Tenofovir: FDA Hearing on Important New Antiretroviral.

The FDA's one-day public hearing on tenofovir (brand name Viread(TM)), a new antiretroviral being developed by Gilead Sciences, took place October 3 near Washington D.C. (see AIDS Treatment News # 370, August 24, 2001). This meeting of the Antiviral Drugs Advisory Committee (a group of outside experts convened by the FDA) also included consultants selected for this particular meeting because of their special expertise.

Everyone who spoke agreed that tenofovir should be approved; the FDA had no issue with approval, which is expected shortly. In clinical trials the drug has shown a 0.6 log decrease sustained for the length of the trial (up to a year so far), when added to an antiretroviral regimen which was failing to suppress the virus -- a difficult test for a drug, and probably not the way tenofovir will generally be used. (Usually at least some of the other drugs in the regimen would be changed, often after resistance testing -- although it is too early to know for sure how tenofovir will be used in practice.) Resistance to tenofovir seems slow to develop, although resistant viruses do occur. The drug is easy to use (it is taken only once a day, with food), and so far has shown excellent safety in human tests, with side effects comparable to those reported by volunteers who received the placebo.

One major issue at the hearing was whether the FDA should recommend tenofovir for combination use in HIV treatment for any patient -including those starting antiretrovirals for the first time -- or only recommend it for advanced patients, where there is currently more data. All activists who spoke wanted the general indication, but for a variety of reasons the committee tended toward the more restrictive one (there was no formal vote). Activists want to free doctors and patients from possible reimbursement hassles if they decide to use the drug in front-line therapy; they also wanted to make sure the company was not punished for testing tenofovir first in advanced patients, which activists and the FDA have urged companies to do, since these patients most need new options.

But committee members were concerned that less is known about first-line use and more will be known next year, when the indication could be changed. Some felt that the lack of complete information about first-regimen use changed the risk/benefit ratio of using a new combination vs. a standard one. Others noted that ADAPs (the AIDS Drug Assistance Programs, run separately by each state) are unlikely to micromanage patients, so they will not deny reimbursement if a physician uses the drug outside of the indications formally approved by the FDA. Some saw the drug's indication as mainly a marketing issue. (Doctors are free to prescribe an approved drug for any patient, without being bound by the indications.)

Some observers think the FDA may approve the general indication but with a note saying that studies in treatment-naive patients are not yet complete.

Long-Term Safety Issues

Human safety data were very good -- in particular, there was none of the kidney toxicity that had been seen in adefovir when studied for HIV at doses of 60 and 120 mg daily. (Adefovir, a much less effective antiretroviral in the same drug class as tenofovir, is no longer being developed for HIV, but is a promising potential treatment for hepatitis B, in much smaller doses.)

But animal studies using tenofovir doses much higher than those given to people had found a bone problem, osteomalacia -- a lack of normal mineralization of the bone (this disease is called rickets in children, osteomalacia in adults). While the danger appears to be low -- the condition can be treated, and reversed completely in animals when the drug was stopped -- two bone experts brought by the FDA as consultants to the committee thought that certain steps should be taken now in order to head off possible problems in the future:

(1) Gilead should do some simple research to find out which potential mechanism caused the problem in the animals. Was bone failing to mineralize properly because of a deficiency of the minerals in the body? Or was the drug interfering with enzymes involved in the mineralization process? The company might be able to learn much by analyzing samples already in its freezers.

(2) The bone specialists recommended that certain baseline tests be done before tenofovir is started -- at least to look for vitamin D deficiency and certain other simple nutritional problems that could easily be corrected with nutritional supplements or other treatments. One of the consultants listed baseline studies he would ideally like to do today -- probably too many to be feasible for widespread clinical practice -- but noted that once the mechanism studies had been done, much of that baseline testing could become unnecessary. Pregnant women and children could be at particular risk for any bone mineralization problem.

We left the hearing with the impression that this issue should not delay approval of tenofovir -- the drug is needed now, and the bone risks are not immediate if they exist at all. But the discussion pointed out the need for biochemical research on the mechanism of the bone changes in animals, and strongly suggested at least some baseline testing when the drug is started, for correction of relevant nutritional deficiencies if necessary.

(According to Gilead, much of this work had already been done but was not presented at the hearing because the FDA was already comfortable with the data. And bone markers are now being measured in study 903, a clinical trial of tenofovir in treatment-naive patients.)

Other Possibilities

Tenofovir may have other important uses than the HIV treatment for which it will be approved:

* Hepatitis B. Tenofovir may prove to be an effective hepatitis B treatment. One activist urged that this use be planned for in co-infected people, instead of left to chance, so that the hepatitis B as well as HIV treatment could be optimized, to reduce the risk of patients developing tenofovir-resistant hepatitis B.

* Mother-to-infant transmission. One committee member noted theoretical reasons why this drug might be effective. If so it would have an advantage over nevirapine, in that resistance to tenofovir is much slower to develop. [We would also like to know if adding a single dose or very short course of tenofovir to the single dose of nevirapine could make the regimen more effective in preventing maternal transmission -- a possibility which would seem to be quite feasible to test, because of the safety of tenofovir, the fact that nevirapine is far from 100% effective (allowing a better regimen to be detected), and the fact that everyone in the trial would get at least the accepted nevirapine regimen.]

* Microbicide use? PMPA, the active form of tenofovir, proved very effective in preventing HIV infection in early animal studies (tenofovir is a chemical modification of PMPA, designed so that the drug could be given orally, as PMPA cannot). We do not recall microbicide possibilities coming up at this hearing, which had a different focus; but PMPA is now being studied by the U.S. National Institute of Allergy and Infectious Diseases as a possible vaginal microbicide. An effective microbicide would have a great impact on the global HIV epidemic because it would provide a prevention method controlled by women.

For More Information

A summary and a transcript will be on the FDA Web site, at: http://www.fda.gov/ohrms/dockets/ac/acmenu.htm (click on '2001', then 'Anti-Viral Drugs Advisory Committee').

Usually the transcript is available 30 days after the meeting, the summary approximately 90 days after. Some other information about the October 3 meeting is already on this site.