disoproxil fumarate in concentrating tenofovir in peripheral blood mononuclear cells (PBMCs) or HIV target cells including lymphocytes and macrophages. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication through incorporation into viral DNA by the HIV RT, which results in DNA chain-termination.

Tenofovir has activity against HIV-1, HIV-2, and HBV.

Antiviral activity in vitro

Emtricitabine and tenofovir alafenamide demonstrated synergistic antiviral activity in cell culture. No antagonism was observed with emtricitabine or tenofovir alafenamide when combined with other antiretroviral agents.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs. The 50% effective concentration (EC₅₀) values for emtricitabine were in the range of 0.0013 to 0.64 μM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC₅₀ values ranged from 0.007 to 0.075 μM) and showed strain specific activity against HIV-2 (EC₅₀ values ranged from 0.007 to 1.5 μM).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells and CD4+-T lymphocytes. The EC₅₀ values for tenofovir alafenamide were in the range of 2.0 to 14.7 nM. Tenofovir alafenamide displayed antiviral activity in cell culture against all HIV-1 groups (M, N, and O), including subtypes A, B, C, D, E, F, and G (EC₅₀ values ranged from 0.10 to 12.0 nM) and showed strain specific activity against HIV-2 (EC₅₀ values ranged from 0.91 to 2.63 nM).

Resistance

In vitro

Reduced susceptibility to emtricitabine is associated with M184V/I mutations in HIV-1 RT.

HIV-1 isolates with reduced susceptibility to tenofovir alafenamide express a K65R mutation in HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed.

In treatment-naïve patients

In a pooled analysis of antiretroviral-naïve patients receiving emtricitabine and tenofovir alafenamide (10 mg) given with elvitegravir and cobicistat as a fixed-dose combination tablet in Phase 3 studies GS-US-292-0104 and GS-US-292-0111, genotyping was performed on plasma HIV-1 isolates from all patients with HIV-1 RNA ≥400 copies/mL at confirmed virological failure, at Week 144, or at the time of early study drug discontinuation. Through Week 144, the development of one or more primary emtricitabine, tenofovir alafenamide, or elvitegravir resistance-associated mutations was observed in HIV-1 isolates from 12 of 22 patients with evaluable genotypic data from paired baseline and E/C/F/TAF treatment-failure isolates (12 of 866 patients [1.4%]) compared with 12 of 20 treatment-failure isolates from patients with evaluable genotypic data in the E/C/F/TDF group (12 of 867 patients [1.4%]). In the E/C/F/TAF group, the mutations that emerged were M184V/I (n=11) and K65R/N (n=2) in RT and T66T/A/I/V (n=2), E92Q (n=4), Q148Q/R (n=1), and N155H (n=2) in integrase. Of the HIV-1 isolates from 12 patients with resistance development in the E/C/F/TDF group, the mutations that emerged were M184V/I (n=9), K65R/N (n=4), and L210W (n=1) in RT and E92Q/V (n=4) and Q148R (n=2), and N155H/S (n=3) in integrase. Most HIV-1 isolates from patients in both treatment groups who developed resistance mutations to elvitegravir in integrase also developed resistance mutations to emtricitabine in RT.

In patients co-infected with HIV and HBV

In a clinical study of HIV virologically suppressed patients co-infected with chronic hepatitis B, who received emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet (E/C/F/TAF), for 48 weeks (GS-US-292-1249, n=72), 2 patients qualified for resistance analysis. In these 2 patients, no amino acid substitutions associated with resistance to any of the components of E/C/F/TAF were identified in HIV-1 or HBV.

Cross-resistance in HIV-1 infected, treatment-naïve or virologically suppressed patients

Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, but retained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.

The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine, emtricitabine, and tenofovir, but retain sensitivity to zidovudine.

Multinucleoside-resistant HIV-1 with a T69S double insertion mutation or with a Q151M mutation complex including K65R showed reduced susceptibility to tenofovir alafenamide.

Clinical data

There are no efficacy and safety studies conducted in treatment-naïve patients with Descovy.

Clinical efficacy of Descovy was established from studies conducted with emtricitabine and tenofovir alafenamide when given with elvitegravir and cobicistat as the fixed-dose combination tablet E/C/F/TAF.

HIV-1 infected, treatment-naïve patients

In studies GS-US-292-0104 and GS-US-292-0111, patients were randomised in a 1:1 ratio to receive either emtricitabine 200 mg and tenofovir alafenamide 10 mg (n=866) once daily or emtricitabine 200 mg + tenofovir disoproxil (as fumarate) 245 mg (n=867) once daily, both given with elvitegravir 150 mg + cobicistat 150 mg as a fixed-dose combination tablet. The mean age was 36 years (range: 18-76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. Nineteen percent of patients were identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.5 log₁₀ copies/mL (range: 1.3-7.0) and 23% had baseline viral loads >100,000 copies/mL. The mean baseline CD4+ cell count was 427 cells/mm³ (range: 0-1,360) and 13% had a CD4+ cell count <200 cells/mm³.

E/C/F/TAF demonstrated statistical superiority in achieving HIV-1 RNA <50 copies/mL when compared to E/C/F/TDF at Week 144. The difference in percentage was 4.2% (95% CI: 0.6% to 7.8%). Pooled treatment outcomes at 48 and 144 weeks are shown in Table 4.

Table 4. Pooled virological outcomes of Studies GS-US-292-0104 and GS-US-292-0111 at Weeks 48 and 144^a,b:

E/C/F/TAF = elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide
E/C/F/TDF = elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate
^a Week 48 window was between Day 294 and 377 (inclusive); Week 144 window was between Day 966 and 1049 (inclusive).
^b In both studies, patients were stratified by baseline HIV-1 RNA (≤100,000 copies/mL, >100,000 copies/mL to ≤400,000 copies/mL, or >400,000 copies/mL), by CD4+ cell count (<50 cells/μL, 50-199 cells/μL, or ≥200 cells/μL), and by region (US or ex-US).
^c Includes patients who had ≥50 copies/mL in the Week 48 or 144 window; patients who discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.
^d Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
^e Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.

The mean increase from baseline in CD4+ cell count was 230 cells/mm³ in patients receiving E/C/F/TAF and 211 cells/mm³ in patients receiving E/C/F/TDF (p=0.024) at Week 48, and 326 cells/mm³ in E/C/F/TAF-treated patients and 305 cells/mm³ in E/C/F/TDF-treated patients (p=0.06) at Week 144.

Clinical efficacy of Descovy in treatment-naïve patients was also established from a study conducted with emtricitabine and tenofovir alafenamide (10 mg) when given with darunavir (800 mg) and cobicistat as a fixed-dose combination tablet (D/C/F/TAF). In Study GS-US-299-0102, patients were randomised in a 2:1 ratio to receive either fixed-dose combination D/C/F/TAF once daily (n=103) or darunavir and cobicistat and emtricitabine/tenofovir disoproxil fumarate once daily (n=50). The proportions of patients with plasma HIV-1 RNA <50 copies/mL and <20 copies/mL are shown in Table 5.

Table 5. Virological outcomes of Study GS-US-299-0102 at Week 24 and 48^a:

D/C/F/TAF = darunavir/cobicistat/emtricitabine/tenofovir alafenamide
^a Week 48 window was between Day 294 and 377 (inclusive).
^b Includes patients who had ≥50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.
^c Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this
resulted in no virologic data on treatment during the specified window.
^d Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.

HIV-1 infected virologically suppressed patients

In Study GS-US-311-1089, the efficacy and safety of switching from emtricitabine/tenofovir disoproxil fumarate to Descovy while maintaining the third antiretroviral agent were evaluated in a randomised, double-blind study of virologically suppressed HIV-1 infected adults (n=663). Patients must have been stably suppressed (HIV-1 RNA <50 copies/mL) on their baseline regimen for at least 6 months and had HIV-1 with no resistance mutations to emtricitabine or tenofovir alafenamide prior to study entry. Patients were randomised in a 1:1 ratio to either switch to Descovy (n=333), or stay on their baseline emtricitabine/tenofovir disoproxil fumarate containing regimen (n=330). Patients were stratified by the class of the third agent in their prior treatment regimen. At baseline, 46% of patients were receiving emtricitabine/tenofovir disoproxil fumarate in combination with a boosted PI and 54% of patients were receiving emtricitabine/tenofovir disoproxil fumarate in combination with an unboosted third agent.

Treatment outcomes of Study GS-US-311-1089 through 48 and 96 weeks are presented in Table 6.

Table 6. Virological outcomes of Study GS-US-311-1089 at Weeks 48^a and 96^b:

PI = protease inhibitor
^a Week 48 window was between Day 294 and 377 (inclusive).
^b Week 96 window was between Day 630 and 713 (inclusive).
^c Includes patients who had ≥50 copies/mL in the Week 48 or Week 96 window; patients who discontinued early due to lack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.
^d Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
^e Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc.

In Study GS-US-311-1717, patients who were virologically suppressed (HIV-1 RNA <50 copies/mL) on their abacavir/lamivudine containing regimen for at least 6 months were randomised in a 1:1 ratio to either switch to Descovy (N=280) while maintaining their third agent at baseline or stay on their baseline abacavir/lamivudine -containing regimen (N=276).

Patients were stratified by the class of the third agent in their prior treatment regimen. At baseline, 30% of patients were receiving abacavir/lamivudine in combination with a boosted protease inhibitor and 70% of patients were receiving abacavir/lamivudine in combination with an unboosted third agent. Virologic success rates at Week 48 were: Descovy Containing Regimen: 89.7% (227 of 253 subjects); Abacavir/lamivudine Containing Regimen: 92.7%% (230 of 248 subjects). At Week 48, switching to a Descovy-containing regimen was non-inferior to staying on a baseline abacavir/lamivudine-containing regimen in maintaining HIV-1 RNA <50 copies/mL

HIV-1 infected patients with mild to moderate renal impairment

In Study GS-US-292-0112, the efficacy and safety of emtricitabine and tenofovir alafenamide were evaluated in an open-label clinical study in which 242 HIV-1 infected patients with mild to moderate renal impairment (eGFR_CG: 30-69 mL/min) were switched to emtricitabine and tenofovir alafenamide (10 mg) given with elvitegravir and cobicistat as a fixed-dose combination tablet. Patients were virologically suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months before switching.

The mean age was 58 years (range: 24-82), with 63 patients (26%) who were ≥65 years of age. Seventy-nine percent were male, 63% were White, 18% were Black, and 14% were Asian. Thirteen percent of patients were identified as Hispanic/Latino. At baseline, median eGFR was 56 mL/min, and 33% of patients had an eGFR from 30 to 49 mL/min. The mean baseline CD4+ cell count was 664 cells/mm³ (range: 126-1,813).

At Week 144, 83.1% (197/237 patients) maintained HIV-1 RNA <50 copies/mL after switching to emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat as a fixed-dose combination tablet.

In Study GS-US-292-1825, the efficacy and safety of emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet were evaluated in a single arm, open-label clinical study in which 55 HIV-1 infected adults with end stage renal disease (eGFR_CG <15 mL/min) on chronic haemodialysis for at least 6 months before switching to emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet. Patients were virologically suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months before switching.

The mean age was 48 years (range 23-64). Seventy-six percent were male, 82% were Black and 18% were White. Fifteen percent of patients identified as Hispanic/Latino. The mean baseline CD4+ cell count was 545 cells/mm³ (range 205-1473). At Week 48, 81.8% (45/55 patients) maintained HIV-1 RNA <50 copies/mL after switching to emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet. There were no clinically significant changes in fasting lipid laboratory tests in patients who switched.

Patients co-infected with HIV and HBV

In open-label Study GS-US-292-1249, the efficacy and safety of emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet (E/C/F/TAF), were evaluated in adult patients co-infected with HIV-1 and chronic hepatitis B. Sixty-nine of the 72 patients were on prior TDF-containing antiretroviral therapy. At the start of treatment with E/C/F/TAF, the 72 patients had been HIV-suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months with or without suppression of HBV DNA and had compensated liver function. The mean age was 50 years (range 28-67), 92% of patients were male, 69% were White, 18% were Black, and 10% were Asian. The mean baseline CD4+ cell count was 636 cells/mm³ (range 263-1498). Eighty-six percent of patients (62/72) were HBV suppressed (HBV DNA <29 IU/mL) and 42% (30/72) were HBeAg positive at baseline.

Of the patients who were HBeAg positive at baseline, 1/30 (3.3%) achieved seroconversion to anti-HBe at Week 48. Of the patients who were HBsAg positive at baseline, 3/70 (4.3%) achieved seroconversion to anti-HBs Week 48.

At Week 48, 92% of patients (66/72) maintained HIV-1 RNA <50 copies/mL after switching to emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet. The mean change from baseline in CD4+ cell count at Week 48 was -2 cells/mm³. Ninety-two percent (66/72 patients) had HBV DNA <29 IU/mL using missing = failure analysis at Week 48. Of the 62 patients who were HBV suppressed at baseline, 59 remained suppressed and 3 had missing data. Of the 10 patients who were not HBV suppressed at baseline (HBV DNA ≥29 IU/mL), 7 became suppressed, 2 remained detectable, and 1 had missing data.

There are limited clinical data on the use of E/C/F/TAF in HIV/HBV co-infected patients who are treatment-naïve.

Changes in measures of bone mineral density

In studies in treatment-naïve patients, emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat as a fixed-dose combination tablet was associated with smaller reductions in bone mineral density (BMD) compared to E/C/F/TDF through 144 weeks of treatment as measured by dual energy X ray absorptiometry (DXA) analysis of hip (mean change: −0.8% vs −3.4%, p<0.001) and lumbar spine (mean change: −0.9% vs −3.0%, p<0.001). In a separate study, emtricitabine and tenofovir alafenamide given with darunavir and cobicistat as a fixed-dose combination tablet was also associated with smaller reductions in BMD (as measured by hip and lumbar spine DXA analysis) through 48 weeks of treatment compared to darunavir, cobicistat, emtricitabine and tenofovir disoproxil fumarate.

In a study in virologically suppressed adult patients, improvements in BMD were noted through 96 weeks after switching to Descovy from a TDF containing regimen compared to minimal changes with maintaining the TDF containing regimen as measured by DXA analysis of hip (mean change from baseline of 1.9% vs -0.3%, p<0.001) and lumbar spine (mean change from baseline of 2.2% vs -0.2%, p<0.001).

In a study in virologically suppressed adult patients, BMD did not change significantly through 48 weeks after switching to Descovy from an abacavir/lamivudine containing regimen compared to maintaining the abacavir/lamivudine containing regimen as measured by DXA analysis of hip (mean change from baseline of 0.3% vs 0.2%, p=0.55) and lumbar spine (mean change from baseline of 0.1% vs <0.1%, p=0.78).

Changes in measures of renal function

In studies in treatment-naïve patients, emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat as a fixed-dose combination tablet through 144 weeks was associated with a lower impact on renal safety parameters (as measured after 144 weeks treatment by eGFR_CG and urine protein to creatinine ratio and after 96 weeks treatment by urine albumin to creatinine ratio) compared to E/C/F/TDF. Through 144 weeks of treatment, no subject discontinued E/C/F/TAF due to a treatment-emergent renal adverse event compared with 12 subjects who discontinued E/C/F/TDF (p<0.001).

In a separate study in treatment-naïve patients, emtricitabine and tenofovir alafenamide given with darunavir and cobicistat as a fixed-dose combination tablet was associated with a lower impact on renal safety parameters through 48 weeks of treatment compared to darunavir and cobicistat given with emtricitabine/tenofovir disoproxil fumarate (see also section 4.4).

In a study in virologically suppressed adult patients measures of tubular proteinuria were similar in patients switching to a regimen containing Descovy compared to patients who stayed on an abacavir/lamivudine containing regimen at baseline. At Week 48, the median percentage change in urine retinol binding protein to creatinine ratio was 4% in the Descovy group and 16% in those remaining on an abacavir/lamivudine containing regimen; and in urine beta-2 microglobulin to creatinine ratio it was 4% vs. 5%.

Paediatric population

In Study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of emtricitabine and tenofovir alafenamide were evaluated in an open-label study in which 50 HIV-1 infected, treatment-naïve adolescents received emtricitabine and tenofovir alafenamide (10 mg) given with elvitegravir and cobicistat as a fixed-dose combination tablet. Patients had a mean age of 15 years (range: 12-17), and 56% were female, 12% were Asian, and 88% were Black. At baseline, median plasma HIV-1 RNA was 4.7 log₁₀ copies/mL, median CD4+ cell count was 456 cells/mm³ (range: 95-1,110), and median CD4+% was 23% (range: 7-45%). Overall, 22% had baseline plasma HIV-1 RNA >100,000 copies/mL. At 48 weeks, 92% (46/50) achieved HIV-1 RNA <50 copies/mL, similar to response rates in studies of treatment-naïve HIV-1 infected adults. The mean increase from baseline in CD4+ cell count at Week 48 was 224 cells/mm³. No emergent resistance to E/C/F/TAF was detected through Week 48.

The European Medicines Agency has deferred the obligation to submit the results of studies with Descovy in one or more subsets of the paediatric population in the treatment of HIV-1 infection (see section 4.2 for information on paediatric use).