Tenofovir DF: results from phase III study released

1 October 2001. Related: Antiretrovirals.

Key data scheduled for presentation at now postponed ICAAC

Gilead Sciences have released 24-week efficacy and safety results from a pivotal Phase III study of its investigational one tablet, once daily antiretroviral agent tenofovir disoproxil fumarate (Viread TM ). The data were to have been presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)in Chicago, which has been rescheduled as a result of recent events in New York and Washington D.C.

Study results demonstrate that patients who received tenofovir DF 300 mg in addition to their existing antiretroviral regimen achieved a significant HIV RNA reduction in mean DAVG24 (time-weighted difference from baseline over 24 weeks) of 0.61 log10 copies/mL (n=368) compared to a eduction of 0.03 log10 copies/mL (n=182) in patients who received placebo (p<0.0001). Patients in this study were highly treatment experienced with a mean of 5.4 years of prior antiretroviral treatment. Consistent with this prior treatment history, at baseline 48 percent of the patients had non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations, 58 percent had protease inhibitor (PI) resistance mutations and 94 percent had nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations.

“After an average of more than five years on multi-drug therapy, most of the patients in the study had developed resistance to available treatments, yet they achieved significant eductions in circulating virus when tenofovir DF was added to their regimens, “said Kathleen Squires, M.D., Associate Professor of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, and investigator on the study. “With this important antiviral effect, a safety profile comparable to placebo over 24 weeks, and convenient once daily dosing, tenofovir DF may provide a much-needed new treatment option for physicians and their patients.”

About study 907

The 48-week study, known as Study 907, enrolled 552 treatment-experienced patients in North America, Europe and Australia.Patients had HIV RNA levels of 400 to 10, 000 copies/mL and had received stable antiretroviral therapy for at least eight weeks prior to entering the study. Upon entry into the study, patients were randomised (2:1) to receive tenofovir DF (one tablet dosed once daily) or placebo in addition to their existing antiretroviral therapy. After 24 weeks of blinded, placebo- controlled dosing, all patients were switched to eceive open-label tenofovir for the remainder of the 48-week study period.

Efficacy results

The results meet the study ‘s primary efficacy endpoint of reduction in viral load. At study entry, patients had a mean HIV RNA level of 3.36 log10 copies/mL and a mean CD4 cell count of 427 cells/mm3.At 24 weeks, patients treated with tenofovir DF experienced an HIV RNA reduction in mean DAVG24 of 0.61 log10 copies/mL, compared with a eduction of 0.03 log10 copies/ mL in the group receiving placebo (p<0.0001).

In addition, 45 percent (155 of 346) of patients treated with tenofovir DF achieved HIV RNA reductions below the level of detection (400 copies/mL) at 24 weeks, compared with 13 percent (23 of 172)in the placebo group (p<0.0001). Reduction in HIV RNA to less than 50 copies/mL was achieved by 22 percent (76 of 346)of patients in the tenofovir DF group compared to one percent (2 of 172) in the placebo group (p<0.0001). In the tenofovir DF group, the DAVG24 for CD4 cells was an increase of 12.6 cells/mm3 compared with a decrease of 10.6 cells/mm3 in the placebo group (p=0.0008).

Safety results

Through the first 24 weeks of Study 907, the incidence of serious side effects (defined as grade 3 and 4 laboratory abnormalities and clinical adverse events) was similar between patients receiving tenofovir DF and placebo. In addition, the proportion of patients who discontinued treatment at 24 weeks was an identical six percent in both the tenofovir DF and placebo arms..

Virology analysis

Results of a virology sub study of 274 patients randomly selected from Study 907 were also to be featured at ICAAC.At baseline, 94 percent of the 253 evaluable patients in the virology sub study had viral mutations associated with resistance to the class of antiretroviral agents known as NRTIs. Of those, 69 percent had ZDV/thymidine analogue mutations (TAMs), 68 percent had the 3TC-associated M184V mutation and 45 percent had both.In comparison to placebo, statistically significant reductions in HIV RNA ranging from 0.47 to 0.97 log10 copies/mL (p<0.0001) were observed for the tenofovir DF treated patients whose HIV contained TAMs, M184V mutations or both.

Genotypic analyses were performed at week 24 in 171 patients. The remaining 103 patients in the virology sub study had insufficient HIV RNA for analysis. Based on week 24 analysis, tenofovir DF treatment was associated with development of the K65R mutation in five patients (3%). Additionally, tenofovir DF treatment significantly reduced the development of mutations associated with PIs (2%), compared with the placebo group (8%;p=0.02).

Source:Gilead press release. http://www.gilead.com/

Comment

Although the results from study 907 provide further evidence that tenofovir DF is active in treatment experienced patients it does not provide any guidance as to how the drug should be used in practice and for which individuals it might be optimal. The establishment of a genotype algorithm from the 907 data may give additional insight into for whom tenofovir DF may work in salvage settings. Although US FDA approval stopped short of recommending use in both treatment naïve and treatment experienced patients one potential utility of tenofovir DF could be as part of once a day regimens either as simplification or initial treatment. It should also be noted that in treatment experienced patients the efficacy of tenofovir will likely be limited without the support of additional active agents.

Expanded access program

In January 2001, Gilead announced the initiation of an expanded access program to provide tenofovir DF to people with advanced HIV infection. In the United States, the Expanded Access Program for tenofovir DF is available for people 18 years or older with HIV infection who have failed HAART, have limited treatment options, and in the opinion of the treating physician, tenofovir DF is required to construct a viable combination of antiretroviral agents. Programs are also open for registration in France, Germany, Italy, Spain and the United Kingdom.

For more information regarding the Viread expanded access program or to request registration materials:

Physicians within Europe may call 33-1-44-90-34-46.Physicians in the United States may call 1-877-226-8802

Currently over 500 people are accessing TDF through the named-patient programme in the UK. Other European EAP programmes are currently running in France, Germany, Italy, Spain and shortly the Republic of Ireland and Gilead are working to broaden this access to other countries.

Anecdotally, there are good indications that use in clinical practice is similar to that seen in the registrational studies. Preliminary data was presented by Dr Anton Pozniak at the BHIVA meeting on 6th October 2001 from 140 patients using TDF on the named-programme in the UK attending the Chelsea and Westminster Hospital. Additional use of TDF in treatment experienced patients included low level viral rebound <1000 copies (n=20), high level rebound >1000 copies (n=77)and switching for toxicity or simplification (n-43). Of the 39 patients with results out to 12 weeks with high level rebound, 51%saw their viral load return to <50 copies and 82% of patients had a viral load reduction of 1 log. The 10 discontinuations in this highly experienced group: 2 deaths (lymphoma and pancreatitis), SJS (1), patient request (1), lactate rise (2)and 4 lost to follow up (the data were collected over a relatively short period).