Safety profile of tenofovir in treatment-experienced patients
Mark Nelson, theBody.com
Tenofovir (TDF, Viread) was originally studied in two trials – 902 and 907 – in which either TDF or a placebo was added to background antiviral therapy.
As a result of the large number of individuals who received TDF in these studies, a lot of clinical experience with TDF 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.
Grade 3 or 4 adverse events or laboratory abnormalities were no more common in the TDF arm than compared with placebo. Indeed, the incidence of drug continuation in the study was 7% in the TDF arm and 9% in the placebo arm. Patients who received a placebo were switched to TDF 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%, although very few patients discontinued TDF due to an adverse event (9%). The most common adverse event seen was diarrhoea in 3% of patients. As for laboratory abnormalities, a raised creatinine kinase was seen in 15% of patients, elevated triglycerides in 13% of patients, a raised serum amylase in 9% of patients and a raised AST elevation in 8% of patients. None of these differed from the placebo arm.
There has been considerable interest in TDF’s potential risk for renal and bone toxicity. Serum creatine of a grade 1 toxicity (ie mild) only developed in 1% of individuals receiving TDF during the first 24 weeks of therapy, a rate equivalent to that of a placebo. Overall, after 95 weeks, 6% 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 TDF and placebo. No patient discontinued the study due to TDF-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% in the TDF arm and 3% in the placebo arm developed peripheral neuritis, and less than 1% in each arm developed pancreatitis or lactic acidosis. Of the two patients who did develop lactic acidosis, in addition to receiving TDF, both were also receiving d4T (stavudine, Zerit) or ddI (didanosine, Videx) concomitantly, either of which are associated with this adverse effect.
During the 24-week placebo-controlled period of 902 and 907, the safety profile of TDF appears similar to placebo.
Implications for clinical practice
TDF 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 TDF has led many individuals to use TDF as a first-line agent, especially after the results of 902, or as a substitute agent. It is important when substituting TDF 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 TDF, it was virologically successful in 37. Of the three patients who failed the therapy switch, all had received previous nucleoside therapy in a non-suppressive regimen. Presumably then they were harbouring resistant mutations (especially important are the thymidine mutations 41 and 210 and the K65 mutation) which then were able to grow back when TDF 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.
Dion Coakley, Andrew Cheng, Shan-Shan Chen, et al. Safety Profile of Tenofovir DF (TDF) in Treatment-Experienced Patients From Randomized, Placebo-Controlled Clinical Trials. 6th International Congress on Drug Therapy in HIV Infection 17-21 November 2002, Glasgow, UK. Poster 910
Source: The Body
© 2002 Body Health Resources Corporation.