JAC Advance Access originally published online on May 9, 2006
Journal of Antimicrobial Chemotherapy 2006 58(1):227-228; doi:10.1093/jac/dkl179
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Correspondence |
Emtricitabine intolerance in treatment-experienced patients switched from lamivudine: a method of assessing toxicity
The St Stephen's Centre, The Chelsea and Westminster Hospital 369 Fulham Road, London SW10 9NH, UK
*Corresponding author. Tel: +44-20-8746-5610; Fax: +44-20-8746-5637; E-mail: j.stebbing{at}ic.ac.uk
Keywords: HIV , drug toxicity , salvage regimens
Sir,
The limitations of highly active antiretroviral therapy (HAART) include adverse effects, drug–drug interactions, limited potency and durability and high pill burden associated with poor compliance. Once-daily HAART may provide a strategy to increase adherence and increase the probability of therapeutic success.
The synthetic cytidine nucleoside analogue, emtricitabine ([–]-FTC), has potent in vitro activity against the HIV and hepatitis B virus reverse transcriptase (RT), a long intracellular half-life of its triphosphate active moiety and a median 1.92 log10 copies/mL reduction in HIV viral load in vivo after 14 days,1 a level comparable to most protease or fusion inhibitors. There may also be a lower incidence of drug-resistant mutants, including the methionine-to-valine substitution at position 184 of the RT (M184V) classically associated with failure of lamivudine therapy.2
Large well-designed multi-centre randomized studies in treatment-naive and treatment-experienced patients have demonstrated that once-daily emtricitabine-based HAART regimens have equivalent, non-inferior or superior rates of virological control and maintenance of CD4 counts, compared with twice-daily stavudine (d4T),2,3 Combivir,4 lamivudine (3TC)5 and continued protease inhibitor-based6 HAART. These studies have demonstrated variable rates of intolerance and treatment discontinuation that may be secondary to emtricitabine (5–12%), with most adverse effects reported being mild in severity. However, there were no significant differences in adverse effects between the arms of these studies, and it is difficult to attribute toxicities to emtricitabine specifically.
We therefore examined the incidence of adverse events attributable to emtricitabine, by examining ‘switched’ patients in a large prospectively followed HIV cohort in Europe.
In this small study we included patients according to the following criteria: (i) stable viraemia (HIV-1 viral load <50 copies/mL for >6 months) on a lamivudine-containing HAART regimen, and who were then switched to emtricitabine (its long half-life and bioavailability being major factors theoretically leading to less resistance); (ii) a subsequent switch back to lamivudine after starting emtricitabine; and (iii) both of the switches occurring between May 2004 and July 2005. HAART was defined as a three-drug regimen in accordance with published guidelines. A comprehensive notes review of these individuals was made. The reason for each switch was reviewed and documented, considering both patient preference and physician-driven interactions. Generic consent was provided for use of clinical data.
We found that emtricitabine was well tolerated with no grade III or IV toxicities. A total of 5873 HIV-1-infected individuals have been followed up in the HAART era, and of these, 158 patients (2.7%) had been switched from lamivudine to emtricitabine, without altering other drugs in their regimen. Of these switched patients, a further 13 individuals (8.2%) had switched back to lamivudine. These last switches occurred within 1 month of starting emtricitabine.
The reasons for returning to lamivudine therapy are shown in Table 1. In the 11 out of 13 patients with clinical symptoms (numbers 1–11 in Table 1), patient-reported symptoms disappeared within 72 h of returning to lamivudine (i.e. after two half-lives of emtricitabine). While this ‘toxicity cohort’ is small and has only sufficient statistical power to pick up more frequent adverse events due to relatively low numbers of patients switching, it is reasonable to suggest that active follow-up of switched patients is a reasonable way to assess toxicity of a single drug in a combined regimen.
|
Randomized studies involving emtricitabine have shown that the probability of developing a treatment-limiting adverse event is not significantly different in each of the study arms. We show here that the patient-reported incidence of adverse effects leading to switching off emtricitabine is 11 out of 158 individuals (7%). While we observed that 6 out of the 11 patient-reported symptoms were secondary to feeling ‘strange or unwell’ (grade II CNS toxicity), none of the randomized studies has assessed this toxicity, due to the presence of other medications in each arm. Since this is a retrospective study and only switches back to lamivudine were considered, it is reasonable to suppose that the incidence of adverse effects attributable to emtricitabine (with or without other drugs) may be underestimated.
Medication side effects and patient-reported symptoms are the foremost variables predictive of non-adherence to HAART. Future HIV standards of care will emphasize the use of once-daily therapies, especially as HAART penetrates the under-developed world. As virological failure is often secondary to interruptions due to intolerability, the low incidence of adverse events with emtricitabine and their rapid resolution following cessation of emtricitabine should reassure clinicians.
Transparency declarations
None to declare. All authors approved of this study and the paper and there is no conflict of interest.
References
1 Molina JM, Ferchal F, Rancinan C, et al. (2000) Once-daily combination therapy with emtricitabine, didanosine, and efavirenz in human immunodeficiency virus-infected patients. J Infect Dis 182:599–602.[CrossRef][Web of Science][Medline]
2 Cahn P, Raffi F, Saag M, et al. Virologic efficacy and patterns of resistance mutations in ART-naivr patients receiving combination therapy with once-daily emtricitabine compared to twice-daily stavudine in a randomized double-blind multi-center clinical trial. Programs and Abstracts of the Tenth Conference on Retroviruses and Opportunistic Infections, 2003Boston, USA Abstract 606, Poster 672.
3
Saag MS, Cahn P, Raffi F, et al. (2004) Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial. JAMA 292:180–9.
4 Feinberg J. (2005) Meeting notes from ICAAC. Tenofovir + emtricitabine vs. AZT + 3TC. AIDS Clin Care 17:7.[Medline]
5 Rousseau FS, Wakeford C, Mommeja-Marin H, et al. (2003) Prospective randomized trial of emtricitabine versus lamivudine short-term monotherapy in human immunodeficiency virus-infected patients. J Infect Dis 188:1652–8.[CrossRef][Medline]
6 Molina JM, Ferchal F, Rancinan C, et al. Once-daily combination of emtricitabine, didanosine, and efavirenz vs continued PI-based HAART in HIV-infected adults with undetectable plasma HIV-RNA: 48-week results of a prospective randomized multicenter trial (ALIZE-ANRS 99). Programs and Abstracts of the Tenth Conference on Retroviruses and Opportunistic Infections, 2003Boston, USA Abstract 551, Poster 566.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Borras-Blasco, A. Navarro-Ruiz, C. Borras, and E. Castera Adverse cutaneous reactions associated with the newest antiretroviral drugs in patients with human immunodeficiency virus infection J. Antimicrob. Chemother., November 1, 2008; 62(5): 879 - 888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Palacios, A. Terron, A. Hidalgo, A. Rivero, J. Santos, and on behalf of the SIMVA Group Minor emtricitabine intolerance in treatment-stable patients switched from tenofovir/lamivudine to a fixed-dose combination of tenofovir/emtricitabine (Truvada(R)) J. Antimicrob. Chemother., February 1, 2008; 61(2): 462 - 463. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||