TENOFOVIR DISOPROXIL MYLAN Film-coated tablet Ref.[7451] Active ingredients:

Pharmacotherapeutic group: Antiviral for systemic use; nucleoside and nucleotide reverse transcriptase inhibitors
ATC code: J05AF07

Mechanism of action and pharmacodynamic effects

Tenofovir disoproxil maleate is the maleate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside monophosphate (nucleotide) analogue. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, an obligate chain terminator, by constitutively expressed cellular enzymes. Tenofovir diphosphate has an intracellular half-life of 10 hours in activated and 50 hours in resting peripheral blood mononuclear cells (PBMCs). Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of cellular polymerases α, β, and γ. At concentrations of up to 300 μmol/l, tenofovir has also shown no effect on the synthesis of mitochondrial DNA or the production of lactic acid in in vitro assays.

Data pertaining to HIV

HIV antiviral activity in vitro

The concentration of tenofovir required for 50% inhibition (EC₅₀) of the wild-type laboratory strain HIV-1 IIIB is 1-6 μmol/l in lymphoid cell lines and 1.1 μmol/l against primary HIV-1 subtype B isolates in PBMCs. Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G, and O and against HIV BaL in primary monocyte/macrophage cells. Tenofovir shows activity in vitro against HIV-2, with an EC₅₀ of 4.9 μmol/l in MT-4 cells.

Resistance

Strains of HIV-1 with reduced susceptibility to tenofovir and a K65R mutation in reverse transcriptase have been selected in vitro and in some patients (see Clinical efficacy and safety). Tenofovir disoproxil should be avoided in antiretroviral-experienced patients with strains harbouring the K65R mutation (see section 4.4). In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir.

Clinical studies in treatment-experienced patients have assessed the anti-HIV activity of tenofovir disoproxil 245 mg against strains of HIV-1 with resistance to nucleoside inhibitors. The results indicate that patients whose HIV expressed 3 or more thymidine-analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced response to tenofovir disoproxil 245 mg therapy.

Clinical efficacy and safety

The effects of tenofovir disoproxil in treatment-experienced and treatment-naïve HIV-1 infected adults have been demonstrated in trials of 48 weeks and 144 weeks duration, respectively.

In study GS-99-907, 550 treatment-experienced adult patients were treated with placebo or tenofovir disoproxil 245 mg for 24 weeks. The mean baseline CD4 cell count was 427 cells/mm³, the mean baseline plasma HIV-1 RNA was 3.4 log₁₀ copies/ml (78% of patients had a viral load of <5,000 copies/ml) and the mean duration of prior HIV treatment was 5.4 years. Baseline genotypic analysis of HIV isolates from 253 patients revealed that 94% of patients had HIV-1 resistance mutations associated with nucleoside reverse transcriptase inhibitors, 58% had mutations associated with protease inhibitors and 48% had mutations associated with non-nucleoside reverse transcriptase inhibitors.

At week 24 the time-weighted average change from baseline in log₁₀ plasma HIV-1 RNA levels (DAVG₂₄) was -0.03 log₁₀ copies/ml and -0.61 log₁₀ copies/ml for the placebo and tenofovir disoproxil 245 mg recipients (p<0.0001). A statistically significant difference in favour of tenofovir disoproxil 245 mg was seen in the time-weighted average change from baseline at week 24 (DAVG₂₄) for CD4 count (+13 cells/mm³ for tenofovir disoproxil 245 mg versus -11 cells/mm³ for placebo, p-value=0.0008). The antiviral response to tenofovir disoproxil was durable through 48 weeks (DAVG₄₈ was -0.57 log₁₀ copies/ml, proportion of patients with HIV-1 RNA below 400 or 50 copies/ml was 41% and 18% respectively). Eight (2%) tenofovir disoproxil 245 mg treated patients developed the K65R mutation within the first 48 weeks.

The 144-week, double-blind, active controlled phase of study GS-99-903 evaluated the efficacy and safety of tenofovir disoproxil 245 mg versus stavudine when used in combination with lamivudine and efavirenz in HIV-1 infected adult patients naïve to antiretroviral therapy. The mean baseline CD4 cell count was 279 cells/mm³, the mean baseline plasma HIV-1 RNA was 4.91 log₁₀ copies/ml, 19% of patients had symptomatic HIV-1 infection and 18% had AIDS. Patients were stratified by baseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads >100,000 copies/ml and 39% had CD4 cell counts <200 cells/ml.

By intent to treat analysis (missing data and switch in antiretroviral therapy (ART) considered as failure), the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml at 48 weeks of treatment was 80% and 76% respectively in the tenofovir disoproxil 245 mg arm, compared to 84% and 80% in the stavudine arm. At 144 weeks, the proportion of patients with HIV-1 RNA below 400 copies/ml and 50 copies/ml was 71% and 68% respectively in the tenofovir disoproxil 245 mg arm, compared to 64% and 63% in the stavudine arm.

The average change from baseline for HIV-1 RNA and CD4 count at 48 weeks of treatment was similar in both treatment groups (-3.09 and -3.09 log₁₀ copies/ml; +169 and 167 cells/mm³ in the tenofovir disoproxil 245 mg and stavudine groups, respectively). At 144 weeks of treatment, the average change from baseline remained similar in both treatment groups (-3.07 and -3.03 log₁₀ copies/ml; +263 and +283 cells/mm³ in the tenofovir disoproxil 245 mg and stavudine groups, respectively). A consistent response to treatment with tenofovir disoproxil 245 mg was seen regardless of baseline HIV-1 RNA and CD4 count.

The K65R mutation occurred in a slightly higher percentage of patients in the tenofovir disoproxil group than the active control group (2.7% versus 0.7%). Efavirenz or lamivudine resistance either preceded or was coincident with the development of K65R in all cases. Eight patients had HIV that expressed K65R in the tenofovir disoproxil 245 mg arm, 7 of these occurred during the first 48 weeks of treatment and the last one at week 96. No further K65R development was observed up to week 144. One patient in the tenofovir disoproxil arm developed the K70E substitution in the virus. From both the genotypic and phenotypic analyses there was no evidence for other pathways of resistance to tenofovir.

Data pertaining to HBV

HBV antiviral activity in vitro

The in vitro antiviral activity of tenofovir against HBV was assessed in the HepG2 2.2.15 cell line. The EC₅₀ values for tenofovir were in the range of 0.14 to 1.5 μmol/l, with CC₅₀ (50% cytotoxicity concentration) values >100 μmol/l.

Resistance

No HBV mutations associated with tenofovir disoproxil resistance have been identified (see Clinical efficacy and safety). In cell based assays, HBV strains expressing the rtV173L, rtL180M, and rtM204I/V mutations associated with resistance to lamivudine and telbivudine showed a susceptibility to tenofovir ranging from 0.7- to 3.4-fold that of wild-type virus. HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V mutations associated with resistance to entecavir showed a susceptibility to tenofovir ranging from 0.6- to 6.9-fold that of wild-type virus. HBV strains expressing the adefovir-associated resistance mutations rtA181V and rtN236T showed a susceptibility to tenofovir ranging from 2.9- to 10-fold that of wild-type virus. Viruses containing the rtA181T mutation remained susceptible to tenofovir with EC₅₀ values 1.5-fold that of wild-type virus.

Clinical efficacy and safety

The demonstration of benefit of tenofovir disoproxil in compensated and decompensated disease is based on virological, biochemical and serological responses in adults with HBeAg positive and HBeAg negative chronic hepatitis B. Treated patients included those who were treatment-naïve, lamivudine-experienced, adefovir dipivoxil-experienced and patients with lamivudine and/or adefovir dipivoxil resistance mutations at baseline. Benefit has also been demonstrated based on histological responses in compensated patients.

Experience in patients with compensated liver disease at 48 weeks (studies GS-US-174-0102 and GS-US-174-0103)

Results through 48 weeks from two randomised, phase 3 double-blind studies comparing tenofovir disoproxil to adefovir dipivoxil in adult patients with compensated liver disease are presented in Table 3 below. Study GS-US-174-0103 was conducted in 266 (randomised and treated) HBeAg positive patients while study GS-US-174-0102 was conducted in 375 (randomised and treated) patients negative for HBeAg and positive for HBeAb.

In both of these studies tenofovir disoproxil was significantly superior to adefovir dipivoxil for the primary efficacy endpoint of complete response (defined as HBV DNA levels <400 copies/ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis). Treatment with tenofovir disoproxil 245 mg was also associated with significantly greater proportions of patients with HBV DNA <400 copies/ml, when compared to adefovir dipivoxil 10 mg treatment. Both treatments produced similar results with regard to histological response (defined as Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis) at week 48 (see Table 3 below).

In study GS-US-174-0103 a significantly greater proportion of patients in the tenofovir disoproxil group than in the adefovir dipivoxil group had normalised ALT and achieved HBsAg loss at week 48 (see Table 3 below).

Table 3. Efficacy parameters in compensated HBeAg negative and HBeAg positive patients at week 48:

* p-value versus adefovir dipivoxil <0.05.
^a Complete response defined as HBV DNA levels <400 copies/ml and Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis.
^b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis.
^c Median change from baseline HBV DNA merely reflects the difference between baseline HBV DNA and the limit of detection (LOD) of the assay.
^d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.
n/a = not applicable.

Tenofovir disoproxil was associated with significantly greater proportions of patients with undetectable HBV DNA (<169 copies/ml [<29 IU/ml]; the limit of quantification of the Roche Cobas Taqman HBV assay), when compared to adefovir dipivoxil (study GS-US-174-0102; 91%, 56% and study GS-US-174-0103; 69%, 9%), respectively.

Response to treatment with tenofovir disoproxil was comparable in nucleoside-experienced (n=51) and nucleoside-naïve (n=375) patients and in patients with normal ALT (n=21) and abnormal ALT (n=405) at baseline when studies GS-US-174-0102 and GS-US-174-0103 were combined. Forty-nine of the 51 nucleoside-experienced patients were previously treated with lamivudine. Seventy-three percent of nucleoside-experienced and 69% of nucleoside-naïve patients achieved complete response to treatment; 90% of nucleoside-experienced and 88% of nucleoside-naïve patients achieved HBV DNA suppression <400 copies/ml. All patients with normal ALT at baseline and 88% of patients with abnormal ALT at baseline achieved HBV DNA suppression <400 copies/ml.

Experience beyond 48 weeks in studies GS-US-174-0102 and GS-US-174-0103

In studies GS-US-174-0102 and GS-US-174-0103, after receiving double-blind treatment for 48 weeks (either tenofovir disoproxil 245 mg or adefovir dipivoxil 10 mg), patients rolled over with no interruption in treatment to open-label tenofovir disoproxil. In studies GS-US-174-0102 and GS-US- 174-0103, 77% and 61% of patients continued in the study through to 384 weeks, respectively. At weeks 96, 144, 192, 240, 288 and 384 viral suppression, biochemical and serological responses were maintained with continued tenofovir disoproxil treatment (see Tables 4 and 5 below).

Table 4. Efficacy parameters in compensated HBeAg negative patients at week 96, 144, 192, 240, 288 and 384 open-label treatment:

^a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator.
^b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label.
^c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil.
^d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.
^e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label.
^f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil.
^g 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label.
^h 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil.
ⁱ 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label.
^j 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil.
^k One patient in this group became HBsAg negative for the first time at the 240 week visit and was ongoing in the study at the time of the data cut-off. However, the subject’s HBsAg loss was ultimately confirmed at the subsequent visit.
^l 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label.
^m 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil.
ⁿ Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition of emtricitabine to open-label tenofovir disoproxil (KM-tenofovir disoproxil).
^o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label.
^p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil.
n/a = not applicable.

Table 5. Efficacy parameters in compensated HBeAg positive patients at week 96, 144, 192, 240, 288 and 384 open-label treatment:

^a Based upon Long Term Evaluation algorithm (LTE Analysis) - Patients who discontinued the study at any time prior to week 384 due to a protocol defined endpoint, as well as those completing week 384, are included in the denominator.
^b 48 weeks of double-blind tenofovir disoproxil followed by 48 weeks open-label.
^c 48 weeks of double-blind adefovir dipivoxil followed by 48 weeks open-label tenofovir disoproxil.
^d The population used for analysis of ALT normalisation included only patients with ALT above ULN at baseline.
^e 48 weeks of double-blind tenofovir disoproxil followed by 96 weeks open-label.
^f 48 weeks of double-blind adefovir dipivoxil followed by 96 weeks open-label tenofovir disoproxil.
^g Figures presented are cumulative percentages based upon a Kaplan Meier analysis including data collected after
the addition of emtricitabine to open-label tenofovir disoproxil (KM-ITT).
^h 48 weeks of double-blind tenofovir disoproxil followed by 144 weeks open-label.
ⁱ 48 weeks of double-blind adefovir dipivoxil followed by 144 weeks open-label tenofovir disoproxil.
^j 48 weeks of double-blind tenofovir disoproxil followed by 192 weeks open-label.
^k 48 weeks of double-blind adefovir dipivoxil followed by 192 weeks open-label tenofovir disoproxil.
^l Figures presented are cumulative percentages based upon a Kaplan Meier analysis excluding data collected after the addition of emtricitabine to open-label tenofovir disoproxil (KM-tenofovir disoproxil).
^m 48 weeks of double-blind tenofovir disoproxil followed by 240 weeks open-label.
ⁿ 48 weeks of double-blind adefovir dipivoxil followed by 240 weeks open-label tenofovir disoproxil.
^o 48 weeks of double-blind tenofovir disoproxil followed by 336 weeks open-label.
^p 48 weeks of double-blind adefovir dipivoxil followed by 336 weeks open-label tenofovir disoproxil.

Paired baseline and week 240 liver biopsy data were available for 331/489 patients who remained in studies GS-US-174-0102 and GS-US-174-0103 at week 240 (see Table 6 below). Ninety-five percent (225/237) of patients without cirrhosis at baseline and 99% (93/94) of patients with cirrhosis at baseline had either no change or an improvement in fibrosis (Ishak fibrosis score). Of the 94 patients with cirrhosis at baseline (Ishak fibrosis score 5-6), 26% (24) experienced no change in Ishak fibrosis score and 72% (68) experienced regression of cirrhosis by week 240 with a reduction in Ishak fibrosis score of at least 2 points.

Table 6. Histological response (%) in compensated HBeAg negative and HBeAg positive subjects at week 240 compared to baseline:

^a The population used for analysis of histology included only patients with available liver biopsy data (Missing = Excluded) by week 240. Response after addition of emtricitabine is excluded (total of 17 subjects across both studies).
^b Knodell necroinflammatory score improvement of at least 2 points without worsening in Knodell fibrosis score.
^c 48 weeks of double-blind tenofovir disoproxil followed by up to 192 weeks open-label.
^d 48 weeks of double-blind adefovir dipivoxil followed by up to 192 weeks open-label tenofovir disoproxil.

Experience in patients with HIV co-infection and prior lamivudine experience

In a randomised, 48-week double-blind, controlled study of tenofovir disoproxil 245 mg in adult patients co-infected with HIV-1 and chronic hepatitis B with prior lamivudine experience (study ACTG 5127), the mean serum HBV DNA levels at baseline in patients randomised to the tenofovir arm were 9.45 log₁₀ copies/ml (n=27). Treatment with tenofovir disoproxil 245 mg was associated with a mean change in serum HBV DNA from baseline, in the patients for whom there was 48-week data, of -5.74 log₁₀ copies/ml (n=18). In addition, 61% of patients had normal ALT at week 48.

Experience in patients with persistent viral replication (study GS-US-174-0106)

The efficacy and safety of tenofovir disoproxil 245 mg or tenofovir disoproxil 245 mg plus 200 mg emtricitabine has been evaluated in a randomised, double-blind study (study GS-US-174-0106), in HBeAg positive and HBeAg negative adult patients who had persistent viraemia (HBV DNA ≥1,000 copies/ml) while receiving adefovir dipivoxil 10 mg for more than 24 weeks. At baseline, 57% of patients randomised to tenofovir disoproxil versus 60% of patients randomised to emtricitabine plus tenofovir disoproxil treatment group had previously been treated with lamivudine. Overall at week 24, treatment with tenofovir disoproxil resulted in 66% (35/53) of patients with HBV DNA <400 copies/ml (<69 IU/ml) versus 69% (36/52) of patients treated with emtricitabine plus tenofovir disoproxil (p=0.672). In addition 55% (29/53) of patients treated with tenofovir disoproxil had undetectable HBV DNA (<169 copies/ml [<29 IU/ml]; the limit of quantification of the Roche Cobas TaqMan HBV assay) versus 60% (31/52) of patients treated with emtricitabine plus tenofovir disoproxil (p=0.504). Comparisons between treatment groups beyond week 24 are difficult to interpret since investigators had the option to intensify treatment to open-label emtricitabine plus tenofovir disoproxil. Long-term studies to evaluate the benefit/risk of bitherapy with emtricitabine plus tenofovir disoproxil in HBV monoinfected patients are ongoing.

Experience in patients with decompensated liver disease at 48 weeks (study GS-US-174-0108)

Study GS-US-174-0108 is a randomised, double-blind, active controlled study evaluating the safety and efficacy of tenofovir disoproxil (n=45), emtricitabine plus tenofovir disoproxil (n=45), and entecavir (n=22), in patients with decompensated liver disease. In the tenofovir disoproxil treatment arm, patients had a mean CPT score of 7.2, mean HBV DNA of 5.8 log₁₀ copies/ml and mean serum ALT of 61 U/l at baseline. Forty-two percent (19/45) of patients had at least 6 months of prior lamivudine experience, 20% (9/45) of patients had prior adefovir dipivoxil experience and 9 of 45 patients (20%) had lamivudine and/or adefovir dipivoxil resistance mutations at baseline. The co-primary safety endpoints were discontinuation due to an adverse event and confirmed increase in serum creatinine ≥0.5 mg/dl or confirmed serum phosphate of <2 mg/dl.

In patients with CPT scores ≤9, 74% (29/39) of tenofovir disoproxil, and 94% (33/35) of emtricitabine plus tenofovir disoproxil treatment groups achieved HBV DNA <400 copies/ml after 48 weeks of treatment.

Overall, the data derived from this study are too limited to draw any definitive conclusions on the comparison of emtricitabine plus tenofovir disoproxil versus tenofovir disoproxil, (see Table 7 below).

Table 7. Safety and efficacy parameters in decompensated patients at week 48:

^a p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 0.622,
^b p-value comparing the combined tenofovir-containing arms versus the entecavir arm = 1.000.

Experience beyond 48 weeks in study GS-US-174-0108

Using a noncompleter/switch = failure analysis, 50% (21/42) of subjects receiving tenofovir disoproxil, 76% (28/37) of subjects receiving emtricitabine plus tenofovir disoproxil and 52% (11/21) of subjects receiving entecavir achieved HBV DNA <400 copies/ml at week 168.

Experience in patients with lamivudine-resistant HBV at 240 weeks (study GS-US-174-0121)

The efficacy and safety of 245 mg tenofovir disoproxil was evaluated in a randomised, double-blind study (GS-US-174-0121) in HBeAg positive and HBeAg negative patients (n=280) with compensated liver disease, viraemia (HBV DNA ≥1,000 IU/ml), and genotypic evidence of lamivudine resistance (rtM204I/V +/- rtL180M). Only five had adefovir-associated resistance mutations at baseline. One hundred forty-one and 139 adult subjects were randomised to a tenofovir disoproxil and emtricitabine plus tenofovir disoproxil treatment arm, respectively. Baseline demographics were similar between the two treatment arms: At baseline, 52.5% of subjects were HBeAg negative, 47.5% were HBeAg positive, mean HBV DNA level was 6.5 log₁₀ copies/ml, and mean ALT was 79 U/l, respectively.

After 240 weeks of treatment, 117 of 141 subjects (83%) randomised to tenofovir disoproxil had HBV DNA <400 copies/ml, and 51 of 79 subjects (65%) had ALT normalisation. After 240 weeks of treatment with emtricitabine plus tenofovir disoproxil, 115 of 139 subjects (83%) had HBV DNA < 400 copies/ml, and 59 of 83 subjects (71%) had ALT normalisation. Among the HBeAg positive subjects randomised to tenofovir disoproxil, 16 of 65 subjects (25%) experienced HBeAg loss, and 8 of 65 subjects (12%) experienced anti-HBe seroconversion through week 240. In the HBeAg positive subjects randomised to emtricitabine plus tenofovir disoproxil, 13 of 68 subjects (19%) experienced HBeAg loss, and 7 of 68 subjects (10%) experienced anti-HBe seroconversion through week 240. Two subjects randomised to tenofovir disoproxil experienced HBsAg loss by Week 240, but not seroconversion to anti-HBs. Five subjects randomised to emtricitabine plus tenofovir disoproxil experienced HBsAg loss with 2 of these 5 subjects experiencing seroconversion to anti- HBs.

Clinical resistance

Four hundred and twenty-six HBeAg negative (GS-US-174-0102, n=250) and HBeAg positive (GS-US-174-0103, n=176) patients initially randomised to double-blind tenofovir disoproxil treatment and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed on all patients with HBV DNA >400 copies/ml at week 48 (n=39), 96 (n=24), 144 (n=6), 192 (n=5), 240 (n=4), 288 (n=6) and 384 (n=2) of tenofovir disoproxil monotherapy showed that no mutations associated with tenofovir disoproxil resistance have developed.

Two hundred and fifteen HBeAg negative (GS-US-174-0102, n=125) and HBeAg positive (GS-US-174-0103, n=90) patients initially randomised to double-blind adefovir dipivoxil treatment and then switched to open-label tenofovir disoproxil treatment were evaluated for genotypic changes in HBV polymerase from baseline. Genotypic evaluations performed on all patients with HBV DNA >400 copies/ml at week 48 (n=16), 96 (n=5), 144 (n=1), 192 (n=2), 240 (n=1), 288 (n=1) and 384 (n=2) of tenofovir disoproxil monotherapy showed that no mutations associated with tenofovir disoproxil resistance have developed.

In study GS-US-174-0108, 45 patients (including 9 patients with lamivudine and/or adefovir dipivoxil resistance mutations at baseline) received tenofovir disoproxil for up to 168 weeks. Genotypic data from paired baseline and on treatment HBV isolates were available for 6/8 patients with HBV DNA >400 copies/ml at week 48. No amino acid substitutions associated with resistance to tenofovir disoproxil were identified in these isolates. Genotypic analysis was conducted for 5 subjects in the tenofovir disoproxil arm post week 48. No amino acid substitutions associated with tenofovir disoproxil resistance were detected in any subject.

In study GS-US-174-0121, 141 patients with lamivudine resistance substitutions at baseline received tenofovir disoproxil for up to 240 weeks. Cumulatively, there were 4 patients who experienced a viremic episode (HBV DNA>400 copies/ml) at their last timepoint on tenofovir disoproxil. Among them, sequence data from paired baseline and on treatment HBV isolates were available for 2 of 4 patients. No amino acid substitutions associated with resistance to tenofovir disoproxil were identified in these isolates.

In a paediatric study (GS-US-174-0115), 52 patients (including 6 patients with lamivudine resistance mutations at baseline) initially received blinded tenofovir disoproxil for up to 72 weeks and then 51/52 patients switched to open-label tenofovir disoproxil (tenofovir disoproxil-tenofovir disoproxil group). Genotypic evaluations were performed on all patients within this group with HBV DNA >400 copies/ml at week 48 (n=6) week 72 (n=5), week 96 (n=4), week 144 (n=2), and week 192 (n=3). Fifty-four patients (including 2 patients with lamivudine resistance mutations at baseline) initially received blinded placebo treatment for 72 weeks, and 52/54 patients followed with tenofovir disoproxil (PLB-tenofovir disoproxil group). Genotypic evaluations were performed on all patients within this group with HBV DNA >400 copies/ml at week 96 (n=17), week 144 (n=7), and week 192 (n=8). No amino acid substitutions associated with resistance to tenofovir disoproxil were identified in these isolates.

Paediatric population

HIV-1

In study GS-US-104-0321, 87 HIV-1 infected treatment-experienced patients 12 to <18 years of age were treated with tenofovir disoproxil (n=45) or placebo (n=42) in combination with an optimised background regimen (OBR) for 48 weeks. Due to limitations of the study, a benefit of tenofovir disoproxil over placebo was not demonstrated based on plasma HIV-1 RNA levels at week 24. However, a benefit is expected for the adolescent population based on extrapolation of adult data and comparative pharmacokinetic data (see section 5.2).

In patients who received treatment with tenofovir disoproxil or placebo, mean lumbar spine BMD Z-score was -1.004 and -0.809, and mean total body BMD Z-score was -0.866 and -0.584, respectively, at baseline. Mean changes at week 48 (end of double-blind phase) were -0.215 and -0.165 in lumbar spine BMD Z-score, and -0.254 and -0.179 in total body BMD Z-score for the tenofovir disoproxil and placebo groups, respectively. The mean rate of BMD gain was less in the tenofovir disoproxil group compared to the placebo group. At week 48, six adolescents in the tenofovir disoproxil group and one adolescent in the placebo group had significant lumbar spine BMD loss (defined as >4% loss). Among 28 patients receiving 96 weeks of treatment with tenofovir disoproxil, BMD Z-scores declined by -0.341 for lumbar spine and -0.458 for total body.

In study GS-US-104-0352, 97 treatment-experienced patients 2 to <12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimens were randomised to either replace stavudine or zidovudine with tenofovir disoproxil (n=48) or continue on their original regimen (n=49) for 48 weeks. At week 48, 83% of patients in the tenofovir disoproxil treatment group and 92% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations <400 copies/ml. The difference in the proportion of patients who maintained <400 copies/ml at week 48 was mainly influenced by the higher number of discontinuations in the tenofovir disoproxil treatment group. When missing data were excluded, 91% of patients in the tenofovir disoproxil treatment group and 94% of patients in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations <400 copies/ml at week 48.

Reductions in BMD have been reported in paediatric patients. In patients who received treatment with tenofovir disoproxil, or stavudine or zidovudine, mean lumbar spine BMD Z-score was -1.034 and -0.498, and mean total body BMD Z-score was -0.471 and -0.386, respectively, at baseline. Mean changes at week 48 (end of randomised phase) were 0.032 and 0.087 in lumbar spine BMD Z-score, and -0.184 and -0.027 in total body BMD Z-score for the tenofovir disoproxil and stavudine or zidovudine groups, respectively. The mean rate of lumbar spine bone gain at week 48 was similar between the tenofovir disoproxil treatment group and the stavudine or zidovudine treatment group. Total body bone gain was less in the tenofovir disoproxil treatment group compared to the stavudine or zidovudine treatment group. One tenofovir disoproxil treated subject and no stavudine or zidovudine treated subjects experienced significant (>4%) lumbar spine BMD loss at week 48. BMD Z-scores declined by -0.012 for lumbar spine and by -0.338 for total body in the 64 subjects who were treated with tenofovir disoproxil for 96 weeks. BMD Z-scores were not adjusted for height and weight.

In study GS-US-104-0352, 8 out of 89 paediatric patients (9.0%) exposed to tenofovir disoproxil discontinued study drug due to renal adverse events. Five subjects (5.6%) had laboratory findings clinically consistent with proximal renal tubulopathy, 4 of whom discontinued tenofovir disoproxil therapy (median tenofovir disoproxil exposure 331 weeks).

Chronic hepatitis B

In study GS-US-174-0115, 106 HBeAg negative and HBeAg positive patients aged 12 to <18 years with chronic HBV infection [HBV DNA ≥10⁵ copies/ml, elevated serum ALT (≥2 x ULN) or a history of elevated serum ALT levels in the past 24 months] were treated with tenofovir disoproxil 245 mg (n=52) or placebo (n=54) for 72 weeks. Subjects must have been naïve to tenofovir disoproxil, but could have received interferon based regimens (>6 months prior to screening) or any other non-tenofovir disoproxil containing oral anti-HBV nucleoside/nucleotide therapy (>16 weeks prior to screening). At week 72, overall 88% (46/52) of patients in the tenofovir disoproxil treatment group and 0% (0/54) of patients in the placebo group had HBV DNA <400 copies/ml. Seventy-four percent (26/35) of patients in the tenofovir disoproxil group had normalised ALT at week 72 compared to 31% (13/42) in the placebo group. Response to treatment with tenofovir disoproxil was comparable in nucleos(t)ide-naïve (n=20) and nucleos(t)ide-experienced (n=32) patients, including lamivudine- resistant patients (n=6). Ninety-five percent of nucleos(t)ide-naïve patients, 84% of nucleos(t)ide-experienced patients, and 83% of lamivudine- resistant patients achieved HBV DNA <400 copies/ml at week 72. Thirty-one of the 32 nucleos(t)ide-experienced patients had prior lamivudine experience. At week 72, 96% (27/28) of immune-active patients (HBV DNA ≥10⁵ copies/ml, serum ALT >1.5 x ULN) in the tenofovir disoproxil treatment group and 0% (0/32) of patients in the placebo group had HBV DNA <400 copies/ml. Seventy-five percent (21/28) of immune-active patients in the tenofovir disoproxil group had normal ALT at week 72 compared to 34% (11/32) in the placebo group.

After 72 weeks of blinded randomized treatment, each subject could switch to open-label tenofovir disoproxil treatment up to week 192. After week 72, virologic suppression was maintained for those receiving double-blind tenofovir disoproxil followed by open-label tenofovir disoproxil (tenofovir disoproxil-tenofovir disoproxil group): 86.5% (45/52) of subjects in the tenofovir disoproxil-tenofovir disoproxil group had HBV DNA <400 copies/ml at week 192. Among the subjects who received placebo during the double-blind period, the proportion of subjects with HBV DNA <400 copies/mL rose sharply after they began treatment with open-label tenofovir disoproxil (PLB-tenofovir disoproxil group): 74.1% (40/54) of subjects in the PLB-tenofovir disoproxil group had HBV DNA <400 copies/ml at week 192. The proportion of subjects with ALT normalization at week 192 in the tenofovir disoproxil-tenofovir disoproxil group was 75.8% (25/33) among those who were HBeAg positive at baseline and 100.0% (2 of 2 subjects) among those who were HBeAg negative at baseline. Similar percentages of subjects in the tenofovir disoproxil-tenofovir disoproxil and PLB-tenofovir disoproxil groups (37.5% and 41.7%, respectively) experienced seroconversion to anti-HBe through week 192.

Bone Mineral Density (BMD) data from Study GS-US-174-0115 are summarized in Table 8.

Table 8. Bone Mineral Density Evaluation at Baseline, Week 72 and 192:

NA = Not Applicable
^a BMD Z-scores not adjusted for height and weight
^b Primary safety endpoint through week 72

The European Medicines Agency has deferred the obligation to submit the results of studies with tenofovir disoproxil in one or more subsets of the paediatric population in HIV and chronic hepatitis B (see section 4.2 for information on paediatric use).