Deoxycytidine nucleoside analogue
Emtricitabine was approved by the FDA in July 2003 for use in combination with other antiretroviral agents in adults with HIV infection. In 2005, it was approved for use in pediatric patients. In 2012, the combination of tenofovir + emtricitabine was was approved by the FDA for use as preexposure prophylaxis by HIV-uninfected adults at high risk of sexually acquired infection with HIV (see Special Uses).
Initial approval of emtricitabine was based on the results of 2 Phase III clinical trials. A double-blind study compared emtricitabine + didanosine + efavirenz with stavudine + didanosine + efavirenz as initial treatment in individuals who had not previously received antiretroviral therapy. At 24 and 48 weeks, patients receiving emtricitabine had significantly higher rates of virologic suppression than did stavudine recipients.(1)
An open-label trial of treatment-experienced patients with HIV RNA levels of <400 copies/mL on a lamivudine-containing regimen randomized patients either to continue lamivudine or to switch to once-daily emtricitabine, in combination with either stavudine or zidovudine and either a protease inhibitor or an NNRTI. The proportion of patients whose viral loads remained suppressed at the <400 copies/mL and <50 copies/mL level were similar in the two treatment groups.(2)
| Clinical Use|
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate a number of regimens containing tenofovir + emtricitabine as "preferred" regimens for initial combination therapy. The guidelines also state that lamivudine may be used in place of emtricitabine and vice versa.
Regimens containing emtricitabine in combination with other antiretroviral medications have been shown to achieve effective viral suppression in initial therapy.
Used in initial treatment, emtricitabine appears to compare favorably with lamivudine and with stavudine. A randomized, double-blind study of initial treatment comparing emtricitabine (dosed daily) with lamivudine (dosed twice daily), each combined with stavudine and either nevirapine or efavirenz, showed similar rates of virologic failure at 48 weeks (Kaplan-Meier probability of virologic failure: 16% for emtricitabine vs 11% for lamivudine; p value not significant).(2) In one licensing study (see Approval), recipients of emtricitabine (dosed once daily) were more likely than recipients of stavudine (dosed twice daily) to achieve viral loads of <50 copies/mL at 48 weeks in an intent-to-treat analysis (78% for emtricitabine vs 59% for stavudine; p < .001).(1) Those receiving emtricitabine also had greater increases in CD4 counts at 48 weeks (mean increase 168 cells/µL vs 134 cells/µL, but this
difference was not statistically significant [p = .15]).(1)
Few data are available on the use of emtricitabine in treatment of individuals who have experienced virologic failure on an initial regimen. Like lamivudine, emtricitabine often has an important role in subsequent therapy, even in situations wherein resistance to these agents has developed. Despite the presence of the signature emtricitabine (or lamivudine) resistance mutation, at reverse transcriptase codon 184, emtricitabine may have a suppressive effect on HIV replication and may increase susceptibility to certain other nucleoside analogues (eg, tenofovir, zidovudine).
Because the mutations associated with resistance to emtricitabine are largely identical to those conferring resistance to lamivudine (see Resistance), it is unlikely that emtricitabine will be of benefit to patients changing treatment because of lamivudine resistance.
Studies of treated individuals with viral load ≤400 copies/mL on treatment have found that switching to emtricitabine-containing regimens does not adversely affect viral suppression in patients on regimens containing lamivudine (2,3) or a protease inhibitor.(4)
Emtricitabine and lamivudine have no significant additive potency and share nearly identical resistance profiles; they should not be used together.
| Potential Adverse Effects|
Symptomatic side effects of emtricitabine may be difficult to distinguish from those of other antiretrovirals with which it is combined. The most common adverse effects noted in clinical trials of emtricitabine with other antiviral agents were headache, diarrhea, nausea, and rash. Side effects were seldom severe, with approximately 1% of participants discontinuing participation because of these events. Skin discoloration, manifested by hyperpigmentation of the palms or soles, or both, and generally mild and asymptomatic, has been associated with emtricitabine.(5)
Nucleoside analogues may be associated with mitochondrial toxicity leading to potentially serious long-term side effects such as lactic acidosis and disorders of lipid metabolism,(6) but the extent to which emtricitabine may contribute to such effects is not known.
Resistance to emtricitabine may develop with only a single viral mutation in the setting of suboptimal viral suppression. It is therefore essential to emphasize patient adherence, to assess motivation, and to discuss possible side effects and strategies for their management before any regimen containing emtricitabine is initiated.
| Interactions with Other Drugs|
Emtricitabine does not appear to interact significantly with enzymes involved in drug metabolism. Clinically significant drug-drug interactions involving emtricitabine have not been identified.(5)
Resistance to emtricitabine, as with resistance to lamivudine, is most frequently associated with the selection of a mutation at codon 184, although in one study no such mutation was detectable in the majority of individuals experiencing viral recurrence on a regimen containing emtricitabine.(7)
To avoid long-term treatment failure resulting from resistance, emtricitabine should be used only in regimens that are expected to be fully suppressive of viral replication.
| Implications of emtricitabine resistance for treatment with other antiretrovirals|
HIV isolates with resistance to emtricitabine by virtue of a mutation at codon 184 have been shown to be cross-resistant to lamivudine, but retained sensitivity to abacavir, didanosine, stavudine, tenofovir, and zidovudine.(5)
| Implications of resistance to other antiretrovirals for treatment with emtricitabine|
HIV strains harboring mutations conferring reduced susceptibility to stavudine and zidovudine (at codons 41, 67, 70, 210, 215, or 219) or didanosine (codon 74) have been found to remain sensitive to emtricitabine.(5)
| Special Uses|
| Treatment of hepatitis B|
Emtricitabine is active against hepatitis B virus,(8,9) but is not currently approved for treatment of hepatitis B infection. Few data are available on the safety and efficacy of emtricitabine in patients coinfected with HIV and hepatitis B.(10) DHHS guidelines suggest inclusion of either emtricitabine or lamivudine, plus tenofovir, in the antiretroviral regimens of patients coinfected with HIV and hepatitis B who require treatment for their HIV infection. This will result in treatment of both HIV and hepatitis B infections. Exacerbation of hepatitis B has been reported in patients after discontinuation of emtricitabine.(5)
| Preexposure prophylaxis|
Several studies have shown that preexposure prophylaxis (PrEP) using the combination of oral TDF and emtricitabine, taken daily by HIV-uninfected individuals, can reduce the risk of sexual acquisition of HIV.(11,12,13) These studies, performed in men who have sex with men and in heterosexual men and women, found that infection risk was reduced by 44% to 73%. However, in another study of high-risk women oral TDF + emtricitabine did not show protective effects.(14) The reasons for the varied study results are not yet clear, but may include differences in adherence (in the studies that showed protective benefit, effectiveness appeared to be strongly correlated with adherence), or other factors.
In 2012, the FDA approved the combination of oral TDF + emtricitabine for use as preexposure prophylaxis by adults at high risk of sexual acquisition of HIV. Prophylactic TDF + emtricitabine is intended only for those who are tested and confirmed to be HIV uninfected, and as one component in a comprehensive prevention strategy that includes other risk-reduction measures and adherence support. Regular ongoing HIV testing is required to identify persons who become infected with HIV while on prophylaxis; TDF + emtricitabine is not sufficient as treatment for established HIV infection, and in persons with HIV infection, its use risks the development of resistance to the antiretroviral agents.
|| || Saag MS, Cahn P, Raffi F, et al; FTC-301A Study Team. Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial. JAMA. 2004 Jul 14;292(2):180-9.|
|| ||Sanne I, van der Horst C, Shaw A, et al. Two randomized, controlled, equivalence trials of emtricitabine (FTC) to lamivudine (3TC). In: Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona. Abstract TuPeB4432.|
|| ||Wakeford C, Shen G, Hulett L, et al. Long-term efficacy and safety of emtricitabine in HIV+ adults switching from a lamivudine containing HAART regimen. In: Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 10-14, 2003; Boston. Abstract 550.|
|| || Campo R, Dejesus E, Bredeek UF, et al. SWIFT: Prospective 48 week study to evaluate efficacy and safety of switching to emtricitibine/tenofovir from lamivudine/abacavir in virologically suppressed HIV-1 infected patients on a boosted protease inhibitor containing antiretroviral regimen. Clin Infect Dis. 2013 Jan 29.|
|| ||Emtriva package insert. Gilead Sciences, July 2003.|
|| || Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther. 2000 Aug;22(8):911-36; discussion 898.|
|| ||Sanne I, Quinn JB, Harris J, et al. Genotypic analysis of HIV-1 infected ART-naive patients receiving emtricitabine (FTC) or lamivudine (3TC) in a double blind equivalence trial. In: Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona. Abstract TuPeB4433.|
|| || Lim SG, Ng TM, Kung N, et al; Emtricitabine FTCB-301 Study Group. A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B. Arch Intern Med. 2006 Jan 9;166(1):49-56.|
|| || Gish RG, Leung NW, Wright TL, et al. Dose range study of pharmacokinetics, safety, and preliminary antiviral activity of emtricitabine in adults with hepatitis B virus infection. Antimicrob Agents Chemother. 2002 Jun;46(6):1734-40.|
|| ||Snow A, Harris J, Borroto-Esoda K, et al. Emtricitabine therapy for hepatitis infection with HIV+ patients co-infected with hepatitis B virus: Efficacy and genotypic findings in antiretroviral treatment-naive patients. 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco. Abstract 836.|
|| || Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99.|
|| || Baeten JM, Donnell D, Ndase P, et al; PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012 Aug 2;367(5):399-410.|
|| || Thigpen MC, Kebaabetswe PM, Paxton LA, et al; TDF2 Study Group. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012 Aug 2;367(5):423-34.|
|| || Van Damme L, Corneli A, Ahmed K, et al; FEM-PrEP Study Group. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012 Aug 2;367(5):411-22.|