A recent Health Affairs blog post on the more than two-decade history of Gilead’s HIV medications misrepresented Gilead’s long-established, patient-driven approach to research and development of HIV therapies. The authors suggest that Gilead “delay[ed] access to safer medications in the name of profit.” This is simply wrong. They ascribe greed to a process that has been driven only by patients’ needs and the urgency of our task. And they discount the difficult decisions with imperfect information that companies frequently must make about how and where to invest limited resources.
In fact, Gilead’s efforts to advance HIV therapy over more than two decades represent the iterative scientific process and incremental progress that are fundamental to the most innovative drug development work being done today. And Gilead’s efforts have helped to make HIV a manageable disease.
Viread And Beyond
On October 26, 2001, after years of Gilead development, the Food and Drug Administration (FDA) approved Viread the first tenofovir disoproxil fumarate (TDF) therapy for HIV. Viread was immediately heralded as a major innovation in the fight against HIV due to its efficacy and tolerability, and TDF-based regimens quickly became the standard of HIV care by filling a large, unmet patient need. To this day, TDF-based medications continue to be approved by the FDA and recommended on HIV treatment guidelines.
After Viread was approved, Gilead—bolstered by strong clinical data regarding TDF’s efficacy and safety—believed the next important step would be to develop combination therapies that would add medications to TDF.
Gilead was also a much smaller company in the early 2000s and therefore had to make choices about where to invest its limited financial and human resources. Specifically, in 2004, this meant setting aside other compounds, including tenofovir alafenamide (TAF), a novel prodrug of tenofovir that we had discovered years earlier as part of a back-up program to TDF. At the time, TAF hadn’t been tested in large clinical studies, and the technology necessary to economically prepare TAF at a commercial scale was not available. Halting our work on TAF in 2004 was driven by strong clinical data regarding the safety and efficacy of TDF and the need to dedicate resources to the development of combination therapies, the first of which, Truvada (TDF + emtricitabine), gained FDA approval for HIV treatment in combination with other medicines in August 2004.
Following the approval of Truvada, Gilead focused on collaborations to develop a single tablet regimen (STR) to further simplify HIV treatment, increase adherence, and reduce the risk of patients failing treatment and developing drug resistance. In July 2006, the FDA approved Atripla, the first STR for treatment of HIV, which simplified treatment and allowed patients to take just one pill once a day rather than a high volume of pills multiple times a day. Today, the Department of Health and Human Services continues to recognize that single tablet regimens, including those with TDF, may increase patients’ ability to stay on and benefit from HIV treatment.
In The Face Of Evolving Data
TDF-based drug labeling always alerted physicians to the possibility of renal effects, which were not seen earlier in clinical studies. Over time, that possibility became a reality for some patients: As people living with HIV began to live longer and many patients had now been taking TDF for nearly a decade, the company became aware of the possibility of longer-term side effects associated with TDF, including a small but significant number of patients who developed renal issues.
In the face of this evolving data on the effects of TDF, Gilead decided in 2010 to evaluate alternative molecules, including TAF whose development we had stopped in October 2004.
As innovation in HIV treatment continued and Gilead worked to bring safer and more effective therapies to patients, our work allowed people living with HIV to live longer, healthier lives. Gilead also recognized that the reality of an aging HIV population brought with it new considerations about conditions associated with aging, such as renal issues and decreases in bone mineral density. Gilead recognized there might be clinical needs for alternatives to TDF, and that decision was revisited. Gilead again followed the science, reassessing the potential use of TAF for HIV patient populations.
It was only after TAF and TDF were compared head to head in clinical trials in 2014 that Gilead was able to show that TAF demonstrated a similar level of efficacy against HIV to TDF with an improved safety profile. For those reasons, Gilead decided to move forward with developing the drug as an alternative to its TDF-based HIV medications. Ultimately, the differences between the chemical structure of TAF and TDF result in significant and substantial differences in their properties, including safety profiles. The development of TAF was a function of Gilead’s efforts to respond to the real needs of patients and was not delayed as a way to avoid generic competition.
An Iterative Process
Drug development remains an iterative process, and there is a balance between getting medicines to patients who urgently need them and pursuing alternative, unproven candidates to address potential but unknown problems. It is easy now, with the omniscience granted by hindsight, to criticize Gilead’s research and development decisions. But those decisions, like every decision we make, were guided by our focus on delivering medications for the patients we serve. At every point in the journey to fight the HIV epidemic, Gilead has endeavored to save lives while providing safer, more effective therapies to patients in need.
TDF medications changed the landscape for HIV patient care, and TAF medications are an evolution that provide important additional choices for physicians and patients. Looking ahead, we will continue to dedicate our time and resources to develop innovative new medicines that will draw us closer to ending the HIV epidemic.
