HIV Drug Therapy: Do Emtricitabine and Lamivudine Have Similar Efficacy for First-line ART?

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First-line antiretroviral regimens containing emtricitabine have superior virological efficacy to combinations containing lamivudine when combined with tenofovir and either nevirapine or efavirenz, Dutch investigators report in the October 1 online edition of Clinical Infectious Diseases and at the HIV Drug Therapy Glasgow conference taking place this week. Lamivudine was associated a significantly increased risk of virological failure when used in these regimens.

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"This study is the largest to date to directly compare lamivudine with emtricitabine in ART naive patients and the first from a resource-rich setting," commented the study authors. "The use of lamivudine...was significantly associated with more virological failure within 48 and 240 weeks of cART [combination antiretroviral therapy]."

But the authors of an accompanying editorial believe the findings were probably due to the design of the study, and that until the results of a large randomized controlled trial show otherwise, emtricitabine and lamivudine should be considered equivalent. The study investigators also believe a randomized comparison is necessary.

Emtricitabine (Emtriva or FTC, also in Truvada and other coformulations) and lamivudine (3TC or Epivir) belong to the nucleoside reverse transcriptase inhibitor (NRTI) class of antiretrovirals. They are a mainstay of first-line ART regimens and are generally considered equivalent and interchangeable in treatment guidelines.

Lamivudine is now available in cheap generic formulations in both poorer and resource-rich countries, and preferring this drug over emtricitabine could result in substantial cost savings.

But are the drugs really equivalent? Some research evidence suggests that lamivudine is associated with a higher risk of virological failure, especially for people with a baseline viral load above 100,000 copies/mL.

Casper Rokx of Erasmus Medical Center in Rotterdam told delegates at the HIV Drug Therapy conference that a study is especially important as pressure grows to switch to generic antiretroviral drugs in order to reduce costs.

To better understand the efficacy of the 2 drugs, investigators in the Netherlands designed an observational study comparing rates of virological failure at weeks 48 and 240 between people starting first-line HIV therapy that contained either emtricitabine or lamivudine.

Emtricitabine or lamivudine were taken in combination with tenofovir (Viread) plus either efavirenz (Sustiva) or nevirapine (Viramune); emtricitabine, tenofovir, and efavirenz are the drugs in the widely used Atripla single-tablet regimen. In the vast majority of cases, nevirapine was dosed once daily, Rokx told delegates.

A total of 4740 people enrolled in the ATHENA cohort, who started HIV therapy between 2002 and 2012, were included in the study. Virological failure was defined as a viral load above 400 copies/mL.

Analysis of people taking efavirenz-based therapy showed that use of lamivudine was associated with higher rates of virological failure at week 48 compared to emtricitabine (11% vs 4%; odds ratio 1.78). Use of lamivudine was also associated with higher rates of 48-week virological failure among people taking nevirapine-containing therapy (27% vs 11%; odds ratio 2.09).

These findings were unaffected when the investigators used a viral load above 50 copies/mL as the cut-off for virological failure and controlled their results to take into account patient characteristics.

At week 240, use of lamivudine compared to emtricitabine was associated with a more than 2-fold increase in the risk of virological failure (adjusted hazard ratio 2.35) when used with efavirenz, and a doubling of the risk of treatment failure when used with nevirapine (adjusted hazard ratio 2.01).

However, time to virological suppression was similar for emtricitabine and lamivudine, and the 2 drugs were associated with a similar risk of virological rebound after successful suppression of viral load.

"Lamivudine and emtricitabine may not be interchangeable in recommended first-line initial [combination] ART. The use of emtricitabine was associated with better virological responses compared to lamivudine," concluded the study authors. "As the potential implications are substantial, a randomized clinical trial is urgently needed."

The authors of the accompanying editorial agree that a large study comparing the 2 drugs is warranted. However, they do not believe the present study proved the virological superiority of emtricitabine over lamivudine.

They highlight important baseline differences in the characteristics of the patients taking the 2 drugs that could -- despite the authors’ efforts to control for such factors -- have affected the results.

"It is reasonable to believe that the observed treatment differences are the result of study design rather than actual differences in efficacy," they comment.

The editorial’s authors also note that a meta-analysis of randomized controlled studies examining the comparative virological potency of emtricitabine and lamivudine did indeed show their equivalence. They therefore concluded, "on the basis of the currently available randomized evidence, we consider that lamivudine and emtricitabine can be considered as interchangeable."

11/4/14

References

C Rokx, A Fibriani, D van de Vijver, et al. More virological failure with lamivudine than emtricitabine in efavirenz and nevirapine regimens in the Dutch nationwide HIV cohort. HIV Drug Therapy 2014. Glasgow, November 2-6, 2014. Abstract O154.

C Rokx, A Fibriani, DA van de Vijver, et al. Increased Virological Failure in Naive HIV-1 Patients Taking Lamivudine Compared to Emtricitabine in Combination with Tenofovir and Efavirenz or Nevirapine in the Dutch Nationwide ATHENA Cohort. Clinical Infectious Diseases. October 1, 2014 (Epub ahead of print).

N Ford, A Hill, M Vitoria, and EJ Mills. Comparative Efficacy of Lamivudine and Emtricitabine: Comparing the Results of Randomized Trials and Cohorts. Clinical Infectious Diseases. October 1, 2014 (Epub ahead of print).