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CROI 2015: Does Emtricitabine Work Better than Lamivudine in Combination ART?

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People with HIV who started an antiretroviral regimen containing emtricitabine (FTC; Emtriva) and NNRTIs were about half as likely to experience virological treatment failure as those who used the similar drug lamivudine (3TC; Epivir), according to an analysis of more than 6000 participants in the Dutch ATHENA cohort presented at the recent 2015 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle. No significant differences between emtricitabine and lamivudine were seen with boosted protease inhibitor regimens.

 

Emtricitabine (also in Truvada and Gilead Sciences' single-tablet regimens) and lamivudine (also in the Combivir and Epzicom coformulations) are structurally similar nucleoside reverse transcriptase inhibitors. The older lamivudine is available in inexpensive generic versions and is widely used in resource-limited settings. Both are frequently included in first-line antiretroviral therapy (ART) regimens and are generally considered functionally equivalent and interchangeable in treatment guidelines. But there is little evidence from randomized clinical trials that directly compare their effectiveness.

Casper Rokx from Erasmus University Medical Center and fellow investigators with the ATHENA (AIDS Therapy Evaluation in the Netherlands) study team evaluated virological response to lamivudine and emtricitabine when used in combination with tenofovir (Viread, also included in Gilead's coformulations with emtricitabine) and either the NNRTIs efavirenz (Sustiva) or nevirapine (Viramune), or a ritonavir-boosted protease inhibitor (PI).

This observational study included 6322 ATHENA participants starting ART for the first time between 2002 and 2012. Rokx presented an earlier version of the analysis with 4740 participants at the 2014 HIV Drug Therapy conference in Glasgow and in the January 1, 2015, edition of Clinical Infectious Diseases.

Most participants were men, a majority were from western countries, and the median age was about 40 years. 14% used lamivudine while 86% used emtricitabine. Participants taking lamivudine rather than emtricitabine were more likely to be women (23% vs 13%), more often came from sub-Saharan Africa (20% vs 10%), had lower pre-treatment CD4 cell counts, and started combination ART earlier in time (median 2005 vs 2009). Just over 60% in both the lamivudine and emtricitabine groups used efavirenz, but lamivudine recipients were more likely to use nevirapine (22% vs 12%) and less likely to use PIs (16% vs 26%).

The researchers compared rates of virological failure, defined as viral load >400 copies/mL at or after 48 weeks, ART regimen switches due to treatment failure, or death occurring while viral load was >400 copies/mL.

Results

 

  • At week 48 virological failure rates in an on-treatment analysis, as reported in the published study abstract, were as follows:

o   Efavirenz regimens: 10.8% among participants taking lamivudine vs 3.6% among those taking emtricitabine (adjusted odds ratio [OR] 1.78);

o   Nevirapine regimens: 27.0% vs 11.0%, respectively (adjusted OR 2.09, or just over double the risk);

o   Boosted PI regimens: 5.3% vs 4.7%, respectively (adjusted OR 1.44).

  • An intent-to-treat analysis gave similar results, as did using a viral load cut-off of 50 rather than 400 copies/mL.
  • At week 240 the adjusted hazard ratio [HR] for virological failure among people using lamivudine instead of emtricitabine were 2.4 for efavirenz regimens and 2.0 for nevirapine regimens, with little difference for PI regimens (HR 1.2).
  • Time to viral suppression did not differ significantly between lamivudine and emtricitabine in any of the regimens (adjusted HR 1.0 for efavirenz and nevirapine, 0.9 for PIs).
  • Time to virological failure after reaching undetectable HIV RNA also did not differ significantly between lamivudine and emtricitabine in any regimen (adjusted HR 1.6 for efavirenz, 1.5 for nevirapine, 0.9 for PIs).

"With efavirenz or nevirapine, the use of lamivudine instead of emtricitabine in combination with tenofovir for ART-naive HIV-1 patients was associated with more virological failure," the researchers concluded. "With a boosted PI, the use of lamivudine instead of emtricitabine in combination with tenofovir for ART-naive HIV-1 patients was not associated with different virological responses."

"Our results support their equivalence in boosted PI-containing combination ART only," they added. "Our observations warrant a direct randomized blinded comparison of lamivudine with emtricitabine in tenofovir and NNRTI containing combination ART."

However, as previously reported, the authors of an editorial accompanying the Clinical Infectious Diseases article suggested that the ATHENA findings were likely due to the study design, especially differences between patients taking the 2 drugs that may not have been adequately controlled. Until the results of a large randomized controlled trial show otherwise, they wrote, "we consider that lamivudine and emtricitabine can be considered as interchangeable."

3/20/15

References

C Rokx, A Fibriani, DA van de Vijver, et al. Virological Responses to Lamivudine and Emtricitabine in the Nationwide ATHENA Cohort. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 566.

C Rokx, A Fibriani, DA van de Vijver, 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. Clinical Infectious Diseases 60(1):143-153. January 1, 2015.

N Ford, A Hill, M Vitoria, and EJ Mills. Comparative Efficacy of Lamivudine and Emtricitabine: Comparing the Results of Randomized Trials and Cohorts (Editorial commentary). Clinical Infectious Diseases 60(1):154-156. January 1, 2015.