Once-daily emtricitabine reduced viral load in patients with HIV infection in a phase I/II study. 80 patients were randomised to receive emtricitabine 25, 100 or 200mg once daily or lamivudine 150mg twice daily for 10 days. Emtricitabine 200mg/day was the most effective treatment. 58% of emtricitabine 200 mg/day recipients had a 2 log10 decrease in viral load or a reduction below detectable levels; 21% of emtricitabine 200 mg/day recipients had both. Two days after completion of therapy, emtricitabine 200 mg/day recipients had an absolute decrease in viral load of 1.63 log10  .
There is a lower incidence of the amino acid mutation M184V in antiretroviral therapy naive patients receiving emtricitabine as part of a triple drug regimen compared with patients who received lamivudine. A randomised double-blind study compared emtricitabine with lamivudine in a background of stavudine and either nevirapine or efavirenz. 47/468 (10%) patients were classified as virological failures and 32/47 had at least one mutation associated with the study mechanism. The incidence of the study associated mutation(s) was higher in the lamivudine arm (88.2%) than in the emtricitabine arm (56.7%). Similarly, the frequency of the M184V mutation was significantly higher in the lamivudine treated patients (58.8% vs 16.7%)  .
The efficacy of a triple-drug regimen containing once-daily emtricitabine in treatment-naïve Black African females was comparable to males treated with the same regimen. In this 48 week study, 234 HIV-infected patients (M=99, F=135) received, emtricitabine 200mg QD in combination with stavudine and either nevirapine (HIV RNA <100,00 copies/mL) or efavirenz (HIV RNA ≥100,000 copies/mL). HIV RNA levels were monitored every 12 weeks and adverse events very 4 weeks. No significant differences were seen in the efficacy of the treatment in males versus females. The rate of virological failure was 14%(M) vs 10%(F); CD4 cell count 203 cells/mL (M) vs 182 cell/mL (F)  .
Emtricitabine treatment resulted in superior and durable increases in absolute CD4+ count from baseline compared to stavudine (163 cells/mm3 (8.6%) vs 137 cells/mm3 (5.1%)) by week 60. Patients were randomised to receive either emtricitabine (200mg once daily) or stavudine (200mg twice daily), didanosine and efavirenz  .
Patients administered the combination therapy tenofovir disproxil fumarate/emtricitabine/efavirenz (tdf/e/e) had a greater response rate than those administered lamivudine/zidovudine/efavirenz (l/z/e) in a phase III trial, Study 934. Initially, 517 patients with HIV infection were randomised to receive tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg and efavirenz 600 mg, all dosed once daily, or lamivudine/zidovudine twice daily and efavirenz 600mg once daily. At 24, 48 and 96 weeks, 88%, 84% and 75% of patients in the tdf/e/e arm had an HIV RNA level <400 copies/mL. Of the patients in the l/z/e arm, 80%, 73% and 62% of patients had an HIV RNA level of <400 copies/mL at 24, 48 and 96 weeks, respectively. In addition, patients receiving tdf/e/e combination therapy consistently had a greater improvement in CD4 count from baseline compared with l/z/e recipients. At 24 weeks, patients had an increase from baseline of 129 and 111 CD4 cells/mm3, at 48 weeks the increase was 190 and 158 cells/mm3, and at 96 weeks it was 270 and 237 cells/mm3, in the tdf/e/e and l/z/e arms, respectively      .
After 144 weeks of treatment in Study 934, 71% of patients who received tdf/e/e achieved and maintained viral load <400 copies/mL compared with 58% of l/z/e patients. Viral load <50 copies/mL was achieved and maintained in 64% of tdf/e/e patients and in 56% of l/z/e patients. Results also showed a mean increase from baseline in CD4 cell counts of 312 cells/mm2 for patients who received tdf/e/e and an increase of 271 cells/mm2 in patients who received l/z/e  .
Oral emtricitabine 3 mg/kg administered to neonates < 3 months old with HIV-1 infection produced plasma levels similar to those found to be safe and efficacious in adults and children ≥ 3 months old  .
In highly active antiretroviral therapy (HAART)
once daily emtricitabine had greater antiviral efficacy than twice daily abacavir when used with stavudine and efavirenz. Treatment-naïve HIV-1-infected patients (n=37) with plasma HIV-1 RNA (VL) ≥5000 copies/mL were randomised to receive FTC 200mg o.d or abacavir 300mg b.i.d in addition to stavudine and efavirenz. At week 24, 83.3% of patients receiving emtricitabine had a VL≤50 copies/mL compared with 62% of patients receiving abacavir  .
Once daily regimen containing emtricitabine in a background of didanosine/efavirenz was statistically superior in efficacy, safety and tolerability to a twice-daily regimen of stavudine in a background of didanosine/efavirenz, once daily. This randomised, double-blind, multicentre, phase III study (FTC-301) compared the administration of emtricitabine once-daily with stavudine twice-daily. Antiretroviral naïve patients (n=571) with baseline viral loads >5000 copies/mL were randomised 1:1 to 200mg emtricitabine (n=286), once-daily or stavudine, twice-daily at standard doses (n=285). All patients also received open-label didanosine and efavirenz twice-daily. Patients were evaluated at baseline, every 4 weeks up to week 48 and then every 12 weeks. The Kaplan-Meier probabilities at week 52 were, for virological failure, 14.1% for stavudine and 4.7% for emtricitabine (p<0.001); for efficacy failure, 35.1% for stavudine and 19.1% for emtricitabine (p<0.001). A significantly greater mean increase in CD4+ cell counts was seen in the emtricitabine arm (152 cells/mm3) compared with the stavudine arm (117 cells/mm3)   . At 60 weeks, Kaplan-Meier analyses demonstrated that 79.4% of 286 patients receiving emtricitabine had persistent suppression of HIV RNA (<400 copies/mL) compared with 62.8% of 285 patients given stavudine (P<0.0001). When the analysis used a viral suppression level of <50 copies/mL at 60 weeks, the results were 75.6% and 53.7%, respectively (P<0.0001)  .
Results from study FTC-302 show that emtricitabine is more effective than standard therapy in reducing viral load (VL). The study compared emtricitabine 200mg o.d with lamivudine 150mg b.i.d in a background of stavudine b.i.d and efavirenz o.d. The Kaplan-Meier probability of virologic failure (not achieving <50 copies/mL or >50 copies/mL on two consecutive visits) at week 48 was 6.5% (emtricitabine) and 11.0% (lamivudine). Overall, emtricitabine was significantly superior to the combined control arms (P=0.01)  .
In an open-label pilot study conducted in France (ANRS 091), the efficacy of emtricitabine was evaluated in 40 HIV-infected antiretroviral-naive patients. In this study participants received once daily emtricitabine 200mg, didanosine 250mg if <60kg or 400mg if >60kg and efavirenz 600mg. At 24 weeks, 39/40 patients (98%) had a viral load of <400 copies/ml and 39/39 evaluable patients (100%) had undetectable viral loads. Intent-to-treat analysis showed that 37/40 patients (93%) had a viral load of <50 copies/ml at 24 weeks. Researchers involved in the study pointed out this is one of the first studies to suggest that potent antiviral activity can be achieved with a once daily HAART regimen. At the 96-week follow-up, 85% of the patients had maintained a plasma HIV RNA level <400 copies/mL and 80% had plasma HIV RNA <50 copies/mL. CD4 cell counts had increased by a median of 259 cells/µL   .
Continued suppression of HIV-1 RNA was seen in HIV-infected adults who switched from a stable HAART regimen containing lamivudine to one containing emtricitabine. In a 48-week, open-label equivalence trial (FTC-303), 294 patients with HIV-1 RNA ≤400 copies/mL were randomised to either continue their lamivudine containing regimen or switch lamivudine 150mg bid to emtricitabine 200mg once daily. At 48 weeks, patients with HIV RNA ≤400 copies/ml were offered emtricitabine as part of the HAART regimen in study FTC-350. 77% of the patients receiving emtricitabine had HIV RNA ≤400 copies/mL at week 48. 214 of these patients elected to continue with emtricitabine in study FTC-350 for 72 weeks. 61% of the patients maintained HIV RNA levels at ≤400 copies/mL and 53% had ≤50 copies/ml at 72 weeks  .
treatment of children with emtricitabine achieved a level of systemic exposure comparable to that observed in adults with good virological activity. In this study, 82 patients aged between 4 months and 16 years received emtricitabine as part of HAART. Treatment-naive patients (n= 51) received 6 mg/kg (up to a maximum of 200 mg/day) plus twice-daily weight-adjusted doses of stavudine and lopinavir/ritonavir. Treatment-experienced patients (n=31) also received emtricitabine 6 mg/kg in place of lamivudine as part of their existing regimen. Interim analysis of data at 24 weeks showed high virological response rates among both groups. In the treatment-naive and treatment-experienced groups, the proprtion patients with HIV RNA levels <400 copies/mL were 92.2 an 83.9%, respectively; the proportion of patients with HIV RNA levels <50 copies/mL were 62.7 and 71 %, respectively. Treatment-experienced patients had no overall change in viral load during emtricitabine-based therapy, whereas the median reduction among treatment-naive patients was 3.08 log10 copies/mL  .
An easily administered once-a-day combination of emtricitabine/didanosine/efavirenz is virologically active for at least 16 weeks. This study (PACTG 1021) involved 30 treatment-naive patients; 17 of these patients were aged 12 years or younger and 13 were aged between 13 and 21 years. The study will eventually involve a total of 42 patients, including a cohort aged between 90 days and 3 years. The patients received once-daily emtricitabine 6 mg/kg, up to a maximum of 200 mg/day in addition to once-daily didanosine 240−400 mg/m2 and weight-adjusted doses of efavirenz (maximum dose of 600 mg/day for capsules or 720 mg/day for oral solution). A 16-week intention-to-treat analysis showed that high proportions of patients, including those aged ≤ 12 years, experienced virological responses. Among the overall patient population, viral loads of < 400 copies/mL and < 50 copies/mL were achieved in 87% and 74% of patients, respectively. Viral loads of < 400 copies/mL were achieved in 92% of the 13 patients aged < 12 years. Furthermore, all patients experienced an improvement in immune function, indicated by increases in CD4+ cell counts from baseline; the median increase was 200 cells/mm3  .
Co-infection with hepatitis B virus and HIV
in a 15-day phase I/II evaluation of emtricitabine for HIV, 2 patients had detectable levels of hepatitis B virus (HBV) DNA. Over the 15-day exposure to emtricitabine these patients demonstrated a mean decrease in HBV DNA of betweeen 0.78 and 1.42 log10 with a maximum reduction in HBV DNA of between 1.55 and 1.99 log10  .
Oral emtricitabine (25-200 mg/day, od) demonstrated efficacy in a phase II trial in 98 patients with chronic hepatitis B/HIV co-infection. At 1 year, 38, 42 and 54%, respectively, of emtricitabine 25, 100 and 200mg recipients had HBV levels < 3700 copies/ml. The incidence of YMDD mutation at 1 year was 4% in the 200mg group  .
Patients treated with emtricitabine as part of HAART demonstrated potent suppression of HBV DNA in co-infected patients with HIV RNA suppression. Median baseline HBV DNA was 8.75 log10 copies/mL and median HBV DNA change from baseline was -2.26, -2.44, 3.13 and 2.75 log10 copies/mL at 12, 24, 36 and 48 weeks. For the inactive d4T control group, the median change in HBV DNA was -0.05, -0.21, -0.60 and 0.02 log10 copies/mL. Among emtricitabine treated patients, 7/19, 8/19, 11/18 and 9/16 had HBV DNA <limit of detection, respectively  .
Chronic hepatitis B virus infections
In a phase I/II dose-selection trial, 98 patients with chronic hepatitis B infection were randomised to receive emtricitabine 25, 100 or 200mg, once daily for 24 weeks. At 24 weeks, median reductions from baseline in viral load of 2.3, 2.9 and 3 log10 were observed in emtricitabine 25mg, 100mg and 200mg recipients, respectively. In addition, HBV DNA levels were suppressed to < 4700 copies/ml (the limit of detection) in 22, 24 and 61% of emtricitabine 25mg, 100mg and 200mg recipients, respectively. At 48 weeks, the median decrease in viral load from baseline was 2.59, 3.12 and 2.92 log10 copies/ml and HBeAg loss occurred in 32, 38 and 50% of HBe antigen positive patients in the 25, 50 and 200mg cohorts respectively   .
At week 48, all patients (n = 94) were switched to open-label emtricitabine, 200mg, once daily (QD), through to week 96, and then followed for an additional six months off therapy. At 96 weeks, 76% of patients had normal ALT levels; 41% had undetectable viremia; 51% had lost HBeAg and 29% had seroconverted to HBeAb. Compared to week 48, ten new patients had lost HbeAg, seven developed HBeAb, two regained HBeAg and two lost HBeAb. The incidence of L526M+/-M550V/I associated resistance was 19% for patients receiving emtricitabine 200mg for the full two years. Preliminary data from the treatment free follow-up period showed that 8 patients experienced viral rebound  .
Emtricitabine at daily doses ≥ 100mg is effective for treating patients with hepatitis B. In this multicentre, open, sequential, dose-escalating, phase II study, 49 patients with hepatitis B infection were treated with emtricitabine 25, 50, 100, 200 and 300 mg/day, PO, for 2 months. 43, 88, 73, 89, and 90% of the patients had decreases in HBV DNA level of ≥ 2 log10 copies/mL, respectively, with median decreases of 1.68, 3.15, 2.65, 3.04 and 3.33 log10 copies/mL at each dose level. Overall, HBV DNA level decreases were maintained for 48h after the final emtricitabine dose. Four weeks after completion, HBV DNA levels approached baseline levels. Viral loads decreased by 1, ≥2, ≥3 log10 copies/mL in 96, 78 and 53% of patients, respectively  .
Preliminary results from a phase III study (FTCB-301) showed that treatment with emtricitabine is associated with improvements in liver histology. In this 48-week, double-blind, placebo-controlled trial, 248 patients with chronic hepatitis B who had not previously received therapy with a nucleoside analogue were randomised (2:1) to receive emtricitabine 200mg once daily or placebo for 48 weeks. At study entry, patients had elevated levels of ALT and detectable serum levels of HBV DNA. After 48 weeks, 62% of patients treated with emtricitabine exhibited improvement in liver histology, compared with 25% of patients receiving placebo (p<0.001). Additionally, emtricitabine resulted in a median reduction in HBV DNA from baseline of 3 log10 copies/mL, compared with 0.44 log10 copies/mL in the placebo group (p<0.001). After 48 weeks, 56% of emtricitabine patients had HBV DNA below the assay lower limit of detection (4700 copies/mL), compared to 7% in the placebo arm (p<0.001). Additionally, patients treated with emtricitabine achieved a median ALT reduction of 52 IU/L, compared to a median ALT reduction of 25 IU/L for patients receiving placebo (p<0.001)  .
In a randomised, double-blind trial, emtricitabine plus adefovir dipivoxil combination therapy showed faster and more effective suppression of hepatitis B than adefovir dipivoxil alone. Thirty patients positive for HBeAg received either emtricitabine 200mg plus adefovir dipivoxil 10mg or adefovir dipivoxil 10mg plus placebo every day for 48 weeks. Median log10 reduction of viraemia was 5.04 versus 3.2 at week 28 and 5.3 versus −3.4 at week 48 for the combination therapy and adefovir dipivoxil alone, respectively; the differences were significant. There was a two-phase decay in hepatitis B virus kinetics; mean t1/2 was 1.4 days for the first phase and 24.4 days for the second phase. The infected cell loss rate was significantly greater with combination therapy than with monotherapy. Patients were either fast responders (< 300 copies/mL of virus at week 12) or slow responders (≥ 300 copies/mL of virus at week 12); significantly more patients receiving combination therapy were fast responders than those receiving monotherapy. HBeAg seroconversion occurred in two combination therapy recipients and one monotherapy recipient; all three cases were fast responders. The fast response was associated with enhanced T-cell reactivity  .
Emtricitabine 200mg alone or in combination with clevudine 10mg for 24 weeks elicited a fabourable antiviral response in 78 hepatitis B e antigen negative (HBeAg-) patients. After 24 weeks, median reductions in viral load from baseline among 52 experienced and 26 naïve patients were similar for emtricitabine + clevudine and emtricitabine alone groups. Among naïve patients, 69% and 67% of patients in the combination and monotherapy groups, respectively, had viral load <250 mg/dL at week 24, while among experienced patients, this proprotion was 86% and 63%, respectively. The overall incidence of emtricitabine-associated resistance mutations was 0% among treatment-naïve patients, compared with 7% in treatment-experienced patients  .
Similarly, emtricitabine, alone or in combination with clevudine10mg for 24 weeks elicited fabourable antiviral response in 85 hepatitis B e antigen positive (HBeAg+) patients. After 24 weeks, median reductions in viral load from baseline among 55 experienced and 30 naïve patients were similar for emtricitabine + clevudine and emtricitabine alone groups. Among experienced patients, the proportion of patients with viral load <250 mg/dL at week 24 was similar between treatment groups, while among naïve patients, this proportion was 50% and 19% in the combination and monotherapy groups, respectively. The overall incidence of emtricitabine-associated resistance mutations was 3% among treatment-naïve patients, compared with 22% in treatment-experienced patients  .