A new drug application for Tenofovir disoproxil fumarate (Tenofovir DF) has been filed with the Food and Drug Administration by Gilead Sciences. Tenofovir DF, also known as PMPA, could be approved within the next six months.
Tenofovir DF is an investigational nucleotide reverse transcriptase inhibitor (NtRTI), similar to nucleoside analogs such as AZT, Zerit, or ddI. Nucleotide analog drugs only require two steps for activation rather than the three steps needed by NRTI agents.
Tenofovir's long half-life allows once-a-day dosing.
Even though resistance to tenofovir has not easily developed, resistance has been reported. Since tenofovir has a rather different resistance profile than nucleoside analogs, it may be active against already resistant approved nucleoside analogs.
Since tenofovir is an agent in a different class of drugs, many clinicians are adding it to existing therapies.
In a Phase II treatment-intensification trial, doses of tenofovir at 75mg, 150mg or 300mg per day, and placebo, were added to the enrollees' antiretroviral regimen. Prior to study entry, participants had received antiretroviral therapy for more than four years and had a baseline viral load of 5,000 copies. Many participants also had resistance to several nucleoside analogs, particularly AZT and Epivir. More than 50 percent of the enrollees also had resistance to protease inhibitors.
Those who received 300mg per day (the preferred dose) had modest viral load reductions of approximately 0.6 log (75 percent) through weeks 24 and 48. No significant changes in CD4 count were reported. Similar preliminary results are reported from a Phase III treatment intensification trial.
These two trials indicate that tenofovir may need to be prescribed with antiretrovirals from other drug classes to successfully suppress HIV replication. Patients who are treatment-naive have shown better response to tenofovir.
In a Phase III trial for individuals with prior treatment experience, Gilead is directly comparing tenofovir to Zerit, each one combined with Epivir and Sustiva, a non-nucleoside reverse transcriptase inhibitor (NNRTI).
In February, Gilead started an expanded-access program for individuals in need of new drugs based on their advanced disease and treatment history. Access to the program was originally restricted to individuals with a viral load above 10,000 copies and a T-cell count below 100, in addition to documented treatment failure including at least two PIs or one PI and one NNRTI. Additionally, the program allowed individuals with a T-cell count between 100 and 200 to apply if they had been diagnosed with an AIDS-defining condition or opportunistic infection within the last three months.
After hearing criticism from community members about the slow pace of enrollment in the program, Gilead abandoned the restricting entry criteria.
Gilead representatives and physicians have reported problems in the expanded-access program. A physician said that Gilead's paperwork requirements and repeated demands for information left him frustrated. A Gilead representative claims that 20 percent of physicians submitted incomplete registration materials, and reports that the company instructed their field representatives to follow up with those healthcare providers.
The Coalition for Salvage Therapy, a national network of activists, has been pressuring Gilead Sciences to expand the access program and has requested a complete report of the its enrollment. In a powerful letter to Gilead, the coalition described applicants to the program as "not only patients with few or no remaining options for treatment, but also patients whose disease has been allowed to progress to the point where waiting for things to get sorted out with the program is simply not an option."
Gilead advises physicians to prescribe at least one other new antiretroviral agent in addition to tenofovir for the expanded-access program.
Enrollment for the tenofovir expanded-access has increased in the U.S. to approximately 150 individuals. Expanded access programs are also in place in England and France. In France, the expanded-access program for tenofovir is suggested for individuals who cannot tolerate nucleoside analogs or have nucleoside-resistant HIV as shown in genotypic or phenotypic assays.
For information, call Gilead Sciences at (800) 445-3235.
| ||Liliana Eagan is a treatment advocate in AIDS Project Los Angeles' Health Education Core. She can be reached by calling (213) 201-1484 or by e-mail at firstname.lastname@example.org.|