The inclusion of lamivudine (3TC) in first-line tenofovir-based regimens with commonly used non-nucleoside reverse transcriptase inhibitors is associated with a greater risk for virologic failure than those containing emtricitabine (FTC) at 48 and 240 weeks, Dutch investigators are reporting.
"Clinicians and patients who read the major guidelines will see the recommendation that FTC and 3TC are interchangeable in tenofovir-based backbones and will probably assume that there is indeed enough evidence to support this recommendation," lead investigator Casper Rokx, MD, from Erasmus University Medical Center, Rotterdam, the Netherlands, told Medscape Medical News.
"However, despite similar recommendations by major guidelines, the actual evidence is inconclusive and the results of our study suggest an important difference in virological responses," he said. "This warrants a blinded comparison of FTC versus 3TC with tenofovir-based regimens and non-nucleoside reverse transcriptase inhibitors to support the recommendation," Dr Rokx told delegates attending the HIV Drug Therapy Congress in Glasgow, United Kingdom.
The Dutch nationwide HIV cohort — known as the ATHENA study — is an observational study involving treatment-naive patients. Combination antiretroviral therapy was initiated in 4836 patients.
Some 546 patients received 3TC plus tenofovir-based regimens in combination with efavirenz. A smaller number, 207 patients, received the same 3TC combination with nevirapine added.
Another 3391 patients received FTC with the tenofovir combination with efavirenz and the final 692 patients received this same combination with nevirapine added.
At week 48, the proportion of patients who experienced virologic failure was higher, at 10.8%, among those who had received the tenofovir combination with 3TC and efavirenz compared with 3.6% of those who received the FTC combination, Dr Rokx reported.
Similarly, among those who received nevirapine add-ons, virologic failure was higher at 27% among those who received the 3TC combination compared with 11% for the FTC counterparts.
Questioning the Guidelines
Multivariable-adjusted odds ratio of virologic failure was statistically significantly higher, at 1.78, for patients receiving the 3TC combination with efavirenz than for those receiving the FTC regimen with efavirenz (P = .016).
The odds ratio for virologic failure was also statistically significantly higher for the 3TC nevirapine combination, at 2.09, compared with the FTC nevirapine alternative (P = .005).
Both propensity score–adjusted models and intention-to-treat analyses showed similar results, report the researchers.
"We found an increased rate and higher cumulative probability of virological failure with 3TC compared to FTC, regardless of the non-nucleoside reverse transcriptase inhibitors," Dr Rokx said. "However, we also found that the cumulative probability of virological suppression and virological failure following successful virological suppression were not different."
Specifically, if HIV-RNA levels less than 400 copies/mL were achieved on initial combination antiretroviral first, no differences in virologic failure rates out to 240 weeks were observed between 3TC- or FTC-containing regimens.
On the other hand, patients in whom 3TC-containing regimens failed had significantly higher median HIV-RNA levels at the time of viral failure compared with FTC-containing antiretrovirals (P < .001). Rates of acquired resistance to 3TC or FTC were only numerically higher, at 89.9% and 81.2%, respectively.
Cost-Saving Switch Strategies
The fact that time to virologic suppression and time to virologic failure following successful virologic suppression did not differ between regimens containing 3TC and those containing FTC might support cost-saving switch strategies to generics after achievement of virologic suppression, Dr Rokx said.
However, he cautioned, this might be inappropriate in the absence of a well-powered randomized trial confirming a presumed equivalence. "Only two clinical trials have compared FTC and 3TC in identical nucleotide reverse transcriptase backbones in antiretroviral-naive HIV-infected patients," Dr Rokx pointed out.
The first was done around 2000 and included stavudine as the second agent. Stavudine is no longer recommended because of its considerable toxicity, he added. The second study has not yet been published and includes 332 predominantly female patients from Zambia in whom 3TC or FTC was initiated with tenofovir-based regimens.
Early results suggest no difference in response rates between the two different regimens over 48 weeks in the Zambian trial, but Dr Rokx said, "the study was underpowered to exclude clinically significant differences, such as those we observed in our study."
More important, two randomized pilot studies evaluating the efficacy of the 3TC regimens with nevirapine were prematurely terminated because of an unexpectedly higher virologic failure rate.
"Well-tolerated single tablet regimens all include FTC with tenofovir, not 3TC with tenofovir," Dr Rokx pointed out, "and most patients prefer once-daily single-tablet regimens, if given the choice."
On the basis of these results and the fact that well-tolerated first-line combination antiretrovirals that include FTC and tenofovir in a single tablet are available in the Netherlands, he said, "I prefer these regimens as first-line therapy."
A systemic review by Tang et al (Clin Infect Dis. 2012;54:852-875) suggested that the use of the 3TC combination was associated with lower virologic responses even though direct comparisons were not available at the time.
The review also demonstrated that the first-line regimen consisting of tenofovir, FTC, and efavirenz was more effective than regimens containing containing 3TC instead of FTC or nevirapine instead of efavirenz.
"A regimen in which 3TC and nevirapine were used instead of FTC and efavirenz was the least efficacious of all four tenofovir-containing first-line regimens," Michele Tang, MD, and Robert Shafer, MD, from Stanford University in Palo Alto, California, who were involved in that review, told Medscape Medical News.
"We proposed that the reduced antiretroviral potency of nevirapine, compared with efavirenz, was responsible for the increased risk of virologic failure for the nevirapine-containing regimens, and that the shorter intracellular half-life of 3TC triphosphate, compared with FTC triphosphate, was responsible for the increased risk of virologic failure for the 3TC-containing regimens," Drs Tang and Shafer explained.
Rachets Up Concern
The team suggests that the retrospective study by Dr Rokx and colleagues "ratchets up" the concern that there are significant differences in the efficacy of currently recommended first-line regimens containing non-nucleoside reverse-transcriptase inhibitors.
"The study also provides constructive insight by noting that the reduced efficacy of certain regimens is most apparent in patients with high plasma HIV-1 RNA levels," they observed, "and we agree with the authors that these findings should ideally be confirmed in a prospective randomized clinical trial."
Drs Tang and Shafer cautioned, however, that until such a study takes place, "we suggest that additional retrospective cohort studies be done rapidly to further quantify the efficacy differences across different virus load strata."
They also suggested that published guidelines be updated to at least note the apparent differences in the efficacy of the recommended first-line regimens containing non-nucleoside reverse-transcriptase inhibitor.
The Amsterdam Cohort Studies on HIV infection and AIDS is a collaboration between the Public Health Service of Amsterdam, the Academic Medical Center of the University of Amsterdam, the Sanquin Blood Supply Foundation, the University Medical Center Utrecht, and the Jan van Goyen Medical Center, and are part of the Netherlands HIV Monitoring Foundation and financially supported by the Center for Infectious Disease Control of the Netherlands National Institute for Public Health and the Environment. Dr. Rokx, Dr. Tang, and Dr. Shafer have disclosed no relevant financial relationships. Dr Rokx, Dr Tang, and Dr Shafer have disclosed no relevant financial relationships.
HIV Drug Therapy. Abstract 154. Presented November 3, 2014.
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Cite this: Antiretroviral Combos With Emtricitabine Outdo Lamivudine - Medscape - Nov 03, 2014.