In the main studies submitted to the FDA, enfuvirtide was used in people who had previously developed resistance to all three classes of drugs and were in need of "salvage" treatment. At Barcelona, researchers reported on two such studies, called Toro 1 and Toro 2. All volunteers were given an "optimized" regimen composed of five to eight anti-HIV drugs and half were also given enfuvirtide. The "optimized regimen" was chosen individually for each person based on expert evaluation of resistance tests and prior anti-HIV drug history. Patient advocates applauded the study design because it closely approximated the real-world choices that people with advanced disease must face.
The main side effect reported in both studies was injection site reactions, which to some degree affected nearly 98 percent of the study volunteers. Not all such reactions, however, were serious. These reactions, while very unpleasant, caused only a small number people to drop out of the study. The study underlined the importance of careful training for both doctors and users in order to minimize such reactions and to maximize benefits.
While the results of Toro 1 and Toro 2 differ slightly, the basic picture is the same. In both, volunteers who received enfuvirtide on top of an optimized regimen fared much better than those receiving only the optimized regimen. In many if not most people, the drug was very likely the only fully active anti-HIV therapy in the mix. Still, the results are impressive, considering the challenge such "salvage" situations present. It is fair to say that enfuvirtide represents an important advance in the treatment of advanced HIV disease.
|Toro 1: Results at 24 Weeks|
|% <400 Copies|
|% <50 Copies |
|HIV RNA Change||CD4 Cell Count Change|
O.R. + T-20
(O.R. = Optimized Regimen)
Volunteers had previously used an average of 12 different drugs.
|Toro 2: Results at 24 Weeks|
|% <400 Copies |
|% <50 Copies |
|HIV RNA Change||CD4 Cell Count Change|
O.R. + T-20
(O.R. = Optimized Regimen)
Volunteers had previously used an average of 11 different drugs.
Study will continue for 48 weeks.
A major concern about enfuvirtide is likely to be cost. No drug of its type has ever been made in such large quantities before nor have even the raw materials from which it is made. Although no price has yet been announced, there is widespread fear that its cost will exceed that of any other anti-HIV drug. This could have widespread consequences for the already troubled programs that provide drugs for people with HIV. The expected high price will almost certainly limit the use of the drug only to people who have failed everything else.
A small expanded access program for enfuvirtide is currently underway for people who have failed previous therapies. The program will provide drug for only about 600 people in the US. To sign up, doctors must fill out an application form over the internet and if accepted they will be required to take part in training as noted above. Although all currently available slots in the program were quickly taken, more may open up if drug supply increases. Also, not every person who gets accepted into the program actually goes on to use the drug. Therefore, some slots may become available between October 2002 and the expected approval date in mid-March of 2003. Applications for access are still being taken at www.T20EAP.com.
The small size of the program is also something of a warning that the company might be unable to meet the initial demand for the drug when it is approved. If so, there will likely be a staged rollout of the drug, focusing first on people with the most advanced disease.
Another important study asked whether switching to atazanavir from another protease inhibitor would reverse the cholesterol changes caused by the other protease inhibitors. The study followed 346 people (217 men, 129 women) who had been in the earlier atazanavir vs. nelfinavir comparative study. Of the people who had previously used nelfinavir, 63 were changed to receive 400 mg of atazanavir (the lower of the two doses of atazanavir used in the prior study). People who had previously been assigned to receive either 400 mg of atazanavir were allowed to switch to 600 mg (still once daily). All volunteers continued to receive d4T and 3TC.
Twelve weeks after the 63 people were switched from nelfinavir to atazanavir, their cholesterol levels were measured again and compared to previous levels. Changing to atazanavir obviously had the desired effect of reducing cholesterol and triglyceride levels as shown in the table above. This indicates that, at least for the first 12 weeks, switching to atazanavir has a positive effect on cholesterol. Volunteers who either stayed on 400 mg atazanavir or switched to 600 mg experience no significant change in these measurements.
|Atazanavir Cholesterol Levels|
|Lab Measure||Comparison to Pre-Switch Values|
|Total cholesterol levels||reduced 16%|
|LDL (bad) cholesterol levels||reduced 21%|
|Triglyceride levels||reduced 28%|
|HDL (good) cholesterol levels||increased 5%|
|% with "undesirable" total cholesterol levels||reduced from 32% to 10%|
|% with "undesirable" LDL cholesterol levels||reduced from 55% to 22%|
Changes in cholesterol levels are believed to be associated with physical changes in the body, such as fat accumulation or loss of fat in the face, arms and legs. Such changes are often called lipodystrophy. Although some people in the original group receiving nelfinavir reported having physical symptoms of lipodystrophy, no obvious or easily measurable changes in these symptoms were noted in the people who switched to atazanavir. This indicates that 12 weeks is too short a time to see improvements, that no improvement happens or that improvements were delayed or blocked by the continued use of d4T in all study volunteers (see article on d4T).
Unless other unforeseen side effects appear later in the study of atazanavir, the drug appears to represent an important advance in field of protease inhibitors. Only time will tell if long-term switching to atazanavir will help correct some of the fat redistribution problems experienced by people on protease inhibitors and nucleoside analogue drugs.
The expanded access program for atazanavir is quite liberal, requiring only evidence of failure on existing protease inhibitors or the presence of fat distribution problems. To apply for the program, have your doctor call 1-877-726-7327.
While there is not much excitement about FTC because it so closely resembles 3TC, regulators and advocates alike must give the drug a fair hearing. Its one clear distinction from 3TC is that it is intended to be used once a day, which is an attractive feature for many people. If FTC is otherwise just a "me too" copy of 3TC, it is unclear whether it warrants either accelerated approval or expanded access. Triangle asserts that there are other important differences between FTC and 3TC, differences that they believe warrant more interest than the drug has been given.
In the earliest studies, people receiving FTC as single agent therapy (monotherapy) for 2 weeks achieved an average 2 log reduction in viral load. Although this finding comes from a small and uncontrolled study, it is still impressive, one that rivals any protease inhibitor and appears somewhat superior to 3TC. In laboratory studies, the drug appears to be 4 to 10 times more potent, by weight, than 3TC and more importantly, seems to be slower to develop resistance than 3TC. Rapid development of resistance is 3TC's Achilles heel.
One FTC study presented at the Barcelona conference followed the experiences of 468 people receiving treatment for the first time. They received either FTC or 3TC, along with d4T and either nevirapine (Viramune) or efavirenz (Sustiva). The main study endpoint was virologic failure, defined as either failing to achieve a viral load below 400 copies, or a return of viral load above 400 copies. Both groups had similar levels of virologic failure. The main benefit seen for FTC was that fewer of the people with virologic failure while on the drug had developed resistance to FTC, compared to those on 3TC who became resistant to that drug. This suggests that more of the failures could be attributed to the other drugs in the mix and that FTC was less likely to develop resistance. It is not clear whether this difference was statistically significant, nor is it clear whether it matters much since the overall failure rate on the two treatment regimens was the same.
In two well-controlled studies comparing FTC to 3TC, study authors concluded that the drug is equivalent to 3TC in terms of anti-HIV effectiveness.
In late September of 2002, the manufacturer announced interim results from a new study comparing a once-daily combination of FTC, efavirenz (Sustiva), and ddI-EC (Videx EC) against once-daily efavirenz and ddI-EC plus twice-daily d4T (Zerit). The study, which includes 571 people (85 percent male), is scheduled to run for 52 weeks, but the initial analysis looked at a mix of 24- and 52-week data accumulated to date.
|% <50 Copies HIV RNA (24-Week Data)||Probability of Viral Breakthrough (52-Week Data)||Mean CD4 Increase||% With Treatment Limiting Toxicity|
Once-Daily FTC + ddI-EC + EFV
Twice-Daily d4T + Once-Daily ddI-EC + EFV
|EFV = efavirenz|
ddI-EC = ddI enteric-coated
The manufacturer claimed the study showed that FTC "outperformed a highly effective standard of care," referring to the group receiving the combination of efavirenz plus ddI and d4T. While the data supports the view that FTC was part of the superior combination, the company statement was meaningless, given new information about problems with the combined use of ddI/d4T. Consequently, the ddI plus d4T combination is not considered "highly effective" and certainly not the "standard of care." While the problems with the ddI/d4T combination may not have been clearly known at the time their study was designed, the information was available to them before they described the results of their new study. It should at least have caused them to be more cautious in promoting these new data. For more information about the problems associated with the ddI/d4T combination, see the article "New Questions About an Old Combination -- ddI + d4T."
The big picture seems to be that FTC is better proven in once-daily use and that it may be slower to develop resistance than 3TC, even though the failure rates of combinations using the drug are the same as when using 3TC. Larger or longer studies will be needed to determine whether FTC offers any practical advantage over 3TC. Whether all of this, taken together, warrants a special place for FTC, or expanded early access, is a decision that will have to be made by the FDA.
As PIP 35 goes to press, Gilead Sciences, maker of tenofovir, announced that it had purchased Triangle Pharmaceuticals, maker of FTC; Gilead also announced that it planned to create a new formulation of tenofovir that included FTC and tenofovir in a single pill.
Enfuvirtide (T-20, Fuzeon)
Emtricitabine (FTC, Coviracil)