December 1, 2014
The Dutch national observational cohort found emtricitabine (FTC) was associated with better virological response than lamivudine (3TC) in a study presented at HIV Drug Therapy Glasgow Congress 2014.1
The study was also published simultaneously in Clinical Infectious Diseases on 3 November 2014, and an accompanying commentary to the journal article compared this finding with data from randomised trials and cohorts with contradictory results.2,3
The AIDS Therapy Evaluation in the Netherlands (ATHENA) study has collected data on people in HIV care since January 1996. By December 2012, the cohort included 21,012 HIV positive people registered in the Netherlands; 20,676 (98.4%) had consented to be included.
Between 2002 and 2012, there were 4740 treatment naive participants who started 3TC- or FTC-containing first-line antiretroviral treatment (ART). Participants received 3TC or FTC in the following regimens: 3TC/efavirenz (EFV)/tenofovir (TDF) (n=535), FTC/EFV/TDF (n=3343), 3TC/nevirapine(NVP)/TDF (n=193) and FTC/NVP/TDF (n=669).
At baseline the participants' mean age was 40 years. A greater proportion of men received FTC (88.0% vs 76.4%): MSM (69.2% vs 47.0%) and originally from Western countries (70% vs 53.7%). The median year of starting ART was 2004 for 3TC vs 2009 for FTC. Participants receiving FTC had higher median CD4 count (260 vs 184 cells/mm3) and lower median viral load (82,173 vs 100,000 copies/mL). About 25% of participants receiving 3TC started treatment with CD4 count <100 cells/mm3 vs 12% receiving FTC.
The investigators presented an on-treatment analysis of 3440 participants at 48 weeks. Of the remainder 100/4740 (2.1%) were lost to follow up and 831 (17.5%) had discontinued treatment (largely because of toxicity). A further 369 (7.8%) had no viral load data close to the 48-week analysis -- the investigators noted that these participants were evenly distributed among the four regimen groups.
At the time of analysis 38/352 (10.8%) participants receiving 3TC/EFV/TDF had virological failure (defined as < 400 copies/mL at 48 weeks + 10 weeks) vs 88/437 (3.6%) receiving FTC/EFV/TDF: odds ratio (OR) 3.23 (95% CI 2.17-4.81). For NVP-based regimens, 43/159 (27.0%) participants receiving 3TC/TDF/NVP vs 54/492 (11.0%) receiving FTC/TDF/NVP had virological failure: OR 3.00 (95% CI 1.92-4.72). Both comparisons p<0.001.
The adjusted OR for virological failure were: 1.78 (95% CI 1.11-2.84), p=0.016, with 3TC/TDF/EFV vs FTC/TDF/EFV, and 2.09 (95% CI 1.25-3.52), p=0.005, with 3TC/TDF/NVP vs FTC/TDF/NVP. Analyses by intention to treat and propensity score adjusted models gave similar results.
The time to virological suppression was not significantly different between 3TC and FTC-based ART by 48 weeks. There was no difference in virological failure within 240 weeks among participants receiving 3TC and FTC-based ART who achieved viral suppression <400 copies/mL on their initial regimen.
In 267/4740 participants -- 234 who failed within 240 weeks and 33 by week 48 -- those receiving 3TC-based regimens had a higher median viral load at failure than those on FTC: respectively 49,231 copies/mL vs 4230 copies mL, p<0.001.
There was no difference in acquired NRTI or NNRTI resistance in 88 participants (44 from the 3TC and 44 from the FTC groups) with >1000 copies/mL at virological failure and no recorded baseline resistance. The prevalence of primary mutations M184V/I and K65R was also no different between the two groups.
The investigators concluded that their findings suggest that 3TC is not interchangeable with FTC for first line ART.
In the accompanying editorial Ford et al note that three randomised clinical trials -- including 1242 participants -- have directly compared 3TC and FTC. The pooled results from the trials found no difference in virological suppression, relative risk (RR) 1.03 (95% CI 0.96-1.10) or virological failure, RR 0.93 (95% CI 0.74-1.18). But the risk of virological failure was three times higher for participants receiving 3TC vs FTC the ATHENA cohort, RR 2.99 (95% CI 2.08-4.30).
"How should clinical guidelines respond to this seemingly contradictory evidence from three randomised trials vs a nonrandomised cohort study?" the authors ask. They note that according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) randomised trials are generally rated as high quality and cohort studies as low quality. Although data from cohort studies can often be very useful in HIV, randomised trials are the best way to make comparisons between drugs. It is not possible to ensure that observed differences between treatments are not due to differences between populations.
They comment that the comparison groups in the ATHENA cohort study by Rokx at al were unbalanced both with respect to region of origin, between Western and sub-Saharan settings, and temporally with median year of ART start 2004 for 3TC and 2009 for FTC. Participants receiving 3TC also had a higher viral load and lower CD4 count at baseline, were more likely to be injection drug users, coinfected with hepatitis B and managed in a large treatment programme. These differences are impossible to fully correct for through methods like propensity scores.
Ford et al point out that the important differences between the two groups in the ATHENA cohort mean the discrepancy between this study and the results from randomised controlled trials could be explained by study design rather than actual differences between the two antiretrovirals.
Rokx et al suggest that additional randomised trials are needed to evaluate 3TC vs FTC, Ford et al agree that such evidence would be valuable and, alongside the evidence to date, might have implications for future guidelines. "In the meantime, on the basis of the currently available randomised evidence, we conclude that lamivudine and emtricitabine can be considered to be interchangeable", they write.
It is unclear why this study was published (and presented) for the reasons Ford et al describe. 3TC and FTC should continue to be considered interchangeable.
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