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Doubled risk of virologic failure with 3TC vs FTC in Dutch cohort analysis
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CROI 2015, February 23-26, 2015, Seattle, Washington
Mark Mascolini
People starting antiretroviral therapy with lamivudine (3TC) had a twice higher risk of virologic failure after 48 weeks or 240 weeks than people starting treatment with emtricitabine (FTC), according to results of a 6322-person analysis of the nationwide Netherlands ATHENA cohort [1]. These findings run counter to a 2013 meta-analysis of 3TC and FTC studies [2] and to combined results of three clinical trials that involved the nucleosides [3]. ATHENA investigators published their findings shortly before CROI 2015 [4] and updated them at CROI.
The ATHENA team noted that HIV treatment guidelines tend to consider 3TC and FTC as "interchangeable components" of first-line regimens. But they suggested evidence for their clinical equivalence is "inconsistent." To determine whether the two nucleosides differ in antiviral impact, ATHENA investigators conducted this observational analysis.
The study involved 6322 antiretroviral-naive people without pretreatment resistance starting a first-line regimen including either 3TC (14%) or FTC (86%) any time from 2002 through 2012. Everyone took one or the other nucleoside with efavirenz/tenofovir, nevirapine/tenofovir, or a boosted protease inhibitor (PI)/tenofovir. The researchers defined virologic failure as a viral load above 400 copies, an antiretroviral switch for failure, or death with a last viral load above 400 copies.
Because this is an observational cohort analysis and not a randomized trial, differences between the groups starting 3TC and FTC are possible. Indeed, the groups differed markedly, and many of the differences favored FTC over 3TC: origin in Western countries versus sub-Saharan Africa, more recent year starting treatment (2009 versus 2004), lower pretreatment viral load and higher pretreatment CD4 count, a lower proportion of injection drug users, and a lower proportion infected with hepatitis B virus.
The ATHENA team took care to adjust for such differences in comparing responses to 3TC versus FTC by multivariable adjusted logistic regression analysis, Cox proportional hazard models, and sensitivity analyses including propensity score-adjusted models. But even the most sophisticated analyses cannot eliminate the chance of bias inherent in observational studies.
Among people starting 3TC, adjusted hazard ratios (aHR) for virologic failure compared with FTC were 2.4 (95% confidence interval [CI] 1.6 to 3.4) with efavirenz and 2.0 (95% CI 1.4 to 3.0) with nevirapine. When 3TC or FTC was taken with a boosted PI, risk of failure was similar with the two nucleosides (aHR 1.2, 95% CI 0.6 to 2.3). Time to viral load below 400 copies and time to rebound after reaching a sub-400 viral load did not differ substantially between 3TC and FTC.
In the original published analysis [4], which did not include people taking a boosted PI, virologic failure results also favored FTC over 3TC in propensity score-adjusted models and intent-to-treat sensitivity analyses, including an analysis defining failure as a viral load above 50 copies.
After 240 weeks of treatment in the original published analysis [4], virologic failure rates were about twice higher with 3TC than FTC among people starting efavirenz/tenofovir (aHR 2.35, 95% CI 1.61 to 3.42) or nevirapine/tenofovir (aHR 2.01, 95% CI 1.36 to 2.98).
In an editorial discussing the ATHENA publication, four antiretroviral experts noted that settling the question of virologic response to 3TC versus FTC is crucial because 3TC comes in several generic formulations and is cheaper than FTC [3]. Given the noted imbalances in the ATHENA FTC and 3TC populations, these experts suggested "it is reasonable to believe that the observed treatment differences are the result of study design rather than actual differences in efficacy between lamivudine and emtricitabine" [3].
Replying to the editorial, the ATHENA team argued that the three randomized trials cited "do not even address the main question of our study which concerned the risk of virological failure in treatment naive patients starting FTC or 3TC" [5]. At CROI they maintained that their findings justify a randomized controlled trial to answer the question.
World Health Organization antiretroviral guidelines anoint two preferred first-line regimens: efavirenz/tenofovir plus either 3TC or FTC. But current US Department of Health and Human Services guidelines lean toward FTC-containing first-line regimens: Six of the 7 preferred initial combinations contain FTC plus tenofovir, while one contains 3TC plus abacavir.
References
1. Rokx C, Fibriani A, van de Vijver DA, et al. Virological responses to lamivudine and emtricitabine in the nationwide ATHENA cohort. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 566.
2. Ford N, Shubber Z, Hill A, et al. Comparative efficacy of lamivudine and emtricitabine: a systematic review and meta-analysis of randomized trials. PLoS One. 2013;8:e79981. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0079981
3. Ford N, Hill A, Vitoria M, Mills EJ. Comparative efficacy of lamivudine and emtricitabine: comparing the results of randomized trials and cohorts. Clin Infect Dis. 2015;60:154-156. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264583/
4. Rokx C, Fibriani A, van de Vijver DA, et al. Increased virological failure in naive HIV-1-infected patients taking lamivudine compared with emtricitabine in combination with tenofovir and efavirenz or nevirapine in the Dutch nationwide ATHENA cohort. Clin Infect Dis. 2015;60:143-153.
5. Rokx C, Rijnders BJA. Evidence gathered from randomized clinical trials and observational studies on the equivalence of emtricitabine and lamivudine. Clin Infect Dis. 2015. In press.
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