More bad news comes in the form of a delay in the expanded access program for atazanavir (Zrivada), a protease inhibitor that is dosed once a day and which may offer important advantages in terms of reduced fat distribution effects. At this point it is not entirely clear why there is a delay in the program, although the likely reason is that in one study of the drug, there was an increased rate of elevated lactate levels (lactic acidosis), a side effect usually associated with nucleoside analogue drugs, which were also used in the study. Certain issues regarding the heart have also been raised as possible evidence of toxicity, though this too is unclear.
The following article will overview these issues. Also in the news is information on a new formulation of d4T (stavudine, Zerit), once daily dosing of indinavir (Crixivan), results from a study of a new non-nucleoside analogue drug called TMC-125 and surprising results from a structured treatment interruption (STI) study.
Volunteers received either tenofovir or placebo in a 2-to-1 fashion, resulting in 368 people on tenofovir and 182 on placebo. All continued on their existing regimens in addition to the tenofovir or placebo. At the start the volunteers, on average, had been on anti-HIV therapy for 5.4 years, had viral load of about 2,300 copies and had CD4+ cell counts averaging 427. The average decrease in viral load between the start of the study and week 24 was 0.59 log among people taking tenofovir. Essentially no changes in viral load were noted among those on placebo. Additionally, about 45% and 22% of the participants had viral loads below 400 and 50 copies respectively compared to 13% and 1% of those taking the placebo respectively. Tenofovir was very well tolerated with no significant differences in moderate-to-severe side effects between the two groups.
Although the reduction in viral load levels may not sound like very much compared to what has been seen in many protease inhibitor studies, such a comparison is misleading. In the protease inhibitor studies, volunteers were just beginning treatment for the first time and were thus much more likely to have large decreases in viral load. In contrast, tenofovir was given to people who were already "failing" on their existing regimens, most likely due to the development of resistance against their current drugs.
Adding a single new drug to a failing regimen usually does very little, but in this case, the addition of tenofovir resulted in significant viral load reductions. This appears to confirm lab studies which showed that tenofovir remains active against many viruses that have developed resistance to older nucleoside analogue drugs. Thus, tenofovir appears able to make up for much of the failure of the older class of drugs.
An additional benefit of tenofovir is its apparently low level of toxicity. Though the data is limited and somewhat short-term, it so far appears to have the fewest side effects of any anti-HIV drug yet seen. Whether this will hold up in long term use is yet to be determined.
Since the initial studies of tenofovir have focused on people who were failing other therapies -- something the manufacturer, Gilead Sciences, should be congratulated for -- the drug is currently recommended primarily for such people. This does not mean, however, that it has no role in people beginning treatment for the first time. Results from another tenofovir study, in people who have not taken anti-HIV therapies before, are expected in early 2002. If these data are positive and show even more potent anti-HIV effects, as some researchers anticipate, it will raise questions about the ideal time to use the drug. Some doctors may prefer to use it initially, thanks to its delayed resistance, low toxicity, ease of dosing and high potency. Others may wish to hold it back for later use, if for no other reason than the fact they can do so without fear of losing its potency. Only time and experience will tell which, if either, is the best strategy.
None of the volunteers had taken anti-HIV therapy before, and they all received nelfinavir (1,250 mg twice a day) or atazanavir (400 mg or 600 mg once a day). In addition, all of them took d4T (stavudine, Zerit) and 3TC (lamivudine, Epivir). The results are found below.
Not surprisingly, people on nelfinavir were more likely to develop diarrhea, a well-known side effect of the drug. Those taking atazanavir were more likely to have headaches, abdominal pain and increases in bilirubin levels. People using the higher dose of atazanavir were more likely to stop taking it due to side effects.
There was, on average, very little change in triglyceride or cholesterol levels among the people taking atazanavir while those on nelfinavir had significant increases in these laboratory markers. Changes in these markers have sometimes been associated with changes in body shape, called lipodystrophy. For more information on lipodystrophy, or call Project Inform's hotline at 1-800-822-7422.
The lack of effect on triglyceride and cholesterol levels and the once a day dosing are clearly what makes atazanavir stand out from the existing protease inhibitors. Starting in spring of 2002 a large expanded access program will provide atazanavir free of charge to people who have failed other therapies. Stay in touch with the Project Inform Hotline and Web site to learn how and when to sign up.
|Results After 48 Weeks: Atazanavir|
|% <400 copies |
|% <50 copies |
|HIV RNA drop|
|ATV (400 mg) + d4T + 3TC||65||31||2.51 logs|
|ATV (600 mg) + d4T + 3TC||62||36||2.58 logs|
|NFV + d4T + 3TC||59||38||2.31 logs|
|ATV = atazanavir|
NFV = nelfinavir
After 48 weeks, 74% of the people who continued taking indinavir had viral load below 500 copies compared to only 58% of those who switched to the indinavir/ritonavir combination. This difference is almost entirely due to an increase in side effects among those on indinavir/ritonavir. Over twice as many people had to stop therapy and/or switch therapies because of side effects compared to those on the thrice-daily indinavir regimen. Side effects included stomach distress, kidney stones, blood in the urine (hematuria) and elevations in lipid levels (lab markers for triglycerides and cholesterol).
Results from this study are somewhat different from many physicians' experience, where the indinavir/ritonavir combination has been generally well tolerated and in fact has become the preferred method of dosing indinavir for many.
Larger studies with TMC-125 are planned in early 2002, including a study for people who have been on all three classes of anti-HIV drugs [protease inhibitors, NNRTIs and nucleoside analogue drugs (NRTIs)]. Other drugs in the same NNRTI class include the approved drugs nevirapine (Viramune), delavirdine (Rescriptor) and efavirenz (Sustiva). For more information about these classes of drugs, call Project Inform or visit the Web site and look for Anti-HIV Therapy Strategies.
At the end of the eight-week STI, there was a small increase in viral load (0.2 log or 1.6 fold) and a decrease in CD4+ counts of 10 cells. Researchers looked at viral load responses after each group had completed 12 weeks of gigaHAART. For the immediate therapy group this was looked at after the first twelve weeks. For the STI group this was evaluated after 20 weeks of study, as the first eight weeks included a therapy interruption.
|Results After 12 Weeks of GigaHAART|
|% viral load drop of at least 1 log||% <400 copies HIV RNA|
|STI + gigaHAART||59%||35%|
The dose of d4T XR used was 100 mg once a day for people weighing over 60kg (about 130 pounds) and 75 mg once a day for those weighing less than 60kg. d4T XR results in lower peak and higher trough concentrations of the drug compared to regular d4T.
Peak concentration is the highest amount of drug in the blood soon after taking a dose. Trough concentration is the lowest amount of drug in the blood after taking a dose. Higher peak concentrations are sometimes associated with a higher risk of side effects. Lower trough concentrations are associated with the development of anti-HIV drug resistance. It's assumed that lower peak concentrations of a drug will sometimes decrease side effects and higher troughs will decrease the risk of developing resistance to the drug.
At the end of the 48-week study, there was essentially no difference in response between the two groups, with about 50% of the participants having viral loads below 50 copies and an increase in CD4+ cell counts of about 200. There appeared to be slightly fewer people experiencing peripheral neuropathy (a tingling or numbness around the extremities, especially fingers and toes) among those on d4T XR, although they experienced slightly more headaches. Only a larger study will truly determine the safety profile and effectiveness of the new formulation.
Back to the Project Inform Perspective March 2002 contents page.