• Safety Profile of Tenofovir DF (TDF) in Treatment-Experienced Patients From Randomized, Placebo-Controlled Clinical Trials
  Authored by A. Cheng
  Poster 910

Background

Tenofovir (TDF, Viread) was originally studied in two trials -- 902 and 907 -- in which either tenofovir or a placebo was added to background antiviral therapy. As a result of the large number of individuals who received tenofovir in these studies, a lot of clinical experience with tenofovir has been gained. Individuals were followed up not only for virological efficacy but also for toxicities associated with this antiviral regimen. In both the 902 and 907 studies, a placebo arm was in place for the initial 24 weeks which allowed comparison of adverse events.

Results

Grade 3 or 4 adverse events or laboratory abnormalities were no more common in the tenofovir arm than compared with placebo. Indeed, the incidence of drug continuation in the study was 7 percent in the tenofovir arm and 9 percent in the placebo arm. Patients who received a placebo were switched to tenofovir at 24 weeks and all patients were followed for a mean of 95 weeks.

During extended follow up, the incidence of drug continuation in the study was 25 percent, although very few patients discontinued tenofovir due to an adverse event (9 percent). The most common adverse event seen was diarrhea in 3 percent of patients. As for laboratory abnormalities, a raised creatinine kinase was seen in 15 percent of patients, elevated triglycerides in 13 percent of patients, a raised serum amylase in 9 percent of patients and a raised AST elevation in 8 percent of patients. None of these differed from the placebo arm.

There has been considerable interest in tenofovir's potential risk for renal and bone toxicity. Serum creatine of a grade 1 toxicity (i.e., mild) only developed in 1 percent of individuals receiving tenofovir during the first 24 weeks of therapy, a rate equivalent to that of a placebo. Overall, after 95 weeks, 6 percent of patients had developed a grade 1 toxicity, but only one patient developed a grade 2 (moderate) toxicity. Serum phosphate was measured as a possible marker of bone and renal toxicity and did not significantly differ between tenofovir and placebo. No patient discontinued the study due to tenofovir-related serum creatine elevation or hypophosphatemia.

In this study, the incidence of adverse events potentially associated with mitochondrial dysfunction was measured. During the first 24 weeks of therapy, 2 percent in the tenofovir arm and 3 percent in the placebo arm developed peripheral neuritis, and less than 1 percent in each arm developed pancreatitis or lactic acidosis. Of the two patients who did develop lactic acidosis, in addition to receiving tenofovir, both were also receiving d4T (stavudine, Zerit) or ddI (didanosine, Videx) concomitantly, either of which are associated with this adverse effect.

Conclusion

During the 24-week placebo-controlled period of 902 and 907, the safety profile of tenofovir appears similar to placebo.

Implications for Clinical Practice

Tenofovir appears to have low toxicity, at least in the short-term. The mean follow up of patients to 95 weeks confirms this, although clearly longer follow up and maintenance of observation is of paramount importance as it is with all drugs. The safety profile of tenofovir has led many individuals to use tenofovir as a first-line agent, especially after the results of 902, or as a substitute agent. It is important when substituting tenofovir for other nucleoside analogues that we consider previous nucleoside non-suppressive treatment.

In a study from Chelsea and Westminster Hospital in London, of 40 patients who switched to tenofovir, it was virologically successful in 37. Of the 3 patients who failed the therapy switch, all had received previous nucleoside therapy in a non-suppressive regimen. Presumably then they were harboring resistant mutations (especially important are the thymidine mutations 41 and 210 and the K65 mutation) which then were able to grow back when tenofovir was substituted for the nucleoside analogue. Although switching is often recommended to deal with toxicities and adherence problems, it is also important to make sure that we do not switch into virological failure.