Emtricitabine and Tenofovir Disoproxil Fumarate

Treatment Of HIV-1 Infection

TRUVADA®, a combination of EMTRIVA® and VIREAD®, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg [see DOSAGE AND ADMINISTRATION and Clinical Studies].

The following points should be considered when initiating therapy with TRUVADA for the treatment of HIV-1 infection:

• It is not recommended that TRUVADA be used as a component of a triple nucleoside regimen.
• TRUVADA should not be coadministered with ATRIPLA®, COMPLERA® , DESCOVY®, EMTRIVA, GENVOYA®, ODEFSEY®, STRIBILD®, VEMLIDY® , VIREAD, or lamivudine-containing products [see WARNINGS AND PRECAUTIONS].
• In treatment experienced patients, the use of TRUVADA should be guided by laboratory testing and treatment history [see Microbiology].

Pre-Exposure Prophylaxis

TRUVADA is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. This indication is based on clinical trials in men who have sex with men (MSM) at high risk for HIV-1 infection and in heterosexual serodiscordant couples [see Clinical Studies].

When considering TRUVADA for pre-exposure prophylaxis the following factors may help to identify individuals at high risk:

• has partner(s) known to be HIV-1 infected, or
• engages in sexual activity within a high prevalence area or social network and one or more of the following:
  • inconsistent or no condom use
  • diagnosis of sexually transmitted infections
  • exchange of sex for commodities (such as money, food, shelter, or drugs)
  • use of illicit drugs or alcohol dependence
  • incarceration
  • partner(s) of unknown HIV-1 status with any of the factors listed above When prescribing TRUVADA for pre-exposure prophylaxis, healthcare providers must:
• prescribe TRUVADA as part of a comprehensive prevention strategy because TRUVADA is not always effective in preventing the acquisition of HIV-1 infection [see WARNINGS AND PRECAUTIONS];
• counsel all uninfected individuals to strictly adhere to the recommended TRUVADA dosing schedule because the effectiveness of TRUVADA in reducing the risk of acquiring HIV-1 was strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials [see WARNINGS AND PRECAUTIONS];
• confirm a negative HIV-1 test immediately prior to initiating TRUVADA for a PrEP indication. If clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection [see WARNINGS AND PRECAUTIONS]; and
• screen for HIV-1 infection at least once every 3 months while taking TRUVADA for PrEP.

Dosage Forms And Strengths

TRUVADA tablets are available in four dose strengths:

• Tablet: 100 mg of emtricitabine and 150 mg of tenofovir DF (equivalent to 123 mg of tenofovir disoproxil): blue, oval shaped, film coated, debossed with “GSI” on one side and with “703” on the other side.
• Tablet: 133 mg of emtricitabine and 200 mg of tenofovir DF (equivalent to 163 mg of tenofovir disoproxil): blue, rectangular shaped, film coated, debossed with “GSI” on one side and with “704” on the other side.
• Tablet: 167 mg of emtricitabine and 250 mg of tenofovir DF (equivalent to 204 mg of tenofovir disoproxil): blue, modified capsule shaped, film coated, debossed with “GSI” on one side and with “705” on the other side.
• Tablet: 200 mg of emtricitabine and 300 mg of tenofovir DF (equivalent to 245 mg of tenofovir disoproxil): blue, capsule shaped, film coated, debossed with “GILEAD” on one side and with “701” on the other side.

Storage And Handling

TRUVADA tablets are available in bottles containing 30 tablets with child-resistant closure as follows:

• 100 mg of emtricitabine and 150 mg of tenofovir DF (equivalent to 123 mg of tenofovir disoproxil) tablets are blue, oval shaped, film coated, debossed with “GSI” on one side and “703” on the other side (NDC 61958-0703-1).
• 133 mg of emtricitabine and 200 mg of tenofovir DF (equivalent to 163 mg of tenofovir disoproxil) are blue, rectangular shaped, film coated, debossed with “GSI” on one side and “704” on the other side (NDC 61958-0704-1).
• 167 mg of emtricitabine and 250 mg of tenofovir DF (equivalent to 204 mg of tenofovir disoproxil) are blue, modified capsule shaped, film coated, debossed with “GSI” on one side and “705” on the other side (NDC 61958-0705-1).
• 200 mg of emtricitabine and 300 mg of tenofovir DF (equivalent to 245 mg of tenofovir disoproxil) are blue, capsule shaped, film coated, debossed with “GILEAD” on one side and “701” on the other side (NDC 61958-0701-1).

Store at 25 °C (77 °F), excursions permitted to 15 °C–30 °C (59 °F–86 °F) (see USP Controlled Room Temperature).

• Keep container tightly closed
• Dispense only in original container
• Do not use if seal over bottle opening is broken or missing

Manufactured for and distributed by: Gilead Sciences, Inc. Foster City, CA 94404. Revised: April 2017

For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, consult the EMTRIVA and VIREAD prescribing information.

Mechanism Of Action

TRUVADA is a fixed-dose combination of antiviral drugs emtricitabine and tenofovir DF [see Microbiology].

Pharmacokinetics

One TRUVADA tablet was bioequivalent to one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).

The pharmacokinetic properties of emtricitabine are summarized in Table 7. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours postdose. Less than 4% of emtricitabine binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02–200 μg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours.

The pharmacokinetic properties of tenofovir DF are summarized in Table 7. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01–25 μg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours.

Table 7 Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovirin Adultsa

TRUVADA may be administered with or without food. Administration of TRUVADA following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when TRUVADA was administered with either a high fat or a light meal.

Specific Populations

Emtricitabine

No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.

Tenofovir DF

There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.

Emtricitabine and Tenofovir DF

Emtricitabine and tenofovir pharmacokinetics are similar in male and female subjects.

The pharmacokinetic data for tenofovir and emtricitabine following administration of TRUVADA in pediatric subjects weighing 17 kg and above are not available. The dosing recommendations of TRUVADA in this population are based on the dosing recommendations of EMTRIVA and VIREAD in this population. Refer to the EMTRIVA and VIREAD prescribing information for pharmacokinetic information on the individual products in pediatric patients.

TRUVADA should not be administered to HIV-1 infected pediatric patients weighing less than 17 kg.

Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older).

The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment [see WARNINGS AND PRECAUTIONS]. In adult subjects with creatinine clearance below 50 mL/min, Cmax, and AUC0-∞ of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for TRUVADA be modified in HIV-infected adult patients with estimated creatinine clearance 30–49 mL/min. No data are available to make dose recommendations in pediatric patients with renal impairment. TRUVADA should not be used in patients with estimated creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis [see DOSAGE AND ADMINISTRATION].

TRUVADA for a PrEP indication should not be used in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [see DOSAGE AND ADMINISTRATION].

The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of TRUVADA or emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir DF were administered together versus each agent dosed alone.

In vitro studies and clinical pharmacokinetic drug-drug interaction trials have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir DF, and zidovudine (Tables 8 and 9). Similarly, no clinically significant drug interactions have been observed between tenofovir DF and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir in trials conducted in healthy volunteers (Tables 10 and 11).

Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters forEmtricitabine in the Presence of the Coadministered Druga

Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Emtricitabinea

Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovira in the Presence of the Coadministered Drug

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TRUVADA: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine.

Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir

Coadministration of tenofovir DF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of tenofovir DF with didanosine enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown. See Drug Interactions (7.1) regarding use of didanosine with VIREAD.

Microbiology

Emtricitabine

Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε and mitochondrial DNA polymerase γ.

Tenofovir DF

Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 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.

Emtricitabine and Tenofovir DF

No antagonism was observed in combination studies evaluating the cell culture antiviral activity of emtricitabine and tenofovir together.

Emtricitabine

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 peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013–0.64 μM (0.0003–0.158 μg/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonism was observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 μM) and showed strain-specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 μM).

Tenofovir DF

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 values for tenofovir were in the range of 0.04–8.5 μM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zidovudine), nonnucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonism was observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5–2.2 μM) and showed strain-specific activity against HIV-2 (EC50 values ranged from 1.6 μM to 5.5 μM).

Emtricitabine and Tenofovir DF

The prophylactic activity of the combination of daily oral emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) was evaluated in a controlled study of macaques inoculated once weekly for 14 weeks with SIV/HIV-1 chimeric virus (SHIV) applied to the rectal surface. Of the 18 control animals, 17 became infected after a median of 2 weeks. In contrast, 4 of the 6 animals treated daily with oral FTC and TDF remained uninfected and the two infections that did occur were significantly delayed until 9 and 12 weeks and exhibited reduced viremia. An M184Iexpressing FTC-resistant variant emerged in 1 of the 2 macaques after 3 weeks of continued drug exposure.

Emtricitabine and Tenofovir DF

HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in reduced susceptibility to tenofovir.

In a clinical trial of treatment-naïve subjects [Study 934, see Clinical Studies], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subject isolates in the EMTRIVA + VIREAD group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R or K70E substitution in their HIV-1 as analyzed through standard genotypic analysis.

Emtricitabine

Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).

Tenofovir DF

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 2–4 fold reduction in susceptibility to tenofovir.

In treatment-naïve subjects, isolates from 8/47 (17%) analyzed subjects developed the K65R substitution in the VIREAD arm through 144 weeks; 7 occurred in the first 48 weeks of treatment and 1 at Week 96. In treatment-experienced subjects, 14/304 (5%) isolates from subjects failing VIREAD through Week 96 showed greater than 1.4fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a K65R amino acid substitution in the HIV-1 RT.

iPrEx Trial

In a clinical study of HIV-1 seronegative subjects [iPrEx Trial, see Clinical Studies], no amino acid substitutions associated with resistance to emtricitabine or tenofovir were detected at the time of seroconversion among 48 subjects in the TRUVADA group and 83 subjects in the placebo group who became infected with HIV-1 during the trial. Ten subjects were observed to be HIV-1 infected at time of enrollment. The M184V/I substitutions associated with resistance to emtricitabine were observed in 3 of the 10 subjects (2 of 2 in the TRUVADA group and 1 of 8 in the placebo group). One of the two subjects in the TRUVADA group harbored wild type virus at enrollment and developed the M184V substitution 4 weeks after enrollment. The other subject had indeterminate resistance at enrollment but was found to have the M184I substitution 4 weeks after enrollment.

Partners PrEP Trial

In a clinical study of HIV-1 seronegative subjects [Partners PrEP Trial, See Clinical Studies], no variants expressing amino acid substitutions associated with resistance to emtricitabine or tenofovir were detected at the time of seroconversion among 12 subjects in the TRUVADA group, 15 subjects in the VIREAD group, and 51 subjects in the placebo group. Fourteen subjects were observed to be HIV-1 infected at the time of enrollment (3 in the TRUVADA group, 5 in the VIREAD group, and 6 in the placebo group). One of the three subjects in the TRUVADA group who was infected with wild type virus at enrollment selected an M184V expressing virus by Week 12. Two of the five subjects in the VIREAD group had tenofovir-resistant viruses at the time of seroconversion; one subject infected with wild type virus at enrollment developed a K65R substitution by Week 16, while the second subject had virus expressing the combination of D67N and K70R substitutions upon seroconversion at Week 60, although baseline virus was not genotyped and it is unclear if the resistance emerged or was transmitted. Following enrollment, 4 subjects (2 in the VIREAD group, 1 in the TRUVADA group, and 1 in the placebo group) had virus expressing K103N or V106A substitutions, which confer high-level resistance to NNRTIs but have not been associated with tenofovir or emtricitabine and may have been present in the infecting virus.

Emtricitabine and Tenofovir DF

Cross-resistance among certain NRTIs has been recognized. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either emtricitabine or lamivudine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions.

Emtricitabine

Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine but retained susceptibility in cell culture to the NRTIs didanosine, stavudine, tenofovir, and zidovudine, and to NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine.

Tenofovir DF

The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R and K70E substitutions also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R or K70E substitutions. 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.

Animal Toxicology And/Or Pharmacology

Tenofovir and tenofovir DF 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.

Evidence of renal toxicity was noted in four animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

Clinical Studies

Clinical Study 934 supports the use of TRUVADA tablets for the treatment of HIV-1 infection. Additional data in support of the use of TRUVADA are derived from clinical Study 903, in which lamivudine and tenofovir DF were used in combination in treatment-naïve adults, and clinical Study 303 in which emtricitabine and lamivudine demonstrated comparable efficacy, safety, and resistance patterns as part of multidrug regimens. For additional information about these trials, consult the prescribing information for tenofovir DF and emtricitabine. The iPrEx study and Partners PrEP study support the use of TRUVADA to help reduce the risk of acquiring HIV-1.

Study 934

Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve subjects. From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. Subjects had a mean age of 38 years (range 18–80); 86% were male, 59% were Caucasian, and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 12.

Table 12 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934)

Through Week 48, 84% and 73% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the emtricitabine + tenofovir DF group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144).

Through 48 weeks, 7 subjects in the emtricitabine + tenofovir DF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks).

iPrEx Trial

The iPrEx trial was a randomized, double-blind, placebo-controlled multinational study evaluating TRUVADA in 2,499 HIV-seronegative men or transgender women who have sex with men and with evidence of high-risk behavior for HIV-1 infection. Evidence of high-risk behavior included any one of the following reported to have occurred up to six months prior to study screening: no condom use during anal intercourse with an HIV-1 positive partner or a partner of unknown HIV status; anal intercourse with more than 3 sex partners; exchange of money, gifts, shelter, or drugs for anal sex; sex with male partner and diagnosis of sexually transmitted infection; no consistent use of condoms with sex partner known to be HIV-1 positive.

All subjects received monthly HIV-1 testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. Of the 2499 enrolled, 1251 received TRUVADA and 1248 received placebo. The mean age of subjects was 27 years; 5% were Asian, 9% Black, 18% White, and 72% Hispanic/Latino.

Subjects were followed for 4,237 person-years. The primary outcome measure for the study was the incidence of documented HIV seroconversion. At the end of treatment, emergent HIV-1 seroconversion was observed in 131 subjects, of which 48 occurred in the TRUVADA group and 83 occurred in the placebo group, indicating a 42% (95% CI: 18–60%) reduction in risk. Risk reduction was found to be higher (53%; 95% CI: 34– 72%) among subjects who reported previous unprotected anal intercourse (URAI) at screening (732 and 753 subjects reported URAI within the last 12 weeks at screening in the TRUVADA and placebo groups, respectively). In a post-hoc case control study of plasma and intracellular drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable intracellular tenofovir. Efficacy was therefore strongly correlated with adherence.

Partners PrEP Trial

The Partners PrEP trial was a randomized, double-blind, placebo-controlled 3-arm trial conducted in 4,758 serodiscordant heterosexual couples in Kenya and Uganda to evaluate the efficacy and safety of TDF (N=1589) and FTC/TDF (N=1583) versus (parallel comparison) placebo (N=1586) in preventing HIV-1 acquisition by the uninfected partner.

All subjects received monthly HIV-1 testing, evaluation of adherence, assessment of sexual behavior, and safety evaluations. Women were also tested monthly for pregnancy. Women who became pregnant during the trial had study drug interrupted for the duration of the pregnancy and while breastfeeding. The uninfected partner subjects were predominantly male (61–64% across study drug groups) and had a mean age of 33–34 years.

Following 7,827 person-years of follow up, 82 emergent HIV-1 seroconversions were reported, with an overall observed seroincidence rate of 1.05 per 100 person-years. Of the 82 seroconversions, 13 and 52 occurred in partner subjects randomized to TRUVADA and placebo, respectively. Two of the 13 seroconversions in the TRUVADA arm and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for pregnancy. The risk reduction for TRUVADA relative to placebo was 75% (95% CI: 55–87%). In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable plasma tenofovir. Efficacy was therefore strongly correlated with adherence.

Emtricitabine and tenofovir are antiviral drugs that work by preventing HIV (human immunodeficiency virus) cells from multiplying in the body.

The combination of emtricitabine and tenofovir is used to treat HIV, which causes acquired immunodeficiency syndrome (AIDS). Emtricitabine and tenofovir is not a cure for HIV or AIDS.

Emtricitabine and tenofovir is also used together with safer-sex practices to reduce the risk of becoming infected with HIV. You must be HIV-negative to use emtricitabine and tenofovir for this purpose. This medication may not provide protection from disease in every person.

Emtricitabine and tenofovir may also be used for purposes not listed in this medication guide.

• HIV and AIDS: Antiretroviral Drugs, Treatments and Medications

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

(em trye SYE ta been & ten OF oh vir dye soe PROX il FUE ma rate)

Nucleoside and nucleotide reverse transcriptase inhibitor combination; emtricitabine is a cytosine analogue while tenofovir is an analog of adenosine 5'-monophosphate. Each drug interferes with HIV viral RNA dependent DNA polymerase resulting in inhibition of viral replication.

See individual agents.

Concerns related to adverse effects:

• Decreased bone mineral density: In clinical trials, tenofovir disoproxil fumarate has been associated with decreases in bone mineral density in HIV-1 infected adults and increases in bone metabolism markers. Serum parathyroid hormone and 1,25 vitamin D levels were also higher. Decreases in bone mineral density have also been observed in clinical trials of HIV-1 infected pediatric patients. Observations in chronic hepatitis B infected pediatric patients (aged 12-18 years) were similar. In all pediatric clinical trials, skeletal growth (height) appears unaffected. Consider monitoring of bone density in adult and pediatric patients with a history of pathologic fractures or with other risk factors for bone loss or osteoporosis. Consider calcium and vitamin D supplementation for all patients; effect of supplementation has not been studied but may be beneficial. Long-term bone health and fracture risk unknown. If abnormalities are suspected, expert assessment is recommended.

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Lactic acidosis/hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with use of nucleoside analogues, alone or in combination with other antiretrovirals. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (marked transaminase elevation may/may not accompany hepatomegaly and steatosis).

• Osteomalacia and renal dysfunction: May cause osteomalacia with proximal renal tubulopathy. Bone pain, extremity pain, fractures, arthralgias, weakness and muscle pain have been reported. In patients at risk for renal dysfunction, persistent or worsening bone or muscle symptoms should be evaluated for hypophosphatemia and osteomalacia.

• Renal toxicity: Tenofovir disoproxil fumarate may cause renal toxicity (acute renal failure and/or Fanconi syndrome); avoid use with concurrent or recent nephrotoxic therapy (including high dose or multiple NSAID use). Acute renal failure has occurred in HIV-infected patients with risk factors for renal impairment who were on a stable tenofovir regimen to which a high dose or multiple NSAID therapy was added. Consider alternatives to NSAIDS in patients taking tenofovir disoproxil fumarate and at risk for renal impairment. Calculate creatinine clearance prior to initiation of therapy and as clinically appropriate during therapy. In patients at risk for renal dysfunction, including patients who have experienced renal events while taking adefovir, assess serum phosphorus, urine glucose, and urine protein prior to and periodically during treatment. IDSA guidelines recommend discontinuing tenofovir (and substituting with alternative antiretroviral therapy) in HIV-infected patients who develop a decline in GFR (a >25% decrease in GFR from baseline and to a level of <60 mL/minute/1.73 m2) during use, particularly in presence of proximal tubular dysfunction (eg, euglycemic glycosuria, increased urinary phosphorus excretion and hypophosphatemia, proteinuria [new onset or worsening]) (IDSA [Lucas 2014]).

Disease-related concerns:

• Chronic hepatitis B: [US Boxed Warning]: Safety and efficacy during coinfection of HIV and HBV have not been established; acute, severe exacerbations of HBV have been reported following discontinuation of antiretroviral therapy. Not approved for the treatment of chronic hepatitis B virus infection. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue this therapy. If appropriate, anti-hepatitis B therapy may be warranted. All patients with HIV should be tested for HBV prior to initiation of treatment.

• Comprehensive prevention program: Preexposure prophylaxis (PrEP) should be accompanied by a comprehensive HIV-1 prevention program (eg, risk reduction counseling, access to condoms), with particular emphasis on medication adherence. In addition, regular monitoring (eg, HIV status of patient and partner(s), risk behavior, adherence, adverse effects, sexually transmitted infections that facilitate HIV-1 transmission) is highly recommended.

• HIV treatment: Appropriate use: Not recommended as a component of a triple nucleoside regimen due to potential for early virological failure. Clinical trials in HIV-infected patients whose regimens contained only three nucleoside reverse transcriptase inhibitors (NRTI) show less efficacy, early virologic failure and high rates of resistance substitutions. Triple drug regimens with two NRTIs in combination with a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor are usually more effective.

• HIV treatment and renal impairment: Use with caution in patients with renal impairment (CrCl <50 mL/minute); dosage adjustment required. Closely monitor renal function and assess serum phosphorus, urine glucose, and urine protein prior to and periodically during treatment. Do not use in patients with CrCl <30 mL/minute or requiring hemodialysis. IDSA guidelines recommend avoiding tenofovir in HIV patients with preexisting kidney disease (CrCl <50 mL/minute and not on hemodialysis or GFR <60 mL/minute/1.73 m2) when other effective HIV treatment options exist because data suggest risk of chronic kidney disease (CKD) is increased (IDSA [Lucas 2014]).

• PrEP and renal impairment: Routinely monitor serum phosphorus, urine glucose, and urine protein prior to and periodically during treatment in patients with mild renal impairment. Do not use in CrCl <60 mL/minute.

• Resistance risk with PrEP: [US Boxed Warning]: Confirm HIV-1 negative status immediately before and at least every 3 months during therapy. Do not start PrEP if signs or symptoms of acute HIV-1 infection are present unless HIV-1 negative status is confirmed by a test approved by the Food and Drug Administration (FDA) as an aid to detect HIV-1 infection (including acute or primary infection). Risk of drug resistant HIV-1 variants with PrEP use if patient had undetected acute HIV-1 infection. Some HIV-1 tests (eg, rapid tests) do not detect acute HIV-1 infection. Screen PrEP candidates for acute viral infections and potential exposure events within 1 month of starting PrEP. If infections or events exist, wait 1 month to start PrEP and reconfirm HIV-1 negative status. If symptoms consistent with acute HIV-1 infection develop following a potential exposure during PrEP, discontinue PrEP until negative infection status is confirmed.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Duplicate therapy: Do not use concurrently with emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, or any combination of these drugs.