Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate: Package Insert and Label Information (Page 5 of 7)

12.4 Microbiology

Mechanism of Action: Efavirenz: EFV is an NNRTI of HIV-1. EFV activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). HIV-2 RT and human cellular DNA polymerases α, β, γ, and δ are not inhibited by EFV.

Lamivudine: 3TC is a synthetic nucleoside analogue with activity against HIV-1 and HBV. Intracellularly, 3TC is phosphorylated to its active 5’-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.

Tenofovir Disoproxil Fumarate: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate (TDF-DP), an obligate chain terminator. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) and HBV 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: Efavirenz: The concentration of EFV inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90 to 95% (EC90 to 95 ) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), and macrophage/monocyte cultures. EFV demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, N), but had reduced antiviral activity against group O viruses.

Lamivudine: The antiviral activity of 3TC against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of 3 to 15,000 nM. (1 mcM = 0.23 mcg/mL). The median EC50 values of 3TC 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. The EC50 values against HIV-2 isolates (n = 4) ranged from 3 to 120 nM in PBMCs. 3TC was not antagonistic to all tested anti-HIV agents. Ribavirin (50 mcM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of 3TC by 3.5-fold in MT-4 cells.

Tenofovir Disoproxil Fumarate: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 mcM to 8.5 mcM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5 mcM to 2.2 mcM) and strain-specific activity against HIV-2 (EC50 values ranged from 1.6 mcM to 5.5 mcM). Please see the full prescribing information for VIREAD® for information regarding the inhibitory activity of TDF against HBV.

Resistance: Efavirenz: In cell culture, HIV-1 isolates with reduced susceptibility to EFV (> 380- fold increase in EC90 value) emerged rapidly in the presence of drug. Genotypic characterization of these viruses identified single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in reverse transcriptase.

Clinical isolates with reduced susceptibility in cell culture to EFV have been obtained. One or more RT substitutions at amino acid positions A98, L100, K101, K103, V106, V108, Y188, G190, P225, F227 and M230 were observed in patients failing treatment with EFV in combination with indinavir, or with 3TC plus zidovudine. The K103N substitution was the most frequently observed.

Lamivudine: 3TC-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that resistance was predominantly due to a methionine to valine or isoleucine (M184V/I) substitution in reverse transcriptase.

Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2- to 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 tenofovir. K65R substitutions developed in some subjects failing a tenofovir disoproxil fumarate regimen.

Cross-Resistance: Efavirenz: Cross-resistance among NNRTIs has been observed. Clinical isolates previously characterized as EFV-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine- resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to EFV in cell culture. Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to EFV.

Lamivudine: Cross-resistance among NRTIs has been observed. 3TC-resistant HIV-1 isolates were cross-resistant in cell culture to didanosine (ddI). Cross-resistance is also expected with abacavir and emtricitabine as these select M184V substitutions.

Cross-resistance among certain HIV-1 NRTIs has been observed. The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1-infected subjects treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to FTC and 3TC. HIV-1 isolates from subjects (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 substitution without zidovudine resistance-associated substitutions (N = 8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N = 3), Q151M substitution (N = 2), or T69 insertion (N = 4), all of whom had a reduced response.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Efavirenz: Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in female established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose.

EFV tested negative in a battery of in vitro and in vivo genotoxicity assays. These included bacterial mutation assays in S. typhimurium and E. coli , mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay.

EFV did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given EFV was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately ≤ 0.15 times that in humans at the recommended clinical dose.

Lamivudine: Long-term carcinogenicity studies with 3TC in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg. 3TC was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in assay for unscheduled DNA synthesis in rat liver. 3TC showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg per kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection. In a study of reproductive performance, 3TC administered to rats at doses up to 4,000 mg per kg per day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring.

Tenofovir Disoproxil Fumarate: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

TDF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice.

13.2 Animal Toxicology and/or Pharmacology

Efavirenz: Nonsustained convulsions were observed in 6 of 20 monkeys receiving EFV at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose [see Warnings and Precautions (5.11)].

Tenofovir Disoproxil Fumarate: Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.


14.1 Clinical Efficacy in Patients with HIV-1 Infection

Treatment-Naïve Adult Patients: The efficacy of EFV 400 mg, 3TC 300 mg, and TDF 300 mg in the treatment of HIV-1 infection in adults with no antiretroviral treatment history was established in trials of:

  • Trial 903 which evaluated the efficacy of a three-drug regimen including EFV 600 mg, 3TC 300 mg and TDF 300 mg
  • ENCORE1, which evaluated the comparability of 400 mg of EFV in a triple drug regimen to a 600 mg dose of EFV in a triple drug regimen.

Trial 903: Data through 144 weeks are reported for Trial 903, a double-blind, active-controlled multicenter trial comparing EFV 600 mg + 3TC 300 mg + TDF 300 mg vs. EFV 600 mg + 3TC 300 mg + stavudine (d4T) 40 mg in 600 antiretroviral-naïve subjects. Subjects had a mean age of 36 years (range 18 to 64); 74% were male, 64% were Caucasian, and 20% were Black. The mean baseline CD4+ cell count was 279 cells/mm3 (range 3 to 956) and median baseline plasma HIV-1 RNA was 77,600 copies/mL (range 417 to 5,130,000). Subjects were stratified by baseline HIV-1 RNA and CD4+ cell count. Forty-three percent of subjects had baseline viral loads > 100,000 copies/mL and 39% had CD4+ cell counts < 200 cells/mm3. Table 11 provides treatment outcomes through 48 and 144 weeks.

Table 11. Outcomes of Randomized Treatment at Week 48 and 144 (Study 903)
a Subjects achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48 and 144.b Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48 and 144.c Includes lost to follow-up, subject’s withdrawal, noncompliance, protocol violation and other reasons.
Outcomes At Week 48 At Week 144
EFV + 3TC + TDF (N = 299) EFV + 3TC + d4T (N = 301) EFV + 3TC + TDF (N = 299) EFV + 3TC + d4T (N = 301)
Respondera 79% 82% 68% 62%
Virologic failureb 6% 4% 10% 8%
Rebound 5% 3% 8% 7%
Never suppressed 0% 1% 0% 0%
Added an antiretroviral agent 1% 1% 2% 1%
Death < 1% 1% < 1% 2%
Discontinued due to adverse event 6% 6% 8% 13%
Discontinued for other reasonsc 8% 7% 14% 15%

Achievement of plasma HIV-1 RNA concentrations of < 400 copies/mL at Week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (> or ≤ 100,000 copies/mL) and CD4+ cell count (< or ≥ 200 cells/mm3). Through 144 weeks of therapy, 62% and 58% of subjects in the TDF and d4T arms, respectively, achieved and maintained confirmed HIV-1 RNA < 50 copies/mL. The mean increase from baseline in CD4+ cell count was 263 cells/mm3 for the TDF arm and 283 cells/mm3 for the d4T arm.

Through 144 weeks, 11 subjects in the TDF group and 9 subjects in the d4T group experienced a new CDC Class C event.

The ENCORE1 trial was a randomized, multinational clinical study comparing EFV 400 mg vs. EFV 600 mg in 630 antiretroviral-naïve adult subjects. Subjects were randomized 1:1 to receive EFV 400 mg in combination with TDF 300 mg plus FTC 200 mg all given once daily or EFV 600 mg in combination with TDF 300 mg/FTC 200 mg given once daily. The randomization was stratified by the clinical sites and the screening visit plasma HIV RNA level, either < 100,000 copies/mL or ≥ 100,000 copies/mL.

Subjects had a mean age of 36 years (range 18 to 69), 68% were male, 37% were of African heritage, 33% were of Asian ethnicity, 17% were Hispanic and 13% were Caucasian.

The mean baseline CD4+ cell count was 273 cells/mm3 (range 38 to 679). Median baseline viral load was 56,469 copies/mL (range 162 to 10,000,000). Thirty-four percent of subjects had baseline viral load of ≥ 100,000 copies/mL.

Treatment outcomes through Week 48 are presented in Table 12.

Table 12. Virologic Outcomes of Randomized Treatment in Trial ENCORE1 in Treatment-Naïve Subjects at Week 48
a Subjects achieved confirmed HIV-1 RNA < 50 copies/mL at Week 48.b Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48. c Includes discontinued due to Adverse Event, lost to follow-up, subject’s withdrawal, noncompliance, protocol violation and other reasons.
Outcomes (< 50 copies/mL) At Week 48
EFV 400 mg + FTC + TDF (N = 321) EFV 600 mg + FTC + TDF (N = 309)
Responder a HIV-1 RNA < 50 copies/mL 86% 84%
Virologic failureb HIV-1 RNA ≥ 50 copies/mL 11% 11%
Rebound 9% 8%
Never suppressed 2% 3%
Death 1% 1%
Discontinued for other reasonsc 2% 4%

Achievement of plasma HIV-1 RNA concentrations of less than 50 copies/mL at Week 48 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration (< or ≥ 100,000 copies/mL). The mean increase at Week 48 from baseline in CD4+ cell count was 183 cells/mm3 for the EFV 400 mg arm and 158 cells/mm3 for the EFV 600 mg arm. Through 48 weeks, 11 subjects in the EFV 400 mg group and 5 subjects in the EFV 600 mg group experienced a new CDC Class C event.

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