High Virological Failure Rate in Patients Switching to a Regimen with Two Nucleoside Reverse Transcriptase Inhibitors Plus Tenofovir

Since the availability of tenofovir DF (Viread), new possibilities of combining the drug with nucleoside reverse transcriptase inhibitors (NRTI) have emerged. Unfortunately, clinical trials with combinations that included abacavir (Ziagen) plus lamivudine (Epivir) plus tenofovir or didanosine (Videx) plus lamivudine plus tenofovir have shown unexpectedly high rates of virological failure.

A high virological failure rate has recently been reported in patients who were switched to a regimen containing abacavir, lamivudine and tenofovir, in the setting of virological suppression. It is therefore recommended that this combination be avoided in most, if not all, patients.

At present there is no information on other combinations of two NRTI and tenofovir. For this reason, in this study researchers investigated treatment response in previously suppressed patients who were switched to a two NRTI plus tenofovir regimen, in order to extend previous observations, and to assess the response rate with combinations of NRTI other than lamivudine/didanosine and lamivudine/abacavir.

The current study was a post-hoc review of the virological outcomes at 24 weeks of patients who switched from a successful (< 50 copies/ml) HAART regimen to a tenofovir plus two NRTI combination.

Results

Fifty-five patients started a two NRTI plus tenofovir regimen mostly because of previous toxicity/intolerance of the original drugs (74%).

After 24 weeks, only 17 patients (31%) remained virologically suppressed.

Patients with a regimen including a didanosine plus tenofovir-based regimen had significantly poorer outcomes than those on other combinations (success rate 5 versus 47.1%, P = 0.001).

In contrast, patients on a regimen including zidovudine (Retrovir) plus tenofovir showed a trend towards a better outcome (75 versus 27%, P = 0.083).

Multivariate analysis confirmed the combination of didanosine plus tenofovir as the only variable associated with a higher rate of failure (P = 0.007).

Patients with previous reverse transcriptase mutations presented virological failure in all cases.

At failure a new pattern, including the K65R mutation with M184V or thymidine analogue mutations, was observed.

The authors conclude, “Even in patients with suppressed viremia, a two NRTI plus tenofovir regimen is associated with a high virological failure rate, but significant variations are found depending on the nucleosides included.”

Discussion

This work highlights the unexpected short-term failure rate observed with triple drug therapies containing two NRTI plus tenofovir in previously treated and virologically suppressed patients. These findings are in agreement with the results of recent reports in naive patients, when combinations including abacavir, lamivudine and tenofovir or didanosine, lamivudine, and tenofovir were used.

The reasons that may help explain these poor results include recently rejected pharmacokinetic interactions, the potency of the combinations, and a high selective pressure for resistant isolates.

It is interesting to note the different response rates observed among the different NRTI combinations. According to our results, regimens containing zidovudine and stavudine (Zerit) with lamivudine presented the highest rate of success.

Genotypic analysis in a small subset of our patients showed that the presence of previous RT mutations at any time in the past precluded any possibility of virological response in patients receiving two NRTI plus tenofovir.

Infectious Diseases Unit, Hospital Ramón y Cajal, Madrid, Spain.

04/11/05

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